UW Neurological Surgery Recent PubMed Publications

Enhancing Medical Students' Interprofessional Teamwork Through Simulated Room of Errors Experience.

J Surg Res. 2020 07;251:137-145

Authors: Turrentine FE, Schroen AT, Hallowell PT, Quatrara BA, Smith PW, Williams MD, Haizlip JA

Abstract
BACKGROUND: Fostering medical students' appreciation for team members particularly those from other disciplines with varying levels of experience promotes a promising beginning to a health care career.
METHODS: During surgical clerkship orientation, third-year medical students completed 30-item TeamSTEPPS Teamwork Attitudes Questionnaire preintervention and postintervention, spent 7 min identifying errors in a simulated operating room, followed by recorded physician-led 30-min discussions.
RESULTS: Postintervention (67) compared with preintervention (141) mean TeamSTEPPS Teamwork Attitudes Questionnaire domain scores were statistically significantly higher for team structure (4.59, 4.70; P = 0.03) and higher but not significant for leadership (4.74, 4.75; P = 0.86), situation monitoring (4.62, 4.68; P = 0.32), communication (4.40, 4.50; P = 0.14), and decreased for mutual support (4.43, 4.36; P = 0.43). Medical students identified 2%-93% of 33 staged errors and 291 additional errors, which were placed into 14 categories. Soiled gloves in the operative field and urinary bag on the floor were the most frequently identified staged errors. Experienced nurses compared with medical students identified significantly more errors (mean, 17.7 versus 11.7, respectively; P < 0.001). Recognizing errors when lacking familiarity with the operative environment and appreciating teammates' perspectives were themes that emerged from discussions.
CONCLUSIONS: This well-received teamwork exercise enabled medical students to appreciate team members' contributions and other disciplines' perspectives, in addition to the synergy that occurs with multidisciplinary teams.

PMID: 32143058 [PubMed - indexed for MEDLINE]

Interplay of Staphylococcal and Host Proteases Promotes Skin Barrier Disruption in Netherton Syndrome.

Cell Rep. 2020 Mar 03;30(9):2923-2933.e7

Authors: Williams MR, Cau L, Wang Y, Kaul D, Sanford JA, Zaramela LS, Khalil S, Butcher AM, Zengler K, Horswill AR, Dupont CL, Hovnanian A, Gallo RL

Abstract
Netherton syndrome (NS) is a monogenic skin disease resulting from loss of function of lymphoepithelial Kazal-type-related protease inhibitor (LEKTI-1). In this study we examine if bacteria residing on the skin are influenced by the loss of LEKTI-1 and if interaction between this human gene and resident bacteria contributes to skin disease. Shotgun sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). Isolates of either species from NS subjects are able to induce skin inflammation and barrier damage on mice. These microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. These findings demonstrate the critical need for maintaining homeostasis of host and microbial proteases to prevent a human skin disease.

PMID: 32130897 [PubMed - in process]

Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy.

Cancer Cytopathol. 2020 07;128(7):491-498

Authors: Williams MPA, Kukkar V, Stemmer MN, Khurana KK

Abstract
BACKGROUND: The cervical cancer screening recommendation for transgender female-to-male (FTM) patients is the same as that for cisgender females. A lack of literature on testosterone-induced changes in cervical cytology in these patients may result in interpretation errors, especially without a proper clinical history. The aim of this study was to delineate the Papanicolaou (Pap) test findings in this patient population.
METHODS: A pathology laboratory information system was used to obtain a cohort of FTM transgender patients on testosterone therapy (2009-2019). A cohort of age-matched, atrophic, control cisgender female patients (postpartum or menopausal) was selected. A retrospective review of the cytomorphologic findings on cervical Pap smears, pertinent follow-up, and human papillomavirus (HPV) test results was performed.
RESULTS: Fourteen transgender patients (age range, 21-64 years; mean age, 42.5 years) receiving testosterone therapy with 17 Pap smears were identified. One of the 5 available HPV tests was positive for HPV, and 4 were negative. A Pap smear review revealed the following: negative for intraepithelial lesion (NILM; 82.4%), unsatisfactory (5.9%), atypical squamous cells of undetermined significance (ASCUS; 5.9%), and low-grade squamous intraepithelial lesion (5.9%). The Pap smears of the atrophic cisgender cohort (102 patients) revealed the following: NILM (92.5%), unsatisfactory (0.9%), ASCUS (5.6%), and high-grade squamous intraepithelial lesion (0.9%). The difference between the rates of epithelial cell abnormality in the 2 cohorts was not statistically significant. Although atrophy was noted in both groups, cytomorphologic findings of transitional cell metaplasia (TCM; 88.2%) and "small cells" (82.4%) were characteristic of the testosterone-treated transgender cohort. Histologic correlates of TCM and small cells were noted in hysterectomy specimens from 6 patients.
CONCLUSIONS: Small cells and TCM are common cytomorphologic findings in Pap smears of testosterone-treated transgender (FTM) patients. On the basis of histologic follow-up, small cells most likely represent atrophic parabasal cells of cervical-vaginal epithelium.

