Publications by authors named "Matthew Parsons"

191 Publications

Novel radiographic presentation of primary syphilis of the tonsil.

Radiol Case Rep 2021 Nov 26;16(11):3217-3221. Epub 2021 Aug 26.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri.

A 61-year-old HIV+ male presented to an infectious disease clinic with a complaint of sore throat. A painless ulcerated mass was discovered on the right tonsil resulting in further evaluation with a CT scan of the neck. Imaging confirmed the presence of a mass centered on the palatine tonsil and associated lymphadenopathy. A presumptive diagnosis of HPV-related squamous cell carcinoma was made due to patient risk factors. However, multiple biopsies found no evidence of carcinoma, but instead revealed the presence of spirochetes that stained positive for . Soon after, the patient developed the characteristic copper-red maculopapular rash of secondary syphilis, indicating that the tonsillar mass was, in fact, a primary chancre. Since such chancres are most often found externally in the genital or anal region, they are seldom radiographically characterized, placing them low on the differential diagnosis for most radiologists. A high index of suspicion could aid future radiologists in placing primary syphilis higher on the differential diagnosis in similar cases in which the patient has appropriate risk factors, such as a known history of genital-oral sexually transmitted infections or an immunocompromised state. Prompt recognition of the nature of a primary syphilitic lesion can lead to rapid resolution of symptoms following treatment with intramuscular benzathine penicillin G, as eventually occurred in this case.
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http://dx.doi.org/10.1016/j.radcr.2021.07.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405937PMC
November 2021

Potential Utility of Natural Killer Cells for Eliminating Cells Harboring Reactivated Latent HIV-1 Following the Removal of CD8 T Cell-Mediated Pro-Latency Effect(s).

Viruses 2021 Jul 26;13(8). Epub 2021 Jul 26.

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.

An impediment to curing HIV-1 infection is the persistence of latently infected cells in ART-treated people living with HIV (PLWH). A key strategy for curing HIV-1 infection is to activate transcription and translation of latent virus using latency reversing agents (LRAs) and eliminate cells harboring reactivated virus via viral cytopathic effect or immune clearance. In this review, we provide an overview of available LRAs and their use in clinical trials. Furthermore, we describe recent data suggesting that CD8 T cells promote HIV-1 latency in the context of ART, even in the presence of LRAs, which might at least partially explain the clinical inefficiency of previous "shock and kill" trials. Here, we propose a novel cure strategy called "unlock, shock, disarm, and kill". The general premise of this strategy is to shut down the pro-latency function(s) of CD8 T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1.
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http://dx.doi.org/10.3390/v13081451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402732PMC
July 2021

Refusal of surgery and survival outcomes in endometrial cancer.

Int J Gynecol Cancer 2021 09 12;31(9):1236-1241. Epub 2021 Aug 12.

Department of Obstetrics and Gynecology, The University of Utah, Salt Lake City, Utah, USA.

Objectives: The goal of this study was to determine the impact refusal of surgery has on overall survival in patients with endometrial cancer.

Methods: From January 2004 to December 2015, the National Cancer Database was queried for patients with pathologically proven endometrial cancer who were recommended surgery and refused. Inverse probability of treatment weighting was used to account for differences in baseline characteristics between patients who underwent surgery and those who refused. Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling were used to analyze overall survival.

Results: Of the 300 675 patients identified, 534 patients (0.2%) were recommended surgical treatment but refused: 18% (95/534) were age ≤40 years. The 5-year overall survival for all patients who refused surgery was significantly decreased compared with patients who underwent surgery (29.2% vs 71.9%, P<0.01). This was demonstrated at ages 41-64 years (65.5% vs 91.0%, P<0.01) and ≥65 years (23.4% vs 75.3%, P<0.01). The 5-year overall survival did not meet statistical significance at age ≤40 years (90.1% vs 87.8% P<0.19). However, there were few patients in this cohort. On multivariate analysis, factors associated with refusal of surgery included: Medicaid insurance, Black race, Hispanic Race, Charlson Comorbidity Index scores of 2 or greater, stage II or III, and if patient received external beam radiation therapy alone. Factors associated with undergoing surgery included: age greater than 41, stage IB, and if the patient received brachytherapy.

Conclusions: Refusal of surgery for endometrial cancer is uncommon and leads to decreased overall survival.
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http://dx.doi.org/10.1136/ijgc-2021-002692DOI Listing
September 2021

Protective efficacy of the anti-HIV broadly neutralizing antibody PGT121 in the context of semen exposure.

EBioMedicine 2021 Aug 9;70:103518. Epub 2021 Aug 9.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia; ARC Centre for Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, Victoria, Australia; Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia. Electronic address:

Background: HIV-1 infections occur following viral exposure at anogenital mucosal surfaces in the presence of semen. Semen contains immunosuppressive and pro-inflammatory factors. Semen from HIV-1-infected donors contains anti-HIV-1 antibodies. We assessed if passively infused anti-HIV-1 neutralizing antibody conferred protection from rectal SHIV challenge at semen exposed mucosae.

Methods: We pooled seminal plasma from HIV-1-infected donors. The pool was screened by ELISA for antibodies against HIV-1 gp140. The ability of seminal plasma to inhibit macaque NK cells from responding to direct and antibody-dependent stimulation was assessed. The ability of seminal plasma to inhibit macaque granulocytes from mediating oxidative burst was also assessed. To demonstrate viral infectivity in the presence of seminal plasma, macaques (n = 4) were rectally challenged with SHIV following exposure to 2.5 mL of seminal plasma. To evaluate if anti-HIV-1 neutralizing antibody confers protection against rectal SHIV challenge at semen exposed mucosae, eight macaques were intravenously infused with PGT121, either wild type (n = 4) or the Fc receptor binding deficient LALA variant (n = 4), and rectally challenged with SHIV following exposure to 2.5 mL of seminal plasma.

