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ayache abbassia

and 3 more

The aim of our study is to know the rate of restoration, the reconstitution of the forest landscape and the impact of fires on the resilience of the soils of the Tenira forest. The frequent fires in the latter are one of the main major disruptive factors for the various components of the soil, regeneration and their dynamics. The uses of remote sensing data reduce the cost and time required to assess damage in the forest. It periodically and automatically provides information on very large areas and on several spectral bands. Our approach is based on the chronic study of this forest through the use of landsat sensor data, after collecting real field data. A supervised classification was applied to the selected images in order to identify the types of soils and the vegetation. The analysis of the results obtained showed remarkable of dominance agricultural soils of the type calcisols, calcaric fluvisols and the regeneration of the forest cover in the study area. There is also an increase areas cleared for agriculture which has accelerated soil erosion in this region. Indeed, the intensification of crops requires an increase in inputs which can lead to a decrease in the biological activities of the soil, in particular earthworms. This type of vegetation existing after this fire; indicates the low water storage capacity and the high risk of erosion. The final results generally showed that the rate of recovery of land use and type of soils in the Tenira forest has changed considerably.
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Samar Thiab

and 5 more

Background Many people are used to administering their drugs with food, beverages, or herbs, which may contain chemicals that interfere with the prescribed drugs that could potentially lead to changes in their efficacy or safety and alteration in their pharmacokinetic properties. Objective To assess the extent of perception and use of food, beverages and herbs alongside with conventional drugs and their potential interactions among Jordanian society. Methods This descriptive cross-sectional survey was conducted in Jordan (20 April - 5 May 2020). The survey was developed using Google forms, validated and distributed via social media platforms. Data was analyzed using Statistical Package for Social Sciences-24. Main outcome measure Use and perception of food, beverages, herbs and their drug interactions among Jordanians. Results Of all participants (n = 789), 77.8% were females, 46.2% were 50-year-old, 69.7% were married, 70.8% were medically insured, and 51.1% had a bachelor’s degrees. Seventy percent of the study participants reported use of medicinal plants. About 66% of participants agreed that medicinal plants or herbs could treat diseases and 58.6% thought that medications could interact with drugs. In general, the participants’ knowledge about food/beverage/herb-drug interactions was considered poor. However, linear regression analysis illustrated that the level of knowledge was significantly affected (p-value <0.05) by gender, marital status, social status, the educational level, and employment sector. Conclusion Jordanians have a positive perception towards herbs and their ability to treat diseases. However, their knowledge about food/beverage-drug interactions was poor. This call needs to enhance the community awareness on food/beverage/herb-drug interactions.

He Cai

and 5 more

Objective To examine early and late pregnancy loss in women with and without polycystic ovary syndrome (PCOS) undergoing IVF/ICSI transfers. Design Retrospective cohort study. Setting Reproductive medicine center at a tertiary hospital. Population Records were reviewed for women with a positive β-hCG after IVF/ICSI treatment from May 2014 to April 2019. Methods Odds ratios (ORs) for early (13 ≤weeks) and late (13-24 weeks) pregnancy loss were calculated among women with and without PCOS for plurality of the pregnancy with adjustment for confounding factors. Main outcomes measures Early and late pregnancy loss. Results A total of 21,820 charts identified with a positive β-hCG, 2,357 (10.8%) subjects had PCOS, and 19,463 (89.2%) controls did not. Early pregnancy loss occurred in 12.4% of women with PCOS versus 12.8% in women with non-PCOS. Women with PCOS demonstrated a higher rate of late pregnancy loss (5.4% in PCOS vs 3.1% in non-PCOS, OR 1.79, 95%CI, 1.46-2.19, P<.001), regardless of the plurality of the pregnancy (one gestational sac: 4.1 vs. 2.7 percent, OR 1.56, 95%CI,1.18-2.05; ≥ two gestational sacs: 8.1 vs. 4.1 percent, OR 2.08, 95%CI,1.54-2.82, PCOS vs. Non-PCOS, respectively). Potential negative impact of PCOS was reduced to marginal level once BMI were taken into account (aOR 1.42, 95% CI, .99-2.03). BMI and maternal comorbidities were independently associated with late pregnancy loss (aOR 1.65, 95%CI, 1.26-2.17 and aOR 2.07,95%CI,1.43-3.00). Conclusions PCOS women with overweight and preexisting comorbidities would benefit from lifestyle intervention and close surveillance throughout the whole pregnancy.

Gendi Yin

and 8 more

Objectives: To study the complications of intratymapanic dexamethasone for Méniere’s disease. Study Design:a randomized controlled trial. Methods:124 patients with Méniere’s disease were randomly divided into two groups: Intratympanic dexamethasone(ITD) group (n=62) and Intratympanic lidocaine(ITL) group (n=62). According to the dose of dexamethasone used during treatment, the patients in ITD group were further divided intoITD1(2mg/ml) group (n=31) and ITD2(5mg/ml) group (n=31).The complications in each group were observed and evaluated after 10 times of intratympanic treatment with ear endoscopy. Results:3 patients suffered from the external auditory canal mycosis after ITD therapy. All the 3 patients were in the ITD2 group and the the infectious rate between patients who used 5mg/ml of dexamethasone and those who used 2mg/ml exhibited significant statistical difference. There were 5 cases of tympanic membrane atrophy thinning in ITD group , while no tympanic membrane atrophy thinning was observed in ITL group, the incidence rate between these two groups showed significant statistical difference. In addition, two patients in the ITD group had perforation accompanied by external auditory meatus mycosis, while no tympanic membrane perforation was observed in the ITL group. There was no statistical difference in the incidence of vertigo, pain, tongue numbness, tinnitus and other complications between the two groups. Conclusions: Our study suggests that the occurrence of external auditory canal mycosis and tympanic membrane atrophy thinning were significantly correlated with the use of dexamethasone and the occurrence of external auditory canal mycosis was closely related to the drug concentration, while the occurrence of tympanic membrane atrophy thinning showed not significantly correlated with the drug concentration. Further understanding of the clinical characteristics of complications after ITD will help clinicians select the appropriate concentration of dexamethasone in the therapy and better manage these complications.
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Ashitha SNM

and 2 more

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder presented with social and communication deficits, restricted, repetitive behaviours and interest. Several recurrently mutated genetic risk-factors have been implicated in ASD manifestation. Chromodomain helicase remodeller (CHD8) is one such gene that is a master regulator mediating the expression of genes controlling neuron functions. We collected 8,124 exonic SNPs in CHD8 from 4 databases representing the general and ASD populations; subjected them to multi-layered analyses on >20 computational tools. We observed that nsSNPs were common in the general population. Distinct hotspots for truncating and nsSNPs were identified within exons encoding the N and C terminals, respectively. Evolutionarily conserved regions involving CHD8 core domains: Helicase-C-terminal, Helicase-ATP-binding and SNF2_N domains, recorded the lowest density but severely pathogenic SNPs. Conversely, evolutionarily variable regions- CHD7-binding and BRK domains- hosted the highest SNPs, but were benign. Post-Translational-Modifications (PTMS) occurred on residues outside domains (P<0.01) i.e., non-conserved regions of CHD8 including the N and C terminals that were determined to be Intrinsically-Disordered-Protein-Regions (IDPRs) with 9 Molecular-Recognition-Features sites. Contrastingly, ASD population recorded significantly higher incidences of truncating SNPs than general population (P<0.0001). ASD-SNPs frequently occurring within core domains were severely damaging and accounted for >30% of all ASD variations. The CHD7-DNA-binding motif, with most PTMs, recorded the highest recurring truncating ASD-SNPs. The CHD8 PPIs effortlessly recapitulated the phenotypes presented by children with CHD8 mutations. 11/13 (84.6%) interacting molecules were IDPs. We identified 9 CHD8 nsSNPs that produced the strongest long-range disturbances, altering the modelled protein’s global conformational dynamics.

