UW Neurological Surgery Recent PubMed Publications

Transcutaneous spinal cord stimulation restores hand and arm function after spinal cord injury.

IEEE Trans Neural Syst Rehabil Eng. 2021 Jan 05;PP:

Authors: Inanici F, Brighton LN, Samejima S, Hofstetter CP, Moritz CT

Abstract
Paralysis of the upper extremity severely restricts independence and quality of life after spinal cord injury. Regaining control of hand and arm movements is the highest treatment priority for people with paralysis, 6-fold higher than restoring walking ability. Nevertheless, current approaches to improve upper extremity function typically do not restore independence. Spinal cord stimulation is an emerging neuromodulation strategy to restore motor function. Recent studies using surgically implanted electrodes demonstrate impressive improvements in voluntary control of standing and stepping. Here we show that transcutaneous electrical stimulation of the spinal cord leads to rapid and sustained recovery of hand and arm function, even after complete paralysis. Notably, the magnitude of these improvements matched or exceeded previously reported results from surgically implanted stimulation. Additionally, muscle spasticity was reduced and autonomic functions including heart rate, thermoregulation, and bladder function improved. Perhaps most striking is that all six participants maintained their gains for at least three to six months beyond stimulation, indicating functional recovery mediated by long-term neuroplasticity. Several participants resumed their hobbies that require fine motor control, such as playing the guitar and oil painting, for the first time in up to 12 years since their injuries. Our findings demonstrate that non-invasive transcutaneous electrical stimulation of the spinal networks restores movement and function of the hands and arm for people with both complete paralysis and long-term spinal cord injury.

PMID: 33400652 [PubMed - as supplied by publisher]

Smaller Regional Brain Volumes Predict Posttraumatic Stress Disorder at 3 Months After Mild Traumatic Brain Injury.

Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Oct 27;:

Authors: Stein MB, Yuh E, Jain S, Okonkwo DO, Mac Donald CL, Levin H, Giacino JT, Dikmen S, Vassar MJ, Diaz-Arrastia R, Robertson CS, Nelson LD, McCrea M, Sun X, Temkin N, Taylor SR, Markowitz AJ, Manley GT, Mukherjee P, TRACK-TBI Investigators

Abstract
BACKGROUND: Brain volumes in regions such as the hippocampus and amygdala have been associated with risk for the development of posttraumatic stress disorder (PTSD). The objective of this study was to determine whether a set of regional brain volumes, measured by magnetic resonance imaging at 2 weeks following mild traumatic brain injury, were predictive of PTSD at 3 and 6 months after injury.
METHODS: Using data from TRACK-TBI (Transforming Research and Clinical Knowledge in TBI), we included patients (N = 421) with Glasgow Coma Scale scores 13-15 assessed after evaluation in the emergency department and at 2 weeks, 3 months, and 6 months after injury. Probable PTSD diagnosis (PTSD Checklist for DSM-5 score, ≥33) was the outcome. FreeSurfer 6.0 was used to perform volumetric analysis of three-dimensional T1-weighted magnetic resonance images at 3T obtained 2 weeks post injury. Brain regions selected a priori for volumetric analyses were insula, hippocampus, amygdala, superior frontal cortex, rostral and caudal anterior cingulate, and lateral and medial orbitofrontal cortices.
RESULTS: Overall, 77 (18.3%) and 70 (16.6%) patients had probable PTSD at 3 and 6 months. A composite volume derived as the first principal component incorporating 73.8% of the variance in insula, superior frontal cortex, and rostral and caudal cingulate contributed to the prediction of 3-month (but not 6-month) PTSD in multivariable models incorporating other established risk factors.
CONCLUSIONS: Results, while needing replication, provide support for a brain reserve hypothesis of PTSD and proof of principle for how prediction of at-risk individuals might be accomplished to enhance prognostic accuracy and enrich clinical prevention trials for individuals at the highest risk of PTSD following mild traumatic brain injury.

PMID: 33386283 [PubMed - as supplied by publisher]

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.

