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  • 1
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    Online Resource
    Brain-derived neurotrophic factor and neurofilament light chain in cerebrospinal fluid are inversely correlated with cognition in Multiple Sclerosis at the time of diagnosis
    Elsevier BV ; 2022
    In:  Multiple Sclerosis and Related Disorders Vol. 63 ( 2022-07), p. 103822-
    Details
    In: Multiple Sclerosis and Related Disorders, Elsevier BV, Vol. 63 ( 2022-07), p. 103822-
    Type of Medium: Online Resource
    ISSN: 2211-0348
    URL: Article
    DOI: 10.1016/j.msard.2022.103822
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2645330-7
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  • 2
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    Intrathecal B-cell accumulation and axonal damage distinguish MRI-based benign from aggressive onset in MS
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 6, No. 5 ( 2019-09), p. e595-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 5 ( 2019-09), p. e595-
    Abstract: We explored the incremental value of adding multiple disease activity biomarkers in CSF and serum for distinguishing MRI-based benign from aggressive MS in early disease course. Methods Ninety-three patients diagnosed with clinically isolated syndrome (CIS) or early MS were divided into 3 nonoverlapping severity groups defined by objective MRI criteria. Ninety-seven patients with noninflammatory neurologic disorders and 48 patients with other inflammatory neurologic diseases served as controls. Leukocyte subsets in the CSF were analyzed by flow cytometry. CSF neurofilament light chain (NfL) and chitinase-3-like protein 1 (CHI3L1) levels were measured by ELISA. Serum NfL levels were examined using single molecule array technology. Results CSF CD20+/CD14+ ratios and NfL levels in CSF and serum were significantly different between high and low MRI severity groups, whereas no difference was found for CSF CHI3L1 levels. NfL levels in CSF and serum highly correlated. Receiver operating characteristic analysis demonstrated that the cumulative sums combining CSF CD20+/CD14+ ratios and NfL levels in serum or CSF considerably improved diagnostic accuracy. A composite score built from these 2 cumulative sums best distinguished MRI severity. These findings were validated by support vector machine analysis, which confirmed that the accuracy of the cumulative sums and composite score outperforms single biomarkers. Conclusion Patients with extreme manifestations of CIS or early MS defined by strict MRI parameters can be best distinguished by combining markers of intrathecal B-cell accumulation and axonal damage. This could stratify individual treatment decisions toward a more personalized immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000000595
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2767740-0
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  • 3
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    Serum Neurofilament Identifies Patients With Multiple Sclerosis With Severe Focal Axonal Damage in a 6-Year Longitudinal Cohort
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 10, No. 1 ( 2023-01), p. e200055-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. 1 ( 2023-01), p. e200055-
    Abstract: Immunomodulatory therapies reduce the relapse rate but only marginally control disability progression in patients with MS. Although serum neurofilament light chain (sNfL) levels correlate best with acute signs of inflammation (e.g., relapses and gadolinium-enhancing [Gd+] lesions), their role in predicting progressive biology and irreversible axonal damage is less clear. We aimed to determine the ability of sNfL to dissect distinct measures of disease severity and predict future (no) evidence of disease activity (EDA/no evidence of disease activity [NEDA] ). Methods One hundred fifty-three of 221 patients with relapsing-remitting MS initially enrolled in the Neurofilament and longterm outcome in MS cohort at the MS outpatient clinic of the University Medical Center Mainz (Germany) met the inclusion criteria for this prospective observational cohort study with a median follow-up of 6 years (interquartile range 4–7 years). Progressive disease forms were excluded. Inclusion criteria consisted of Expanded Disability Status Scale (EDSS) assessment within 3 months and MRI within 12 months around blood sampling at baseline (y0) and follow-up (y6). EDSS progression at y6 had to be confirmed 12 weeks later. sNfL was measured by single-molecule array, and the following additional variables were recorded: therapy, medical history, and detailed MRI parameters (T2 hyperintense lesions, Gd+ lesions, and new persistent T1 hypointense lesions). Results Patients experiencing EDSS progression or new persistent T1 lesions at y6 showed increased sNfL levels at y0 compared with stable patients or patients with inflammatory activity only. As a potential readily accessible marker of neurodegeneration, we incorporated the absence of persistent T1 lesions to the NEDA-3 concept (NEDA-3 T1 : n = 54, 35.3%; EDA T1 : n = 99, 64.7%) and then evaluated a risk score with factors that distinguish patients with and without NEDA-3 T1 status. Adding sNfL to this risk score significantly improved NEDA-3 T1 prediction (0.697 95% CI 0.616–0.770 vs 0.819 95% CI 0.747–0.878, p 〈 0.001). Patients with sNfL values ≤8.6 pg/mL showed a 76% risk reduction for EDA T1 at y6 (hazard ratio 0.244, 95% CI 0.142–0.419, p 〈 0.001). Discussion sNfL levels associate with severe focal axonal damage as reflected by development of persistent T1 lesions. Baseline sNfL values predicted NEDA-3 T1 status at 6-year follow-up.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000200055
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 4
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    Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy
    Wiley ; 2021
    In:  Epilepsia Vol. 62, No. 1 ( 2021-01), p. 176-189
    Details
    In: Epilepsia, Wiley, Vol. 62, No. 1 ( 2021-01), p. 176-189
    Abstract: Adult drug‐resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well‐controlled epilepsy (WCE). Methods Peripheral blood mononuclear cells and serum from 〉 120 age‐ and sex‐matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array. Results Using a data‐driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)‐17A, IL‐22, tumor necrosis factor, interferon‐γ, and granulocyte‐macrophage colony–stimulating factor, but not anti‐inflammatory cytokines IL‐10 and IL‐4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17‐related circulating proinflammatory cytokines are elevated, but Th2‐related cytokine IL‐4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals. Significance Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.
