WashU weekly Neuroscience publications

N-acetylcysteine reduces brain injury after delayed hypoxemia following traumatic brain injury
(2021) Experimental Neurology, 335, art. no. 113507, .

Celorrio, M., Rhodes, J., Vadivelu, S., Davies, M., Friess, S.H.

Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, One Children’s Place, St. Louis, MO 63110, United States

Abstract
Preclinical investigations into neuroprotective agents for traumatic brain injury (TBI) have shown promise when administered before or very early after experimental TBI. However clinical trials of therapeutics demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, a lost in translation phenomenon. N-acetylcysteine (NAC) is a potent anti-oxidant with demonstrated efficacy in pre-clinical TBI when administered early after primary injury. Utilizing our clinically relevant mouse model, we hypothesized that NAC administration in a clinically relevant timeframe could improve the brain’s resilience to the secondary insult of hypoxemia. NAC or vehicle administered daily starting 2 h prior to hypoxemia (24 h after controlled cortical impact) for 3 doses in male mice reduced short-term axonal injury and hippocampal neuronal loss. Six month behavioral assessments including novel object recognition, socialization, Barnes maze, and fear conditioning did not reveal performance differences between sham controls and injured mice receiving NAC or saline vehicle. At 7 months after injury, NAC administered mice had reduced hippocampal neuronal loss but no reduction in lesion volume. In summary, our preclinical trial to test the neuroprotective efficacy of NAC against a secondary hypoxic insult after TBI demonstrated short and long-term neuropathological evidence of neuroprotection but a lack of detectable differences in long-term behavioral assessments between sham controls and injured mice limits conclusions on its impact on long-term neurobehavioral outcomes. © 2020 Elsevier Inc.

Author Keywords
Hypoxemia;  N-acetylcysteine;  Neuroprotection;  Pre-clinical trial;  Secondary injury;  Traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

Neural Indicators of Anhedonia: Predictors and Mechanisms of Treatment Change in a Randomized Clinical Trial in Early Childhood Depression
(2020) Biological Psychiatry, 88 (11), pp. 879-887.

Barch, D.M.^a b c , Whalen, D.^b , Gilbert, K.^b , Kelly, D.^b , Kappenman, E.S.^d , Hajcak, G.^e , Luby, J.L.^b

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychology, San Diego State University, San Diego, CA, United States
^e Department of Biomedical Science and Psychology, Florida State University, Tallahassee, FL, United States

Abstract
Background: Early childhood depression is associated with anhedonia and reduced event-related potential (ERP) responses to rewarding or pleasant stimuli. Whether these neural measures are indicators of target engagement or treatment outcome is not yet known. Methods: We measured ERP responses to win and loss feedback in a guessing task and to pleasant versus neutral pictures in young (4.0–6.9 years of age) depressed children before and after randomization to either 18 weeks of Parent-Child Interaction Therapy–Emotion Development (PCIT-ED) or waitlist. Results: Analyses included reward positivity (RewP) data from 118 children randomly assigned to PCIT-ED (n = 60) or waitlist (n = 58) at baseline and late positive potential (LPP) data from 99 children (44 assigned to PCIT-ED vs. 55 assigned to waitlist) at baseline. Children undergoing PCIT-ED showed a greater reduction in anhedonia (F1,103 = 10.32, p = .002, partial η2 = .09). RewP reward responses increased more (F1,86 = 5.98, p = .02, partial η2 = .07) for PCIT-ED, but a greater change in RewP was not significantly associated with a greater reduction in major depressive disorder symptoms (r = −.12, p > .4). Baseline RewP did not predict treatment change. LPPs to positive pictures did not change across treatment, but greater baseline LPPs to positive pictures predicted a higher likelihood of remission from major depressive disorder in children undergoing PCIT-ED (B = 0.14; SE = 0.07; odds ratio = 1.15; p = .03). Conclusions: The ERP reward response improved in young children with depression during a treatment designed to enhance emotion development, providing evidence of target engagement of the neural systems associated with reward. Further, greater baseline LPP responses to positive pictures was associated with a greater likelihood of depression remission, suggesting that this ERP measure can predict which children are most likely to respond to treatment. © 2020 Society of Biological Psychiatry

Author Keywords
Anhedonia;  Clinical trial;  Depression;  ERP;  Preschool;  Reward

Document Type: Article
Publication Stage: Final
Source: Scopus

Immigration in science
(2020) The Journal of Experimental Medicine, 217 (11), .

Casanova, J.-L.^a , Holtzman, D.M.^b , Kaech, S.M.^c , Lanier, L.L.^d , Nathan, C.F.^e , Rudensky, A.Y.^f , Tuveson, D.^g , Wolchok, J.D.^h

^a Rockefeller University, NY, NY
^b Washington University School of Medicine, St. Louis, MO
^c Salk Institute for Biological Studies, La Jolla, CA, Italy
^d Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA
^e Department of Microbiology and Immunology, Weill Cornell Medicine, NY, NY
^f Howard Hughes Medical Institute and Immunology Program, Memorial Sloan Kettering Cancer Center, NY, NY
^g Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
^h Memorial Sloan Kettering Cancer Center, NY, NY

Abstract
The advance of science is dependent upon collaboration, which does not have a visa attached to it. Indeed, over 40% of all American-based Nobel Prize winners are immigrants, and data from the National Science Foundation show that 49% of postdocs and 29% of science and engineering faculty in the US are foreign-born. However, restrictive new immigration policies in the US have left many scientists deeply concerned about their future and many American-based laboratories worried about attracting the best talent. At JEM, we’re celebrating immigration by sharing the experiences of immigrant and nonimmigrant scientists on our editorial board. Alexander Rudensky and Jean-Laurent Casanova give their firsthand perspective on immigrating to the US, while Jedd Wolchok, Carl Nathan, David Holtzman, Susan Kaech, Lewis Lanier, and David Tuveson reflect on how immigration has affected their laboratories. © 2020 Casanova et al.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Cognitive function following diabetic ketoacidosis in children with new-onset or previously diagnosed type 1 diabetes
(2020) Diabetes Care, 43 (11), pp. 2768-2775.