Lancet Oncol. 2021 01;22(1):118-131

Authors: O'Hara MH, O'Reilly EM, Varadhachary G, Wolff RA, Wainberg ZA, Ko AH, Fisher G, Rahma O, Lyman JP, Cabanski CR, Mick R, Gherardini PF, Kitch LJ, Xu J, Samuel T, Karakunnel J, Fairchild J, Bucktrout S, LaVallee TM, Selinsky C, Till JE, Carpenter EL, Alanio C, Byrne KT, Chen RO, Trifan OC, Dugan U, Horak C, Hubbard-Lucey VM, Wherry EJ, Ibrahim R, Vonderheide RH

Abstract
BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

PMID: 33387490 [PubMed - indexed for MEDLINE]

Development of a Machine Learning Model Using Multiple, Heterogeneous Data Sources to Estimate Weekly US Suicide Fatalities.

JAMA Netw Open. 2020 12 01;3(12):e2030932

Authors: Choi D, Sumner SA, Holland KM, Draper J, Murphy S, Bowen DA, Zwald M, Wang J, Law R, Taylor J, Konjeti C, De Choudhury M

Abstract
Importance: Suicide is a leading cause of death in the US. However, official national statistics on suicide rates are delayed by 1 to 2 years, hampering evidence-based public health planning and decision-making.
Objective: To estimate weekly suicide fatalities in the US in near real time.
Design, Setting, and Participants: This cross-sectional national study used a machine learning pipeline to combine signals from several streams of real-time information to estimate weekly suicide fatalities in the US in near real time. This 2-phase approach first fits optimal machine learning models to each individual data stream and subsequently combines predictions made from each data stream via an artificial neural network. National-level US administrative data on suicide deaths, health services, and economic, meteorological, and online data were variously obtained from 2014 to 2017. Data were analyzed from January 1, 2014, to December 31, 2017.
Exposures: Longitudinal data on suicide-related exposures were obtained from multiple, heterogeneous streams: emergency department visits for suicide ideation and attempts collected via the National Syndromic Surveillance Program (2015-2017); calls to the National Suicide Prevention Lifeline (2014-2017); calls to US poison control centers for intentional self-harm (2014-2017); consumer price index and seasonality-adjusted unemployment rate, hourly earnings, home price index, and 3-month and 10-year yield curves from the Federal Reserve Economic Data (2014-2017); weekly daylight hours (2014-2017); Google and YouTube search trends related to suicide (2014-2017); and public posts on suicide on Reddit (2 314 533 posts), Twitter (9 327 472 tweets; 2015-2017), and Tumblr (1 670 378 posts; 2014-2017).
Main Outcomes and Measures: Weekly estimates of suicide fatalities in the US were obtained through a machine learning pipeline that integrated the above data sources. Estimates were compared statistically with actual fatalities recorded by the National Vital Statistics System.
Results: Combining information from multiple data streams, the machine learning method yielded estimates of weekly suicide deaths with high correlation to actual counts and trends (Pearson correlation, 0.811; P < .001), while estimating annual suicide rates with low error (0.55%).
Conclusions and Relevance: The proposed ensemble machine learning framework reduces the error for annual suicide rate estimation to less than one-tenth of that of current forecasting approaches that use only historical information on suicide deaths. These findings establish a novel approach for tracking suicide fatalities in near real time and provide the potential for an effective public health response such as supporting budgetary decisions or deploying interventions.

PMID: 33355678 [PubMed - indexed for MEDLINE]

Management of Moderate Blunt Thoracic Aortic Injuries in Patients with Intracranial Hemorrhage.

Ann Vasc Surg. 2020 Dec 23;:

Authors: Quiroga E, Levitt MR, Czerwonko ME, Starnes BW, Tran NT, Singh N

Abstract
OBJECTIVE: Blunt thoracic aortic injuries (BTAI's) are the second most common cause of death due to blunt-force trauma in the United States. Patients with minimal injuries do not typically require surgical repair, while patients with severe injuries are treated emergently. Moderate aortic injuries are repaired in a semi-elective fashion but the optimal management of moderate BTAI patients with associated intracranial hemorrhage (ICH) is unknown. We sought to analyze the management and outcomes of patients presenting with concomitant moderate BTAI and ICH.
METHODS: Consecutive patients who received a Thoracic Endovascular Aortic Repair (TEVAR) at our institution for treatment of moderate BTAI between January 2014 and December 2017 were retrospectively reviewed as part of an Institutional Review Board (IRB)- approved protocol. Patients were classified by our BTAI classification into "minimal", "moderate", or "severe". ICH was identified on CT scan and its severity determined by the neurosurgical team. Outcome measures included surgical timing and surgical outcomes.
RESULTS: 52 patients had a moderate BTAI and underwent TEVAR, 20 (38 %) of whom presented with ICH. Median time from admission to surgery was 58.5 hours for patients with ICH and 26.5 hours for non-ICH patients. Intraoperative heparin was administered in all patients without ICH and in 19/20 (95%) of ICH patients after the ICH met criteria for stability. Protamine reversal was utilized in 80% of patients with ICH and 75% of non-ICH patients. No patient developed ischemic stroke or spinal cord ischemia. Worsening ICH was seen in only one patient, who also received heparin infusion for pulmonary embolus 24 hours before TEVAR. There were no aortic related mortalities in either group. 30-day all-cause mortality was 5% for ICH patients, and 3% for non-ICH patients.
CONCLUSIONS: Patients with moderate BTAI and stable ICH are not at increased risk of TEVAR-related complications. Administration of intraoperative heparin during TEVAR appears to be safe and does not worsen ICH.

PMID: 33359706 [PubMed - as supplied by publisher]

Segmentation of Chronic Subdural Hematomas Using 3D Convolutional Neural Networks.

World Neurosurg. 2020 Dec 23;:

Authors: Kellogg RT, Vargas J, Barros G, Sen R, Bass D, Mason JR, Levitt M

Abstract
OBJECTIVE: Chronic subdural hematomas (cSDH) are an increasingly prevalent neurological disease that often requires surgical intervention to alleviate compression of the brain. Management of cSDHs relies heavily upon computed tomography (CT) imaging, and serial imaging is frequently obtained to help direct management. The volume of hematoma provides critical information in guiding therapy and evaluating new methods of management. We set out to develop an automated program to compute the volume of hematoma on CT scans for both preoperative and postoperative images.
METHODS: A total of 21,710 images (128 CT scans) were manually segmented and used to train a convolutional neural network to automatically segment chronic subdural hematomas. We included both preoperative and postoperative coronal head CTs from patients undergoing surgical management of cSDHs.
RESULTS: Our best model achieved a Dice score of 0.8351 on the testing dataset and an average Dice score of 0.806 +/- 0.06 on the validation set. This model was trained on the full data set with reduced volumes, a network depth of 4, and post activation residual blocks within the context modules of the encoder pathway. Patch trained models did not perform as well and decreasing the network depth from 5 to 4 did not appear to significantly improve performance.
CONCLUSIONS: We successfully trained a convolutional neural network on a dataset of pre and postoperative head CTs containing cSDH. This tool could assist with automated, accurate measurements for evaluating treatment efficacy.

PMID: 33359736 [PubMed - as supplied by publisher]

Evolution of Cranioorbital Shape in Nonsyndromic, Muenke, and Saethre-Chotzen Bilateral Coronal Synostosis: A Case-Control Study of 2-Year Outcomes.

Plast Reconstr Surg. 2021 Jan 01;147(1):148-159

Authors: Adidharma W, Mercan E, Purnell C, Birgfeld CB, Lee A, Ellenbogen RG, Hopper RA

Abstract
BACKGROUND: The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up.
METHODS: Volumetric, linear, and angular analyses were performed on computed tomographic scans of consecutive bilateral coronal synostosis patients. Comparisons were made across three time points, between syndromic and nonsyndromic cases, and against normal controls. Significance was set at p < 0.05.
RESULTS: Twenty-five patients were included: 11 were nonsyndromic, eight had Saethre-Chotzen syndrome, and six had Muenke syndrome. Total cranial volume was comparable to normal, age-matched control subjects before and 2 years after surgery despite an expansion during surgery. Axial and sagittal vector analyses showed advancement and widening of the lower forehead beyond control values with surgery and comparable anterior position, but increased width compared to controls at 2 years. Frontal bossing decreased with a drop in anterior cranial height and advanced lower forehead position. Middle vault height was not normalized and turricephaly persisted at follow-up. Posterior fossa volume remained lower at all three time points compared to control subjects. Supraorbital retrusion relative to anterior corneal position was overcorrected by surgery, with values comparable to those of control subjects at 2 years because of differential growth. There was no difference at 2 years between syndromic and nonsyndromic groups.
CONCLUSIONS: Open fronto-orbital advancement successfully remodels the anterior forehead but requires overcorrection to be comparable to normal at 2 years. Although there are differences in syndromic cases at presentation, they do not result in significant morphometric differences on follow-up. Posterior fossa volume remains lower at all time points.
CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

