UW Neurological Surgery Recent PubMed Publications

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life.

Front Immunol. 2020;11:578505

Authors: Bennike TB, Fatou B, Angelidou A, Diray-Arce J, Falsafi R, Ford R, Gill EE, van Haren SD, Idoko OT, Lee AH, Ben-Othman R, Pomat WS, Shannon CP, Smolen KK, Tebbutt SJ, Ozonoff A, Richmond PC, van den Biggelaar AHJ, Hancock REW, Kampmann B, Kollmann TR, Levy O, Steen H

Abstract
Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.

PMID: 33329546 [PubMed - in process]

Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort.

Front Immunol. 2020;11:578801

Authors: Shannon CP, Blimkie TM, Ben-Othman R, Gladish N, Amenyogbe N, Drissler S, Edgar RD, Chan Q, Krajden M, Foster LJ, Kobor MS, Mohn WW, Brinkman RR, Le Cao KA, Scheuermann RH, Tebbutt SJ, Hancock REW, Koff WC, Kollmann TR, Sadarangani M, Lee AH

Abstract
Background: Vaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.
Methods: We applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.
Results: Using both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.
Conclusion: This study provides further evidence that baseline cellular and molecular characteristics of an individual's immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.

PMID: 33329547 [PubMed - in process]

A Bovine Enteric Mycobacterium Infection Model to Analyze Parenteral Vaccine-Induced Mucosal Immunity and Accelerate Vaccine Discovery.

Front Immunol. 2020;11:586659

Authors: Facciuolo A, Lee AH, Trimble MJ, Rawlyk N, Townsend HGG, Bains M, Arsic N, Mutharia LM, Potter A, Gerdts V, Napper S, Hancock REW, Griebel PJ

Abstract
Mycobacterial diseases of cattle are responsible for considerable production losses worldwide. In addition to their importance in animals, these infections offer a nuanced approach to understanding persistent mycobacterial infection in native host species. Mycobacterium avium ssp. paratuberculosis (MAP) is an enteric pathogen that establishes a persistent, asymptomatic infection in the small intestine. Difficulty in reproducing infection in surrogate animal models and limited understanding of mucosal immune responses that control enteric infection in the natural host have been major barriers to MAP vaccine development. We previously developed a reproducible challenge model to establish a consistent MAP infection using surgically isolated intestinal segments prepared in neonatal calves. In the current study, we evaluated whether intestinal segments could be used to screen parenteral vaccines that alter mucosal immune responses to MAP infection. Using Silirum® - a commercial MAP bacterin - we demonstrate that intestinal segments provide a platform for assessing vaccine efficacy within a relatively rapid period of 28 days post-infection. Significant differences between vaccinates and non-vaccinates could be detected using quantitative metrics including bacterial burden in intestinal tissue, MAP shedding into the intestinal lumen, and vaccine-induced mucosal immune responses. Comparing vaccine-induced responses in mucosal leukocytes isolated from the site of enteric infection versus blood leukocytes revealed substantial inconsistences between these immune compartments. Moreover, parenteral vaccination with Silirum did not induce equal levels of protection throughout the small intestine. Significant control of MAP infection was observed in the continuous but not the discrete Peyer's patches. Analysis of these regional mucosal immune responses revealed novel correlates of immune protection associated with reduced infection that included an increased frequency of CD335+ innate lymphoid cells, and increased expression of IL21 and IL27. Thus, intestinal segments provide a novel model to accelerate vaccine screening and discovery by testing vaccines directly in the natural host and provides a unique opportunity to interrogate mucosal immune responses to mycobacterial infections.

PMID: 33329565 [PubMed - in process]

Activation of the Gluteus Maximus During Performance of the Back Squat, Split Squat, and Barbell Hip Thrust and the Relationship With Maximal Sprinting.

