Distinct regional brain atrophy pattern in multiple sclerosis and neuropsychiatric systemic lupus erythematosus patients

Lupus ◽  
2018 ◽  
Vol 27 (10) ◽  
pp. 1624-1635
Author(s):  
A Kalinowska-Lyszczarz ◽  
M A Pawlak ◽  
A Pietrzak ◽  
K Pawlak-Bus ◽  
P Leszczynski ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Systemic Lupus Erythematosus ◽  
Nervous System ◽  
Corpus Callosum ◽  
Lupus Erythematosus ◽  
Brain Atrophy ◽  
Fourth Ventricle ◽  
Disease Duration ◽  
Third Ventricle ◽  
Systemic Lupus

Differentiation of systemic lupus erythematosus (SLE) from multiple sclerosis (MS) can be challenging, especially when neuropsychiatric (NP) symptoms are accompanied by white matter lesions in the brain. Given the lack of discriminative power of currently applied tools for their differentiation, there is an unmet need for other measures that can aid in distinguishing between the two autoimmune disorders. In this study we aimed at exploring whether brain atrophy measures could serve as markers differentiating MS and SLE. Thirty-seven relapsing–remitting MS and 38 SLE patients with nervous system manifestations, matched according to age and disease duration, underwent 1.5 Tesla magnetic resonance imaging (MRI), including volumetric sequences, and clinical assessment. Voxelwise analysis was performed using ANTS-SyN elastic registration protocol, FSL Randomise and Gamma methods. Cortical and subcortical segmentation was performed with Freesurfer 5.3 pipeline using T1-weighted MPRAGE sequence data. Using MRI volumetric markers of general and subcortical gray matter atrophy and clinical variables, we built a stepwise multivariable logistic diagnostic model to identify MRI parameters that best differentiate MS and SLE patients. We found that the best volumetric predictors to distinguish them were: fourth ventricle volume (sensitivity 0.86, specificity 0.57, area under the curve, AUC 0.77), posterior corpus callosum (sensitivity 0.81, specificity 0.57, AUC 0.68), and third ventricle to thalamus ratio (sensitivity 0.42, specificity 0.84, AUC 0.65). The same classifiers were identified in a subgroup analysis that included patients with a short disease duration. In MS brain atrophy and lesion load correlated with clinical disability, while in SLE age was the main determinant of brain volume. This study proposes new imaging parameters for differential diagnosis of MS and SLE with central nervous system involvement. We show there is a different pattern of atrophy in MS and SLE, and the key structural volumes that are differentially affected include fourth ventricle and posterior section of corpus callosum, followed by third ventricle to thalamus ratio. Different correlation patterns between volumetric and clinical data may suggest that while in MS atrophy is driven mainly by disease activity, in SLE it is mostly associated with age. However, these results need further replication in a larger cohort.

Inflammatory and autoimmune disorders in neuropsychiatry

2020 ◽  
pp. 245-258
Author(s):  
Thomas A. Pollak ◽  
Ester Coutinho ◽  
Emma Palmer-Cooper ◽  
Angela Vincent
Keyword(s):  
Multiple Sclerosis ◽  
Systemic Lupus Erythematosus ◽  
Central Nervous System ◽  
Nervous System ◽  
Lupus Erythematosus ◽  
Autoimmune Disorders ◽  
Systemic Lupus ◽  
Close Link ◽  
The Central Nervous System ◽  
Surface Antibodies

Evidence continues to be found to suggest a close link between the central nervous system and the immune system in neuropsychiatric disorders. With increasing interest over the last decade in autoimmune encephalitides, caused by the interaction of neuronal surface antibodies (NSAbs) with proteins, such as the NMDA receptor (NMDAR) and leucine-rich glioma inactivated 1 (LGI1), the clinical interface between psychiatry and neurology has undergone significant advances. This chapter provides a basic overview of autoimmunity, before discussing recent findings. Firstly, autoimmune disorders which commonly present with psychiatric comorbidities are explored such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Then, the psychiatric presentations of various autoimmune forms of encephalitis are discussed, along with their treatment and outcomes. Finally, the relevance of NSAbs to psychiatry is discussed in greater detail.

