Subject(s)
Glomerulonephritis, IGA , Graves Disease , IgA Vasculitis , Lymphoma, Mantle-Cell , Humans , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , Lymphoma, Mantle-Cell/complications , Lymphoma, Mantle-Cell/pathology , Graves Disease/complications , Glomerulonephritis, IGA/complications , Glomerulonephritis, IGA/pathology , Male , Middle AgedABSTRACT
OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and safety between glucocorticoids combined with mycophenolate mofetil (MMF) versus glucocorticoids combined with cyclophosphamide (CTX) for henoch schonlein purpura nephritis (HSPN) in children. METHODS: Databases including PubMed, EMbase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database were searched from the inception to April 5th, 2024. Eligible studies comparing glucocorticoids combined with MMF versus glucocorticoids combined with CTX for HSPN in children were included. Data were analyzed using Review Manager Version 5.3. RESULTS: Ten studies were included in the meta-analysis. Six randomized controlled trials (RCTs) and 4 non-randomized studies involving 675 patients were identified. Compared with CTX therapeutic schedule, MMF therapeutic schedule had a higher complete remission (CR) within the 6 months (OR 1.61, 95%CI 1.16-2.22, Pâ =â .004) and CR within the 12 months (OR 1.73, 95%CI 1.00-2.97, Pâ =â .05). However, there was no significant difference between MMF and CTX therapeutic schedule concerning total remission (TR) within the 6 months (OR 1.54, 95%CI 0.82-2.92, Pâ =â .18) and TR within the 12 months (OR 2.08, 95%CI 0.86-5.01, Pâ =â .10). In addition, incidences of gastrointestinal discomfort (OR 0.33, 95%CI 0.19-0.56, Pâ <â .0001), liver function injury (OR 0.28, 95%CI 0.09-0.87, Pâ =â .03), myelosuppression (OR 0.15, 95%CI 0.06-0.41, Pâ =â .0001), alopecia (OR 0.25, 95%CI 0.07-0.91, Pâ =â .03) in MMF therapeutic schedule were all lower than CTX therapeutic schedule. There was no statistically significant difference between the 2 therapeutic schedules concerning infection (OR 0.90, 95%CI 0.50-1.61, Pâ =â .72), rash (OR 0.38, 95%CI 0.07-2.04, Pâ =â .26). CONCLUSION: Glucocorticoids combined with MMF had a higher CR and lower incidence of adverse effects compared with glucocorticoids combined with CTX in the treatment of HSPN in children.
Subject(s)
Cyclophosphamide , Drug Therapy, Combination , IgA Vasculitis , Immunosuppressive Agents , Mycophenolic Acid , Nephritis , Humans , IgA Vasculitis/drug therapy , IgA Vasculitis/complications , Cyclophosphamide/therapeutic use , Cyclophosphamide/adverse effects , Mycophenolic Acid/therapeutic use , Mycophenolic Acid/adverse effects , Child , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/administration & dosage , Nephritis/drug therapy , Glucocorticoids/therapeutic use , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Treatment Outcome , Randomized Controlled Trials as Topic , Child, PreschoolABSTRACT
BACKGROUND: Immumoglobulin A (IgA) vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is a self-limiting systemic vasculitis in children. Kidney involvement is associated with a long-term unfavorable outcome and can lead to significant morbidity. This study was conducted to describe the clinical and laboratory characteristics of childhood IgAV with kidney involvement and to identify risk factors associated with IgAV nephritis (IgAVN). METHODS: This was an ambidirectional descriptive study of 77 children with IgAV. All demographic data, clinical features, and laboratory tests were collected from electronic medical records from January 2010 to December 2022. Risk factors for kidney involvement in IgAV were assessed using multivariate logistic regression. Kaplan-Meier survival analysis was used to calculate the time to commencement of kidney involvement. RESULTS: Twenty-five children (32.4% of the IgAV patients) developed IgAVN. The common findings in IgAV with kidney involvement were microscopic hematuria (100%), nephrotic range proteinuria (44%), and non-nephrotic range proteinuria (40%). Multivariate logistic regression showed that age greater than 10 years (adjusted hazard ratio, AHR 4.66; 95% confidence interval, CI, 1.91-11.41; p = 0.001), obesity (body mass index, BMI, z-score ≥ +2 standard deviations, SDs) (AHR 3.59; 95% CI 1.41-9.17; p = 0.007), and hypertension at onset (AHR 4.78; 95% CI 1.76-12.95; p = 0.002) were associated significantly with kidney involvement. During follow up, most IgAV patients developed nephritis within the first 9 months. CONCLUSION: Age greater than 10 years, obesity, and hypertension at presentation were predictive factors for IgAVN. Our study emphasized that IgAV patients with risk factors should be closely monitored for at least 1 year after the onset of the disease.
