Neurology Commons^™

Universal Connection Through Art: Role Of Mirror Neurons In Art Production And Reception., Bartlomiej Piechowski-Jozwiak, François Boller, Julien Bogousslavsky

Neurology Faculty Publications

Art is defined as expression or application of human creative skill and imagination producing works to be appreciated primarily for their aesthetic value or emotional power. This definition encompasses two very important elements—the creation and reception of art—and by doing so it establishes a link, a dialogue between the artist and spectator. From the evolutionary biological perspective, activities need to have an immediate or remote effect on the population through improving survival, gene selection, and environmental adjustment, and this includes art. It may serve as a universal means of communication bypassing time, cultural, ethnic, and social differences. The neurological mechanisms …

Biomarkers Of Acute Stroke Etiology (Base) Study Methodology., Edward C Jauch, Andrew D Barreto, Joseph P Broderick, Doug M Char, Brett L Cucchiara, Thomas G Devlin, Alison J Haddock, William J Hicks, Brian C Hiestand, Glen C Jickling, Jeff June, David S Liebeskind, Ted J Lowenkopf, Joseph B Miller, John O'Neill, Tim L Schoonover, Frank R Sharp, W Frank Peacock

Articles, Abstracts, and Reports

Acute ischemic stroke affects over 800,000 US adults annually, with hundreds of thousands more experiencing a transient ischemic attack. Emergent evaluation, prompt acute treatment, and identification of stroke or TIA (transient ischemic attack) etiology for specific secondary prevention are critical for decreasing further morbidity and mortality of cerebrovascular disease. The Biomarkers of Acute Stroke Etiology (BASE) study is a multicenter observational study to identify serum markers defining the etiology of acute ischemic stroke. Observational trial of patients presenting to the hospital within 24 h of stroke onset. Blood samples are collected at arrival, 24, and 48 h later, and RNA …

Pediatric Intrafalcine Empyema From A Sinogenic Origin: A Case Report., Kyle Mueller, John Myseros

Neurological Surgery Faculty Publications

Sinusitis and otitis are common within the pediatric population. If left untreated, these can extend intracranially and lead to the development of infections in the various intracranial compartments resulting in a high rate of morbidity and mortality. We report the first case of an intrafalcine empyema, absent subdural purulence, in a patient with the likely spread from a sinogenic origin. This case illustrates the novelty of this as a pathological entity as well as the surgical considerations for intrafalcine purulence in the absence of expected subdural collections.

Buprenorphine For The Treatment Of The Neonatal Abstinence Syndrome., Walter K. Kraft, Susan C. Adeniyi-Jones, Inna Chervoneva, Jay S. Greenspan, Diane J. Abatemarco, Karol Kaltenbach, Michelle E. Ehrlich

Department of Obstetrics and Gynecology Faculty Papers

Background: Current pharmacologic treatment of the neonatal abstinence syndrome with morphine is associated with a lengthy duration of therapy and hospitalization. Buprenorphine may be more effective than morphine for this indication. Methods: In this single-site, double-blind, double-dummy clinical trial, we randomly assigned 63 term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and who had signs of the neonatal abstinence syndrome to receive either sublingual buprenorphine or oral morphine. Infants with symptoms that were not controlled with the maximum dose of opioid were treated with adjunctive phenobarbital. The primary end point was the duration of …

Undetected Small Accessory Mental Foramina Using Cone-Beam Computed Tomography., Joe Iwanaga, Koichi Watanabe, Tsuyoshi Saga, Shogo Kikuta, Yoko Tabira, Sadaharu Kitashima, Christian Fisahn, Fernando Alonso, R Shane Tubbs, Jingo Kusukawa, Koh-Ichi Yamaki

Articles, Abstracts, and Reports

INTRODUCTION: The accessory foramina could not be identified on some imaging modalities such as surface-rendered images. The purpose of this study was to investigate the ability of surface-rendered images in detecting these foramina.

MATERIALS AND METHODS: We analyzed 20 accessory mental foramina (AMF) in nine mandibles removed from cadavers with cone-beam computed tomography (CBCT) and assessed in surface-rendered images. All AMF were divided into three groups depending on their visibility.