PMID: 32125771 [PubMed - indexed for MEDLINE]

Factors associated with syrinx size in pediatric patients treated for Chiari malformation type I and syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

J Neurosurg Pediatr. 2020 Mar 06;:1-11

Authors: Hale AT, Adelson PD, Albert GW, Aldana PR, Alden TD, Anderson RCE, Bauer DF, Bonfield CM, Brockmeyer DL, Chern JJ, Couture DE, Daniels DJ, Durham SR, Ellenbogen RG, Eskandari R, George TM, Grant GA, Graupman PC, Greene S, Greenfield JP, Gross NL, Guillaume DJ, Heuer GG, Iantosca M, Iskandar BJ, Jackson EM, Johnston JM, Keating RF, Leonard JR, Maher CO, Mangano FT, McComb JG, Meehan T, Menezes AH, O'Neill B, Olavarria G, Park TS, Ragheb J, Selden NR, Shah MN, Smyth MD, Stone SSD, Strahle JM, Wait SD, Wellons JC, Whitehead WE, Shannon CN, Limbrick DD, Park-Reeves Syringomyelia Research Consortium Investigators

Abstract
OBJECTIVE: Factors associated with syrinx size in pediatric patients undergoing posterior fossa decompression (PFD) or PFD with duraplasty (PFDD) for Chiari malformation type I (CM-I) with syringomyelia (SM; CM-I+SM) are not well established.
METHODS: Using the Park-Reeves Syringomyelia Research Consortium registry, the authors analyzed variables associated with syrinx radiological outcomes in patients (< 20 years old at the time of surgery) with CM-I+SM undergoing PFD or PFDD. Syrinx resolution was defined as an anteroposterior (AP) diameter of ≤ 2 mm or ≤ 3 mm or a reduction in AP diameter of ≥ 50%. Syrinx regression or progression was defined using 1) change in syrinx AP diameter (≥ 1 mm), or 2) change in syrinx length (craniocaudal, ≥ 1 vertebral level). Syrinx stability was defined as a < 1-mm change in syrinx AP diameter and no change in syrinx length.
RESULTS: The authors identified 380 patients with CM-I+SM who underwent PFD or PFDD. Cox proportional hazards modeling revealed younger age at surgery and PFDD as being independently associated with syrinx resolution, defined as a ≤ 2-mm or ≤ 3-mm AP diameter or ≥ 50% reduction in AP diameter. Radiological syrinx resolution was associated with improvement in headache (p < 0.005) and neck pain (p < 0.011) after PFD or PFDD. Next, PFDD (p = 0.005), scoliosis (p = 0.007), and syrinx location across multiple spinal segments (p = 0.001) were associated with syrinx diameter regression, whereas increased preoperative frontal-occipital horn ratio (FOHR; p = 0.007) and syrinx location spanning multiple spinal segments (p = 0.04) were associated with syrinx length regression. Scoliosis (HR 0.38 [95% CI 0.16-0.91], p = 0.03) and smaller syrinx diameter (5.82 ± 3.38 vs 7.86 ± 3.05 mm; HR 0.60 [95% CI 0.34-1.03], p = 0.002) were associated with syrinx diameter stability, whereas shorter preoperative syrinx length (5.75 ± 4.01 vs 9.65 ± 4.31 levels; HR 0.21 [95% CI 0.12-0.38], p = 0.0001) and smaller pB-C2 distance (6.86 ± 1.27 vs 7.18 ± 1.38 mm; HR 1.44 [95% CI 1.02-2.05], p = 0.04) were associated with syrinx length stability. Finally, younger age at surgery (8.19 ± 5.02 vs 10.29 ± 4.25 years; HR 1.89 [95% CI 1.31-3.04], p = 0.01) was associated with syrinx diameter progression, whereas increased postoperative syrinx diameter (6.73 ± 3.64 vs 3.97 ± 3.07 mm; HR 3.10 [95% CI 1.67-5.76], p = 0.003), was associated with syrinx length progression. PFD versus PFDD was not associated with syrinx progression or reoperation rate.
CONCLUSIONS: These data suggest that PFDD and age are independently associated with radiological syrinx improvement, although forthcoming results from the PFDD versus PFD randomized controlled trial (NCT02669836, clinicaltrials.gov) will best answer this question.

