UW Neurological Surgery Recent PubMed Publications

Comparison of Clinical Outcomes 1 and 5 Years Post-Injury Following Combat Concussion.

Neurology. 2021 01 19;96(3):e387-e398

Authors: Mac Donald CL, Barber J, Patterson J, Johnson AM, Parsey C, Scott B, Fann JR, Temkin NR

Abstract
OBJECTIVE: To compare 1-year and 5-year clinical outcomes in 2 groups of combat-deployed service members without brain injury to those of 2 groups with combat-related concussion to better understand long-term clinical outcome trajectories.
METHODS: This prospective, observational, longitudinal multicohort study examined 4 combat-deployed groups: controls without head injury with or without blast exposure and patients with combat concussion arising from blast or blunt trauma. One-year and 5-year clinical evaluations included identical batteries for neurobehavioral, psychiatric, and cognitive outcomes. A total of 347 participants completed both time points of evaluation. Cross-sectional and longitudinal comparisons were assessed. Overall group effect was modeled as a 4-category variable with rank regression adjusting for demographic factors using a 2-sided significance threshold of 0.05, with post hoc Tukey p values calculated for the pairwise comparisons.
RESULTS: Significant group differences in both combat concussion groups were identified cross-sectionally at 5-year follow-up compared to controls in neurobehavioral (Neurobehavioral Rating Scale-Revised [NRS]; Cohen d, -1.10 to -1.40, confidence intervals [CIs] [-0.82, -1.32] to [-0.97, -1.83] by group) and psychiatric domains (Clinician-Administered PTSD Scale for DSM-IV [CAPS]; Cohen d, -0.91 to -1.19, CIs [-0.63, -1.19] to [-0.76, -1.62] by group) symptoms with minimal differences in cognitive performance. Both combat concussion groups also showed clinically significant decline from 1- to 5-year evaluation (66%-76% neurobehavioral NRS; 41%-54% psychiatric CAPS by group). Both control groups fared better but a subset also had clinically significant decline (37%-50% neurobehavioral NRS; 9%-25% psychiatric CAPS by group).
CONCLUSIONS: There was an evolution, not resolution, of symptoms from 1- to 5-year evaluation, challenging the assumption that chronic stages of concussive injury are relatively stable. Even some of the combat-deployed controls worsened. The evidence supports new considerations for chronic trajectories of concussion outcome in combat-deployed service members.

PMID: 33177226 [PubMed - indexed for MEDLINE]

Aryl Amination Using Soluble Weak Base Enabled by a Water-Assisted Mechanism.

J Am Chem Soc. 2020 Nov 12;:

Authors: Lau SH, Yu P, Chen L, Madsen-Duggan CB, Williams MJ, Carrow BP

Abstract
The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

PMID: 33179489 [PubMed - as supplied by publisher]

Segmented quantitative diffusion tensor imaging evaluation of acute traumatic cervical spinal cord injury.

Br J Radiol. 2021 Feb 01;94(1118):20201000

Authors: Mossa-Basha M, Peterson DJ, Hippe DS, Vranic JE, Hofstetter C, Reyes M, Bombardier C, Jarvik JG

Abstract
OBJECTIVES: To evaluate segmented diffusion tensor imaging (DTI) white matter tract fractional anisotropy (FA) and mean diffusivity (MD) values in acute cervical spinal cord injury (CSCI).
METHODS: 15 patients with acute CSCI and 12 control subjects were prospectively recruited and underwent axial DTI as part of the spine trauma MRI. Datasets were put through a semi-automated probabilistic segmentation algorithm that analyzed white matter, motor and sensory tracts. FA and MD values were calculated for white matter, sensory (spinal lemniscal) and motor tracts (ventral/lateral corticospinal) at the level of clinical injury, levels remote from injury and in normal controls.
RESULTS: There were significant differences in FA between the level of injury and controls for total white matter (0.65 ± .09 vs 0.68 ± .07; p = .044), motor tracts (0.64 ± .07 vs 0.7 ± .09; p = .006), and combined motor/sensory tracts (0.63 ± .09 vs 0.69 ± .08; p = .022). In addition, there were significant FA differences between the level of injury and one level caudal to the injury for combined motor tracts (0.64 ± .07 vs 0.69 ± .05; p = .002) and combined motor/sensory tracts (0.63 ± .09 vs 0.7 ± .07; p = .011). There were no significant differences for MD between the level of injury and one level caudal to the injury or normal controls.
CONCLUSION: Abnormalities in DTI metrics of DTI-segmented white matter tracts were detected at the neurological level of injury relative to normal controls and levels remote from the injury site, confirming its value in CSCI assessment.
ADVANCES IN KNOWLEDGE: Segmented DTI analysis can help identify microstructural spinal cord abnormalities in the setting of traumatic cervical spinal cord injury.

