The challenge of multiple paediatric febrile neutropenia clinical decision rules has been well described, and the difficulties with ever-expanding variants based on individual datasets discussed extensively.1 The re-calibration of the SPOG rule undertaken by Haeusler and colleagues2 (creating the ‘AUS’ rule) for a practical, bedside tool which would be able to risk stratify episodes of FN. This letter reports a further validation in a meta-analytic dataset from the ‘Predicting Infectious Complications in Children with Cancer’ (PICNICC) collaboration.Briefly, the PICNICC collaboration was formed to develop a robust prediction rule for febrile neutropenia, with methods and materials detailed in previous publications.1,3 Over 8000 episodes of 33 different candidate predictor variables and seven clinically relevant outcomes have been collated from 26 study groups, with varied completeness. The ‘AUS’ rule uses three equally weighted factors to scale the risk of complications in an episode of FN, summed between 0 and 3.These factors are: preceding chemotherapy more intensive than acute lymphoblastic leukaemia maintenance, platelet count less than 50 g/L, total white cell count lower than 300 cells/mm3. The clinical response can be scaled according to this score, with values of 0 and 1 considered as ‘lower risk’.We evaluated the association between the AUS rule and bacterial infection using these data, reporting the discrimination (Area Under the receiver-operator Curve, AUC) and proportion of episodes classed as lower risk (scoring 0 or 1). Analyses were undertaken using R (v3.2.0).1520 episodes contributed to the analysis, with 301 episodes of documented bacterial infection. The discriminatory ability appeared very similar to Haeusler’s values; AUC 0.64 (95% CI 0.61 to 0.68) compared with the original AUC 0.67 (95% CI 0.63 to 0.71). Using the AUS rule on the PICNICC dataset would have identified 44% (668/1520) of the population as a lower risk group (score 1 or 0).This reassuring data has led to the introduction of an AUS rule based system to shorten the duration of antibiotic therapy, in concordance with UK National and International guidelines[3,4]. This now-validated rule will reduce hospitalisation for febrile neutropenic episodes in the UK, which was of particular importance during the 2020 SARS-CoV-2 coronavirus pandemic.
Phenotypic variation among individuals and species is a fundamental principle of natural selection. In this review, we focus on numerous experiments involving the model species Daphnia (Crustacea) and categorize the factors, especially secondary ones, affecting intraspecific variations in inducible defense. Primary factors, such as predator type and density, determine the degree to which inducible defense expresses and increases or decreases. Secondary factors, on the other hand, act together with primary factors to inducible defense, or without primary factors on inducible defense. The secondary factors increase intra-species variation in inducible defense, and thus the level of adaptation of organisms varies within species. Future research will explore the potential for new secondary factors, as well as the relative importance between factors needs to be clarified.
It is known that LIMA-to-LAD is the major determinant of the patient’s prognosis and long term survival for a large percentage of the population with coronary artery disease Off pump, minimally invasive LIMA-to-LAD provides excellent long-term results ). As Awad et al state, this pandemic has disrupted and challenged delivery of health care services worldwide ). LIMA-to-LAD can be performed with minimal resources in an isolated area from COVID-19 facilities within the hospital.Hybrid treatment of coronary heart disease is another option for patients under these circumstances . Surgeons must take the lead and play an active role in the decision process. . As the authors conclude, given fluidity of the current situation, there is need for new processes and clinical decision – making that will allow patients to receive appropriate treatment,
Although most autoimmune diseases are considered to be CD4 T-cell or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab that is used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities, notably multiple sclerosis, where ofatumumab is in late stage development and ocrelizumab is approved for use. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of multiple sclerosis and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B-cell subset inhibition that controls multiple sclerosis and other autoimmunities, would not influence innate and CD8 T-cell responses, which are central to SARS-CoV-2 elimination, nor the hyper-coagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority (mortality rate n=~5/392) of SARS-CoV-2 infected, CD20-depleted people with multiple sclerosis have recovered. However, protective neutralising-antibody and vaccination responses are predicted to be blunted, until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control in MS and other autoimmune diseases, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.