PMID: 32114543 [PubMed - as supplied by publisher]

[Clinical practice guideline of integrated traditional Chinese and western medicine：atlantoaxial dislocation (AAD) (2019)].

Zhongguo Gu Shang. 2020 Jan 25;33(1):27-37

Authors: Professional Committee of Spine Medicine of Chinese Association of Integrated Traditional and Western Medicine, Tan MS, Atul G, Kuniyoshi A, Zhang F, Dong FH, Hao DJ, Zhao Y

Abstract
EDITOR'S NOTE: EDITOR'S NOTE In 2019, the clinical practice guideline of integrated traditional Chinese and western medicine atlantoaxial dislocation (ADD) was developed by the professional committee of spine medicine of the Chinese Association for Integration of Chinese and Western medicine, aiming at the major clinical problems of atlantoaxial dislocation (AAD) endangering the life center of the medulla oblongata in the field of spine surgery. More than 40 experts at home and abroad in the field of cervical spine surgery organized the first guide for the diagnosis and treatment of AAD. Guided by the principles of evidence based medicine and the consensus of experts, this guideline is based on the theory of "combination of disease and syndrome, from supervision to treatment" for the diagnosis and treatment of AAD；based on the treatment principles of "spinal cord decompression, reconstruction of atlantoaxial stability"；based on Tan technology, Goel technology, Abumi technology and other core technologies for surgical treatment. The main content includes four parts：AAD diagnosis standard, TCM syndrome differentiation, clinical classification, treatment strategy and method. It provides academic guidance to solve the clinical situation of AAD, which is "unclear definition of diagnosis and classification, confused choice of treatment strategy".
ABSTRACT: Clinical Practice Guideline of Integrated Traditional Chinese and Western Medicine：Atlantoaxial Dislocation (AAD) was enacted by the academic committee of spine surgery of integrated traditional Chinese and Western medicine. The guideline's recommendations forms by evidence-based medicine and the expert consensus of Integrative Medicine. The guidement principles is "spinal cord decompression, reconstruction of atlantoaxial stability". The objective of the guideline is providing an academic suggestion. The main contents include diagnostic criteria, traditional Chinese medicine's (TCM) dialectical method, clinical classification, treatment strategies and methods.

PMID: 32115921 [PubMed - indexed for MEDLINE]

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

Eur Heart J. 2020 Feb 29;:

Authors: Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, Zlotoff DA, Murphy SP, Stone JR, Golden DLA, Alvi RM, Rokicki A, Jones-O'Connor M, Cohen JV, Heinzerling LM, Mulligan C, Armanious M, Barac A, Forrestal BJ, Sullivan RJ, Kwong RY, Yang EH, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Coelho-Filho OR, Ganatra S, Rizvi MA, Sahni G, Tocchetti CG, Mercurio V, Mahmoudi M, Lawrence DP, Reynolds KL, Weinsaft JW, Baksi AJ, Ederhy S, Groarke JD, Lyon AR, Fradley MG, Thavendiranathan P, Neilan TG

Abstract
AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.
METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.
CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

PMID: 32112560 [PubMed - as supplied by publisher]

Patient and Treatment Characteristics by Infecting Organism in Cerebrospinal Fluid Shunt Infection.

J Pediatric Infect Dis Soc. 2019 Jul 01;8(3):235-243

Authors: Simon TD, Kronman MP, Whitlock KB, Browd SR, Holubkov R, Kestle JRW, Kulkarni AV, Langley M, Limbrick DD, Luerssen TG, Oakes J, Riva-Cambrin J, Rozzelle C, Shannon CN, Tamber M, Wellons Iii JC, Whitehead WE, Mayer-Hamblett N, Hydrocephalus Clinical Research Network

