Drug hypersensitivity reactions (DHRs) represent a global threat to healthcare systems due to their incidence, with a significant increase over last years1. DHR figures are overestimated in the general population since less than 40% of cases initially labelled as allergic can be confirmed as such when evaluated in an allergy unit2. Achieving an accurate diagnosis is complex and time consuming; besides, tests must be tailored to specific clinical manifestations and underlying mechanisms and will depend on the culprit drugs. Diagnosis often requires performing drug provocation tests (DPTs), which are especially problematic for severe reactions, making management of these patients challenging and expensive for the health care system.Clinically, DHRs are classified into immediate and non-immediate, based on the time interval between drug exposure and onset of the symptoms3. The most severe immediate reaction is anaphylaxis. This issue of the journal has been dedicated o drug hypersensitivity, which is becoming a major public health issue during the last decade, especially with the introduction of biologicals to medicine. Bilo et al. 4 evaluated the anaphylaxis mortality rate in Italy from 2004 to 2016 and found an average mortality rate for definite anaphylaxis (ICD-10 code) of 0.51 per million population per year, mostly due to the use of medications (73.7%), although in 98% of the cases culprit drugs were not identified. Regarding non-immediate reactions, one of the most challenging diagnoses is drug reaction with eosinophilia and systemic symptoms (DRESS), which is sometimes difficult, at an early stage, due to overlapping clinical symptoms with maculopapular exanthema (MPE). Pedruzzi et al. 5 identified 7 microRNAs (miRNAs) that correctly classified DRESS or MPE patients and were associated with keratinocyte differentiation/skin inflammation, type I IFN pathway viral replication, ATP-binding cassette transporters, and T lymphocyte polarisation, being all of them potential biomarkers. Non-immunologically mediated adverse reactions, such as attention-deficit/hyperactivity disorder (ADHD) are reported by Fuhrmannet al. 6 in association with systemic H1-antihistamines administration in school-age children, especially the 1st generation agents.The mechanism underlying DHR and the reason why patients treated with the same drug develop a tolerance response or an immediate or non-immediate DHR is not completely understood (Figure 1). Therefore, the prediction of who may experience a DHR, and if so, in what form, remains clinically obscure for most drugs. Goh SJR et al. 7 elegantly analyse this complexity, using non-immediate reactions to penicillins as a model. They focus on the understanding of the role of nature of the lesional T cells, the characterisation of drug-responsive T cells isolated from patient blood, and the potential mechanisms by which penicillins enter the antigen-processing and presentation pathway to stimulate these deleterious responses.Regarding specific drugs involved in allergy, betalactam antibiotics (BL) are the most frequent culprit, being many reactions mediated by IgE. This type of reaction varies among patients, with some reacting only to one BL and others to several of them; it tends to change over time and differs between European countries, depending on BL consumption. Nowadays, amoxicillin (AX), alone or in combination with the β-lactamase inhibitor clavulanic acid (CLV), is the most often prescribed BL worldwide (Figure 2) and the most common elicitor of reactions in both children and adults. It is unclear why patients after the administration of AX-CLV develop selective hypersensitivity to AX, while tolerating CLV and vice-versa. Ariza et al. 8 generated drug-specific T-cell clones from AX- or CLV-selective immediate hypersensitivity patients and found that both AX- and CLV-specific clones were generated irrespective of whether AX or CLV was the culprit, although a higher secretion of Th2 cytokines (IL-13 and IL-5) was detected when clones were activated with the culprit BL compared with clones stimulated with the tolerated BL, in which higher secretion of Th1 cytokines (IFN-γ) was observed. Regarding selective non-immediate reactions to CLV, Copaescu A et al. 9 report on a cohort of patients with a history of non-immediate reaction to CLV, who demonstrated a delayed intradermal skin test response to CLV, 17% were allergic to both CLV and ampicillin, and 83% were selective reactors with good tolerance to AX. IFN-γ release enzyme-linked immunospot (ELISpot) was performed giving a sensitivity of 33%. Other drugs such as sulphonamides, either antibiotic or non-antibiotics are important triggers of non-immediate DHRs. Vilchez-Sanchez et al. 10 showed that lymphocyte transformation tests (LTT) can help avoid the performance of DPT with a sensitivity of 75%, a specificity of 100%, and negative and positive predictive values of 72.7% and 100%, respectively.There has been a great expansion in the use of biological agents (mainly monoclonal antibodies (mAbs)), and they have greatly improved the treatment landscape of hemato-oncologic, autoimmune, inflammatory and rheumatologic diseases. In parallel, the incidence rate of reported DHRs associated with these products has increased considerably within the last years, ranging from mild to life-threatening. Yang BC et al. 11 recommend risk stratification as the first step for managing patients with DHRs to these drugs. In cases with negative skin test and mild reactions, DPT is an option, and in moderate or severe reactions, desensitisation becomes the preferred approach. In cases with positive skin test, desensitisation is the recommended course of action, especially when there is no alternative medication. Desensitisation is also widely used in the management of immediate hypersensitivity reactions to chemotherapy agents, such as platinums. There is suspicion about the presence of a longer memory of tolerance in subsequent desensitisation protocols partially resembling the regulatory tolerance mechanisms induced by allergen immunotherapy. Tüzer et al. 12 demonstrate the possible role of IL-10 in desensitisation with platinums, as they found a dynamic change in serum IL-10 levels observed as an increase during desensitisation and a decrease in between the protocols.Finally, a wide spectrum of drugs has been considered for treatment of coronavirus disease 2019 (COVID-19) and all of them can potentially induce DHRs. Gelincik A et al .13 reviewed DHRs in COVID-19 times to these drugs, with knowledge mainly coming from previous clinical experience in patients not infected with COVID-19. As in other viral infections, skin symptoms, including exanthemas, may appear during the evolution of the disease, leading to differential diagnosis with DHRs. Whether COVID-19 can aggravate T–cell mediated DHRs reactions as some viruses is at present unknown.We can conclude that new drugs are continuously introduced into the markets and confirmed as inducers of hypersensitivity reactions. We still do not completely understand the mechanisms underlying many of these reactions and further studies for improving diagnostic and management are needed even in classic and well-studied drugs as BLs.Abbreviations: AX: Amoxicillin; CLV: Clavulanic acid; COVID-19: Coronavirus disease 2019; DHR: Drug hypersensitivity reactions; DPT: Drug provocation tests; DRESS: Drug reaction with eosinophilia and systemic symptoms; ELISpot: enzyme-linked immunospot; LTT: Lymphocyte transformation tests; MPE: Maculopapular exanthema.