The COVID-19 has posed a wide range of urgent questions: about the disease, testing, immunity, treatments, and outcomes. Extreme situations, such as pandemics, call for exceptional measures. However, this threatens the production and application of evidence. This paper directs evidence production towards four types of uncertainty in order to address the challenges of the pandemic: Risk, Fundamental uncertainty, Ignorance, and Ambiguity. Eliminating ambiguity, being alert to the unknown, and gathering data to estimate risks are crucial to preserve evidence and save lives. Hence, in order to avoid fake facts and to provide sustainable solutions we need to pay attention to the various kinds of uncertainty. Producing high quality evidence is the solution, not the problem.
Sir ,We read with great interest the study by Zhou et al.1, where the authors demonstrated a significant association between preconception paternal smoking and birth defects in the offspring. The study is timely given the increasing recognition of the role that paternal factors play in pregnancy outcomes. The authors must be congratulated on performing a large scale, nationwide study, in which a potential link between preconception paternal smoking and birth defects in offspring was made.A salient point discussed by Zhou and colleagues is the difficulty in estimating the effect of paternal smoking as an independent variable on the risk of birth defects due to a myriad of confounding factors. Although the authors had adequately adjusted for maternal biological, environmental and behavioural factors, as well as paternal alcohol consumption, it may be prudent to note that paternal age could be a potentially significant confounder in this relationship.Advanced paternal age has shown robust links with increases in sperm DNA fragmentation.2 DNA damage is attributed to environmental, hormonal and degenerative changes.2Over time, multiple cycles of mitotic replications generate greater stress on the DNA repair mechanisms.2 The failure to control the DNA repair mechanisms invariably amounts to ejaculated spermatozoa containing a higher proportion of abnormal paternal DNA.2 In the same vein, children born to fathers of advanced age are at a slightly increased risk of birth defects including cardiac, respiratory, gastrointestinal tract and musculoskeletal abnormalities.3 It has been speculated that mutations accumulate over repeated spermatogenesis, subsequently increasing the number of birth defects in the offspring.3 At the opposite end of the age spectrum, young paternal age has also been associated with a slight increased risk of selected birth defects.3At large, prenatal smoke exposure has unfavourable effects on pregnancies. Effects of maternal smoking has been comprehensively studied and is associated with fetal and developmental conditions. Harmful substances in tobacco smoke such as nicotine, carbon monoxide and polycyclic aromatic hydrocarbons are able to cross the placenta and negatively affect the fetal development.4 On the other hand, the extent of paternal smoking has not been well-established. Exposure to cigarette smoke has been found to affect sperm parameters, as well as increase sperm chromatin structural abnormalities and DNA damage.5 Infant low birth weight, increased obesity risk in childhood and high blood pressure have been identified as potential complications of paternal smoking.4 This study provides new evidence that birth defects are also complications of paternal smoking.In conclusion, Zhou et al. have accomplished a tremendous job of investigating the effects of paternal smoking on birth defects. The current study has laid the groundwork for future research to be built upon and to elucidate the true effects of paternal smoking during pregnancy. As exposure to first or second-hand smoke poses a major risk to pregnancies, it might be worthwhile to recommend smoking cessation in both parents during preconception counselling.Jania J. Y. Wu1, Kyla Ng Yin2, Keng Siang Lee3, John J. Y. Zhang11Yong Loo Lin School of Medicine, National University of Singapore, Singapore2Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK3Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK
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.
We present the case of a patient with patch-stage mycosis fungoides who developed ulcerative tumors compatible with large cell transformation. Tumor cells were positive for CD30 and CXCR3 and negative for CCR3, and subsequently exhibited spontaneous regression. Thus, large cell transformation in early mycosis fungoides may not indicate poor prognosis.
In the present paper, we study the stochastically-induced behavior of a non-linear volcanic model containing three prognostic variables: the plug velocity $u$, the pressure under the plug, and the conduit volume $V$. The nouvelle phenomena of noise-induced transitions from the equilibrium to the cycle in the bistability parametric zone and noise-induced excitement with the generation of spike oscillations in the monostability zone are found in the presence of N-shaped friction force. To study these phenomena numerically, we used the computations of random solutions, the phase trajectories and time series, the statistics of interspike intervals, and the mean square variations. To study these phenomena analytically, we applied the stochastic sensitivity function technique and the confidence domains method. This approach is used to predict the noise-induced transition from a “dormant volcano” state to the “active volcano” mode. From the physical point of view, the volcano is capable to become active under the influence of external noises in the friction force, which model various compositions and properties of volcanic rocks. What is more, the volcanic plug can pop out when it is slipping heavily, and the volcano can erupt.