Abstract
BACKGROUND: Previous studies of cerebrospinal fluid (CSF) shunt infection treatment have been limited in size and unable to compare patient and treatment characteristics by infecting organism. Our objective was to describe variation in patient and treatment characteristics for children with first CSF shunt infection, stratified by infecting organism subgroups outlined in the 2017 Infectious Disease Society of America's (IDSA) guidelines.
METHODS: We studied a prospective cohort of children <18 years of age undergoing treatment for first CSF shunt infection at one of 7 Hydrocephalus Clinical Research Network hospitals from April 2008 to December 2012. Differences between infecting organism subgroups were described using univariate analyses and Fisher's exact tests.
RESULTS: There were 145 children whose infections were diagnosed by CSF culture and addressed by IDSA guidelines, including 47 with Staphylococcus aureus, 52 with coagulase-negative Staphylococcus, 37 with Gram-negative bacilli, and 9 with Propionibacterium acnes. No differences in many patient and treatment characteristics were seen between infecting organism subgroups, including age at initial shunt, gender, race, insurance, indication for shunt, gastrostomy, tracheostomy, ultrasound, and/or endoscope use at all surgeries before infection, or numbers of revisions before infection. A larger proportion of infections were caused by Gram-negative bacilli when antibiotic-impregnated catheters were used at initial shunt placement (12 of 23, 52%) and/or subsequent revisions (11 of 23, 48%) compared with all other infections (9 of 68 [13%] and 13 of 68 [19%], respectively). No differences in reinfection were observed between infecting organism subgroups.
CONCLUSIONS: The organism profile encountered at infection differs when antibiotic-impregnated catheters are used, with a higher proportion of Gram-negative bacilli. This warrants further investigation given increasing adoption of antibiotic-impregnated catheters.

PMID: 29771360 [PubMed - indexed for MEDLINE]

The Discrepancy Between Cognitive Complaints and Neuropsychological Test Findings in Persons With Traumatic Brain Injury.

J Head Trauma Rehabil. 2020 Feb 26;:

Authors: Vos L, Williams MW, Poritz JMP, Ngan E, Leon-Novelo L, Sherer M

Abstract
OBJECTIVE: To better identify variables related to discrepancies between subjective cognitive complaints and objective neuropsychological findings in persons with traumatic brain injury (TBI).
SETTING: Three rehabilitation centers in the United States.
PARTICIPANTS: In total, 504 community-dwelling adult survivors of TBI following discharge from inpatient rehabilitation.
DESIGN: Prospective cohort observation study.
MAIN MEASURES: Wechsler Adult Intelligence Scale, Fourth Edition, Digit Span; Rey Auditory Verbal Learning Test; Trail Making Test, Part B; Word Memory Test; Patient Health Questionnaire-9; Neurobehavioral Symptom Inventory; TBI-Quality of Life item bank.
RESULTS: Statistical analyses revealed multiple factors associated with subjective-objective discrepancies in attention, memory, and executive functions. Depression was consistently associated with underestimation of cognitive abilities. However, subjective-objective discrepancies varied by cognitive domains in regard to other factors related to underestimation and overestimation of abilities.
CONCLUSIONS: Reconciling and interpreting subjective-objective discrepancies regarding cognitive functions following TBI are important tasks for case conceptualization and treatment planning. Depression is an important patient characteristic to consider when discrepancy patterns indicate underestimation of cognitive abilities. This study highlights the importance of assessing mood, a modifiable patient characteristic, with self-report symptom inventories. Future studies are needed to connect these findings with TBI outcomes.

PMID: 32108707 [PubMed - as supplied by publisher]

Intraoperative electrophysiology during single-level selective dorsal rhizotomy: technique, stimulation threshold, and response data in a series of 145 patients.

J Neurosurg Pediatr. 2020 Feb 28;:1-10

Authors: De Vloo P, Huttunen TJ, Forte D, Jankovic I, Lee A, Hair M, Cawker S, Chugh D, Carr L, Crowe BHA, Pitt M, Aquilina K

Abstract
OBJECTIVE: Selective dorsal rhizotomy (SDR) is effective at permanently reducing spasticity in children with spastic cerebral palsy. The value of intraoperative neurophysiological monitoring in this procedure remains controversial, and its robustness has been questioned. This study describes the authors' institutional electrophysiological technique (based on the technique of Park et al.), intraoperative findings, robustness, value to the procedure, and occurrence of new motor or sphincter deficits.
METHODS: The authors analyzed electrophysiological data of all children who underwent SDR at their center between September 2013 and February 2019. All patients underwent bilateral SDR through a single-level laminotomy at the conus and with transection of about 60% of the L2-S2 afferent rootlets (guided by intraoperative electrophysiology) and about 50% of L1 afferent roots (nonselectively).
RESULTS: One hundred forty-five patients underwent SDR (64% male, mean age 6 years and 7 months, range 2 years and 9 months to 14 years and 10 months). Dorsal roots were distinguished from ventral roots anatomically and electrophysiologically, by assessing responses on free-running electromyography (EMG) and determining stimulation thresholds (≥ 0.2 mA in all dorsal rootlets). Root level was determined anatomically and electrophysiologically by assessing electromyographic response to stimulation. Median stimulation threshold was lower in sacral compared to lumbar roots (p < 0.001), and 16% higher on the first operated (right) side (p = 0.023), but unrelated to age, sex, or functional status. Similarly, responses to tetanic stimulation were consistent: 87% were graded 3+ or 4+, with similar distributions between sides. This was also unrelated to age, sex, and functional status. The L2-S2 rootlets were divided (median 60%, range 50%-67%), guided by response to tetanic stimulation at threshold amplitude. No new motor or sphincter deficits were observed, suggesting sparing of ventral roots and sphincteric innervation, respectively.
CONCLUSIONS: This electrophysiological technique appears robust and reproducible, allowing reliable identification of afferent nerve roots, definition of root levels, and guidance for rootlet division. Only a direct comparative study will establish whether intraoperative electrophysiology during SDR minimizes risk of new motor or sphincter worsening and/or maximizes functional outcome.

