Remote sensing of specific climatic and biogeographical factors is an effective means of evaluating the desertification status of dryland regions affected by negative human impacts. Here, we identify and analyse land desertification trends in Iran via a combination of three indices of vegetation (NPP—net primary production, NDVI—normalized difference vegetation index, and LAI—leaf area index); and two climate indices (LST—land surface temperature, and P—precipitation) during the period 2001–2015. The Mann-Kendall non-parametric test, the Theil–Sen estimator, and a simple linear regression method were then applied to identify trends and to map regions of Iran that are susceptible to desertification. Our results show that an area of 680,000 km2 (~ 56 %) of Iran is classified with a very high level, indicating that a large fraction of Iran is susceptible to land desertification. We suggest that spatial and temporal trends in the three vegetation indices (NPP, NDVI, and LAI) and the two climate indices (LST and P) are a cost-effective choice for the prediction and management of future environmental trends in the world’s developing regions, and are a step towards achieving land-use sustainability by helping to locate the most degraded areas.

Runoff and erosion can increase after wildfires, but little is known about the effects of wildfire plus post-fire salvage logging, or mitigating these effects. Past research has identified soil compaction and reduced surface cover as controls on runoff and erosion, but the relative contributions of these changes are not clear. Two years after high severity burning by the 2015 Valley Fire in California, replicated rainfall simulations were carried out in four soil conditions across compaction and cover factors: uncompacted/compacted by logging machinery and bare soil/60% wood slash-cover. Runoff after 71 mm of rainfall totaled 27 mm in the uncompacted bare plots and 39 mm in the compacted bare plots. Runoff in the slash-covered plots decreased by 50% and 33% as compared to the uncompacted and compacted bare plots, respectively, although none of the differences in runoff were significant. Rainsplash averaged 30 g for the bare plots, regardless of compaction, and decreased significantly by 70% on slash-covered plots. Sediment yield totaled 460 and 818 g m-2 for the uncompacted and compacted bare plots, respectively, and slash significantly reduced these amounts by 72% and 69%, respectively. Our results showed that post-fire soil erosion in high severity burned unlogged areas was still very high two years after the wildfire. The combination of wildfire and salvage logging doubled soil erosion by increases in both runoff amount and sediment concentration. Antecedent soil moisture (dry or wet) was the dominant factor for runoff, while surface cover was the dominant factor for erosion and sediment delivery. Covering the soil with slash reduced both runoff and erosion, suggesting this treatment would reduce long‐term sediment delivery from burned areas and skid trails. Saturated hydraulic conductivity (Ks) and interrill erodibility (Ki) calculated from these simulations confirmed previous research and will support modeling efforts related to wildfire and post-fire salvage logging.

In this analysis, we observed that human development index (an integrated index of life expectation, education and living standard) correlates with case rate (proportion of confirmed cases among the population) and the fatality rates of COVID-19 in Italy based on data as of May 15, 2020.

Objective: Multi-dose dexamethasone pretreatment prevents postextubation airway obstruction (PEAO), however, its optimal dose in children is not known. We planned to compare effect of 24h pretreatment of low dose (LD) (0.25mg/kg/dose) versus high dose (HD) (0.5mg/kg/dose) dexamethasone for prevention of PEAO. Design: Stratified (for age and intubation duration) randomized open-label non-inferiority trial. Setting: 15-bed Pediatric Intensive Care Unit in a tertiary care teaching hospital of a lower-middle income country. Patients: Children (3mo-12yrs) intubated for ≥48h and planned for first extubation over 26 months (Feb’17 to Mar’19). Children with preexisting upper airway conditions, chronic respiratory diseases, steroid or IVIG therapy in last 7 days, gastrointestinal bleeding, hypertension and hyperglycemia were excluded. Interventions: Low dose (n=144) or high dose (n=143) dexamethasone (q6h) for 6 doses. Extubation was planned after 5th dose. Measurements and Main Results: Patients were monitored for PEAO (Westley’s Croup Score >4) for 24 hours. 238 patients were included in per-protocol analysis. 78 patients (33%) developed PEAO; both groups were similar (LD, 41/121, 34% vs HD, 37/117, 32% p=0.71). Risk difference of LD vs HD touches the non-inferiority margin of 0.12 and hence the overall result is non-significant. Incidence of reintubation was also similar (LD, 10/121, 8.3% vs HD, 9/117, 7.7%; p=0.87). Intubation for more than 7 days was an independent risk factor for development of PEAO. Conclusions: Multi-dose 24-hour pretreatment with low dose dexamethasone is not inferior to high dose in preventing PEAO and reintubation among unselected patients in the studied clinical setting. Multi-centric trials with larger sample size among children at high risk of developing PEAO are needed.