Laila Al Yazidi

and 2 more

To the editor, Coronavirus Disease 2019 (COVID-19) has emerged as a major new public health threat, with high rates of morbidity and mortality among patients with chronic medical conditions. The Disease was classified as pandemic by March 2020 after its widespread over the world.(1)Globally, up to 28th July 2020, there has been more than 16 millions of confirmed cases of COVID-19, causing more than 650,000 deaths with the fatality rate of almost 4%.(2)As of 28th July 2020, a total of 77,904 laboratory confirmed COVID-19 cases reported in Oman with mortality rate of 0.52%. Up to this date, 6315 children <14 years of age were diagnosed with COVID-19 which account for 8.1% of total confirmed cases with no recorded deaths.(3) In Oman, children with mild COVID-19 are managed at home and those with moderate and severe disease are managed as inpatients. Ludvigssonet al in their systematic review found that COVID-19 in children tend to have a milder course and better prognosis compared to adults. (4)There is a limited literature describing SARS-CoV-2 infection in children with cancers and post haematopiotic stem cell transplantations . (5)Despite extensive testing of any fever or URTI symptoms in these vulnerable children, there were only 3 children with cancersand post-haematopiotic stem cell transplantations (HSCT) tested positive and required admission for COVID-19 in Oman for the last 5 months; 2 with acute leukemia and one is post-HSCT for primary immune deficiency. Patients were tested for SARS-CoV-2 infection by sending nasopharyngeal specimens either for clinical suspicion of COVID-19 or as a screening following exposure to SARS-CoV-2. The first one has relapsed acute lymphoid leukemia (ALL) and was admitted for non-COVID-19 related issues. He has mild course of COVID-19 and chemotherapy was stopped with no additional management. Another child with ALL who has just completed his chemotherapy courses was admitted for pneumonia and started on oral azithromycin for 3 days and IV ceftriaxone for 1 week. His CBC remained normal with normal coagulation profile, D-dimers andCRP of 7 mg/l. He was discharged in excellent good general condition. The 3rd patient is post-HSCT for primary immunodeficiency tested positive for SARS-CoV-2 following surveillance done following exposure and was admitted for short period for non-COVID-19 related issues.Although there is a theoretical concern that children with cancers are at risk of severe COVID-19 because they are immunocompromized, the limited available data does suggest that COVID-19 in this population is generally mild with self-limited course similar to the presentationof SARS-CoV-2 infection in healthy children. (5)Our series of children with cancers and post-HSCT showed similar results to what have been described in Italy, France and United States. Boulad et al. reported a low overall morbidity of COVID-19 in children with cancer with only 5% (1/20) required hospitalization for management of COVID-19. (6)Rossoff et al described their experience from Chicago where they reported 6 children with cancers and post HSCT who got SARS-COV-2 infection. All of them had mild SARS-CoV-2-related symptoms and none were admitted for COVID-19 related issues. (5)Nazon et al described 6 children managed by their haematology/oncology unit at Strasbourg, France over 3 months period and all were either asymptomatic or have mild disease and none require admission for management of COVID-19.(7)Flash survey on children with cancer from 25 countries which follow up about 10,000 children at risk by March 2020, revealed that 9 out of >200 children tested for COVID-19 had the infection and 8/9 were either asymptomatic or have mild course.(8)Severe COVID-19 has been described among five children (5/33, 15%) by a prospective nationalsurvey conducted by the French society of pediatriconcology among 30 French centers by Mid-April. These children required intensive care for respiratory support following mild initial course of COVID-19. At the time of writing the report, 4 of them were still managed in ICU and none have died.(9)The Spanish Group of Transplantreported their experience of 8 children post HSCT with COVID-19; 5 required management as inpatients and 3 managed at home. Two children required intensive care admission for mechanical ventilation; one was still on extracorporeal membrane oxygenation (ECMO) and one died secondary to alveolar haemorrhage. Lymphopenia and low ratio CD4/CD8 was associated with severe COVID-19 in this small cohort. (10)Our case series and the available experience reported from different countries showed that most of the children with cancer and post-HSCT have either asymptomatic or mild COVID-19 and these children have similar vulnerability and risk morbidity resulting from COVID-19 to healthy children.(11). Decisions on whether or not to postpone chemotherapy/HSCT need to made on a case-by-case basis and according to the risk of cancer progression which can results in a poor outcome.(5, 6)
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Kazi Ahsan Habib

and 6 more

Understanding the evolutionary processes that have molded the genetic structure to adapt to environmental changes is an important component of successful and sustainable long-term management for the fisheries resources. In this study, we analyzed mitochondrial control region (D-loop) sequence data to reveal population genetic variation, phylogeography and demographic history of T. ilisha collected from six locations of the Indian Ocean regions (Bay of Bengal, Arabian Sea and Persian Gulf). High haplotype diversity was found for all of the populations of T. ilisha. The Analysis of Molecular Variance (AMOVA) and conventional population FST comparisons detected both high population-level genetic variation and high degrees of divergence between groups within the Bay of Bengal (Irrawaddy river, MP; the coast of Cox’s Bazar, XP; the delta of Meghna, MP and Hooghly river, IP) and Arabian Sea (the delta of Indus river, PP and the coast of Kuwait, KP). Four cryptic genetic barriers were found for the studied populations of T. ilisha, and the highest degree of population divergence was found between the Eastern Indian Ocean (Arabian Sea and Persian Gulf) and Western Indian Ocean (the Bay of Bengal region) regions based on the Voronoï tessellation of BARRIER analysis. The gene flow analysis detected almost no migration between Eastern and Western part of the Indian Ocean regions. Besides, one-way migration was found from IP to MP population in the Bay of Bengal and from PP of Arabian Sea to KP population of Persian Gulf. Mismatch distribution showed that T. ilisha underwent long-time stable population size. Distinct cryptic genetic barriers, limited gene flows and complex evolutionary process resulted a significant population genetic and phylogeographic structure, and intricate demographic histories of T. ilisha populations. Further, the study provided additional insights for conserving and managing of this fishery resource in its broad geographical distribution coverage.

soheila zareifar

and 4 more

Abstract Background: Primary pediatric brain tumors are the most prevalent type of childhood tumors and the most common cause of cancer death among children. However, there is insufficient literature regarding the use of novel chemotherapy agents to treat such tumors. Therefore, the purpose of this study is to evaluate the effectiveness of Irinotecan-based chemotherapy regimen for the treatment of primary brain tumors as well as minimizing morbidity and mortality rates. Procedure: In this cross-sectional study, 88 children aged 0 to 18 years old with primary brain tumors were investigated. Data was extracted from patients’ medical records. 38 patients received Irinotecan treatment from the beginning (B) or after relapse (AB). At study termination, the response rate to the treatment as well as the Overall Survival (OS) and 6 months Progression Free Survival (6-mo-PFS) were estimated using Kaplan-Meier survival analysis and PFS estimation. Results: According to the findings of this study, pediatric brain tumors in males are more common than in females (60% in comparison to 40%). The highest incidence of brain tumors was reported in the age range of 6 to 12 years old. The findings of this study suggest that there is no statistically significant correlation between OS/6-mo-PFS and age, sex, tumor type, type of treatment and relapse. Conclusions: The administration of combination Irinotecan-based regimen leads to a high response rate and low toxicity in some types of primary pediatric brain tumors especially embryonal tumors, while it has little effect on others such as astrocytoma and ependymoma.
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Lars Ahlbeck

and 13 more

Background: There is need for a fast, efficient, and safe way to induce tolerance in patients with allergic rhinitis. Methods: Patients with birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Rhinoconjunctivitis Total Symptom Score, Medication Score and Rhinoconjunctivitis Quality of Life Questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analyzed by flow cytometry and Luminex. Results: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment. Nine patients had severe adverse events which were judged to be unrelated to the therapy. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased independently of treatment. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased three years after treatment. Conclusion: Intralymphatic immunotherapy against grass and birch pollen allergy was effective, safe and associated with bystander immune modulatory responses.