Multipolar mapping has primarily been studied in complex arrhythmia substrates or re-entrant circuits. Chieng et al. use a Case-Control design to compare multipolar mapping and point-by-point mapping with an ablation catheter for focal atrial and ventricular tachycardias, showing reduced procedure times and earlier electrograms in the multipolar mapping group but no difference in clinical outcomes. It is plausible that faster mapping and better delineation of earliest signals may translate to improved clinical outcomes if studied in a randomized trial in a larger population. Future multipolar mapping systems will guide the operator toward the focus in real-time and may even triangulate the source in three dimensions, giving an estimate of depth within the myocardium or likely focus in the opposite chamber.
The “coronavirus disease 2019 (COVID-19)” outbreak was first reported in December 2019 (China). Since then, this disease has rapidly spread across the globe and in March 2020 the World Health Organization (WHO) declared the COVID-19 pandemic.1 Since the outbreak was first announced, our journal has extensively focused on the clinical features, outcomes, diagnosis, immunology, and pathogenesis of COVID-19 and its infectious agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We published our first COVID-19 article on 19 February, focusing for the first time on the clinical characteristics of 140 cases of human-to-human coronavirus transmission without any links to the Huanan Wet Market.2 Hypertension and diabetes were mentioned as risk factors and there was no increased prevalence in allergic patients. This early study reported that the main symptoms at hospital admission were fever (91.7%), cough (75.0%), fatigue (75.0%), gastrointestinal symptoms (39.6%), and dyspnea (36.7%). Lymphopenia and eosinopenia were also reported as important signs and biomarkers for monitoring and severity of the patients.2 The prevalent eosinopenia in COVID-19 patients and the possible anti-viral role of eosinophils were further discussed in several following publications inAllergy .3,4 Our second COVID-19 paper brought attention to the wide range of clinical manifestations of this disease, from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia as well as with only diarrhea.5Patients with common allergic diseases did not develop distinct symptoms and severe courses. Cases with pre-existing chronic obstructive pulmonary disease or complicated with a secondary bacterial pneumonia were severe. Another article, timely appearing in our journal, alerted the scientific community that even in experienced hands there was a 14.1% false negative polymerase chain reaction (PCR) diagnosis in COVID-19 cases and were later diagnosed positive after repeated tests.6 A pediatric article was also published extensively analyzing 182 cases and it was reported that children with COVID-19 showed a mild clinical course.7 Patients with pneumonia had a higher proportion of fever and cough and increased inflammatory biomarkers compared to those without pneumonia. There were 43 allergic patients in this series and there was no significant difference between allergic and non-allergic COVID-19 children in disease incidence, clinical features, laboratory, and immunological findings. Allergy was not a risk factor for disease and severity of SARS-CoV-2 infection and did not significantly influence the disease course of COVID-19 in children.7The immunology of COVID-19 was extensively reviewed in two articles from leading experts with a comprehensive discussion of the tip of the iceberg in COVID-19 epidemiology, anti-viral response, antibody response to SARS-CoV-2, acute phase reactants, cytokine storm, and pathogenesis of tissue injury and severity. 8,9Two studies timely reported the role of possible trained immunity in countries with a Bacillus Calmette-Guérin (BCG) vaccination programme and a relatively low COVID-19 prevalence and mortality rate.10,11 In an extensive RNA sequencing analyses of SARS-CoV-2 receptor and their molecular partners revealed that ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and related molecules were expressed in both, epithelium and in immune cells.12Allergists, respiratory physicians, pediatricians, and other health care providers treating patients with allergic diseases are frequently in contact with patients potentially infected with SARS-CoV-2. Practical considerations and recommendations given by experts in the field of allergic diseases can provide useful recommendations for clinical daily work. Since the beginning of this current pandemic, our journal has disseminated clinical reports, 2,3,5,6,13 statements on the urgent need for accuracy in designing and reporting clinical trials in COVID-19,14 preventive measures,10,11,15 and Position Statements elaborated by experts in the field in close collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) and its task force “Allergy and Its Impact on Asthma (ARIA) ”.16-28 (keynote information in table 1). A compendium answering 150 frequently encountered questions regarding COVID-19 and allergic diseases has been recently published by experts in their respective area.29 In addition, readers can put further questions regarding this “living ” compendium electronically to the authors and their answers will be available through a new category in the journal’s webpage.30Besides, EAACI in collaboration with ARIA, has provided recommendations on operational plans and practical procedures for ensuring optimal standards in the daily clinical care of patients with allergic diseases, whilst ensuring the safety of patients and healthcare workers.23Table 1: Examples of recently published recommendations, statements and Position Papers of the EAACI