Introduction: Lung cancer is the most important cause of cancer related deaths across the world. The aim of the study is to find key genes and enriched pathways associated with lung cancer using bioinformatics and statistical techniques, hence providing potential targets for the identification and treatment of the cancer. Methods: Differentially expressed genes (DEGs) data of 54674 genes based on stage, tumor and status of the lung cancer was taken from 66 patients of African American (AAs) origin. 2392 DEGs were found based on stage, 13502 DEGs were found based on tumor, 2927 DEGs were found based on status having p value (p<0.05). Results: Total 33 common DEGs were found from stage, tumor and status of lung cancer patients. Gene ontology (GO) and KEGG pathway enrichment analysis is performed and 49 significant pathways were obtained, out of which 10 pathways were found that were exclusively involved in lung cancer development. Protein-protein interaction (PPI) network analysis found 69 nodes and 324 edges and identified 10 hub genes based on their highest degrees. Additionally, module analysis of PPI found that ‘Viral carcinogenesis’, ‘pathways in cancer’, ‘notch signaling pathway’, ‘AMPK signaling pathways’ had close association with lung cancer. Conclusion: it is seen that these identified DEGs do not directly participate in growth of lung cancer but regulate other genes which play important role in growth of lung cancer. The key genes and enriched pathways identified can thus help in better identification and prediction of lung cancer.
Our article reported risk factors for ICD lead failure at our medical center, and we found an elevated risk of ICD lead failure in multiple lead ICD systems implanted via cephalic venous access.(1) Our analysis was prompted by recent literature related to durability of the Linox ICD lead (Biotronik, Inc., Berlin, Germany), and we found similar, elevated risk of ICD lead failure implanted in multiple lead systems via cephalic access in Linox and non-Linox ICD leads. Given the small number of total lead failures in the overall cohort (6 of 660), and the retrospective, single-center nature of our analysis, we reviewed prior Linox ICD lead durability manuscripts for evidence of increased risk of failure in multiple lead ICD systems implanted via cephalic venous access. While no prior manuscript evaluated this specific risk, we did find a trend towards increased risk of lead failure in cohorts with greater proportions of multiple lead systems, and greater proportions of systems implanted via cephalic access, however these variables were included in the analysis in a minority of prior studies.Dr. Maas and colleagues express surprise at the high failure rate when implanting multiple leads in our cohort. We would clarify that we reported ICD lead failure in 4 of the 304 patients in our cohort with multiple ICD leads, and that the frequency of lead failure in multiple lead ICD systems was not statistically significantly different compared to that of single lead ICD systems. In contrast, and surprisingly to us, 3 of 30 patients with multiple lead ICD systems implanted via cephalic access experienced ICD lead failure, and the frequency of ICD lead failure was significantly greater in this group compared to the remaining cohort in Kaplan-Meier survival analyses.Maas and colleagues question the reason for utilization of cephalic access in 18% of patients, hypothesize that suboptimal implantation technique may be responsible for the elevated lead failure rate, and request clarification of lead failure mechanism. We did not systematically collect rationale for venous access technique, and venous access techniques was at the discretion of the implanting physician. Of the 6 lead failures, 3 were related to lead noise, and 3 were related to rising pacing thresholds. Of the three lead failures amongst patients with multiple lead systems implanted via cephalic venous access, 2 were related to lead noise, and 1 was related to a rising pacing threshold. We believe that the lead noise may be related to insulation breach that may be predisposed by lead-lead interactions in the region of the cephalic vein. ICD leads were returned to the manufacturer on an ad hoc basis, and no specific feedback was received from manufacturers related to leads included in our analysis. All implanting physicians were experienced operators, and there were no significant differences in frequency of ICD lead failure by operator. We agree that implantation technique may play an important role in lead failure risk, and our analysis should prompt extra caution when implanting multiple leads via cephalic venous access.Citing the above limitations of our analysis, Dr Maas and colleagues state that it is “too early to abandon cephalic vein access, even for multiple lead systems.” They also review recent literature reporting favorable acute outcomes of ultrasound guided axillary venous access. We agree that our analysis paired with our literature review is best considered hypothesis generating, and we hope that our analysis encourages future studies to consider our findings when selecting variables of interest in ICD lead durability studies. We share Dr. Maas and colleagues’ favorable view of data supporting axillary venous access, particularly in combination with ultrasound guidance. As a result, given the available evidence of acceptable alternative techniques, our practice is to favor axillary venous access during implantation of multiple lead ICD systems, but we would not hesitate to implant via cephalic venous access in the appropriate clinical scenario.References1. Barbhaiya CR, Niazi O, Bostrom J et al. Early ICD lead failure in defibrillator systems with multiple leads via cephalic access. Journal of cardiovascular electrophysiology 2020;31:1462-1469.