Ioana Maris

and 26 more

Background: Peanut allergy has a rising prevalence in high-income countries, affecting 0.5–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods: Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food induced anaphylaxis cases in a tertiary paediatric allergy centre. Results: 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs 38%; p=0.001), asthma comorbidity (47% vs 35%; p<0.001), relevant co-factors (29% vs 22%; p=0.004) and biphasic reactions (10% vs 4%; p=0.001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs 56% and grade IV 1.1% vs 0.9%; p=0.001). Self-administration of intramuscular adrenaline was low (17% vs 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs 26%; p=0.003). Hospitalisation was higher for peanut anaphylaxis (67% vs 54%; p=0.004). Conclusions: The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g. presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.
Figure 1  wawrzyniak et al

Paulina Wawrzyniak

and 12 more

To the Editor: Asthma is a complex and heterogeneous chronic airway inflammatory disease with the involvement of environmental factors through epigenetic mechanisms.1 Accordingly, repeated injury, repair and regeneration of the airway epithelium following exposure to environmental factors and inflammation results in histological changes and functional abnormalities in the airway mucosal epithelium, which are associated with the pathophysiology of asthma.2Epigenetics is defined by heritable changes in gene expression without changes in the DNA sequence.3 Regulation of gene expression is mediated by different mechanisms such as DNA methylation, histone modifications and RNA-associated silencing by small non-coding RNAs. CpG sites are dinucleotides consisting of guanine and cytosine concentrated in clusters referred to CpG islands found at important regulatory sites, such as promoter and enhancer regions.4 Their de novo methylation occurs in response to various cellular stressors and signals by DNA methyltransferases (DNMT3a and 3b), which add a methyl group to position 5 of cytosine residues at the CpG site. During DNA replication both of the separated strands of DNA carry one methylated cytosine to be used as a template for duplication. Daughter DNA duplex strands will thus be hemi-methylated, which is recognized by a different DNA methyltransferase isoform (DNMT1).5 Because DNA methylation is a reversible process, the DNMTs are considered as a therapeutic target. Several DNMT inhibitors have been identified recently, among the non-nucleoside inhibitors, 4-aminoquoline-based inhibitors, such as SGI-1027 showed potent inhibitory activity. SGI-1027 occupies the binding site of DNMTs resulting in the prevention of access of target DNA to the substrate binding pocket.6We have demonstrated in previous studies from our laboratory that human primary bronchial epithelial cells (HBEC) isolated from patients with asthma showed lower barrier integrity compared to controls.7 To investigate the level of global methylation in HBEC, we investigated control and asthma samples for the long interspersed nuclear element-1 (LINE-1) methylation levels (Figure 1A). HBEC from asthma patients showed a tendency for higher global methylation levels, together with higher expression of 5-methylcytosine (5-mc) in immunofluorescence staining (Figure 1B). Next, we performed methylation profiling (Illumina Infinium EPIC array) to investigate genes methylated in ALI cultures of HBEC. Interestingly, in a highly methylated group of top 100 genes, we found many genes associated with cell growth, ion transport, and cytoskeletal remodeling (Figure S1). We kept our attention on the methylated epigenetic and tight junction (TJ) genes and further focused on TJs, especially zonula occludens and claudins which showed higher methylation in contrast to occludin, which was not methylated (Figure S2). As higher methylation levels were observed in HBEC of asthmatic origin, we inhibited the DNA methyltransferase enzyme with a specific inhibitor, SGI-1027, to demonstrate the role of CpG methylation on epithelial barrier integrity. ALI cultures were treated with the DNA methyltransferase inhibitor for 72 hours. Significantly decreased expression of 5-mc was observed after 48 hours of DNA-methyltransferase inhibition, demonstrating that the methylation of 5-methylcytosine (5-mc) in bronchial epithelium was reversed (Figure 2A). This prompted us to investigate the changes triggered by the inhibitor in epithelial cells. Further experiments showed increased transepithelial electric resistance (TER) in bronchial epithelial cells, in ALI from asthmatic donors after 48 hours of DNMT inhibition (Figure 2B). The link between barrier integrity and TER results were confirmed by the significantly decreased paracellular passage of FITC-labelled 4kD dextran after inhibition of DNMTs (Figure 2C). The reconstitution of TER in asthmatic ALI was associated with decreased protein DNMT1 expression and increased ZO-1 and claudin-18 proteins (Figure 2D). We also observed increased claudin-4, but not occludin expression upon DNMT inhibition (Figure S3). Increased expression of ZO-1 with an intact and honeycomb-like structure in the immunofluorescence staining of bronchial epithelial cells confirmed the effect on protein expression of bronchial epithelial barrier in asthma donors (Figure S4).Defective epithelial barrier has been established in asthma in addition to several chronic inflammatory diseases.8 Direct targeting of the epithelial barrier leakiness for the treatments represents an important target, however so far there is no treatment possibility targeting epigenetic mechanisms. The present study demonstrates an increased global methylation level in HBEC from asthmatic individuals. CpG methylation of specific genes is essential for the defect of epithelial barrier integrity, which is reversed upon DNMT inhibition. The inversion of CpG methylation, restores leakiness in the epithelium in asthma by increasing TER, decreasing paracellular flux and improves the structure of bronchial epithelial cells by increasing the expression of TJ proteins. The better understanding of the importance of epigenetic memory in chronic tissue inflammatory diseases together with the availability of treatment modalities targeting epigenetic mechanisms and transition of these molecules into the clinical studies may lead to curative treatment of allergic and autoimmune inflammatory diseases.9Paulina Wawrzyniak1, PhD,Krzysztof Krawczyk1,3, MSc,Swati Acharya5, PhD,Ge Tan1,7, PhD,Marcin Wawrzyniak1, PhD,Emmanuel Karouzakis4, PhD,Anita Dreher, Sci. Tech.,Bogdan Jakiela2, MD, PhD,Can Altunbulakli1, PhD,Marek Sanak2, MD, PhD,Liam O‘Mahony1,6, PD, PhD,Kari Nadeau5, MD, PhD,Cezmi A. Akdis1, MD1Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE)2Department of Medicine, Jagiellonian University Medical College, Krakow, Poland3Faculty of Biology and Environmental Protection, Department of Cellular Immunology, Lodz, Poland4Department of Rheumatology, University Hospital of Zurich5Departament of Medicine, Stanford University, United States6 Department of Medicine and School of Microbiology, APC Microbiome Ireland, University College Cork, Cork, Ireland.7 Functional Genomics Center Zurich, ETH Zurich/University of ZurichCorresponding author:Paulina WawrzyniakSwiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, SwitzerlandObere Strasse 22,7270 Davos, SwitzerlandTel: +41 81 410 08 48Fax: +41 81 410 08 40paulina.wawrzyniak@uzh.chConflict of interest:The authors declare that they have no conflicts of interest.Founding sources:Supported by Swiss National Science Foundation grants 310030_156823, and 320030_176190.Word count: 765Keywords: asthma, tight junction, CpG methylation, DNA methyltransferases,
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David Birnkrant

and 1 more

Neuromuscular respiratory medicine has traditionally focused on mechanically assisted lung ventilation and mucus clearance. These therapies have prolonged survival for patients with Duchenne muscular dystrophy (DMD). However, the field is rapidly evolving in a new direction: it is being revolutionized by molecular and genetic therapies. A good correlation between a patient’s dystrophin mutation and his cardiopulmonary phenotype would allow accurate prediction of patient prognosis and would facilitate the design of studies that assess new DMD therapies. Instead, patient prognosis and the design of valid therapeutic studies are complicated by cardiopulmonary phenotypic discordance and variability, by which a notable proportion of DMD patients have unexpectedly good or poor cardiopulmonary function. The likely cause of phenotypic variability and discordance is genetic modifiers. Once the modifiers that affect cardiopulmonary function are better understood, it should be possible to create a personalized genetic profile that accurately predicts the prognosis of each individual DMD patient. This would allow investigators to assess the effect of new therapies in the context of each patient’s particular cardiopulmonary natural history. Amplification of beneficial cardiopulmonary genetic modifiers and blocking of detrimental modifiers is a promising strategy for creating new DMD therapies. When patients with chronic respiratory failure are treated with assisted ventilation, cardiac function determines their survival. Therefore, prioritizing new cardiac therapies is most likely to prolong patient survival. By focusing on these topics we aim to move neuromuscular respiratory medicine beyond assisted ventilation and coughing and into the age of translational medicine.

