UW Neurological Surgery Recent PubMed Publications

Intracranial aneurysms at higher clinical risk for rupture demonstrate increased wall enhancement and thinning on multicontrast 3D vessel wall MRI.

Br J Radiol. 2019 Apr;92(1096):20180950

Authors: Hartman JB, Watase H, Sun J, Hippe DS, Kim L, Levitt M, Sekhar L, Balu N, Hatsukami T, Yuan C, Mossa-Basha M

Abstract
OBJECTIVE:: Identification of aneurysms at risk for rupture is important and challenging. We sought to evaluate if intracranial vessel wall (IVW) imaging characteristics of unruptured aneurysms correlate with clinical risk factors for rupture.
METHODS:: Patients with unruptured intracranial aneurysms were prospectively recruited and underwent a multi contrast 3D IVW protocol between April 6, 2016 and August 29, 2017. Two independent raters, blinded to aneurysm vulnerability, evaluated each aneurysm for wall enhancement, extent of enhancement in terms of the numbers of quadrants enhancing circumferentially, intensity of enhancement, and qualitative wall thinning. PHASES score was calculated for each aneurysm. Univariate logistic regression analysis was used to compare IVW characteristics between aneurysms at higher clinical risk for rupture (PHASES score > 3) and lower clinical risk for rupture (PHASES score ≤ 3).
RESULTS:: 45 patients with 65 unruptured aneurysms were analyzed; 38 aneurysms with PHASES score > 3 (58%) and 27 aneurysms with PHASES score ≤ 3 (42%). Aneurysms with PHASES score > 3 were more likely to demonstrate enhancement (42.1% vs 14.8%, p = 0.022), greater extent of enhancement (mean: 2.9 vs 2.2 quadrants, p = 0.063), and wall thinning (9.2% vs 0%, p = 0.044). Inter-reader agreement was moderate-to-good for the presence (κ = 0.64), extent (κ = 0.64), and intensity of enhancement (κ = 0.60) but relatively low for wall thinning (κ = 0.25).
CONCLUSION:: Aneurysms at higher risk of rupture by PHASES score are more likely to demonstrate wall enhancement, more diffuse enhancement, and wall thinning on IVW.
ADVANCES IN KNOWLEDGE:: This study prospectively compares IVW-detected wall enhancement and thinning between unruptured aneurysms stratified into high and low risk groups by clinical scores (PHASES) of vulnerability.

PMID: 30653339 [PubMed - indexed for MEDLINE]

Loss of host-derived osteopontin creates a glioblastoma-promoting microenvironment.

Neuro Oncol. 2018 02 19;20(3):355-366

Authors: Szulzewsky F, Schwendinger N, Güneykaya D, Cimino PJ, Hambardzumyan D, Synowitz M, Holland EC, Kettenmann H

Abstract
Background: Microglia and periphery-derived monocytes infiltrate human and mouse glioblastoma and their density is positively correlated with malignancy. Using microarray and RNA sequencing, we have previously shown that glioblastoma-associated microglia/monocytes (GAMs) express osteopontin/SPP1.
Methods: We used quantitative reverse transcriptase PCR, immunofluorescence stainings, western blot, and flow cytometry to identify the various sources of osteopontin (OPN) expression in human and mouse glioblastoma. We implanted wild type GL261 glioblastoma cells, which do not express significant levels of OPN, into wild type and OPN-/- mice to investigate the role of microenvironment-derived OPN on glioblastoma progression.
Results: Our data indicate that GAMs are the predominant source of OPN in both human and mouse glioblastoma and express only the secreted form of OPN. Loss of microenvironment-derived OPN enhanced tumor progression. Staining by Ki67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling showed no difference in overall cell proliferation but a decreased apoptosis rate in tumors in OPN-/- mice. CD31 staining showed a significantly decreased number of microvessels in tumors in OPN-/- mice, accompanied by reduced coverage of vessels with platelet derived growth factor receptor β+ pericytes. Flow cytometry analysis revealed a significant increase of CD11b+/CD45low microglia but not of CD11b+/CD45high macrophages/monocytes in tumors in OPN-/- mice. Sorted CD11b+ cells from wild type and OPN-/- naïve brains and tumors did not show a significant difference in the expression pattern of activation marker genes.
Conclusion: Our results show that in tested human and mouse glioblastoma samples, OPN is predominantly expressed and secreted by GAMs and that, in contrast to OPN expression in the tumor cells per se, loss of stroma-derived OPN creates a glioblastoma-promoting microenvironment.