Ghetti, S.^a b , Kuppermann, N.^c d , Rewers, A.^e , Myers, S.R.^f , Schunk, J.E.^g , Stoner, M.J.^h , Garro, A.ⁱ , Quayle, K.S.^j , Brown, K.M.^k , Trainor, J.L.^l , Tzimenatos, L.^c , Depiero, A.D.^m , McManemy, J.K.ⁿ , Nigrovic, L.E.^o , Kwok, M.Y.^p , Perry, C.S., III^b q , Olsen, C.S.^g , Casper, T.C.^g , Glaser, N.S.^d , Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group^r

^a Department of Psychology, University of California, Davis, Davis, CA, United States
^b Center for Mind and Brain, University of California, Davis, Davis, CA, United States
^c Department of Emergency Medicine, UC Davis Health, UC Davis School of Medicine, Sacramento, CA, United States
^d Department of Pediatrics, UC Davis Health, UC Davis School of Medicine, Sacramento, CA, United States
^e Division of Emergency Medicine, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado, School of Medicine, University of Colorado Denver, Aurora, CO, United States
^f Division of Emergency Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Penn-sylvania, Philadelphia, PA, United States
^g Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, United States
^h Division of Emergency Medicine, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
ⁱ Departments of Emergency Medicine and Pediatrics, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, RI, United States
^j Division of Emergency Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^k Division of Emergency Medicine, Department of Pediatrics, Children’s National Medical Center, The School of Medicine & Health Sciences, The George Washington University, Washington, DC, United States
^l Division of Emergency Medicine, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^m Division of Emergency Medicine, Nemours/Alfred I. duPont Hospital for Children, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
ⁿ Division of Emergency Medicine, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^o Division of Emergency Medicine, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^p Division of Emergency Medicine, Department of Pediatrics, New York Presbyterian Morgan Stanley Children’s Hospital, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
^q Department of Psychology, Tufts University, Medford, MA, United States

Abstract
OBJECTIVE This study assessed whether a single diabetic ketoacidosis (DKA) episode is associated with cognitive declines in children with newly diagnosed type 1 diabetes and whether the same is true in children who had previously been diagnosed after accounting for variations in glycemic control and other relevant factors. RESEARCH DESIGN AND METHODS We prospectively enrolled 758 children, 6–18 years old, who presented with DKA in a randomized multisite clinical trial evaluating intravenous fluid protocols for DKA treatment. DKA was moderate/severe in 430 children and mild in 328 children. A total of 392 children with DKA had new onset of type 1 diabetes, and the rest were previously diagnosed. Neurocognitive assessment occurred 2–6 months after the DKA episode. A comparison group of 376 children with type 1 diabetes, but no DKA exposure, was also enrolled. RESULTS Among all patients, moderate/severe DKA was associated with lower intelligence quotient (IQ) (b 5 20.12, P < 0.001), item-color recall (b 5 20.08, P 5 0.010), and forward digit span (b 5 20.06, P 5 0.04). Among newly diagnosed patients, moderate/severe DKA was associated with lower item-color recall (b 520.08, P 5 0.04). Among previously diagnosed patients, repeated DKA exposure and higher HbA1c were independently associated with lower IQ (b 5 20.10 and b 5 20.09, respectively, P < 0.01) and higher HbA1c was associated with lower item-color recall (b 5 20.10, P 5 0.007) after hypoglycemia, diabetes duration, and socioeconomic status were accounted for. CONCLUSIONS A single DKA episode is associated with subtle memory declines soon after type 1 diabetes diagnosis. Sizable IQ declines are detectable in children with known diabetes, suggesting that DKA effects may be exacerbated in children with chronic exposure to hyperglycemia. © 2020 by the American Diabetes Association.

Document Type: Article
Publication Stage: Final
Source: Scopus

Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion
(2020) Pain, 161 (11), pp. 2592-2602.

Salvo, E.^a b , Campana, W.M.^c d , Scheff, N.N.^a b , Nguyen, T.H.^a b , Jeong, S.-H.^e , Wall, I.^e , Wu, A.K.^a , Zhang, S.^e , Kim, H.^a , Bhattacharya, A.^a b , Janal, M.N.^f , Liu, C.^g , Albertson, D.G.^a b , Schmidt, B.L.^a b , Dolan, J.C.^a b , Schmidt, R.E.^h , Boada, M.D.ⁱ , Ye, Y.^a b

^a Bluestone Center for Clinical Research, New York University College of Dentistry, NY, NY, United States
^b Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, NY, NY, United States
^c Department of Anesthesiology, School of Medicine, University of California, San Diego, CA, United States
^d San Diego Veterans Health System, San Diego, CA, United States
^e D.D.S. program, New York University College of Dentistry, NY, NY, United States
^f Department of Epidemiology and Health Promotion, New York University College of Dentistry, NY, NY, United States
^g Department of Pathology, New York University Langone Medical Center, NY, NY, United States
^h Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, United States

Abstract
Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here, we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting that unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. Perineural invasion induced afterdischarge in A high-threshold mechanoreceptors (HTMRs), mechanical sensitization (ie, decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low-threshold mechanoreceptors. Perineural invasion resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically insensitive and electrically unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.

Document Type: Article
Publication Stage: Final
Source: Scopus

Endovascular thrombectomy in acute ischemic stroke patients with COVID-19: Prevalence, demographics, and outcomes
(2020) Journal of NeuroInterventional Surgery, 12 (11), pp. 1045-1048.

De Havenon, A.^a , Yaghi, S.^b , Mistry, E.A.^c , Delic, A.^a , Hohmann, S.^d , Shippey, E.^d , Stulberg, E.^a , Tirschwell, D.^e , Frontera, J.A.^b , Petersen, N.H.^f , Anadani, M.^g

^a Department of Neurology, University of Utah Health, Salt Lake City, UT 84132, United States
^b Neurology, NYU School of Medicine, Brooklyn, NY, United States
^c Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
^d Vizient Inc, Irving, TX, United States
^e University of Washington, Seattle, WA, United States
^f Yale University, New Haven, CT, United States
^g Washington University School of Medicine in St Louis, St Louis, MI, United States