Findings: Anti-HIV-1 gp140 antibodies were detected in seminal plasma. Seminal plasma inhibited direct and antibody-dependent NK cell activation and granulocyte oxidative burst in vitro. Rectal SHIV challenge of control macaques following seminal plasma exposure resulted in infection of all animals. All macaques infused with wild type or LALA PGT121 and challenged with SHIV following seminal plasma exposure were protected.

Interpretation: PGT121 conferred protection against rectal SHIV challenge at semen exposed mucosae. Future research should investigate if semen alters protection conferred by antibodies more dependent on non-neutralizing functions.

Funding: This work was supported by a grant from the Australian National Health and Medical Research Council (APP1124680).
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http://dx.doi.org/10.1016/j.ebiom.2021.103518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361295PMC
August 2021

Cancer Misinformation and Harmful Information on Facebook and Other Social Media: A Brief Report.

J Natl Cancer Inst 2021 Jul 22. Epub 2021 Jul 22.

Department of Population Sciences, University of Utah, Salt Lake City, UT, USA.

There are little data on the quality of cancer treatment information available on social media. Here, we quantify the accuracy of cancer treatment information on social media and its potential for harm. Two cancer experts reviewed 50 of the most popular social media articles on each of the 4 most common cancers. The proportion of misinformation and potential for harm were reported for all 200 articles, and their association with the number of social media engagements using a 2-sample Wilcoxon rank-sum test. All statistical tests were 2-sided. Of 200 total articles, 32.5% (n = 65) contained misinformation and 30.5% (n = 61) contained harmful information. Among articles containing misinformation, 76.9% (50 of 65) contained harmful information. The median number of engagements for articles with misinformation was greater than factual articles (median [IQR] = 2300 [1200-4700] vs 1600 [819-4700], P = .05). The median number of engagements for articles with harmful information was statistically significantly greater than safe articles (median [IQR] = 2300 [1400-4700] vs 1500 [810-4700], P = .007).
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http://dx.doi.org/10.1093/jnci/djab141DOI Listing
July 2021

Huntingtin and the Synapse.

Front Cell Neurosci 2021 15;15:689332. Epub 2021 Jun 15.

Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada.

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin () gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.
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http://dx.doi.org/10.3389/fncel.2021.689332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239291PMC
June 2021

Temporal Trends and Predictors in Diagnosing Pathologic Node-Positive Prostate Cancer in Clinically Node-Negative Patients.

Clin Genitourin Cancer 2021 May 15. Epub 2021 May 15.

Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, Utah. Electronic address:

Introduction: Managing pathologically node positive (pN+) prostate cancer (PCa) is controversial. We describe temporal patterns and predictors of pN+ PCa in men with initially surgically managed clinically node negative (cN-) PCa.

Materials And Methods: This observational retrospective analysis of nonmetastatic, cN- PCa uses the National Cancer Database. Multivariable logistic regression was used to identify covariates associated with pN+ disease. Cox proportional hazards modeling and Kaplan-Meier analysis were used to evaluate survival patients undergoing radical prostatectomy with or without pelvic lymph node dissection (PLND).

Results: The rates of radical prostatectomy in men with grade group (GG) 4 and GG5 increased from 47.6% to 53.1% and from 42.5% to 49.5%, respectively. The annual rate increased from 2.02% in 2010 to 5.12% in 2017 (P < .001). The annual rates of PLND increased from 54.3% to 71.7%. The most significant predictor of pN+ PCa was ISUP GG4 (odds ratio [OR] 12.5, P< .001) and GG 5 (OR 26.2, P < .001). Rates of pN+ identification increased from 5.5% to 9.4% in men with GG4 and from 13.4% to 19.5% in men with GG5 (P< .001). In GG4 and GG5, patients undergoing PLND had superior survival to those managed without PLND (P < .01).

Conclusion: Among patients with cN- PCa, the diagnosis of pN+ PCa has become more common over time. GG4 and GG5 are the strongest independent predictors of pN+ disease. Because incidental pN+ results in upstaging these data are useful for informing discussions before radical prostatectomy.
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http://dx.doi.org/10.1016/j.clgc.2021.05.003DOI Listing
May 2021

Risk of secondary malignancies in ovarian cancer survivors: 52,680 patients analyzed with over 40 years of follow-up.

Gynecol Oncol 2021 Aug 3;162(2):454-460. Epub 2021 Jun 3.

Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 2000 Circle of Hope Drive #1950, Salt Lake City, UT 84112, USA. Electronic address:

Objective: Survivors of ovarian cancer are at risk of developing a secondary malignancy (SM). We sought to evaluate the risk of developing SM, stratified by treatment modality.

Methods: Standardized incidence ratios (SIR, observed-to-expected [O/E] ratio) were assessed in 52,680 patients diagnosed with ovarian cancer between 1975 and 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program.

Results: Of the 52,680 patients, 3366 patients (6.4%) developed SM, which was more than the endemic rate (O/E 1.13; p < .05). Patients who received any radiation (RT) had an increased risk of overall SM compared to those who didn't (O/E 1.42 vs 1.11; p < .05), and specifically, in the bladder (O/E 2.81). Patients who received any chemotherapy (CT) had an increased risk of leukemia (O/E 3.06), and a similar risk of overall SM compared to those not treated with CT (O/E 1.11 vs 1.14; p < .05). The excess risk of developing a solid tumor SM was greatest at latencies of 10-20 years. Patients younger than 50 had the highest risk of developing SM. Non-White patients had a higher risk of SM compared to White patients.