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Rand Ibrahim

and 1 more

Sudden Cardiac Death (SCD) remains a global threat.1The most common causes of SCD are ischemic heart diseases and structural cardiomyopathies in the elderly. Additional causes can be arrhythmogenic, respiratory, metabolic, or even toxigenic.2,3,4 Despite the novel diagnostic tools and our deeper understanding of pathologies and genetic associations, there remains a subset of patients for whom a trigger is not identifiable. When associated with a pattern of Ventricular Fibrillation, the diagnosis of exclusion is deemed Idiopathic Ventricular Fibrillation (IVF).2,5 IVF accounts for 5% of all SCDs6 – and up to 23% in the young male subgroup5 – and has a high range of recurrence rates (11-45%).7,8,9 There are still knowledge gaps in the initial assessment, follow-up approach, risk stratification and subsequent management for IVF.1,10,11 While subsets of IVF presentations have been better characterized into channelopathies, such as Brugada’s syndrome (BrS), Long QT Syndrome (LQTS), Early Repolarization Syndrome (ERS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), much remains to be discovered.12,13 Implantable Cardioverter Device (ICD) placement as secondary prevention for IVF is the standard of care. This is warranted in the setting of high recurrence rates of arrhythmias (11-43%). Multiple studies have shown potential complications from ICDs and a significant number of cases experiencing inappropriate shock after ICD placement.14In their article, Stampe et al. aim to further understand clinical presentation and assessment, and risk factors for recurrent ventricular arrhythmias in IVF patients. Using a single-centered retrospective study, they followed a total of 84 Danish patients who were initially diagnosed with IVF and received a secondary ICD placement between December 2007 and June 2019. Median follow-up time was 5.2 years (ICR=2-7.6). To ensure detection of many possible underlying etiologies ranging from structural, ischemic, arrhythmogenic, metabolic, or toxicologic, the researchers found that a wide array of diagnostic tools were necessary: standard electrocardiograms (ECGs), high-precordial leads ECGs, standing ECGs, Holter monitoring, sodium-channel blocker provocation tests, exercise stress tests, echocardiograms, cardiac magnetic resonance imaging, coronary angiograms, cardiac computed tomography, electrophysiological studies, histological assessment, blood tests, toxicology screens, and genetic analysis.The study by Stampe et al. highlights the importance of thorough and continuous follow-up with rigorous evaluation: Three (3.6%) patients initially diagnosed with IVF were later found to have underlying cardiac abnormalities (LQTS and Dilated Cardiomyopathy) that explained their SCA. Like other studies, the burden of arrhythmia was found to be high, but unlike reported data, the overall prognosis of IVF was good. Despite the initial pattern of ventricular fibrillation in those who experienced appropriate ICD placement (29.6%), ventricular tachycardia and ventricular fibrillation had a comparable predominance. As for patients with inappropriate ICD placements, atrial fibrillation was a commonly identified pathological rhythm (16.7%). Recurrent cardiac arrest at presentation (19.8%) was a risk factor for appropriate ICD therapy (HR=2.63, CI=1.08-6.40, p=0.033). However, in contrast to previous studies, early repolarization detected on baseline ECG (12.5%), was not found to be a risk factor (p=0.842).The study by Stampe et al. has few limitations. First, the study design, a retrospective cohort, precluded standardized follow-up frequencies and diagnostic testing. Second, while the study was included many of the cofounders tested in previous studies (baseline characteristics, baseline ECG patterns, comorbidities), medication use was not included. Third, the follow-up period may have been insufficient to detect effect from some of the confounding factors. Finally, the sample size was small and it was from a single center.There are several strengths of the Stampe et al. study. Firstly, the wide range of diagnostic tests used at index presentation and during the follow-up period ensured meticulous detection of most underlying etiologies. Secondly, appropriate and well-defined inclusion and exclusion criteria were used. Thirdly, funding by independent parties ensured no influence on study design, result evaluation, and interpretation. Finally, the study has succeeded in improving our understanding of IVF. Future studies should include though a larger population size and a more diverse population.References:1.AlJaroudi WA, Refaat MM, Habib RH, Al-Shaar L, Singh M, et al. Effect of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Appropriate Implantable Cardiac Defibrillator Shock: Insights from the GRADE Multicenter Registry. Am J Cardiol Apr 2015; 115 (7): 115(7):924-31.2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary. J Am Coll Cardiol 2018;72:e91–e220.3. Refaat MM, Hotait M, London B: Genetics of Sudden Cardiac Death. Curr Cardiol Rep Jul 2015; 17(7): 6064. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–1963.5. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36(41):2793-2867.6. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998;98:2334–2351.7. Ozaydin M, Moazzami K, Kalantarian S, Lee H, Mansour M, Ruskin JN. Long-term outcome of patients with idiopathic ventricular fibrillation: a meta-analysis. J Cardiovasc Electrophysiol 2015;26:1095–1104.8. Herman AR, Cheung C, Gerull B, Simpson CS, Birnie DH, Klein GJ, et al. Outcome of apparently unexplained cardiac arrest: results from investigation and follow-up of the prospective cardiac arrest survivors with preserved ejection fraction registry. Circ Arrhythm Electrophysiol 2016;9:e003619.9. Siebermair J, Sinner MF, Beckmann BM, Laubender RP, Martens E, Sattler S, et al.Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: results from a single centre long-term follow-up over 20 years. Europace 2016;18:718-25.10. Refaat MM, Hotait M, Tseng ZH: Utility of the Exercise Electrocardiogram Testing in Sudden Cardiac Death Risk Stratification. Ann Noninvasive Electrocardiol 2014; 19(4): 311-318.11. Gray B, Ackerman MJ, Semsarian C, Behr ER. Evaluation after sudden death in the young: a global approach. Circ Arrhythm Electrophysiol 2019;12: e007453.12. Herman AR, Cheung C, Gerull B, Simpson CS, Birnie DH, Klein GJ, et al. Response to Letter Regarding Article, Outcome of apparently unexplained cardiac arrest: results from investigation and follow-up of the prospective cardiac arrest survivors with preserved ejection fraction registry”. Circ Arrhythm Electrophysiol 2016;9:e004012.13. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–296.14. Baranchuk A, Refaat M, Patton KK, Chung M, Krishnan K, et al. What Should You Know About Cybersecurity For Cardiac Implantable Electronic Devices? ACC EP Council Perspective. J Am Coll Cardiol Mar 2018; 71(11):1284-1288.