Subject(s)
IgA Vasculitis , Humans , Male , Female , Child , Risk Factors , IgA Vasculitis/complications , IgA Vasculitis/epidemiology , IgA Vasculitis/diagnosis , Child, Preschool , Adolescent , Retrospective Studies , Proteinuria/etiology , Proteinuria/epidemiology , Kaplan-Meier Estimate , Hematuria/etiology , Hematuria/epidemiology , Logistic Models , Kidney/pathology , Glomerulonephritis, IGA/complications , Glomerulonephritis, IGA/epidemiologyABSTRACT
IgA nephropathy (IgAN) is a fairly common association with alcoholic liver disease. However, IgA vasculitis (IgAV) is quite an uncommon association with alcoholic liver cirrhosis and only a handful of cases have been reported in literature. Secondary IgAN usually presents in a docile manner, progressing slowly in about 5-25 years. It is usually responsive to steroid therapy, very rarely progressing to End-Stage Renal Disease. Here, we present a man in his late 50s, a known hypertensive and alcohol related liver-cirrhotic, who presented to our hospital with rash and rapidly progressive renal failure (RPRF). He was diagnosed with IgA nephritis with IgA vasculitis (IgAVN). His diagnosis was confirmed with skin and renal biopsy. He was started on renal replacement therapy for his renal failure and began oral steroid therapy. After administration of steroid therapy for 6 months, the patient recovered and was dialysis independent with stable renal parameters.
Subject(s)
Glomerulonephritis, IGA , Humans , Male , Glomerulonephritis, IGA/complications , Glomerulonephritis, IGA/diagnosis , Middle Aged , Disease Progression , Liver Diseases, Alcoholic/complications , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , IgA Vasculitis/drug therapy , Vasculitis/complications , Vasculitis/etiology , Vasculitis/diagnosis , Vasculitis/drug therapyABSTRACT
A girl in middle childhood was referred to the paediatric surgical team with acute colicky abdominal pain and bile-stained vomiting. This was preceded by a viral illness. Investigations revealed raised inflammatory markers, and imaging of the abdomen demonstrated ileal and jejunal thickening. Concerns were raised regarding whether she had inflammatory bowel disease. Endoscopy revealed gastritis and duodenitis, and colonoscopy was unremarkable. Video capsule endoscopy demonstrated ulcers in the jejunum and ileum.On day 8 of admission, she developed a symmetrical purpuric rash over both ankles leading to the diagnosis of Henoch-Schonlein-related ileitis. Multidisciplinary team working led to appropriate management of the patient and avoided surgery. Video capsule endoscopy enabled visualisation of the small bowel. She was managed with 5 days of methylprednisolone followed by oral steroids. She made a good recovery with no sequelae. This case highlighted that terminal ileitis is a rare complication of IgA vasculitis with a good prognosis.