PMID: 33370058 [PubMed - as supplied by publisher]

Qualitative and Quantitative Wall Enhancement on Magnetic Resonance Imaging Is Associated With Symptoms of Unruptured Intracranial Aneurysms.

Stroke. 2020 Dec 22;:STROKEAHA120029685

Authors: Fu Q, Wang Y, Zhang Y, Zhang Y, Guo X, Xu H, Yao Z, Wang M, Levitt MR, Mossa-Basha M, Zhu J, Cheng J, Guan S, Zhu C

Abstract
BACKGROUND AND PURPOSE: Aneurysmal wall enhancement (AWE) on vessel wall magnetic resonance imaging (VW-MRI) has been described as a new imaging biomarker of unstable unruptured intracranial aneurysms (UIAs). Previous studies of symptomatic UIAs are limited due to small sample sizes and lack of AWE quantification. Our study aims to investigate whether qualitative and quantitative assessment of AWE can differentiate symptomatic and asymptomatic UIAs.
METHODS: Consecutive patients with UIAs were prospectively recruited for vessel wall magnetic resonance imaging at 3T from October 2014 to October 2019. UIAs were categorized as symptomatic if presenting with sentinel headache or oculomotor nerve palsy directly related to the aneurysm. Evaluation of wall enhancement included enhancement pattern (0=none, 1=focal, and 2=circumferential) and quantitative wall enhancement index (WEI). Univariate and multivariate analyses were used to identify the parameters associated with symptoms.
RESULTS: Two hundred sixty-seven patients with 341 UIAs (93 symptomatic and 248 asymptomatic) were included in this study. Symptomatic UIAs more frequently showed circumferential AWE than asymptomatic UIAs (66.7% versus 17.3%, P<0.001), as well as higher WEI (median [interquartile range], 1.3 [1.0-1.9] versus 0.3 [0.1-0.9], P<0.001). In multivariate analysis, both AWE pattern and WEI were independent factors associated with symptoms (odds ratio=2.03 across AWE patterns [95% CI, 1.21-3.39], P=0.01; odds ratio=3.32 for WEI [95% CI, 1.51-7.26], P=0.003). The combination of AWE pattern and WEI had an area under the curve of 0.91 to identify symptomatic UIAs, with a sensitivity of 95.7% and a specificity of 73.4%.
CONCLUSIONS: In a large cohort of UIAs with vessel wall magnetic resonance imaging, both AWE pattern and WEI were independently associated with aneurysm-related symptoms. The qualitative and quantitative features of AWE can potentially be used to identify unstable intracranial aneurysms.

PMID: 33349014 [PubMed - as supplied by publisher]

Corrigendum: Paraburkholderia madseniana sp. nov., a phenolic acid-degrading bacterium isolated from acidic forest soil.

Int J Syst Evol Microbiol. 2020 Dec;70(12):6534-6538

Authors: Wilhelm RC, Murphy SJL, Feriancek NM, Karasz DC, DeRito CM, Newman JD, Buckley DH

PMID: 33351737 [PubMed - as supplied by publisher]

Advances in meningioma genomics, proteomics, and epigenetics: insights into biomarker identification and targeted therapies.