PMID: 29016864 [PubMed - indexed for MEDLINE]

Left External Carotid Artery to the Middle Cerebral Artery Bypass with Radial Artery Graft and Clip Reconstruction of a Large Middle Cerebral Artery Fusiform Aneurysm: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2019 Jan 11;:

Authors: Cheng CY, Qazi Z, Sekhar LN

Abstract
This 16-yr-old boy presented with episodes of severe headaches, blurred vision, dizziness, and muffled hearing and was discovered to have a large fusiform aneurysm of the left middle cerebral artery (MCA), M1 segment, 20 × 12 mm in dimension. The lenticulostriate arteries were arising proximal and distal to the aneurysm, but the anterior temporal artery was arising from the aneurysm. The aneurysm culminated in the distal M1 segment, and M1 immediately branched into 3 M2 vessels, the lower one being the larger. Due to origin of the lenticulostriate arteries and the anterior temporal artery and patient's age, a bypass was preferred to a flow diversion stent. He underwent left frontotemporal craniotomy and orbital osteotomy, left cervical external carotid artery exposure followed by radial artery graft extraction. The Sylvian fissure was opened and intracranial ICA was exposed for proximal control. The distal M2 vessels traced back toward the aneurysm. The aneurysm was not clippable and a bypass to the larger inferior M2 branch was performed followed by aneurysm trapping. The radial artery graft bypass was placed from the left external carotid artery to the M2 segment of left MCA, followed by clip reconstruction and occlusion of the MCA aneurysm with the preservation of the anterior temporal branch and the lenticulostriate vessels. The patient had no postoperative complications. At the follow-up, one month after surgery, he was doing well, and his angiogram demonstrated patency of the bypass. This video shows the management of a complex fusiform M1 aneurysm with bypass and trapping. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 30649501 [PubMed - as supplied by publisher]

Comparison of clinical outcomes following minimally invasive or lumbar endoscopic unilateral laminotomy for bilateral decompression.

J Neurosurg Spine. 2019 Jan 11;:1-9

Authors: McGrath LB, White-Dzuro GA, Hofstetter CP

Abstract
OBJECTIVEMinimally invasive lumbar unilateral tubular laminotomy for bilateral decompression has gradually gained acceptance as a less destabilizing but efficacious and safe alternative to traditional open decompression techniques. The authors have further advanced the principles of minimally invasive surgery (MIS) by utilizing working-channel endoscope-based techniques. Full-endoscopic technique allows for high-resolution off-axis visualization of neural structures within the lateral recess, thereby minimizing the need for facet joint resection. The relative efficacy and safety of MIS and full-endoscopic techniques have not been directly compared.METHODSA retrospective analysis of 95 consecutive patients undergoing either MIS (n = 45) or endoscopic (n = 50) unilateral laminotomies for bilateral decompression in cases of lumbar spinal stenosis was performed. Patient demographics, operative details, clinical outcomes, and complications were reviewed.RESULTSThe patient cohort consisted of 41 female and 54 male patients whose average age was 62 years. Half of the patients had single-level, one-third had 2-level, and the remaining patients had 3- or 4-level procedures. The surgical time for endoscopic technique was significantly longer per level compared to MIS (161.8 ± 6.8 minutes vs 99.3 ± 4.6 minutes; p < 0.001). Hospital stay for MIS patients was on average 2.4 ± 0.5 days compared to 0.7 ± 0.1 days for endoscopic patients (p = 0.001). At the 1-year follow-up, endoscopic patients had a significantly lower visual analog scale score for leg pain than MIS patients (1.3 ± 0.3 vs 3.0 ± 0.5; p < 0.01). Moreover, the back pain disability index score was significantly lower in the endoscopic cohort than in the MIS cohort (20.7 ± 3.4 vs 35.9 ± 4.1; p < 0.01). Two patients in the MIS group (epidural hematoma) and one patient in the endoscopic group (disc herniation) required a return to the operating room acutely after surgery (< 14 days).CONCLUSIONSLumbar endoscopic unilateral laminotomy for bilateral decompression is a safe and effective surgical procedure with favorable complication profile and patient outcomes.

PMID: 30641853 [PubMed - as supplied by publisher]

Assessment of Follow-up Care After Emergency Department Presentation for Mild Traumatic Brain Injury and Concussion: Results From the TRACK-TBI Study.