PMID: 32109863 [PubMed - as supplied by publisher]

Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma.

Sci Transl Med. 2020 Feb 26;12(532):

Authors: Huang M, Zhang D, Wu JY, Xing K, Yeo E, Li C, Zhang L, Holland E, Yao L, Qin L, Binder ZA, O'Rourke DM, Brem S, Koumenis C, Gong Y, Fan Y

Abstract
Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces β-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.

PMID: 32102932 [PubMed - in process]

Signal recovery from stimulation artifacts in intracranial recordings with dictionary learning.

J Neural Eng. 2020 Feb 26;:

Authors: Caldwell DJ, Cronin J, Rao RPN, Collins K, Weaver K, Ko A, Ojemann JG, Kutz N, Brunton BW

Abstract
OBJECTIVE: Electrical stimulation of the human brain is commonly used for eliciting and inhibiting neural activity for clinical diagnostics, modifying abnormal neural circuit function for therapeutics, and interrogating cortical connectivity. However, recording electrical signals with concurrent stimulation results in dominant electrical artifacts that mask the neural signals of interest. Here we develop a method to reproducibly and robustly recover neural activity during concurrent stimulation. We concentrate on signal recovery across an array of electrodes without channel-wise fine-tuning of the algorithm. Our goal includes signal recovery with trains of stimulation pulses, since repeated, high-frequency pulses are often required to induce desired effects in both therapeutic and research domains. We have made all of our code and data publicly available.
APPROACH: We developed an algorithm that automatically detects templates of artifacts across many channels of recording, creating a dictionary of learned templates using unsupervised clustering. The artifact template that best matches each individual artifact pulse is subtracted to recover the underlying activity. To assess the success of our method, we focus on whether it extracts physiologically interpretable signals from real recordings.
MAIN RESULTS: We demonstrate our signal recovery approach on invasive electrophysiologic recordings from human subjects during stimulation. We show the recovery of meaningful neural signatures in both electrocorticographic (ECoG) arrays and deep brain stimulation (DBS) recordings. In addition, we compared cortical responses induced by the stimulation of primary somatosensory (S1) by natural peripheral touch, as well as motor cortex activity with and without concurrent S1 stimulation.
SIGNIFICANCE: Our work will enable future advances in neural engineering with simultaneous stimulation and recording.

PMID: 32103828 [PubMed - as supplied by publisher]

Drug compound screening in single and integrated multi-organoid body-on-a-chip systems.

Biofabrication. 2020 02 26;12(2):025017

Authors: Skardal A, Aleman J, Forsythe S, Rajan S, Murphy S, Devarasetty M, Pourhabibi Zarandi N, Nzou G, Wicks R, Sadri-Ardekani H, Bishop C, Soker S, Hall A, Shupe T, Atala A

Abstract
Current practices in drug development have led to therapeutic compounds being approved for widespread use in humans, only to be later withdrawn due to unanticipated toxicity. These occurrences are largely the result of erroneous data generated by in vivo and in vitro preclinical models that do not accurately recapitulate human physiology. Herein, a human primary cell- and stem cell-derived 3D organoid technology is employed to screen a panel of drugs that were recalled from market by the FDA. The platform is comprised of multiple tissue organoid types that remain viable for at least 28 days, in vitro. For many of these compounds, the 3D organoid system was able to demonstrate toxicity. Furthermore, organoids exposed to non-toxic compounds remained viable at clinically relevant doses. Additional experiments were performed on integrated multi-organoid systems containing liver, cardiac, lung, vascular, testis, colon, and brain. These integrated systems proved to maintain viability and expressed functional biomarkers, long-term. Examples are provided that demonstrate how multi-organoid 'body-on-a-chip' systems may be used to model the interdependent metabolism and downstream effects of drugs across multiple tissues in a single platform. Such 3D in vitro systems represent a more physiologically relevant model for drug screening and will likely reduce the cost and failure rate associated with the approval of new drugs.