    Type of Medium: Online Resource
    ISSN: 0013-9580 , 1528-1167
    URL: Issue
    URL: Article
    DOI: 10.1111/epi.v62.1
    DOI: 10.1111/epi.16742
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2002194-X
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  • 5
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    Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 5 ( 2022-06-03), p. 1711-1725
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 5 ( 2022-06-03), p. 1711-1725
    Abstract: Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing–remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac064
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 6
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    Improved prediction of early cognitive impairment in multiple sclerosis combining blood and imaging biomarkers
    Oxford University Press (OUP) ; 2022
    In:  Brain Communications Vol. 4, No. 4 ( 2022-07-04)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 4, No. 4 ( 2022-07-04)
    Abstract: Disability in multiple sclerosis is generally classified by sensory and motor symptoms, yet cognitive impairment has been identified as a frequent manifestation already in the early disease stages. Imaging- and more recently blood-based biomarkers have become increasingly important for understanding cognitive decline associated with multiple sclerosis. Thus, we sought to determine the prognostic utility of serum neurofilament light chain levels alone and in combination with MRI markers by examining their ability to predict cognitive impairment in early multiple sclerosis. A comprehensive and detailed assessment of 152 early multiple sclerosis patients (Expanded Disability Status Scale: 1.3 ± 1.2, mean age: 33.0 ± 10.0 years) was performed, which included serum neurofilament light chain measurement, MRI markers (i.e. T2-hyperintense lesion volume and grey matter volume) acquisition and completion of a set of cognitive tests (Symbol Digits Modalities Test, Paced Auditory Serial Addition Test, Verbal Learning and Memory Test) and mood questionnaires (Hospital Anxiety and Depression scale, Fatigue Scale for Motor and Cognitive Functions). Support vector regression, a branch of unsupervised machine learning, was applied to test serum neurofilament light chain and combination models of biomarkers for the prediction of neuropsychological test performance. The support vector regression results were validated in a replication cohort of 101 early multiple sclerosis patients (Expanded Disability Status Scale: 1.1 ± 1.2, mean age: 34.4 ± 10.6 years). Higher serum neurofilament light chain levels were associated with worse Symbol Digits Modalities Test scores after adjusting for age, sex Expanded Disability Status Scale, disease duration and disease-modifying therapy (B = −0.561; SE = 0.192; P = 0.004; 95% CI = −0.940 to −0.182). Besides this association, serum neurofilament light chain levels were not linked to any other cognitive or mood measures (all P-values  & gt; 0.05). The tripartite combination of serum neurofilament light chain levels, lesion volume and grey matter volume showed a cross-validated accuracy of 88.7% (90.8% in the replication cohort) in predicting Symbol Digits Modalities Test performance in the support vector regression approach, and outperformed each single biomarker (accuracy range: 68.6–75.6% and 68.9–77.8% in the replication cohort), as well as the dual biomarker combinations (accuracy range: 71.8–82.3% and 72.6–85.6% in the replication cohort). Taken together, early neuro-axonal loss reflects worse information processing speed, the key deficit underlying cognitive dysfunction in multiple sclerosis. Our findings demonstrate that combining blood and imaging measures improves the accuracy of predicting cognitive impairment, highlighting the clinical utility of cross-modal biomarkers in multiple sclerosis.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcac153
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3020013-1
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  • 7
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    Immunoadsorption versus double-dose methylprednisolone in refractory multiple sclerosis relapses
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Neuroinflammation Vol. 19, No. 1 ( 2022-09-07)
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2022-09-07)
    Abstract: Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing. Methods In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030). Results 42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes (“full/best” vs. “average” vs. “worse/none”). Upon discharge, the adjusted odds ratio for any treatment response (“full/best” + ”average” vs. “worse/none”) was 10.697 favouring immunoadsorption ( p  = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response (“full/best” vs. “average” + ”worse/none”) was 103.236 favouring IA patients ( p  = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors. Interpretation Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/s12974-022-02583-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2156455-3
