doi : 10.1212/WNL.0000000000013167
Volume 98(5), 1 February 2022, p 173-174
doi : 10.1212/WNL.0000000000013166
Volume 98(5), 1 February 2022, p 177-178
Chen, Hsin Yi BS; Elmer, Jonathan MD; Zafar, Sahar F. MD; Ghanta, Manohar MS; Moura Junior, Valdery MS; Rosenthal, Eric S. MD; Gilmore, Emily J. MD; Hirsch, Lawrence J. MD; Zaveri, Hitten P. PhD; Sheth, Kevin N. MD; Petersen, Nils H. MD, PhD; Westover, M. Brandon MD, PhD*; Kim, Jennifer A. MD, PhD*
doi : 10.1212/WNL.0000000000013126
Volume 98(5), 1 February 2022, p e459-e469
Delayed cerebral ischemia (DCI) is the leading complication of subarachnoid hemorrhage (SAH). Because DCI was traditionally thought to be caused by large vessel vasospasm, transcranial Doppler ultrasounds (TCDs) have been the standard of care. Continuous EEG has emerged as a promising complementary monitoring modality and predicts increased DCI risk. Our objective was to determine whether combining EEG and TCD data improves prediction of DCI after SAH. We hypothesize that integrating these diagnostic modalities improves DCI prediction.
Chong, Michael Robert MSc; Narula, Sukrit BA; Morton, Robert PhD; Judge, Conor MB; Akhabir, Loubna PhD; Cawte, Nathan BSc; Pathan, Nazia BSc; Lali, Ricky MSc; Mohammadi-Shemirani, Pedrum BSc; Shoamanesh, Ashkan MD; O'Donnell, Martin PhD; Yusuf, Salim DPhil; Langhorne, Peter PhD; Pare, Guillaume MD, MSc
doi : 10.1212/WNL.0000000000013165
Volume 98(5), 1 February 2022, p e470-e482
Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies.
Smirnov, Denis S. PhD; Salmon, David P. PhD; Galasko, Douglas MD; Goodwill, Vanessa S. MD; Hansen, Lawrence A. MD; Zhao, Yu MS; Edland, Steven D. PhD; Leger, Gabriel C. MD; Peavy, Guerry M. PhD; Jacobs, Diane M. PhD; Rissman, Robert PhD; Pizzo, Donald P. PhD; Hiniker, Annie MD, PhD
doi : 10.1212/WNL.0000000000013107
Volume 98(5), 1 February 2022, p e506-e517
Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology.
Topiwala, Karan K. MBBS; Patel, Smit D. MBBS; Saver, Jeffrey L. MD; Streib, Christopher D. MD; Shovlin, Claire L. PhD
doi : 10.1212/WNL.0000000000013169
Volume 98(5), 1 February 2022, p 188-198
The potential of covert pulmonary arteriovenous malformations (PAVMs) to cause early onset, preventable ischemic strokes is not well known to neurologists. This is evident by their lack of mention in serial American Heart Association/American Stroke Association (AHA/ASA) Guidelines and the single case report biased literature of recent years. We performed PubMed and Cochrane database searches for major studies on ischemic stroke and PAVMs published from January 1, 1974, through April 3, 2021. This identified 24 major observational studies, 3 societal guidelines, 1 nationwide analysis, 3 systematic reviews, 21 other review/opinion articles, and 18 recent (2017-2021) case reports/series that were synthesized. Key points are that patients with PAVMs have ischemic stroke a decade earlier than routine stroke, losing 9 extra healthy life-years per patient in the recent US nationwide analysis (2005-2014). Large-scale thoracic CT screens of the general population in Japan estimate PAVM prevalence to be 38/100,000 (95% confidence interval 18-76), with ischemic stroke rates exceeding 10% across PAVM series dating back to the 1950s, with most PAVMs remaining undiagnosed until the time of clinical stroke. Notably, the rate of PAVM diagnoses doubled in US ischemic stroke hospitalizations between 2005 and 2014. The burden of silent cerebral infarction approximates to twice that of clinical stroke. More than 80% of patients have underlying hereditary hemorrhagic telangiectasia. The predominant stroke mechanism is paradoxical embolization of platelet-rich emboli, with iron deficiency emerging as a modifiable risk factor. PAVM-related ischemic strokes may be cortical or subcortical, but very rarely cause proximal large vessel occlusions. Single antiplatelet therapy may be effective for secondary stroke prophylaxis, with dual antiplatelet or anticoagulation therapy requiring nuanced risk-benefit analysis given their risk of aggravating iron deficiency. This review summarizes the ischemic stroke burden from PAVMs, the implicative pathophysiology, and relevant diagnostic and treatment overviews to facilitate future incorporation into AHA/ASA guidelines.