PMID: 33180553 [PubMed - indexed for MEDLINE]

Cardiologist Evaluation of Patients with Type 2 Myocardial Infarction.

Circ Cardiovasc Qual Outcomes. 2020 Nov 09;:

Authors: McCarthy CP, Olshan DS, Rehman S, Jones-O'Connor M, Murphy S, Cohen JA, Singh A, Vaduganathan M, Januzzi JL, Wasfy JH

PMID: 33161772 [PubMed - as supplied by publisher]

High-sensitivity C-Reactive Protein is a Prognostic Biomarker of 6-month Disability After Traumatic Brain Injury: Results from the TRACK-TBI Study.

J Neurotrauma. 2020 Nov 09;:

Authors: Xu L, Yue JK, Korley FK, Puccio AM, Yuh EL, Sun X, Rabinowitz M, Vassar M, Taylor SR, Winkler EA, Puffer R, Deng H, McCrea M, Stein MB, Robertson CS, Levin H, Dikmen S, Temkin N, Giacino JT, Mukherjee P, Wang KKW, Okonkwo DO, Markowitz AJ, Jain S, Manley GT, Diaz-Arrastia R

Abstract
BACKGROUND: Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI.
METHODS: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver Operating Characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE).
RESULTS: We included 1206 TBI subjects, 122 orthopedic trauma controls (OTC), and 209 healthy controls (HC). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1-5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HC (p<0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC=0.892). Combining hsCRP and GFAP at 2 weeks produced AUC=0.939 for prediction of disability.
CONCLUSIONS: Serum high-sensitivity CRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.

PMID: 33161875 [PubMed - as supplied by publisher]

Complicated versus uncomplicated mild traumatic brain injuries: A comparison of psychological, cognitive, and post-concussion symptom outcomes.

J Clin Exp Neuropsychol. 2020 Nov 09;:1-10

Authors: Karr JE, Iverson GL, Williams MW, Huang SJ, Yang CC

Abstract
INTRODUCTION: A complicated mild traumatic brain injury (MTBI) is defined as mild by all clinical severity indicators but is complicated due to a traumatic intracranial abnormality visible on neuroimaging. Researchers have reported mixed findings regarding whether neuropsychological and functional outcomes following complicated MTBI are worse than, or similar to, outcomes following uncomplicated MTBI. This study examined patients referred from a Taiwanese emergency department to a neurosurgical outpatient clinic. Participants with complicated MTBI, uncomplicated MTBI, and those who did not undergo head computed tomography (CT) were compared on psychological, neuropsychological, and post-concussion symptom outcomes within 21 days of injury.
METHOD: Participants with complicated MTBI (n = 42), uncomplicated MTBI (n = 77), and no head CT (n = 172) completed the Paced Auditory Serial Attention Test, Taiwanese Word Sequence Learning Test, a semantic Verbal Fluency Test, the Checklist of Post-Concussion Symptoms, and the Beck Depression and Anxiety Inventories.
RESULTS: No significant differences were observed between groups on any measure. For individual post-concussion symptoms, dizziness, anxiety, and attention difficulty were endorsed more often after uncomplicated MTBIs, but these group differences were not significant after controlling for multiple comparisons.
CONCLUSIONS: Participants with complicated MTBIs did not have worse acute or subacute outcomes than participants with uncomplicated MTBIs or no head CT. These results are consistent with many studies finding comparable outcomes between those with complicated and uncomplicated MTBIs. This study is limited by small sample size and minimal information on intracranial abnormalities, broadly categorizing groups based on positive or negative neuroimaging as opposed to specific lesion types and locations.