Macrolides and corticosteroid resistant have been reported in mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult even by sensitive antibiotics in severe MPP (SMPP). SMPP children might develop into airway remodeling even bronchiolitis/bronchitis obliterans. There is an urgent need to identify serum biomarkers indicating the progress of MPP and to discover new target drugs for the treatment of SMPP. In this study, we collected serum samples from general MPP (GMPP) and SMPP patients to perform proteomics profiling. Total 130 differentially expressed proteins with 61 up-regulated in GMPP and 69 up-regulated in SMPP were identified. Among these, FCGBP was one of the most altered protein with highest fold change. Biological enrichment analysis indicated an uncontrolled inflammation catastrophe in SMPP. In addition, complement, coagulation cascades, collagen-containing extracellular matrix and platelet degranulation pathway were enriched in both groups. KEGG analysis indicated an enriched platelet activation in SMPP. ELISA was then performed to verify the dynamic serum FCGBP expression level between other GMPP and SMPP patients. FCGBP level in SMPP was significantly higher than that in GMPP. FCGBP level in GMPP exhibited a decreased trend while SMPP showed the opposite trend during the disease course. Our study demonstrates the first proteomics characteristic of GMPP and SMPP and provides FCGBP as a new serum biomarker indicating the progress of SMPP. Further CMap analysis identified 25 drugs target for the treatment of SMPP. Among them, MTOR inhibitor, a macrolide compound and cell proliferation inhibitor, is the most promising drug targeting for the treatment of SMPP.

The accurate determination of the spatial trends on the variability of the gene pool of a species is essential to elucidate the underlying demographic-evolutionary events and, ultimately, to unravel the microevolutionary history of the species or population under examination. In this work, we present a new software tool called GenoCline, which is essentially devised to assist in detecting genetic clines from allele and phenotypic frequency data, and even from genome-wide data. This program package allows identifying the geographic orientation of clinal genetic variation through a system of iterative rotation of a virtual coordinate axis. At the same time, GenoCline can also be used to carry out complementary statistical analyses aimed at clarifying the potential origin of the genetic clines found, among which stand out spatial autocorrelation, isolation by distance, centroid method, multidimensional scaling and Sammon projection. Among the main advantages of this software are those related to ease in data entry and potential interconnection with other programs. Data entry is user-friendly. Genetic frequencies and geographic coordinates can be easily entered in spreadsheet table formatting, while genome-wide data can be imported in Eigensoft format. Genetic frequencies can also be exported in a format compatible with other programs dealing with population genetics and evolutionary biology. All illustrations of results are saved in eps format so that there will be high quality and easily editable vectorial graphs available for the researcher. GenoCline is implemented in Java, so it can be used with different operating systems.