Dietrichs, Espen MD, PhD
doi : 10.1212/WNL.0000000000013149
Volume 98(5), 1 February 2022, p 199-203
The Norwegian physician Carl Wilhelm Sem-Jacobsen (1912-1991) was a pioneer in deep brain stimulation and aerospace neurophysiology, but for several reasons, his story has remained untold. During WW2, he collaborated with a renowned military underground resistance group against the Nazi occupants and then had to flee to neutral Sweden. He returned to participate in the liberation of Northern Norway as a Captain in the US Special Forces also working with the OSS (Office of Strategic Services-precursor for CIA) and received a citation from General Eisenhower for his contributions. Sem-Jacobsen then spent several years in the US training in psychiatry and clinical neurophysiology at the Mayo Clinic. He constructed his own medical technical devices, was among the first to develop deep brain stimulation, and made the smallest EEG and EKG recording systems yet produced, also used by the American astronauts walking on the Moon. But he was more an inventor than a researcher, and few of his observations were published in peer-reviewed medical journals. He built his own neurophysiologic institute for neurosurgery, deep brain recordings, and deep brain stimulation in Oslo's main psychiatric hospital, but was sponsored by US military forces and NASA. He knew CIA Director William E. Colby personally, and rumors soon flourished that Sem-Jacobsen conducted secret mind control experiments for American authorities and the CIA. These accusations were investigated, and long after his death, he was officially absolved by a Hearing Committee appointed by the Norwegian Government. Nevertheless, all his personal files were burnt by his family who was still harassed by investigative journalists. Sem-Jacobsen also documented some of his work on film, but the whereabouts of these films have remained unknown. I searched for them for several years and recently discovered numerous films and photographs in an old barn in rural Norway. These films and photographs document in-action neurophysiology recordings in divers, pilots, and astronauts, and they show how Sem-Jacobsen in collaboration with experienced neurosurgeons in Oslo conducted the very first trials with deep brain stimulation in patients with Parkinson disease. He apparently even tried subthalamic stimulation as early as in the 1950s.
Nishijima, Haruo MD, PhD; Kon, Tomoya MD, PhD; Seino, Yusuke MD, PhD; Yagihashi, Norito MD, PhD; Suzuki, Chieko MD, PhD; Nakamura, Takashi MD; Tanaka, Hisashi MD, PhD; Sakamoto, Yui MD; Wakabayashi, Koichi MD, PhD; Tomiyama, Masahiko MD, PhD
doi : 10.1212/WNL.0000000000013091
Volume 98(5), 1 February 2022, p 204-205
Pastre, Romain MD; Perignon, Renan MD; Sia, Mary-Angel MD
doi : 10.1212/WNL.0000000000013086
Volume 98(5), 1 February 2022, p 206-207
Karschnia, Philipp MD, DSc; Kaulen, Leon MD; Thon, Niklas MD, DSc, MBA; Baehring, Joachim M. MD, DSc
doi : 10.1212/WNL.0000000000013085
Volume 98(5), 1 February 2022, p 208-213
A 64-year-old man presented for evaluation of proximally pronounced weakness of the arms with preserved facial and lower extremity strength. Symptoms slowly developed over the last 2 years, and the patient's history was notable for severe Listeria monocytogenes meningitis 4 years before presentation, which was adequately treated with antibiotics. On examination, symptoms clinically reassembled man-in-the-barrel syndrome and localized to the cervicothoracic central cord. Blood analysis was unremarkable, and CSF analysis showed no recurrent or persistent infection. Spinal MRI revealed pockets of sequestered CSF from C3 to C4 and areas of CSF space effacement from C3 to T12. MRI findings were interpreted as cord tethering suggestive of adhesive arachnoiditis. CT myelogram showed insufficient contrast agent migration above T10 and contour irregularities of the conus medullaris, confirming the postulated pathomechanism of cord tethering. Final diagnosis was therefore cervicothoracic central cord damage due to cord tethering in the setting of postinfectious adhesive arachnoiditis following bacterial meningitis. The patient failed a course of pulsed methylprednisolone therapy, and symptoms progressed. Best supportive care was provided. The clinical presentation of adhesive arachnoiditis is variable, and advanced imaging techniques and invasive studies such as CT myelogram may be required to establish the diagnosis. Timely diagnosis is warranted as early surgical or medical therapy can improve symptoms.
