Genetic and transcriptomic analyses support a switch to lytic phase in Epstein Barr virus infection as an important driver in developing Systemic Lupus Erythematosus.

To investigate the molecular mechanisms through which Epstein-Barr virus (EBV) may contribute to Systemic Lupus Erythematosus (SLE) pathogenesis, we interrogated SLE genetic risk loci for signatures of EBV infection. We first compared the gene expression profile of SLE risk genes across 459 different cell/tissue types. EBV-infected B cells (LCLs) had the strongest representation of highly expressed SLE risk genes. By determining an SLE risk allele effect on gene expression (expression quantitative trait loci, eQTL) in LCLs and 16 other immune cell types, we identified 79 SLE risk locus:gene pairs putatively interacting with EBV infection. A total of 10 SLE risk genes from this list (CD40, LYST, JAZF1, IRF5, BLK, IKZF2, IL12RB2, FAM167A, PTPRC and SLC15A) were targeted by the EBV transcription factor, EBNA2, differentially expressed between LCLs and B cells, and the majority were also associated with EBV DNA copy number, and expression level of EBV encoded genes. Our final gene network model based on these genes is suggestive of a nexus involving SLE risk loci and EBV latency III and B cell proliferation signalling pathways. Collectively, our findings provide further evidence to support the interaction between SLE risk loci and EBV infection that is in part mediated by EBNA2. This interplay may increase the tendency towards EBV lytic switching dependent on the presence of SLE risk alleles. These results support further investigation into targeting EBV as a therapeutic strategy for SLE.

Regulation of the methylome in differentiation from adult stem cells may underpin vitamin D risk in MS.

Multiple lines of evidence indicate Multiple Sclerosis (MS) is affected by vitamin D. This effect may be mediated by methylation in immune cell progenitors. We aimed to determine (1) if haematopoietic stem cell methylation constrains methylation in daughter cells and is variable between individuals, and (2) the interaction of methylation with the vitamin D receptor binding sites. We interrogated genomic methylation levels from matching purified CD34+ haematopoietic stem cells and progeny CD14+ monocytes and CD56+ NK cells from 11 individuals using modified reduced representation bisulfite sequencing. Differential methylation of Vitamin D Receptor binding sites and MS risk genes was assessed from this and using pyrosequencing for the vitamin D regulated MS risk gene ZMIZ1. Although DNA methylation states at CpG islands and other sites are almost entirely recapitulated between progenitor and progeny immune cells, significant variation was detected at some regions between cell subsets and individuals; including around the MS risk genes HLA DRB1 and the vitamin D repressor NCOR2. Methylation of the vitamin D responsive MS risk gene ZMIZ1 was associated with risk SNP and disease. We conclude that DNA methylation settings in adult haematopoietic stem cells may contribute to individual variation in vitamin D responses in immune cells.

Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein-Barr Virus hypomethylated regions.

Epstein-Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines-LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three individuals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation.

Bradyarrhythmias in patients with COVID-19: Marker of poor prognosis?

BACKGROUND: Despite descriptions of various cardiovascular manifestations in patients with coronavirus disease 2019 (COVID-19), there is a paucity of reports of new onset bradyarrhythmias, and the clinical implications of these events are unknown. METHODS: Seven patients presented with or developed severe bradyarrhythmias requiring pacing support during the course of their COVID-19 illness over a 6-week period of peak COVID-19 incidence. A retrospective review of their presentations and clinical course was performed. RESULTS: Symptomatic high-degree heart block was present on initial presentation in three of seven patients (43%), and four patients developed sinus arrest or paroxysmal high-degree atrioventricular block. No patients in this series demonstrated left ventricular systolic dysfunction or acute cardiac injury, whereas all patients had elevated inflammatory markers. In some patients, bradyarrhythmias occurred prior to the onset of respiratory symptoms. Death from complications of COVID-19 infection occurred in 57% (4/7) patients during the initial hospitalization and in 71% (5/7) patients within 3 months of presentation. CONCLUSIONS: Despite management of bradycardia with temporary (3/7) or permanent leadless pacemakers (4/7), there was a high rate of short-term morbidity and death due to complications of COVID-19. The association between new-onset bradyarrhythmias and poor outcomes may influence management strategies for acutely ill patients with COVID-19.

Structural Characteristics of Two-Sender Index Coding.