The current pandemic of the novel coronavirus SARS-CoV-2 infection has affected over 6 million humans around the planet. The clinical manifestations of Coronavirus disease 2019 (COVID-19) are diverse, ranging from asymptomatic or mild flu-like symptoms to atypical pneumonia, severe respiratory distress syndrome, systemic inflammation, immune dysregulation and dyscoagulation.Inborn errors of immunity (IEI) are a heterogenous group of more than 430 rare congenital disorders with increased susceptibility to infection, autoimmunity, atopy, hyperinflammation and cancer. Autosomal recessive ARPC1B deficiency is an actinopathy, as are DOCK8 deficiency and the Wiskott-Aldrich Syndrome. Defective actin polymerization affects hematopoietic cells, impairing their migration and immunological synapse1, which results in a combined immune deficiency characterized by leukocytosis, eosinophilia, platelet abnormalities and hypergammaglobulinemia; and clinically, by eczema and food allergy, infections caused by bacteria, fungi and viruses, vasculitis, and bleeding diathesis2.Here, we describe a male infant patient with known ARPC1B deficiency who was hospitalized for COVID-19 pneumonia and improved without requiring intensive care or mechanical ventilation.An 8-month-old infant was brought to the emergency department with high-grade fever. His family history is remarkable for one brother who died as a newborn from intracranial bleeding, and an 11-year-old sister with the same genetic defect who underwent hematopoietic stem-cell transplantation twice without success, and is currently on antimycobacterial treatment, antimicrobial prophylaxis and regular subcutaneous immunoglobulin. The patient was first seen at age 1-month old for eczema and rectal bleeding attributed to cow milk protein allergy. At age 4 months, he developed bronchiolitis caused by respiratory syncytial virus (RSV) and oral candidiasis. Laboratory workup revealed leukocytosis (17,500-33,600/mm3), eosinophilia (5,600-20,100/mm3) and a marginally high (467,000) platelet count; as well as high serum IgG (737 mg/dL) and IgA (165 mg/dL) with normal IgM (37.7 mg/dL). CD8+ T lymphocytes were low at 3% (257 cells) and B cells were elevated at 48% (4,116 cells). Whole exome sequencing identified a homozygous 46 base-pair deletion in exon 8 of ARPC1B(chr7:99,392,784 hg38; p.Glu300fs).Upon his arrival to the emergency department he was febrile with tachycardia and signs of septic shock requiring rapid fluid resuscitation. He showed no respiratory or gastrointestinal signs. He also had a post-traumatic ulcerated lesion under the tongue with dark discoloration, which raised a concern for fungal infection. Intravenous antibiotics (ciprofloxacin) with antifungal coverage were started within the first hour, and a dose of intravenous immunoglobulin (IVIG) at 1g/kg. Blood counts revealed leukocytosis, neutrophilia, and mild eosinophilia without lymphopenia, while platelets were initially found within normal limits. A day later, blood culture had grownPseudomonas aeruginosa .During his second day of hospitalization, the patient persisted febrile, tachycardic and tachypneic, with oxygen desaturation into the low 80s. Chest X-ray showed nonspecific bilateral interstitial opacities in the perihilar regions (Figure 1 ). Real-time Polymerase chain reaction (RT-PCR) for SARS-Cov2 came back positive, and he was then transferred to a COVID-19 isolation area. The potassium hydroxide (KOH) test for oral thrush was negative for yeast cells, after which amphotericin was switched to fluconazole. Supplemental oxygen was discontinued on day 6 of hospitalization, when mild thrombocytopenia and a prolonged thromboplastin time (aPTT) (but normal fibrinogen and ferritin serum levels) were reported. After completing 14 days of antimicrobial treatment, the patient was discharged without ever requiring intensive care unit admission or mechanical ventilation.The behavior of COVID-19 in patients with IEI might help dissect the immune response to SARS-Cov2. A few cases of adults with COVID-19 and predominantly antibody deficiencies have been reported3,4; some of them developed acute respiratory distress syndrome (ARDS), while some had a milder course of illness. Based on what we know, innate immune defects in genes involved in type 1 interferon response (such as IRF7, IRF9, TLR3) are the most likely candidates to result in severe disease and death in patients with flu-like virus infection5. In a few cases of fatal influenza A (H1N1), variants in genes associated with familial hemophagocytic lymphohistiocytosis (FHL) and a decreased cytolytic function of NK cells, were also reported6.Our patient was on monthly supplemental IVIG treatment, and he received an additional dose during his hospital stay. This, and his young age, might have ameliorated the clinical course7. He had a favorable evolution, despite the known susceptibility to viral infection and immune dysregulation in ARPC1B deficient patients1. There were no signs of severe infection, ARDS, hyperinflammation or of “cytokine storm” unleashed by SARS-CoV-2. Despite his having a combined immune deficiency, our patient fully recovered without the need of additional supportive measures other than IVIG, supplemental oxygen and antibiotic treatment directed against the documented bacteremia.Although pediatric cases of COVID-19 are fewer compared to adults, some severe presentations and deaths among children have been reported. The presence of a restricted repertoire of IgG (since infants have no previous exposure to coronaviruses) might play a role in the better outcome seen in pediatric patients. Antibody-dependent enhancement has been implicated in the development of severe COVID-19 in the elderly8. Additionally, lung cells from children and women show a lower expression of membrane-bound ACE-2, which may also be protective against severe pneumonia.Conceivably, some immune defects could protect patients with certain IEIs from mounting a full uncontrolled inflammatory response against SARS-Cov2. The cytoskeleton is a regulator of gene transcription, coupling cell mechanics with the activity of NF-κB. Coronaviruses are thought to alter the cytoskeleton architecture to facilitate viral replication and output9. Thus, ARPC1B deficiency and other actinopathies might limit SARS-CoV-2 replication. Furthermore, Th2 cytokines modulate ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 expression in airway epithelial cells10, and children with allergies (asthma and/or allergic rhinitis) have a lower expression of ACE211. Patients with ARPC1B deficiency often have allergic diseases; their Th2-biased response could help explain the milder presentation seen in our patient. Insights from protective mechanisms in children, with and without certain immune defects, could facilitate the identification of therapeutic targets.Lina Maria Castano-Jaramillo1, MDMarco Antonio Yamazaki-Nakashimada1, MDSelma Cecilia Scheffler Mendoza1, MD, MSJuan Carlos Bustamante-Ogando2, MD, MSSara Elva Espinosa-Padilla2, MD, PhDSaul O. Lugo Reyes2, MD, MS.From the (1) Clinical Immunology Service, and the (2) Immunodeficiencies Research Unit, at the National Institute of Pediatrics, Mexico City, Mexico.Conflict of interests: NoneEthical statement: The patient and his family gave written informed consent for the diagnostic procedures and for publication of the case report.KEY WORDS: Primary immune deficiency, inborn errors of immunity, combined immune deficiency, ARPC1B deficiency, actinopathy, children, COVID-19, SARS-Cov-2, allergy, pneumonia, sepsis.

In this work, for the first time, snail slime from garden snails “Helix Aspersa Müller”, has been used to induce the formation of eco-friendly gold nanoparticles (AuNPs-SS), suitable for biomedical applications. An AuNPs-SS comprehensive investigation was performed observing AuNPs with an average particle size of 14±6 nm, stabilized by a slime snail-based organic layer. Indeed, as recognised in high-resolution MALDI-MS analyses, and corroborated by FESEM, UV-Vis, ATR-FTIR and XPS results, it was possible to assess the main presence of peptides and amino acids as main components of the slime, that, combined with the AuNPs confers them interesting properties. More specifically, we tested, in vitro, the AuNPs-SS safety in human keratinocytes and their potential effect on wound healing as well as their anti-inflammatory properties in Murine Macrophages. Moreover, the AuNPs-SS treatment resulted in a significant increase of the urokinase-type plasminogen activator receptor (uPAR), essential for keratinocyte adhesion, spreading and migration, together with the reduction of LPS-induced IL1-β and IL-6 cytokine levels, and completely abrogated the synthesis of the inducible nitric oxide synthase (iNOS).

The contact properties between metal and monolayer chemical vapor deposition (CVD) graphene were investigated, and coplanar waveguides (CPWs) composed of CVD graphene-based signal lines and Au-based ground lines were fabricated. The reflection coefficients of the CPWs were experimentally measured from 1 to 15 GHz. The contact properties were represented using the equivalent circuit model, which consists of paralell contact resistance Rc and paralell contact capacitance Cc. The calculated reflection coefficients of the model nearly agreed with the measured ones, which indicated that this model is suitable for analyzing the contact properties between metal and graphene up to 15 GHz. Bacause the impedance of Cc (|1/(ωCc )| = 4.8×10-3 Ω) is four orders of magnitude lower than that of Rc (50 Ω) at 15 GHz, the current flow is more capacitive and efficient than that in the DC band. The ratio of power consumption and power storage in the microwave band to the total power consumption in the DC band decreased with increasing frequency and incresing Cc. Therefore, higher Cc is preferable in designing microwave devices with a metal/graphene-based feeding structure, such as antennas and transmission lines.