RESULTS: Group 1 included AMF that were clearly visible as foramina, Group 2 were not clearly visible but could be recognized with concave parts, and Group 3 were not visible …

Choriocarcinoma With Brain, Lung And Vaginal Metastases Successfully Treated Without Brain Radiation Or Intrathecal Chemotherapy: A Case Report, Anja Frost, Jonathan Sherman, M. Katayoon Rezaei, Alivia Aron, Micael Lopez-Acevedo

Neurological Surgery Faculty Publications

Highlights:

• • There is no consensus on optimal treatment for GTN and brain metastases.
• • Brain metastasis treated with craniotomy and intravenous, EMA-CO chemotherapy
• • Intravenous high-dose methotrexate may be adequate to treat brain metastases.

Presurgical Language Fmri: Mapping Of Six Critical Regions, Christopher Benjamin, Patricia Walshaw, Kayleigh Hale, William D. Gaillard, +Several Additional Authors

Neurology Faculty Publications

Language mapping is a key goal in neurosurgical planning. fMRI mapping typically proceeds with a focus on Broca's and Wernicke's areas, although multiple other language-critical areas are now well-known. We evaluated whether clinicians could use a novel approach, including clinician-driven individualized thresholding, to reliably identify six language regions, including Broca's Area, Wernicke's Area (inferior, superior), Exner's Area, Supplementary Speech Area, Angular Gyrus, and Basal Temporal Language Area. We studied 22 epilepsy and tumor patients who received Wada and fMRI (age 36.4[12.5]; Wada language left/right/mixed in 18/3/1). fMRI tasks (two × three tasks) were analyzed by two clinical neuropsychologists who flexibly …

Prognostic Significance Of Idh 1 Mutation In Patients With Glioblastoma Multiforme, Inamullah Khan, Muhammad Waqas, Muhammad Shahzad Shamim

Section of Neurosurgery

Focus of brain tumour research is shifting towards tumour genesis and genetics, and possible development of individualized treatment plans. Genetic analysis shows recurrent mutation in isocitrate dehydrogenase (IDH1) gene in most Glioblastoma multiforme (GBM) cells. In this review we evaluated the prognostic significance of IDH 1 mutation on the basis of published evidence. Multiple retrospective clinical analyses correlate the presence of IDH1 mutation in GBM with good prognostic outcomes compared to wild-type IDH1. A systematic review reported similar results. Based on the review of current literature IDH1 mutation is an independent factor for longer overall survival (OS) and progression free …

Restriction Spectrum Imaging Improves Risk Stratification In Patients With Glioblastoma., A P Krishnan, R Karunamuni, K M Leyden, T M Seibert, R L Delfanti, J M Kuperman, H Bartsch, P Elbe, A Srikant, A M Dale, Santosh Kesari, D E Piccioni, J A Hattangadi-Gluth, N Farid, C R Mcdonald, N S White

Articles, Abstracts, and Reports

BACKGROUND AND PURPOSE: ADC as a marker of tumor cellularity has been promising for evaluating the response to therapy in patients with glioblastoma but does not successfully stratify patients according to outcomes, especially in the upfront setting. Here we investigate whether restriction spectrum imaging, an advanced diffusion imaging model, performed after an operation but before radiation therapy, could improve risk stratification in patients with newly diagnosed glioblastoma relative to ADC.

MATERIALS AND METHODS: Pre-radiation therapy diffusion-weighted and structural imaging of 40 patients with glioblastoma were examined retrospectively. Restriction spectrum imaging and ADC-based hypercellularity volume fraction (restriction spectrum imaging-FLAIR volume fraction, …

Demographics, Patterns Of Care, And Survival In Pediatric Medulloblastoma, Emily V. Dressler, Therese A. Dolecek, Meng Liu, John L. Villano