This paper studies index coding with two senders. In this setup, source messages are distributed among the senders possibly with common messages. In addition, there are multiple receivers, with each receiver having some messages a priori, known as side-information, and requesting one unique message such that each message is requested by only one receiver. Index coding in this setup is called two-sender unicast index coding (TSUIC). The main goal is to find the shortest aggregate normalized codelength, which is expressed as the optimal broadcast rate. In this work, firstly, for a given TSUIC problem, we form three independent sub-problems each consisting of the only subset of the messages, based on whether the messages are available only in one of the senders or in both senders. Then, we express the optimal broadcast rate of the TSUIC problem as a function of the optimal broadcast rates of those independent sub-problems. In this way, we discover the structural characteristics of TSUIC. For the proofs of our results, we utilize confusion graphs and coding techniques used in single-sender index coding. To adapt the confusion graph technique in TSUIC, we introduce a new graph-coloring approach that is different from the normal graph coloring, which we call two-sender graph coloring, and propose a way of grouping the vertices to analyze the number of colors used. We further determine a class of TSUIC instances where a certain type of side-information can be removed without affecting their optimal broadcast rates. Finally, we generalize the results of a class of TSUIC problems to multiple senders.

Continuous invasive hemodynamic monitoring using steerable guide catheter to optimize mitraclip transcatheter mitral valve repair: A multicenter, proof-of-concept study.

OBJECTIVES: We report our multicenter experience on continuous hemodynamic monitoring using exclusively the steerable guide catheter (SGC) during MitraClip repair. BACKGROUND: Left atrial pressure (LAP) and V-wave are useful to evaluate MitraClip repair but no simple method of continuous monitoring exists. METHODS: From 11/2016 to 8/2017, 74 patients from four centers with symptomatic moderate-severe to severe mitral regurgitation (MR), underwent MitraClip NT repair with continuous hemodynamic monitoring via the SGC. Real-time LAP/V-wave changes were compared with transesophageal echocardiography (TEE). When mitral stenosis was suspected, transmitral gradients were verified by invasive hemodynamics. Clinical and echocardiographic outcomes were determined. RESULTS: Mean age was 78 ± 10 years and STS score 9.1 ± 11.0%. Pathology included leaflet prolapse/flail (45%), restriction (35%), and mixed (20%). Number of clips averaged 1.7 ± 0.7 per case. There was a significant reduction in LAP (21 ± 10 to 15 ± 7 mmHg, P < 0.0001) and V-wave(37 ± 19 to 24 ± 10 mmHg, P < 0.0001) post MitraClip, but the decrease was less in patients with atrial fibrillation (P < 0.05). Transmitral gradient significantly increased from 2.0 ± 1.2 to 4.0 ± 1.7 mmHg (P < 0.0001). Paradoxical increases in LAP and V-wave despite MR reduction were observed in three cases requiring MitraClip repositioning or retrieval to avoid stenosis. Follow-up averaged 5.0 ± 2.9 months and was 100% complete. KCCQ improvement was significant and MR reduction to <1+ was 67% and <2+ was 93% at 30 days. CONCLUSIONS: Continuous hemodynamic monitoring using the SGC complements TEE to assess and optimize MitraClip repair in real-time. Further validation is necessary but this feature may be part of future MitraClip and other transcatheter mitral repair systems.

The impact of sex, body mass index and chronic kidney disease on outcomes following percutaneous coronary intervention.