Background: Although diastolic dysfunction is common among patients treated with cancer therapy, no clear evidence has been shown that it predicts systolic dysfunction. This study evaluated the correlation of longitudinal diastolic strain time (Dst) with the routine echocardiography diastolic parameters and to estimated its role in the early detection of cardiotoxicity among patients with active breast cancer. Methods: Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling all adult patients referred to the cardio-oncology clinic. All patients with breast cancer, planned for Doxorubicin therapy were included. Echocardiography, including Global longitudinal systolic strain (GLS) and Dst, was assessed at baseline before chemotherapy (T1), during Doxorubicin therapy (T2) and after the completion of Doxorubicin therapy (T3). Cardiotoxicity were determined by GLS relative reduction of ≥15%. Dst was assessed as the time measured (ms) of the myocardium lengthening during diastole. =diastolic time (ms) measured. Results: Among 69 patients, 67 (97.1%) were females with a mean age 52±13years. Diastolic strain timeDst measurement was significantly associated with the standard routine diastolic parameters. Significant GLS reduction was observed in 10 (20%) patients at T3 . Both in a univariate and a multivariate analyses the change in Ds basal time from T1 to T2 emerged to be significantly associated with GLS reduction at T3 (p<0.04). Conclusions: Among breast cancer patients, Dst time showed high correlation to standard the routine diastolic echocardiography parameters. Relative reductionChange in Ds basal time emerged associated with clinically significant systolic dysfunction as measured by GLS reduction.
Effective Cervical screening involves a complex sequence of interactions between women, clinical staff and systems. Even in well organised screening programmes, achieving high population coverage is challenging. The transition to using Human Papilloma Virus (HPV) testing as the primary screening modality, rather than cytology, has introduced the possibility of using a self-collected sample for the primary HPV test. This has been shown to be a reliable method of detecting CIN2+ (Polman et al, Lancet Oncology 2019;20(2):229-38).Regardless of the way the sample is collected, the low specificity of a positive HPV test means that positive results must be triaged. In all cases where self-sampling has been integrated into a cervical screening programme to date, this triage is by cytology on a subsequent, clinician taken sample. Other molecular tests which can be performed on the original sample may in the future be an alternative, but are not yet fully evaluated.It has generally been assumed that a self-collected sample would not be suitable for cytology because the cervix is unlikely to be thoroughly (if at all) sampled.However, the authors have shown that using a well-established self-sampling device, 95.8% samples had at least 5000 cells, the usual threshold for adequacy for cytology. (ThinPrep LBC method). Results were highly specific, and in fact the positive predictive value (PPV) for high grade disease was higher on the self-collected specimens than on the subsequent professionally taken samples (Loopik et al. BJOG 2020 xxxx).As expected, the sensitivity of the test was lower than for a professionally taken sample, but it still detected 29.4 % of CIN2+. In this study, an impressive 91.9% of women returned for their reflex cytology test. This is higher than in other studies, possibly because the study was not focussed on women who have previously not responded to invitation.It is likely that a significant proportion of women needing treatment could be reliably identified by self-sampling alone by this method.It is worth noting that despite implementation in several organised screening programmes, self-sampling tests for HPV have yet to achieve regulatory approval, and the process for doing so for cytology from self-collected samples is likely to require studies with more extended monitoring of clinical outcomes.Self-sampling is not yet widely implemented internationally and the pathways can be challenging. There is a concern about how to address loss to follow up, design of multistep pathways for management, and potential delays in diagnosis. A pathway which could reliably prioritise women for referral for immediate colposcopy, with a high PPV for CIN2+, without requiring a face to face clinical interaction would be extremely valuable. This is potentially even more topical in the post COVID-19 world where there are new challenges in risks of consultations and in capacity of health care delivery.No disclosures: A completed disclosure of interest form is available to view online as supporting information.