Conclusions: This is the largest study to examine the risk of SM in patients with ovarian cancer and has the longest follow-up. Risk of SM was increased after ovarian cancer and varied with treatment modality, race, latency, and age. These results may help inform SM screening protocols for women diagnosed with ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.034DOI Listing
August 2021

Application of an evidence-based, out-patient treatment strategy for COVID-19: Multidisciplinary medical practice principles to prevent severe disease.

J Neurol Sci 2021 Jul 20;426:117463. Epub 2021 Apr 20.

Laboratory of Neuroimmunology, Professor Lawrence Steinman, Stanford University School of Medicine, United States of America. Electronic address:

The COVID-19 pandemic has devastated individuals, families, and institutions throughout the world. Despite the breakneck speed of vaccine development, the human population remains at risk of further devastation. The decision to not become vaccinated, the protracted rollout of available vaccine, vaccine failure, mutational forms of the SARS virus, which may exhibit mounting resistance to our molecular strike at only one form of the viral family, and the rapid ability of the virus(es) to hitch a ride on our global transportation systems, means that we are will likely continue to confront an invisible, yet devastating foe. The enemy targets one of our human physiology's most important and vulnerable life-preserving body tissues, our broncho-alveolar gas exchange apparatus. Notwithstanding the fear and the fury of this microbe's potential to raise existential questions across the entire spectrum of human endeavor, the application of an early treatment intervention initiative may represent a crucial tool in our defensive strategy. This strategy is driven by evidence-based medical practice principles, those not likely to become antiquated, given the molecular diversity and mutational evolution of this very clever "world traveler".
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http://dx.doi.org/10.1016/j.jns.2021.117463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055502PMC
July 2021

ACR Appropriateness Criteria® Myelopathy: 2021 Update.

J Am Coll Radiol 2021 May;18(5S):S73-S82

Specialty Chair, Atlanta VA Health Care System and Emory University, Atlanta, Georgia.

Myelopathy is a clinical diagnosis with localization of the neurological findings to the spinal cord, rather than the brain or the peripheral nervous system, and then to a particular segment of the spinal cord. Myelopathy can be the result of primary intrinsic disorders of the spinal cord or from secondary conditions, which result in extrinsic compression of the spinal cord. While the causes of myelopathy may be multiple, the acuity of presentation and symptom onset frame a practical approach to the differential diagnosis. Imaging plays a crucial role in the evaluation of myelopathy with MRI the preferred modality. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2021.01.020DOI Listing
May 2021

Enhancement of Antibody-Dependent Cellular Cytotoxicity and Phagocytosis in Anti-HIV-1 Human-Bovine Chimeric Broadly Neutralizing Antibodies.

J Virol 2021 06 10;95(13):e0021921. Epub 2021 Jun 10.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Australia.

No prophylactic vaccine has provided robust protection against human immunodeficiency virus type 1 (HIV-1). Vaccine-induced broadly neutralizing antibodies (bNAbs) have not been achieved in humans and most animals; however, cows vaccinated with HIV-1 envelope trimers produce bNAbs with unusually long third heavy complementarity-determining regions (CDRH3s). Alongside neutralization, Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), may be critical for bNAb antiviral activity. Here, we aimed to augment the Fc-dependent effector functions of a chimeric human-bovine bNAb, NC-Cow1, which binds the CD4 binding site (CD4bs) and exhibits broader and more potent neutralization than most human CD4bs bNAbs by using an exceptionally long 60-amino acid (aa) CDRH3. The bovine variable region of NC-Cow1 was paired with a human IgG1 Fc region mutated to create the following three variants: G236R/L328R (GRLR) that abrogates Fc-gamma receptor (FcγR) binding, and two variants that enhance binding, namely, G236A/S239D/I332E (GASDIE) and G236A/S239D/A330L/I332E (GASDALIE). Both GASDIE and GASDALIE improved binding to human FcγRIIA and FcγRIIIA, enhanced human natural killer (NK) cell activation, and mediated higher levels of ADCC and ADP activity than the wild-type human IgG1 Fc. GASDALIE mediated higher phagocytic activity than GASDIE. As expected, GRLR eliminated binding to FcγRs and did not mediate ADCC or ADP. We demonstrated that mutations in the human Fc region of bovine chimeric antibodies with ultralong CDRH3s could enhance antibody effector functions while maintaining envelope binding and neutralization. This study will have significant implications in the development of multifunctional anti-HIV antibodies, which may be important to prevent HIV-1 transmission in an antibody-based topical microbicide. Despite successful antiviral chemotherapy, human immunodeficiency virus (HIV) is still a lifelong persistent virus, and no vaccine yet prevents HIV transmission. Topical microbicides offer an important alternative method to prevent sexual transmission of HIV-1. With the production of highly potent anti-HIV-1 broadly neutralizing antibodies (bNAbs) and multifunctional antibodies, monoclonal antibodies are now important prophylactic agents. Recently discovered anti-HIV-1 bovine bNAbs (with higher potency and breadth than most human bNAbs) could be novel candidates as potent topical microbicides. Our study is significant as it demonstrates the compatibility of combining bovine-derived neutralization with human-derived antibody-effector functions. This study is a new approach to antibody engineering that strengthens the feasibility of using high-potency bovine variable region bNAbs with augmented Fc function and promotes them as a strong candidate for antibody-mediated therapies.
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http://dx.doi.org/10.1128/JVI.00219-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316091PMC
June 2021

The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics.

