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Id Subject Object Predicate Lexical cue
T1 0-60 Sentence denotes Microvascular Injury in the Brains of Patients with Covid-19
T2 62-76 Sentence denotes To the Editor:
T3 77-686 Sentence denotes We conducted postmortem high-resolution magnetic resonance imaging (magnetic resonance microscopy) of the brains of patients with coronavirus disease 2019 (Covid-19) (median age, 50 years) and histopathological examination that focused on microvascular changes in the olfactory bulb and brain stem. (See the Materials and Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) Images were obtained from the brains of 13 patients with the use of an 11.7-Tesla scanner at a resolution of 25 μm for the olfactory bulb and at a resolution of 100 μm for the brain.
T4 687-740 Sentence denotes Abnormalities were seen in the brains of 10 patients.
T5 741-921 Sentence denotes We examined the brains of patients that showed abnormalities by means of multiplex fluorescence imaging (in 5 patients) and by means of chromogenic immunostaining (in 10 patients).
T6 922-1007 Sentence denotes We performed conventional histopathological examination of the brains of 18 patients.
T7 1008-1151 Sentence denotes Fourteen patients had chronic illnesses, including diabetes and hypertension, and 11 had been found dead or had died suddenly and unexpectedly.
T8 1152-1401 Sentence denotes Of the 16 patients with available medical histories, 1 had delirium, 5 had mild respiratory symptoms, 4 had acute respiratory distress syndrome, 2 had pulmonary embolism, and the symptoms were not known in 3 (Table S1 in the Supplementary Appendix).
T9 1402-1551 Sentence denotes Magnetic resonance microscopy showed punctate hyperintensities in 9 patients, which represented areas of microvascular injury and fibrinogen leakage.
T10 1552-1694 Sentence denotes These features were observed on corresponding histopathological examination performed with the use of fluorescence imaging (Figure 1A and 1B).
T11 1695-1846 Sentence denotes These areas showed thinning of the basal lamina of the endothelial cells, as determined by collagen IV immunostaining in 5 patients (Fig. 1B1 and 1B2).
T12 1847-2065 Sentence denotes Punctate hypointensities on imaging in 10 patients corresponded to congested blood vessels (Figure 1C) with surrounding areas of fibrinogen leakage (Figure 1D and Fig. S1) and relatively intact vasculature (Figure 1E).
T13 2066-2159 Sentence denotes Areas of linear hypointensities were interpreted as microhemorrhages (Figure 1F and Fig. S2).
T14 2160-3021 Sentence denotes There was minimal perivascular inflammation in the specimens examined, but there was no vascular occlusion, as previously described in the Journal.1 Perivascular-activated microglia, macrophage infiltrates, and hypertrophic astrocytes were seen in 13 patients (Figure 1G and 1H, Fig. S3, and Table S4).2 There were CD3+ and CD8+ T cells in the perivascular spaces and in lumens adjacent to endothelial cells in 8 patients, which may have contributed to vascular injury (Figure 1I and 1J), as suggested in a previous report.3 Activated microglia were found adjacent to neurons in 5 patients, which is suggestive of neuronophagia in the olfactory bulb, substantia nigra, dorsal motor nucleus of the vagal nerve, and the pre-Bötzinger complex in the medulla, which is involved in the generation of spontaneous rhythmic breathing (Figure 1K through 1N and Fig. S3).
T15 3022-3257 Sentence denotes Severe acute respiratory syndrome coronavirus 2 was not detected by means of polymerase chain reaction with multiple primer sets, RNA sequencing of several areas of the brain, or RNA in situ hybridization and immunostaining (Table S5).
T16 3258-3396 Sentence denotes It is possible that the virus was cleared by the time of death or that viral copy numbers were below the level of detection by our assays.
T17 3397-3708 Sentence denotes In a convenience sample of patients who had died from Covid-19, multifocal microvascular injury was observed in the brain and olfactory bulbs by means of magnetic resonance microscopy, histopathological evaluation, and immunohistochemical analysis of corresponding sections, without evidence of viral infection.
T18 3709-3886 Sentence denotes These findings may inform the interpretation of changes observed on magnetic resonance imaging of punctate hyperintensities and linear hypointensities in patients with Covid-19.