Internal Medicine Faculty Publications

We evaluated the American College of Surgeon’s National Cancer Data Base (NCDB) to describe current hospital-based epidemiologic frequency, survival, and patterns of care of pediatric medulloblastoma. We analyzed NCDB 1998–2011 data on medulloblastoma for children ages 0–19 years using logistic and poisson regression, Kaplan–Meier survival estimates, and Cox proportional hazards models. 3647 cases of medulloblastoma in those aged 0–19 years were identified. Chemotherapy was received by 79 and 74% received radiation, with 65% receiving both therapies. Those who received radiation were more likely to be older than four, while those who received chemotherapy were more likely to be age four …

Quality Of Life In Individuals Surgically Treated For Congenital Hydrocephalus During Infancy: A Single-Institution Experience, Saad Akhtar Khan, Muhammad Faheem Khan, Saqib Kamran Bakhshi, Omar Irfan, Hamza Abdur Rahim Khan, Asad Abbas, Safia Awan, Muhammad Ehsan Bari

Section of Neurosurgery

Background: Congenital hydrocephalus (CH) is a frequently encountered birth anomaly that can hinder long-term neurologic maturity and social well-being of affected children. This study was undertaken to assess quality of life (QOL) 10-15 years after surgical treatment for primary CH during infancy at a tertiary care hospital in a developing country.
Methods: This retrospective cohort study included individuals who presented to Aga Khan University Hospital, Karachi, Pakistan, between 1995 and 2005 at QOL.
Results: Of 118 patients, 90 patients participated in the study. Mean age at first admission was 6.2 months. Mean length of follow-up was 5.4 years. Of these, …

Incidence Of Cns Tumors In Appalachian Children, Bin Huang, Alice Luo, Eric B. Durbin, Ellen Lycan, Thomas Tucker, Quan Chen, Craig Horbinski, John L. Villano

Markey Cancer Center Faculty Publications

Determine whether the risk of astrocytomas in Appalachian children is higher than the national average. We compared the incidence of pediatric brain tumors in Appalachia versus non-Appalachia regions, covering years 2000–2011. The North American Association of Central Cancer Registries (NAACCR) collects population-based data from 55 cancer registries throughout U.S. and Canada. All invasive primary (i.e. non-metastatic tumors), with age at diagnosis 0–19 years old, were included. Nearly 27,000 and 2200 central nervous system (CNS) tumors from non-Appalachia and Appalachia, respectively comprise the cohorts. Age-adjusted incidence rates of each main brain tumor subtype were compared. The incidence rate of pediatric CNS …

Adaptation Of The Recent Life Changes Questionnaire (Rlcq) To Measure Stressful Life Events In Adults Residing In An Urban Megapolis In Pakistan, Azmina Artani, Shireen Shehzad, Iqbal Azam Syed, Moiz Abdul Sultan, Adeel Khoja, Ayeesha Kamran Kamal

Section of Neurology

Background: Contextually relevant stressful life events are integral to the quantification of stress. None such measures have been adapted for the Pakistani population.

Methods: The RLCQ developed by Richard Rahe measures stress of an individual through recording the experience of life changing events. We used qualitative methodology in order to identify contextually relevant stressors in an open ended format, using serial in-depth interviews until thematic saturation of reported stressful life events was achieved. In our next phase of adaptation, our objective was to scale each item on the questionnaire, so as to weigh each of these identified events, in terms …

A Case Matched Study Examining The Reliability Of Using Impact To Assess Effects Of Multiple Concussions., Trevor Barker, Stephen A. Russo, Gaytri Barker, Mark A Rice, Mary G Jeffrey, Gordon Broderick, Travis J A Craddock

Department of Neurology Faculty Papers

BACKGROUND: Approximately 3.8 million sport and recreational concussions occur per year, creating a need for accurate diagnosis and management of concussions. Researchers and clinicians are exploring the potential dose-response cumulative effects of concussive injuries using computerized neuropsychological exams, however, results have been mixed and/or contradictory. This study starts with a large adolescent population and applies strict inclusion criteria to examine how previous mild traumatic brain injuries affect symptom reports and neurocognitive performance on the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) computerized tool.

METHODS: After applying exclusion criteria and case matching, 204 male and 99 female participants remained. These participants …

A Ruptured Basilar Aneurysm Resulting In Takotsubo Cardiomyopathy., Ryan Murphy Do, Apurva Vyas Md, Megan Leary Md

Department of Medicine

No abstract provided.