The outbreak of the Covid-19 pandemic obliged us all to handle many dilemmas, some of which we took upon ourselves as philosophers, ethicists, doctors and nurses to discuss around four key ethical notions : responsibility, dignity, fairness and honouring death. The following collection of the symposium acts held online in May 2020 with the Paris Global Center of Columbia University and Columbia Global Centers, attempts to testify to the ongoing pandemic emergency and difficult challenges while evaluating whether the ethical principles in the official recommendations were able to meet the lived reality. Looking at accountability and consistency in regard to the context of exercise, it seemed equally important to examine, through an international exchange, whether the contextuality of Coronavirus across countries and cultures affected the ethical decision making processes. We hope that our discussion can serve as a resource for advanced care planning, helping medical providers and other specialists to consider the shared important aspects of medical ethics in times of great uncertainty.

A surge in pediatric patients presenting with an unfamiliar “multi-system inflammatory state” has been recorded since the coronavirus pandemic. A subgroup of these children tested positive for COVID-19 or had antibodies against SARS-CoV-2 indicating prior infection. [2] Despite patients under 20 years of age who exhibit mild symptoms, comprise no more than two percent of COVID-19 cases, recent fatalities due to a pediatric hyper inflammatory state suggests an unexplored bigger picture. [1, 2]Multi-System Inflammatory Syndrome in Children (MIS-C) have been reported in Europe and North America. New York, being the epicenter of this disorder, recorded over 100 cases with three fatalities. [3] Patients should present with persistent fever, multisystem organ involvement (shock, hypotension), inflammation (neutrophilia, elevated CRP, lymphopenia), and/or COVID-19 positivity or exposure for a definitive diagnosis of MIS-C. Moreover, other microbial causes such as (Staphyloccocal shock) should be excluded. [9] These patients display overlapping symptoms with Toxic Shock Syndrome (TSS) and Kawasaki disease. [2] MIS-C patients do not exhibit typical COVID-19 symptoms like cough or difficulty in breathing as it is considered to be a post infectious state generated by the body’s own immune system. [4]Kawasaki Disease (KD) is an acquired vasculitis of medium-sized arteries that primarily affects children younger than 5 years of age and is a leading cause of acquired cardiac disease in the United States. The hallmark of Kawasaki Disease includes a persistent high fever (over 101°F) for at least 4 days in addition to rash, redness to eyes, lips swelling, pallor in distal limbs and neck swelling. [5] Although MIS-C borrows its signs and symptoms from both KD and TSS, it is considered a separate disease. Kawasaki disease commonly affects children of Asian ancestry, while MIS-C hasn’t been reported in Asian countries. [6] Moreover, some MIS-C patients tend to be older than typical KD patients. According to a few case reports, a higher abnormality of biomarkers of inflammation and immune function is found than in Kawasaki Disease patients. [5]MIS-C shows a spectrum of Kawasaki resembling states which also define the management regimen of the patient. This includes a viral sepsis with shock and hypotension requiring fluid resuscitation and inotropic support which is usually found in older teens and young adults. The second resembles Kawasaki Disease more closely, affecting young children. The latter is treated using intravenous immunoglobulin, corticosteroids and biologics including infliximab and anakinra. [6, 7] In case of myocardial involvement (elevated troponin I, ECG fluctuations), the patient should be provided critical care with Enoxaparin (anti-coagulant) prophylaxis and disease modifying agents. Daily lab tests for inflammatory markers including CRP, ESR along with chest X-ray and ECG should be conducted to monitor treatment and adjust dosages accordingly. [8, 9]Although a rare condition, prompt diagnosis and treatment of MIS-C is critical to decrease both the death toll and current burden on the healthcare system. A procedure developed by Royal College of Pediatrics and Child Health has been developed for the management and treatment of these kids which can be used by health experts worldwide. [9] Increased research regarding this disease would allow for efficient treatment of patients.

Andersen-Tawil syndrome (ATS) is a rare inherited ventricular arrhythmia (VA). Here, we reported two KCNJ2-associated ATS patients who got pregnant and underwent vaginal birth safely. Both individuals had VA, micrognathia without periodic paralysis. β-blocker plus flecainide could be an effective treatment combination when monotherapy failed to control arrhythmia.

A document by Bedrettin Boyraz, written on Authorea.

Left bundle branch pacing (LBBP) provides synchronized contraction of ventricles and overcomes the limitation of His bundle pacing (HBP). The pacing lead is placed deep inside the septum 1-1.5 cm apical to the distal His bundle region. The criteria for capture of left bundle branch (LBB) have been proposed but it has never been validated. LBB potentials may not be demonstrable in all patients. Premature ventricular complexes (PVC) are often noted while positioning the lead in the interventricular septum. The morphology of the PVCs depends on the depth of the lead in the septum. We describe a novel method for lead placement to capture LBB by monitoring the morphology and duration of PVCs in four patients with different pacing indications. Rapid rotations were stopped immediately on observing a PVC with narrow QRS duration and qR (right bundle branch delay) pattern in lead V1. LBB potential and non-selective to selective LBB capture could be demonstrated after placing the lead. PVC guided lead placement would help in final positioning of the lead, avoid perforation into left ventricle cavity and to confirm conduction system capture.