Ever since the war on cancer was declared in 1971, there has been an explosion in our understanding of this diverse group of diseases. The application of molecular genetics and molecular biology technologies have enabled a deep understanding of the genetic, epigenetic, signaling cascades, survival pathways, and invasive mechanisms that underlie the cancer phenotype. Concomitantly this has translated in the development of ever more effective and safe medications that work through different mechanisms of action and target fundamental aspects of the biology of the tumor. The paradigm has been chronic myeloid leukemia where the discovery of the Philadelphia chromosome, ultimately led to the identification of the BCR-ABL oncogene and the development of tyrosine kinase inhibitors such as imatinib, nilotinib, dasatinib and others and lead to rapid, deep and long-lasting remissions in this disease. Another success story has been acute promyelocytic leukemia with the vast majority of patients now being cured of the disease without the need for any classical chemotherapy.
Dear editor/Sir,We thank Song et al. for their insightful comments (1) on our article (2) and commend them for their study about human papillomavirus (HPV)-genotyping on self-samples and their analysis on different triage strategies for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) (3). They report that cytology on physician-sampled material has a sensitivity of 74.8% for detecting CIN2+, while HPV-genotyping for 16/18 has a sensitivity of 52.6% for detecting CIN2+. This means that HPV-genotyping in their hands, is still inferior to cytology testing and cannot fully replace this triage strategy. However, adding HPV-genotyping to cytology testing could increase the sensitivity, as has been described by others as well. While our study shows that reflex cytology on self-samples cannot replace triage with regular cytology for HPV-positive women, because of the low sensitivity of 29.4% for detecting CIN2+, it is valuable as an additional method for triage (2). With a positive predictive value (PPV) of 68.1% for detecting CIN2+ it is effective to refer HPV-positive women with abnormal cytology on self-sampling directly for colposcopic evaluation without the requirement of an extra visit to the general practitioner. A PPV of 21.2% for HPV-genotyping for 16/18 on self-samples for detecting CIN2+ is not enough to refer these women directly for colposcopy. We agree that cost-effectiveness is important. It is not sure if 15% of direct referral will completely cover the costs for 85% of double cytology testing. As the collection in PreservCyt (Cytyc Corporation, Boxborough, MA, USA) has already been performed for HPV-testing on the self-samples, extra costs will include the use of ThinPrep slides (Hologic Inc, Marlborough, MA, USA) and cytotechnicians’ time for analysing the slides. On the other hand, there will be a reduction in costs for consulting the general practitioner and for regular cytology testing, including material costs (Cervex brush (Rovers® Medical Devices B.V., Oss, the Netherlands), PreservCyt jar, ThinPrep slide), transportation costs, and cytotechnicians’ time for analysing the slides. However, besides cost-effectiveness, patient comfort is at least as important, as well as reduction in loss-to-follow-up and diagnostic delay, in which the latter also positively influences the costs. It remains a challenge to find a triage method on HPV-positive self-samples which could fully replace regular cytology. Molecular tests, such as methylation markers and microRNA detection, are promising future triage methods (4, 5). They are more objective than cytology testing and highly reproducible, however not ready yet for full implementation in cervical cancer screening. Further research on self-samples is warranted to find an optimal triage strategy. Until then, reflex cytology on self-samples could be easily implemented in the current screening programme and improve cervical cancer prevention.Diede L Loopik 1; Willem JG Melchers 2; Judith EM Vedder 3; Adriaan JC van den Brule4; Leon FAG Massuger 1; Ruud LM Bekkers5; Albert G Siebers 3,61 Department of Obstetrics and Gynaecology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;2 Department of Medical Microbiology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;3 Department of Pathology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands;4 Department of Pathology, Lab for Molecular Diagnostics, Pathologie-DNA, Jeroen Bosch Hospital, PO Box 90153, 5200ME,‘s-Hertogenbosch, the Netherlands; 5 Department of Obstetrics and Gynaecology, Catharina Hospital, PO Box 1350, 5602ZA, Eindhoven, the Netherlands; 6 PALGA, the nationwide network and registry of histo- and cytopathology, Randhoeve 225a, 3995 GA, Houten, the NetherlandsPresent address Ruud LM Bekkers: GROW, School for Oncology & Developmental Biology, Maastricht University Medical Centre, PO Box 616, 6200MD, Maastricht, the Netherlands
Minimally Invasive Aortic Valve Replacement is not just a metric of the incision, but rather a holistic approach to minimize the surgical trauma: the technique should reproduce the gold-standard conventional procedure in terms of safety, effectiveness and operative times through a small and different incision. Moreover, the procedure should be simple and reproducible in every Center all over the world. In our experience, we rely more on surgical skills and technique optimization, rather than CT-scan planning: definitely, the pre-operative imaging is helpful in the beginning of the experience to rule out difficult cases.
