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

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

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

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

A document by Bedrettin Boyraz. Click on the document to view its contents.

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

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

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

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

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

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

A document by Cristiano Pisani. Click on the document to view its contents.

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

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

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

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

In this issue of BJOG, Mendoza and colleagues report in an observational study the occurrence of a preeclampsia-like syndrome in six out of eight pregnant patients with novel coronavirus disease (COVID-19) who were admitted to the Intensive Care Unit (ICU) with severe pneumonia (Mendoza M, et al. BJOG 2020). There were no symptoms of preeclampsia amongst the 34 pregnant women who had mild forms of COVID-19. Importantly, the authors recorded not only routine laboratory test results, but also measured biophysical and biochemical markers that are typically altered in women with preeclampsia (uterine artery pulsatility index on Doppler ultrasound, serum soluble fms-like tyrosine kinase-1 [sFLT-1] and placental growth factor [PlGF]). Such markers were normal in five of the six cases, in whom the symptoms of preeclampsia resolved after improvement of the maternal clinical situation.The intriguingly high cumulative incidence of preeclampsia symptoms in women with severe coronavirus disease needs to be interpreted with caution due to the observational nature of the study, the small number of pregnant women with severe infection and the possible role of confounding factors. The normal biomarker results in most cases, nevertheless, suggest that severe coronavirus disease can lead to symptoms that mimic those of preeclampsia in the absence of defective placentation, which is further corroborated by the resolution of the symptoms without the delivery of the placenta when overall clinical improvement occurs. It is plausible that such manifestations are the result of widespread inflammation and endothelial damage, in a process that has been denominated “cytokine storm”, responsible for many of the symptoms of the coronavirus-related organ injury (Mehta P, et al. Lancet 2020;395:1033-34) This mechanism includes activation of inflammation pathways that convert arachidonic acid to prostaglandins, thromboxane and eicosanoids, ultimately provoking significant cytokine release. The cascade of events, however, does not appear to influence the levels of specific preeclampsia angiogenic and anti-angiogenic markers such as sFLT-1 and PlGF.A normal sFLT-1: PlGF ratio in women with clinically suspected preeclampsia can be reliably used predict the short-term absence of disease (Zeisler H, et al. N Engl J Med 2016;374:13-22). Although the definition of preeclampsia has changed over the last 20 years to incorporate less specific clinical features of end-organ damage, biomarkers will likely become part of the disease definition in the years to come or, at least, a valuable tool to select subgroups of women at higher risk of preeclampsia-related morbidity and mortality who require closer monitoring or immediate delivery.While larger cohorts derived from national datasets or international registries of coronavirus disease in pregnancy will be essential to confirm or refute this association, the preliminary data published in this study indicate that delivery during severe coronavirus disease should not be based on preeclampsia symptoms alone, particularly at early gestational ages, and that the use of ultrasound and serum biomarkers such as the sFLT-1: PlGF ratio might help to guide clinical management by distinguishing hypertension and endothelial dysfunction caused by COVID-19-related inflammation from true preeclampsia.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Rapid environmental change forces long-lived plants like trees to immigrate into zones still occupied by phylogenetically distantly related species. Does such phylogenetic isolation (PI) change the trees’ ecosystem functioning such as litter decomposition? We studied oaks (Quercus petraea) of low and high PI, reciprocally transplanting their litters to identify effect of aboveground litter quality and belowground decomposer biota. Across 8 and 14 months we quantified decomposition (mass loss, C-loss and N-loss), decomposer biota (Acari, Collembola, microbes) and 13C/12C ratio. Across 14 months, aboveground PI retarded decomposition (mass and C loss). Across 8 and 14 months, above- and belowground PI extensively altered relationships between decomposition and abundances/diversities of different soil biota, reduced microbial activity and 13C/12C ratios. Overall, coexistence of trees with distant relatives impedes and severely re-organizes C and N recycling. Such negative ecosystem feedback might prevent trees from tracking and conserving abiotic niches under environmental change.

Ectotherms in cold environments often spend long winters underground. In 1941 Raymond Cowles proposed a novel ecological trade-off involving depth at which ectotherms overwintered. On warm days, only shallow reptiles could detect warming soils and become active; but on cold days, they risked freezing. Cowles discovered that most reptiles at a desert site overwintered at shallow depths. To extend his study we compiled hourly soil temperatures (5 depths, 90 sites, continental USA) and physiological data, and then simulated consequences of overwintering at fixed depths. In warm localities shallow ectotherms have low energy costs and largest reserves in spring; but in cold localities, shallow ectotherms risk freezing. Ectotherms shifting to the coldest depth potentially reduce energy expenses, but paradoxically sometimes have higher expenses than those at fixed depths. Biophysical simulations for one desert site predict that shallow ectotherms should have elevated opportunities for mid-winter activity but may need to move deep to digest captured food. Our simulations generate testable eco-physiological predictions but rely on physiological responses to acute cold rather to natural cooling profiles. Furthermore, testing ecological predictions requires natural-history data that do not exist. Thus, our simulation approach uncovers “unknown unknowns” and suggests research agendas for studying ectotherms overwintering underground.