PMID: 32101533 [PubMed - indexed for MEDLINE]

Mental Health Costs of Inflammatory Bowel Diseases.

Inflamm Bowel Dis. 2020 Feb 25;:

Authors: Szigethy E, Murphy SM, Ehrlich OG, Engel-Nitz NM, Heller CA, Henrichsen K, Lawton R, Meadows P, Allen JI

Abstract
BACKGROUND: Mental health diagnoses (MHDs) were identified as significant drivers of inflammatory bowel disease (IBD)-related costs in an analysis titled "Cost of Care Initiative" supported by the Crohn's & Colitis Foundation. In this subanalysis, we sought to characterize and compare IBD patients with and without MHDs based on insurance claims data in terms of demographic traits, medical utilization, and annualized costs of care.
METHODS: We analyzed the Optum Research Database of administrative claims from years 2007 to 2016 representing commercially insured and Medicare Advantage insured IBD patients in the United States. Inflammatory bowel disease patients with and without an MHD were compared in terms of demographics (age, gender, race), insurance type, IBD-related medical utilization (ambulatory visits, emergency department [ED] visits, and inpatient hospitalizations), and total IBD-related costs. Only patients with costs >$0 in each of the utilization categories were included in the cost estimates.
RESULTS: Of the total IBD study cohort of 52,782 patients representing 179,314 person-years of data, 22,483 (42.6%) patients had at least 1 MHD coded in their claims data with a total of 46,510 person-years in which a patient had a coded MHD. The most commonly coded diagnostic categories were depressive disorders, anxiety disorders, adjustment disorders, substance use disorders, and bipolar and related disorders. Compared with patients without an MHD, a significantly greater percentage of IBD patients with MHDs were female (61.59% vs 48.63%), older than 75 years of age (9.59% vs 6.32%), white (73.80% vs 70.17%), and significantly less likely to be younger than 25 years of age (9.18% vs 11.39%) compared with those without mental illness (P < 0.001). Patients with MHDs had significantly more ED visits (14.34% vs 7.62%, P < 0.001) and inpatient stays (19.65% vs 8.63%, P < 0.001) compared with those without an MHD. Concomitantly, patients with MHDs had significantly higher ED costs ($970 vs $754, P < 0.001) and inpatient costs ($39,205 vs $29,550, P < 0.001) compared with IBD patients without MHDs. Patients with MHDs also had significantly higher total annual IBD-related surgical costs ($55,693 vs $40,486, P < 0.001) and nonsurgical costs (medical and pharmacy) ($17,220 vs $11,073, P < 0.001), and paid a larger portion of the total out-of-pocket cost for IBD services ($1017 vs $905, P < 0.001).
CONCLUSION: Patients whose claims data contained both IBD-related and MHD-related diagnoses generated significantly higher costs compared with IBD patients without an MHD diagnosis. Based on these data, we speculate that health care costs might be reduced and the course of patients IBD might be improved if the IBD-treating provider recognized this link and implemented effective behavioral health screening and intervention as soon as an MHD was suspected during management of IBD patients. Studies investigating best screening and intervention strategies for MHDs are needed.

PMID: 32095835 [PubMed - as supplied by publisher]

Real-world experience with mechlorethamine gel in patients with mycosis fungoides-cutaneous lymphoma: Preliminary findings from a prospective observational study.

J Am Acad Dermatol. 2020 Feb 20;:

Authors: Kim EJ, Geskin L, Guitart J, Querfeld C, Girardi M, Musiek A, Mink DR, Williams MJ, Angello JT, Bailey WL

PMID: 32089294 [PubMed - as supplied by publisher]

The Modern Physical Exam - A Transatlantic Perspective from the Resident Level.