Decreased Body Mass Index In The Preclinical Stage Of Autosomal Dominant Alzheimer's Disease, Stephan A. Müller, Oliver Preische, Hamid R. Sohrabi, Susanne Gräber, Mathias Jucker, Janko Dietzsch, John M. Ringman, Ralph Martins, Eric M. Mcdade, Peter R. Schofield, Bernardino F. Ghetti, Martin N. Rossor, Neill R. Graff-Radford, Johannes Levin, Douglas R. Galasko, Kimberly A. Quaid, Stephen P. Salloway, Chengjie Xiong, Tammie L. Benzinger, Virginia D. Buckles, C. L. Masters, Reisa A. Sperling, Randall J. Bateman, John C. Morria, Christoph Laske

Research outputs 2014 to 2021

The relationship between body-mass index (BMI) and Alzheimeŕs disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before …

Socioeconomic Status And Stroke Outcome, Sophia Dang, Jonathan C. Li, Kimon Bekelis, Md, Stavropoula Tjoumakaris, Md

Sigma Xi Student Research Day

Introduction

• International studies find socioeconomic status (SES) to be predictive of functional impairment after stroke.^1,2
• Lower socioeconomic status (LSE) is associated with increased severity of stroke onset, higher incidence of risk factors, and worse outcomes.³
• We sought to confirm the predictive significance of SES on acute ischemic stroke patient outcomes at a large urban, U.S. stroke center.

Stroke Quality Measures In Mexican Americans And Non-Hispanic Whites, Darin B. Zahuranec, Lynda D. Lisabeth, Jonggyu Baek, Eric E. Adelman, Nelda M. Garcia, Erin C. Case, Morgan S. Campbell, Lewis Morgenstern

Journal of Health Disparities Research and Practice

Mexican Americans (MAs) have been shown to have worse outcomes after stroke than non-Hispanic Whites (NHWs), but it is unknown if ethnic differences in stroke quality of care may contribute to these worse outcomes. We investigated ethnic differences in the quality of inpatient stroke care between MAs and NHWs within the population-based prospective Brain Attack Surveillance in Corpus Christi (BASIC) Project (February 2009- June 2012). Quality measures for inpatient stroke care, based on the 2008 Joint Commission Primary Stroke Center definitions were assessed from the medical record by a trained abstractor. Two summary measure of overall quality were also created …

Chronic Neuropsychological Sequelae In A Patient With Nontumorous Anti-Nmda-Receptor Encephalitis, Dong Y. Han, Lisa M. Mason, Aarti Patel, Zhengqiu Zhou, Sarah Phillips, Siddharth Kapoor

Neurology Faculty Publications

Anti-N-methyl-D-aspartate receptor encephalitis is a neurological, autoimmune disorder tightly conceptualized only as recently as the mid-2000s. It presents itself in a combination of psychiatric, neurological, and autonomic features. We observe a unique case with probable earlier episode (prior to the mid-2000s conceptualization of the disease) and a later relapse, accompanying a comprehensive neuropsychological profile tracked after the relapse and subsequent improvement. Neurocognitive findings revealed residual frontal deficits with mood changes even in the state after plasmapheresis. This case is the first to describe posttreatment cognition in anti-NMDAR encephalitis after probable serial autoimmune episodes.

Association Of Magnet Status With Hospitalization Outcomes For Ischemic Stroke Patients., Kimon Bekelis, Symeon Missios, Todd A. Mackenzie

Department of Neurosurgery Faculty Papers

BACKGROUND: It is not clear whether Magnet recognition by the American Nurses Credentialing Center (nursing excellence program) is associated with improved patient outcomes. We investigated whether hospitalization in a Magnet hospital is associated with improved outcomes for patients with ischemic stroke.