Subject(s)
IgA Vasculitis , Ileitis , Humans , Female , Ileitis/diagnosis , Ileitis/complications , Child , IgA Vasculitis/diagnosis , IgA Vasculitis/complications , Capsule Endoscopy , Methylprednisolone/therapeutic use , Immunoglobulin A/immunologyABSTRACT
IgA-associated vasculitis (IgAV) known as Henoch - Schönlein purpura (HSP) disease is an inflammatory disorder of small blood vessels. It's the most common type of systemic vasculitis in children which can be associated with the inflammatory process following infections. IgA vasculitis is a rare and poorly understood systemic vasculitis in adults. Coronavirus disease 2019 (COVID-19) has been associated with HSP in both adults and children. A 58-year-old woman was diagnosed with HSP, fulfilling the clinical criteria: palpable purpura, arthritis, hematuria. The disclosure of the HSP disease was preceded by a infection of the respiratory tract. COVID-19 infection was confirmed via the presence of IgM and IgG antibodies. This case indicates the possible role of SARS-CoV-2 in the development of HSP. The clinical course of IgAV in adults appears to be different from pediatric IgAV, especially due to higher risk of renal complications. Symptoms of the disease quickly resolved with low-dose of steroids.
Subject(s)
COVID-19 , IgA Vasculitis , SARS-CoV-2 , Humans , COVID-19/complications , COVID-19/immunology , IgA Vasculitis/immunology , IgA Vasculitis/diagnosis , IgA Vasculitis/complications , IgA Vasculitis/drug therapy , Female , Middle Aged , SARS-CoV-2/immunology , Immunoglobulin A/blood , Immunoglobulin A/immunologyABSTRACT
Importance: Henoch-Schönlein purpura (HSP) is the most common type of vasculitis in children. The factors that trigger the disease are poorly understood. Although several viruses and seasonal bacterial infections have been associated with HSP, differentiating the specific associations of these pathogens with the onset of HSP remains a challenge due to their overlapping seasonal patterns. Objective: To analyze the role of seasonal pathogens in the epidemiology of HSP. Design, Setting, and Participants: This cohort study comprised an interrupted time-series analysis of patient records from a comprehensive national hospital-based surveillance system. Children younger than 18 years hospitalized for HSP in France between January 1, 2015, and March 31, 2023, were included. Exposure: Implementation and relaxation of nonpharmaceutical interventions (NPIs) for the COVID-19 pandemic, such as social distancing and mask wearing. Main Outcomes and Measures: The main outcomes were the monthly incidence of HSP per 100â¯000 children, analyzed via a quasi-Poisson regression model, and the estimated percentage of HSP incidence potentially associated with 14 selected common seasonal pathogens over the same period. Results: The study included 9790 children with HSP (median age, 5 years [IQR, 4-8 years]; 5538 boys [56.4%]) and 757â¯110 children with the infectious diseases included in the study (median age, 0.7 years [IQR, 0.2-2 years]; 393â¯697 boys [52.0%]). The incidence of HSP decreased significantly after implementation of NPIs in March 2020 (-53.6%; 95% CI, -66.6% to -40.6%; P < .001) and increased significantly after the relaxation of NPIs in April 2021 (37.2%; 95% CI, 28.0%-46.3%; P < .001). The percentage of HSP incidence potentially associated with Streptococcus pneumoniae was 37.3% (95% CI, 22.3%-52.3%; P < .001), the percentage of cases associated with Streptococcus pyogenes was 25.6% (95% CI, 16.7%-34.4%; P < .001), and the percentage of cases associated with human rhino enterovirus was 17.1% (95% CI, 3.8%-30.4%; P = .01). Three sensitivity analyses found similar results. Conclusions and Relevance: This study found that significant changes in the incidence of HSP simultaneously with major shifts in circulating pathogens after NPIs for the COVID-19 pandemic indicated that approximately 60% of HSP incidence was potentially associated with pneumococcus and group A streptococcus. This finding suggests that preventive measures against these pathogens could reduce the incidence of pediatric HSP.