Obituary PBC Dr Pat Morris JonesDr Morris Jones who was President of SIOP in 1980/81 died on March 16 2020 at the age of 87. She was one of the first doctors in the UK to specialise in the care of children with cancer and over her 40 year career from 1953 to 1993 she saw survival rates improve from cancer being mainly a fatal disease to one where there was a real chance of cure with more than half of children surviving. She was an only child ,born in Oswestry ,close to the border with Wales. She trained in medicine at the Royal Free Medical School in London and found her way to Manchester to specialise in paediatrics. There she came under the influence of Basil Marsden, a paediatric pathologist and Dr Dorothy Pearson a radiotherapist. In 1954 Marsden had established the world’s first population based children’s malignant disease registry which became a prototype for registries all over the world. Dr Pearson was a founding member of SIOP and its second president. In the late 50s and early 60s the only real treatments available were surgery and radiotherapy but the emerging success of chemotherapy pioneered in the US, France and Germany led to a need for paediatricians to sub specialise in paediatric oncology. By the time Pat became involved the antagonism towards giving children chemotherapy had largely dissipated but how to use it to best advantage remained to be determined. She took up this challenge and built up one of the largest units in the UK. For many years she was single handed and absolutely dedicated to the care of children. She rarely took a day off. . Before people were talking about evidence based medicine she was adamant that treatment should be given in trials where we could learn what was best for the future. She was especially interested in Wilms’ tumour and very involved in the Medical Research Council embryonal tumour group and in the MRC UKALL trials. In 1977 she helped found the UK Children’s Cancer Study Group (UKCCSG) which eventually ensured that all children in the UK with cancer had access to the most up to date treatment. The early involvement of Manchester in the pre chemotherapy era using radiotherapy, and the registry, led her to take a real interest in the late effects of treatment. She had a collection of slides which she used to illustrate the late effects of radiotherapy when given to young children. Failure of skeletal growth could ensue from radiotherapy to growing bones and second malignancies occurred within radiation fields. She became heavily involved with Anna Meadows in Philadelphia in setting up the Late Effects Study Group which received substantial funding from NIH. This work was extended and has been perpetuated by Les Robison and his colleagues and has hugely influenced the design of clinical treatment protocols in recent years. She wrote an influential paper in 1990 entitled Childhood Cancer; Cure at what cost? In which she described the evolution of treatment for childhood cancer from one of cure at any cost to cure at least cost. Her fervent hope was that we would eventually get to a stage of cure at no cost. Pat was an inspirational teacher and leader and many of the young aspiring paediatric oncologists in the 70s turned to her for career advice and then once appointed to a post used her as a source of support and advice on patient management. She was most people’s “phone a friend”.The psychosocial problems faced by both children and parents became much more obvious once potentially curative treatments were being used. Paradoxically parents seemed to be able to cope better with the near certainty of death of their child than with the possibility, but by no means certainty, of long term survival. She worked closely with Peter McGuire, a psychiatrist, and with social workers to define the problems faced by children and their families and devised interventions to try and help. It was clear from the early leukaemia trials, which involved cranial irradiation and brain tumours that endocrine insufficiency was a real problem and she worked closely with Professor Steve Shalet, a paediatric endocrinologist, to not only define what these problems were but also how to follow up and screen survivors. She was always much in demand for conferences once causing consternation in Bruges when, invited to take a shot at the men only archery club she hit the bull’s eye first time. The local tradition was that anyone who did this was invited to become a member.Her retirement at the age of 60 was marked by an enormous party in Manchester Town Hall attended by many of the patients whom she had successfully treated and the parents of many of those who had died. She remembered all of their names. She was short in stature but big in personality, loved clothes and is remembered for her leather skirts and red shoes. In later years her hair was often a shade of blue and always well coiffeured . She was always a straight talker and had lots to say in meetings. She was direct and always had strong opinions. She was once quoted in a national newspaper that money was being wasted on sending children to Disneyland.Throughout her career she loved foreign travel which was often associated with scientific meetings. She built up a wide circle of friends including Anna Meadows, Dan D’Angio, Mark Nesbit and Audrey Evans whom she would call upon to offer training places to her aspiring young colleaguesWhen she retired from clinical work in 1993 she decided to move to London. “As a single lady why would I want to move into a country cottage? Soon after her move to central London she met and married her Italian hairdresser, Alfonso Cassarini, and enjoyed 20 blissful years travelling widely and exploring the capital’s culture.Pat Morris Jones was a forceful and formidable pioneer who always had the best interests of children and their families at the forefront of everything that she did. The incredible survival rates for children with cancer in the present era using treatments which are designed to minimise late effects are built on the shoulders of giants like her who dared to try.Alan CraftTim Eden
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.