scholarly journals POS0712 “EXTRA”- CRITERIA ANTIPHOSPHOLIPID ANTIBODIES IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS (PRELIMINARY DATA)

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 605.2-606
Author(s):  
F. Cheldieva ◽  
T. Reshetnyak ◽  
M. Cherkasova ◽  
N. Seredavkina ◽  
A. Lila
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Preliminary Data ◽  
Antiphospholipid Antibodies ◽  
Disease Duration ◽  
Past History ◽  
Igg Antibodies ◽  
Systemic Lupus ◽  
Pregnancy Morbidity

Background:The study of antiphospholipid antibodies (aPL), not included in the Sydney diagnostic criteria, in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) is poorly understood.Objectives:To determine the frequency of detection of IgA-aCL and IgA-aβ2GP1 and IgG antibodies to β2GP1 domain 1 (IgG-aβ2GP1-D1) in patients with APS with and without SLE.Methods:ELISA and chemiluminescence assays (CMA) were used to test 63 sera of patients: 22 (35%) with primary APS (pAPS) and 41 (65%) patients with APS and with SLE (secondary APS (sAPS)), with mean age 38,0 [33,0 – 43,0] years and disease duration 4,0 [0,1 – 9,9]. Both methods were used to test of IgG/IgM-aCL and IgG/IgM-aβ2GP1. CMA was used for research IgG/IgM/IgA-aCL, IgG/IgM/IgA-aβ2GPI and IgG-aβ2GP1-D1. Of them 49 (78%) (18 – with pAPS; 31 – with sAPS) displayed major thrombotic events and 18 of 22 pregnant women had pregnancy morbidity in past history. Lupus anticoagulant (LA) positivity was in 9 out of 12 patients who had it determined. LA was not investigated due to anticoagulant therapy in the remaining 52 patients.Results:IgG/IgM-aCL and IgG/IgM-aß2GP1 were recorded in 44/18 and 50/17 patients by ELISA and in 55/19 and 59/16 by CMA, respectively.IgA-aCL positivity was found in 35 (56%) of 63 patients. Thirty IgA-positive patients were positive for IgG-aCL by ELISA: 22 – IgG-aCL – highly positive, 6 – medium positive and 2 – low positive patients. IgM-aCL by ELISA was detected in 13 (37%) of 35 IgA-aCL positive patients: 11 – highly positive, 1 – medium positive and 1 – low positive. IgA-aCL was combined with IgG-aCL in 34 patients and with IgM-aCL in 16 patients in the CMA. IgG-aß2GP1 in ELISA was detected in 32 patients with IgA-aCL (24 –highly positive, 5 – medium positive and 3 – low positive) and in 34 – in CMA. IgM-aß2GP1 was combined with IgA-aß2GP1 with the same frequency in both methods (in 13 patients).IgA-aß2GP1 was detected in 30 (48%) of 63 patients. They were combined with both IgG-aCL and IgG-aß2GP1 in all cases in both methods. IgM-aCL and IgM-aß2GP1 were detected in 14 and 11 of 30 patients with IgA-aß2GP1, respectively. The combination of IgA-aß2GP1 with IgG-aCL by ELISA was in 27 (in most cases highly positive – 20) and with IgM-aCL – in 10 (highly positive - 8). IgG-aß2GP1 was detected in 28 patients with IgA-aß2GP1 (high positive – 21) and in 11 patients with IgM-aß2GP1 (high positive –7).IgG-aß2GP1-D1 was revealed in 48 (76%) patients. It was combined with IgG-aCL – in 38, with IgM-aCL – in 15 patients by the ELISA. The combination of IgG-aß2GP1-D1 by CMA was as follows: with IgG-aCL – in 46, with IgM-aCL – in 17, and with IgA-aCL – in 33 patients. In most cases, IgG-aß2gp1-D1 was combined with highly positive aCL levels. IgG-aß2GP1-D1 positivity was associated with IgG-aß2GP1 positivity in 42 – by ELISA and 47 – by CMA, IgМ-aβ2GP1 – in 13 and 14 patients by ELISA and CMA, respectively, and IgA-aß2GP1 – in 29. Isolated IgG-aß2GP1-D1 positivity was not observed.Conclusion:The frequency of IgA-aCL detection was 56% (35 patients out of 63), IgA-aβ2GP1 – 48% (30 patients out of 63), IgG-aβ2GP1-D1 – 76% (48 patients out of 63). There was not isolated positivity of this “extra” criterial antibodies. The presence of IgA-aCL, IgA-aβ2GP1, IgG-aβ2GP1-D1 was associated with highly positivity of IgG/IgM-aCL and IgG/IgM- aβ2GP1.Disclosure of Interests:None declared