OBJECTIVE: This study sought to evaluate 1) the relationship between body mass index (BMI), chronic kidney disease (CKD) and bleeding complications in patients undergoing percutaneous coronary intervention (PCI); and 2) whether CKD modified the effect of BMI on major bleeding and major adverse cardiac and cerebrovascular events (MACCE). BACKGROUND: The interaction of CKD, sex and BMI in patients undergoing PCI is unclear. METHODS: Between 2010 and 2018, a total of 31,116 patients underwent PCI at six New York metropolitan area hospitals. Bleeding complications were classified by the Bleeding Academic Research Consortium (BARC). Major bleeding was defined as BARC≥3. MACCE was the composite of in-hospital death; myocardial infarction; cerebrovascular events and major bleeding complications. Interaction on multiplicative scales was assessed adjusting for other factors. A three-way multiplicative interaction between BMI, CKD and sex were considered and evaluated for both endpoints of primary interest (BARC≥3 and MACCE). RESULTS: Patients with BARC≥3 bleeding were older (p < 0.0001) and more likely female (p < 0.0001). A 3-way interaction existed between sex, BMI, and CKD on BARC≥3 (p = 0.02). Specifically, the effect of CKD status on odds of BARC≥3 depended on BMI group among males, whereas BMI did modify the relationship between CKD and BARC≥3 among females; after stratification by sex, a significant interaction between BMI and CKD was present in females (p = 0.03) but not in males (p = 0.43). Among females without CKD, normal BMI patients had the greatest odds of BARC≥3 compared to obese or overweight females. Contrasted to females without CKD, among females with CKD there was no significant increased odds of BARC≥3 in normal BMI patients compared to obese or overweight females. However, overweight females with CKD had a significantly increased odds of BARC≥3 compared to obese females with CKD. Furthermore, obese females with CKD had significantly greater BARC≥3 odds compared to obese females without CKD. Similarly, overweight females with CKD had an increased odds of BARC≥3 compared to overweight females without CKD. No significant interactions were found for the odds of MACCE. CONCLUSION: In patients undergoing PCI, there was evidence of a significant and complex 3-way interaction between BMI, CKD and sex for major bleeding events. The predicted probability of major bleeding was greater for females than for male patients, and for both sexes, greater among those with CKD, but BMI group influences these probabilities. Obese females with kidney disease had the lowest incidence of bleeding complications when compared with overweight or normal weight female patients undergoing PCI. This interaction was not seen in the male group or for MACCE. Furthermore, age, cardiogenic shock, STEMI and use of IABP/Impella were each independently associated with odds of major bleeding (among both males and females) and MACCE.

Percutaneous coronary intervention with Impella support with and without intra-aortic balloon in cardiogenic shock patients.

OBJECTIVE: To assess the clinical characteristics and in-hospital bleeding complications and major adverse cardiac and cerebrovascular events (MACCE) associated with the use of Impella alone or the combination of an intra-aortic balloon pump (IABP) with Impella in cardiogenic shock (CS) patients undergoing percutaneous coronary intervention (PCI). METHODS: All CS patients who underwent PCI and were treated with an Impella mechanical circulatory support (MCS) device were identified. Patients were divided into two groups: having MCS support with Impella alone or with both, IABP and Impella simultaneously (dual MCS group). Bleeding complications were classified by a modified Bleeding Academic Research Consortium (BARC) classification. Major bleeding was defined as BARC≥3 bleeding. MACCE was the composite of in-hospital death, myocardial infarction, cerebrovascular events and major bleeding complications. RESULTS: Between 2010 and 2018 a total of 101 patients were treated at six tertiary care New York hospitals with either Impella (n = 61) or dual MCS with Impella and IABP (n = 40). Clinical characteristics were similar for both groups. Dual MCS patients presented more often with a STEMI (77.5 % vs. 45.9 %, p = 0.002) and had left main coronary artery intervention (20.3 % vs. 8.6 %, p = 0.03). Major bleeding complications (69.4 % vs. 74.1 %, p = 0.62) and MACCE rates (80.6 % vs. 79.3 %, p = 0.88) were very high but similar in both groups, however access site bleeding complications were lower in patients treated with dual MCS. In-hospital mortality was 29.5 % for the Impella group and 25.0 % for the dual MCS group (p = 062). Access site bleeding complications were lower in in patients treated with dual MCS (5.0 % vs. 24.6 %, p = 0.01). CONCLUSION: In CS patients undergoing PCI with either the Impella device alone or with Impella and IABP, major bleeding complications and MACCE rates were high but not significantly different between the two groups. In hospital mortality was relatively low in both MCS groups despite the high-risk characteristics of these patients. Future studies should assess the risks and benefits of the simultaneous use of these two MCS in CS patients undergoing PCI.

Age-dependent VDR peak DNA methylation as a mechanism for latitude-dependent multiple sclerosis risk.

BACKGROUND: The mechanisms linking UV radiation and vitamin D exposure to the risk of acquiring the latitude and critical period-dependent autoimmune disease, multiple sclerosis, is unclear. We examined the effect of vitamin D on DNA methylation and DNA methylation at vitamin D receptor binding sites in adult and paediatric myeloid cells. This was accomplished through differentiating CD34+ haematopoietic progenitors into CD14+ mononuclear phagocytes, in the presence and absence of calcitriol. RESULTS: Few DNA methylation changes occurred in cells treated with calcitriol. However, several VDR-binding sites demonstrated increased DNA methylation in cells of adult origin when compared to cells of paediatric origin. This phenomenon was not observed at other transcription factor binding sites. Genes associated with these sites were enriched for intracellular signalling and cell activation pathways involved in myeloid cell differentiation and adaptive immune system regulation. CONCLUSION: These results suggest vitamin D exposure at critical periods during development may contribute to latitude-related differences in autoimmune disease incidence.