Abstract
Background We aimed to compare the outcome of acute ischemic stroke (AIS) patients who received endovascular thrombectomy (EVT) with confirmed COVID-19 to those without. Methods We performed a retrospective analysis using the Vizient Clinical Data Base and included hospital discharges from April 1 to July 31 2020 with ICD-10 codes for AIS and EVT. The primary outcome was in-hospital death and the secondary outcome was favorable discharge, defined as discharge home or to acute rehabilitation. We compared patients with laboratory-confirmed COVID-19 to those without. As a sensitivity analysis, we compared COVID-19 AIS patients who did not undergo EVT to those who did, to balance potential adverse events inherent to COVID-19 infection. Results We identified 3165 AIS patients who received EVT during April to July 2020, in which COVID-19 was confirmed in 104 (3.3%). Comorbid COVID-19 infection was associated with younger age, male sex, diabetes, black race, Hispanic ethnicity, intubation, acute coronary syndrome, acute renal failure, and longer hospital and intensive care unit length of stay. The rate of in-hospital death was 12.4% without COVID-19 vs 29.8% with COVID-19 (P<0.001). In mixed-effects logistic regression that accounted for patient clustering by hospital, comorbid COVID-19 increased the odds of in-hospital death over four-fold (OR 4.48, 95% CI 3.02 to 6.165). Comorbid COVID-19 was also associated with lower odds of a favorable discharge (OR 0.43, 95% CI 0.30 to 0.61). In the sensitivity analysis, comparing AIS patients with COVID-19 who did not undergo EVT (n=2139) to the AIS EVT patients with COVID-19, there was no difference in the rate of in-hospital death (30.6% vs 29.8%, P=0.868), and AIS EVT patients had a higher rate of favorable discharge (32.4% vs 47.1%, P=0.002). Conclusion In AIS patients treated with EVT, comorbid COVID-19 infection was associated with in-hospital death and a lower odds of favorable discharge compared with patients without COVID-19, but not compared with AIS patients with COVID-19 who did not undergo EVT. AIS EVT patients with COVID-19 were younger, more likely to be male, have systemic complications, and almost twice as likely to be black and over three times as likely to be Hispanic. ©

Author Keywords
infection;  stroke;  thrombectomy

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Strategies to reduce the impact of demand for concurrent endovascular thrombectomy
(2020) Journal of NeuroInterventional Surgery, 12 (11), pp. 1072-1075.

Dalsania, A.K.^a , Kansagra, A.P.^b c d

^a Rutgers New Jersey Medical School, Newark, NJ, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background The rise in demand for endovascular thrombectomy (EVT) has increased the possibility that multiple patients with acute ischemic stroke may present concurrently and exceed local capacity to provide timely treatment. In this work, we quantitatively compared the efficacy of various strategies to mitigate demand in excess of capacity (DEC). Methods Strategies evaluated included a backup neurointerventional team for 3 hours, 8 hours, or 24 hours per day; a separate pre-intervention imaging team; and a 30% decrease in procedure duration. For each strategy, empirical distributions were used to probabilistically generate arrival time and case duration for 16 000 independent trials repeated across a range of annual case volumes. DEC was calculated from time series representing the number of concurrent cases at each minute of the year for each trial at each case volume. Results All strategies decreased DEC compared with baseline. At a representative volume of 250 cases per year, availability of a backup team for 3 hours, 8 hours, and 24 hours per day reduced DEC by 27.0%, 60.3%, and 97.2%, respectively, compared with baseline. Similarly, availability of a pre-intervention imaging team and a 30% decrease in procedure duration reduced DEC by 26.6% and 17.7%, respectively, compared with baseline. Conclusions A backup neurointerventional team, even if available only part time, was an effective strategy for decreasing DEC for EVT. Understanding the actual quantitative benefit of each strategy can facilitate rational cost-benefit analyses underlying the development of efficient and sustainable models of care. ©

Author Keywords
economics;  stroke;  thrombectomy

Document Type: Article
Publication Stage: Final
Source: Scopus

Role of Endothelial Nitric Oxide Synthase in Isoflurane Conditioning-Induced Neurovascular Protection in Subarachnoid Hemorrhage
(2020) Journal of the American Heart Association, 9 (20), p. e017477.

Athiraman, U.^a , Jayaraman, K.^b , Liu, M.^a , Giri, T.^a , Yuan, J.^b , Zipfel, G.J.^b

^a Department of Anesthesiology Washington University St. Louis MO
^b Department of Neurological surgery Washington University St. Louis MO

Abstract
Background Delayed cerebral ischemia remains a common and profound risk factor for poor outcome after subarachnoid hemorrhage (SAH). The aim of our current study is to define the role of endothelial nitric oxide synthase (eNOS) in isoflurane conditioning-induced neurovascular protection after SAH. Methods and Results Ten- to 14-week-old male wild-type mice (C57BL/6) as controls and eNOS knockout male mice (strain # 002684) were obtained for the study. Animals underwent either sham surgery, SAH surgery, or SAH with isoflurane conditioning. Anesthetic post conditioning was performed with isoflurane 2% for 1 hour, 1 hour after SAH. Normothermia was maintained with the homeothermic blanket. In a separate cohort, nitric oxide synthase was inhibited by a pan nitric oxide synthase inhibitor, L-nitroarginine methyl ester. Vasospasm measurement was assessed 72 hours after SAH and neurological function was assessed daily. Isoflurane-induced changes in the eNOS protein expression were measured. eNOS protein expression was significantly increased by isoflurane conditioning in naïve mice as well as mice subjected to SAH. Vasospasm of the middle cerebral artery and neurological deficits were evident following SAH versus sham surgery, both in wild-type mice and eNOS knockout mice. Isoflurane conditioning attenuated vasospasm and neurological deficits in wild-type mice. This delayed cerebral ischemia protection was lost in L-nitroarginine methyl ester -administered mice and eNOS knockout mice. Conclusions Our data indicate isoflurane conditioning provides robust protection against SAH-induced vasospasm and neurological deficits, and that this delayed cerebral ischemia protection is critically mediated via isoflurane-induced augmentation of eNOS.

Author Keywords
aneurysmal subarachnoid hemorrhage;  delayed cerebral ischemia;  endothelial nitric oxide synthase;  isoflurane conditioning

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Regional, not global, functional connectivity contributes to isolated focal dystonia
(2020) Neurology, 95 (16), pp. e2246-e2258.

Norris, S.A., Morris, A.E., Campbell, M.C., Karimi, M., Adeyemo, B., Paniello, R.C., Snyder, A.Z., Petersen, S.E., Mink, J.W., Perlmutter, J.S.

From the Departments of Neurology (S.A.N., M.C.C., M.K., A.B., A.Z.S., S.E.P., J.S.P.), Radiology (S.A.N., M.C.C., A.Z.S., S.E.P., J.S.P.), Otolaryngology (R.C.P.), Neuroscience (S.E.P., J.S.P.), Psychology (S.E.P.), Physical Therapy (J.S.P.), and Occupational Therapy (J.S.P.), Washington University School of Medicine, St. Louis, MO; University of Rochester Medical Scientist Training Program and Neurosciences Graduate Program (A.E.M.); and Departments of Neurology, Neuroscience, and Pediatrics (J.W.M.), University of Rochester, NY

Abstract
OBJECTIVE: To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort of patients with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study, we obtained resting-state MRI scans (three or four 7.3-minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], or limb [10]) and age- and sex-matched controls. METHODS: Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia n = 58, control n = 47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia, and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences. RESULTS: Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups. CONCLUSION: Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiologic mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between patients with focal dystonia and control participants. © 2020 American Academy of Neurology.