Subject(s)
COVID-19 , IgA Vasculitis , Male , Child , Humans , Child, Preschool , Infant , Seasons , IgA Vasculitis/epidemiology , IgA Vasculitis/complications , Cohort Studies , Pandemics , COVID-19/epidemiology , COVID-19/complicationsABSTRACT
INTRODUCTION AND OBJECTIVES: Henoch Schönlein purpura (HSP) and Kawasaki disease (KD) are two main inflammatory diseases among childhood vasculitis. Considering the anti-inflammatory effects of 25-hydroxyvitamin D3, we decided to investigate the association of serum 25-hydroxy vitamin D3 level with the type and severity of these conditions. MATERIALS AND METHODS: The present study was performed as a historical cohort of 254 affected children with KD and HSP vasculitis. The required data were extracted, using a researcher-made questionnaire from patients' electronic file, and then they were analyzed after collecting information of the patients. RESULTS: In HSP group, 54% of participants were boys. Similarly, in KD group, boys were more affected than girls. The comparative 25-hydroxyvitamin vitamin D3 level in HSP patients with and without renal involvement (P=0.02), hematuria (P=0.14), and in two groups with and without heart disease, and also with and without coronary artery dilatation in KD patients (P<0.001) were significant. DISCUSSION AND CONCLUSIONS: The findings showed that insufficient level of vitamin D3 were significantly associated with the exacerbation of complications of both diseases, and therefore it seems that vitamin D deficiency can be an effective predictive factor of severity in HSP and KD patients.
Subject(s)
IgA Vasculitis , Mucocutaneous Lymph Node Syndrome , Humans , IgA Vasculitis/blood , IgA Vasculitis/complications , Male , Female , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/blood , Child , Child, Preschool , Vitamin D Deficiency/complications , Vitamin D Deficiency/blood , Calcifediol/blood , Retrospective Studies , Hematuria/etiology , Adolescent , Infant , Vitamin D/blood , Vitamin D/analogs & derivatives , Vitamin D/therapeutic use , Severity of Illness IndexSubject(s)
IgA Vasculitis , Humans , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , PrognosisABSTRACT
Henoch-Schönlein purpura nephritis (HSPN) is the most severe manifestation of Henoch-Schönlein purpura (HSP). This study aimed to determine the role of urine metabolomics in predicting HSPN and explore the potential mechanisms of HSP. A liquid chromatography-tandem mass spectrometry-based untargeted metabolomics analysis was performed to investigate the urinary metabolic profiles of 90 participants, comprising 30 healthy children (group CON) and 60 patients with HSP, including 30 HSP patients without renal involvement (group H) and 30 HSPN patients (group HSPN). The differentially expressed metabolites (DEMs) were identified using orthogonal partial least squares discriminant analysis (OPLS-DA), and subsequent bioinformatics analysis was conducted to elucidate the perturbed metabolic pathways. A total of 43 DEMs between H and HSPN groups were analyzed by the Kyoto Encyclopedia of Gene and Genome (KEGG) database, and the result indicates that glycine, serine and threonine metabolism, and cysteine and methionine metabolism were significantly disturbed. A composite model incorporating propionylcarnitine and indophenol sulfate was developed to assess the risk of renal involvement in pediatric patients with HSP. Conclusion: This study reveals the metabolic alterations in healthy children, HSPN patients, and HSP patients without renal involvement. Furthermore, propionylcarnitine and indophenol sulfate may be potential predictive biomarkers of the occurrence of HSPN. What is Known: ⢠HSP is the predominant type of vasculitis observed in children. The long-term prognosis of HSP is contingent upon the extent of renal impairment. In severe nephritis, a delay in appropriate treatment may lead to fibrosis progression and subsequent development of chronic kidney disease (CKD), even leading to renal failure. ⢠The application of metabolomics in investigating diverse renal disorders has been documented. Urine is a robust and sensitive medium for metabolomics detection. What is New: ⢠The metabolic profiles were identified in urine samples of healthy children and those with HSP at the early stage of the disease. Different metabolites were identified between HSP patients without nephritis and those who developed HSPN. ⢠These different metabolites may affect oxidative stress in the progression of HSPN.