JAMA Netw Open. 2018 05 18;1(1):e180210

Authors: Seabury SA, Gaudette É, Goldman DP, Markowitz AJ, Brooks J, McCrea MA, Okonkwo DO, Manley GT, TRACK-TBI Investigators, Adeoye O, Badjatia N, Boase K, Bodien Y, Bullock MR, Chesnut R, Corrigan JD, Crawford K, Diaz-Arrastia R, Dikmen S, Duhaime AC, Ellenbogen R, Feeser VR, Ferguson A, Foreman B, Gardner R, Giacino J, Gonzalez L, Gopinath S, Gullapalli R, Hemphill JC, Hotz G, Jain S, Korley F, Kramer J, Kreitzer N, Levin H, Lindsell C, Machamer J, Madden C, Martin A, McAllister T, Merchant R, Mukherjee P, Nelson L, Noel F, Palacios E, Perl D, Puccio A, Rabinowitz M, Robertson C, Rosand J, Sander A, Satris G, Schnyer D, Sherer M, Stein M, Taylor S, Temkin N, Toga A, Valadka A, Vassar M, Vespa P, Wang K, Yue J, Yuh E, Zafonte R

Abstract
Importance: Mild traumatic brain injury (mTBI) affects millions of Americans each year. Lack of consistent clinical practice raises concern that many patients with mTBI may not receive adequate follow-up care.
Objective: To characterize the provision of follow-up care to patients with mTBI during the first 3 months after injury.
Design, Setting, and Participants: This cohort study used data on patients with mTBI enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study between February 26, 2014, and August 25, 2016. We examined site-specific variations in follow-up care, the types of clinicians seen by patients receiving follow-up care, and patient and injury characteristics associated with a higher likelihood of receiving follow-up care. The TRACK-TBI study is a prospective, multicenter, longitudinal observational study of patients with TBI presenting to the emergency department of 1 of 11 level I US trauma centers. Study data included patients with head trauma who underwent a computed tomography (CT) scan within 24 hours of injury, had a Glasgow Coma Scale score of 13 to 15, were aged 17 years or older, and completed follow-up care surveys at 2 weeks and 3 months after injury (N = 831).
Main Outcomes and Measures: Follow-up care was defined as hospitals providing TBI educational material at discharge, hospitals calling patients to follow up, and patients seeing a physician or other medical practitioner within 3 months after the injury. Unfavorable outcomes were assessed with the Rivermead Post Concussion Symptoms Questionnaire.
Results: Of 831 patients (289 [35%] female; 483 [58%] non-Hispanic white; mean [SD] age, 40.3 [16.9] years), less than half self-reported receiving TBI educational material at discharge (353 patients [42%]) or seeing a physician or other health care practitioner within 3 months after injury (367 patients [44%]). Follow-up care varied by study site; adjusting for patient characteristics, the provision of educational material varied from 19% to 72% across sites. Of 236 patients with a positive finding on a CT scan, 92 (39%) had not seen a medical practitioner 3 months after the injury. Adjusting for injury severity and demographics, patient admission to the hospital ward or intensive care unit, patient income, and insurance status were not associated with the probability of seeing a medical practitioner. Among the patients with 3 or more moderate to severe postconcussive symptoms, only 145 of 279 (52%) reported having seen a medical practitioner by 3 months.
Conclusions and Relevance: There are gaps in follow-up care for patients with mTBI after hospital discharge, even those with a positive finding on CT or who continue to experience postconcussive symptoms.

PMID: 30646055 [PubMed - indexed for MEDLINE]

Association Between 5-Year Clinical Outcome in Patients With Nonmedically Evacuated Mild Blast Traumatic Brain Injury and Clinical Measures Collected Within 7 Days Postinjury in Combat.