Introduction. Catheter-based or surgical procedures in patients with long-standing persistent atrial fibrillation (LSPAF) remain a challenge. As a result, different approaches including hybrid (surgical and endocardial) ablation have been developed. Bachmann’s bundle (BB) is a mainly epicardial structure capable of sustaining arrhythmic reentry that could be involved in the development and perpetuation of atrial fibrillation. We investigated the efficacy and safety of an adjunctive BB ablation in LSPAF patients undergoing hybrid ablation. Methods. In a two arm non randomized study, consecutive LSPAF patients undergoing epicardial isolation of pulmonary veins with left atrial posterior wall (box-lesion) with (n=30, BB-group) and without additional BB ablation (n=30, CONV-group) were enrolled in the study. All patients underwent an endocardial procedure within 6 weeks post-surgery to assess for potential lesion gaps and additional atrial substrate modification. The primary endpoint was freedom from AF through 12 months of follow-up. Results. The two-staged hybrid ablation was successfully completed in all patients. One-year freedom from atrial arrhythmias recurrence rates was 96.6% in the BB group vs 76.6% in the CONV group (p=0.025). At procedure completion, 30 (100%) and 17 (56%) patients had a spontaneous cardioversion in BB and CONV group respectively (p < 0.001). No significant differences in quality of life or complication rates were observed. Conclusions. This initial experience shows, for the first time, that adjunctive BB ablation in the setting of hybrid ablation for LSPAF is a feasible and effective approach in increasing maintenance of sinus rhythm without increasing complication rates.

A 45-year-old man who was diagnosed with idiopathic ventricular fibrillation (IVF) 12 years ago experienced multiple implantable cardioverter defibrillator shocks due to ventricular tachycardia (VT). The recorded electrocardiogram showed VT originating from the right ventricular outflow tract (RVOT). He underwent catheter ablation for VT, and 3-dimensional (3D) mapping revealed a low voltage area in the RVOT. VT was successfully ablated at this site, and his final diagnosis was scar-related VT, not IVF. We suggest that 3D mapping is useful for the reassessment of IVF because an arrhythmic substrate might have been missed in patients who were initially diagnosed with IVF.

Introduction Integration of intracardiac echocardiography (ICE) and 3D electroanatomic mapping (EAM) system allows transseptal punctures (TSP) without the use of fluoroscopy. Compared to fluoroscopy, ICE provides better visualization of the anatomy relevant to TSP and early recognition of complications. The aim was to evaluate efficacy and safety of entirely ICE- guided TSPs in patients who underwent fluoroless catheter ablation of left-sided tachycardias. Methods and results Consecutive 524 adult and pediatric patients referred to our institution from July 2014 to December 2019 were analyzed. Patients with cardiac implantable electronic devices (CIEDs) were also included. All procedures were performed with ICE-guided TSP combined with 3D EAM. Adverse events fol-lowing TSP and within 30 days of the procedure were analyzed. Altogether 949 TSPs (363 double punctures, 76.5%) were performed in 586 fluoroless ablation procedures: 451 (77%) were ablation of atrial fibrillation or atypical flutter, 75 (12.8%) of left-sided accessory pathway, 33 (5.6%) of ventricu-lar tachycardia, and 27 (4.6%) of focal atrial tachycardia. Forty-six (7.8%) procedures were performed in pediatric population and 36 procedures (6.1%) in patients with CIED. Only 2 TSPs were unsuc-cessful (2/949, 0.2%). Overall procedural complication rate was 1.9% (11/586 procedures). There was only 1 TSP related pericardial tamponade (2/949, 0.2%). In CIED patients there was 1 lead dislo-cation following TSP. Conclusion Entirely ICE-guided TSPs for different left-sided tachycardias can be safely and effectively performed in adult and pediatric population without the use of fluoroscopy. However, caution is advised in CIED patients due to possible lead dislocation risk.