Front Cell Neurosci 2021 26;15:661412. Epub 2021 Mar 26.

Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada.

Pharmacological upregulation of glutamate transporter-1 (GLT-1), commonly achieved using the beta-lactam antibiotic ceftriaxone, represents a promising therapeutic strategy to accelerate glutamate uptake and prevent excitotoxic damage in neurological conditions. While excitotoxicity is indeed implicated in numerous brain diseases, it is typically restricted to select vulnerable brain regions, particularly in early disease stages. In healthy brain tissue, the speed of glutamate uptake is not constant and rather varies in both an activity- and region-dependent manner. Despite the widespread use of ceftriaxone in disease models, very little is known about how such treatments impact functional measures of glutamate uptake in healthy tissue, and whether GLT-1 upregulation can mask the naturally occurring activity-dependent and regional heterogeneities in uptake. Here, we used two different compounds, ceftriaxone and LDN/OSU-0212320 (LDN), to upregulate GLT-1 in healthy wild-type mice. We then used real-time imaging of the glutamate biosensor iGluSnFR to investigate functional consequences of GLT-1 upregulation on activity- and regional-dependent variations in glutamate uptake capacity. We found that while both ceftriaxone and LDN increased GLT-1 expression in multiple brain regions, they did not prevent activity-dependent slowing of glutamate clearance nor did they speed basal clearance rates, even in areas characterized by slow uptake (e.g., striatum). Unexpectedly, ceftriaxone but not LDN decreased glutamate release in the cortex, suggesting that ceftriaxone may alter release properties independent of its effects on GLT-1 expression. In sum, our data demonstrate the complexities of glutamate uptake by showing that GLT-1 expression does not necessarily translate to accelerated uptake. Furthermore, these data suggest that the mechanisms underlying activity- and regional-dependent differences in glutamate dynamics are independent of GLT-1 expression levels.
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http://dx.doi.org/10.3389/fncel.2021.661412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032948PMC
March 2021

Editorial: Exploring Novel Approaches to Eliminate HIV Reservoirs to Achieve a Cure for HIV.

Front Cell Infect Microbiol 2021 25;11:658848. Epub 2021 Feb 25.

Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States.

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http://dx.doi.org/10.3389/fcimb.2021.658848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946826PMC
July 2021

Evaluating the effect of a post-processing algorithm in detection of annular fissure on MR imaging.

Eur Spine J 2021 08 8;30(8):2150-2156. Epub 2021 Mar 8.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO, 63110, USA.

Background And Purpose: Visualization of annular fissures on MRI is becoming increasingly important but remains challenging. Our purpose was to test whether an image processing algorithm could improve detection of annular fissures.

Materials And Methods: In this retrospective study, two neuroradiologists identified 56 IVDs with annular fissures and 97 IVDs with normal annulus fibrosus in lumbar spine MRIs of 101 patients (58 M, 43 F; age ± SD 15.1 ± 3.0 years). Signal intensities of diseased and normal annulus fibrosus, and contrast-to-noise ratio between them on sagittal T2-weighted images were calculated before and after processing with a proprietary software. Effect of processing on detection of annular fissures by two masked neuroradiologists was also studied for IVDs with Pfirrmann grades of ≤ 2 and > 2.

Results: Mean (SD) signal baseline intensities of diseased and normal annulus fibrosus were 57.6 (23.3) and 24.4 (7.8), respectively (p < 0.001). Processing increased (p < 0.001) the mean (SD) intensity of diseased annulus to 110.6 (47.9), without affecting the signal intensity of normal annulus (p = 0.14). Mean (SD) CNR between the diseased and normal annulus increased (p < 0.001) from 11.8 (14.1) to 29.6 (29.1). Both masked readers detected more annular fissures after processing in IVDs with Pfirrmann grade of ≤ 2 and > 2, with an apparent increased sensitivity and decreased specificity using predefined image-based human categorization as a reference standard.

Conclusions: Image processing improved CNR of annular fissures and detection rate of annular fissures. However, further studies with a more stringent reference standard are needed to assess its effect on sensitivity and specificity.
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http://dx.doi.org/10.1007/s00586-021-06793-5DOI Listing
August 2021

The Effect of Measured Radiotherapy Dose on Intrathecal Drug Delivery System Function.

Neuromodulation 2021 Feb 23. Epub 2021 Feb 23.

Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Objectives: Radiation therapy (RT) and intrathecal drug delivery systems (IDDS) are often used concurrently to optimize pain management in patients with cancer. Concern remains among clinicians regarding the potential for IDDS malfunction in the setting of RT. Here we assessed the frequency of IDDS malfunction in a large cohort of patients treated with RT.

Materials And Methods: Cancer patients with IDDS and subsequent RT at our institution from 2011 to 2019 were eligible for this study. Patients were excluded in the rare event that their IDDS was managed by an outside clinic and follow-up documentation was unavailable. Eighty-eight patients aged 22-88 years old (43% female, 57% male) representing 106 separate courses of RT were retrospectively identified. Patients received varying levels of radiation for treatment of cancer and cumulative dose to the IDDS was calculated. IDDS interrogation was subsequently performed by a pain specialist. Malfunction was recorded as deviation from the expected drug volume and/or device errors reported upon interrogation as defined by the manufacturer.