Alkabie, Samir MD, MSc; Tanweer, Omar MD; Hutton, George J. MD; Cuascut, Fernando X. MD, MPH
doi : 10.1212/WNL.0000000000013090
Volume 98(5), 1 February 2022, p e555-e560
We present the case of a 57-year-old man with protein S deficiency and left leg deep vein thrombosis (DVT) 5 years earlier, who developed stepwise progressive bilateral lower limb weakness, numbness/paresthesia, gait imbalance, hesitancy of micturition, and constipation in the setting of recurrent left common femoral DVT treated with apixaban. Symptoms amplified with Valsalva, corticosteroids, and postlumbar puncture, with longitudinally extensive midthoracic T2-hyperintense lesion extending to the conus associated with hazy holocord enhancement on magnetic resonance imaging (MRI), raising suspicion for spinal dural arteriovenous fistula (sDAVF). Initial digital subtraction angiography (DSA) was negative for sDAVF. However, cerebral spinal fluid (CSF) was herpes simplex virus (HSV)-2 positive, and he was treated with antiviral therapy. Unfortunately, he continued to worsen despite treatment. Repeat neuroimaging 12 months after initial presentation demonstrated persistent lower thoracic/conus lesion in addition to cauda equina enhancement and subtle dorsal T2-hypointense flow voids. We raised red flags (e.g., lack of clinical prodrome, no herpetic rash, no CSF pleocytosis, and rostral extent of the lesion) that suggested the HSV2 nucleic acid detection was perhaps unrelated to the neurologic syndrome. Given the high index of suspicion for sDAVF, we repeated spinal vascular imaging. Spinal MRA demonstrated dilated right dorsal perimedullary veins from T10 to T11. Repeat DSA revealed a right T10 sDAVF. Microsurgical treatment rather than embolization of the fistula was successful without complication, with significant improvement in motor, sphincter, and to a lesser extent sensory function, with residual gait imbalance after inpatient rehabilitation 3 weeks postoperatively.
Kroeff, Bruna MD; Hummelgen, Eduardo MD; Fabiani, Giorgio MD; Martins Cervellini, Ana Rosa MD, MSc
doi : 10.1212/WNL.0000000000013020
Volume 98(5), 1 February 2022, p e561-e562
Peeters, Michael T.J. MD; Sutedja, Nadia A. MD, PhD; Broen, Martinus P.G. MD, PhD
doi : 10.1212/WNL.0000000000013019
Volume 98(5), 1 February 2022, p e563
Siegler, James E. MD; Galetta, Steven MD
doi : 10.1212/WNL.0000000000013178
Volume 98(5), 1 February 2022, p 214
Sethi, Nitin K.
doi : 10.1212/WNL.0000000000013179
Volume 98(5), 1 February 2022, p 214
Solomon, Jacqueline M.