J Strength Cond Res. 2021 Jan 01;35(1):16-24

Authors: Williams MJ, Gibson NV, Sorbie GG, Ugbolue UC, Brouner J, Easton C

Abstract
ABSTRACT: Williams, MJ, Gibson, N, Sorbie, GG, Ugbolue, UC, Brouner, J, and Easton, C. Activation of the gluteus maximus during performance of the back squat, split squat, and barbell hip thrust and the relationship with maximal sprinting. J Strength Cond Res 35(1): 16-24, 2021-The purpose of this research was to compare muscle activation of the gluteus maximus and ground reaction force between the barbell hip thrust, back squat, and split squat and to determine the relationship between these outcomes and vertical and horizontal forces during maximal sprinting. Twelve, male, team sport athletes (age, 25.0 ± 4.0 years; stature, 184.1 ± 6.0 cm; body mass, 82.2 ± 7.9 kg) performed separate movements of the 3 strength exercises at a load equivalent to their individual 3 repetition maximum. The ground reaction force was measured using force plates and the electromyography (EMG) activity of the upper and lower gluteus maximus and was recorded in each leg and expressed as percentage of the maximum voluntary isometric contraction (MVIC). Subjects then completed a single sprint on a nonmotorized treadmill for the assessment of maximal velocity and horizontal and vertical forces. Although ground reaction force was lower, peak EMG activity in the gluteus maximus was higher in the hip thrust than in the back squat (p = 0.024; 95% confidence interval [CI] = 4-56% MVIC) and split squat (p = 0.016; 95% CI = 6-58% MVIC). Peak sprint velocity correlated with both anterior-posterior horizontal force (r = 0.72) and peak ground reaction force during the barbell hip thrust (r = 0.69) but no other variables. The increased activation of gluteus maximus during the barbell hip thrust and the relationship with maximal running speed suggests that this movement may be optimal for training this muscle group in comparison to the back squat and split squat.

PMID: 33332802 [PubMed - as supplied by publisher]

Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease-specific changes in sleep and incongruous peripheral inflammation.

J Neurosci Res. 2020 Dec 14;:

Authors: Saber M, Murphy SM, Cho Y, Lifshitz J, Rowe RK

Abstract
Elderly populations (≥65 years old) have the highest risk of developing Alzheimer's disease (AD) and/or obtaining a traumatic brain injury (TBI). Using translational mouse models, we investigated sleep disturbances and inflammation associated with normal aging, TBI and aging, and AD. We hypothesized that aging results in marked changes in sleep compared with adult mice, and that TBI and aging would result in sleep and inflammation levels similar to AD mice. We used female 16-month-old wild-type (WT Aged) and 3xTg-AD mice, as well as a 2-month-old reference group (WT Adult), to evaluate sleep changes. WT Aged mice received diffuse TBI by midline fluid percussion, and blood was collected from both WT Aged (pre- and post-TBI) and 3xTg-AD mice to evaluate inflammation. Cognitive behavior was tested, and tissue was collected for histology. Bayesian generalized additive and mixed-effects models were used for analyses. Both normal aging and AD led to increases in sleep compared with adult mice. WT Aged mice with TBI slept substantially more, with fragmented shorter bouts, than they did pre-TBI and compared with AD mice. However, differences between WT Aged and 3xTg-AD mice in immune cell populations and plasma cytokine levels were incongruous, cognitive deficits were similar, and cumulative sleep was not predictive of inflammation or behavior for either group. Our results suggest that in similarly aged individuals, TBI immediately induces more profound sleep alterations than in AD, although both diseases likely include cognitive impairments. Unique pathological sleep pathways may exist in elderly individuals who incur TBI compared with similarly aged individuals who have AD, which may warrant disease-specific treatments in clinical settings.

PMID: 33319441 [PubMed - as supplied by publisher]

Comparison of Rates of Overdose and Hospitalization After Initiation of Medication for Opioid Use Disorder in the Inpatient vs Outpatient Setting.

JAMA Netw Open. 2020 12 01;3(12):e2029676

Authors: Morgan JR, Barocas JA, Murphy SM, Epstein RL, Stein MD, Schackman BR, Walley AY, Linas BP