Subject(s)
Biomarkers , IgA Vasculitis , Metabolomics , Nephritis , Humans , IgA Vasculitis/urine , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , Male , Female , Child , Nephritis/urine , Nephritis/etiology , Pilot Projects , Biomarkers/urine , Metabolomics/methods , Case-Control Studies , Child, Preschool , Chromatography, Liquid , Tandem Mass Spectrometry , AdolescentSubject(s)
Axial Spondyloarthritis , Humans , Male , Female , Axial Spondyloarthritis/diagnosis , Immunoglobulin A/immunology , Immunoglobulin A/blood , Adult , Middle Aged , IgA Vasculitis/diagnosis , IgA Vasculitis/complications , IgA Vasculitis/immunology , Vasculitis/diagnosis , Vasculitis/immunologyABSTRACT
OBJECTIVES: To study the association of hypercoagulability with urinary protein and renal pathological damage in children with immunoglobulin A vasculitis with nephritis (IgAVN). METHODS: Based on the results of coagulation function, 349 children with IgAVN were divided into a hypercoagulability group consisting of 52 children and a non-hypercoagulability group consisting of 297 children. Urinary protein and renal pathological features were compared between the two groups, and the factors influencing the formation of hypercoagulability in children with IgAVN were analyzed. RESULTS: Compared with the non-hypercoagulability group, the hypercoagulability group had significantly higher levels of urinary erythrocyte count, 24-hour urinary protein, urinary protein/creatinine, urinary immunoglobulin G/creatinine, and urinary N-acetyl-ß-D-glucosaminidase (P<0.05). The hypercoagulability group also had a significantly higher proportion of children with a renal pathological grade of III-IV, diffuse mesangial proliferation, capillary endothelial cell proliferation, or >25% crescent formation (P<0.05). The multivariate logistic regression analysis showed that capillary endothelial cell proliferation and glomerular crescent formation >25% were associated with the formation of hypercoagulability in children with IgAVN (P<0.05). CONCLUSIONS: The renal injury in IgAVN children with hypercoagulability is more severe, with greater than 25% crescent formation and increased proliferation of glomerular endothelial cells being important contributing factors that exacerbate the hypercoagulable state in IgAVN.
Subject(s)
IgA Vasculitis , Nephritis , Thrombophilia , Child , Humans , Creatinine , Endothelial Cells , Kidney , IgA Vasculitis/complications , Thrombophilia/etiology , Immunoglobulin AABSTRACT
INTRODUCTION: Schönlein-Henoch disease is a small vessel vasculitis resulting from IgA-mediated inflammation. It is the most common acute systemic vasculitis in childhood, mainly affecting the skin, gastrointestinal tract, joints, and kidneys. Although the prognosis of Schönlein-Henoch is generally good, gastrointestinal tract involvement is a potential complication, presenting as massive gastrointestinal bleeding, bowel infarction, perforation, as well as intussusception and peritonitis.
Subject(s)
IgA Vasculitis , Humans , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , Skin , Kidney , AbdomenABSTRACT
BACKGROUND: Immune complex vasculitides may be subdivided into adult IgA small vessel vasculitis (aIgA-SVV; i.e. adult Henoch-Schönlein purpura) and non-IgA-SVV (hypersensitivity vasculitis, etc.). OBJECTIVES: To evaluate the clinical and laboratory parameters of inpatients fulfilling the diagnostic criteria for aIgA-SVV and non-IgA-SVV. METHODS: Twenty-nine adults aged ≥ 20â years with aIgA-SVV [according to the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria] and 53 adults with non-IgA-SVV (according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides) were compared with respect to a variety of clinical and laboratory parameters by uni- and multivariable analyses. RESULTS: Compared with patients with aIgA-SVV, the platelet-to-lymphocyte ratio was significantly higher in patients with non-IgA-SVV. Serum C3 levels and mean corpuscular haemoglobin concentration in patients with non-IgA-SVV were significantly lower compared with patients with aIgA-SVV. Proteinuria and haematuria were significantly more common in patients with aIgA SVV, and were significantly correlated with systemic immune-inflammation biomarkers only in patients with aIgA-SVV. In patients with aIgA-SVV, higher lactate dehydrogenase and C-reactive protein were strong independent predictors for the presence of proteinuria and proteinuria. In patients with non-IgA-SVV, female sex was a protective factor for proteinuria, while skin lesions on the upper extremities proved to be a significant independent predictor of haematuria. CONCLUSIONS: We detected several clinical and laboratory differences between patients with aIgA-SVV and non-IgA-SVV. Distinct predictors for renal involvement were not observed in either group, indicating that aIgA-SVV and non-IgA-SVV are similar conditions but do not appear to represent the same entity.