doi : 10.1212/WNL.0000000000013180
Volume 98(5), 1 February 2022, p 215
Meador, Kimford J. MD; Jobst, Barbara C. MD
doi : 10.1212/WNL.0000000000013132
Volume 98(5), 1 February 2022, p 175-176
doi : 10.1212/WNL.0000000000012887
Volume 98(5), 1 February 2022, p 215
doi : 10.1212/WNL.0000000000011198
Volume 98(5), 1 February 2022, p 215
Ostendorf, Adam P. MD*; Ahrens, Stephanie M. DO*; Lado, Fred Alexander MD, PhD; Arnold, Susan T. MD; Bai, Shasha PhD; Bensalem Owen, Meriem K. MD; Chapman, Kevin E. MD; Clarke, Dave F. MD; Eisner, Mariah MS; Fountain, Nathan B. MD; Gray, Johanna M. MPA; Hopp, Jennifer L. MD; Riker, Ellen MHA; Schuele, Stephan U. MD, MPH; Small, Barbara V. BA; Herman, Susan T. MD
doi : 10.1212/WNL.0000000000013130
Volume 98(5), 1 February 2022, p e449-e458
Patients with drug-resistant epilepsy (DRE) may benefit from specialized testing and treatments to better control seizures and improve quality of life. Most evaluations and procedures for DRE in the United States are performed at epilepsy centers accredited by the National Association of Epilepsy Centers (NAEC). On an annual basis, the NAEC collects data from accredited epilepsy centers on hospital-based epilepsy monitoring unit (EMU) size and admissions, diagnostic testing, surgeries, and other services. This article highlights trends in epilepsy center services from 2012 through 2019.
Balasubramanian, Raji ScD; Hu, Jie MD, PhD; Guasch-Ferre, Marta PhD; Li, Jun MD, PhD; Sorond, Farzaneh MD; Zhao, Yibai MS; Shutta, Katherine H. MS; Salas-Salvado, Jordi MD, PhD; Hu, Frank MD, PhD; Clish, Clary B. PhD; Rexrode, Kathryn M. MD, MPH
doi : 10.1212/WNL.0000000000013129
Volume 98(5), 1 February 2022, p e483-e492
Women have higher lifetime risk of stroke than men, and metabolic factors seem more strongly associated with stroke for women than men. However, few studies in either men or women have evaluated metabolomic profiles and incident stroke.
Dauvilliers, Yves MD; Barateau, Lucie MD; Middleton, Benita PhD; van der Veen, Daan R. PhD; Skene, Debra J. PhD
doi : 10.1212/WNL.0000000000013128
Volume 98(5), 1 February 2022, p e493-e505
Narcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m2). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status.
Doets, Alex Y. MD, PhD candidate; Lingsma, Hester F. PhD; Walgaard, Christa MD, PhD candidate; Islam, Badrul MBBS, PhD; Papri, Nowshin MD, PhD candidate; Davidson, Amy MD, PhD candidate; Yamagishi, Yuko MD, PhD; Kusunoki, Susumu MD, PhD; Dimachkie, Mazen M. MD; Waheed, Waqar MD; Kolb, Noah MD; Islam, Zhahirul PhD; Mohammad, Quazi Deen MD; Harbo, Thomas MD, PhD; Sindrup, Soren H. MD, PhD; Chavada, Govindsinh MD, PhD; Willison, Hugh J. MD, PhD; Casasnovas, Carlos MD, PhD; Bateman, Kathleen MBChB; Miller, James A.L. MD, PhD; van den Berg, Bianca MD, PhD candidate; Verboon, Christine MD, PhD candidate; Roodbol, Joyce MD, PhD candidate; Leonhard, Sonja E. MD, PhD candidate; Benedetti, Luana MD, PhD; Kuwabara, Satoshi MD, PhD; Van den Bergh, Peter MD, PhD; Monges, Soledad MD; Marfia, Girolama A. MD; Shahrizaila, Nortina FRCP, PhD; Galassi, Giuliana MD; Pereon, Yann MD, PhD; Burmann, Jan MD; Kuitwaard, Krista MD, PhD; Kleyweg, Ruud P. MD, PhD; Marchesoni, Cintia MD; Sedano Tous, Maria