Abstract
Importance: Whereas outpatient treatment with medication for opioid use disorder (MOUD) is evidence based, there is a large network of inpatient facilities in the US that are reimbursed by commercial insurers and do not typically offer MOUD.
Objective: To compare the rates of opioid-related overdose and all-cause hospitalization after outpatient MOUD treatment vs inpatient care.
Design, Setting, and Participants: This comparative effectiveness research study used deidentified claims of commercially insured individuals in the US from the MarketScan Commercial Claims and Encounters Database from January 1, 2010, to December 31, 2017, to obtain a sample of 37 090 individuals with opioid use disorder who initiated treatment with inpatient care and/or MOUD. Data were analyzed from October 1, 2019, to May 1, 2020. To address nonrandom treatment assignment, individuals with opioid use disorder who initiated MOUD or who entered inpatient care were matched 1:1 based on propensity scores.
Exposures: The independent variable of interest was the type of treatment initiated. Individuals could initiate 1 of 5 potential treatments: (1) outpatient MOUD, (2) short-term inpatient care, (3) short-term inpatient care followed by outpatient MOUD within 30 days, (4) long-term inpatient care, or (5) long-term inpatient care followed by outpatient MOUD within 30 days.
Main Outcomes and Measures: Opioid-related overdose and all-cause hospitalization at any point within the 12 months after treatment of opioid use disorder. The hazard for each outcome was estimated using a time-to-event Cox proportional hazards regression model.
Results: The cohort included 37 090 individuals matched 1:1 between inpatient and outpatient treatment (20 723 [56%] were younger than 30 years; 23 250 [63%] were male). After propensity score matching, compared with the inpatient treatments, initiation of outpatient MOUD alone was followed by the lowest 1-year overdose rate (2.2 [95% CI, 2.0-2.5] per 100 person-years vs 3.5 [95% CI, 2.7-4.4] to 7.0 [95% CI, 4.6-10.7] per 100 person-years) and hospitalization rate (39 [95% CI, 38-40] per 100 person-years vs 57 [95% CI, 54-61] to 74 [95% CI, 73-76] per 100 person-years). Outpatient MOUD was also associated with the lowest hazard of these events compared with inpatient care, which had hazard ratios ranging from 1.71 (95% CI, 1.35-2.17) to 2.67 (95% CI, 1.68-4.23) for overdose and 1.33 (95% CI, 1.23-1.44) to 1.90 (95% CI, 1.83-1.97) for hospitalizations.
Conclusions and Relevance: The results of this comparative effectiveness research study suggest that lower rates of subsequent overdose and hospitalization are associated with outpatient MOUD compared with short- or long-term inpatient care. When patients and clinicians have a choice of treatment, outpatient MOUD treatment may be associated with lower overdose and hospitalization on balance. Future research should assess which patients benefit most from inpatient care and how best to leverage existing inpatient treatment infrastructure.

PMID: 33320266 [PubMed - indexed for MEDLINE]

The Western United States has Greater Antibiotic Resistance Among Salmonella Recovered from Intestinal Cecal Samples of Food Animals.

J Food Prot. 2020 Dec 15;:

Authors: Nyirabahizi E, Tyson GH, Tate H, Williams MS, Saini GS, Strain E

Abstract
As part of the National Antimicrobial Resistance Monitoring System (NARMS) activities, the United States Department of Agriculture (USDA) Food Safety Inspection Service (FSIS) collected cecal samples from food animal slaughter facilities throughout the country between 2014 and 2018. Of the 26,780 cecal samples from cattle, swine, chicken and turkey , 6,350 (23.71%) tested positive for Salmonella . NARMS tested Salmonella for susceptibility to aminoglycosides, folate pathway inhibitors, macrolides, phenicols, quinolones, beta lactams, and tetracyclines. Using the regional subdivisions defined in the USDA Office of Investigation, we used chi-square test to assess potential association between the region from which the samples were collected and both Salmonella prevalence and susceptibility. The results show a significant association between region and Salmonella prevalence, when accounting for source and establishment size, with the southeast region having the highest probability of finding Salmonella . However, the western region had the highest resistance probability across all antimicrobial classes except for macrolides, which showed no regional association. This association between region and resistance was strongest among isolates from cattle. Analysis of whole-genome sequencing data indicated that a significantly higher prevalence of Salmonella Newport in cattle in the western region (accounting for 9.52% of cattle isolates, compared to 3.44% in other regions) may account for the greater resistance to multiple drug classes. Approximately 90% of Salmonella Newport in the west exhibited the MDR-AmpC phenotype encoded by aph(3'')-Ib/aph(6)-Id , bla CMY-2 , floR , sul2 , and tetA. . Thus, differences in resistance across regions may be due to geographical differences in the prevalence of specific Salmonella serotypes and their accompanying resistance genes.