Teach Learn Med. 2020 Feb 24;:1-7

Authors: Jacobsen AP, Khiew YC, Murphy SP, Lane CM, Garibaldi BT

Abstract
Issue: The physical examination has been in decline for many years and poorer skills contribute to medical errors and adverse events. Diagnostic error is also increasing with the complexity of medicine. Comparing the physical examination in Ireland and the United States with a focus on education, assessment, culture, and health systems may provide insight into the decline of the physical exam in the United States, uncover possible strategies to improve clinical skills, and limit diagnostic error. Evidence: The physical exam is a core component of both undergraduate and postgraduate medical education in Ireland. This is reflected by the time and effort invested by medical schools and medical societies in Ireland in teaching and assessing skills. This high standard of skills results in the physical exam being a key component of the diagnostic process and a gatekeeper to expensive investigations essential in a resource-limited health system such as Ireland. Use of the physical exam in the United States is hindered by the high-tech transformation of healthcare and a more litigious society. Known strategies to highlight the role of the physical exam in clinical practice include creating an evidence base to show that better physical exam skills improve outcomes, identifying accurate physical exam maneuvers, stressing the therapeutic alliance the physical exam brings to the patient encounter, and the incorporation of technology into the bedside exam. Implications: Contrasting the education and clinical use of the physical examination in the United States with Ireland allowed us to identify a number of strategies which could be used to promote the physical exam among learners in both countries. Highlighting simple and pragmatic physical exam maneuvers combined with evidence-based physical exam diagnostic data may renew confidence in the physical exam as a core diagnostic tool. Use of the hypothesis-driven approach may streamline a clinician's physical exam during a patient encounter, focusing on the key examination components and avoiding unnecessary and low yield maneuvers. The absence of assessment of physical exam skills using real patients in United States licensing exams communicates to learners that these skills are not important. However, steps to introduce a culture of assessment to drive learning are being introduced. One area Ireland could learn from the United States is incorporating more technology into the bedside exam. Enhanced physical examination skills in both countries could reduce reliance on expensive investigations and improve diagnostic accuracy.

PMID: 32090631 [PubMed - as supplied by publisher]

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

Lancet. 2020 03 14;395(10227):878-887

Authors: Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Demchuk AM, Poppe AY, Buck BH, Field TS, Dowlatshahi D, van Adel BA, Swartz RH, Shah RA, Sauvageau E, Zerna C, Ospel JM, Joshi M, Almekhlafi MA, Ryckborst KJ, Lowerison MW, Heard K, Garman D, Haussen D, Cutting SM, Coutts SB, Roy D, Rempel JL, Rohr AC, Iancu D, Sahlas DJ, Yu AYX, Devlin TG, Hanel RA, Puetz V, Silver FL, Campbell BCV, Chapot R, Teitelbaum J, Mandzia JL, Kleinig TJ, Turkel-Parrella D, Heck D, Kelly ME, Bharatha A, Bang OY, Jadhav A, Gupta R, Frei DF, Tarpley JW, McDougall CG, Holmin S, Rha JH, Puri AS, Camden MC, Thomalla G, Choe H, Phillips SJ, Schindler JL, Thornton J, Nagel S, Heo JH, Sohn SI, Psychogios MN, Budzik RF, Starkman S, Martin CO, Burns PA, Murphy S, Lopez GA, English J, Tymianski M, ESCAPE-NA1 Investigators

Abstract
BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke.
METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018.
FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups.
INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo.
FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

PMID: 32087818 [PubMed - indexed for MEDLINE]

Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) Alterations in Low-Grade Gliomas: Report of a Novel Gene Fusion Partner in a Pilocytic Astrocytoma and Review of the Literature.

Case Rep Pathol. 2020;2020:5903863

Authors: Pattwell SS, Konnick EQ, Liu YJ, Yoda RA, Sekhar LN, Cimino PJ

Abstract
Pilocytic astrocytoma is a low-grade glial neoplasm of the central nervous system (CNS) that tends to occur in the pediatric population and less commonly presents in adults. Hereditary pilocytic astrocytoma is often associated with germline genetic alterations in the tumor suppressor NF1, the gene responsible for the syndrome neurofibromatosis type 1. Sporadic pilocytic astrocytoma frequently harbors somatic alterations in BRAF, with rare pilocytic astrocytomas containing alterations in FGFR1 and NTRK2. NTRK2 encodes for the protein tropomyosin receptor kinase B (TrkB), which is a neurotrophin receptor with high affinity for Brain-Derived Neurotrophic Factor (BDNF), and plays a role in several physiological functions of neurons, including cell survival and differentiation. In this report, we describe a novel PML-NTRK2 gene fusion occurring in an adult sporadic pilocytic astrocytoma and review the biology and implications of specific NTRK2 mutations occurring in CNS neoplasms.

PMID: 32082673 [PubMed]

Contrast-Enhanced Ultrasound for Assessment of Local Hemodynamic Changes Following a Rodent Contusion Spinal Cord Injury.