Zengguo Cao

and 17 more

Ebolavirus (EBOV) is responsible for several EBOV disease (EVD) outbreaks in Africa, with a fatality rate of up to 90%. During 2014-2016, An epidemic of EVD spread throughout Sierra Leone, Guinea and Liberia, and killed over 11,000 people. EBOV began to circulate again in the Democratic Republic of Congo in 2018. Due to the need for a BSL-4 facility to manipulate this virus, the development and improvement of specific therapeutics has been hindered. As a result, it is imperative to perform reliable research on EBOV under lowered BSL restrictions. In this study, we developed a safe neutralization assay based on pseudotyped EBOV, which incorporates the glycoprotein of the 2014 EBOV epidemic strain into a lentivirus vector. Our results demonstrated that the tropism of pseudotyped EBOV was similar to that of authentic EBOV, but with only one infection cycle. And neutralizing activity of both authentic EBOV and pseudotyped EBOV were compared in neutralization assay using three different samples of antibody-based reagents against EBOV, similar results were obtained. In addition, an indirect ELISA was performed to show the relationship between IgG and neutralizing antibody against EBOV detected by our pseudotyped EBOV-based neutralization assay. As expected, the neutralizing antibody titers varied with the IgG titers detected by indirect ELISA, and a correlation between the results of the two assays was identified. By comparison with two different assays, the reliability of the results detected by the pseudotyped EBOV-based neutralization assay was confirmed. Collectively, in the absence of BSL-4 restrictions, pseudotyped EBOV production and neutralizing activity evaluation can be performed safely and in a manner that is neither labor- nor time-consuming, providing a simple and safe method for EBOV-neutralizing antibody detection and the assessment of immunogenicity of EBOV vaccines. All these remarkable advantages of the newly established assay highlight its potential to further application in assessment of immunogenicity of EBOV vaccine candidates.

Bachir Lakkis

and 1 more

Long QT syndrome (LQTS) is characterized by prolongation of the QT interval on the electrocardiogram (ECG). Clinically, LQTS is associated with the development of Torsades de Pointes (TdP), a well-defined polymorphic ventricular tachycardia and the development of sudden cardiac death (1). The most common type is the acquired form caused mainly by drugs, it is also known as the drug induced LQTS (diLQTS) (2-5). The diLQTS is caused by certain families of drugs which can markedly prolong the QT interval on the ECG most notably antiarrhythmic drugs (class IA, class III), anti-histamines, antipsychotics, antidepressants, antibiotics, antimalarial, and antifungals (2-5). Some of these agents including the antimalarial drug hydroxycholoquine and the antibiotic azithromycin which are being used in some countries as therapies for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)(6,7). However, these drugs have been implicated in causing prolongation of the QT interval on the ECG (2-5).There is a solution for monitoring this large number of patients which consists of using mobile ECG devices instead of using the standard 12-lead ECG owing to the difficulty of using the 12-lead ECG due to its medical cost and increased risk of transmitting infection. These mobile ECG devices have been shown to be effective in interpreting the QT interval in patients who are using QT interval prolonging drugs (8, 9). However, the ECG mobile devices have been associated with decreased accuracy to interpret the QT interval at high heart rates (9). On the other hand, some of them have been linked with no accuracy to interpret the QT interval (10). This can put some patients at risk of TdP and sudden cardiac death.In this current issue of the Journal of Cardiovascular electrophysiology, Krisai P et al. reported that the limb leads underestimated the occurrence of diLQTS and subsequent TdP compared to the chest leads in the ECG device, this occurred in particular with the usage of mobile standard ECG devices which use limb leads only. To illuminate these findings, the authors have studied the ECGs of 84 patients who have met the requirements for this study, which are diLQTS and subsequent TdP. Furthermore, the patients in this study were also taking a QT interval prolonging drug. Krisai P et al. additionally reported the morphology of the T-wave in every ECG and classified them into flat, broad, notched, late peaked, biphasic and inverted. The authors showed that in 11.9% of these patients the ECG was non reliable in diagnosing diLQTS and subsequent Tdp using only limb leads due to T-wave flattening in these leads, in contrast to chest leads where the non- interpretability of the QT interval was never attributable to the T-wave morphology but to other causes. The authors further examined the QT interval duration in limb leads and chest leads and found that the QT interval in limb leads was shorter compared to that of the chest leads, but reported a high variability in these differences. Therefore, it should be taken into account when screening patients with diLQTS using only mobile ECG devices and these patients should be screened using both limb leads and chest leads. Moreover, the authors have highlighted the limitations of using ECG mobile devices as limb leads to interpret the QT interval especially in high heart rates (when Bazett’s equation overcorrects the QTc and overestimates the prevalence of the QT interval) and have advocated the usage of ECG mobile devices as chest leads instead of limb leads due to their superior ability to interpret the QT interval.The authors should be praised for their efforts in illustrating the difference in the QT interval interpretability between the chest leads and the limb leads in patients with diLQTS. The authors also pointed out the limitation of using mobile ECG devices as limb leads for the diagnosis of diLQTS and recommended their usage as chest leads by applying their leads onto the chest due to their better diagnostic accuracy for detecting the diLQTS. The study results are very relevant, it further expanded the contemporary knowledge about the limitation of the QT interval interpretability using ECG mobile device only (11). Future investigation is needed to elucidate the difference in chest and limb leads interpretability of the QT interval and to assess the ability of the mobile ECG devices to interpret the QT interval.ReferencesRefaat MM, Hotait M, Tseng ZH: Utility of the Exercise Electrocardiogram Testing in Sudden Cardiac Death Risk Stratification. Ann Noninvasive Electrocardiol 2014; 19(4): 311-318.Kannankeril P, Roden D, Darbar D. Drug-Induced Long QT Syndrome. Pharmacological Reviews. 2010;62(4):760-781.Nachimuthu S, Assar M, Schussler J. Drug-induced QT interval prolongation: mechanisms and clinical management. Therapeutic Advances in Drug Safety. 2012;3(5):241-253.Jankelson L, Karam G, Becker M, Chinitz L, Tsai M. QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review. Heart Rhythm. 2020 ; S1547-5271(20)30431-8.Li M, Ramos LG. Drug-Induced QT Prolongation And Torsades de Pointes. P T . 2017;42(7):473-477.Singh A, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;14(3):241-246.Hashem A, Alghamdi B, Algaissi A, Alshehri F, Bukhari A, Alfaleh M et al. Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review. Travel Medicine and Infectious Disease. 2020; 35:101735.Chung E, Guise K. QTC intervals can be assessed with the AliveCor heart monitor in patients on dofetilide for atrial fibrillation. J Electrocardiol. 2015;48(1):8-9.Garabelli P, Stavrakis S, Albert M et al. Comparison of QT Interval Readings in Normal Sinus Rhythm Between a Smartphone Heart Monitor and a 12-Lead ECG for Healthy Volunteers and Inpatients Receiving Sotalol or Dofetilide. Journal Cardiovasc Electrophysiol. 2016;27(7):827-832.Bekker C, Noordergraaf F, Teerenstra S, Pop G, Bemt B. Diagnostic accuracy of a single‐lead portable ECG device for measuring QTc prolongation. Annals Noninvasive Electrocardiol. 2019;25(1): e12683.Malone D, Gallo T, Beck J, Clark D. Feasibility of measuring QT intervals with a portable device. American Journal of Health-System Pharmacy. 2017;74(22):1850-1851.
Figure 1

Volkan Sen

and 9 more

Objectives: There is no standardized and up-to-date education model for urology residents in our country. We aimed to describe our National E learning education model for urology residents. Methodology: The ERTP working group; consisting of urologists was established by Society of Urological Surgery to create E-learning model and curriculum at April 2018. Learning objectives were set up in order to determine and standardize the contents of the presentations. In accordance with the Bloom Taxonomy, 834 learning objectives were created for a total of 90 lectures (18 lectures for each PGY year). Totally 90 videos were shoot by specialized instructors and webcasts were prepared. Webcasts were posted at uropedia.com.tr, which is the web library of Society of Urological Surgery. Satisfaction of residents and instructors was evaluated with feedbacks. An assessment of knowledge was measured with multiple-choice exam. Results: A total of 43 centers and 250 urology residents were included in ERTP during the academic year 2018/2019. There were 93/38/43/34/25 urology residents at 1st/2nd/3rd/4th and 5th year of residency, respectively. Majority of the residents (99.1%) completed the ERTP. The overall satisfaction rate of residents and instructors were 4,29 and 4,67(min:1 so bad, max:5 so good). An assessment exam was performed to urology residents at the end of the ERTP and the mean score was calculated as 57.99 points (min:20, max:82). Conclusion: Due to the Covid-19 pandemic, most of the educational programs had to move online platforms. We used this reliable and easily accessible e-learning platform for standardization of training in urology on national basis. We aim to share this model with international residency training programs.