PMID: 33320944 [PubMed - as supplied by publisher]

Syndemic of Lifetime Mental Illness, Substance Use Disorders, and Trauma and Their Association With Adverse Perinatal Outcomes.

J Interpers Violence. 2020 01;35(1-2):476-495

Authors: McDonald LR, Antoine DG, Liao C, Lee A, Wahab M, Coleman JS

Abstract
Adverse perinatal outcomes are a significant contributor to neonatal and infant deaths. Mental illness, substance use disorders, and interpersonal trauma are often prevalent within obstetrical populations. Previous literature has documented the individual associations between these psychosocial factors and adverse perinatal outcomes. The co-occurrence of these three psychosocial factors might represent a syndemic among pregnant women, although they have not been described as such in the literature. Analysis of the interrelatedness and aggregate effect of these factors may allow for a more effective screening process that may reduce adverse perinatal outcomes. The objective of this article is to examine whether psychosocial factors (mental illness, substance use disorders, and interpersonal trauma) were independently and synergistically associated with adverse perinatal outcomes. This is a retrospective cohort study of 1,656 pregnant women at a single institution. Perinatal outcome and psychosocial data were abstracted from each participant's electronic medical record. Univariate and bivariate analyses, and multiple logistic regression were performed. Mean age was 27.5 (SD = 6.2) years. The majority was Black (60.6%) and single (58%). Psychosocial factors were reported in 35% of women. The incidence of adverse perinatal outcomes increased with greater number of psychosocial factors: 21.2% if no psychosocial factor, 27.0% if one psychosocial factor, 27.4% if two, and 35.3% if all three (for trend, p = .01). Women who reported all three psychosocial factors had twice the odds of adverse perinatal outcomes (adjusted odds ratio = 2.04, 95% confidence interval = [1.09, 3.81], p = .03) compared with those who reported none. Our data suggest there is a synergistic relationship between the psychosocial factors that is associated with increased adverse perinatal outcomes. A validated screening tool is needed to stratify patient's risk of adverse perinatal outcomes based on psychosocial factors. Such screening could lead to tailored interventions that could decrease adverse perinatal outcomes.

PMID: 29294630 [PubMed - indexed for MEDLINE]

Development and validation of language and visuospatial composite scores in ADNI.

Alzheimers Dement (N Y). 2020;6(1):e12072

Authors: Choi SE, Mukherjee S, Gibbons LE, Sanders RE, Jones RN, Tommet D, Mez J, Trittschuh EH, Saykin A, Lamar M, Rabin L, Foldi NS, Sikkes S, Jutten RJ, Grandoit E, Mac Donald C, Risacher S, Groot C, Ossenkoppele R, Alzheimer's Disease Neuroimaging Initiative, Crane PK

Abstract
Introduction: Composite scores may be useful to summarize overall language or visuospatial functioning in studies of older adults.
Methods: We used item response theory to derive composite measures for language (ADNI-Lan) and visuospatial functioning (ADNI-VS) from the cognitive battery administered in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We evaluated the scores among groups of people with normal cognition, mild cognitive impairment (MCI), and Alzheimer's disease (AD) in terms of responsiveness to change, association with imaging findings, and ability to differentiate between MCI participants who progressed to AD dementia and those who did not progress.
Results: ADNI-Lan and ADNI-VS were able to detect change over time and predict conversion from MCI to AD. They were associated with most of the pre-specified magnetic resonance imaging measures. ADNI-Lan had strong associations with a cerebrospinal fluid biomarker pattern.
Discussion: ADNI-Lan and ADNI-VS may be useful composites for language and visuospatial functioning in ADNI.

PMID: 33313380 [PubMed]

Occipital-Cervical Fusion and Ventral Decompression in the Surgical Management of Chiari-1 Malformation and Syringomyelia: Analysis of Data From the Park-Reeves Syringomyelia Research Consortium.