Vitamin D and its Effects on DNA Methylation in Development, Aging, and Disease.

DNA methylation is increasingly being recognized as a mechanism through which environmental exposures confer disease risk. Several studies have examined the association between vitamin D and changes in DNA methylation in areas as diverse as human and animal development, genomic stability, chronic disease risk, and malignancy. In many cases, they have demonstrated clear associations between vitamin D and DNA methylation in candidate disease pathways. Despite this, a clear understanding of the mechanisms by which these factors interact is unclear. This paper reviews the current understanding of the effects of vitamin D on DNA methylation. In light of current knowledge in the field, the potential mechanisms mediating vitamin D effects on DNA methylation are discussed, as are the limiting factors and future avenues for research into this exciting area.

Mandatory diagnostic angiography for carotid artery stenosis prior to carotid artery intervention.

INTRODUCTION: Revascularization is an important strategy for reducing stroke risk in patients with severe carotid atherosclerosis. Magnetic resonance angiography (MRA) and/or carotid ultrasound have traditionally been used as the only diagnostic modalities prior to revascularization. Patients undergoing CEA frequently have no further assessments of carotid anatomy prior to surgery. Evaluation with carotid ultrasound and MRA can often overestimate the degree of stenosis. We sought to determine if noninvasive imaging was sufficient for determining whether a patient should be referred for carotid intervention. METHODS: We performed an analysis of 101 patients referred for carotid artery stenting (CAS). All patients had previously been evaluated with carotid ultrasound and 94% had undergone MRA as well. We sought to determine if noninvasive diagnostic imaging for carotid stenosis was sufficient to determine the necessity for endovascular intervention. RESULTS: Of the 101 patients referred for carotid intervention, 36 (36%) were shown to have <70% stenoses and did not require intervention. Of those who had significant disease, 49 (75%) underwent successful CAS, 15 (23%) underwent CEA, and 1 patient was treated medically for a total occlusion. Three of the 36 patients not requiring carotid intervention were found to have subclavian stenosis. Two (4%) of the patients undergoing CAS and 4 (27%) of the patients undergoing CEA had minor complications. No patients suffered a major stroke, MI, or death at follow-up. CONCLUSION: This analysis demonstrates that 36% of patients referred for endovascular intervention based on noninvasive imaging did not meet criteria by angiography. This emphasizes the need for carotid angiography prior to carotid intervention.

Value of electrocardiographically gated single-photon emission computed tomographic myocardial perfusion scintigraphy in a cohort of symptomatic postmenopausal women.

The aim of this study is to prospectively evaluate the clinical value of electrocardiographically gated single-photon emission computed tomographic myocardial perfusion scintigraphy (MPS) imaging in a cohort of postmenopausal women with symptoms suggestive of ischemic heart disease. Forty-six postmenopausal women with no history of coronary artery disease (CAD), but with typical or atypical angina and >or=1 risk factor for CAD, were enrolled and underwent both coronary angiography and technetium-99m sestamibi MPS with exercise (n = 36) or pharmacologic stress (n = 10). All women were followed up for 5.0 +/- 3 years for the occurrence of hospitalization for acute coronary syndrome, myocardial infarction, and/or new-onset or worsening angina. CAD prevalence (>or=50% diameter stenosis) was 62% (26 of 42 patients). Fifteen patients (36%) had 1-vessel disease, 7 (17%) had 2-vessel disease, and 4 (10%) had 3-vessel disease. Diagnostic sensitivity and specificity of the exercise electrocardiogram were 67% and 69%, respectively. By comparison, sensitivity of MPS was 88% and specificity was 87.5% (p <0.0001). Cox survival analysis showed 3- and 5-year cumulative event-free survival rates of 97% and 94% for patients with normal MPS results compared with 60% and 48% for those with abnormal MPS findings (p <0.001). In conclusion, results of this study indicate high diagnostic and prognostic accuracy for MPS in symptomatic postmenopausal women.

Primary Sjogren's Syndrome Associated With Treatment-Resistant Obsessive-Compulsive Disorder.