Dear Sir We congratulate Dr Guy and colleagues on their paper1which demonstrates that implementation of combined screening using the FMF algorithm2 is feasible in practice and is better than the existing NICE guidelines in prevention of preeclampsia, especially preterm preeclampsia with delivery before 34 weeks. We hope that this will lead to wider application of combined screening for prediction and prevention of preeclampsia.The authors acknowledge that treatment with aspirin will have led to underestimation of screening performance. We would like to highlight this and emphasise the importance of accounting for the effect of aspirin when assessing predictive performance. To make the point, consider the most extreme case with 100% compliance with a treatment that prevents 100% of cases. In the screen positive group, all cases would be prevented by the treatment and classified as false positives. Adopting the same analysis presented in this paper would result in a detection rate and positive predictive value of zero regardless of performance without treatment.In the data presented in this study, for the FMF algorithm with 99% compliance to aspirin at a dose of 150 mg / day and assuming 62% reduction in risk,3 99%×62% = 61.4% of cases of preterm preeclampsia would be prevented and classed as false positives. The remaining 100-61.4% = 38.6% would be classed as true positives so the 15 cases of preterm preeclampsia which led to the detection rate of 15/27 = 55.6% represent just 38.6% of the cases of preterm preeclampsia detected. An estimate of the number detected, including those prevented by aspirin is, 15/0.386 = 39. The estimated number of cases in total is therefore 39 + 12 = 51, obtained by adding the false negatives 27-15 = 12 to the estimated true positives. This gives a detection rate of 39/51 = 76% compared to the figure of 55.6% given in Table 2. Applying similar calculations to the positive predictive value (i.e. proportion of women in the screen positive group who would, without aspirin, have developed preterm preeclampsia) of 9.8%. This should be compared with the 3.8% presented in the paper. Applying the same arithmetic to the NICE group gives a detection rate of 41.6% and a positive predictive value of 2.4%. These are much closer to the figures in Table 2 of the paper because of the relatively low compliance in the NICE group. Other measures of screening performance presented on this paper including the likelihood ratios, negative predictive value the receiver operating characteristic (ROC) curve analysis are also affected by this problem.The arithmetic presented above is intended for illustration; for the SPREE study4 we applied Markov chain monte carlo (MCMC) methods for inferences about screening performance. These or similar methods should be applied in future studies of screening performance.Dave Wright,1 Kypros Nicolaides2Institute of Health Research, University of Exeter, Exeter, UKHarris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK.
Dear Editor, With great interest, I read the article by Flécher et al1 and congratulate them on the quality of the review carried out on the history of surgical treatment of cardiac wounds. It is an exciting topic, so I would like to briefly comment on some facts narrated in this work.The well-known surgical approach to the heart, described by Larrey in the subxiphoid region, should not be placed in a close historical relationship with the pericardiotomy he performed in 1810 through a thoracotomy. It was not until 1824 that, after treating a soldier who had suffered a penetrating wound between the xiphoid appendix and the 7th costal cartilage, the French surgeon began experimenting on cadavers in search of a faster route to the heart. In 1829 he proposed his oblique subcostal incision which is currently practically not used.2During Milton’s service in Egypt, he surely performed several thoracic surgeries in extremis situation, but there is no evidence to support the claim that median longitudinal sternotomy (MLS) was created during an emergency approach3 or that has been designed for this type of procedure. When he decided to operate on a living human being on January 25, 1897, he used it for an elective total sternectomy in a patient with sternal tuberculosis and ruled out its use in patients with true mediastinal tumors, who needed more urgent surgeries.On the other hand, it can hardly be said that MLS is currently the gold standard for cardiac surgeons to safely and quickly manage a cardiac stab wound. In patients such as those shown in the article,1 an approach using a MLS would be very difficult since lateral mobilization of the costal wall during the necessary separation of the two halves of the sternum would displace the knife, causing probably fatal bleeding.In the emergency room, the gold standard for quickly managing a penetrating cardiac injury is anterolateral thoracotomy in the fifth intercostal space. A 1906 article on experimental surgery in dogs has led some authors to mistakenly consider Spangaro to be the creator of this incision.4 They forget that in 1893 Daniel Hale William performed his famous pericardioraphy (the second in history) precisely using that approach.5References1. Flécher E, Leguerrier A, Nesseler N. An odyssey of suturing cardiac wounds: Lessons from the past. J Card Surg. 2020;35(7):1597-9.2. López de la Cruz Y, Quintero Fleites YF. Modifications to the classic simple-longitudinal inferior pericardiotomy (Sauerbruch technique). CorSalud. 2019;11(3):225-32.3. Milton H. Mediastinal Surgery. Lancet. 1897;1:872 - 5.4. Pust GD, Namias N. Resuscitative thoracotomy. International Journal of Surgery. 2016;33:202-8.5. Buckler H. Doctor Dan. Pioneer in American surgery. Boston: Little, Brown and Company; 1954.Correspondence: “July 26” Ave., No. 306, Apt. 18. Santa Clara. Villa Clara. Cuba. Postal code: 50 200. E-mail: firstname.lastname@example.org
Reduced representation genome sequencing has popularized the application of single nucleotide polymorphisms (SNPs) to address evolutionary and conservation questions in non-model organisms. Patterns of genetic structure and diversity based on SNPs often diverge from those obtained with microsatellites to different degrees, but few studies have explicitly compared their performance under similar sampling regimes in a shared analytical framework. We compared range-wide patterns of genetic structure and diversity in two amphibians endemic to the Iberian Peninsula: Hyla molleri and Pelobates cultripes, based on microsatellite (18 and 14 loci) and SNP (15,412 and 33,140 loci) datasets of comparable sample size and spatial extent. Model-based clustering analyses with STRUCTURE revealed minor differences in genetic structure between marker types, but inconsistent values of the optimal number of populations (K) inferred. SNPs yielded more repeatable and less admixed ancestries with increasing K compared to microsatellites. Genetic diversity was weakly correlated between marker types, with SNPs providing a better representation of southern refugia and of gradients of genetic diversity congruent with the demographic history of both species. Our results suggest that the larger number of loci in a SNP dataset can provide more reliable inferences of patterns of genetic structure and diversity than a typical microsatellite dataset, at least at the spatial and temporal scales investigated.