scholarly journals FRI0224 IDENTIFICATION OF RISK AND PROGNOSTIC FACTORS FOR POLYARTERITIS NODOSA PATIENTS WITH DIGITAL GANGRENE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 695.2-695
Author(s):  
D. Xu ◽  
X. Tian ◽  
X. Zeng ◽  
F. Zhang ◽  
L. Zhao ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Prognostic Factors ◽  
Retrospective Study ◽  
Polyarteritis Nodosa ◽  
Lupus Erythematosus ◽  
Disease Duration ◽  
Response To Therapy ◽  
Smoking History ◽  
Systemic Lupus ◽  
Poor Outcomes

Background:Polyarteritis nodosa (PAN) is a segmental, necrotizing vascular disease that primarily impacts medium-sized muscle arteries. The estimated annual incidence of PAN is still lacking in China. Digital gangrene is an ischemic manifestation of the limb. However, the causes and the treatment methods vary from case to case, and the outcome is unpredictable. These features emphasize the need to identify measurable variables that accelerate digital gangrene development in PAN patients. However, little effort has been made to identify the clinical and laboratory factors that affect PAN patients with digital gangrene to anticipate their natural history and response to therapy.Objectives:Many patients with polyarteritis nodosa (PAN) complicated with digital gangrene have poor outcomes and related research information is limited. This study was carried out to identify the associated risk and prognostic factors.Methods:We conducted a retrospective study of 148 PAN patients admitted to Peking Union Medical College Hospital (PUMCH) from September 1986 to December 2018. The characteristics, therapeutic regimens, and outcome data for patients with and without gangrene were compared. The Kaplan–Meier method and Cox hazard regression model were used to evaluate the prognostic factors.Results:Forty-seven (31.8%) PAN patients had digital gangrene complications. The average age was 40.4±17.9 years and the average disease duration was 11 (4-27) months. The presence of digital gangrene was correlated with smoking history [odds ratio (OR), 4.27; 95% confidence interval (95% CI), 1.56-11.66] and eosinophil elevation (28.12; 10.30-76.8). Thirty-two (68.1%) gangrene patients received methylprednisolone pulse therapy and all of these patients were treated with cyclophosphamide. Nine patients suffered irreversible organ injury and two died. Disease duration ≥ 24 months and elevated serum C-reactive protein (CRP) were identified as hazardous factors for poor prognosis in patients with gangrene (P=0.003, HR=8.668, 95% CI 2.11, 35.55 andP=0.042, HR=27.062, 95% CI 1.13, 648.57, respectively).Conclusion:Smoking history and eosinophil elevation in PAN patients were more prone to digital gangrene and high serum CRP level predicted poor outcomes. PAN patients with smoking history and elevated eosinophils need to be seriously evaluated by clinicians. Furthermore, the CRP level should be efficiently controlled for good prognosis.References:[1]De Virgilio A, Greco A, Magliulo G, Gallo A, Ruoppolo G, Conte M, et al. Polyarteritis nodosa: A contemporary overview. Autoimmun Rev. 2016;15:564-70.[2]Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010;62:616-26.[3]Xu D, You X, Wang Z, Zeng Q, Xu J, Jiang L, et al. Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry VI: Effect of Cigarette Smoking on the Clinical Phenotype of Chinese Patients with Systemic Lupus Erythematosus. PLoS One. 2015;10:e0134451.Acknowledgments:NoDisclosure of Interests:Dong Xu: None declared, Xinping Tian: None declared, Xiaofeng Zeng Consultant of: MSD Pharmaceuticals, Fengchun Zhang: None declared, Lin Zhao: None declared, Shangzhu Zhang: None declared, Jiaxin Zhou: None declared, Jiu-liang Zhao: None declared, Xiaodan Kong: None declared