Neurosurgery. 2020 Dec 11;:

Authors: CreveCoeur TS, Yahanda AT, Maher CO, Johnson GW, Ackerman LL, Adelson PD, Ahmed R, Albert GW, Aldana PR, Alden TD, Anderson RCE, Baird L, Bauer DF, Bierbrauer KS, Brockmeyer DL, Chern JJ, Couture DE, Daniels DJ, Dauser RC, Durham SR, Ellenbogen RG, Eskandari R, Fuchs HE, George TM, Grant GA, Graupman PC, Greene S, Greenfield JP, Gross NL, Guillaume DJ, Haller G, Hankinson TC, Heuer GG, Iantosca M, Iskandar BJ, Jackson EM, Jea AH, Johnston JM, Keating RF, Kelly MP, Khan N, Krieger MD, Leonard JR, Mangano FT, Mapstone TB, McComb JG, Menezes AH, Muhlbauer M, Oakes WJ, Olavarria G, O'Neill BR, Park TS, Ragheb J, Selden NR, Shah MN, Shannon C, Shimony JS, Smith J, Smyth MD, Stone SSD, Strahle JM, Tamber MS, Torner JC, Tuite GF, Wait SD, Wellons JC, Whitehead WE, Limbrick DD

Abstract
BACKGROUND: Occipital-cervical fusion (OCF) and ventral decompression (VD) may be used in the treatment of pediatric Chiari-1 malformation (CM-1) with syringomyelia (SM) as adjuncts to posterior fossa decompression (PFD) for complex craniovertebral junction pathology.
OBJECTIVE: To examine factors influencing the use of OCF and OCF/VD in a multicenter cohort of pediatric CM-1 and SM subjects treated with PFD.
METHODS: The Park-Reeves Syringomyelia Research Consortium registry was used to examine 637 subjects with cerebellar tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and at least 1 yr of follow-up after their index PFD. Comparisons were made between subjects who received PFD alone and those with PFD + OCF or PFD + OCF/VD.
RESULTS: All 637 patients underwent PFD, 505 (79.2%) with and 132 (20.8%) without duraplasty. A total of 12 subjects went on to have OCF at some point in their management (PFD + OCF), whereas 4 had OCF and VD (PFD + OCF/VD). Of those with complete data, a history of platybasia (3/10, P = .011), Klippel-Feil (2/10, P = .015), and basilar invagination (3/12, P < .001) were increased within the OCF group, whereas only basilar invagination (1/4, P < .001) was increased in the OCF/VD group. Clivo-axial angle (CXA) was significantly lower for both OCF (128.8 ± 15.3°, P = .008) and OCF/VD (115.0 ± 11.6°, P = .025) groups when compared to PFD-only group (145.3 ± 12.7°). pB-C2 did not differ among groups.
CONCLUSION: Although PFD alone is adequate for treating the vast majority of CM-1/SM patients, OCF or OCF/VD may be occasionally utilized. Cranial base and spine pathologies and CXA may provide insight into the need for OCF and/or OCF/VD.

PMID: 33313928 [PubMed - as supplied by publisher]

Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation.

NPJ Regen Med. 2020 Nov 23;5(1):22

Authors: Norat P, Soldozy S, Sokolowski JD, Gorick CM, Kumar JS, Chae Y, Yağmurlu K, Prada F, Walker M, Levitt MR, Price RJ, Tvrdik P, Kalani MYS

Abstract
Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

PMID: 33298971 [PubMed]

Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects.

Sci Rep. 2020 Dec 09;10(1):21584

Authors: Williams MT, Sugimoto C, Regan SL, Pitzer EM, Fritz AL, Mascia AE, Sertorio M, Vatner RE, Perentesis JP, Vorhees CV

Abstract
Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes. Adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy irradiation (the 20 Gy group was not used because 50% died). Rats were tested once/week for 5 weeks post-irradiation for activity, coordination, and startle. Cognitive assessment began 6-weeks post-irradiation with novel object recognition (NOR), egocentric learning, allocentric learning, reference memory, and proximal cue learning. Proton exposure had the largest effect on activity and prepulse inhibition of startle 1-week post-irradiation that dissipated each week. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (Cincinnati water maze) and allocentric learning and caused reference memory deficits (Morris water maze), but did not affect proximal cue learning or swimming performance. Proton groups also had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. This new model will facilitate investigations of different proton dose rates and drugs to ameliorate the cognitive sequelae of proton radiotherapy.

PMID: 33299021 [PubMed - in process]

Quantifying neurologic disease using biosensor measurements in-clinic and in free-living settings in multiple sclerosis.