With no end in sight to the convergence of COVID-19, countries are struggling with strategies to halt the “second wave” and mitigate economic decline. Estimated to account for around half of the infections, asymptomatic transmission of SARS-CoV-2 has been hampering the containment of the virus. A positive case rate of 10% was reported by Prabhu et al. among 625 pregnant women who were universally screened for SARS-CoV-2 on the day of admission for delivery at 3 institutions in New York City, of which 80% were asymptomatic at the time of testing including pre- and post-symptomatic patients. As evidence shows that virus sheds before symptoms appear and even after their cessation, these populations may have increased the chances of COVID-19 outbreak in the hospitals. Utilization of testing results for isolation practices was not mentioned in the report, possibly given the long turnaround time for the testing platforms at the time.While the risk of nosocomial transmission is affected by clinical settings, the intimate and prolonged nature of childbirth elevates the risk of cross-infection between midwives and women. The role of nosocomial transmission has been increasingly recognized, and its severity risk may be greater than those of community-acquired infections. A recent report has suggested facilities to consider testing pregnant women for SARS-CoV-2 at the time of admission (Rasmussen SA, et al. JAMA. 2020). International Confederation of Midwives has also called for governments to prioritize testing for all pregnant women and their care providers. Identification of infectious women prior to delivery could contribute to prevention of further transmission to patients and healthcare workers. Importance should also be emphasized on evaluating contact history due to the nature of false-negative PCR results (Woloshin S, et al. NEJM. 2020).Another significance of performing testing for SARS-CoV-2 on pregnant women is for the adequate medical management of the women and the fetuses. While outcome for mothers and neonates seems generally favorable, data suggest that pregnancy can be associated with increased risk for severity, including intensive care unit admission and receipt of mechanical ventilation (Ellington S, et al., MMWR Morb Mortal Wkly Rep 2020;69:769–775). Furthermore, a recent article has raised concerns over transplacental transmission of SARS-CoV-2 to the fetus (Vivanti AJ, et al. Nat Commun. 2020;11:3572). Collection of longitudinal data is crucial to understand the effects of SARS-CoV-2 infection on maternal and neonatal outcomes. Results of large-scale prospective cohort studies, such as INTERCOVID study, are expected to add high-quality evidence on the effects of COVID-19 in pregnancy on the health of the mothers, fetuses, and newborns.Screening a maternity population under a pandemic can be a way to provide a glimpse of the distribution of the population, since capacity constraints still impede widespread testing in many countries. Recent development of faster diagnostic testing could bring improvement, but test sensitivity will remain a challenge. Fundamental preventive measures and clinical management should be continued; that is, hygiene and social distancing practices for women themselves, and careful evaluation of each mother and fetus for care providers.
Authors’ reply re: ’Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: A systematic review and critical analysis (Response to BJOG-20-1416)Kate F Walker1, Keelin O’Donoghue2, Nicky Grace3, Jon Dorling4, Jeannette L Comeau4, Wentao Li5 Jim G Thornton11Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham2The Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork, Ireland3 School of English, University of Nottingham4Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada5Department of Obstetrics and Gynaecology, Monash University, Clayton, AustraliaThank you for the opportunity to comment on the letter by Dr Xue from Shanghai Jiao Tong University. We agree there are many weaknesses in the data we reviewed. Dr Xue has identified one. Others are the incomplete reporting of infant feeding and mother-child interactions, and the frequent lack of infant testing to confirm or refute the possibility of vertical transmission of COVID-19. Finally, although we simply provided summary totals, it would be statistically preferable to combine series using the Mantel-Haenszel method and calculate a relative risk. We judged that doing this in light of the uncertainties around the data which Dr Xue has identified, might give a spurious precision to our results. As he says, more work is needed. For now we think it remains reasonable to not regard COVID-19 in itself, as an indication for Caesarean, artificial feeding or separation, in the mother and baby’s interest.
