scholarly journals IgG and IgA autoantibodies against L1 ORF1p expressed in granulocytes correlate with granulocyte consumption and disease activity in pediatric systemic lupus erythematosus

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Kennedy C. Ukadike ◽  
Kathryn Ni ◽  
Xiaoxing Wang ◽  
Martin S. Taylor ◽  
John LaCava ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Rna Binding ◽  
Neutrophil Activation ◽  
Complement C3 ◽  
Healthy Children ◽  
Systemic Lupus ◽  
Active Disease

Abstract Background Most patients with systemic lupus erythematosus (SLE) have IgG autoantibodies against the RNA-binding p40 (ORF1p) protein encoded by the L1 retroelement. This study tested if these autoantibodies are also present in children with pediatric SLE (pSLE) and if the p40 protein itself could be detected in immune cells. Methods Autoantibodies in the plasma of pSLE patients (n = 30), healthy children (n = 37), and disease controls juvenile idiopathic arthritis (JIA) (n = 32) and juvenile dermatomyositis (JDM) (n = 60), were measured by ELISA. Expression of p40 in immune cells was assessed by flow cytometry. Markers of neutrophil activation and death were quantitated by ELISA. Results IgG and IgA autoantibodies reactive with p40 were detected in the pSLE patients, but were low in healthy controls and in JIA or JDM. pSLE patients with active disease (13 of them newly diagnosed) had higher titers than the same patients after effective therapy (p = 0.0003). IgG titers correlated with SLEDAI (r = 0.65, p = 0.0001), ESR (r = 0.43, p = 0.02), and anti-dsDNA antibodies (r = 0.49, p < 0.03), and inversely with complement C3 (r = -0.55, p = 0.002) and C4 (r = -0.51, p = 0.006). p40 protein was detected in a subpopulation of CD66b+ granulocytes in pSLE, as well as in adult SLE patients. Myeloperoxidase and neutrophil elastase complexed with DNA and the neutrophil-derived S100A8/A9 were elevated in plasma from pSLE patients with active disease and correlated with anti-p40 autoantibodies and disease activity. Conclusions Children with active SLE have elevated IgG and IgA autoantibodies against L1 p40, and this protein can be detected in circulating granulocytes in both pediatric and adult SLE patients. P40 expression and autoantibody levels correlate with disease activity. Markers of neutrophil activation and death also correlate with these autoantibodies and with disease activity, suggesting that neutrophils express L1 and are a source of p40.

SLEDAI-2K Does Not Conceal Worsening in a Particular System When There Is Overall Improvement

2015 ◽  
Vol 42 (8) ◽  
pp. 1401-1405 ◽  
Author(s):  
Zahi Touma ◽  
Dafna D. Gladman ◽  
Jiandong Su ◽  
Dominique Ibañez ◽  
Murray B. Urowitz
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Disease Activity Index ◽  
Systemic Lupus Erythematosus Disease ◽  
Systemic Lupus ◽  
Baseline Visit ◽  
Clinically Significant ◽  
Active Disease

Objective.To determine whether the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) is valid in identifying patients who had a clinically important overall improvement with no worsening in other descriptors/systems.Methods.Consecutive patients with systemic lupus erythematosus with active disease who attended the Lupus Clinic between 2000 and 2012 were studied. Based on the change in the total SLEDAI-2K scores on last visit, patients were grouped as improved, flared/worsened, and unchanged. Patients showing improvement were evaluated for the presence of new active descriptors at last visit compared with baseline visit.Results.Of the 158 patients studied, 109 patients had improved, 38 remained unchanged, and 11 flared/worsened at last visit. In the improved group, 11 patients had a new laboratory descriptor that was not present at baseline visit. In those 11 patients, this new laboratory descriptor was not clinically significant and did not require a change in disease management.Conclusion.The SLEDAI-2K identifies improvement in disease activity overall without concealing clinically important worsening.