scholarly journals Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus (NPSLE): Can They Be Used as Biomarkers for the Differential Diagnosis of This Disease?

2021 ◽  
Author(s):  
Elias Manca
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Central Nervous System ◽  
Nervous System ◽  
Differential Diagnosis ◽  
Human Body ◽  
Lupus Erythematosus ◽  
Neuropsychiatric Symptoms ◽  
Systemic Lupus ◽  
Neuropsychiatric Systemic Lupus Erythematosus ◽  
The Central Nervous System

AbstractSystemic lupus erythematosus is a complex immunological disease where both environmental factors and genetic predisposition lead to the dysregulation of important immune mechanisms. Eventually, the combination of these factors leads to the production of self-reactive antibodies that can target any organ or tissue of the human body. Autoantibodies can form immune complexes responsible for both the organ damage and the most severe complications. Involvement of the central nervous system defines a subcategory of the disease, generally known with the denomination of neuropsychiatric systemic lupus erythematosus. Neuropsychiatric symptoms can range from relatively mild manifestations, such as headache, to more severe complications, such as psychosis. The evaluation of the presence of the autoantibodies in the serum of these patients is the most helpful diagnostic tool for the assessment of the disease. The scientific progresses achieved in the last decades helped researchers and physicians to discover some of autoepitopes targeted by the autoantibodies, although the majority of them have not been identified yet. Additionally, the central nervous system is full of epitopes that cannot be found elsewhere in the human body, for this reason, autoantibodies that selectively target these epitopes might be used for the differential diagnosis between patients with and without the neuropsychiatric symptoms. In this review, the most relevant data is reported with regard to mechanisms implicated in the production of autoantibodies and the most important autoantibodies found among patients with systemic lupus erythematosus with and without the neuropsychiatric manifestations.

scholarly journals AB0421 EFFECT OF BODY WEIGHT ON COMPLEMENT LEVELS IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1510.3-1510
Author(s):  
L. Kondrateva ◽  
T. Popkova ◽  
E. Nasonov ◽  
A. Lila
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Disease Duration ◽  
Normal Weight ◽  
World Health ◽  
Systemic Lupus ◽  
Obesity Status ◽  
Health Organization ◽  
The Complement System