PMID: 33161877 [PubMed - as supplied by publisher]

CG4928 Is Vital for Renal Function in Fruit Flies and Membrane Potential in Cells: A First In-Depth Characterization of the Putative Solute Carrier UNC93A.

Front Cell Dev Biol. 2020;8:580291

Authors: Ceder MM, Aggarwal T, Hosseini K, Maturi V, Patil S, Perland E, Williams MJ, Fredriksson R

Abstract
The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK1 channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

PMID: 33163493 [PubMed]

Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source.

Biomed Res Int. 2020;2020:2608318

Authors: Levitt DG, Levitt JE, Levitt MD

Abstract
Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer ("shuttle") of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

PMID: 33150168 [PubMed - in process]

Health economic design for cost, cost-effectiveness and simulation analyses in the HEALing Communities Study.

Drug Alcohol Depend. 2020 Oct 03;217:108336

Authors: Aldridge AP, Barbosa C, Barocas JA, Bush JL, Chhatwal J, Harlow KJ, Hyder A, Linas BP, McCollister KE, Morgan JR, Murphy SM, Savitzky C, Schackman BR, Seiber EE, E Starbird L, Villani J, Zarkin GA

Abstract
BACKGROUND: The HEALing Communities Study (HCS) is designed to implement and evaluate the Communities That HEAL (CTH) intervention, a conceptually driven framework to assist communities in selecting and adopting evidence-based practices to reduce opioid overdose deaths. The goal of the HCS is to produce generalizable information for policy makers and community stakeholders seeking to implement CTH or a similar community intervention. To support this objective, one aim of the HCS is a health economics study (HES), the results of which will inform decisions around fiscal feasibility and sustainability relevant to other community settings.
METHODS: The HES is integrated into the HCS design: an unblinded, multisite, parallel arm, cluster randomized, wait list-controlled trial of the CTH intervention implemented in 67 communities in four U.S. states: Kentucky, Massachusetts, New York, and Ohio. The objectives of the HES are to estimate the economic costs to communities of implementing and sustaining CTH; estimate broader societal costs associated with CTH; estimate the cost-effectiveness of CTH for overdose deaths avoided; and use simulation modeling to evaluate the short- and long-term health and economic impact of CTH, including future overdose deaths avoided and quality-adjusted life years saved, and to develop a simulation policy tool for communities that seek to implement CTH or a similar community intervention.
DISCUSSION: The HCS offers an unprecedented opportunity to conduct health economics research on solutions to the opioid crisis and to increase understanding of the impact and value of complex, community-level interventions.

PMID: 33152672 [PubMed - as supplied by publisher]

Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome.

Neurobiol Dis. 2020 Oct 31;:105154

Authors: Sahai N, Bard AM, Devinsky O, Kalume F

Abstract
OBJECTIVE: To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS).
METHODS: We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise.
RESULTS: Core body temperatures of WT and DS mice were similar during baseline. After 15 mins of heat exposure, the peak value was lower in DS than WT mice. In the following mins of heat exposure, the temperature slowly returned close to baseline level in WT, whereas it remained elevated in DS mice. KO of Scn1a in GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The heart rate variability (HRV) was lower in DS than WT mice during baseline and higher in DS during exercise-recovery periods.
SIGNIFICANCE: We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was a significantly blunted correction of body temperature, and a less suppression of both HR and respiration rate in DS than WT mice. These effects were seen in mice with selective KO of Scn1A in GABAergic neurons. During exercise stress, there was diminished increase in HR, followed by an exaggerated HR suppression and HRV elevation during recovery in DS mice compared to controls. These findings suggest that different environmental stressors can uncover distinct autonomic disturbances in DS mice. Interneurons play an important role in thermoregulation. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP.