Mil Med. 2020 01 07;185(Suppl 1):470-475

Authors: Khaing ZZ, Cates LN, Hyde J, DeWees DM, Hammond R, Bruce M, Hofstetter CP

Abstract
INTRODUCTION: Severe trauma to the spinal cord leads to a near complete loss of blood flow at the injury site along with significant hypoperfusion of adjacent tissues. Characterization and monitoring of local tissue hypoperfusion is currently not possible in clinical practice because available imaging techniques do not allow for assessment of blood flow with sufficient spatial and temporal resolutions. The objective of the current study was to determine whether ultrafast contrast-enhanced ultrasound (CEUS) imaging could be used to visualize and quantify acute hemodynamic changes in a rat traumatic spinal cord injury (SCI) model.
MATERIALS AND METHODS: We used novel ultrasound acquisition and processing methods that allowed for measurements of local tissue perfusion as well as for assessment of structural and functional integrity of spinal vasculature.
RESULTS: CEUS imaging showed that traumatic SCI results in (1) an area with significant loss of perfusion, which increased during the first hour after injury, (2) structural alterations of the spinal cord vasculature, and (3) significant slowing of arterial blood flow velocities around the injury epicenter.
CONCLUSION: We conclude that CEUS has the spatial and temporal sensitivity and resolution to visualize local tissue perfusion and vessel architecture, which maybe useful clinically to determine injury extent and severity in patients with SCI.

PMID: 32074323 [PubMed - indexed for MEDLINE]

Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression.

Transl Psychiatry. 2020 Jan 16;10(1):6

Authors: Zoubovsky SP, Hoseus S, Tumukuntala S, Schulkin JO, Williams MT, Vorhees CV, Muglia LJ

Abstract
Postpartum depression (PPD) affects up to 20% of mothers and has negative consequences for both mother and child. Although exposure to psychosocial stress during pregnancy and abnormalities in the hypothalamic pituitary adrenal (HPA) axis have been linked to PPD, molecular changes in the brain that contribute to this disease remain unknown. This study utilized a novel chronic psychosocial stress paradigm during pregnancy (CGS) to investigate the effects of psychosocial stress on maternal behavior, neuroendocrine function, and gene expression changes in molecular regulators of the HPA axis in the early postpartum period. Postpartum female mice exposed to CGS display abnormalities in maternal behavior, including fragmented and erratic maternal care patterns, and the emergence of depression and anxiety-like phenotypes. Dysregulation in postpartum HPA axis function, evidenced by blunted circadian peak and elevation of stress-induced corticosterone levels, was accompanied by increased CRH mRNA expression and a reduction in CRH receptor 1 in the paraventricular nucleus of the hypothalamus (PVN). We further observed decreased PVN expression of nuclear steroid hormone receptors associated with CRH transcription, suggesting these molecular changes could underlie abnormalities in postpartum HPA axis and behavior observed. Overall, our study demonstrates that psychosocial stress during pregnancy induces changes in neuroendocrine function and maternal behavior in the early postpartum period and introduces our CGS paradigm as a viable model that can be used to further dissect the molecular defects that lead to PPD.

PMID: 32066677 [PubMed - in process]

Variability in estimated gene expression among commonly used RNA-seq pipelines.

Sci Rep. 2020 02 17;10(1):2734

Authors: Arora S, Pattwell SS, Holland EC, Bolouri H

Abstract
RNA-sequencing data is widely used to identify disease biomarkers and therapeutic targets using numerical methods such as clustering, classification, regression, and differential expression analysis. Such approaches rely on the assumption that mRNA abundance estimates from RNA-seq are reliable estimates of true expression levels. Here, using data from five RNA-seq processing pipelines applied to 6,690 human tumor and normal tissues, we show that nearly 88% of protein-coding genes have similar gene expression profiles across all pipelines. However, for >12% of protein-coding genes, current best-in-class RNA-seq processing pipelines differ in their abundance estimates by more than four-fold when applied to exactly the same samples and the same set of RNA-seq reads. Expression fold changes are similarly affected. Many of the impacted genes are widely studied disease-associated genes. We show that impacted genes exhibit diverse patterns of discordance among pipelines, suggesting that many inter-pipeline differences contribute to overall uncertainty in mRNA abundance estimates. A concerted, community-wide effort will be needed to develop gold-standards for estimating the mRNA abundance of the discordant genes reported here. In the meantime, our list of discordantly evaluated genes provides an important resource for robust marker discovery and target selection.

PMID: 32066774 [PubMed - indexed for MEDLINE]