Document Type: Note
Publication Stage: Final
Source: Scopus

Transfacet Minimally Invasive Transforaminal Lumbar Interbody Fusion With an Expandable Interbody Device-Part I: 2-Dimensional Operative Video and Technical Report
(2020) Operative Neurosurgery (Hagerstown, Md.), 19 (5), pp. E473-E479.

Khalifeh, J.M., Dibble, C.F., Stecher, P., Dorward, I., Hawasli, A.H., Ray, W.Z.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Advances in operative techniques and minimally invasive technologies have evolved to maximize patient outcomes and radiographic results, while reducing morbidity and recovery time. OBJECTIVE: To describe the operative technique for a transfacet minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) as a proposed modification to the standard approach MIS-TLIF. METHODS: We present the case of a 72-yr-old man with left-sided lumbar radiculopathy. Preoperative imaging demonstrated degenerative lumbar anterolisthesis at L4-5, with associated canal and neuroforaminal stenosis. The patient underwent transfacet MIS-TLIF at L4-L5. We describe the preoperative planning, patient positioning, incision and dissection, pedicle screw insertion, transfacet approach to the working access corridor, discectomy, interbody device placement, fixation, and closure. RESULTS: The transfacet MIS-TLIF utilizes 3 key techniques to safely maximize surgical correction: (1) a limited bony resection based on the superior articular process, leaving the medial inferior articular process, lateral superior articular process, and rostral pars intact, providing a working bony corridor that protects the traversing and exiting nerve roots; (2) decortication and release of the contralateral facet joint to provide additional capacity for indirect decompression and provide the first point of osseous fusion; and (3) placement of an expandable interbody device that provides additional indirect decompression to the working side and contralateral foramen. CONCLUSION: The transfacet MIS-TLIF uniquely leverages a bony working corridor to access the disc space for discectomy and interbody placement. Transfacet MIS-TLIF is a feasible solution for lumbar spinal reconstruction to maximize direct and indirect decompression of the neuroforamina and central spinal canal in patients with lumbar degenerative diseases and low-grade spondylolisthesis. Copyright © 2020 by the Congress of Neurological Surgeons.

Author Keywords
Transfacet MIS-TLIF;  Expandable interbody device;  Indirect decompression;  Minimally invasive lumbar fusion;  Spondylolisthesis

Document Type: Article
Publication Stage: Final
Source: Scopus

Impact of 3-Dimensional Versus 2-Dimensional Image Distortion Correction on Stereotactic Neurosurgical Navigation Image Fusion Reliability for Images Acquired With Intraoperative Magnetic Resonance Imaging
(2020) Operative Neurosurgery (Hagerstown, Md.), 19 (5), pp. 599-607.

Yahanda, A.T.^a , Goble, T.J.^b , Sylvester, P.T.^a , Lessman, G.^b , Goddard, S.^c , McCollough, B.^c , Shah, A.^a , Andrews, T.^d , Benzinger, T.L.S.^a d , Chicoine, M.R.^a

^a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^b IMRIS, Minnetonka, MN, United States
^c Barnes-Jewish Hospital, St. Louis, MO, United States
^d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Fusion of preoperative and intraoperative magnetic resonance imaging (iMRI) studies during stereotactic navigation may be very useful for procedures such as tumor resections but can be subject to error because of image distortion. OBJECTIVE: To assess the impact of 3-dimensional (3D) vs 2-dimensional (2D) image distortion correction on the accuracy of auto-merge image fusion for stereotactic neurosurgical images acquired with iMRI using a head phantom in different surgical positions. METHODS: T1-weighted intraoperative images of the head phantom were obtained using 1.5T iMRI. Images were postprocessed with 2D and 3D image distortion correction. These studies were fused to T1-weighted preoperative MRI studies performed on a 1.5T diagnostic MRI. The reliability of the auto-merge fusion of these images for 2D and 3D correction techniques was assessed both manually using the stereotactic navigation system and via image analysis software. RESULTS: Eight surgical positions of the head phantom were imaged with iMRI. Greater image distortion occurred with increased distance from isocenter in all 3 axes, reducing accuracy of image fusion to preoperative images. Visually reliable image fusions were accomplished in 2/8 surgical positions using 2D distortion correction and 5/8 using 3D correction. Three-dimensional correction yielded superior image registration quality as defined by higher maximum mutual information values, with improvements ranging between 2.3% and 14.3% over 2D correction. CONCLUSION: Using 3D distortion correction enhanced the reliability of surgical navigation auto-merge fusion of phantom images acquired with iMRI across a wider range of head positions and may improve the accuracy of stereotactic navigation using iMRI images. Copyright © 2020 by the Congress of Neurological Surgeons.

Author Keywords
Distortion correction;  Image fusion;  Intraoperative MRI;  Neurosurgery;  Stereotactic navigation

Document Type: Article
Publication Stage: Final
Source: Scopus

Transfacet Minimally Invasive Transforaminal Lumbar Interbody Fusion With an Expandable Interbody Device-Part II: Consecutive Case Series
(2020) Operative Neurosurgery (Hagerstown, Md.), 19 (5), pp. 518-529.

Khalifeh, J.M., Dibble, C.F., Stecher, P., Dorward, I., Hawasli, A.H., Ray, W.Z.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Advances in operative techniques and instrumentation technology have evolved to maximize patient outcomes following minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). The transfacet MIS-TLIF is a modified approach to the standard MIS-TLIF that leverages a bony working corridor to access the disc space for discectomy and interbody device placement. OBJECTIVE: To evaluate clinical and radiographic results following transfacet MIS-TLIF using an expandable interbody device. METHODS: We performed a retrospective review of consecutive patients who underwent transfacet MIS-TLIF for degenerative lumbar spondylolisthesis. Patient-reported outcome measures for pain and disability were assessed. Sagittal lumbar segmental parameters and regional lumbopelvic parameters were assessed on upright lateral radiographs obtained preoperatively and during follow-up. RESULTS: A total of 68 patients (61.8% male) underwent transfacet MIS-TLIF at 74 levels. The mean age was 63.4 yr and the mean follow-up 15.2 mo. Patients experienced significant short- and long-term postoperative improvements on the numeric rating scale for low back pain (-2.3/10) and Oswestry Disability Index (-12.0/50). Transfacet MIS-TLIF was associated with an immediate and sustained reduction of spondylolisthesis, and an increase in index-level disc height (+0.71 cm), foraminal height (+0.28 cm), and segmental lordosis (+6.83°). Patients with preoperative hypolordosis (<40°) experienced significant increases in segmental (+9.10°) and overall lumbar lordosis (+8.65°). Pelvic parameters were not significantly changed, regardless of preoperative alignment. Device subsidence was observed in 6/74 (8.1%) levels, and fusion in 50/53 (94.3%) levels after 12 mo. CONCLUSION: Transfacet MIS-TLIF was associated with clinical improvements and restoration of radiographic sagittal segmental parameters. Regional alignment correction was observed among patients with hypolordosis at baseline. Copyright © 2020 by the Congress of Neurological Surgeons.