PMID: 33144172 [PubMed - as supplied by publisher]

A Genital Infection-Attenuated Chlamydia muridarum Mutant Infects the Gastrointestinal Tract and Protects against Genital Tract Challenge.

mBio. 2020 Nov 03;11(6):

Authors: Morrison SG, Giebel AM, Toh E, Banerjee A, Nelson DE, Morrison RP

Abstract
Chlamydia spp. productively infect mucosal epithelial cells of multiple anatomical sites, including the conjunctiva, lungs, gastrointestinal (GI) tract, and urogenital tract. We, and others, previously established that chlamydial GI tropism is mediated by distinct chromosomal and plasmid factors. In this study, we describe a genital infection-attenuated Chlamydia muridarum mutant (GIAM-1) that is profoundly and specifically attenuated in the murine genital tract. GIAM-1 infected the murine GI tract similarly to wild-type (WT) Chlamydia muridarum but did not productively infect the lower genital tract of female mice, ascend to infect the upper genital tract, or cause hydrosalpinx. However, GI infection of mice with GIAM-1 elicited a transmucosal immune response that protected against subsequent genital challenge with WT Chlamydia muridarum Collectively, our results demonstrate that chlamydia mutants that are profoundly attenuated for specific organ tissues can be derived and demonstrate that live-attenuated vaccine strains that infect the GI tract, but do not elicit genital tract disease, could be used to protect against chlamydia genital tract infection and disease.IMPORTANCE Chlamydia is the most common sexually transmitted bacterial infection in the United States. Most chlamydia genital infections resolve without serious consequences; however, untreated infection in women can cause pelvic inflammatory disease and infertility. Antibiotics are very effective in treating chlamydia, but most genital infections in both men and women are asymptomatic and go undiagnosed. Therefore, there is a critical need for an effective vaccine. In this work, we show that a mutant chlamydia strain, having substantially reduced virulence for genital infection, colonizes the gastrointestinal tract and produces robust immunity to genital challenge with fully virulent wild-type chlamydia. These results are an important advance in understanding chlamydial virulence and provide compelling evidence that safe and effective live-attenuated chlamydia vaccines may be feasible.

PMID: 33144378 [PubMed - in process]

Medicolegal issues in abusive head trauma for the pediatric neurosurgeon.

Neurosurg Focus. 2020 Nov;49(5):E23

Authors: Bass DI, Lee A, Browd SR, Ellenbogen RG, Hauptman JS

Abstract
The purpose of this article is to serve as a rational guide for the pediatric neurosurgeon in navigating common medicolegal issues that arise in the management of abusive head trauma (AHT). Many of these issues may be unfamiliar or unpleasant to surgeons focused on addressing disease. The authors begin with a brief history on the origins of the diagnosis of AHT and the controversy surrounding it, highlighting some of the facets of the diagnosis that make it particularly unique in pediatric neurosurgery. They then review some special medical considerations in these patients through the perspective of the neurosurgeon and provide several examples as illustration. The authors discuss how to appropriately document these cases in the medical record for expected legal review, and last, they provide an overview of the legal process through which the neurosurgeon may be called to provide testimony.

PMID: 33130608 [PubMed - in process]

The effect of durotomy versus myelotomy on tissue sparing and functional outcome after spinal cord injury.

J Neurotrauma. 2020 Oct 29;:

Authors: Khaing ZZ, Cates LN, Dewees DM, Hyde JE, Gaing A, Birjandian Z, Hofstetter CP

Abstract
Various surgical strategies have been developed to alleviate elevated intraspinal pressure (ISP) following acute traumatic spinal cord injury (tSCI). Surgical decompression of either the dural (durotomy) or the dural and pial (myelotomy) lining of the spinal cord has been proposed. However, a direct comparison of these two strategies is lacking. Here, we compare the histological and functional effects of durotomy alone and durotomy + myelotomy in a rodent model of acute thoracic tSCI. Our results indicate that tSCI causes local tissue edema and significantly elevates intraspinal pressure (ISP, 7.4 ± 0.3 mmHg) compared to physiological ISP (1.7 ± 0.4 mmHg; P < 0.001). Both durotomy alone and durotomy + myelotomy effectively mitigate elevated local ISP (P < 0.001). Histological examination at 10 weeks after tSCI revealed that durotomy + myelotomy promoted spinal tissue sparing by 13.7% compared to durotomy alone and by 25.9% compared to tSCI-only (P < 0.0001). Both types of decompression surgeries elicited a significant beneficial impact onto grey matter sparing (P < 0.01). Impressively, durotomy + myelotomy surgery increased preservation of motoneurons by 174.3% compared to tSCI-only (P < 0.05). Durotomy + myelotomy surgery also significantly promoted recovery of hindlimb locomotor function in an open-field test (P < 0.001). Interestingly, only durotomy alone resulted in favorable recovery of bladder and Ladder Walk performance. Combined, our data suggest that durotomy + myelotomy following acute tSCI facilitates tissue sparing and recovery of locomotor function. In the future, biomarkers identifying spinal cord injuries that can benefit from either durotomy alone or durotomy + myelotomy need to be developed.