JAMA Netw Open. 2019 01 04;2(1):e186676

Authors: Mac Donald CL, Barber J, Patterson J, Johnson AM, Dikmen S, Fann JR, Temkin N

Abstract
Importance: Although previous work has examined clinical outcomes in combat-deployed veterans, questions remain regarding how symptoms evolve or resolve following mild blast traumatic brain injury (TBI) treated in theater and their association with long-term outcomes.
Objective: To characterize 5-year outcome in patients with nonmedically evacuated blast concussion compared with combat-deployed controls and understand what clinical measures collected acutely in theater are associated with 5-year outcome.
Design, Setting, and Participants: A prospective, longitudinal cohort study including 45 service members with mild blast TBI within 7 days of injury (mean 4 days) and 45 combat deployed nonconcussed controls was carried out. Enrollment occurred in Afghanistan at the point of injury with evaluation of 5-year outcome in the United States. The enrollment occurred from March to September 2012 with 5-year follow up completed from April 2017 to May 2018. Data analysis was completed from June to July 2018.
Exposures: Concussive blast TBI. All patients were treated in theater, and none required medical evacuation.
Main Outcomes and Measures: Clinical measures collected in theater included measures for concussion symptoms, posttraumatic stress disorder (PTSD) symptoms, depression symptoms, balance performance, combat exposure intensity, cognitive performance, and demographics. Five-year outcome evaluation included measures for global disability, neurobehavioral impairment, PTSD symptoms, depression symptoms, and 10 domains of cognitive function. Forward selection multivariate regression was used to determine predictors of 5-year outcome for global disability, neurobehavior impairment, PTSD, and cognitive function.
Results: Nonmedically evacuated patients with concussive blast injury (n = 45; 44 men, mean [SD] age, 31 [5] years) fared poorly at 5-year follow-up compared with combat-deployed controls (n = 45; 35 men; mean [SD] age, 34 [7] years) on global disability, neurobehavioral impairment, and psychiatric symptoms, whereas cognitive changes were unremarkable. Acute predictors of 5-year outcome consistently identified TBI diagnosis with contribution from acute concussion and mental health symptoms and select measures of cognitive performance depending on the model for 5-year global disability (area under the curve following bootstrap validation [AUCBV] = 0.79), neurobehavioral impairment (correlation following bootstrap validation [RBV] = 0.60), PTSD severity (RBV = 0.36), or cognitive performance (RBV = 0.34).
Conclusions and Relevance: Service members with concussive blast injuries fared poorly at 5-year outcome. The results support a more focused acute screening of mental health following TBI diagnosis as strong indicators of poor long-term outcome. This extends prior work examining outcome in patients with concussive blast injury to the larger nonmedically evacuated population.

PMID: 30646193 [PubMed - indexed for MEDLINE]

Intranasal Sufentanil Versus Intravenous Morphine for Acute Pain in the Emergency Department: A Randomized Pilot Trial.

J Emerg Med. 2019 Mar;56(3):301-307

Authors: Sin B, Jeffrey I, Halpern Z, Adebayo A, Wing T, Lee AS, Ruiz J, Persaud K, Davenport L, de Souza S, Williams M

Abstract
BACKGROUND: Patients in the United States frequently seek medical attention in the emergency department (ED) to address their pain. The intranasal (i.n.) route provides a safe, effective, and painless alternative method of drug administration. Sufentanil is an inexpensive synthetic opioid with a high therapeutic index and rapid onset of action, making it an attractive agent for management of acute pain in the ED.
OBJECTIVE: The objective of our study was to evaluate the safety and efficacy of i.n. sufentanil as the primary analgesic for acute pain in the ED.
METHODS: This was a single-center, prospective, randomized, double-blind, double-dummy, controlled trial that evaluated the use of i.n. sufentanil 0.7 μg/kg via mucosal atomizer device vs. intravenous morphine 0.1 mg/kg in adult patients who presented to the ED with acute pain. The primary outcome was patient's pain score at 10 min after administration of intervention. Secondary outcomes were adverse events, the need for rescue analgesia, and patient satisfaction after treatment.
RESULTS: Thirty patients were enrolled in each group. There was no significant difference in pain scores at 10 min after administration of intervention (sufentanil: 2.0, interquartile range = 2.0-3.3 vs. morphine: 3.0, interquartile range = 2.0-5.3, p = 0.198). No serious adverse events were reported. Rescue analgesia was not requested in either group. No significant difference in median satisfaction scores was found.
CONCLUSION: The use of i.n. sufentanil at 0.7 μg/kg/dose resulted in rapid and safe analgesia with comparable efficacy to i.v. morphine for up to 30 min in patients who presented with acute pain in the ED.

PMID: 30638644 [PubMed - indexed for MEDLINE]

A Pilot Study Identifying Brain-Targeting Adaptive Immunity in Pediatric Extracorporeal Membrane Oxygenation Patients With Acquired Brain Injury.