Author Keywords
Transfacet MIS-TLIF;  Expandable interbody device;  Indirect decompression;  Minimally invasive lumbar fusion;  Spondylolisthesis

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Daylight saving time: an American Academy of Sleep Medicine position statement
(2020) Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine, 16 (10), pp. 1781-1784.

Rishi, M.A.^a , Ahmed, O.^b , Barrantes Perez, J.H.^c , Berneking, M.^d , Dombrowsky, J.^e , Flynn-Evans, E.E.^f , Santiago, V.^g , Sullivan, S.S.^h i , Upender, R.^j , Yuen, K.^k , Abbasi-Feinberg, F.^l , Aurora, R.N.^m , Carden, K.A.ⁿ , Kirsch, D.B.^o , Kristo, D.A.^p , Malhotra, R.K.^q , Martin, J.L.^r s , Olson, E.J.^t , Ramar, K.^t , Rosen, C.L.^u , Rowley, J.A.^v , Shelgikar, A.V.^w , Gurubhagavatula, I.^x y

^a Department of Pulmonology, Critical Care and Sleep Medicine, Mayo Clinic, Eau Claire, WI, United States
^b Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of MedicineNY
^c Baylor College of Medicine, Houston, TX
^d Concentra, Inc., Grand RapidsMI
^e El Paso, TX, Mexico
^f Fatigue Countermeasures Laboratory, Human Systems Integration Division, NASA Ames Research Center, Moffett FieldCA
^g Sleep Medicine, Permanente Medical Group, Manteca, CA, United States
^h Department of Pediatrics, Division of Pulmonary, Asthma & Sleep Medicine, Stanford University School of Medicine, Palo Alto, CA, Mexico
ⁱ Eval Research Institute, Palo Alto, CA, Mexico
^j Department of Neurology, Division of Sleep Medicine, Vanderbilt Medical Center, Nashville, TN, United States
^k Sleep Disorders Center, UCSF Health, San Francisco, CA, Mexico
^l Sleep Medicine, Millennium Physician Group, Fort Myers, FL, United States
^m Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
ⁿ Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^o Sleep Medicine, Atrium Health, Charlotte, North Carolina
^p University of Pittsburgh, Pittsburgh, PA, United States
^q Sleep Medicine Center, Washington University School of Medicine, St. Louis, MO, United States
^r Veteran Affairs Greater Los Angeles Healthcare System, North HillsCA
^s David Geffen School of Medicine at the University of California, Los Angeles, CA, Mexico
^t Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN
^u Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States
^v Wayne State University, Detroit, MI, United States
^w University of Michigan Sleep Disorders Center, University of Michigan, Ann Arbor, MI, United States
^x Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^y Corporal Michael Crescenz Virginia Medical Center, Philadelphia, PA, United States

Abstract
None: The last several years have seen intense debate about the issue of transitioning between standard and daylight saving time. In the United States, the annual advance to daylight saving time in spring, and fall back to standard time in autumn, is required by law (although some exceptions are allowed under the statute). An abundance of accumulated evidence indicates that the acute transition from standard time to daylight saving time incurs significant public health and safety risks, including increased risk of adverse cardiovascular events, mood disorders, and motor vehicle crashes. Although chronic effects of remaining in daylight saving time year-round have not been well studied, daylight saving time is less aligned with human circadian biology-which, due to the impacts of the delayed natural light/dark cycle on human activity, could result in circadian misalignment, which has been associated in some studies with increased cardiovascular disease risk, metabolic syndrome and other health risks. It is, therefore, the position of the American Academy of Sleep Medicine that these seasonal time changes should be abolished in favor of a fixed, national, year-round standard time. © 2020 American Academy of Sleep Medicine.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Emerging immunotherapies for malignant glioma: from immunogenomics to cell therapy
(2020) Neuro-oncology, 22 (10), pp. 1425-1438.

Dunn, G.P.^a b , Cloughesy, T.F.^c d e , Maus, M.V.^d f g , Prins, R.M.^e h i , Reardon, D.A.^g j k , Sonabend, A.M.^l

^a Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^b rew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, Mexico
^d Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, Mexico
^e Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, Mexico
^f Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Charlestown, MA, United States
^g Harvard Medical School, Boston, MA
^h Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, Mexico
ⁱ Parker Institute for Cancer Immunotherapy, San Francisco, CA, Mexico
^j Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
^k Department of Medicine, Brigham and Women’s Hospital, Boston, MA
^l Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, Mexico

Abstract
As immunotherapy assumes a central role in the management of many cancers, ongoing work is directed at understanding whether immune-based treatments will be successful in patients with glioblastoma (GBM). Despite several large studies conducted in the last several years, there remain no FDA-approved immunotherapies in this patient population. Nevertheless, there are a range of exciting new approaches being applied to GBM, all of which may not only allow us to develop new treatments but also help us understand fundamental features of the immune response in the central nervous system. In this review, we summarize new developments in the application of immune checkpoint blockade, from biomarker-driven patient selection to the timing of treatment. Moreover, we summarize novel work in personalized immune-oncology by reviewing work in cancer immunogenomics-driven neoantigen vaccine studies. Finally, we discuss cell therapy efforts by reviewing the current state of chimeric antigen receptor T-cell therapy. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
cancer immunogenomics;  CNS immunosurveillance;  glioblastoma;  neoantigen;  personalized vaccine

Document Type: Article
Publication Stage: Final
Source: Scopus

Motor outcome measures in patients with FKRP mutations: A longitudinal follow-up
(2020) Neurology, 95 (15), pp. e2131-e2139.