PMID: 33121382 [PubMed - as supplied by publisher]

Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma.

J Immunother Cancer. 2020 Oct;8(2):

Authors: Gardell JL, Matsumoto LR, Chinn H, DeGolier KR, Kreuser SA, Prieskorn B, Balcaitis S, Davis A, Ellenbogen RG, Crane CA

Abstract
BACKGROUND: Targeted and effective treatment options are needed for solid tumors, including glioblastoma (GBM), where survival rates with standard treatments are typically less than 2 years from diagnosis. Solid tumors pose many barriers to immunotherapies, including therapy half-life and persistence, tumor penetrance, and targeting. Therapeutics delivered systemically may not traffic to the tumor site. If cellular therapies or drugs are able to access the tumor site, or can be delivered directly within the tumor, treatments may not persist for the duration necessary to reduce or eliminate tumor burden. An approach that allows durable and titratable local therapeutic protein delivery could improve antitumor efficacy while minimizing toxicities or unwanted on-target, off-tissue effects.
METHODS: In this study, human monocyte-derived macrophages were genetically engineered to secrete a bispecific T cell engager (BiTE) specific to the mutated epidermal growth factor variant III (EGFRvIII) expressed by some GBM tumors. We investigated the ability of lentivirally modified macrophages to secrete a functional BiTE that can bind target tumor antigen and activate T cells. Secreted BiTE protein was assayed in a range of T cell functional assays in vitro and in subcutaneous and intracranial GBM xenograft models. Finally, we tested genetically engineered macrophages (GEMs) secreting BiTE and the proinflammatory cytokine interleukin (IL)-12 to amplify T cell responses in vitro and in vivo.
RESULTS: Transduced human macrophages secreted a lentivirally encoded functional EGFRvIII-targeted BiTE protein capable of inducing T cell activation, proliferation, degranulation, and killing of antigen-specific tumor cells. Furthermore, BiTE secreting macrophages reduced early tumor burden in both subcutaneous and intracranial mouse models of GBM, a response which was enhanced using macrophages that were dual transduced to secrete both the BiTE protein and single chain IL-12, preventing tumor growth in an aggressive GBM model.
CONCLUSIONS: The ability of macrophages to infiltrate and persist in solid tumor tissue could overcome many of the obstacles associated with systemic delivery of immunotherapies. We have found that human GEMs can locally and constitutively express one or more therapeutic proteins, which may help recruit T cells and transform the immunosuppressive tumor microenvironment to better support antitumor immunity.

PMID: 33122397 [PubMed - in process]

Expansile duraplasty and obex exploration compared with bone-only decompression for Chiari malformation type I in children: retrospective review of outcomes and complications.

J Neurosurg Pediatr. 2020 Oct 30;:1-8

Authors: Ene CI, Wang AC, Collins KL, Bonow RH, McGrath LB, Durfy SJ, Barber JK, Ellenbogen RG