NPJ Digit Med. 2019 Dec 11;2(1):123

Authors: Chitnis T, Glanz BI, Gonzalez C, Healy BC, Saraceno TJ, Sattarnezhad N, Diaz-Cruz C, Polgar-Turcsanyi M, Tummala S, Bakshi R, Bajaj VS, Ben-Shimol D, Bikhchandani N, Blocker AW, Burkart J, Cendrillon R, Cusack MP, Demiralp E, Jooste SK, Kharbouch A, Lee AA, Lehár J, Liu M, Mahadevan S, Murphy M, Norton LC, Parlikar TA, Pathak A, Shoeb A, Soderberg E, Stephens P, Stoertz AH, Thng F, Tumkur K, Wang H, Rhodes J, Rudick RA, Ransohoff RM, Phillips GA, Bruzik E, Marks WJ, Weiner HL, Snyder TM

Abstract
Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p = 0.0070), several aspects of turning including turn angle (0.437; p = 0.0372), and maximum angular velocity (0.653; p = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting.

PMID: 33299125 [PubMed]

Impact of New Motor Deficit on HRQOL after Adult Spinal Deformity Surgery: Subanalysis from Scoli Risk 1 Prospective Study.

Spine (Phila Pa 1976). 2020 Dec 07;:

Authors: Saigal R, Lau D, Berven SH, Carreon L, Dekutoski MB, Kebaish KM, Qiu Y, Matsuyama Y, Kelly M, Dahl BT, Mehdian H, Pellisé F, Lewis SJ, Cheung KM, Shaffrey CI, Fehlings MG, Lenke LG, Ames CP, AOSpine Knowledge Forum Deformity

Abstract
STUDY DESIGN: International, multi-center, prospective, longitudinal observational cohort.
OBJECTIVE: To assess how new motor deficits affect patient reported quality of life scores after adult deformity surgery.
SUMMARY OF BACKGROUND DATA: Adult spinal deformity surgery is associated with high morbidity, including risk of new post-operative motor deficit. It is unclear what effect new motor deficit has on HRQOL scores.
METHODS: Adult spinal deformity patients were enrolled prospectively at 15 sites worldwide. Other inclusion criteria included major Cobb >80 degrees, C7-L2 curve apex, and any patient undergoing 3 column osteotomy. ASIA scores and standard HRQOL scores were recorded pre-op, 6 weeks, 6 months, and 2 years.
RESULTS: 272 complex adult spinal deformity (ASD) patients enrolled. HRQOL scores were worse for patients with lower LEMS scores. Mean HRQOL changes at 6 weeks and 2 years compared to pre-op for patients with motor worsening were: ODI (+12.4 at 6 weeks and -4.7 at 2 years), SF-36v2 physical (-4.5 at 6 weeks and +2.3 at 2 years), SRS-22r (0.0 at 6 weeks and +0.4 at 2 years). Mean HRQOL changes for motor-neutral patients were: ODI (+0.6 at 6 weeks and -12.1 at 2 years), SF-36v2 physical (-1.6 at 6 weeks and +5.9 at 2 years), and SRS-22r (+0.4 at 6 weeks and +0.7 at 2 years). For patients with LEMS improvement, mean HRQOL changes were: ODI (-0.6 at 6 weeks and -16.3 at 2 years), SF-36v2 physical (+1.0 at 6 weeks and +7.0 at 2 years), and SRS-22r (+0.5 at 6 weeks and +0.9 at 2 years).
CONCLUSION: In the subgroup of deformity patients who developed a new motor deficit, total HRQOLs and HRQOL changes were negatively impacted. Patients with more than 2 points of LEMS worsening had the worst changes, but still showed overall HRQOL improvement at 6 months and 2 years compared to pre-op baseline.
LEVEL OF EVIDENCE: 3.

PMID: 33290376 [PubMed - as supplied by publisher]

Short chain fatty acids produced by Cutibacterium acnes inhibit biofilm formation by Staphylococcus epidermidis.