Oncotarget. 2020 Dec 08;11(49):4544-4553

Authors: Nazem AA, Ruzevick J, Ferreira MJ

Abstract
Meningiomas are a heterogeneous group of tumors, defined histo-pathologically by World Health Organization (WHO) grading. The WHO grade of meningiomas does not always correlate with clinical aggressiveness. Despite maximal surgical resection and adjuvant radiation, a subset of tumors are clinically aggressive; displaying early recurrence and invasion. Current methods for identifying aggressive meningiomas solely focus on genomics, proteomics, or epigenetics and not a combination of all for developing a real-time clinical biomarker. Improved methods for the identification of these outlying tumors can facilitate better classification and potentially adjuvant treatment planning. Understanding the pathways of oncogenesis using multiple markers driving aggressive meningiomas can provide a foundation for targeted therapies, which currently do not exist.

PMID: 33346248 [PubMed]

Pain anxiety and rehabilitation outcomes after acquired brain injury.

Brain Inj. 2020 Dec 21;:1-9

Authors: Williams MW, Rapport LJ, Sander AM, Parker HA

Abstract
Purpose: The purpose of this study was to examine pain anxiety after acquired brain injury (ABI) and its relationship to rehabilitation outcomes. Materials and Method: Participants consisted of 89 adults with an ABI participating in outpatient rehabilitation therapy. They completed a battery of neuropsychological tests at baseline along with surveys of mood, health-related self-efficacy, and pain anxiety. Separately, occupational therapists assessed basic and instrumental activities of daily living (ADLs) as well as therapy engagement across treatment after the sixth session. Results: Individuals who reported high pain anxiety had fewer years of formal education, lower self-efficacy, and more emotional distress than those with low pain anxiety. Although Blacks were about half (56%) of the study sample, they comprised the majority (73.1%) of individuals in the high pain anxiety group. Pain anxiety was negatively related to therapy engagement. Moderation analysis using linear regression indicated that pain anxiety moderated the influence of self-efficacy on basic ADLs. Conclusions: Pain anxiety, particularly when high, is negatively associated with rehabilitation outcomes for individuals with ABI. Among those with high pain anxiety, health-related self-efficacy is an important resilience characteristic to improve functional outcomes. In rehabilitation therapy, pain anxiety provides a novel intervention target to enhance ABI recovery.

PMID: 33347375 [PubMed - as supplied by publisher]

A clinical protocol of a comparative effectiveness trial of extended-release naltrexone versus extended-release buprenorphine with individuals leaving jail.

J Subst Abuse Treat. 2020 Dec 11;:108241

Authors: Gordon MS, Mitchell SG, Blue TR, Vocci FJ, Fishman MJ, Murphy SM, Couvillion K, Maher K, Ryan D, Wenzel K, Danner ML, Jarvis DK

Abstract
This study is a randomized, open label, controlled trial of extended-release buprenorphine (XR-B; BRIXADI™ formulation) versus extended-release naltrexone (XR-NTX) in Maryland jails. A 7-site, open-label, equivalence design will randomly assign 240 adults with a history of opioid use disorder (OUD), stratified by gender and jail, who are nearing release to one of two treatment arms: 1) XR-B in jail or 2) XR-NTX in jail, both followed by 6 monthly injections postrelease at a community treatment program. The primary aim is to determine the rate of pharmacotherapy adherence (number of monthly injections received) of XR-B compared to XR-NTX. The proposed study is innovative because it will be the first randomized clinical trial in the U.S. assessing the effectiveness of receiving XR-B vs. XR-NTX in county jails. The public health impact of the study will be highly significant and far-reaching because most individuals with OUD do not receive treatment while incarcerated, thereby substantially raising their likelihood of relapse to drug use, overdose death, and re-incarceration. Understanding how to expand acceptance of medications for OUD in jails, particularly extended-release medications, and supporting treatment engagement and medication adherence in transition to the community, has far-reaching implications for improving treatment access and success in this population.

PMID: 33339633 [PubMed - as supplied by publisher]

Directed differentiation into insulin-producing cells using microRNA manipulation.

Open Med (Wars). 2020;15(1):567-570

Authors: Williams MD, Joglekar MV, Hardikar AA, Wong WKM

Abstract
Our commentary is focused on three studies that used microRNA overexpression methods for directed differentiation of stem cells into insulin-producing cells. Islet transplantation is the only cell-based therapy used to treat type 1 diabetes mellitus. However, due to the scarcity of cadaveric donors and limited availability of good quality and quantity of islets for transplant, alternate sources of insulin-producing cells are being studied and used by researchers. This commentary provides an overview of distinct studies focused on manipulating microRNA expression to optimize differentiation of embryonic stem cells or induced pluripotent stem cells into insulin-producing cells. These studies have used different approaches to overexpress microRNAs that are highly abundant in human islets (such as miR-375 and miR-7) in their differentiation protocol to achieve better differentiation into functional islet beta (β)-cells.