Abstract
OBJECTIVE: While a select population of pediatric patients with Chiari malformation type I (CM-I) remain asymptomatic, some patients present with tussive headaches, neurological deficits, progressive scoliosis, and other debilitating symptoms that necessitate surgical intervention. Surgery entails a variety of strategies to restore normal CSF flow, including increasing the posterior fossa volume via bone decompression only, or bone decompression with duraplasty, with or without obex exploration. The indications for duraplasty and obex exploration following bone decompression remain controversial. The objective of this study was to describe an institutional series of pediatric patients undergoing surgery for CM-I, performed by a single neurosurgeon. For patients presenting with a syrinx, the authors compared outcomes following bone-only decompression with duraplasty only and with duraplasty including obex exploration. Clinical outcomes evaluated included resolution of syrinx, scoliosis, presenting symptoms, and surgical complications.
METHODS: A retrospective review was conducted of the medical records of 276 consecutive pediatric patients with CM-I operated on at a single institution between 2001 and 2015 by the senior author. Imaging findings of tonsillar descent, associated syrinx (syringomyelia or syringobulbia), basilar invagination, and clinical assessment of CM-I-attributable symptoms and scoliosis were recorded. In patients presenting with a syrinx, clinical outcomes, including syrinx resolution, symptom resolution, and impact on scoliosis progression, were compared for three surgical groups: bone-only/posterior fossa decompression (PFD), PFD with duraplasty (PFDwD), and PFD with duraplasty and obex exploration (PFDwDO).
RESULTS: PFD was performed in 25% of patients (69/276), PFDwD in 18% of patients (50/276), and PFDwDO in 57% of patients (157/276). The mean follow-up was 35 ± 35 months. Nearly half of the patients (132/276, 48%) had a syrinx. In patients presenting with a syrinx, PFDwDO was associated with a significantly higher likelihood of syrinx resolution relative to PFD only (HR 2.65, p = 0.028) and a significant difference in time to symptom resolution (HR 2.68, p = 0.033). Scoliosis outcomes did not differ among treatment groups (p = 0.275). Complications were not significantly higher when any duraplasty (PFDwD or PFDwDO) was performed following bone decompression (p > 0.99).
CONCLUSIONS: In this series of pediatric patients with CM-I, patients presenting with a syrinx who underwent expansile duraplasty with obex exploration had a significantly greater likelihood of syrinx and symptom resolution, without increased risk of CSF-related complications, compared to those who underwent bone-only decompression.

PMID: 33126216 [PubMed - as supplied by publisher]

Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses.

J Immunother Cancer. 2020 Oct;8(2):

Authors: Brempelis KJ, Cowan CM, Kreuser SA, Labadie KP, Prieskorn BM, Lieberman NAP, Ene CI, Moyes KW, Chinn H, DeGolier KR, Matsumoto LR, Daniel SK, Yokoyama JK, Davis AD, Hoglund VJ, Smythe KS, Balcaitis SD, Jensen MC, Ellenbogen RG, Campbell JS, Pierce RH, Holland EC, Pillarisetty VG, Crane CA

Abstract
BACKGROUND: Though currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies.
METHODS: Using lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies.
RESULTS: Here, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins.
CONCLUSIONS: Our data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.

PMID: 33115946 [PubMed - in process]

Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).

Transl Vis Sci Technol. 2020 Oct;9(11):19

Authors: Waldner DM, Ito K, Chen LL, Nguyen L, Chow RL, Lee A, Rancourt DE, Tremblay F, Stell WK, Bech-Hansen NT

Abstract
Purpose: Congenital stationary night blindness 2A (CSNB2A) is a genetic retinal disorder characterized by poor visual acuity, nystagmus, strabismus, and other signs of retinal dysfunction resulting from mutations in Cacna1f -the gene coding for the pore-forming subunit of the calcium channel CaV1.4. Mouse models of CSNB2A have shown that mutations causing the disease deleteriously affect photoreceptors and their synapses with second-order neurons. This study was undertaken to evaluate whether transgenic expression of Cacna1f could rescue morphology and visual function in a Cacna1f-KO model of CSNB2A.
Methods: Strategic creation, breeding and use of transgenic mouse lines allowed for Cre-driven retina-specific expression of Cacna1f in a CSNB2A model. Transgene expression and retinal morphology were investigated with immunohistochemistry in retinal wholemounts or cross-sections. Visual function was assessed by optokinetic response (OKR) analysis and electroretinography (ERG).
Results: Mosaic, prenatal expression of Cacna1f in the otherwise Cacna1f-KO retina was sufficient to rescue some visual function. Immunohistochemical analyses demonstrated wild-type-like photoreceptor and synaptic morphology in sections with transgenic expression of Cacna1f.
Conclusions: This report describes a novel system for Cre-inducible expression of Cacna1f in a Cacna1f-KO mouse model of CSNB2A and provides preclinical evidence for the potential use of gene therapy in the treatment of CSNB2A.
Translational Relevance: These data have relevance in the treatment of CSNB2A and in understanding how photoreceptor integration might be achieved in retinas in which photoreceptors have been lost, such as retinitis pigmentosa, age-related macular degeneration, and other degenerative conditions.