Gedlinske, A.M., Stephan, C.M., Mockler, S.R.H., Laubscher, K.M., Laubenthal, K.S., Crockett, C.D., Zimmerman, M.B., Mathews, K.D.

From the Department of Pediatrics (A.M.G., C.M.S., C.D.C., K.D.M.) and Center for Disabilities and Development (S.R.H.M., K.M.L., K.S.L.), University of Iowa Hospitals and Clinics; and Department of Biostatistics (M.B.Z.), University of Iowa College of Public Health, Iowa City. C.D.C. is now affiliated with Washington University, St. Louis, MO

Abstract
OBJECTIVE: To test the hypothesis that we will be able to detect change in motor outcome measures over time in a cohort with mutations in FKRP. METHODS: Individuals with documented FKRP mutations were evaluated annually with a battery of established motor outcome measures including limited quantitative myometry and timed function measures. Results were analyzed using random coefficient regression to determine annual change in each measure. Due to the nonlinear progression through the lifespan of the study participants, pediatric (<19 years) and adult (≥19 years) cohorts were analyzed separately. Effect of genotype was evaluated in each cohort. RESULTS: Sixty-nine participants (30 pediatric, 44 adult) with at least 2 evaluations were included. There was a small but statistically significant decline in timed motor function measures in both pediatric and adult cohorts. Genotype significantly affected rate of decline in the pediatric but not the adult cohort. Some pediatric patients who are homozygous for the c.826C>A mutation showed improving motor performance in adolescence. Performance on the 10-meter walk/run was highly correlated with other timed function tests. CONCLUSIONS: There is a slow annual decline in motor function in adults with FKRP mutations that can be detected with standard motor outcome measures, while the results in the pediatric population were more variable and affected by genotype. Overall, these analyses provide a framework for development of future clinical trials. The dystroglycanopathies natural history study (Clinical Trial Readiness for the Dystroglycanopathies) may be found on clinicaltrials.gov (NCT00313677). © 2020 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Measures of Sleep in Rheumatologic Diseases: Sleep Quality Patient-Reported Outcomes in Rheumatologic Diseases
(2020) Arthritis Care and Research, 72 (S10), pp. 410-430.

Chu, P.^a , Ju, Y.-E.S.^b , Hinze, A.M.^c , Kim, A.H.J.^b

^a Duke University School of Medicine, Durham, NC, United States
^b Washington University School of Medicine in St Louis, St Louis, MO, United States
^c Mayo Clinic, Rochester, MN, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

The gut microbiome defines social group membership in honey bee colonies
(2020) Science Advances, 6 (42), art. no. eabd3431, .

Vernier, C.L.^a g , Chin, I.M.^a , Adu-Oppong, B.^b , Krupp, J.J.^c , Levine, J.^c , Dantas, G.^b d e f , Ben-Shahar, Y.^a

^a Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^b Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Biology, University of Toronto Mississauga, Mississauga, ON, Canada
^d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^g Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, United States

Abstract
In the honey bee, genetically related colony members innately develop colony-specific cuticular hydrocarbon profiles, which serve as pheromonal nestmate recognition cues. Yet, despite high intracolony relatedness, the innate development of colony-specific chemical signatures by individual colony members is largely determined by the colony environment, rather than solely relying on genetic variants shared by nestmates. Therefore, it is puzzling how a nongenic factor could drive the innate development of a quantitative trait that is shared by members of the same colony. Here, we provide one solution to this conundrum by showing that nestmate recognition cues in honey bees are defined, at least in part, by shared characteristics of the gut microbiome across individual colony members. These results illustrate the importance of host-microbiome interactions as a source of variation in animal behavioral traits. Copyright © 2020 The Authors, some rights reserved;

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Evidence for normal novel object recognition abilities in developmental prosopagnosia: OBJECT RECOGNITION PROSOPAGNOSIA
(2020) Royal Society Open Science, 7 (9), art. no. 0988, .

Fry, R.^a c , Wilmer, J.^d , Xie, I.^e f , Verfaellie, M.^b g , Degutis, J.^a c

^a Boston Attention and Learning Laboratory, VA Boston Healthcare System, Boston, MA, United States
^b Memory Disorders Research Center, VA Boston Healthcare System, Boston, MA, United States
^c Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^d Department of Psychology, Wellesley College, Wellesley, MA, United States
^e Washington University in St Louis, St Louis, MO, United States
^f Harvard Decision Science Lab, Harvard Kennedy School, Cambridge, MA, United States
^g Department of Psychiatry, Boston University, School of Medicine, Boston, MA, United States

Abstract
The issue of the face specificity of recognition deficits in developmental prosopagnosia (DP) is fundamental to the organization of high-level visual memory and has been increasingly debated in recent years. Previous DP investigations have found some evidence of object recognition impairments, but have almost exclusively used familiar objects (e.g. cars), where performance may depend on acquired object-specific experience and related visual expertise. An object recognition test not influenced by experience could provide a better, less contaminated measure of DPs’ object recognition abilities. To investigate this, in the current study we tested 30 DPs and 30 matched controls on a novel object memory test (NOMT Ziggerins) and the Cambridge Face Memory Test (CFMT). DPs with severe impairment on the CFMT showed no differences in accuracy or reaction times compared with controls on the NOMT. We found similar results when comparing DPs with a larger sample of 274 web-based controls. Additional individual analyses demonstrated that the rate of object recognition impairment in DPs did not differ from the rate of impairment in either control group. Together, these results demonstrate unimpaired object recognition in DPs for a class of novel objects that serves as a powerful index for broader novel object recognition capacity. © 2020 The Authors.

Author Keywords
developmental prosopagnosia;  face specificity;  novel object memory test;  object recognition

Document Type: Article
Publication Stage: Final
Source: Scopus

Challenges and future directions for representations of functional brain organization
(2020) Nature Neuroscience, .