Background:The complement system is a recognized biomarker for diagnosis or monitoring of disease activity in systemic lupus erythematosus (SLE) patients (pts). But on the other hand, it has been linked to insulin resistance and obesity in general population.Objectives:To find out whether overweight/obesity can modify C3 or C4 levels in SLE pts.Methods:A total of 92 SLE pts (83 women, 9 men, 39 [34;47] years old) were enrolled in the study. Median disease duration was 6[2;14] years, and SLE activity using SLEDAI-2K was 4[2;8]. SLE pts were treated with glucocorticoids (89%), hydroxychloroquine (78%), immunosuppressants (28%), biologics (10%). The overweight/obesity status was determined by World Health Organization criteria in patients with body mass index (BMI) ≥25kg/m2.Results:Overweight/obesity were established in 46% SLE pts. Overweight/obese SLE pts were older than pts with normal BMI (40[36;48] vs 37[31;44] years, р=0,02), and had lower SLEDAI-2K (3[2;6] vs 6[4;8], p<0,01). Lower C3 concentrations were found in 36% overweight/obese pts vs 68% pts with normal weight (р<0,01), decreased C4 levels - in 19% vs 30% pts (p=0,33), median C3 concentrations were 0,98[0,81;1,14] g/l vs 0,84[0,69;0;96] g/l (р<0,01), and C4 levels were 0,15[0,10;0,19] g/l vs 0,12[0,09;0,16] g/l, respectively (p=0,03). C3 and C4 levels negatively correlated with SLEDAI-2K (r=-0,5, p<0,01 for both), the effect was more strongly pronounced in patients with BMI≥25kg/m2 (r=-0,6, p<0,01 for both) than in those with normal weight (r=-0,2, p=0,09 for C3, r=-0,3, p=0,04 for C4).Conclusion:Overweight/obesity status in SLE pts was associated with increased levels of complement proteins, therefore decreased C3 or C4 levels in patients with BMI≥25kg/m2 are more likely related to disease activity and, can potentially induce SLE flares.Disclosure of Interests: :None declared

scholarly journals SAT0232 PERCEPTION OF THE DISEASE IN PATIENTS WITH EARLY SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1059.3-1059
Author(s):  
M. Garabajiu ◽  
L. Mazur-Nicorici ◽  
T. Rotaru ◽  
V. Salaru ◽  
S. B. Victoria ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Disease Duration ◽  
Activity Index ◽  
Damage Index ◽  
Organ Damage ◽  
Systemic Lupus

Background:Systemic lupus erythematosus is an autoimmune disease with a major impact on patient’s quality of life.Objectives:To evaluate patient’s attitude toward early disease and factors that influence it.Methods:Performed case-control study included SLE patients that fulfilled SLICC, 2012 classification criteria. The research included two groups of patients: early SLE – 1stgroup (disease duration ≤24 months) and non-early SLE – 2ndgroup control (disease duration >24 months). The pattern of the disease activity was assessed by patient global assessment (PGA), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus Activity Measure (SLAM), for SLE activity, SLICC/ACR Damage Index (DI) for disease irreversible changes and SF-8 for the Quality of Life (QoL).Results:A total of 101 SLE patients with 34 in the 1stgroup (early SLE) and 67 in the 2ndgroup (non-early SLE) was analyzed. The disease activity showed high disease activity in both groups by SLEDAI (7,02±4,16 and 6,26±4,43 points, p>0,05) and SLAM (7,47±4,40 and 7,31±4,10 points, p>0,05) such as (46,97±19,39 vs 47,98±22,41 points). The QoL was appreciated as low, by both components (mental and physical), in groups. The damage index was higher in the 2nd group (0,23±0,43 and 1,07±1,29, p<0,001), which can be explained by the development of irreversible changes with the increase of disease duration.The PGA in early SLE was influenced by subjective symptoms contained in SLAM index (r=0,48, p<0,05), such as fatigue and depression, and the level of the quality of life (r=0,65, p<0,001). Meantime, PGA in patients with longer disease duration (>2 years), was influenced by the presence of organ damage by SLICC/ACR DI (0,23, p<0,05) and objective findings of the disease activity contained in SLEDAI (r=0,33, p<0,005) and SLAM (0,44, p<0,001).Conclusion:The disease recognition in patients with early SLE was determined by subjective and psycho-emotional signs, while in patients with longer disease duration it was influenced by organ damage and complications.References:no referencesDisclosure of Interests:None declared

scholarly journals AB0383 EXTREME FATIGUE IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND NEUROPSYCHIATRIC SYMPTOMS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1491.2-1492
Author(s):  
R. Monahan ◽  
R. Fronczek ◽  
J. Eikenboom ◽  
H. Middelkoop ◽  
L. J. J. Beaart- van de Voorde ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Nervous System ◽  
Standard Deviation ◽  
Lupus Erythematosus ◽  
Neuropsychiatric Symptoms ◽  
Systemic Lupus ◽  
System Involvement ◽  
Vas Score ◽  
Age Related ◽  
Sf 36