METHODS AND RESULTS: We performed a cohort study of patients with ischemic stroke from 2009 to 2013, who were registered in the New York Statewide Planning and Research Cooperative System database. Propensity-score-adjusted multivariable regression models were used to adjust for known confounders, with mixed effects methods to control for clustering at the facility level. An instrumental variable analysis was …

Comparison Of Stroke Cohorts Cared For By Two Different Specialties In A Practice-Based Tele-Stroke Population, Elias Atallah, Kimon Bekelis, Hassan Saad, Ayan Kumar, Justin Turpin, Randa Barsoom, Sophia Dang, Jonathan Li, Stavropoula Tjoumakaris, David Hasan, Maureen Deprince, Giuliana Labella, Robert H. Rosenwasswer, Pascal Jabbour

Department of Neurosurgery Posters

Conclusion

• Telemedicine is allowing for more patients suffering from AIS to receive care by dedicated stroke physicians including neurovascular surgeons.
• Our study does not find any difference in outcome between neurologists, who have traditionally managed stroke care, and neurosurgeons.
• Although ischemic stroke is a matter of multidisciplinary management, these surgeons are appropriately knowledgeable to prescribing IVrt-PA and concurrently performing MT in a highly-specialized stroke unit.

Fate Of Neural Progenitor Cells Transplanted Into Jaundiced And Nonjaundiced Rat Brains., Fu-Chen Yang, Sean M. Riordan, Michelle Winter, Li Gan, Peter G. Smith, Jay L. Vivian, Steven Shapiro, John A. Stanford

Manuscripts, Articles, Book Chapters and Other Papers

High levels of bilirubin in infants can cause kernicterus, which includes basal ganglia damage and dystonia. Stem cell transplantation may be an effective treatment for this disease. In this study, we transplanted human neural progenitor cells differentiated toward propriospinal interneurons into the striatum of 20-day-old spontaneously jaundiced (jj) Gunn rats and nonjaundiced (Nj) littermates. Using immunohistochemical methods, we found that grafted cells survived and grew fibers in jj and Nj brains 3 weeks after transplantation. Grafted cells had a higher survival rate in jj than in Nj brains, suggesting that slightly elevated bilirubin may protect graft survival due to its …

Multiple Large Perineural (Tarlov) Cysts In The Sacrum Of A Cadaver: A Case Report And Review., Jocelyn Gonzales, Joe Iwanaga, Nitsa Topale, Rod J Oskouian, R Shane Tubbs

Articles, Abstracts, and Reports

Tarlov or perineural cysts are cerebrospinal fluid (CSF)-filled sacs found between the perineurium and epineurium of the nerve roots. It is still unsure whether the origin of these cysts is intradural or extradural. They can either be asymptomatic or create a variety of negative impacts on comfort and quality of life. In this case report, we describe the presentation of multiple Tarlov cysts including one large cyst discovered during a routine cadaveric spinal dissection and the relevant and related literature. To our knowledge, this is the only cadaveric case report of Tarlov cysts and offers an interesting window into their …

Unmet Need For Surgery In South Asia, Sanjay Nagral, Maharra Hussain, Sarder A. Nayeem, Ranjan Dias, S. Ather Enam, Samiran Nundy

Section of Neurosurgery

No abstract provided.

Secondary Hematoma Expansion And Perihemorrhagic Edema After Intracerebral Hemorrhage: From Bench Work To Practical Aspects., Krista Lim-Hing, Fred Rincon

Department of Neurology Faculty Papers

Intracerebral hemorrhages (ICH) represent about 10-15% of all strokes per year in the United States alone. Key variables influencing the long-term outcome after ICH are hematoma size and growth. Although death may occur at the time of the hemorrhage, delayed neurologic deterioration frequently occurs with hematoma growth and neuronal injury of the surrounding tissue. Perihematoma edema has also been implicated as a contributing factor for delayed neurologic deterioration after ICH. Cerebral edema results from both blood-brain barrier disruption and local generation of osmotically active substances. Inflammatory cellular mediators, activation of the complement, by-products of coagulation and hemolysis such as thrombin …

Noninvasive Monitoring Intracranial Pressure - A Review Of Available Modalities, Marium Naveed Khan, Hussain Shallwani, Muhammad Ulusyar Khan, Muhammad Shahzad Shamim