Crit Care Med. 2019 03;47(3):e206-e213

Authors: Ortega SB, Pandiyan P, Windsor J, Torres VO, Selvaraj UM, Lee A, Morriss M, Tian F, Raman L, Stowe AM

Abstract
OBJECTIVES: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury.
DESIGN: A single center prospective observational study.
SETTING: Pediatric and cardiac ICUs at a single tertiary care, academic center.
PATIENTS: Twenty pediatric extracorporeal membrane oxygenation patients (0-14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients INTERVENTIONS:: None.
MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10-23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation.
CONCLUSIONS: We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS.

PMID: 30640221 [PubMed - indexed for MEDLINE]

Creation across culture: Children's tool innovation is influenced by cultural and developmental factors.

Dev Psychol. 2019 Apr;55(4):877-889

Authors: Neldner K, Redshaw J, Murphy S, Tomaselli K, Davis J, Dixson B, Nielsen M

Abstract
Prior research suggests that human children lack an aptitude for tool innovation. However, children's tool making must be explored across a broader range of tasks and across diverse cultural contexts before we can conclude that they are genuinely poor tool innovators. To this end, we investigated children's ability to independently construct 3 new tools using distinct actions: adding, subtracting, and reshaping. We tested 422 children across a broad age range from 5 geographic locations across South Africa (N = 126), Vanuatu (N = 190), and Australia (N = 106), which varied in their levels of exposure to Westernized culture. Children were shown a horizontal, transparent tube that had a sticker in its middle. Children were sequentially given each incomplete tool, which when accurately constructed could be used to push the sticker out of the tube. As predicted, older children were better at performing the innovation tasks than younger children across all cultures and innovation actions. We also found evidence for cultural variation: While all non-Western groups performed similarly, the Western group of children innovated at higher rates. However, children who did not innovate often adopted alternate methods when using the tools that also led to success. This suggests that children's innovation levels are influenced by the cultural environment, and highlights the flexibility inherent in human children's tool use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

PMID: 30640502 [PubMed - indexed for MEDLINE]

Moving from late to early stage disease: lessons learned from erlotinib in pancreatic cancer.

Hepatobiliary Surg Nutr. 2018 Oct;7(5):406-408

Authors: Ko AH

PMID: 30498720 [PubMed]

Long-term therapeutic effect of cell therapy on improvement in erectile function in a rat model with pelvic neurovascular injury.

BJU Int. 2019 07;124(1):145-154

Authors: Gu X, Shi H, Matz E, Zhong L, Long T, Clouse C, Li W, Chen D, Chung H, Murphy S, Yoo J, Lin G, Lue T, Atala A, Jackson J, Zhang Y

Abstract
OBJECTIVE: To determine the long-term therapeutic effect amongst three human cell types on erectile function recovery in a rat model of dual neurovascular-injury erectile dysfunction (NVED).
MATERIALS AND METHODS: A dual NVED model was established in athymic rats by crushing the bilateral cavernous nerves and ligating the bilateral internal pudendal neurovascular bundles. At the time of defect creation, three different types of human cell populations (2.5 × 106  cells/0.2 mL: umbilical vein endothelial cells, adipose-derived stem cells, and amniotic fluid-derived stem cells) were injected intracavernously into the penile tissue. Saline injection (0.2 mL) served as a control group. Erectile function and histomorphological analyses of penile tissues were assessed 12 weeks after defect creation and cell or saline injection.
RESULTS: The ratio of intracavernous pressure to mean arterial pressure (functional indicator) was significantly higher in the cell therapy groups compared to the saline-injected control group (P < 0.05). Immunofluorescence staining showed more cells expressing biomarkers of endothelial, smooth muscle, and nerve cells within the penile tissue in the cell therapy groups when compared to the control group.
CONCLUSIONS: Cell therapy enhanced erectile function and ameliorated the histological changes 12 weeks after pelvic neurovascular injury in vivo, indicating that cell therapy may improve the long-term outcomes in neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED.

PMID: 30499626 [PubMed - indexed for MEDLINE]

Wearable Activity Technology And Action-Planning (WATAAP) to promote physical activity in cancer survivors: Randomised controlled trial protocol.