As we celebrate 2020 as the Year of the Nurse and the Midwife and recognize the Global Initiative for Childhood Cancer, members of the International Society of Pediatric Oncology (SIOP) Baseline Nursing Standards Taskforce would like to highlight advocacy efforts promoting the baseline nursing standards.1, 2 Your published article, An ethical imperative: safety and specialization as nursing priorities of WHO Global Initiative for Childhood Cancer(Pergert and colleagues) reveals the importance of ongoing efforts to support implementation of the Baseline Nursing Standards.3 Given that the majority of hospitals are not meeting the standards in low- and middle-income countries (LMIC), as well as some high-income countries (HIC),4, 5 advocacy initiatives are required to raise awareness of the need to meet these standards. During the COVID-19 pandemic, health facilities face new challenges in meeting the standards. To achieve the WHO global initiative’s goal to save one million children’s lives by 2030, it is important to continue efforts to address baseline nursing standards.Pediatric oncology as a subspecialty requires a nursing workforce with specialized education and clinical skills to achieve optimal patient outcomes. Knowledge itself is not enough if nurses lack the resources and support to practice or implement appropriate nursing care in their work settings. The six Baseline Nursing Standards focus on key elements essential to delivering quality and safe care (Table 1). Collectively, they serve as a framework and foundation for positive pediatric oncology nursing practice environments internationally.Advocacy efforts to disseminate the baseline standards are well established. To date, fourteen organizations have endorsed the Standards. Members of the SIOP PODC Nursing Working Group hosted a “Leadership and Advocacy Workshop: Disseminating the Baseline Nursing Standards” prior to the SIOP Conference in October 2017. Twenty-two pediatric hematology/oncology nurse leaders and four stakeholder-group representatives (parent, physicians, advocates) from 14 countries met and established goals and strategic priorities for advocacy of the standards. As a result, the Baseline Nursing Standards Advocacy Toolkit was developed and can be found on the SIOP Nursing Website https://siop-online.org/baseline-nursing-standards-advocacy-toolkit. The toolkit contains practical advocacy resources, including a PowerPoint presentation, an endorsement letter template, publications, podcasts, a social media campaign and examples of elevator speeches for each standard. Furthermore, the Standards have been featured in international presentations, such as a keynote presentation (S. Day) in SIOP Lyon, an award session and nursing abstract presentations at SIOP congresses and continental meetings.To reach the WHO target of doubling the global childhood cancer survival rate to 60%, achievement of baseline nursing standards for pediatric oncology must be prioritized and appropriately resourced by hospital administrators, governments and other stakeholders. Amid a global pandemic where nursing resources are stretched, creative ways to support and advocate for implementation of the standards is needed. In recognition of the recent publication by the Nurse Specialists of the Global Initiative for Childhood Cancer noting the baseline standards, now is the time to act and improve childhood and adolescent cancer outcomes through raising the standard of pediatric oncology nursing practice around the world.Linda Abramovitz, Rehana Punjwani, Glenn M. Afungchwi and Courtney Sullivan and the SIOP PODC Baseline Standards Nursing Task Force.A special thank you to Rachel Hollis for her commitment and ongoing advocacy efforts focused on the baseline nursing standards.ReferencesDay S, Hollis R, Challinor J, Bevilacqua G, Bosomprah E, SIOP PODC Nursing Working Group. Baseline standards for paediatric oncology nursing care in low to middle income countries: position statement of the SIOP PODC Nursing Working Group. Lancet Oncol. 2014; 15(7):681-682 PMID: 24872097.Day S, Challinor J, Hollis R, Abramovitz L, Hanaratri Y, Punjwani R. Paediatric Oncology nursing care in low-and middle-income countries: a need for baseline standards. Cancer Control. 2015;2015:111-116Pergert P, Sullivan CE, Adde M, et al. An ethical imperative: Safety and specialization as nursing priorities of WHO Global Initiative for Childhood Cancer. Pediatr Blood Cancer. 2019;e28143. https://doi.org/ 10.1002/pbc.28143Morrissey L, Lurvey M, Sullivan C, et al. Disparities in the delivery of pediatric oncology nursing care by country income classification: international survey results. Pediatr Blood Cancer. 2019;66(6):e27663.Sullivan CE, Morrissey L, Day SW, Chen Y, Shirey M, Landier W. Predictors of Hospitals’ Nonachievement of Baseline Nursing Standards for Pediatric Oncology. Cancer Nurs. 2019 Mar 29;
The field of electrophysiology continues to move further towards low fluoroscopy procedures. The deleterious effects of radiation exposure and of the radiation protection clothing themselves are the primary drivers of this approach. Radiation exposure is known to increase the risk of cancer and cataracts for all operators, and namely those who are subjected to accumulating doses of radiation over time. (1). Proper radiation protective clothing can significantly decrease these risks however this strategy has serious weaknesses. For instance, the protective clothing does not cover the whole body, leaving the face and the skull exposed. Roguin et al (2) showed that the risk of radiation exposure to the unprotected areas of the body is real and has serious consequences. In a cohort of 31 interventional cardiologists who developed brain cancer, the investigators showed that 22 (85%) of them had left sided tumors, and 17 (55%) of them had glioblastoma multiforme. This remarkable finding suggests that the dose left side of the brain, the side that gets more radiation exposure, is much more likely to develop a cancer that carries a poor prognosis and a median expected survival of 12 months. Furthermore, the radiation protective clothing itself can cause orthopedics injuries common among interventional cardiologists such those of the spine and the knees. Given the deleterious effects of radiation, low fluoroscopy approaches are welcomed by the electrophysiology community if they can show a safety profile similar to that with the use of fluoroscopy.The transseptal puncture (TSP) is arguably the most critical step during which fluoroscopy is used. In this study Singh et al describe an approach for TSP under electoanatomic guidance. The authors then retrospectively compare the total procedure duration, fluoroscopy time, radiation exposures, and complications related to the TSP using this method with those of conventional fluoroscopy. This was a single center study that included 145 consecutive patients, with no previous history of cardiac surgery, who underwent de novo and redo AF ablations between June 2018 and April 2019. These patients were then compared to cases performed by the same operators before June 2018. The procedure was done under conscious sedation. A dense electroanatomic map of the right atrium was acquired using CARTO 3 Fast Anatomical Mapping and Confidence Software, with emphasis on the atrial septum, His Bundle, coronary sinus ostium, and superior vena cava. The authors observed that the fossa ovalis was an area of low voltage potential (0.37±0.19 mV vs 1.73±0.74 mV) and low impedance (125±11 Ω vs 138±15 Ω), and electrically distinct from the rest of the atrial septum. The authors were able to localize the fossa ovalis using a combination of anatomical landmarks and the use of a voltage threshold of 0.75mV. The transseptal needle was then advanced through this desired location. The authors reported no significant complications related to the TSP.The authors argue that the safety profile is like the TSP under fluoroscopy, however this is a single center study. In fact the most senior operator performed three- quarters of all the procedures. Given the high risk of such an approach, the main question for the wide adoption of such a technique will again be safety in the hands of less experienced operators. A major factor that can increase the safety profile as well as the preciseness of the TSP is the routine use of ICE. ICE can confirm the precise positioning of the needle even in cases with unusual atrial septal anatomies (floppy, bulging, hypertrophic septum or in the presence of devices such as CardioSEAL or other atrial septal defect occlusion devices). Furthermore, ICE can confirm the location of the needle in the LA with microbubble injections after the TSP; it can confirm the location of the wire thus making it safer to advance the sheath knowing that it will not end up in the LAA or causing a perforation. As such ICE is arguably more important in the low fluoroscopy approach than in a one with fluoroscopy.Low fluoroscopy approach to TSP is a welcomed change in the field of electrophysiology given the significant adverse outcomes of radiation and radiation protective clothing to providers. The main concern in such a change is the safety and precise localization of the TSP. New technologies are allowing the development of new approaches such as the one described by Troisi et al to achieve the goal of safe low fluoroscopy procedures.References:Klein LW, Miller DL, Balter S, et al. Occupational health hazards in the interventional laboratory: time for a safer environment. Radiology 2009; 250:538-544.Roguin A, Goldstein J, Bar O, Goldstein JA. Brain and neck tumors among physicians performing interventional procedures. Am J Cardiol 2013;111(9):1368-72.