Results: Total measured RT dose to the IDDS ranged from 0 to 18.0 Gy (median = 0.2 Gy) with median dose of 0.04 Gy/fraction (range, 0-3.2 Gy/fraction). Ten pumps received a total dose >2 Gy and three received ≥5 Gy. Eighty-two percentage of patients had follow-up with a pain specialist for IDDS interrogation and all patients underwent follow-up with a healthcare provider following RT. There were zero incidences of IDDS malfunction related to RT. No patient had clinical evidence of radiation related pump malfunction at subsequent encounters.

Conclusions: We found no evidence that RT in patients with IDDS led to device failure or dysfunction. While radiation oncologists and pain specialists should coordinate patient care, it does not appear that RT dose impacts the function of the IDDS to warrant significant clinical concern.
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http://dx.doi.org/10.1111/ner.13372DOI Listing
February 2021

Entering a new era of quantifying glutamate clearance in health and disease.

J Neurosci Res 2021 Jun 22;99(6):1598-1617. Epub 2021 Feb 22.

Faculty of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland, St. John's, NL, Canada.

Glutamate transporter proteins, expressed on both neurons and glia, serve as the main gatekeepers that dictate the spatial and temporal actions of extracellular glutamate. Glutamate is essential to the function of the healthy brain yet paradoxically contributes to the toxicity associated with many neurodegenerative diseases. Rapid transporter-mediated glutamate uptake, primarily occurring at astrocytic processes, tightens the efficiency of excitatory network activity and prevents toxic glutamate build-up in the extracellular space. Glutamate transporter dysfunction is thought to underlie myriad central nervous system (CNS) diseases including Alzheimer and Huntington disease. Over the past few decades, techniques such as biochemical uptake assays and electrophysiological recordings of transporter currents from individual astrocytes have revealed the remarkable ability of the CNS to efficiently clear extracellular glutamate. In more recent years, the rapidly evolving glutamate-sensing "sniffers" now allow researchers to visualize real-time glutamate transients on a millisecond time scale with single synapse spatial resolution in defined cell populations. As we transition to an increased reliance on optical-based methods of glutamate visualization and quantification, it is of utmost importance to understand not only the advantages that glutamate biosensors bring to the table but also the associated caveats and their implications for data interpretation. In this review, we summarize the strengths and limitations of the commonly used methods to quantify glutamate uptake. We then discuss what these techniques, when viewed as a complementary whole, have told us about the brain's ability to regulate glutamate levels, in both health and in the context of neurodegenerative disease.
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http://dx.doi.org/10.1002/jnr.24810DOI Listing
June 2021

Super-resolution imaging reveals extrastriatal synaptic dysfunction in presymptomatic Huntington disease mice.

Neurobiol Dis 2021 05 5;152:105293. Epub 2021 Feb 5.

Division of Biomedical Science, Faculty of Medicine, Memorial University, St. John's, NL A1B 3V6, Canada. Electronic address:

Synaptic structure and function are compromised prior to cell death and symptom onset in a variety of neurodegenerative diseases. In Huntington disease (HD), a CAG repeat expansion in the gene encoding the huntingtin protein results in a presymptomatic stage that typically spans multiple decades and is followed by striking degeneration of striatal tissue and the progression of debilitating motor symptoms. Many lines of evidence demonstrate that the HD presymptomatic window is associated with injurious effects to striatal synapses, many of which appear to be prerequisites to subsequent cell death. While the striatum is the most vulnerable region in the HD brain, it is widely recognized that HD is a brain-wide disease, affecting numerous extrastriatal regions that contribute to debilitating non-motor symptoms including cognitive dysfunction. Currently, we have a poor understanding of the synaptic integrity, or lack thereof, in extrastriatal regions in the presymptomatic HD brain. If early therapeutic intervention seeks to maintain healthy synaptic function, it is important to understand early HD-associated synaptopathy at a brain-wide, rather than striatal-exclusive, level. Here, we focused on the hippocampus as this structure is generally thought to be affected only in manifest HD despite the subtle cognitive deficits known to emerge in prodromal HD. We used super-resolution microscopy and multi-electrode array electrophysiology as sensitive measures of excitatory synapse structure and function, respectively, in the hippocampus of presymptomatic heterozygous HD mice (Q175FDN model). We found clear evidence for enhanced AMPA receptor subunit clustering and hyperexcitability well before the onset of a detectable HD-like behavioral phenotype. In addition, activity-dependent re-organization of synaptic protein nanostructure, and functional measures of synaptic plasticity were impaired in presymptomatic HD mice. These data demonstrate that synaptic abnormalities in the presymptomatic HD brain are not exclusive to the striatum, and highlight the need to better understand the region-dependent complexities of early synaptopathy in the HD brain.
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http://dx.doi.org/10.1016/j.nbd.2021.105293DOI Listing
May 2021

Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 2: From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2021 01 15;8(1). Epub 2020 Dec 15.