Bijsterbosch, J.^a b , Harrison, S.J.^b c , Jbabdi, S.^b , Woolrich, M.^d , Beckmann, C.^e , Smith, S.^b , Duff, E.P.^b f

^a Mallinckrodt Institute of Radiology, Washington University in St Louis, Saint Louis, MO, United States
^b Centre for Functional MRI of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford. John Radcliffe Hospital, Oxford, United Kingdom
^c Translational Neuromodeling Unit, University of Zurich & ETH Zurich, Zurich, Switzerland
^d Oxford Centre for Human Brain Activity (OHBA), Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
^e Donders Institute and Department of Cognitive Neurosciences, Radboud University Medical Centre, Nijmegen, Netherlands
^f Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Abstract
A key principle of brain organization is the functional integration of brain regions into interconnected networks. Functional MRI scans acquired at rest offer insights into functional integration via patterns of coherent fluctuations in spontaneous activity, known as functional connectivity. These patterns have been studied intensively and have been linked to cognition and disease. However, the field is fractionated. Diverging analysis approaches have segregated the community into research silos, limiting the replication and clinical translation of findings. A primary source of this fractionation is the diversity of approaches used to reduce complex brain data into a lower-dimensional set of features for analysis and interpretation, which we refer to as brain representations. In this Primer, we provide an overview of different brain representations, lay out the challenges that have led to the fractionation of the field and that continue to form obstacles for convergence, and propose concrete guidelines to unite the field. © 2020, Springer Nature America, Inc.

Document Type: Review
Publication Stage: Article in Press
Source: Scopus

PTSD improvement and substance use disorder treatment utilization in veterans: Evidence from medical record data
(2020) Drug and Alcohol Dependence, art. no. 108365, .

Salas, J.^a b , Norman, S.B.^c , Tuerk, P.W.^d , den Berk-Clark, C.V.^a , Cohen, B.E.^e , Schneider, F.D.^f , Chard, K.M.^g , Lustman, P.J.^h , Schnurr, P.P.ⁱ , Friedman, M.J.ⁱ , Grucza, R.^a , Scherrer, J.F.^a b

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
^b Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States
^c National Center for PTSD and Department of Psychiatry, University of California San Diego, United States
^d Sheila C. Johnson Center for Clinical Services, Department of Human Services, University of Virginia, Charlottesville, VA, United States
^e Department of Medicine, University of California San Francisco School of Medicine and San Francisco VAMC, United States
^f Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
^g Trauma Recovery Center Cincinnati VAMC and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States
^h Department of Psychiatry, Washington University School of Medicine, St. Louis MO. and The Bell Street Clinic Opioid Addiction Treatment Programs, VA St. Louis Healthcare System, St. Louis, MO, United States
ⁱ National Center for PTSD and Department of Psychiatry, Geisel School of Medicine at Dartmouth, United States

Abstract
Background: Clinical trials reveal posttraumatic stress disorder (PTSD) improvement leads to decreased substance use among patients with comorbid substance use disorder (SUD). Using administrative medical record data, we determined whether clinically meaningful PTSD Checklist (PCL) (≥20 points) score decreases were positively associated with SUD treatment utilization. Methods: We used a retrospective cohort of Veterans Health Affairs (VHA) medical record data (2008–2015). PTSD Checklist (PCL) scores were used to categorize patients into those with a clinically meaningful PTSD improvement (≥20 point decrease) or not (<20 point decrease or increase). PTSD and SUD were measured by ICD-9 codes. Propensity score weighting controlled for confounding in logistic and negative binomial models that estimated the association between clinically meaningful PTSD improvement and use of SUD treatment and number of SUD clinic visits. Results: The 699 eligible patients were, on average, 40.4 (±13.2) years old, 66.2% white and 33.1% were married. After controlling for confounding, there was a 56% increased odds of any SUD treatment utilization among those with a PCL decrease ≥20 vs < 20 (OR = 1.56; 95%CI = 1.04−2.33) but there was no association with number of SUD treatment visits. Conclusions: Clinically meaningful reductions in PTSD symptoms were associated with any SUD treatment utilization but not amount of utilization. Improvement in PTSD symptoms, independent of the treatment modality, may enable SUD treatment seeking. © 2020 Elsevier B.V.

Author Keywords
Alcohol dependence;  Cohort;  Drug dependence;  Epidemiology;  Posttraumatic stress disorder;  Veteran health services

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Medical management of muscle weakness in Duchenne muscular dystrophy
(2020) PLoS ONE, 15 (10 October), art. no. e0240687, .

Rivera, S.R.^a , Jhamb, S.K.^b , Abdel-Hamid, H.Z.^c , Acsadi, G.^d , Brandsema, J.^e , Ciafaloni, E.^f , Darras, B.T.^g , Iannaccone, S.T.^h , Konersman, C.G.ⁱ , Kuntz, N.L.^j , McDonald, C.M.^k , Parsons, J.A.^l , Rocha, C.T.^m , Zaidman, C.M.ⁿ , Butterfield, R.J.^o , Connolly, A.M.^p , Mathews, K.D.^q

^a Department of Clinical Services, Optum Lifesciences Wolfeboro, Wolfeboro, New Hampshire, United States
^b Department of Clinical Services, Optum Global Solutions, Noida, Uttar Pradesh, India
^c Division of Child Neurology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
^d Department of Neurology, Connecticut Children’s Medical Center, Farmington, CT, United States
^e Division of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Department of Pediatric Neuromuscular Medicine, University of Rochester Medical Center, Rochester, NY, United States
^g Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^h Department of Pediatrics, UT Southwestern, Dallas, TX, United States
ⁱ Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
^j Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital, Chicago, IL, United States
^k Department of Physical Medicine and Rehabilitation, UC Davis Health, Sacramento, CA, United States
^l Department of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, United States
^m Department of Neurology, Stanford University, Palo Alto, CA, United States
ⁿ Department of Neurology, Divisions of Child Neurology and Neuromuscular, Washington, University in St. Louis School of Medicine, St. Louis, MO, United States
^o Department of Neurology and Pediatrics, University of Utah, Salt Lake City, UT, United States
^p Department of Neurology, Nationwide Children’s Hospital, Columbus, OH, United States
^q Departments of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, United States

Abstract
Introduction Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. Methods A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists’ responses were collected using a modified Delphi approach. Results Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. Discussion The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects. Copyright: © 2020 Rivera et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD through Multiple Phenotypes
(2020) Journal of Alzheimer’s Disease, 77 (4), pp. 1469-1482.

Olive, C.^a b , Ibanez, L.^a b , Farias, F.H.G.^a b , Wang, F.^a b , Budde, J.P.^a b , Norton, J.B.^a b c , Gentsch, J.^a b c , Morris, J.C.^b c , Li, Z.^a b , Dube, U.^a b , Del-Aguila, J.^a b , Bergmann, K.^a b , Bradley, J.^a b , Benitez, B.A.^a b , Harari, O.^a b , Fagan, A.^d , Ances, B.^d , Cruchaga, C.^a b , Fernandez, M.V.^a b

^a Neurogenomics and Informatics Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer’s disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. Methods: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease. © 2020-IOS Press and the authors. All rights reserved.