Urinary neopterin in patients with systemic lupus erythematosus

1991 ◽  
Vol 37 (1) ◽  
pp. 47-50 ◽  
Author(s):  
Lakana Leohirun ◽  
Phlchal Thuvasethakul ◽  
Vasant Sumethkul ◽  
Trithar Pholcharoen ◽  
VlJitr Boonpucknavig
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Inactive Disease ◽  
Clinical Activity ◽  
High Concentration ◽  
Systemic Lupus ◽  
Neopterin Concentration ◽  
Urinary Neopterin ◽  
Active Disease

Abstract Concentrations of neopterin were measured in urine specimens from 35 patients with active and eight with inactive systemic lupus erythematosus (SLE). Compared with those of apparently healthy controls, neopterin concentrations were higher in patients with active disease (P less than 0.001) and with inactive disease (P less than 0.01), those in patients with active disease being significantly higher than those in patients with inactive disease (P less than 0.001). The correlation between the neopterin concentration and evidence of disease activity was good. All of the patients with clinically active SLE had increased neopterin, but for only 37.5% (three of eight) did the neopterin concentration exceed the upper normal limit during clinical remission. The increase in neopterin concentration did not correlate with clinical courses or severity of renal function. Moreover, serial determinations of neopterin in active SLE patients showed a rapid decrease of initially high concentration, paralleling a decline of clinical activity after initiation of medical therapy. Thus, urinary neopterin may be a useful marker for monitoring disease activity in SLE patients.

Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome

2018 ◽  
Vol 77 (12) ◽  
pp. 1810-1814 ◽  
Author(s):  
Lucas L van den Hoogen ◽  
Joël A G van Roon ◽  
Jorre S Mertens ◽  
Judith Wienke ◽  
Ana Pinheiro Lopes ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Complement C3 ◽  
Tumour Necrosis Factor Receptor ◽  
Systemic Lupus ◽  
Dsdna Antibody

ObjectiveThe interferon (IFN) signature is related to disease activity and vascular disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and represents a promising therapeutic target. Quantification of the IFN signature is currently performed by gene expression analysis, limiting its current applicability in clinical practice. Therefore, the objective of this study was to establish an easy to measure biomarker for the IFN signature.MethodsSerum levels of galectin-9, CXCL-10 (IP-10) and tumour necrosis factor receptor type II (TNF-RII) were measured in patients with SLE, SLE+APS and primary APS (PAPS) and healthy controls (n=148) after an initial screening of serum analytes in a smaller cohort (n=43). Analytes were correlated to measures of disease activity and the IFN signature. The performance of galectin-9, CXCL-10 and TNF-RII as biomarkers to detect the IFN signature was assessed by receiver operating characteristic curves.ResultsGalectin-9, CXCL-10 and TNF-RII were elevated in patients with SLE, SLE+APS and PAPS (p<0.05) and correlated with disease activity and tissue factor expression. Galectin-9 correlated stronger than CXCL-10 or TNF-RII with the IFN score (r=0.70, p<0.001) and was superior to CXCL-10 or TNF-RII in detecting the IFN signature (area under the curve (AUC) 0.86). Importantly, in patients with SLE(±APS), galectin-9 was also superior to anti-dsDNA antibody (AUC 0.70), or complement C3 (AUC 0.70) and C4 (AUC 0.78) levels in detecting the IFN signature.ConclusionGalectin-9 is a novel, easy to measure hence clinically applicable biomarker to detect the IFN signature in patients with systemic autoimmune diseases such as SLE and APS.

scholarly journals Serum complement levels as prognostic marker for monitoring treatment response in lupus nephritis

2021 ◽  
Vol 11 (2) ◽  
pp. 97-102
Author(s):  
Saiful Bahar Khan ◽  
Rafi Nazrul Islam ◽  
Md Saif Bin Mizan ◽  
AKM Shahidur Rahman ◽  
Shah Md Zakir Hossain ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Disease Activity ◽  
Treatment Response ◽  
Lupus Erythematosus ◽  
Treatment Initiation ◽  
Complement C3 ◽  
P Value ◽  
Serum Complement ◽  
Systemic Lupus