Dear Editor,We read with interest the published article by Ikeda et al. , they performed thoracic endovascular aortic repair (TEVAR) in a patient with Marfan syndrome (MFS) for acute complicated type B aortic dissection (TBAD) during COVID-19 pandemic.The evidence around TEVAR for MFS is scarce and open repair remains the gold treatment. During the COVID-19 pandemic, many patients are either being denied treatment or given inferior options on the basis of age, comorbidities and risk of COVID pneumonia; however, the guidelines for aortic intervention in the United Kingdom have remained largely unchanged from pre-COVID-19 era . Our questions to the authors relate to whether their solution was an unnecessary compromise. There is no clear indication defined in their case as a cold leg doesn’t necessary means an ischaemic limb. The TEVAR procedure performed aiming to minimise hospital stay, yet this approach may have put the patient at higher risk of developing paraplegia and visceral organ malperfusion, while compromising her long-term care.There is need to clarify if she had risk factors that prone her to a higher risk acquiring severe COVID-19 which necessitated deviating from the traditional open surgery recommended for MFS patients with TBAD . The authors did not report on renal function, evidence of bowel malperfusion or whether there was resistant hypertension that needed immediate intervention. If the need to expediate intervention was the fear of limb ischaemia, is it conceivable a femoro-femoral bypass could have saved the limb and definitive open surgery on her aorta could have been performed at a later stage, especially since she was haemodynamically stable.Moreover, as Marfan-diseased aortas are prone to further dilatation, we believe their justification for opting for endovascular repair should also have been more balanced, exploring the know high rate of long-term TEVAR-associated complications in MFS patients including endoleaks, retrograde dissection, stent-graft-induced new entry tears, surgical conversions and reintervention. There is also need for imaging follow-up to assess the success of TEVAR and early detection of aforementioned complications.
Bird feathers serve multiple functions through their physical structure and coloration, but the evolution of functional novelty in bird feathers remains poorly understood. We investigated how selective pressures gave rise to seasonal coloration change in the feathers of the New World Warblers (Aves: Parulidae), a family with a remarkable diversity of plumage, molt, and life history strategies. Seasonal color changes in the plumages of migratory warblers are hypothesized to reflect a tradeoff between natural and sexual selection on the breeding and non-breeding distributions. We used comparative methods including phylogenetic path analysis to examine nested hypotheses relating to the evolution of seasonal dichromatism (i.e. breeding and nonbreeding plumages) and the molts that produce these plumages. We found that biannual molts likely evolved in response to increased feather wear and that changes in feather coloration evolved after the biannual molt itself. These results demonstrate that structural needs, not seasonal selection on coloration, drive the evolution of molt strategies in Parulidae. Importantly, once a biannual molt evolves, it served as a preadaptation for seasonal changes in plumage color. These results reveal how life history strategies act upon multiple and separate feather functions to drive the evolution of feather replacement patterns and bird coloration.