In their interesting paper published in the British Journal of Clinical Pharmacology, Mackey et al. present an analysis aiming at characterizing resonance (i.e., neutrophils oscillations) in young patients treated by cyclic chemotherapy [1]. The authors used further Quantitative Systems Pharmacology (QSP) modeling applied to granulopoïesis to demonstrate that timing of chemotherapy could impact on the dynamics of neutrophils. Consequently, the authors suggest that model-informed scheduling could help limiting hematological toxicity, e.g. by delaying supportive G-CSF therapy. The issue of controlling drug-induced side effects, especially hematological toxicities with cytotoxics, is critical in many respects. Pancytopenia can be rapidly life-threatening, especially in frail patients. When they do not directly lead to toxic-death, such severe toxicities frequently oblige practitioners to postpone or discontinue chemotherapy or associated radiation therapy, thus affecting clinical outcome and survival eventually. In addition, severe neutropenia with sepsis require antibiotics which history of use is suspected now to compromise the efficacy of immune checkpoint inhibitors, probably because of disruption of gut microbiota [2]. In addition, it is now acknowledged that prolonged lymphopenia can have deleterious effect as well, especially in the era of immunotherapy. For instance, high neutrophils-to-lymphocytes basal ratios have been repeatedly associated with poor response to immunotherapy because it could promote immune desert at the tumor level [3]. Altogether, developing strategies to control or reduce the risk of drug-induced hematological toxicities is therefore a major concern in clinical oncology, especially because as stated by the authors, cytotoxics are still today the backbone of most treatments of solid tumors and hematological malignancies. Developing in silico approaches as decision-making tools to optimize anticancer therapies has been a rising trend for decades now in clinical oncology [4]. Pharmacokinetically-guided regimen with Bayesian adaptive dosing procedures have been already proposed for several years to tailor the administration of a variety of cytotoxics and oral targeted therapies [5]. However, implementing adaptive dosing strategies in routine clinical setting remains challenging. Real-life precision medicine requires indeed mathematical models that are kept simple enough to allow proper identification of their parameters. This is a prerequisite for being easily applied prospectively in actual patients next, and not to be used solely as part of retrospective in silico modeling. This calls for using primarily top-down approaches, such as compartmental analysis prior to developing pharmacokinetics/pharmacodynamics (PK/PD) models likely to help oncologists to determine the optimal dosing and scheduling of a given drug to a given patient. More intricate modeling and QSP approaches are appealing strategies which are unfortunately impaired by their intrinsic complexity, which has made them unfit for routine use at bedside so far (Figure 1). Conversely, phenomenological modeling could in many respects look like an over-simplistic, suboptimal strategy, often mocked as being black-boxes simply linking an output to a given input. In turn, such models are more likely to be actually used in real-life setting, not despite the fact that they are black-boxes simply linking an output to a given input, but precisely because they are black-boxes simply linking an output to a given input. For instance, the Friberg model, as cited by the authors, is a simplified representation of hematopoiesis, using a semi-mechanistic, compartmental description of the proliferation and dynamics of the maturation of blood progenitors. Because of its simplicity, this top-down approach has allowed the Friberg model to be extensively used over the last 15 years, both by academics and pharmaceutical companies, to describe the myelosuppressive effects of a variety of cytotoxics [6]. Countless phenomenological models have been derived from the Friberg model ever since. For instance, the Meille model is based upon a similar simplified and semi-mechanistic representation of hematopoiesis and granulopoiesis, which encapsulates additionally a PK/PD model describing effects of supportive G-CSF administration on blood cells progenitors [7]. When further combined with another phenomenological model for antiproliferative efficacy, it was used next to build an original constraint-model determining the optimal dosing and scheduling of densified chemotherapy combo plus G-CSF support. Once calibrated with pre-defined acceptable levels of hematological toxicity and desired level of tumor shrinkage, this mathematical-driven regimen was finally tested prospectively in metastatic breast cancer patients and showed excellent performances such as prolonged overall survival in heavily pretreated patients with fully controlled hematological toxicities [8]. Importantly, the prospective use of such a mathematical model was made possible thanks to a first identification step with few blood samples taken from patients when treatment starts, providing individual data on drugs PK profile and blood counts . This critical step allowed fine tuning of individual PK/PD model parameters in real-time, thus ensuring optimal, personalized dosing next. Transposing such model-driven regimen at bedside seems to be only achievable when the whole modeling strategy is primarily built upon the parsimony principle, so as to be able to identify next individual parameters from sparse, routine data collected from patients in a real-life setting. Of note, no in-depth understanding of biological mechanisms can be provided by such models – dosing and scheduling of anticancer agents and G-CSF are connected to efficacy and toxicity endpoints through phenomenological black-boxes, not multi-scales models providing biological explanations of the phenomenon. In contrast, QSP models, such as the ones developed by the Craig group in this BJCP issue, offer appealing mechanistic features, thus allowing a better understanding of all the underlying mechanisms at play to explain pharmacodynamic endpoints. The downside is that the Mackey model is complex. It is based indeed upon more than 30 parameters, a large number of them having been fixed from the literature and thus are dependent on the variability and possible biases of the experiments used for their identification [9]. Furthermore, in contrast to standard approaches in pharmacometrics using nonlinear mixed-effects (NLME) modeling, inter-individual variability of the parameters is not quantified. The issue with such a large number of parameters is that the practical identifiability from sparse individual data collected at bedside is expected to be poor, resulting in a large uncertainty for quantitative model predictions in real-life practice.Nevertheless, the qualitative observation of the resonance effect in neutrophils time dynamics induced by the administration of periodic chemotherapies, highlighted by Mackey et al., should prompt modelers to include such pivotal phenomenon, including in their phenomenological representations of hematological toxicity. This new concept could be easily integrated and quantitatively tested in NLME models by means of inter-occasion variability (IOV) between administrations. Such IOV could allow to describe the resonance effect and improve model predictions. A covariate analysis could be performed to identify potential factors explaining the origin of this observation. Furthermore, as stated by the authors, to avoid this deleterious phenomenon and to reduce cytotoxic-induced hematological toxicities with subsequent negative impact on tumor immunity, it is an absolute prerequisite to optimize empirical chemotherapy regimens and G-CSF support administrations, based on robust PK/PD compartmental modeling.Altogether, the Mackay study highlights how the very way we use anticancer agents does matter, and how a same drug can have diametrically different pharmacodynamics effects, depending on its scheduling. In this respect, this work is an important contribution to the field of Precision Medicine in Oncology, by suggesting that there is much room left to improve standard use of canonical cytotoxics and thatin silico strategies could help to achieve a better way to administrate anticancer drugs. To transform this theoretical concept into a practical decision-making tool for oncologists, mathematicians and modelers must compose with the issue of parameters identifiability, and what kind of accessible individual data are actually made available in routine patients. As long as these issues are nor fixed, modeling will remain an elegant but theoretical field disconnected from bedside practice. To the ever-rising complexity of cancer biology and the amazing amount of knowledge regarding in-depth mechanisms of action of drugs (such as molecular signaling pathways, genetic and epigenetic regulations affecting targets or key-proteins involved in pharmacodynamics responses), the temptation to implement all this knowledge into super-models should be resisted. Indeed for a proper and rapid in silico -to-bedside transposition, we believe that in the era of Precision Medicine, the more complex is a phenomenon, the simpler should be the mathematical model describing it.Competing Interest: the authors declare noneFunding: none