Section of Neurosurgery

Background: Intracranial pressure (ICP) monitoring is important in many neurosurgical and neurological patients. The gold standard for monitoring ICP, however, is via an invasive procedure resulting in the placement of an intraventricular catheter, which is associated with many risks. Several noninvasive ICP monitoring techniques have been examined with the hope to replace the invasive techniques. The goal of this paper is to provide an overview of all modalities that have been used for noninvasive ICP monitoring to date.
Methods: A thorough literature search was conducted on PubMed, selected articles were reviewed in completion, and pertinent data was included in the …

Perioperative Steroids For Lumbar Disc Surgery: A Meta-Analysis Of Randomized Controlled Trials, Muhammad Waqas, Hussain Shallwani, Muhammad Shahzad Shamim, Khabir Ahmed

Department of Surgery Docs

Background: Our review question was "Does perioperative steroids administration, in comparison with other treatments or placebo, improve either postoperative pain control, length of hospital stay, or return to work in patients undergoing lumbar disc surgery?"
Methods: We searched PubMed, CINAHL PLUS, and Cochrane databases for randomized control trials (RCTs) studying the role of steroids for lumbar disc surgery. Studies that compared perioperative steroids with other treatments or placebo were included. Study outcomes included postoperative back pain, leg pain, length of hospital stay, and return to work. Data was extracted through a proforma. Means and mean differences were calculated for continuous …

Update On The Notochord Including Its Embryology, Molecular Development, And Pathology: A Primer For The Clinician., Tushar Ramesh, Sai V Nagula, Gabrielle G Tardieu, Erfanul Saker, Mohammadali Shoja, Marios Loukas, Rod J Oskouian, R Shane Tubbs

Articles, Abstracts, and Reports

The notochord is a rod-like embryological structure, which plays a vital role in the development of the vertebrate. Though embryological, remnants of this structure have been observed in the nucleus pulposus of the intervertebral discs of normal adults. Pathologically, these remnants can give rise to slow-growing and recurrent notochord-derived tumors called chordomas. Using standard search engines, the literature was reviewed regarding the anatomy, embryology, molecular development, and pathology of the human notochord. Clinicians who interpret imaging or treat patients with pathologies linked to the notochord should have a good working knowledge of its development and pathology.

Ar2, A Novel Automatic Muscle Artifact Reduction Software Method For Ictal Eeg Interpretation: Validation And Comparison Of Performance With Commercially Available Software., Shennan Aibel Weiss, Ali Akbar Asadi-Pooya, Sitaram Vangala, Stephanie Moy, Dale H. Wyeth, Iren Orosz, Michael Gibbs, Lara Schrader, Jason Lerner, Christopher K Cheng, Edward Chang, Rajsekar Rajaraman, Inna Keselman, Perdro Churchman, Christine Bower-Baca, Adam L Numis, Michael G Ho, Lekha Rao, Annapoorna Bhat, Joanna Suski, Marjan Asadollahi, Timothy Ambrose, Andres Fernandez, Maromi Nei, Christopher T. Skidmore, Scott Mintzer, Dawn S. Eliashiv, Gary W Mathern, Marc R Nuwer, Michael R. Sperling, Jerome Engel, John M Stern

Department of Neurology Faculty Papers

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of …

Medical Resource Utilization Of Outpatient Care For Children With Neurofibromatosis Type 1, Rabia Idrees, Michael Fisher, Rachel Hachen, Brian Callaghan, Robert A. Avery

GW Research Days 2016 - 2020

Background:

Neurofibromatosis Type 1 (NF1) is an autosomal dominant syndrome with manifestations affecting the central nervous system, musculoskeletal system, peripheral nervous system, and cognitive/behavioral functions. Many of these manifestations persist throughout life and require medical/surgical interventions.

The resource utilization and economic burden of caring for children with NF1 is unknown. Prior research has inherent selection bias and does not accurately reflect the incidence/resource utilization of morbidities. In order to identify which disease manifestations are in the most need of improved clinical algorithms and novel therapeutics, the frequency/type of resources utilized (i.e., diagnostic imaging and specialty visits) must be determined.

The …