Int J Clin Health Psychol. 2018 May-Aug;18(2):124-132

Authors: Maxwell-Smith C, Cohen PA, Platell C, Tan P, Levitt M, Salama P, Makin GB, Tan J, Salfinger S, Kader Ali Mohan GR, Kane RT, Hince D, Jiménez-Castuera R, Hardcastle SJ

Abstract
Background/Objective: Colorectal and gynecologic cancer survivors are at cardiovascular risk due to comorbidities and sedentary behaviour, warranting a feasible intervention to increase physical activity. The Health Action Process Approach (HAPA) is a promising theoretical framework for health behaviour change, and wearable physical activity trackers offer a novel means of self-monitoring physical activity for cancer survivors. Method: Sixty-eight survivors of colorectal and gynecologic cancer will be randomised into 12-week intervention and control groups. Intervention group participants will receive: a Fitbit Alta™ to monitor physical activity, HAPA-based group sessions, booklet, and support phone-call. Participants in the control group will only receive the HAPA-based booklet. Physical activity (using accelerometers), blood pressure, BMI, and HAPA constructs will be assessed at baseline, 12-weeks (post-intervention) and 24-weeks (follow-up). Data analysis will use the Group x Time interaction from a General Linear Mixed Model analysis. Conclusions: Physical activity interventions that are acceptable and have robust theoretical underpinnings show promise for improving the health of cancer survivors.

PMID: 30487917 [PubMed]

Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma.

Sci Rep. 2018 01 19;8(1):1180

Authors: Connolly NP, Shetty AC, Stokum JA, Hoeschele I, Siegel MB, Miller CR, Kim AJ, Ho CY, Davila E, Simard JM, Devine SE, Rossmeisl JH, Holland EC, Winkles JA, Woodworth GF

Abstract
Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.

PMID: 29352201 [PubMed - indexed for MEDLINE]

A Randomized Study of Exercise and Fitness Trackers in Obese Patients After Total Knee Arthroplasty.

Orthop Clin North Am. 2019 Jan;50(1):35-45

Authors: Smith WA, Zucker-Levin A, Mihalko WM, Williams M, Loftin M, Gurney JG

Abstract
Functional limitations persist in obese patients after total knee arthroplasty (TKA). This study assessed the effect of an exercise program (EP) and fitness trackers (FT) in obese patients with TKA. Sixty patients 1 year after orthopedic surgery were recruited and received a 16-week tailored EP; half were randomized to receive an FT. FT had no measurable effect compared with EP alone. EP improved knee range of motion, strength, and quality-of-life scores. This study provides preliminary evidence that a 16-week EP in obese individuals 1 year post TKA is feasible and effective in improving function and quality of life.

PMID: 30477705 [PubMed - in process]

β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions.

Nat Commun. 2017 02 01;8:14295

Authors: Zhu L, Almaça J, Dadi PK, Hong H, Sakamoto W, Rossi M, Lee RJ, Vierra NC, Lu H, Cui Y, McMillin SM, Perry NA, Gurevich VV, Lee A, Kuo B, Leapman RD, Matschinsky FM, Doliba NM, Urs NM, Caron MG, Jacobson DA, Caicedo A, Wess J

Abstract
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.

PMID: 28145434 [PubMed - indexed for MEDLINE]

The Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in severe traumatic brain injury: a single-centre hybrid implementation and effectiveness study.

Lancet Child Adolesc Health. 2019 01;3(1):23-34

Authors: Vavilala MS, King MA, Yang JT, Erickson SL, Mills B, Grant RM, Blayney C, Qiu Q, Chesnut RM, Jaffe KM, Weiner BJ, Johnston BD