Background:Fatigue is commonly described in chronic illnesses, especially auto-immune disorders such as systemic lupus erythematosus (SLE).Objectives:We aim to study the prevalence of fatigue in SLE patients with NP symptoms and compare fatigue in SLE patients with NP symptoms attributed to major organ involvement due to SLE (NPSLE) with SLE patients with NP symptoms not caused by major nervous system involvement (non-NPSLE).Methods:All patients visiting the tertiary referral center for NPSLE in the LUMC between 2007-2019 with the clinical diagnosis of SLE and age >18 years that signed informed consent were included in this study. Patients underwent a standardized multidisciplinary assessment, including two questionnaires: SF-36 (2007-2019) and multidimensional fatigue index (MFI, 2011-2019). Patients were classified as NPSLE in this study if NP symptoms were attributed to SLE and immunosuppressive or anticoagulant therapy was initiated, otherwise patients were classified as non-NPSLE. The vitality (VT) domain of the SF-36 domain was used to assess fatigue, which generates a score from 0-100, 100 representing the complete absence of fatigue. Patients with a score more than 1 standard deviation (SD) removed from age-related controls of the Dutch general population were classified as fatigued; patients more than 2 SD removed were classified as extremely fatigued1. The MFI was also used, which consists of 5 subdomain scores between 0-20, leading to a total score between 0-100, 100 representing the most extreme fatigue. All scores are presented as mean and standard deviation.Results:373 patients fulfilled the inclusion criteria and SF-36 questionnaires of 328 patients were available (88%). The majority of these patients was female (87%) and 98 were classified as NPSLE (30%). In NPSLE patients, average age was 41 ± 13 years and in non-NPSLE the average age was 45 ± 14 years. The average score of the SF-36 vitality domain was 36.0 ± 20.7 in NPSLE vs 33.9 ± 18.8. in non-NPSLE. Overall, 73.5% of the patients were fatigued and 46.9% extremely fatigued in NPSLE vs 77.8% fatigued and 45.7% extremely fatigued in non-NPSLE.The MFI questionnaire and VAS score were available for 222 patients, of which 65 patients were classified as NPSLE (29.3%). Table 1 depicts the scores of NPSLE and non-NPSLE patients on the MFI subdomains and the VAS score.Table.Patient characteristics at registry entry.NPSLE(N = 65)Non-NPSLE (N = 157)MFI(mean, sd)General Fatigue10.8 (1.8)11.1 (1.5)Physical Fatigue11.4 (2.4)12.3 (1.9)Reduced Activity9.6 (2.9)10.7 (2.2)Reduced Motivation10.7 (2.6)11.1 (1.9)Mental Fatigue9.5 (3.0)9.8 (2.7)Total score51.8 (9.9)54.9 (6.9)SF-36 Vitality (mean, sd)35 (20.7)32.7 (18.2)Conclusion:Nearly half of patients with SLE and NP symptoms are as extremely fatigued as only 2.5% of the general Dutch population. Extreme fatigue is not influenced by major nervous system involvement.References:[1]Aaronsonet al.J Clin Epidemiol. Vol. 51, No. 11, pp. 1055–1068, 1998Disclosure of Interests:Rory Monahan: None declared, Rolf Fronczek: None declared, Jeroen Eikenboom: None declared, Huub Middelkoop: None declared, L.J.J. Beaart- van de Voorde: None declared, Gisela Terwindt: None declared, Nic van der Wee: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Margreet Kloppenburg: None declared, G.M. Steup-Beekman: None declared

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