T19 3887-4026 Sentence denotes Because of the limited clinical information that was available, no conclusions can be drawn in relation to neurologic features of Covid-19.
T20 4028-4152 Sentence denotes Supported by intramural funds (K23NS109284 [to Dr. Hefti]) from the National Institute of Neurological Disorders and Stroke.
T21 4153-4454 Sentence denotes The reagent used in this study (Genomic RNA from SARS-CoV-2, Isolate USA-WA1/2020, NR-52285) was deposited by the Centers for Disease Control and Prevention and obtained through BEI Resources Repository of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
T22 4455-4556 Sentence denotes Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
T23 4558-4705 Sentence denotes The opinions expressed here are those of the authors and are not necessarily representative of those of the Uniformed Services University, the U.S.
T24 4706-4740 Sentence denotes Department of Defense, or the U.S.
T25 4741-4794 Sentence denotes Army, Navy, or Air Force or any other federal agency.
T26 4795-4855 Sentence denotes This letter was published on December 30, 2020, at NEJM.org.
T27 4857-4879 Sentence denotes Supplementary Appendix
T28 4880-4916 Sentence denotes Click here for additional data file.
T29 4918-4934 Sentence denotes Disclosure Forms
T30 4935-4971 Sentence denotes Click here for additional data file.
T31 4973-5077 Sentence denotes Figure 1 Pathological Studies of Microvascular Injury in the Brains of Patients Who Died from Covid-19.
T32 5078-5185 Sentence denotes Panel A (magnetic resonance microscopy of the olfactory bulb) shows an area of hyperintense signal (arrow).
T33 5186-5419 Sentence denotes Panel B shows the corresponding area on multiplex immunofluorescence imaging, which revealed a focal area of fibrinogen leakage (in the box, fibrinogen is shown in green, collagen IV is shown in yellow, and nuclei are shown in blue).
T34 5420-5576 Sentence denotes Panel B1 shows diffuse leakage of fibrinogen in the parenchyma (an enlarged view showing marked blood vessel staining for collagen IV is shown in Panel B2).
T35 5577-5717 Sentence denotes Panel B2 (collagen IV immunostaining) shows intact (arrowhead) and thinned (arrow) basal lamina with fibrinogen leakage into the parenchyma.
T36 5718-5930 Sentence denotes Panel C shows magnetic resonance microscopy of the pons, and Panel D (fibrinogen staining) shows areas of increased signal intensity corresponding to the vascular leakage visible on magnetic resonance microscopy.
T37 5931-6027 Sentence denotes The arrows and the area within the dashed lines in Panels C and D indicate the vascular leakage.
T38 6028-6090 Sentence denotes Panels A through E represent imaging performed in Patient IA1.
T39 6091-6194 Sentence denotes Panel E (collagen IV immunostaining) shows areas of fibrinogen leakage in blood vessels in Patient IA1.
T40 6195-6269 Sentence denotes Panel F shows magnetic resonance microscopy of the medulla in Patient IA3.
T41 6270-6381 Sentence denotes The yellow arrows indicate linear hypointense signals, and the red arrows indicate linear hyperintense signals.
T42 6382-6454 Sentence denotes Panel G shows CD68+ perivascular macrophages in the pons in Patient NY6.
T43 6455-6531 Sentence denotes Panel H shows perivascular astrocytosis in the basal ganglia in Patient NY5.
T44 6532-6603 Sentence denotes Panel I shows perivascular CD3+ cells in the cerebellum in Patient IA1.
T45 6604-6686 Sentence denotes Panel J shows intraluminal and perivascular CD8+ cells in the pons in Patient NY6.
T46 6687-6752 Sentence denotes Panel K shows perineuronal IBA1 cells in the pons in Patient NY6.
T47 6753-6841 Sentence denotes Panel L shows CD68+ cells in the dorsal motor nucleus of the vagus nerve in Patient IA1.
T48 6842-7007 Sentence denotes Panel M shows a solitary nucleus in the medulla and Panel N shows a pre-Bötzinger complex in Patient IA1. (Diaminobenzidine staining was used in Panels G through N.)