Subject(s)
IgA Vasculitis , Humans , Female , Male , IgA Vasculitis/immunology , IgA Vasculitis/blood , IgA Vasculitis/complications , Adult , Middle Aged , Aged , Immunoglobulin A/blood , Proteinuria , Hematuria/etiology , Vasculitis/immunology , Vasculitis/blood , Complement C3/metabolism , Complement C3/analysis , C-Reactive Protein/metabolism , C-Reactive Protein/analysis , Young AdultSubject(s)
Plasma Exchange , Adult , Humans , Male , Gastrointestinal Diseases , IgA Vasculitis/complications , IgA Vasculitis/therapy , IgA Vasculitis/diagnosis , IgA Vasculitis/drug therapy , Immunoglobulin A/blood , Plasma Exchange/methods , Treatment Outcome , Vasculitis/drug therapy , Vasculitis/immunologySubject(s)
IgA Vasculitis , Rectum , Humans , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , Male , Rectum/pathology , Rectum/diagnostic imaging , ColonoscopyABSTRACT
Hemophilia A and B are one of the most common hereditary bleeding disorders. Patients are predisposed to bleeding spontaneously or after minor trauma in different areas such as the skin, gastrointestinal, or joints. COVID-19 infection has been associated with various clinical manifestations and complications including rarely triggering IgA vasculitis. We report a 23-year-old man who was previously diagnosed with severe hereditary hemophilia A. He presented to our hospital with classic symptoms of IgA vasculitis, complaining of petechiae and purpura in his limbs, fatigue, body aches, poor oral intake, abdominal pain, and watery non-bloody diarrhea. He did not present with respiratory symptoms or fever typical of COVID-19 infection. Abnormal blood tests were mildly elevated C-reactive protein, elevated d-dimers, and low Factor VIII activity. Extensive immunological tests were negative. CT abdomen with contrast was unremarkable. A skin biopsy strongly indicated IgA vasculitis. COVID-19 test came back positive. The patient was managed symptomatically and with glucocorticosteroids which significantly improved his symptoms. The available literature on clinical features, laboratory tests, and management of COVID-19-associated IgA vasculitis is discussed. However, there is no case reported on the associations between hemophilia, COVID-19 infection, and IgA vasculitis. This is the first case of atypical COVID-19 infection masquerading as de novo IgA vasculitis in an adult patient with underlying hemophilia. Our case contributes to the growing body of literature about hemophilia being a possible predisposing factor that a COVID-19 virus relies on to amplify immune dysregulation resulting in IgA vasculitis.
Subject(s)
COVID-19 , Hemophilia A , IgA Vasculitis , Male , Adult , Humans , Young Adult , IgA Vasculitis/complications , IgA Vasculitis/diagnosis , IgA Vasculitis/pathology , Hemophilia A/complications , Hemophilia A/diagnosis , Hemophilia A/pathology , COVID-19/complications , COVID-19/diagnosis , Skin/pathology , Gastrointestinal TractABSTRACT
We investigated the polarisation of CD68+ macrophages and perforin and granulysin distributions in kidney lymphocyte subsets of children with IgA vasculitis nephritis (IgAVN). Pro-inflammatory macrophage (M)1 (CD68/iNOS) or regulatory M2 (CD68/arginase-1) polarisation; spatial arrangement of macrophages and lymphocytes; and perforin and granulysin distribution in CD3+ and CD56+ cells were visulaised using double-labelled immunofluorescence. In contrast to the tubules, iNOS+ cells were more abundant than the arginase-1+ cells in the glomeruli. CD68+ macrophage numbers fluctuated in the glomeruli and were mostly labelled with iNOS. CD68+/arginase-1+ cells are abundant in the tubules. CD56+ cells, enclosed by CD68+ cells, were more abundant in the glomeruli than in the tubuli, and co-expressed NKp44. The glomerular and interstitial/intratubular CD56+ cells express perforin and granulysin, respectively. The CD3+ cells did not express perforin, while a minority expressed granulysin. Innate immunity, represented by M1 macrophages and CD56+ cells rich in perforin and granulysin, plays a pivotal role in the acute phase of IgAVN.