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  • 8
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    Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis
    SAGE Publications ; 2021
    In:  Therapeutic Advances in Neurological Disorders Vol. 14 ( 2021-01), p. 175628642110034-
    Details
    In: Therapeutic Advances in Neurological Disorders, SAGE Publications, Vol. 14 ( 2021-01), p. 175628642110034-
    Abstract: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients ( n = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes. Results: In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients ( B = −0.016, SE = 0.006, p = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients ( B = −6.734, SE = 2.514, p = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy ( B = 5.974, SE = 2.420, p = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning. Conclusions: In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration.
    Type of Medium: Online Resource
    ISSN: 1756-2864 , 1756-2864
    URL: Article
    DOI: 10.1177/17562864211003478
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2442245-9
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  • 9
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    Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus
    SAGE Publications ; 2021
    In:  Therapeutic Advances in Neurological Disorders Vol. 14 ( 2021-01), p. 175628642110514-
    Details
    In: Therapeutic Advances in Neurological Disorders, SAGE Publications, Vol. 14 ( 2021-01), p. 175628642110514-
    Abstract: The aim was to evaluate the diagnostic potential of serum neurofilament light chain (sNfL) measurements in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: sNfL levels were determined by single molecule array assay in a retrospective cross-sectional cohort of 144 patients with systemic lupus erythematosus (SLE). After log-transformation of sNfL levels, mean sNfL levels were compared between NPSLE patients and SLE patients without neuropsychiatric disease using Student’s t test. Furthermore, the association of different neuropsychiatric manifestations with sNfL levels was assessed using a one-way analysis of variance (ANOVA) with post hoc analysis. Associations of sNfL with clinical and laboratory parameters were assessed by correlation and multiple linear regression analysis. Results: NPSLE patients ( n = 69) had significantly higher sNfL levels than SLE patients without neuropsychiatric disease manifestations ( n = 75; mean difference: 0.13, 95% CI: 0.04–0.22, p = 0.006). With regard to the category of NPSLE manifestation, mean sNfL levels were only increased in NPSLE patients with focal central nervous system (CNS) involvement ( n = 45; mean difference: 0.16, 95% CI: 0.02–0.30, p = 0.019), whereas mean sNfL levels of NPSLE patients with diffuse CNS and peripheral nervous system involvement did not differ from those of SLE patients without neuropsychiatric manifestations. Age and serum creatinine concentrations were identified as relevant contributors to sNfL levels. Conclusion: sNfL is a promising, easily accessible biomarker for neuropsychiatric involvement in SLE patients and might therefore complement the diagnostic workup of SLE patients with suspected involvement of the nervous system.
    Type of Medium: Online Resource
    ISSN: 1756-2864 , 1756-2864
    URL: Article
    DOI: 10.1177/17562864211051497
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
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  • 10
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    Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke
    American Association for the Advancement of Science (AAAS) ; 2022
    In:  Science Translational Medicine Vol. 14, No. 641 ( 2022-04-20)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 14, No. 641 ( 2022-04-20)
    Abstract: After stroke, excessive glutamate release from damaged cells contributes to secondary injury in the stroke penumbra. Preserving the penumbra is critical for improving stroke outcome; however, current pharmacological approaches have not been successful. Here, Bitar et al . studied the mechanisms mediating excitotoxicity in the penumbra and showed that autotaxin (ATX) was increased in astrocytes after stroke in mice, and ATX increase was also found in the cerebrospinal fluid of patients after stroke. ATX increase mediated lysophosphatidic acid (LPA)–induced hyperexcitability in rodents, and its inhibition ameliorated stroke outcome, suggesting that the ATX-LPA signaling might be a potential target for treating stroke.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.abk0135
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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