From the Department of Neurology (R.A.C., E. Melamed, T.C.V., E. Meltzer), Dell Medical School, University of Texas at Austin; Department of Ophthalmology (N.H.), University of Texas Southwestern, Dallas; Wellness Care Centers and Pediatric Rehabilitation (J.S.), Denton, TX; Ascension Seton Medical Center (M.S.), Austin, TX; National Institutes of Health (E.O.M.), Bethesda, MD; Departments of Neurology, and Biochemistry, Microbiology and Immunology (R.P.L.), Wayne State University, Detroit, MI; Colangelo College of Business (T.C.V.), Grand Canyon University, Phoenix, AZ; Department of Neurology (A.G.), University of Rochester, NY; Department of Computer Science (O.K.), Texas State University, San Marcos; Division of Microbiology and Immunology (M.S.P.), Yerkes National Primate Research Center, and Department of Pathology and Laboratory Medicine (M.S.P.), Emory University, Atlanta, GA; The National Multiple Sclerosis Society (K.C.), New York, NY; Department of Neurology (J.S.G.), University of California at San Diego; Department of Neurology (S.N.), Johns Hopkins Hospital, Bethesda, MD; Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco; andDepartments of Neurology, Ophthalmology & Neurosurgery (E.M.F., T.C.F.), Dell Medical School at the University of Texas at Austin.

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http://dx.doi.org/10.1212/NXI.0000000000000930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803334PMC
January 2021

The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression.

Sci Rep 2021 01 11;11(1):431. Epub 2021 Jan 11.

Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada.

The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1-38), interacts with the AD-related variant, Aβ(1-42), and the predominant physiological variant, Aβ(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1-38) interacts differently with Aβ(1-40) and Aβ(1-42) and, in general, Aβ(1-38) interferes with the conversion of Aβ(1-42) to a β-sheet-rich aggregate. Functionally, Aβ(1-38) reverses the negative impact of Aβ(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1-42) phenotype in Caenorhabditis elegans. Aβ(1-38) also reverses any loss of MTT conversion induced by Aβ(1-40) and Aβ(1-42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1-38) and Aβ(1-42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1-42)/Aβ(1-38) [and Aβ(1-42)/Aβ(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1-42).
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http://dx.doi.org/10.1038/s41598-020-80164-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801637PMC
January 2021

Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 1: From the National Multiple Sclerosis Society Case Conference Proceedings.

Neurol Neuroimmunol Neuroinflamm 2021 01 15;8(1). Epub 2020 Dec 15.

From the University of Rochester (N.A.), NY. N. Anadani is now with Department of Neurology, University of Oklahoma Health Science Center; Department of Neurology (M.H., A.D.G.), University of Rochester, NY; Department of Neurology (R.A.C., E.M., T.C.V.), Dell Medical School at the University of Texas at Austin; Department of Neurology (R.L.), Wayne State University, Detroit, MI; The National Multiple Sclerosis Society (K.C.), New York, NY; Laboratory of Molecular Medicine and Neuroscience (E.O.M.), Neurological Institute of Neurological Disorder and Stroke (Y.J.), Bethesda, MD. Y. Jassam is now with Department of Neurology, The University of Kansas Health System; Colangelo College of Business (T.C.V.), Grand Canyon University, Phoenix, AZ; Division of Microbiology and Immunology (M.S.P.), Yerkes National Primate Research Center, and Department of Pathology and Laboratory Medicine (M.S.P.), Emory University, Atlanta, GA; Department of Neurosciences (J.S.G.), University of California at San Diego; Department of Neurology (S.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco; and Department of Neurology, Neurosurgery, and Ophthalmology (E.M.F., T.C.F.), Dell Medical School at the University of Texas at Austin.

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http://dx.doi.org/10.1212/NXI.0000000000000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803340PMC
January 2021

The use and efficacy of chemotherapy and radiotherapy in children and adults with pilocytic astrocytoma.

J Neurooncol 2021 Jan 31;151(2):93-101. Epub 2020 Oct 31.

Huntsman Cancer Institute, 1950 Circle of Hope, Rm. 1570, Salt Lake City, UT, 84112, USA.

Purpose: The aim of this study was to understand the use of chemotherapy (CMT) and radiotherapy (RT) in pilocytic astrocytoma (PA) and their impact on overall survival (OS).

Methods: Data from the National Cancer Database (NCDB) for patients with non-metastatic WHO grade I PA from 2004 to 2014 were analyzed. Pearson's chi-squared test and multivariate logistic regression analyses were performed to assess the distribution of demographic, clinical, and treatment factors. Inverse probability of treatment weighting (IPTW) was used to account for differences in baseline characteristics. Kaplan-Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling were used to analyze OS.

Results: Of 3865 patients analyzed, 294 received CMT (7.6%), 233 received RT (6.0%), and 42 (1.1%) received both. On multivariate analyses, decreasing extent of surgical resection was associated with receipt of both CMT and RT. Brainstem tumors were associated with RT, optic nerve tumors were associated with CMT. Cerebellar tumors were inversely associated with both CMT and RT. Younger age was associated with receipt of CMT; conversely, older age was associated with receipt of RT. After IPTW, receipt of CMT and/or RT were associated with an OS decrement compared with matched patients treated with surgery alone or observation (HR 3.29, p < 0.01).

Conclusions: This is the largest study to date to examine patterns of care and resultant OS outcomes in PA. We identified patient characteristics associated with receipt of CMT and RT. After propensity score matching, receipt of CMT and/or RT was associated with decreased OS.
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http://dx.doi.org/10.1007/s11060-020-03653-yDOI Listing
January 2021

Testing dataset for head segmentation accuracy for the algorithms in the 'BGSLibrary' v3.0.0 developed by Andrews Sobral.

Data Brief 2020 Dec 8;33:106385. Epub 2020 Oct 8.

Faculty of Science, University of Auckland, New Zealand.