Background: Lupus nephritis (LN) is one of the most common and serious manifestations of systemic lupus erythematosus (SLE) that causes significant morbidity and mortality. Certain biomarkers for LN are sometimes able to assess treatment response in lupus nephritis. This study aimed to compare serum complement levels (C3 and C4) as markers of treatment response of LN and their relation to the LN class in renal biopsy. Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with LN after kidney biopsy were included in this study. Serum complement levels (C3 and C4), 24 hours urinary total protein (24-hr UTP) and anti-double-stranded DNA (anti-ds DNA) were measured in all patients at baseline, 3 months and 6 months after treatment initiation. These biomarker values before and after treatment were compared between the proliferative and non-proliferative LN patients. Results: Serum C3 levels were significantly different between patients with proliferative LN (Class III and Class IV) and non-proliferative LN (Class V) at baseline (0.47 ± 0.32 g/l versus 0.89 ± 0.43 g/l, p=0.009) and levels changed significantly 6 months after treatment initiation (p<0.001) and likewise for serum C4 levels (0.10 ± 0.06 g/l versus 0.24 ± 0.26 g/l, p=0.040). The values of 24-hr UTP and anti-ds-DNA were significantly different 6 months after treatment with p value <0.05 in both groups but C3 (p<0.001) and renal Systemic Lupus Erythematosus Disease Activity Index (rSLEDAI) (p<0.001) were only significant in the proliferative group. On the other hand, after 6 months treatment, C4 levels became relatively higher but that was not significant in both groups (p>0.05). Conclusion: After 6 months of treatment, serum C3 and C4 levels increased towards normal in both LN groups. Serum C3 and C4 levels in patients with LN correlate with disease activity. Therefore, serum complement (C3 and C4) levels may be utilized as serological biomarkers for treatment response of LN. Birdem Med J 2021; 11(2): 97-102

scholarly journals Th Cytokine Profile in Childhood-Onset Systemic Lupus Erythematosus

2021 ◽  
Author(s):  
Wei Quan ◽  
Jingnan An ◽  
Gang Li ◽  
Guanghui Qian ◽  
Meifang Jin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Healthy Control Group ◽  
Control Group ◽  
Healthy Children ◽  
Childhood Onset ◽  
Systemic Lupus ◽  
Healthy Control

Abstract Background: Childhood-onset systemic lupus erythematosus (cSLE) is a kind of chronic inflammatory disease characterized by a highly abnormal immune system. This study aimed to detect expression of the Th cytokines IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ and TNF-α in the peripheral blood of children with cSLE; clinical symptoms; and a disease index and discuss the relationship between the Th cell cytokine regulatory network and onset of systemic lupus erythematosus (SLE) in children and disease outcome.Methods: A total of 33 children with cSLE and 30 healthy children were enrolled in this study. Children in the cSLE group were classified into the inactive cSLE group or active cSLE group according to their SLE disease activity index 2000 (SLEDAI-2K). Th cytokine profiles in peripheral blood of different groups were detected and analyzed.Results: The levels of IL-2, IL-10 and IL-21 in the cSLE group were significantly higher than those in the healthy control group (P < 0.05, P<0.01 and P<0.01, respectively). The expression of IL-2, IL-10 and IL-21 in the active cSLE group was significantly higher than that in the healthy control group (P<0.05, P<0.01 and P<0.05, respectively), but IL-22 expression was remarkably lower in the active cSLE group than in the healthy control group (P<0.001). IL-21 in the inactive SLE group was significantly higher than that in the healthy control group (P<0.05). The levels of IL-2 and IL-10 in the active cSLE group were significantly higher than those in the inactive cSLE group (P<0.01 and P<0.05). In-depth analysis showed that the expression levels of IL-2 (r=0.382, P=0.028), IL-6 (r=0.514, P=0.002) and IL-10 (r=0.429, P=0.016) were positively correlated with disease activity. Conclusion: This study provides a theoretical basis for the discovery of effective methods to regulate imbalance in T lymphocyte subsets in cSLE, which may open up potential new approaches for the diagnosis of cSLE.

scholarly journals Prolactin as a marker of active disease in systemic lupus erythematosus

2021 ◽  
Author(s):  
Jorge Medina Castillo ◽  
Nayeli Nicté López Villa
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Serum Prolactin ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Systemic Lupus ◽  
Cross Sectional ◽  
Active Disease