PMID: 33336012 [PubMed]

Building longitudinal medication dose data using medication information extracted from clinical notes in electronic health records.

J Am Med Inform Assoc. 2020 Dec 18;:

Authors: McNeer E, Beck C, Weeks HL, Williams ML, James NT, Bejan CA, Choi L

Abstract
OBJECTIVE: To develop an algorithm for building longitudinal medication dose datasets using information extracted from clinical notes in electronic health records (EHRs).
MATERIALS AND METHODS: We developed an algorithm that converts medication information extracted using natural language processing (NLP) into a usable format and builds longitudinal medication dose datasets. We evaluated the algorithm on 2 medications extracted from clinical notes of Vanderbilt's EHR and externally validated the algorithm using clinical notes from the MIMIC-III clinical care database.
RESULTS: For the evaluation using Vanderbilt's EHR data, the performance of our algorithm was excellent; F1-measures were ≥0.98 for both dose intake and daily dose. For the external validation using MIMIC-III, the algorithm achieved F1-measures ≥0.85 for dose intake and ≥0.82 for daily dose.
DISCUSSION: Our algorithm addresses the challenge of building longitudinal medication dose data using information extracted from clinical notes. Overall performance was excellent, but the algorithm can perform poorly when incorrect information is extracted by NLP systems. Although it performed reasonably well when applied to the external data source, its performance was worse due to differences in the way the drug information was written. The algorithm is implemented in the R package, "EHR," and the extracted data from Vanderbilt's EHRs along with the gold standards are provided so that users can reproduce the results and help improve the algorithm.
CONCLUSION: Our algorithm for building longitudinal dose data provides a straightforward way to use EHR data for medication-based studies. The external validation results suggest its potential for applicability to other systems.

PMID: 33338223 [PubMed - as supplied by publisher]

Predictors of fast and ultrafast shunt failure in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study.

J Neurosurg Pediatr. 2020 Dec 18;:1-10

Authors: Hauptman JS, Kestle J, Riva-Cambrin J, Kulkarni AV, Browd SR, Rozzelle CJ, Whitehead WE, Naftel RP, Pindrik J, Limbrick DD, Drake J, Wellons JC, Tamber MS, Shannon CN, Simon TD, Pollack IF, McDonald PJ, Krieger MD, Chu J, Hankinson TC, Jackson EM, Alvey JS, Reeder RW, Holubkov R, Hydrocephalus Clinical Research Network

Abstract
OBJECTIVE: The primary objective of this study was to use the prospective Hydrocephalus Clinical Research Network (HCRN) registry to determine clinical predictors of fast time to shunt failure (≤ 30 days from last revision) and ultrafast time to failure (≤ 7 days from last revision).
METHODS: Revisions (including those due to infection) to permanent shunt placements that occurred between April 2008 and November 2017 for patients whose entire shunt experience was recorded in the registry were analyzed. All registry data provided at the time of initial shunt placement and subsequent revision were reviewed. Key variables analyzed included etiology of hydrocephalus, age at time of initial shunt placement, presence of slit ventricles on imaging at revision, whether the ventricles were enlarged at the time of revision, and presence of prior fast failure events. Univariable and multivariable analyses were performed to find key predictors of fast and ultrafast failure events.
RESULTS: A cohort of 1030 patients with initial shunt insertions experienced a total of 1995 revisions. Of the 1978 revision events with complete records, 1216 (61.5%) shunts remained functional for more than 1 year, and 762 (38.5%) failed within 1 year of the procedure date. Of those that failed within 1 year, 423 (55.5%) failed slowly (31-365 days) and 339 (44.5%) failed fast (≤ 30 days). Of the fast failures, 131 (38.6%) were ultrafast (≤ 7 days). In the multivariable analysis specified a priori, etiology of hydrocephalus (p = 0.005) and previous failure history (p = 0.011) were independently associated with fast failure. Age at time of procedure (p = 0.042) and etiology of hydrocephalus (p = 0.004) were independently associated with ultrafast failure. These relationships in both a priori models were supported by the data-driven multivariable models as well.
CONCLUSIONS: Neither the presence of slit ventricle syndrome nor ventricular enlargement at the time of shunt failure appears to be a significant predictor of repeated, rapid shunt revisions. Age at the time of procedure, etiology of hydrocephalus, and the history of previous failure events seem to be important predictors of fast and ultrafast shunt failure. Further work is required to understand the mechanisms of these risk factors as well as mitigation strategies.