Mohammad Ramadan

and 1 more

Atrial fibrillation (AF) is the most common cardiac arrhythmia and often occurs with heart failure (HF) [1]. AF prevalence increases with increasing severity of HF: for instance its prevalence ranges from 5 percent in patients with New York Heart Association (NYHA) functional class I HF to 40 percent in patients with NYHA class IV HF [2]. Its presence with HF plays a significant prognostic role and increases morbidity and mortality. Heart Failure with reduced ejection fraction (HFrEF) is associated with cardiac arrhythmias [3]. HFrEF is also one of the indications for Cardiac resynchronization therapy (CRT) placement [4]. Therefore, many patients undergoing CRT implantation will concomitantly have HF and AF. As the benefit from CRT in HF patients has been established, the data on patients with both HF and AF is limited, because patients with atrial arrhythmias were excluded from most of the major CRT trials, such as CARE-HF and COMPANION [5]. However, a number of observational studies and small randomized clinical trials suggest a benefit from CRT in AF and HF patients such as a CRT-mediated ejection fraction (EF) increase [6, 7]. Other studies showed a high non-response rate in patients with AF as compared to those in sinus rhythm (SR) [8]. Thus, it is important to determine whether CRT has a beneficial role in these patients to decide on adding an atrial lead at the time of CRT implantation especially in patients with longstanding-persistent AF.In their published study, Ziegelhoeffer et al. investigated the outcomes of CRT placement with an atrial lead in patients with HF and AF. This was done by conducting a retrospective analysis of all patients with AF who received CRT for HF at the Kerckhoff Heart Center since June 2004 and were observed until July 2018- completing a 5-year follow-up. The authors identified 328 patients and divided them into 3 subgroups: paroxysmal (px) AF, persistent (ps) AF, and longstanding-persistent (lp) AF, with all patients receiving the same standard operative management. During the observation period, the authors analyzed the rhythm course of the patients, cardiac parameters (NYHA class, MR, LVEF, left atrial diameter) and performed a subgroup analysis for patients who received an atrial lead. The study showed that all groups had a high rate of sinus rate (SR) conversion and rhythm maintenance at 1 and 5 years. Specifically, the patients who received an atrial lead among the lp AF group were shown to have a stable EF, less pronounced  left ventricular end-systolic diameter (LVESD) and  left ventricular end diastolic diameter (LVEDD) and lower mitral regurgitation (MR) rates at one year follow-up as compared to the group without atrial lead placement. Moreover, the results of the lp group were similar to the ps-AF group, although the latter had a lower number of participants (n=4) without initial implantation of the atrial lead. The authors attributed the improvement in cardiac function and SR conversion to CRT and the implantation of an additional atrial lead.Although some studies showed that CRT therapy reduced secondary MR in HF [9, 10], this study additionally suggests that CRT with an atrial lead was associated with improved myocardial function and improvement of interventricular conduction delay triggering cardiac remodeling in patients with HF and AF. Although the results showed better cardiac function in the subgroup analysis of the patients with an additional atrial lead, these results were reported as percentages with no level of significance specified, hence statistical significance of the difference in the described parameters (such as LVESD, LVEDD) could not be determined. Further investigation via prospective studies is needed with larger sample size in the future to further support the results of the study especially that it was done in a single center and had a relatively small sample size.References:1. Chung MK, Refaat M, Shen WK, et al. Atrial Fibrillation: JACC Council Perspectives. J Am Coll Cardiol. Apr 2020; 75 (14): 1689-1713.2. Maisel, W.H. and L.W. Stevenson, Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol, 2003. 91 (6a): p. 2d-8d.3. AlJaroudi WA, Refaat MM, Habib RH, et al. Effect of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Appropriate Implantable Cardiac Defibrillator Shock: Insights from the GRADE Multicenter Registry. Am J Cardiol Apr 2015; 115 (7): 115(7):924-31.4. Yancy, C.W., et al., 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 2013. 62 (16): p. e147-239.5. Cleland, J.G., et al., The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med, 2005.352 (15): p. 1539-49.6. Leclercq, C., et al., Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J, 2002. 23 (22): p. 1780-7.7. Upadhyay, G.A., et al., Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol, 2008. 52 (15): p. 1239-46.8. Wilton, S.B., et al., Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm, 2011. 8 (7): p. 1088-94.9. van Bommel, R.J., et al., Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation, 2011.124 (8): p. 912-9.10. Breithardt, O.A., et al., Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol, 2003. 41 (5): p. 765-70.