J. MD; Querol, Luis MD, PhD; Illa, Isabel MD, PhD; Wang, Yuzhong MD; Nobile-Orazio, Eduardo MD, PhD; Rinaldi, Simon MBChB, PhD; Schenone, Angelo MD; Pardo, Julio MD, PhD; Vermeij, Frederique H. MD; Lehmann, Helmar C. MD, PhD; Granit, Volkan MD; Cavaletti, Guido MD; Gutierrez-Gutierrez, Gerardo MD; Barroso, Fabio A. MD; Visser, Leo H. MD, PhD; Katzberg, Hans D. MD; Dardiotis, Efthimios MD; Attarian, Shahram MD, PhD; van der Kooi, Anneke J. MD, PhD; Eftimov, Filip MD, PhD; Wirtz, Paul W. MD, PhD; Samijn, Johnny P.A. MD; Gilhuis, H. Jacobus MD, PhD; Hadden, Robert D.M. MD, PhD; Holt, James K.L. FRCP, PhD; Sheikh, Kazim A. MD; Karafiath, Summer MD; Vytopil, Michal MD; Antonini, Giovanni MD; Feasby, Thomas E. MD; Faber, Catharina G. MD, PhD; Gijsbers, Cees J. MD; Busby, Mark MD; Roberts, Rhys C. MB BChir PhD; Silvestri, Nicholas J. MD; Fazio, Raffaella MD; van Dijk, Gert W. MD; Garssen, Marcel P.J. MD, PhD; Straathof, Chiara S.M. MD, PhD; Gorson, Kenneth C. MD; Jacobs, Bart C. MD, PhD; on behalf of the IGOS Consortium; on behalf of the IGOS Consortium; Hughes, R.A.C. MD; Cornblath, D.R. MD; Hartung, H.P. MD, PhD; van Doorn, P.A. MD, PhD; de Koning, L.C. B AS; van Woerkom, M.; Mandarakas, M.; MPhty, BHIthSci(Hons) PhD; Reisin, R.C. MD; Reddel, S.W. MD, PhD; Ripellino, P. MD; Hsieh, S.T. MD, PhD; Addington, J.M. MD; Ajroud-Driss, S. MD; Andersen, H. MD, PhD; Badrising, U.A. MD, PhD; Bella, I.R. MD; Bertorini, T.E. MD; Bhavaraju-Sanka, R. MD; Bianco, M. MD; Brannagan, T.H. MD; Briani, Chiara MD; Butterworth, S. MD; Chao, C.C. MD, PhD; Chen, S. MD, PhD; Claeys, K.G. MD, PhD; Conti, M.E. MD; Cosgrove, J.S. MD; Dalakas, M.C. MD, M.A. Derejko, MD, PhD; Dornonville de la Cour, C. MD; Echaniz-Laguna, A. MD, PhD; Fehmi, J. MRCP; Fokke, C. MD; Fujioka, T. MD; Fulgenzi, E.A. MD; Garcia-Sobrino, T. MD; Gilchrist, J.M. MD; Goldstein, J.M. MD; Goyal, N.A. MD; Grisanti, S.G. MD; Gutman, L. MD; Holbech, J.V. MD, PhD; Homedes, C. MD; Htut, M. MD; Jellema, K. MD, PhD; Pascual, I. Jerico MD, PhD; JimenoMontero, M.C.; Kaida, K. MD, PhD; Khoshnoodi, M. MD; Kiers, L. MD; Kimpinski, K. MD; Kohler, A.A. MD; Kokubun, N. MD; Kuwahara, M. MD, PhD; Kwan, J.Y. MD; Ladha, S.S. MD; Lassen, L. Landschoff MD; Lawson, V. MD; Pan, E.B. Lee MBChB; Cejas, L. Leon MD; Lunn, M.P.T. MD, PhD; Magot, A. MD; Manji, H. MD, FRCP; Infante, C. Marquez MD; Martin-Aguilar, L. MD; Hernandez, E. Martinez MD, PhD; Mataluni, G. MD, PhD; Mattiazzi, M.G. MD; McDermott, C.J. MD; Meekins, G.D. MD; Moris de la Tassa, G. MD; Nascimbene, C. MD, PhD; Nowak, R.J. MD; Osei-Bonsu, M. MD; Pascuzzi, R.M. MD; Prada, V. PhD, M.T. Pulley, MD, PhD; Rojas-Marcos, I. MD; Rudnicki, S.A. MD; Sachs, G.M. MD; Samukawa, M. MD, PhD; Santoro, L. MD, PhD; Savransky, A.G. MD; Schwindling, L. MD; Sekiguchi, Y. MD, PhD; Sommer, C.L. MD; Spyropoulos, A. MD; Stein, B. MD; Stino, A.M. MD; Tan, C.Y. MRCP; Tankisi, H. MD, PhD; Twydell, P.T. DO, MS, FAAN; van Damme, P. MD, PhD; van der Ree, T. MD; van Koningsveld, R. MD, PhD; Varrato, J.D. DO; Xing, C.; Zhou, L. MD, PhD; Zivkovic, S. MD, PhD
doi : 10.1212/WNL.0000000000013139
Volume 98(5), 1 February 2022, p e518-e532
The clinical course and outcome of the Guillain-Barre syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity.