To the Editor, For the EU funded project PERMEABLE (PERsonalized MEdicine Approach for Asthma and Allergy Biologicals SeLEction), which addresses the availability of and access to advanced therapy of asthma in children across Europe, we performed a survey including 37 major pediatric asthma and allergy centers between September 2019 and July 2020. In total, the centers contributing to the survey treated approximately 1.000 young patients with severe asthma in 25 major European countries and Turkey with biologicals. In the light of the Corona Pandemic, we extended our survey asking the responsible clinicians if they experienced a SARS-CoV-2 infection in any of the children they are caring for. The questions pertaining to Corona infections were asked between March and July 2020.Given the prevalence of SARS-CoV-2 infections in the general population and in children, one would expect that at least 1% of the patients would be affected (1). In fact, none of the centers was aware of any symptomatic COVID-19 case in their patient populations or any positive SARS-CoV-2 tests.This leads to the conclusion, that either SARS-CoV-2 infections have a mild or even asymptomatic course also in children with severe asthma or that children with severe asthma (and their parents) were extremely successful in avoiding SARS-CoV-2 infections. Thus, we investigated by structured interview, how centers in those 26 countries had instructed their patients to avoid COVID-19. Interestingly, only 4 European countries (UK, Ireland, Portugal and Malta) had a strict, so called shielding policy in place which followed a principle of maximal segregation of severe asthmatics from the rest of the population: not leaving the house at all, not attending school even when they reopened, wearing face masks also at home, and social distancing even with family members. All other countries followed the principle of continuing or even enforcing asthma treatment in patients and advising to follow the same Corona rules as the general population.Both strategies led to the same result: An absence of COVID-19 cases in children with severe asthma. We conclude from this observation, that shielding is not necessary in children with severe asthma as they and their families are perfectly able to avoid Corona infections. The harm done to children by enforcing seclusion, separation and stigmatization needs to be acknowledged. Deprivation of school, social contact and friends weights heavy on children and the absence of any COVID-19 cases in major European centers for severe asthma in children does not justify a policy of compulsory shielding of children with severe asthma, neither in the first nor in any further Corona wave.Michael Kabesch, M.D.University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany.Member of the Research and Development Campus Regensburg (WECARE) at the Hospital St. Hedwig of the Order of St. John, Regensburg, Germany.ReferencesStringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study [published online ahead of print, 2020 Jun 11]. Lancet . 2020;S0140-6736(20)31304-0.
Rationale, aims and objectives In the US, the reluctance of the federal government to impose a national stay-at-home policy in wake of COVID19 pandemic has left the decision of how to achieve social distancing to individual state governors. We hypothesized that in the absence of formal guidelines, the decision to close a state reflects the classic Weber-Fechner law of psychophysics- the amount by which a stimulus (such as number of cases or deaths) must increase in order to be noticed as a fraction of the intensity of that stimulus. Methods On April 12, 2020 we downloaded data from the New York Times database from all 50 states and the District of Columbia; by that time all but 7 states had issued the stay-at-home orders. We fitted the Weber-Fechner logarithmic function by regressing the log2 of cases and deaths respectively against the daily counts. We also conducted Cox regression analysis to determine if the probability of issuing the stay-at-home order increases proportionally as the number of cases or deaths increases. Results We found that the decision to issue the state-at-home order reflects the Weber-Fechner law. Both the number of infections (p=<0.0001; R2=0.79) and deaths (p<0.0001; R2=0.63) were significantly associated with the decision to issue the stay-at-home orders. The results indicate that for each doubling of infections or deaths, an additional 4 to 6 states will issue stay-at-home orders. Cox regression showed that when the number of deaths reached 256 and the number of infected people were over 16,000 the probability of issuing “stay-at-home” order was close to 100%. We found no difference in decision-making according to the political affiliation; the results remain unchanged on July 16,2020. Conclusions when there are not clearly articulated rules to follow, decision-makers resort to simple heuristics, in this case one consistent with the Weber-Fechner law.