Abstract
BACKGROUND: As far as we know, there are no tested in-hospital care programmes for paediatric traumatic brain injury. We aimed to assess implementation and effectiveness of the Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in children with severe traumatic brain injury.
METHODS: We did a prospective hybrid implementation and effectiveness study at the Harborview Medical Center (Seattle, WA, USA). We included children (aged <18 years) with traumatic brain injury (trauma mechanism and image findings). We assessed service provision, adherence to three key performance indicators, and discharge outcomes associated with the PEGASUS programme. The three key performance indicators were early initiation of enteral (oral or tube feeds) or parenteral nutrition; avoidance of any unwanted hypocarbia (PaCO2 <30 mm Hg) without brain herniation; and maintenance of cerebral perfusion pressure (>40 mm Hg) for 72 h after the diagnosis of severe traumatic brain injury. Poisson regression with robust standard errors was used to estimate the association between adhering to key performance indicators and discharge outcomes.
FINDINGS: Between May 1, 2011, and July 1, 2017, 199 children (median age 11·9 years [IQR 3·4-16·1]) participated in the PEGASUS programme, of whom 193 (97%) had severe traumatic brain injury and six (3%) had moderate traumatic brain injury. 105 patients contributed data for all three key performance indicators. Adherence to at least one key performance indicator was achieved by 101 (96%) of 105 participants, and 44 (42%) achieved adherence to all three key performance indicators. Programme participants achieved adherence to the key performance indicators of hypocarbia (76 of 105 [72%]), nutrition (162 of 199 [81%]), and cerebral perfusion pressure (128 of 199 [64%]). Adherence to the nutrition key performance indicator was associated with higher discharge survival (relative risk [RR] 2·70, 95% CI 1·54-4·73) and a more favourable discharge disposition (3·05, 1·52-6·11). Adherence to the cerebral perfusion pressure key performance indicator was also associated with higher discharge survival (RR 1·33, 95% CI 1·12-1·59) and favourable disposition (1·53, 1·19-1·96). Adherence to each additional key performance indicator was associated with higher survival (RR 1·27, 1·12-1·44) and a more favourable discharge disposition (1·46, 1·23-1·72), in a dose-response manner.
INTERPRETATION: The multilevel, hospital-wide, high-fidelity PEGASUS programme might benefit children and adolescents admitted to the emergency department with severe traumatic brain injury. Cerebral perfusion pressure, nutrition, and hypocarbia targets are essential components of the PEGASUS programme and are associated with favourable discharge outcomes.
FUNDING: National Institutes of Health.

PMID: 30473440 [PubMed - indexed for MEDLINE]

Importance of neuropsychological screening in physicians referred for performance concerns.

PLoS One. 2018;13(11):e0207874

Authors: Williams BW, Flanders P, Welindt D, Williams MV

Abstract
INTRODUCTION: The literature suggests that 6-12% of practicing physicians are dyscompetent. Dyscompetence can manifest as failures in direct provision of care, but also issues with interpersonal and communications skills and professionalism. There is a growing literature suggesting the value of neurocognitive screening in physicians with clinical competency issues. The contribution of such screening in physicians with workplace behavioral issues is not as established. The aim of this exploratory study was to examine patterns of performance on a commonly used neuropsychological screening instrument. Performances differences, if present, could have implications for remediation and/or monitoring.
METHODS: Published data on a computerized neurocognitive screening instrument (MicroCog) for normative physician samples, published data on physicians referred for clinical competency issues, and newly collected data on physicians with workplace behavioral issues were analyzed. A two-way analysis of variance (Sample X Index) and post-hoc paired comparisons were conducted. A second analysis was performed employing an aggregated estimate of normative physician performance.
RESULTS: Results revealed a significant main effect for Sample and Index and a significant interaction effect. The second analysis of variance employing the pooled samples (Sample X Index) was conducted. The workplace behavior issues sample differed significantly from each of the samples. The Sample by Index interaction was significant.
DISCUSSION: Significant differences in performance on a neurocognitive screening instrument were found between non-referred physicians and physicians with behavioral or medical/technical competency concerns. Those with workplace behavioral issues performed significantly better than those with medical/technical issues, but significantly worse than non-referred physicians. Using these findings, 2.0% of the normal sample versus 35.1% of the medical/technical sample, and 10.9% of the behavioral sample would fail the screen using typical, conservative cutoffs. Further study of the potential role of neurocognitive factors in physicians referred for behavioral comportment issues is warranted.

PMID: 30475869 [PubMed - in process]

Reconstructing patient-specific cerebral aneurysm vasculature for in vitro investigations and treatment efficacy assessments.

J Clin Neurosci. 2019 Mar;61:153-159

Authors: Chivukula VK, Levitt MR, Clark A, Barbour MC, Sansom K, Johnson L, Kelly CM, Geindreau C, Rolland du Roscoat S, Kim LJ, Aliseda A