PMID: 33338993 [PubMed - as supplied by publisher]

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life.

Front Immunol. 2020;11:578505

Authors: Bennike TB, Fatou B, Angelidou A, Diray-Arce J, Falsafi R, Ford R, Gill EE, van Haren SD, Idoko OT, Lee AH, Ben-Othman R, Pomat WS, Shannon CP, Smolen KK, Tebbutt SJ, Ozonoff A, Richmond PC, van den Biggelaar AHJ, Hancock REW, Kampmann B, Kollmann TR, Levy O, Steen H

Abstract
Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.

PMID: 33329546 [PubMed - in process]

Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort.

Front Immunol. 2020;11:578801

Authors: Shannon CP, Blimkie TM, Ben-Othman R, Gladish N, Amenyogbe N, Drissler S, Edgar RD, Chan Q, Krajden M, Foster LJ, Kobor MS, Mohn WW, Brinkman RR, Le Cao KA, Scheuermann RH, Tebbutt SJ, Hancock REW, Koff WC, Kollmann TR, Sadarangani M, Lee AH

Abstract
Background: Vaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.
Methods: We applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.
Results: Using both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.
Conclusion: This study provides further evidence that baseline cellular and molecular characteristics of an individual's immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.

PMID: 33329547 [PubMed - in process]

A Bovine Enteric Mycobacterium Infection Model to Analyze Parenteral Vaccine-Induced Mucosal Immunity and Accelerate Vaccine Discovery.

Front Immunol. 2020;11:586659

Authors: Facciuolo A, Lee AH, Trimble MJ, Rawlyk N, Townsend HGG, Bains M, Arsic N, Mutharia LM, Potter A, Gerdts V, Napper S, Hancock REW, Griebel PJ

Abstract
Mycobacterial diseases of cattle are responsible for considerable production losses worldwide. In addition to their importance in animals, these infections offer a nuanced approach to understanding persistent mycobacterial infection in native host species. Mycobacterium avium ssp. paratuberculosis (MAP) is an enteric pathogen that establishes a persistent, asymptomatic infection in the small intestine. Difficulty in reproducing infection in surrogate animal models and limited understanding of mucosal immune responses that control enteric infection in the natural host have been major barriers to MAP vaccine development. We previously developed a reproducible challenge model to establish a consistent MAP infection using surgically isolated intestinal segments prepared in neonatal calves. In the current study, we evaluated whether intestinal segments could be used to screen parenteral vaccines that alter mucosal immune responses to MAP infection. Using Silirum® - a commercial MAP bacterin - we demonstrate that intestinal segments provide a platform for assessing vaccine efficacy within a relatively rapid period of 28 days post-infection. Significant differences between vaccinates and non-vaccinates could be detected using quantitative metrics including bacterial burden in intestinal tissue, MAP shedding into the intestinal lumen, and vaccine-induced mucosal immune responses. Comparing vaccine-induced responses in mucosal leukocytes isolated from the site of enteric infection versus blood leukocytes revealed substantial inconsistences between these immune compartments. Moreover, parenteral vaccination with Silirum did not induce equal levels of protection throughout the small intestine. Significant control of MAP infection was observed in the continuous but not the discrete Peyer's patches. Analysis of these regional mucosal immune responses revealed novel correlates of immune protection associated with reduced infection that included an increased frequency of CD335+ innate lymphoid cells, and increased expression of IL21 and IL27. Thus, intestinal segments provide a novel model to accelerate vaccine screening and discovery by testing vaccines directly in the natural host and provides a unique opportunity to interrogate mucosal immune responses to mycobacterial infections.