Mohamad El Moheb

and 1 more

Idiopathic ventricular arrhythmias (VA) is defined as premature ventricular complexes (PVCs) or ventricular tachycardias (VT) that occur in the absence of structural heart disease. Endocardial radiofrequency (RF) ablation is often curative for idiopathic VA. The success of the procedure depends on the ability to localize the abnormal foci accurately. These arrhythmias typical originate from the right ventricular outflow tract (RVOT), specifically from the superior septal aspect, but can also originate from the left ventricular outflow tract (LVOT) and the coronary cusps.1 The QRS electrocardiogram (ECG) characteristics have been helpful in patients with VAs, patient with accessory pathways and patients who have pacemakers.2 VAs originating from the RVOT have typical ECG findings with a left bundle branch block (LBBB) morphology and an inferior axis.3In the current issue of the Journal of Cardiovascular Electrophysiology, Hisazaki et al. describe five patients with idiopathic VA suggestive of RVOT origin and who required ablation in the left-sided outflow tract (OT) in addition to the initial ablation in the RVOT for cure to be achieved. Patients exhibited monomorphic, LBBB QRS pattern with an inferior axis on ECG, consistent with the morphology of VAs originating from the RVOT. Interestingly, all patients had a common distinct ECG pattern: qs or rs (r ≤ 5 mm) pattern in lead I, Q wave ratio[aVL/aVR]>1, and dominant S-waves in leads V1 and V2. Mapping of the right ventricle demonstrated early local activation time during the VA in the posterior portion of the RVOT, matching the QRS morphology obtained during pacemapping. Despite RF energy delivery to the RV, the VAs recurred shortly after ablation in four patients and had no effect at all in one patient. A change in the QRS morphology was noted on the ECG that had never been observed before the procedure. The new patterns were suggestive of left-sided OT origin: the second VAs exhibited an increase in the Q wave ratio [aVL/aVR] and R wave amplitude in lead V1, decrease in the S wave amplitude in lead V1, and a counterclockwise rotation of the precordial R-wave transition. Early activation of the second VA could not be found in the RVOT, and the earliest activation time after mapping the LV was found to be relatively late. Real-time intracardiac echocardiography and 3D mapping systems were used to determine the location immediately contralateral to the initial ablation site in the RVOT. Energy was then delivered to that site which successfully eliminated the second VA. The authors postulated that the second VAs shared the same origins as the first VAs, and the change in QRS morphology is likely attributed to a change in the exit point or in the pathway from the origin to the exit point. The authors further explained that the VAs originated from an intramural area of the superior basal LV surrounded by the RVOT, LVOT and the transitional zone from the great cardiac vein to the anterior interventricular vein (GCV-AIV).A limitation of this study is that GCV-AIV ablation was not attempted; however, the authors’ approach is safer and was successful in eliminating VA. Another limitation is that left-sided OT mapping was not initially performed. Nevertheless, given the ECG characteristics, local activation time, and mapping, it was appropriate to attempt a RVOT site ablation.Overall, the authors should be commended for their effort to describe in detail patients with idiopathic VAs that required ablation in the left-sided OT following ablation in the RVOT. Although change in QRS morphology after ablation has been previously described, the authors were the first to describe the ECG patterns of these patients.4–7 The results of this study have important clinical implications. First, the authors have demonstrated the importance of anatomical approach from the left-sided OT for cure to be achieved. Second, insight into the location of the origin of the VA may be helpful to physicians managing patients with VAs from the RVOT. Finally, continuous monitoring of the ECG during ablation for a change in QRS morphology should be considered to identify patients who will require further ablation. We have summarized in Table 1 important ECG characteristics indicative VA of specific origins, based on the findings of this study and previous studies in the literature.3,8–15
Pulmonary Vein Isolation (PVI) remains the cornerstone for catheter ablation for atrial fibrillation (AF). Achieving durable PVI safely with Radiofrequency Catheter Ablation (RFCA) has proven challenging until recently, even with the use of Contact Force (CF) sensing catheters and electroanatomical mapping1. Ablation success rates improve markedly, including in persistent AF, when permanent PVI can be achieved1,2, which only underscores the critical role of the Pulmonary Veins (PV) in AF arrhythmogenesis.Historically, the only way to assess PVI durability has been through invasive electrophysiology study, with all its associated risk, inconvenience, and costs. This price appears particularly galling to pay if the PVs are found to be isolated at repeat study, as is now becoming increasingly common3. Multiple randomised studies have failed to show additional benefit from ablating extra-PV structures4,5, and the best outcomes following repeat AF ablation procedures are restricted to those where PV reconnection is identified and treated6. As such, there remains a pressing need for a non-invasive tool that can accurately assess PVI durability, and ideally, the size and location of residual gaps. As Magnetic Resonance Imaging (MRI) has increasingly been shown capable of delineating atrial scar, there is much anticipation that it may serve this important purpose7.RFCA and Cryoballoon ablation (CBA) are by far the most common modalities used for PVI, and there is remarkable equivalence in their clinical results8. However, the handling of the two technologies in the catheter laboratory is very different, and ultrahigh density mapping has shown important differences in the number and location of chronic gaps between the two9. The use of MRI in characterizing these differences has not been well described so far.In this issue of the journal, Kurose and colleagues present a small but elegant study10, in which 30 consecutive patients who underwent PVI (18 with CBA, 12 with RFCA) were assessed by LGE-MRI two months later, where lesion width and visual gap(s) around each vein were assessed. The RF applications were delivered using a CF sensing catheter, with a target lesion size index (LSI) of 5, and an inter-lesion distance of <6mm. They found that the mean lesion width on MRI was significantly wider in the CBA group (8.1±2.2 mm) as compared to the RFCA group (6.3±2.2 mm), p=0.032. However, there were more visual gaps seen in the CBA group, especially in the bottom segments of the two inferior veins. In the RFCA group, gaps were seen most often seen in the left posterior segments where the target LSI value could not be achieved because of esopheageal temperature rise. Furthermore, the number of gaps visualised on MRI was linked to freedom from AF at 12 months; receiver operating characteristic curve analysis suggested a cut off value of less than 5 visual gaps per patient as being predictive of a good outcome.The authors deserve to be congratulated for their study, which builds on their previous work where LGE-MRI was used to compare chronic lesions between CBA and RFCA with non-CF sensing catheters11. It is notable that whilst the lesion width in their previous study was also significantly greater in the CBA group than the RFCA group, the mean number of gaps in the RFCA group was higher. This suggests that the modern technique of delivering LSI-guided contiguous RFCA lesions has resulted in a material improvement in PVI durability, something that is borne out in clinical studies too3.Some limitations of the work should be mentioned. Patients were not randomised to RFCA or CBA; rather, patients undergoing CBA were pre-selected with those with left common PV or large PVs excluded. The ablation technique used for CBA was unusual in that the use of RFCA was allowed if PVI could not be achieved after a single 3-minute freeze. This low bar for defining CBA failure led to as many as 3 patients out of 25 being excluded from the study. Many readers will feel that the mean procedural times of 129 minutes and fluoroscopy times of 39 minutes for CBA are much longer than what is the norm today. They may also find the RF powers used in this study unusual; only 30W was used on the anterior wall, and 20-25W on the posterior wall, which was reduced even further if esophageal temperature rise was observed. The field is moving towards using higher power short duration (HPSD) RF applications, and as HPSD lesions have been shown to be wider12, it is possible that the gaps on the posterior wall identified in this study may not have been present had HPSD applications been used. Finally, the definition of visual gap on MRI used in this study, a non-LGE site larger than 4 mm, almost certainly overestimated the number of true gaps. For instance, the authors observed at least one visual gap in each of the 16 segments around the PVs in more than 10% CB patients; this is at odds with data obtained with ultrahigh density mapping9, and also with the good clinical outcomes reported here. Future research should look at correlating these MRI-visualised gaps with actual gaps seen on repeat electrophysiological study, so that the clinical significance of these can be better defined.What can we take away from this study? Firstly, the use of MRI to assess post-ablation scar is now a reality in many labs, allowing assessment of PVI durability to help decide whether or not to offer a repeat procedure to a patient with AF recurrence. Secondly, the evolution of the RFCA technique to include target lesion indices and inter-lesion distance has made RFCA at least as effective as CBA in achieving durable PVI. Finally, this is an area ripe for further research, and we look forward to similarly valuable contributions from Kurose and colleagues in the future.