Sci Rep. 2020 Dec 04;10(1):21237

Authors: Nakamura K, O'Neill AM, Williams MR, Cau L, Nakatsuji T, Horswill AR, Gallo RL

Abstract
Biofilm formation by bacterial pathogens is associated with numerous human diseases and can confer resistance to both antibiotics and host defenses. Many strains of Staphylococcus epidermidis are capable of forming biofilms and are important human pathogens. Since S. epidermidis coexists with abundant Cutibacteria acnes on healthy human skin and does not typically form a biofilm in this environment, we hypothesized that C. acnes may influence biofilm formation of S. epidermidis. Culture supernatants from C. acnes and other species of Cutibacteria inhibited S. epidermidis but did not inhibit biofilms by Pseudomonas aeruginosa or Bacillus subtilis, and inhibited biofilms by S. aureus to a lesser extent. Biofilm inhibitory activity exhibited chemical properties of short chain fatty acids known to be produced from C. acnes. The addition of the pure short chain fatty acids propionic, isobutyric or isovaleric acid to S. epidermidis inhibited biofilm formation and, similarly to C. acnes supernatant, reduced polysaccharide synthesis by S. epidermidis. Both short chain fatty acids and C. acnes culture supernatant also increased sensitivity of S. epidermidis to antibiotic killing under biofilm-forming conditions. These observations suggest the presence of C. acnes in a diverse microbial community with S. epidermidis can be beneficial to the host and demonstrates that short chain fatty acids may be useful to limit formation of a biofilm by S. epidermidis.

PMID: 33277548 [PubMed - as supplied by publisher]

Economic modeling of reSET-O, a prescription digital therapeutic for patients with opioid use disorder.

J Med Econ. 2020 Dec 03;:1

Authors: Wang W, Gellings Lowe N, Jalali A, Murphy SM

Abstract
AIMS: reSET-O is a Food and Drug Administration-cleared prescription digital therapeutic indicated to improve outpatient-treatment retention of patients with opioid use disorder (OUD). This study examined the cost-effectiveness and budget impact of reSET-O in conjunction with treatment as usual (reSET-O + TAU) relative to TAU.
MATERIALS AND METHODS: Adult patients with ≥1 OUD diagnosis, treated with buprenorphine from January 1, 2015 to March 30, 2018, were identified from Truven Health MarketScan® Commercial and Medicare Supplemental Research Databases. Twelve-week healthcare resource utilization (HCRU) costs for patients categorized as adherent and nonadherent to buprenorphine treatment were estimated. Total 12-week costs included OUD treatment and other HCRU costs. The cost-effectiveness of reSET-O + TAU was modeled in accordance with prior clinical trial outcomes. The 12-week budget impact of reSET-O was modeled for a 1 million-member healthcare plan.
RESULTS: Higher buprenorphine adherence was associated with lower HCRU costs in claims data. Twelve-week per-patient total costs were $305 more for those receiving reSET-O + TAU than those receiving TAU. The incremental cost-effectiveness ratio was $18.70 per 1 percentage-point increase in the treatment retention rate. The probability that reSET-O + TAU would be considered cost-effective was over 92% for willingness-to-pay thresholds of $6,000 or more. The 12-week budget impact of reSET-O was $8,908, translating to $0.003 per member per month.
LIMITATIONS: The findings of the cost-effectiveness and budget impact modeling are limited by the assumptions of the models due to uncertainty around some inputs. While no model is free of bias, the inputs for this model were carefully selected to reflect contemporary treatment patterns.
CONCLUSIONS: Depending on the payer's willingness to pay, reSET-O may be cost-effective in increasing buprenorphine treatment retention rates. reSET-O results in an approximate budget impact of $0.003 per member per month, depending on market share and the prevalence of the population receiving treatment for OUD.

PMID: 33267633 [PubMed - as supplied by publisher]

Reducing Intracranial Pressure by Reducing Central Venous Pressure: Assessment of potential countermeasures to spaceflight associated neuro-ocular syndrome.