PMID: 33329565 [PubMed - in process]

Activation of the Gluteus Maximus During Performance of the Back Squat, Split Squat, and Barbell Hip Thrust and the Relationship With Maximal Sprinting.

J Strength Cond Res. 2021 Jan 01;35(1):16-24

Authors: Williams MJ, Gibson NV, Sorbie GG, Ugbolue UC, Brouner J, Easton C

Abstract
ABSTRACT: Williams, MJ, Gibson, N, Sorbie, GG, Ugbolue, UC, Brouner, J, and Easton, C. Activation of the gluteus maximus during performance of the back squat, split squat, and barbell hip thrust and the relationship with maximal sprinting. J Strength Cond Res 35(1): 16-24, 2021-The purpose of this research was to compare muscle activation of the gluteus maximus and ground reaction force between the barbell hip thrust, back squat, and split squat and to determine the relationship between these outcomes and vertical and horizontal forces during maximal sprinting. Twelve, male, team sport athletes (age, 25.0 ± 4.0 years; stature, 184.1 ± 6.0 cm; body mass, 82.2 ± 7.9 kg) performed separate movements of the 3 strength exercises at a load equivalent to their individual 3 repetition maximum. The ground reaction force was measured using force plates and the electromyography (EMG) activity of the upper and lower gluteus maximus and was recorded in each leg and expressed as percentage of the maximum voluntary isometric contraction (MVIC). Subjects then completed a single sprint on a nonmotorized treadmill for the assessment of maximal velocity and horizontal and vertical forces. Although ground reaction force was lower, peak EMG activity in the gluteus maximus was higher in the hip thrust than in the back squat (p = 0.024; 95% confidence interval [CI] = 4-56% MVIC) and split squat (p = 0.016; 95% CI = 6-58% MVIC). Peak sprint velocity correlated with both anterior-posterior horizontal force (r = 0.72) and peak ground reaction force during the barbell hip thrust (r = 0.69) but no other variables. The increased activation of gluteus maximus during the barbell hip thrust and the relationship with maximal running speed suggests that this movement may be optimal for training this muscle group in comparison to the back squat and split squat.

PMID: 33332802 [PubMed - as supplied by publisher]

Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease-specific changes in sleep and incongruous peripheral inflammation.

J Neurosci Res. 2020 Dec 14;:

Authors: Saber M, Murphy SM, Cho Y, Lifshitz J, Rowe RK

Abstract
Elderly populations (≥65 years old) have the highest risk of developing Alzheimer's disease (AD) and/or obtaining a traumatic brain injury (TBI). Using translational mouse models, we investigated sleep disturbances and inflammation associated with normal aging, TBI and aging, and AD. We hypothesized that aging results in marked changes in sleep compared with adult mice, and that TBI and aging would result in sleep and inflammation levels similar to AD mice. We used female 16-month-old wild-type (WT Aged) and 3xTg-AD mice, as well as a 2-month-old reference group (WT Adult), to evaluate sleep changes. WT Aged mice received diffuse TBI by midline fluid percussion, and blood was collected from both WT Aged (pre- and post-TBI) and 3xTg-AD mice to evaluate inflammation. Cognitive behavior was tested, and tissue was collected for histology. Bayesian generalized additive and mixed-effects models were used for analyses. Both normal aging and AD led to increases in sleep compared with adult mice. WT Aged mice with TBI slept substantially more, with fragmented shorter bouts, than they did pre-TBI and compared with AD mice. However, differences between WT Aged and 3xTg-AD mice in immune cell populations and plasma cytokine levels were incongruous, cognitive deficits were similar, and cumulative sleep was not predictive of inflammation or behavior for either group. Our results suggest that in similarly aged individuals, TBI immediately induces more profound sleep alterations than in AD, although both diseases likely include cognitive impairments. Unique pathological sleep pathways may exist in elderly individuals who incur TBI compared with similarly aged individuals who have AD, which may warrant disease-specific treatments in clinical settings.

PMID: 33319441 [PubMed - as supplied by publisher]