There is emerging evidence that a keen understanding of atrial myofiber architecture is paramount to characterizing and treating atrial arrhythmias. Heterogeneity in the three dimensional anatomic structure of the atrium has previously been shown to create distinct endocardial and epicardial activation patterns during tachycardia in a canine model (1). In the clinical setting, the epicardial atrial architecture and its contribution to arrhythmias have been less well explored until recently. There has been a renewed interest in and appreciation of epicardial and interatrial connections, particularly in the treatment of left atrial arrhythmias refractory to traditional endocardial ablation.The vein of Marshall has been postulated to harbor epicardial connections between the coronary sinus (CS) and the left atrium (LA), sustaining peri-mitral flutters refractory to endocardial ablation (2,3). Conduction across the intercaval bundle, which connects the right atrium to the right superior pulmonary vein, has been reported to render isolation of the RSPV challenging requiring ablation at the carina or from the RA (4,5). Similarly, the Bachmann bundle, the main pathway of interatrial connection, has been shown to be critical for maintenance of biatrial flutters (6,7). More recently, conduction across the subepicardial septopulmonary bundle has been implicated in the maintenance roof dependent flutter despite isolation of the endocardial posterior wall (8). In contrast, the role of epicardial connections in sustaining right atrial arrhythmias has been less well described.In this edition of the Journal, Chaumont et al. describe five patients who underwent electrophysiology study for typical atrial flutter, who had persistent arrhythmia despite achieving a line of block along the endocardial aspect of cavotricuspid isthmus (CTI) (9). Using entrainment and activation mapping during tachycardia, they identified atrial tissue critical to the arrhythmia circuit in the middle cardiac vein in four patients, and in close proximity to the CS ostium in one patient. Ablation at these locations restored sinus rhythm. Electroanatomic mapping was not available for most of these cases. Rather than a limitation, this absence allowed an amazing demonstration “old school” deductive electrophysiology.The authors should be commended for this series of cases which demonstrate connections that sustain atrial flutter by bypassing the endocardially blocked CTI. This study elucidates the complex, layered physiology underpinning atrial flutter, considered among the simpler of arrhythmias we treat in the electrophysiology laboratory. The strength of the study is the elegant intracardiac electrograms for each case which allowed the authors to infer the mechanism of refractory arrhythmia and eliminate it by targeting critical areas guided by EGMs within the coronary venous system. Prior studies of atrial fibrillation have suggested that epicardial-endocardial breakthrough maybe an important mechanism in maintenance of persistent AF (10). It appears that a similar mechanism maybe responsible for maintaining typical flutter refractory to endocardial CTI ablation.Based on their findings, the authors propose a CS to low right atrium (RA) epicardial connection in the first four patients, and an RA to RA epicardial connection in one patient critical to the tachycardia circuit. Anatomically, however, it is unclear whether discrete connections akin to accessory pathways exist between these regions of interest to explain the observed findings. It is more likely that the atrial flutter circuit encompasses the entire thickness of the atrium, and owing to fiber orientation across the two layers, there are regions where the endocardial and epicardial surfaces communicate with each other. At these locations we appreciate the epicardial component of persistent flutter once the endocardium is ablated and line of block is achieved but tachycardia continues uninterrupted. This concept is illustrated in Figure 1, which demonstrates a case of persistent mitral annular flutter refractory to endocardial mitral annular line. Epicardial conduction necessary for maintaining tachycardia was observed after endocardial ablation, and ablation from the coronary sinus slowed and terminated the tachycardia.The advent of high resolution 3-dimensional mapping systems has allowed characterization of atrial activation patterns in detail during tachycardia. Pathik et al investigated epicardial-endocardial breakthrough in activation mapping of right atrial macro-reentry tachycardia in 26 patients (11). They defined breakthrough as the presence of focal endocardial activation with radial spread unaccounted for by an endocardial wavefront, with same timing on every tachycardia cycle. Epicardial-endocardial breakthrough was observed in over 50% of the patients, with majority at the posterior RA, and one each at cavotricuspid isthmus postablation, RA septum, and the inferolateral RA. In four patients, areas of breakthrough were within the tachycardia circuit, and in one patient the breakthrough region was critical for arrhythmia maintenance. In all cases, breakthrough sites were adjacent to endocardial slowing or line of block—as mentioned above this finding is not entirely surprising, given that endocardial block is necessary to observe epicardial breakthrough while activation mapping.A detailed morphologic and histologic study of the inferior right atrial isthmus by Cabrera et al may provide some anatomical insight to explain the current study findings (12). The authors establish the isthmus to be an anatomically heterogeneous region, with the anterior aspect being consistently muscular, while the posterior membranous and the middle trabeculated aspects having variable ratios of muscle fibers to fibrofatty tissue, with myocardial bundles extending from terminal crest toward the Eustachian ridge to cover the mouth of the coronary sinus. In refractory atrial flutter following endocardial CT ablation, it maybe that ablation from the CS allows the elimination of residual conduction through these muscle fibers which is critical for maintenance of tachycardia.In conclusion, Chaumont et al should be congratulated for elegantly demonstrating the multi-layer physiological architecture of typical atrial flutter—a reflection of the anatomic complexity and heterogeneity of the cavotricuspid isthmus and its inputs, and of the atrial musculature in general. Appreciation of this complexity will undoubtedly empower us to characterize and treat this arrhythmia and others more effectively.