Selioutski, Olga DO; Auinger, Peggy MS; Siddiqi, Omar K. MD, MPH; Michael, Benedict Daniel MRCP, PhD; Buback, Clayton MD; Birbeck, Gretchen L. MD, MPH
doi : 10.1212/WNL.0000000000013127
Volume 98(5), 1 February 2022, p e533-e540
The utility of the Glasgow Coma Scale (GCS) in intubated patients is limited due to reliance on language function evaluation. The Full Outline of Unresponsiveness (FOUR) Score was designed to circumvent this shortcoming, instead adding evaluations of brainstem reflexes (FOUR B) and specific respiratory patterns (FOUR R). We aimed to determine whether the verbal component of the GCS (GCS V) among nonintubated patients with encephalopathy significantly contributes to mortality prediction and to assess GCS vs FOUR Score performance.
Tortorella, Carla MD, PhD*; Aiello, Alessandra PhD*; Gasperini, Claudio MD, PhD; Agrati, Chiara PhD; Castilletti, Concetta PhD; Ruggieri, Serena MD, PhD; Meschi, Silvia PhD; Matusali, Giulia PhD; Colavita, Francesca PhD; Farroni, Chiara PhD; Cuzzi, Gilda MSc; Cimini, Eleonora PhD; Tartaglia, Eleonora MSc; Vanini, Valentina MLT; Prosperini, Luca MD, PhD; Haggiag, Shalom MD; Galgani, Simona MD; Quartuccio, Maria Esmeralda MD; Salmi, Andrea MLT; Repele, Federica MSc; Altera, Anna Maria Gerarda MLT; Cristofanelli, Flavia MSc; D'Abramo, Alessandra MD; Bevilacqua, Nazario MD; Corpolongo, Angela MD; Puro, Vincenzo MD; Vaia, Francesco MD; Capobianchi, Maria Rosaria PhD; Ippolito, Giuseppe MD; Nicastri, Emanuele MD, PhD; Goletti, Delia MD, PhD; on behalf of the INMI COVID-19 Vaccine Study Group; on behalf of the INMI COVID-19 Vaccine Study Group; Lapa, Daniele MSc; Francalancia, Massimo MLT; Bettini, Aurora MLT; Gramigna, Giulia MSc; Forbici, Federica MSc; Gall`[latin dotless i], Paola MD; Marani, Alessandra MD; Possi, Adriano MSc; Capri, Andrea MD; Santoro, Annapaola MD; Orchi, Nicoletta MD; Butera, Ornella MLT; Fard, Saeid Najafi PhD; Petrone, Linda PhD; Petruccioli, Elisa PhD
doi : 10.1212/WNL.0000000000013108
Volume 98(5), 1 February 2022, p e541-e554
To evaluate the immune-specific response after full severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination of patients with multiple sclerosis (MS) treated with different disease-modifying drugs by the detection of both serologic and T-cell responses.
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