Author Keywords
ABI3;  endophenotypes;  late onset Alzheimer’s disease;  PLCG2;  progression;  TREM2

Document Type: Article
Publication Stage: Final
Source: Scopus

Incidence of Nerve Injury After Extremity Trauma in the United States
(2020) Hand, .

Padovano, W.M.^a , Dengler, J.^a , Patterson, M.M.^b , Yee, A.^a , Snyder-Warwick, A.K.^a , Wood, M.D.^a , Moore, A.M.^a , Mackinnon, S.E.^a

^a Washington University School of Medicine, St. Louis, MO, United States
^b The University of North Carolina at Chapel Hill, United States

Abstract
Background: Traumatic peripheral nerve injuries cause chronic pain, disability, and long-term reductions in quality of life. However, their incidence after extremity trauma remains poorly understood. Methods: The Truven MarketScan Commercial Claims and Encounters database from 2010 to 2015 was used to identify patients aged 18 to 64 who presented to emergency departments for upper and/or lower extremity traumas. Cumulative incidences were calculated for nerve injuries diagnosed within 2 years of trauma. Cox regression models were developed to evaluate the associations between upper extremity nerve injury and chronic pain, disability, and use of physical therapy or occupational therapy. Results: The final cohort consisted of 1 230 362 patients with employer-sponsored health plans. Nerve injuries were diagnosed in 2.6% of upper extremity trauma patients and 1.2% of lower extremity trauma patients. Only 9% and 38% of nerve injuries were diagnosed by the time of emergency department and hospital discharge, respectively. Patients with nerve injuries were more likely to be diagnosed with chronic pain (hazard ratio [HR]: 5.9, 95% confidence interval [CI], 4.3-8.2), use physical therapy services (HR: 10.7, 95% CI, 8.8-13.1), and use occupational therapy services (HR: 19.2, 95% CI, 15.4-24.0) more than 90 days after injury. Conclusions: The incidence of nerve injury in this national cohort was higher than previously reported. A minority of injuries were diagnosed by emergency department or hospital discharge. These findings may improve practitioner awareness and inform public health interventions for injury prevention. © The Author(s) 2020.

Author Keywords
administrative database;  diagnosis;  epidemiology;  incidence;  nerve;  nerve injury;  outcomes;  research & health outcomes;  specialty;  surgery

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Accurate assessment of hearing and cognition in older adults
(2020) Hearing Journal, 73 (1), pp. 38-39.

McClannahan, K.

Department of Psychological and Brain Sciences, Washington University in St. Louis, United States

Document Type: Note
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Hearing Loss–Related Issues Affecting Quality of Life in Preschool Children
(2020) Otolaryngology – Head and Neck Surgery (United States), .

Lindburg, M.^a , Ead, B.^a , Jeffe, D.B.^b , Lieu, J.E.C.^a

^a Washington University, Department of Otolaryngology–Head and Neck Surgery, St Louis, MO, United States
^b Washington University, Department of Medicine, Division of General Medical Sciences, St Louis, MO, United States

Abstract
Objective: The impact of hearing loss (HL) on quality of life (QOL) in young children has not been examined systematically. The objective of this study was to examine patient, parent, and professional perspectives on experiences and situations that affect the QOL in young children with HL and to identify themes that emerged from coded data to develop a parent-proxy QOL measure for young children with HL. Study Design: Qualitative study with 6 focus groups followed by semistructured interviews with other parents and professionals as stakeholder checks. Setting: Academic medical center and local schools for the deaf. Methods: Audiology department clinic lists were used to identify eligible participants, who included 5- to 7-year-old children with permanent HL and parents of 2- to 7-year-old children with permanent HL. A sample of 6 children and 12 parents participated in focus groups. An audiology department and multiple schools for the deaf in the area were contacted to recruit for professional participants, resulting in a sample of 10 professionals who participated in focus groups. Focus groups and interviews were audiotaped and transcribed verbatim. Inductive thematic analysis of focus group transcripts identified key concepts and emerging themes of how HL affects young children. Results: Six themes emerged from the data: behavior, feelings, environments, social/activities, family, and hearing equipment. Child, parent, and professional focus group themes overlapped well, and data saturation was reached. Conclusion: These qualitative data provided insight into HL-related issues affecting young children’s QOL and were used to create items for a new parent-proxy QOL questionnaire. © American Academy of Otolaryngology–Head and Neck Surgery Foundation 2020.

Author Keywords
children;  focus groups;  hearing loss;  quality of life

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Liposomes embedded within fibrin gels facilitate localized macrophage manipulations within nerve
(2020) Journal of Neuroscience Methods, art. no. 108981, .

Pan, D., Sayanagi, J., Acevedo-Cintrón, J.A., Schellhardt, L., Snyder-Warwick, A.K., Mackinnon, S.E., Wood, M.D.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Background: Understanding the role of macrophages at discrete spatial locations during nerve regeneration after injury is important. But, methodologies that systemically manipulate macrophages can obscure their roles within discrete spatial locations within nerve. New method: Liposomes were embedded within fibrin gels to construct a delivery system that facilitated macrophage-specific manipulations at a sole spatial region, as macrophages accumulated within the fibrin. Clodronate liposomes were characterized for their toxicity to specific cells composing nerve in vitro, then tested for macrophage-specific depletion in vivo. This delivery system using clodronate liposomes was used to repair a mouse sciatic nerve gap to evaluate its efficacy and effects. Result: Clodronate liposomes showed specific toxicity to macrophages without affecting dorsal root ganglia (DRG)-derived neurons, endothelial cells, or Schwann cells in culture. The delivery system demonstrated sustained release of liposomes for more than 7 days while still retaining liposomes within the fibrin. In vivo, the delivery system demonstrated macrophages were targeted by liposomes, and the use of clodronate liposomes minimized macrophage accumulation within fibrin, while not affecting macrophage accumulation within DRG. Nerve regeneration across the nerve gap repaired using this delivery system was associated with decreased angiogenesis, Schwann cell accumulation, axon growth, and reinnervation of affected muscle. Comparison with existing methods: This delivery system allowed specific perturbation of macrophages locally in nerve. This method could be applicable across species without the need for genetic manipulations or systemic pharmaceuticals. Conclusion: Liposomes embedded within fibrin gels locally target macrophages at the site of nerve injury, which enables greater precision in conclusions regarding their roles in nerve. © 2020 Elsevier B.V.

Author Keywords
Clodronate liposome;  Macrophage;  Nerve regeneration

Document Type: Article
Publication Stage: Article in Press
Source: Scopus