This dataset consists of video files that were created to test the accuracy of background segmentation algorithms contained in the ++ wrapper 'BGSLibrary' v3.0.0 developed by Andrews Sobral. The comparison is based on segmentation accuracy of the algorithms on a series of indoor color-depth video clips of a single person's head and upper body, each highlighting a common factor that can influence the accuracy of foreground-background segmentation. The algorithms are run on the color image data, while the 'ground truth' is semi-automatically extracted from the depth data. The camera chosen for capturing the videos features paired color-depth image sensors, with the color sensor having specifications typical of mobile devices and webcams, which cover most of the use cases for these algorithms. The factors chosen for testing are derived from a literature review accompanying the dataset as being able to influence the efficacy of background segmentation. The assessment criteria for the results were set based on the requirements of common use cases such as gamecasting and mobile communications to allow the readers to make their own judgements on the merits of each algorithm for their own purposes.
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http://dx.doi.org/10.1016/j.dib.2020.106385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567919PMC
December 2020

Defining nocturnal polyuria in women.

Neurourol Urodyn 2021 01 21;40(1):265-271. Epub 2020 Oct 21.

Birmingham Women's Hospital, Birmingham, England.

Aims: Nocturnal polyuria (NP) is defined by the International Continence Society (ICS) as "excessive production of urine during the main sleep period" and is one of the main causes of nocturia. The ICS recognized that "excessive" is not clearly defined and that this needs to be highlighted in both clinical and research settings. The aim of this study was to identify different definitions of NP and apply them to a population of women attending the Urogynaecology clinic.

Methods: This was a retrospective study of complete bladder diaries collected from women attending a tertiary Urogynaecology Unit. Six different definitions were identified and were divided into "absolute," "relative," and "functional definitions." Prevalence data were calculated and values generated for sensitivity, specificity, positive and negative predictive values when related to women voiding ≥ 2 times per night.

Results: Complete bladder diaries were obtained from 1398 women, over 6 years, with a mean age of 57 years. Prevalence varied across the definitions from 21.5% (absolute definition) to 77% (relative definition). Sensitivity ranged from 43% (absolute) to 87% (relative). The definitions that showed the highest combined sensitivity and specificity were the functional definitions.

Conclusion: From this study it is clear that more work needs to be done to arrive at a consensus for defining NP to enable accurate diagnosis and development of treatment pathways. We propose that a relative definition may provide a more clinically relevant method of defining NP.
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http://dx.doi.org/10.1002/nau.24546DOI Listing
January 2021

Anatomy, Imaging, and Pathologic Conditions of the Brachial Plexus.

Radiographics 2020 Oct;40(6):1686-1714

From the Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Ill (B.M.G., S.D.D.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd, Box 8131, St Louis, MO 63110 (M.S.P.).

The brachial plexus is an intricate anatomic structure with an important function: providing innervation to the upper extremity, shoulder, and upper chest. Owing to its complex form and longitudinal course, the brachial plexus can be challenging to conceptualize in three dimensions, which complicates evaluations in standard orthogonal imaging planes. The components of the brachial plexus can be determined by using key anatomic landmarks. Applying this anatomic knowledge, a radiologist should then be able to identify pathologic appearances of the brachial plexus by using imaging modalities such as MRI, CT, and US. Brachial plexopathies can be divided into two broad categories that are based on disease origin: traumatic and nontraumatic. In the traumatic plexopathy group, there are distinct imaging findings and management methods for pre- versus postganglionic injuries. For nontraumatic plexopathies, having access to an accurate patient history is often crucial. Knowledge of the timing of radiation therapy is critical to diagnosing post-radiation therapy brachial plexopathy. In acute brachial neuritis, antecedent stressors occur within a specific time frame. Primary and secondary tumors of the brachial plexus are not uncommon, with the most common primary tumors being peripheral nerve sheath tumors. Direct extension and metastasis from primary malignancies such as breast and lung cancer can occur. Although diagnosing a brachial plexus anomaly is potentially perplexing, it can be straightforward if it is based on foundational knowledge of anatomy, imaging findings, and pathologic features. RSNA, 2020.
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http://dx.doi.org/10.1148/rg.2020200012DOI Listing
October 2020

Neuroimaging of Adult Lacrimal Drainage System.

Curr Probl Diagn Radiol 2021 Sep-Oct;50(5):687-702. Epub 2020 Aug 26.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO.

The lacrimal drainage system (LDS) pathology is frequently encountered in the ophthalmology setting but is rarely discussed in the radiology literature. This is even truer for adult LDS lesions despite increase utilization of computed tomography and magnetic resonance in imaging for diagnosis of LDS pathology. The purpose of this image rich review is to highlight common adult LDS pathologies and introduce the radiologist to rare disease entities affecting this pathology rich anatomical region with emphasis on imaging findings, clinical presentation, and differential generation.
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http://dx.doi.org/10.1067/j.cpradiol.2020.08.006DOI Listing
August 2020

Mitigating alemtuzumab-associated autoimmunity in MS: A "whack-a-mole" B-cell depletion strategy.

Neurol Neuroimmunol Neuroinflamm 2020 11 7;7(6). Epub 2020 Aug 7.

From the Department of Neurology (E.M., S.C., B.E., R.A.C.), Dell Medical School, University of Texas at Austin; Department of Neurology (L.S.), Stanford University School of Medicine, Palo Alto, CA; Division of Microbiology and Immunology (M.S.P.), Yerkes National Primate Research Center, and Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; Department of Neurology and Program in Immunology (S.S.Z.), University of California San Francisco; and Departments of Neurology (E.M.F., T.C.F.), Ophthalmology & Neurosurgery, Dell Medical School at the University of Texas at Austin.

Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19 B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.

Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.

Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.

Conclusions: An anti-CD20 "whack-a-mole" B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.