Nontuberculous mycobacteria are rare causes of cardiac implantable electronic device (CIED) pocket infections. The defibrillators are more prone to infections when compared to pacemakers. Pocket infections may lead to device-related endocarditis, so preventing them is key. Presence of acid-fast bacilli on smears may aid in the diagnosis. These bacteria grow within 3-7 days on standard agar blood culture media. Accurate diagnosis requires PCR-restriction enzyme analysis. More often than not, with these infections, it is strongly recommended that entire device or hardware be removed urgently. A minimum of 4 months of therapy with at least two agents is necessary.

We thank Dr Shah and colleagues for their interest, analysis of the presented data and comments related to our paper1. Circumferential PV isolation using 8mm tip catheter is still currently used in our institution for some patients due to economic reasons, so we can provide AF ablation for a portion of the population for whom there is no private insurance available, with adequate safety and results (recurrence rate in this series was 15.6% in a follow-up of 11±5 months)2. Those catheters have two temperature sensors, thus reducing the risk of clot formation on the tip of the catheter. For the same reason, our institutional standard when using such catheters is to deliver RF applications in temperature-controlled mode with maximum temperature of 55ºC. This mode of RF application is different compared to irrigated tip catheters and the mode of application used in the cited experimental study mentioned by the authors, in which it was used power-controlled RF applications.3 Due to the temperature-controlled mode of RF application, the cooling of esophagus generates a convective cooling of the atrial wall close to the esophagus and the catheter interface, leading to the higher power RF application that was observed in Group III.2 Probably due to this higher power of application, there was a higher rate of esophageal and periesophageal lesions injuries in the esophageal cooling group. This rate was however acceptable, since we used esophagogastroduodenoscopies (EGD) combined with radial endosonographies (EUS), that is a high sensitivity method of screening for esophageal lesion. Additionally, there were no severe or clinically significant lesions in any of the patients. A prior experimental model we performed some years ago also suggests this hypothesis.4 This model was similar to the one used by Montoya and cols3 and we could find deeper lesions with esophageal cooling and temperature-controlled applications, but similar depth, when power-controlled applications were performed.4 In silico models could also be used to evaluate the different effects of esophageal cooling using temperature or power-controlled RF applications. So, we think that the flow used in our studied balloon was not the reason for the findings, but the mode of application, although even in the esophageal cooling group the incidence of lesions was low.    This was a prototype balloon used for the first time in clinical studies, and it was not possible to measure inflow and outflow temperature, being not possible to define heat transfer capacity. However, as presented before, as there was a higher RF power in group III we can infer that we achieved some cooling on the esophagus-atrium interface. Tsuchiya and cols showed a reduction in luminal esophageal temperature using an esophageal balloon with irrigation flow similar to our study.5We strongly agree with the authors that a higher flow of irrigation and consequential higher temperature reduction could be more protective, especially using power-controlled RF applications. Additionally, we think that esophageal cooling strategies are a promising strategy to avoid severe esophageal lesions, especially with contact sensor, power-controlled RF applications, allowing more effective atrial lesions close to the esophagus, thus improving AF ablation results.   References 1.         Shah S, Mercado Montoya M, Zagrodzky J, Kulstad E. Letter to the Editor regarding the paper "Comparative study of strategies to prevent esophageal and periesophageal injury during atrial fibrillation ablation". Journal of Cardiovascular Electrophysiology. 2020.2.         de Oliveira BD, Oyama H, Hardy CA, et al. Comparative study of strategies to prevent esophageal and periesophageal injury during atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2020;31(4):924-933.3.         Montoya MM, Mickelsen S, Clark B, et al. Protecting the esophagus from thermal injury during radiofrequency ablation with an esophageal cooling device. J Atr Fibrillation. 2019;11(5):2110.4.         Scanavacca MI, Neto S, Pisani CF, et al. Cooled intra-esophageal balloon to prevent thermal injury of esophageal wall during radiofrequency ablation. Heart rhythm. 2007;4(5):S117.5.         Tsuchiya T, Ashikaga K, Nakagawa S, Hayashida K, Kugimiya H. Atrial fibrillation ablation with esophageal cooling with a cooled water-irrigated intraesophageal balloon: a pilot study. J Cardiovasc Electrophysiol. 2007;18(2):145-150.