Abstract
Perianeurysmal hemodynamics play a vital role in the initiation, growth and rupture of intracranial aneurysms. In vitro investigations of aneurysmal hemodynamics are helpful to visualize and measure blood flow, and aiding surgical planning approaches. Improving in vitro model creation can improve the feasibility and accuracy of hemodynamic investigations and surgical planning, improving clinical value. In this study, in vitro models were created from three-dimensional rotational angiography (3DRA) of six patients harboring intracranial aneurysms using a multi-step process involving 3D printing, index of refraction matching and silicone casting that renders the models transparent for flow visualization. Each model was treated with the same commercially-available, patient-specific, endovascular devices (coils and/or stents). All models were scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the vessel lumen, aneurysmal sac and endovascular devices. Dimensional accuracy was compared by quantifying the differences between the microtomographic reconstructions of the fabricated phantoms and the original 3DRA obtained during patient treatment. True-scale in vitro flow phantoms were successfully created for all six patients. Optical transparency was verified by using an index of refraction matched working fluid that replicated the mechanical behavior of blood. Synchrotron imaging of vessel lumen, aneurysmal sac and endovascular devices was successfully obtained, and dimensional errors were found to be O(100 μm). The creation of dimensionally-accurate, optically-transparent flow phantoms of patient-specific intracranial aneurysms is feasible using 3D printing technology. Such models may enable in vitro investigations of aneurysmal hemodynamics to aid in treatment planning and outcome prediction to devise optimal patient-specific neurointerventional strategies.

PMID: 30470652 [PubMed - indexed for MEDLINE]

Exploiting induced pluripotent stem cell-derived macrophages to unravel host factors influencing Chlamydia trachomatis pathogenesis.

Nat Commun. 2017 04 25;8:15013

Authors: Yeung ATY, Hale C, Lee AH, Gill EE, Bushell W, Parry-Smith D, Goulding D, Pickard D, Roumeliotis T, Choudhary J, Thomson N, Skarnes WC, Dougan G, Hancock REW

Abstract
Chlamydia trachomatis remains a leading cause of bacterial sexually transmitted infections and preventable blindness worldwide. There are, however, limited in vitro models to study the role of host genetics in the response of macrophages to this obligate human pathogen. Here, we describe an approach using macrophages derived from human induced pluripotent stem cells (iPSdMs) to study macrophage-Chlamydia interactions in vitro. We show that iPSdMs support the full infectious life cycle of C. trachomatis in a manner that mimics the infection of human blood-derived macrophages. Transcriptomic and proteomic profiling of the macrophage response to chlamydial infection highlighted the role of the type I interferon and interleukin 10-mediated responses. Using CRISPR/Cas9 technology, we generated biallelic knockout mutations in host genes encoding IRF5 and IL-10RA in iPSCs, and confirmed their roles in limiting chlamydial infection in macrophages. This model can potentially be extended to other pathogens and tissue systems to advance our understanding of host-pathogen interactions and the role of human genetics in influencing the outcome of infections.

PMID: 28440293 [PubMed - indexed for MEDLINE]

Diagnostic challenges of prolonged post-treatment clearance of Plasmodium nucleic acids in a pre-transplant autosplenectomized patient with sickle cell disease.

Malar J. 2018 01 10;17(1):23

Authors: Luethy PM, Murphy SC, Seilie AM, Xie YL, Lau CY, Tisdale JF, Hsieh MM, Reinhardt JL, Lau AF, Fahle GA

Abstract
BACKGROUND: Autosplenectomy, as a result of sickle cell disease, is an important risk factor for severe malaria. While molecular methods are helpful in providing rapid and accurate infection detection and species identification, the effect of hyposplenism on result interpretation during the course of infection should be carefully considered.
CASE PRESENTATION: A 32-year old autosplenectomized Nigerian male with severe sickle cell disease was referred to the National Institutes of Health for allogenic hematopoietic stem cell transplant. Despite testing negative for malaria by both smear and PCR 2 weeks after arrival in the USA, the patient developed fever and diffuse bilateral lower rib cage and upper abdominal pain 2 weeks later and subsequently tested positive for Plasmodium falciparum. Parasitaemia was tracked over time by microscopy and nucleic acid tests to evaluate the therapeutic response in the setting of hyposplenism. The patient showed prompt resolution of patent infection by microscopy but remained positive by molecular methods for > 30 days after treatment initiation.
CONCLUSION: While molecular testing can provide sensitive Plasmodium nucleic acid detection, the persistence of Plasmodium nucleic acids following adequate treatment in functionally asplenic patients can lead to a diagnostic dilemma. In such patients, clinical response and peripheral blood smears should guide patient management following treatment. Nonetheless, in pre-transplant patients at high-risk for pre-existing Plasmodium infections, highly sensitive molecular assays can be useful to rule out infection prior to transplantation.

PMID: 29321025 [PubMed - indexed for MEDLINE]