Classification Of Evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.
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http://dx.doi.org/10.1212/NXI.0000000000000868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643549PMC
November 2020

ASO Author Reflections: The Impact of Local Therapy on Non-metastatic Esophageal Cancer.

Ann Surg Oncol 2020 Dec 13;27(Suppl 3):818-819. Epub 2020 Jul 13.

Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, USA.

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http://dx.doi.org/10.1245/s10434-020-08808-9DOI Listing
December 2020

Refusal of Local Therapy in Esophageal Cancer and Impact on Overall Survival.

Ann Surg Oncol 2021 Feb 9;28(2):663-675. Epub 2020 Jul 9.

Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Objective: The aim of this study was to understand factors associated with refusal of local therapy in esophageal cancer and compare the overall survival (OS) of patients who refuse therapies with those who undergo recommended treatment.

Methods: National Cancer Database data for patients with non-metastatic esophageal cancer from 2006 to 2013 were pooled. T1N0M0 tumors were excluded. Pearson's Chi-square test and multivariate logistic regression analyses were used to assess demographic, clinical, and treatment factors. After propensity-score matching with inverse probability of treatment weighting, OS was compared between patients who refused therapies and those who underwent recommended therapy, using Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling.

Results: In total, 37,618 patients were recommended radiation therapy (RT) and/or esophagectomy; we found 1403 (3.7%) refused local therapies. Specifically, 890 of 18,942 (4.6%) patients refused surgery and 667 of 31,937 (2.1%) refused RT. Older patients, females, those with unknown lymphovascular space invasion, and those uninsured or on Medicare were more likely to refuse. Those with squamous cell carcinoma, N1 disease, higher incomes, living farther from care, and those who received chemotherapy were less likely to refuse. Five-year OS was decreased in patients who refused (18.1% vs. 27.6%). The survival decrement was present in adenocarcinoma but not squamous cell carcinoma. In patients who received surgery or ≥ 50.4 Gy RT, there was no OS decrement to refusing the other therapy.

Conclusions: We identified characteristics that correlate with refusal of local therapy. Refusal of therapy was associated with decreased OS. Patients who received either surgery or ≥ 50.4 Gy RT had no survival decrement from refusing the opposite modality.
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http://dx.doi.org/10.1245/s10434-020-08761-7DOI Listing
February 2021

High CD26 and Low CD94 Expression Identifies an IL-23 Responsive Vδ2 T Cell Subset with a MAIT Cell-like Transcriptional Profile.

Cell Rep 2020 06;31(11):107773

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia. Electronic address:

Vδ2 T cells play a critical role in immunity to micro-organisms and cancer but exhibit substantial heterogeneity in humans. Here, we demonstrate that CD26 and CD94 define transcriptionally, phenotypically, and functionally distinct Vδ2 T cell subsets. Despite distinct antigen specificities, CD26CD94 Vδ2 cells exhibit substantial similarities to CD26 mucosal-associated invariant T (MAIT) cells, although CD26 Vδ2 cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2Vγ9 population is dominated by CD26CD94 cells; during adolescence and adulthood, Vδ2 cells acquire CD94/NKG2A expression and the relative frequency of the CD26CD94 subset declines. Critically, exposure of the CD26CD94 subset to phosphoantigen in the context of interleukin-23 (IL-23) and CD26 engagement drives the acquisition of a cytotoxic program and concurrent loss of the MAIT cell-like phenotype. The ability to modulate the cytotoxic potential of CD26CD94 Vδ2 cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer.
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http://dx.doi.org/10.1016/j.celrep.2020.107773DOI Listing
June 2020

Hippocampal Synaptic Dysfunction in a Mouse Model of Huntington Disease Is Not Alleviated by Ceftriaxone Treatment.

eNeuro 2020 May/Jun;7(3). Epub 2020 May 21.

Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada

Glutamate transporters, particularly glutamate transporter 1 (GLT-1), help to prevent the adverse effects associated with glutamate toxicity by rapidly clearing glutamate from the extracellular space. Since GLT-1 expression and/or function are reduced in many neurodegenerative diseases, upregulation of GLT-1 is a favorable approach to treat the symptoms of these diseases. Ceftriaxone, a β-lactam antibiotic reported to increase GLT-1 expression, can exert neuroprotective effects in a variety of neurodegenerative diseases; however, many of these diseases do not exhibit uniform brain pathology. In contrast, as a drug that readily crosses the blood-brain barrier, ceftriaxone administration is likely to increase GLT-1 levels globally throughout the neuroaxis. In Huntington disease (HD), low GLT-1 expression is observed in the striatum in postmortem tissue and animal models. While ceftriaxone was reported to increase striatal GLT-1 and ameliorate the motor symptoms in a mouse model of HD, the extrastriatal effects of ceftriaxone in HD are unknown. Using electrophysiology and high-speed imaging of the glutamate biosensor iGluSnFR, we quantified real-time glutamate dynamics and synaptic plasticity in the hippocampus of the Q175FDN mouse model of HD, following intraperitoneal injections of either saline or ceftriaxone. We observed an activity-dependent increase in extracellular glutamate accumulation within the HD hippocampus, which was not the result of reduced GLT-1 expression. Surprisingly, ceftriaxone had little effect on glutamate clearance rates and negatively impacted synaptic plasticity. These data provide evidence for glutamate dysregulation in the HD hippocampus but also caution the use of ceftriaxone as a treatment for HD.
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http://dx.doi.org/10.1523/ENEURO.0440-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242817PMC
June 2021
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