Abstract Objetives. To determine the correlation between prolactin levels and disease activity classified based on the Mexican lupus erythematosus disease systemic activity index (MEX SLEDAI).Methods. In this cross-sectional observational study, serum prolactin, age, sex, treatment, as well as manifestations of active disease were determined. Disease activity was evaluated using the Mexican Systemic Lupus Erythematosus Activity Index (MEX-SLEDAI). The correlation of MEX-SLEDAI with prolactin was determined using the Spearman correlation coefficient. The significance of differences between continuous variables was determined with the non-paired Student’s t test and the significance of differences between categorical variables was determined with Chi-square test.Results. 55 patients were included, 10 (18.1%) had MEX-SLEDAI ≥ 7 and 45 (81.8%) less than 7. A positive correlation was found with a Spearman rho 0.387 (p = 0.004) between the MEX-SLEDAI and the levels serum prolactin. Subjects with active disease and hyperprolactinemia had 80% manifestations at the renal level (p = 0.001).Conclusion. There is significant correlation between prolactin levels and disease activity. Hyperprolactinemia were detected in patients with renal activity as well as those with MEX-SLEDAI ≥ 7.

scholarly journals Dietary Intake of Free Sugars is Associated with Disease Activity and Dyslipidemia in Systemic Lupus Erythematosus Patients

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1094
Author(s):  
María Correa-Rodríguez ◽  
Gabriela Pocovi-Gerardino ◽  
José-Luis Callejas-Rubio ◽  
Raquel Ríos Fernández ◽  
María Martín-Amada ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Dietary Intake ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Complement C3 ◽  
Free Sugar ◽  
Systemic Lupus ◽  
Free Sugars ◽  
Sugar Intake

Diet has been closely associated with inflammatory autoimmune diseases, including systemic lupus erythematosus (SLE). Importantly, the consumption of dietary sugars has been positively linked to elevated levels of some inflammation markers, but the potential role of their consumption on the prognosis of autoimmune diseases has not yet been examined. The aim of this study was to evaluate the association between the dietary intake of free sugars and clinical parameters and cardiovascular (CVD) risk markers in patients with SLE. A cross-sectional study including a total of 193 patients with SLE (aged 48.25 ± 12.54 years) was conducted. The SLE Disease Activity Index (SLEDAI-2K) and the SDI Damage Index were used to asses disease activity and disease-related damage, respectively. Levels of C-reactive protein (CRP; mg/dL), homocysteine (Hcy; µmol/L), anti-double stranded DNA antibodies (anti-dsDNA) (IU/mL), complement C3 (mg/dL), and complement C4 (mg/dL), among other biochemical markers, were measured. The main factors we considered as risk factors for CVD were obesity, diabetes mellitus, hypertension, and blood lipids. The dietary-intrinsic sugar and added-sugar content participants consumed were obtained via a 24-h patient diary. Significant differences were observed in dietary sugar intake between patients with active and inactive SLE (in grams: 28.31 ± 24.43 vs. 38.71 ± 28.87; p = 0.035) and free sugar intake (as a percentage: 6.36 ± 4.82 vs. 8.60 ± 5.51; p = 0.020). Linear regression analysis revealed a significant association between free sugars intake (by gram or percentage) and the number of complications (β (95% CI) = 0.009 (0.001, 0.0018), p = 0.033)); (β (95% CI) = 0.046 (0.008, 0.084), p = 0.018)), and SLEDAI (β (95% CI) = 0.017 (0.001, 0.034), p = 0.043)); (β (95% CI) = 0.086 (0.011, 0.161), p = 0.024)) after adjusting for covariates. Free sugars (g and %) were also associated with the presence of dyslipidaemia (β (95% CI) = −0.003 (−0.005, 0.000), p = 0.024)) and (β (95% CI) = −0.015 (−0.028, −0.002), p = 0.021)). Our findings suggest that a higher consumption of free sugars might negatively impact the activity and complications of SLE. However, future longitudinal research on SLE patients, including dietary intervention trials, are necessary to corroborate these preliminary data.

Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus and lupus nephritis

Lupus ◽  
2019 ◽  
Vol 28 (6) ◽  
pp. 713-721 ◽  
Author(s):  
Z Adhya ◽  
M El Anbari ◽  
S Anwar ◽  
A Mortimer ◽  
N Marr ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Response To Therapy ◽  
Complement C3 ◽  
Systemic Lupus ◽  
Multiplex Bead ◽  
Urine Markers ◽  
Serum And Urine

Background Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy. Methods A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1α (MIP-1α) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas’ Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay. Results The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups ( p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF ( p = 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores ( p < 0.001), while serum VEGF correlated weakly with SLEDAI ( p = 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio. Conclusion These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN.

scholarly journals POS0710 ANALYSIS OF 5-YEAR HOSPITALIZATION DATA OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: DAMAGE IS A RISK FACTOR FOR FREQUENT AND LONGER STAYS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 604.2-605
Author(s):  
C. Cetin ◽  
M. G. Can ◽  
S. Oztaskin ◽  
Y. Yalçinkaya ◽  
A. Gül ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Hospitalized Patients ◽  
Alveolar Haemorrhage ◽  
Systemic Lupus ◽  
Duration Of Hospitalization ◽  
Duration Of Disease ◽  
The Mean ◽  
Active Disease

Background:The rates of hospitalization in patients with SLE is around 10% per year.1Objectives:In this study, we aimed to examine the hospitalization data of patients with SLE in the last 5 years at our center and determine the factors that affect hospitalization.Methods:Hospitalization data of patients with SLE (2012 SLICC classification) admitted to our rheumatology ward between January 2015 and 2020 were analyzed. Cumulative clinical and laboratory findings were retrieved from the existing SLE database and revised. SLICC SLE damage index (SDI), and the disease activity at admission were determined (SLEDAI-2K).Results:Eighty-six % (n=138) of 161 hospitalized patients were female. The mean age of the patients was 38 ± 13 years whilst mean duration of disease was 97.3 ±96.9 months. Thirty-eight% of the patients were hospitalized more than once and the mean number of hospitalizations was 1.8±1.5 The mean hospitalization duration covering all stays for each patient was 25±27 days. Active disease followed by infection and damage-related complications ranked the first three among all causes of hospitalization.Compared to patients hospitalized for active disease or other reasons, patients hospitalized for infection had a significantly higher number of readmissions (p<0.05) and their total duration of hospitalization was longer (p<0.01). Duration of disease was significantly shorter in patients hospitalized for active disease compared to patients hospitalized for infection and damage related causes (p<0.05).The frequency of patients with damage and the mean SDI score was significantly lower in the group with active disease (68% and 1.9 ± 2) compared to patients hospitalized for infection (90% and 2.7±1.6) and other causes (96% and 3±1.7) (p<0.05 for both). Distribution of damage according to organ/systems is presented in Graph 1. Highest frequency of damage was detected in the cardiovascular (30%), followed by neuropsychiatric (26.7%), renal (23%), pulmonary (23%) and musculoskeletal (20.5%) domains. A positive correlation was found between the mean SDI score and duration of hospitalization (r=0.551, p<0.001) as well as the number of hospitalizations (r=0.393, p<0.001). Regarding disease activity at the time of admission, the mean score of patients hospitalized for active disease was 11.0 ± 6.1 whilst was 3.2 ± 2.8 in patients hospitalized for infection and 2.9 ± 3.3 in patients hospitalized for other reasons (p<0.001). Renal active disease was the most common (44%), followed by hematological (34.8%), articular (21.7%) and mucocutaneous (21%) activity. Ten% of the patients all of whom had damage were admitted to intensive care unit (ICU). Total hospitalization duration (p=0.012), mean SDI (p=0.008), antiphospholipid syndrome (p=0.033), lupus anticoagulant (p=0.010), thrombocytopenia (p=0.015), serositis (p=0.034), pulmonary hypertension (p=0.021), history of alveolar haemorrhage (p<0.001) and cardiac valve involvement (p=0.002) were associated with ICU hospitalization.Conclusion:Disease activity, infections and damage are the leading causes of hospitalization in patients with SLE. Damage increases the frequency of hospitalizations, prolongs the duration of stay, and increases the need for follow-up in the ICU. Tight control of disease activity with rational use of immunosuppressive treatment is important to reduce damage and hospitalizations.Graphic 1.Distribution of damage according to organs/systems in hospitalized patientsReferences:[1]Gu K, Gladman DD, Su J, Urowitz MB. Hospitalizations in patients with systemic lupus erythematosus in an academic health science center. The Journal of rheumatology 2017;44:1173-8.Disclosure of Interests:None declared

Sign in / Sign up

Export Citation Format

Share Document