Alessandro Perri

and 2 more

Image1

Enrico Heffler

and 16 more

To the Editor Since the end of February 2020 Italy, first non- Asian Country, has reported an ever increasing number of COronaVIrus Disease 19 (COVID-19) patients, which has reached over 200,000 confirmed Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected subjects and resulted in more than 34000 deaths (data updated to June 19th, 20201).Patients with asthma are potentially more severely affected by by SARS-CoV-2 infection 2 and it is well established that respiratory viral infections are associated with severe adverse outcomes in patients with asthma, including increased risk of asthma exacerbation episodes 3. Nonetheless, according to the epidemiological studies published so far, chronic pulmonary diseases are not amongst the most common clinical conditions in COVID-19 patients4About 5-10% of entire asthma population, are severe asthmatics5 and one would expect increased vulnerability to SARS-CoV-2 infection, but no data is so fare available ti confirm this hypothesis.We investigated the incidence of COVID-19, describing its clinical course, in the population of the Severe Asthma Network in Italy (SANI), one of the largest registry for severe asthma worldwide6, and in an additional Center (Azienda Ospedaliero Univeristaria di Ferrara, Ferrara, Italy). All centers, have been contacted and inquired to report confirmed (i.e. patients with positive test result for the virus SARS-CoV-2 from analysis of nasopharyngeal or oropharyngeal swab specimens) or highly suspect cases of COVID-19 (i.e. patients with symptoms, laboratory findings and lung imaging typical of COVID-19 but without access to nasopharyngeal or oropharyngeal swab specimens because of clinical contingencies/emergency) among their cohorts of severe asthma. Demographic and clinical data of the entire cohort of severe asthmatics enrolled in the study and all reported cases of confirmed or suspect cases of COVID-19, have been obtained from the registry platform and collected from the additional Center. Additional data about COVID-19 symptoms, treatment and clinical course have been collected for all cases reported.Ethical issues and statistical analysis are reported in the online supplementary material.Twenty-six (1.73%) out of 1504 severe asthmatics had confirmed (11 out of 26) or highly suspect COVID-19 (15 out 26); eighteen (69.2%) were females and mean age was 56.2 ± 10 years. The geographical distribution of COVID-19 cases is presented in Figure 1.Nine (34.6%) infected patients experienced worsening of asthma during the COVID-19 symptomatic period; four of them needed a short course of oral corticosteroids for controlling asthma exacerbation symptoms.The most frequent COVID-19 symptoms reported were fever (100% of patients), malaise (84.6%), cough (80.8%), dyspnea (80.8%), headache (42.3%) and loss of smell (42.3%). Four patients (15.3%) have been hospitalized, one of which in intensive care unit; among hospitalized patients, two (7.7%) died for COVID-19 interstitial pneumonia. No deaths have been reported among the non-hospitalized patients.Severe asthmatics affected by COVID-19, had a significantly higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) compared to non-infected severe asthma patients (15.4% vs 3.8%, p=0.002; odds ratio: 4.7). No difference was found in other comorbidities (including rhinitis, chronic rhinosinusitis with or without nasal polyps, bronchiectasis, obesity, gastroesophageal reflux, arterial hypertension, cardiovascular diseases).Twenty-one patients with COVID-19 were on biological treatments: 15 (71%) were on anti-IL-5 or anti-IL5R agents (Mepolizumab n= 13; Benralizumab n=2 - counting for the 2.9% of all severe asthmatics treated with anti-IL5 in our study population) and 6 (29%) were on anti IgE (Omalizumab - 1.3% of all severe asthmatics treated with omalizumab in our study population).Table I summarizes demographic and clinical characteristics of the 26 COVID-19 patients.In conclusion, in our large cohort of severe asthmatics, COVID-19 was infrequent, not supporting the concept of asthma as a particularly susceptible condition to SARS-COV2 infection 2. This is in line with the first published large epidemiological data on COVID-19 patients, in which asthma is under-reported as comorbidity4. The COVID-19 related mortality rate in our cohort of patients was 7.7%, lower than the COVID-19 mortality rate in the general population (14.5% in Italy 1). These findings suggest that severe asthmatics are not at high risk of the SARS-CoV-2 infection and of severe forms of COVID-19. There are potentially different reasons for this. Self-containment is the first, because of the awareness of virus infections acting as a trigger for exacerbations, and therefore they could have acted with greater caution, scrupulously respecting social distancing, lockdown and hygiene rules of prevention, and being more careful in regularly taking asthma medications.Another possible explanation stands in the intrinsic features of type-2 inflammation, that characterizes a great proportion of severe asthmatics. Respiratory allergies and controlled allergen exposures are associated with significant reduction in angiotensin-converting enzyme 2 (ACE2) expression 7, the cellular receptor for SARS-CoV-2. Interestingly, ACE2 and Transmembrane Serine Protease 2 (TMPRSS2) (another protein mediating SARS-CoV-2 cell entry) have been found highly expressed in asthmatics with concomitant NIDDM8, the only comorbidity that was more frequent reported in our COVID-19 severe asthmatics.The third possible explanation refers to the possibility that inhaled corticosteroids (ICS) might prevent or mitigate the development of Coronaviruses infections. By definition, patients with severe asthma are treated with high doses of ICS 5 and this may have had a protective effect for SARS-CoV-2 infection.Noteworthy, among the patients of our case-series of severe asthmatics with COVID-19, the proportion of those treated anti-IL5 biologics was higher (71%) compared to the number of patients treated with anti-IgE (29%). Although the number of cases is too small to draw any conclusion, it is tempting to speculate that different biological treatments can have specific and different impact on antiviral immune response. In addition we may speculate of the consequence of blood eosinophils reduction: eosinopenia has been reported in 52-90% of COVID-19 patients worldwide and it has been suggested as a risk factor for more severe COVID-19 9.In conclusion, in our large cohort of severe asthmatics only a small minority experienced symptoms consistent with COVID-19, and these patients had peculiar clinical features including high prevalence of NIDDM as comorbidity. Further real-life registry-based studies are needed to confirm our findings and to extend the evidence that severe asthmatics are at low risk of developing COVID-19.
Figure 1

Chan Sol Park

and 7 more

Background and Purpose: After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption results in secondary injury including apoptotic cell death of neurons and oligodendrocytes, thereby leads to permanent neurological deficits. Recently, we reported that the histone H3K27me3 demethylase Jmjd3 plays a role in regulating BSCB integrity after SCI. Here, we investigated whether gallic acid (GA), a natural phenolic compound that is known to be anti-inflammatory, regulates Jmjd3 expression and activation, thereby attenuates BSCB disruption following the inflammatory response and improves functional recovery after SCI. Experimental Approach: Rats were contused at T9 and treated with GA (50 mg/kg) via intraperitoneal injection immediately, 6 h and 12 h after SCI, and further treated for 7 d with the same dose once a day. To elucidate the underlying mechanism, we evaluated Jmjd3 activity and expression, and assessed BSCB permeability by Evans blue assay after SCI. Key Results: GA significantly inhibited Jmjd3 expression and activation after injury both in vitro and in vivo. GA also attenuated the expression and activation of matrix metalloprotease-9, which is well known to disrupt the BSCB after SCI. Consistent with these findings, GA attenuated BSCB disruption and reduced the infiltration of neutrophils and macrophages compared with the vehicle control. Finally, GA significantly alleviated apoptotic cell death of neurons and oligodendrocytes and improved behavior functions. Conclusions and Implications: Based on these data, we propose that GA can exert a neuroprotective effect by inhibiting Jmjd3 activity and expression followed the downregulation of matrix metalloprotease-9, eventually attenuating BSCB disruption after SCI.
Image1

Enrico Heffler

and 16 more

BACKGROUND: COronaVIrus Disease 19 (COVID-19) pandemic is affecting almost the entire world since February 2020. Patients with chronic pulmonary diseases, such as asthma and chronic obstructive lung disease potentially and theoretically may be more vulnerable and therefore seriously ill if infected by SARS-CoV-2; however, according to the first epidemiological studies published so far, chronic pulmonary diseases are under-reported. No data is available, so far, about the incidence of COVID-19 in severe asthmatics and about which are the COVID-19 outcomes in this subgroup of patients. METHODS:: In this study, we investigated the incidence of COVID-19 cases in a large population of severe asthmatics in Italy, describing their clinical characteristics and clinical course of COVID-19 disease. RESULTS: Twenty-six (1.73%) out of 1504 severe asthmatics were identified as confirmed or highly suspect with COVID-19. Nine (34.6%) of infected patients experienced worsening of asthma during the COVID-19 symptomatic period. Severe asthmatics affected by COVID-19, compared to those who did not contracted the infection, had a significantly higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) (15.4% vs 3.8%, p=0.002); among COVID-19 patients the proportion of those treated anti-IL5 biologic agents was higher (71%) compared to the number of patients treated with anti-IgE (29%). CONCLUSIONS: In our large cohort of severe asthmatics, the incidence of COVID-19 was particularly low, with higher prevalence of NIDDM as comorbidity, suggesting that NIDDM might be a risk factor for COVID-19 in severe asthmatics.

Jorge Casanova

and 4 more

ABSTRACT Background: COVID-19 was declared a pandemic by the World Health Organization (WHO) on March 11st, 2020. Responses to this crisis integrated resource allocation for the increased amount of infected patients, while maintaining an adequate response to other severe and life-threatening diseases. Though cardiothoracic patients are at high risk for Covid-19 severe illness, postponing surgeries would translate in increased mortality and morbidity. We reviewed our practice during the initial time of pandemic, with emphasis on safety protocols. Methods: From March 11st to May 15th 2020, 148 patients underwent surgery at the Department of Cardiothoracic Surgery of CHUSJ. The clinical characteristics of the patients were retrospectively registered, along with novel containment and infection prevention measures targeting the new Corona Virus. Results: The majority of adult cardiac patients were operated on an urgent basis. Hospital mortality was 1.9% (n = 2 patients). Most of adult thoracic patients were admitted from home, with a diagnosis of neoplasic disease in 60% patients. Hospital mortality was 3.3% (1). Fifteen children underwent cardiothoracic surgery. There was no mortality. The infection prevention procedures applied, totally excluded the transmission of Covid-19 in the Department. Conclusion: While guaranteeing a prompt response to emergent, urgent and high priority cases, novel safety measures in individual protection, patients circuits and pre-operative diagnose of symptomatic and asymptomatic infection were adopted. The surgical results corroborate that it was safe to undergo cardiothoracic surgery during the initial time of Covid-19 pandemic. The new policies will be maintained while the virus stays in the community.

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