There is an increasing awareness that autoimmune diseases can present with neuropsychiatric manifestations. We present the case of a 17-year-old female requiring psychiatric hospitalization for obsessive-compulsive disorder and major depressive disorder with mixed affective features, who was subsequently diagnosed with primary Sjogren's syndrome. Treatment with potent immunosuppression resulted in remission of psychiatric illness. Due to a lack of awareness and/or the lack of specific biomarkers, clinicians may not associate psychiatric symptoms with autoimmune disease, including primary Sjogren's syndrome. This case demonstrates that Sjogren's syndrome may be a causative or aggravating factor in mental disorders and that autoimmune diseases should be carefully considered in the differential diagnosis of psychiatric illness especially in cases of concurrent physical symptomatology and severity or treatment resistance of psychiatric disease.

Selective His-bundle Pacing May Preserve Intrinsic Repolarization as Well as Depolarization.

A 79-year-old man with chronic atrial fibrillation underwent single-chamber His-bundle pacemaker implantation. The post-implant electrocardiogram (ECG) demonstrated selective His-bundle capture, with a narrow paced QRS and repolarization pattern similar to that of the baseline ECG. Furthermore, repolarization changes prototypic of ventricular pacing did not occur with selective His-bundle capture. While His-bundle pacing, with or without selective His-bundle capture, can preserve physiologic patterns of depolarization, only His-bundle selective pacing can preserve intrinsic ST- and T-wave patterns. Thus, the maintenance of physiologic repolarization may have various advantages, including accurate interpretation of ECG changes that are not generally interpretable in the setting of ventricular pacing.

A novel nucleotide oligomerisation domain 2 mutation in a family with Blau syndrome: Phenotype and function.

Mutations in the nucleotide binding domain of the PRR, NOD2, are associated with the autoinflammatory diseases Blau syndrome and early-onset sarcoidosis. Current theories suggest that constitutive activation of the NOD2 pathway may be responsible for pathogenesis of these diseases. Here, we report the phenotype of a kindred with Blau syndrome caused by a novel NOD2 mutation (p.E383D). Signaling protein and cytokine expression were examined, and the results of these experiments challenge current theories of constitutive NOD2 activation in the pathophysiology of Blau syndrome.

Validation of a phospholipase A2 receptor antibody ELISA in an Australian cohort with membranous glomerulonephritis.

A commercial PLA2R Ab ELISA was validated by examining its ability to distinguish primary from secondary membranous nephropathy, correlating results with clinical markers of disease activity, and comparing its performance with an indirect immunofluorescence test (IIFT). PLA2R Ab levels were measured in 77 patients with biopsy proven membranous nephropathy, divided into either idiopathic (n = 61) or secondary groups (n = 6). In the idiopathic group, measures of contemporaneous disease activity (proteinuria, serum creatinine) were compared between seropositive and seronegative subjects. ELISA values were then compared with semi-quantitative results from an IIFT using PLA2R transfected HEK293 cells as substrate. The PLA2R Ab ELISA was positive in only 15 of 61 (25%) patients with idiopathic membranous nephropathy (IMN), but there was a significant negative relationship with time since diagnosis. Thus, in a subgroup of patients diagnosed within 6 months of analysis, the sensitivity was 6/15 (55%), rising to 6/8 (75%) in those recently-diagnosed patients who had not been treated. In the entire cohort, there was a significant positive correlation between ELISA values and degree of proteinuria, but our analysis did not control for variation of both variables with time. The PLA2R Ab ELISA also showed very high agreement with IIFT (96%). Therefore, the PLA2R Ab ELISA is a highly specific test for distinguishing primary from secondary membranous nephropathy that is most sensitive in newly diagnosed patients who have not received immunosuppression. Antibody levels correlated with degree of proteinuria, but this relationship was not shown to be independent of time. Both IIFT and ELISA platforms performed comparably.

Intracardiac echocardiography using the AcuNav ultrasound catheter during percutaneous balloon mitral valvuloplasty.

During the past 10 years, there has been a trend toward and an interest in the use of catheter-based interventions to perform procedures that were once only approached surgically. The problem with the catheter-based approach has been procedure-related complications. Improved imaging of cardiac structures while undertaking interventional procedures may help to prevent or allow for early identification of these complications. Transesophageal echocardiography has been used during catheter-based procedures as a guide, and has both advantages and disadvantages. Intracardiac echocardiography is a relatively new imaging technique that also provides an enhanced view of cardiac structures and may also allow for the safe and efficient performance of catheter-based procedures. We report the first case of successful percutaneous balloon mitral valvuloplasty done under ultrasound guidance using an intracardiac echocardiography catheter (10F, 5-10 MHz) (Acunav). The strengths and weaknesses of this approach are described and compared with transesophageal echocardiography and older intracardiac echocardiography devices.