PMID: 33117610 [PubMed]

Healthcare utilization patterns among persons who use drugs during the COVID-19 pandemic.

J Subst Abuse Treat. 2021 02;121:108177

Authors: Murphy SM, Yoder J, Pathak J, Avery J

Abstract
Persons with drug use disorders are an underserved and stigmatized population, and the COVID-19 pandemic could exacerbate these issues. The discussion around those with drug use disorders in the midst of the pandemic has focused on the need to ensure uninterrupted treatment access; however, very few in this population actually receive treatment, and retention is a substantial issue among those who do. Evidence from other chronic conditions suggests persons at high risk for severe COVID-19 complications are foregoing care due to fear of contracting the virus. Persons with drug use disorders tend to fall into this high-risk category, and thus may be avoiding healthcare facilities. Our data suggest this is true. If so, adverse outcomes, and increased severity of use disorders and associated health complications, could become prevalent. Clinicians should identify persons with drug use disorders who may be foregoing treatment, and engage them using methods that minimize the risk of COVID-19 transmission.

PMID: 33109432 [PubMed - indexed for MEDLINE]

Satisfaction with life following mild traumatic brain injury: A TRACK-TBI Study.

J Neurotrauma. 2020 Oct 27;:

Authors: Agtarap SD, Campbell-Sills L, Jain S, Sun X, Dikmen S, Levin H, McCrea M, Mukherjee P, Nelson LD, Temkin N, Yuh EL, Giacino J, Manley GT, Investigators TT

Abstract
Identifying the principal determinants of life satisfaction following mild TBI (mTBI) may inform efforts to improve subjective well-being in this population. We examined life satisfaction among participants in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study who presented with mTBI (Glasgow Coma Scale=13-15; N=1,152). An L1-regularization path algorithm was used to select optimal sets of baseline and concurrent symptom measures for prediction of scores on the Satisfaction with Life Scale (SWLS) at 2 weeks and 3, 6, and 12 months post-injury. Multivariable linear regression models (ns=744-894) were then fit to evaluate associations between the empirically-selected predictors and SWLS scores at each follow-up visit. Results indicated that emotional post-TBI symptoms (b's= -1.27 to -0.77, ps<.05), anhedonia (b's = -1.59 to -1.08, ps<.01), and pain interference (b's= -1.38 to -0.89, ps<.001) contributed to the prediction of lower SWLS scores at all follow-ups. Insomnia predicted lower SWLS scores at 2 weeks, 3 months, and 6 months (b's= -1.11 to -0.83, ps<.01); and negative affect predicted lower SWLS scores at 2 weeks, 3 months, and 12 months (b's= -1.38 to -0.80, ps<.005). Other post-TBI symptom domains and baseline socio-demographic, injury-related, and clinical characteristics did not emerge as robust predictors of SWLS scores during the year after mTBI. Efforts to improve satisfaction with life following mTBI may benefit from a focus on the detection and treatment of affective symptoms, pain, and insomnia. The results reinforce the need for tailoring of evidence-based treatments for these conditions to maximize efficacy in patients with mTBI.

PMID: 33107371 [PubMed - as supplied by publisher]

Validity of the Brief Test of Adult Cognition by Telephone (BTACT) in Level 1 Trauma Center Patients 6 Months Post-Traumatic Brain Injury: A TRACK-TBI Study.

J Neurotrauma. 2020 Oct 27;:

Authors: Nelson LD, Barber J, Temkin N, Dams-O'Connor K, Dikmen S, Giacino J, Kramer MD, Levin H, McCrea M, Whyte J, Bodien YG, Yue JK, Manley GT

Abstract
Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1,422 TBI patients and 170 orthopedic trauma controls (OTC) from the multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6-months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising brief, phone-based cognitive screening tool for patients with TBI. While the BTACT's memory items appear to index verbal episodic memory, items that purport to assess executive functions may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.

PMID: 33107388 [PubMed - as supplied by publisher]