Percutaneous atrial septal defect (ASD) closure is the mainstay treatment for ostium secundum ASD and patent foramen ovale1. Patients with ASD may develop atrial fibrillation (AF), mostly due to structural atrial remodeling creating the substrate for macroreentry2,3. Timing of ASD closure is crucial to prevent further development of electrophysiological heterogeneity, thereby reducing morbidity associated with AF, even though patients with ASD closure devices remain at high risk of developing AF4.The rising number of patients undergoing percutaneous ASD closure poses a new challenge in the treatment of coexistent AF. Furthermore, the reduction of surgical ASD treatment with concurrent cryo- or radiofrequency ablation (modified Maze procedure) is contributing to increase the number of patients who would benefit from catheter ablation after transcatheter ASD closure. Although some studies have shown a high acute success rate of catheter ablation in this population5, this treatment is often denied due the higher perceived risk of performing the transseptal puncture (TSP) after percutaneous repair of the defect.Given the lack of definitive data on this topic, in this issue of the Journal, Garg et al. performed the first meta-analysis evaluating the safety and the efficacy of catheter ablation for AF in this subset of high-risk patients with ASD closure devices.

Purpose: Degenerative mitral stenosis (DMS) is an increasingly recognized cause of mitral stenosis. Echocardiographic evaluation of DMS severity is limited. The goal of this study was to compare echocardiographic differences between DMS and rheumatic mitral stenosis (RMS), identify echocardiographic variables reflective of DMS severity, and propose a dimensionless mitral stenosis index (DMSI) for assessment of DMS severity. Methods: This is a single-center, retrospective cohort study. We included patients with at least mild MS and a mean transmitral pressure gradient (TMPG) ≥ 4 mmHg. Mitral valve area by the continuity equation (MVACEQ) was used as an independent reference. The DMSI was calculated as follows: DMSI = VTILVOT / VTIMV. Results: A total of 64 patients with DMS and 24 patients with RMS were identified. MVACEQ was larger in patients with DMS (1.43  0.4 cm2) than RMS (0.9  0.3 cm2) by ~0.5 cm2 (p = <0.001) and mean TMPG was lower in the DMS group (6.0 2 vs. 7.93 mmHg, p=0.003) despite similar left ventricular stroke volume, left atrial volume index and pulmonary arterial systolic pressure. A DMSI of  0.50 and ≤ 0.351 were associated with MVACEQ ≤ 1.5 and MVACEQ ≤ 1.0 cm2 (p<0.001), respectively. With the progression of DMS from severe to very severe, there was a significant drop in DMSI. Conclusion: Our results show that TMPG correlates poorly with MVA in patients with DMS. Proposed DMSI may serve as a simple echocardiographic indicator of hemodynamically significant DMS. More extensive studies are needed to validate these findings.

Azithromycin has shown antiviral and immunomodulatory actions that may be of interest in coronavirus disease-19 (COVID-19). The objective of this review was to summarize the potential usefulness of azithromycin in the COVID-19. Azithromycin has shown in vitro activity against SARS-CoV-2. The potential mechanisms of action include the impairment of virus binding and of membrane fusion, endocytosis, and lysosomal protease activation due to its lysosomotropic character. Among other immunomodulatory actions, azithromycin downregulates the production of proinflammatory cytokines, maintains epithelial cell integrity and may prevent lung fibrosis. These properties, which have been related to positive clinical outcomes in other settings as influenza pneumonia, may be beneficial throughout the course of COVID-19. However, scientific evidence is still scarce. Azithromycin has mostly been studied with hydroxychloroquine/chloroquine. In outpatients, this combination showed a reduction in time to clinical recovery or need for hospitalization without safety concerns. In hospitalized patients presented an increased risk of mortality and cardiovascular events. In the few studies that assessed the efficacy of azithromycin monotherapy, a reduction in the time to clinical recovery in outpatients and a trend towards a reduction in mortality in inpatients was observed. Data on critically ill patients are lacking. The quality of data was low, as most of the studies were observational and retrospective. Azithromycin may play a role in the treatment of COVID-19. Despite the paucity of data and associated limitations, azithromycin has shown promising results that deserve further study. The upcoming clinical trials will elucidate the role of this macrolide in COVID-19.

AIM In university hospital settings most prescriptions are written by junior doctors, who are more likely to make mistakes than experienced doctors. Prescribing errors can cause serious harm to patients. In Brazil, few studies have investigated the causes of these errors. Our aim was to investigate the causes of prescribing errors from the perspective of junior doctors. METHOD Qualitative, descriptive and exploratory study that used a semi-structured individual interview with questions related to the planning and execution of prescriptions. It was conducted with 34 junior doctors who graduated from twelve different universities located in six Brazilian states. The data were analyzed according to the Reason's Accident Causation model. RESULTS Among a 105 errors reported, medication omission stood out. Most errors resulted from unsafe acts during execution, followed by mistakes in planning and rule violations. Many errors reached the patients, rule violations and slips accounted for the majority. Work overload and time pressure were the most frequently reported causes. Difficulties faced by the National Health System and organizational problems of the institution were identified as latent conditions. CONCLUSION The results reaffirm the multifactorial causes of the errors. Unlike other studies, the large number of violations may be related to the misuse of junior doctors to fill gaps in the health system combined with inadequacies in the prescription and training systems. We suggest conducting other local or multicenter studies to investigate cultural and contextual aspects that help to understand the causes of prescribing errors in Brazil and other low and middle-income countries.