J Appl Physiol (1985). 2020 Dec 03;:

Authors: Hansen AB, Lawley JS, Rickards CA, Howden EJ, Sarma S, Cornwell WK, Amin SB, Mugele H, Marume K, Possnig C, Whitworth LA, Williams MA, Levine BD

Abstract
Spaceflight-associated neuro-ocular syndrome (SANS) involves unilateral or bilateral optic disc edema, widening of the optic nerve sheath, and posterior globe flattening. Due to posterior globe flattening, it is hypothesized that microgravity causes a disproportionate change in intracranial pressure (ICP) relative to intraocular pressure. Countermeasures capable of reducing ICP include thigh cuffs and breathing against inspiratory resistance. Due to the coupling of central venous (CVP) and intracranial pressure, we hypothesized that both ICP and CVP will be reduced during both countermeasures. In four male participants (32±13 yrs) who were previously implanted with Ommaya reservoirs for treatment of unrelated clinical conditions, ICP was measured invasively through these ports. Subjects were healthy at the time of testing. CVP was measured invasively by a peripherally inserted central catheter. Participants breathed through an Impedance Threshold Device (ITD, -7 cm.H2O) to generate negative intrathoracic pressure for five-mins, and subsequently, wore bilateral thigh cuffs at 30-mmHg for two-mins. Breathing through an ITD reduced both CVP (6±2 vs 3±1 mmHg; P=0.02) and ICP (16±3 vs 12±1 mmHg; P=0.04) compared to the supine posture, which was not observed during the free breathing condition (CVP, 6±2 vs 6±2 mmHg; P=0.87 and ICP, 15±3 vs 15±4 mmHg; P=0.68). Inflation of the thigh cuffs to 30-mmHg caused no meaningful reduction in CVP in all four individuals (5±4 vs 5±4 mmHg; P=0.1), coincident with a minimal reduction in ICP (15±3 vs 14±4 mmHg; P=0.13). The application of inspiratory resistance breathing resulted in reductions in both ICP and CVP, likely due to intrathoracic unloading.

PMID: 33270516 [PubMed - as supplied by publisher]

Insights on cross-species transmission of SARS-CoV-2 from structural modeling.

PLoS Comput Biol. 2020 12;16(12):e1008449

Authors: Rodrigues JPGLM, Barrera-Vilarmau S, M C Teixeira J, Sorokina M, Seckel E, Kastritis PL, Levitt M

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 31 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic and confirmed cases of cross-species transmission, the question of the extent to which this transmission is possible emerges, as well as what molecular features distinguish susceptible from non-susceptible animal species. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also allow us to predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

PMID: 33270653 [PubMed - indexed for MEDLINE]

The authors reply.

Crit Care Med. 2020 Dec;48(12):e1366-e1367

Authors: Chesnut RM, Videtta W

PMID: 33255133 [PubMed - in process]

Effect of bodyweight on VerifyNow Aspirin platelet function test: a retrospective review.

J Neurointerv Surg. 2020 Nov 30;:

Authors: Sandler M, Hoang C, Mak HY, Levitt MR

Abstract
BACKGROUND: Antiplatelet therapy is used to prevent stent thrombosis in intracranial stents, but the optimal dose of aspirin is unknown. This study sought to determine whether the degree of platelet inhibition with aspirin is affected by bodyweight as observed through a platelet reactivity assay.
METHODS: This is a retrospective review of patients who underwent neurovascular stent placement and had a VerifyNow Aspirin assay result. The primary outcome was the correlation between the VerifyNow Aspirin result, bodyweight, and the initial dose of aspirin. Secondary outcomes included the impact of the VerifyNow P2Y12 result and of weight on the incidence of bleeding or a thrombotic event.
RESULTS: Of the 142 included patients, 62.7% weighed ≥70 kg and 88.7% were initiated on aspirin 300-325 mg daily. 83.8% achieved a therapeutic VerifyNow Aspirin result. There was minimal correlation between the VerifyNow Aspirin result, bodyweight, and aspirin dose (R2=0.02). Between patients who weighed <70 kg versus ≥70 kg, there was no difference in the mean aspirin reaction units (ARU) (449 vs 435, p=0.32) or in the incidence of bleeding (28% vs 17.1%, p=0.14) or a thrombotic event (4% vs 5.3%, p=0.59). No patient experienced stent thrombosis and eight patients experienced in-stent stenosis. In a multivariate analysis, only the VerifyNow P2Y12 result predicted the development of either bleeding or a thrombotic event (p<0.01).
CONCLUSIONS: Bodyweight did not influence the likelihood of obtaining a therapeutic VerifyNow Aspirin result. The clinical utility of obtaining VerifyNow Aspirin assays for this patient population is unknown.

PMID: 33257413 [PubMed - as supplied by publisher]