Under the unprecedented pressures of the global coronavirus disease 2019 (COVID-19) pandemic, there is an urgent requisite for successful strategies to safely deliver cardiac surgery. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first described in early December 2019, and the rapid spread and emergence of this virus has caused significant disruptions in the delivery of healthcare services worldwide.1,2 In particular, provision of cardiac surgery has been disproportionally affected due to reallocation of intensive care resources, such as ventilators.2Additionally, patients with pre-existing cardiovascular disease are likely to have comorbidities which are associated with poorer clinical outcomes in confirmed SARS-CoV-2 cases.3,4 Despite this, Yandrapalli and colleagues have reported the first case of a successful coronary artery bypass graft (CABG) operation in a patient with asymptomatic SARS-CoV-2 infection, which offers insights into how cardiac surgery could be adapted to solve the challenges of this pandemic.5In response to the burden of COVID-19 on healthcare systems in the United Kingdom (UK), elective cardiac surgeries have been delayed owing to the redistribution of intensive care resources and the unquantifiable risk of acquiring COVID-19.2 Likewise, cardiac surgery services have undergone structural remodelling into a centralised system in an attempt to continue provisions of emergency surgery alongside hospital management of COVID-19 patients.2Unsurprisingly, most cardiac surgery units across the globe have seen a sharp decline in surgeries as a result, and one unit reported an 83% reduction in cardiac index cases between 23rd March to 4th May 2020.2 Similar models have been used in Europe to manage healthcare services and increase intensive care capacity. For example in the Lombardy region of Italy, 16 out of 20 cardiac surgical units discontinued services and all urgent cases have been consequently diverted to the remaining four units for centralised services.6 Whilst these measures have been beneficial for supporting the focused management of COVID-19 patients, it is important to reflect upon the future consequences of delayed elective cardiac surgery. Indeed, such patients are likely to have progressive conditions and further work is needed to investigate the long-term impact of COVID-19 on mortality and morbidity in this cohort.The case report by Yandrapalli and colleagues highlight the importance of routine SARS-CoV-2 testing for all patients requiring cardiac surgery, especially for detecting asymptomatic or subclinical infections.5 Active SARS-CoV-2 infection may precipitate an overproduction of early response proinflammatory cytokines in post-operative period, leading to unfavourable surgical outcomes.7,8 Moreover, preliminary studies have shown that patients with established cardiovascular diseases may have a greater risk of increased SARS-CoV-2 infection severity and prognosis.9 Taken together, assessment for active infection is crucial for risk stratification. In addition, clinicians should consider the threshold for surgery when selecting patients for cardiac surgery. An international, multi-centre cohort study by COVIDSurg Collaborative which included 1128 confirmed SARS-CoV-2 patients undergoing a broad range of surgeries revealed that 30-day mortality risk was significantly associated with the patient demographics of male sex, an age of 70 years or older, and poor preoperative physical health status.10 Collectively, the risks and benefits of cardiac surgery should be carefully considered in such patients due to higher mortality risk.10Alternative therapeutic procedures with rapid discharge, such as percutaneous intervention or medical therapy, may be more appropriate to reduce SARS-CoV-2 related mortality and nosocomial infection risk.11Current evidence is limited for postoperative outcomes in cardiac surgery cases. In the aforementioned cohort study by COVIDSurg Collaborative, the 30-day mortality rate was 23.8%.10In addition, the study reported that 51.2% of patients had postoperative pulmonary complications, which was associated with a higher mortality rate of 38.0%.10 In another case report describing an emergency CABG operation, the asymptomatic patient succumbed to pulmonary complications arising from a SARS-CoV-2 infection confirmed postoperatively.12 The authors acknowledge that the undiagnosed infection may have triggered a refractory pathological response after cardiac surgery. Indeed, recent literature has suggested that patients with SARS-CoV-2 are at higher risk of developing thromboembolisms, possibly mediated by the interaction with angiotensin-converting enzyme 2 (ACE2) receptors.13Similarly, there is a consensus that SARS-CoV-2 has direct adverse effects on the myocardium due to high expression of ACE2.14 As such, SARS-CoV-2 can potentially trigger multisystem complications which require vigilant monitoring, especially in patients requiring cardiopulmonary bypass and at high risk of developing thromboembolisms. Cardiac surgery patients represent a vulnerable patient population, and this cohort may experience worse outcomes with SARS-CoV-2 infection based on the current available evidence. In the latest recommendation, UK currently advises all patients who are listed for elective cardiac surgery to self-isolate for 14 days prior to surgery date, in a measure to limit and contain the exposure of such cohort to the smallest possibilities of acquiring COVID-19.Currently, the future of cardiac surgery after the pandemic is unclear as the evidence is still emerging. However, the lessons learnt from these unprecedented times can be taken forward to inform future service planning. Moving forwards, routine screening of patients for SARS-CoV-2 infection will undoubtedly play a key role in identifying asymptomatic or subclinical infections. The preoperative UK National Health Service testing recommendations should be broadened so that all patients undergoing cardiac surgery are screened, given the higher risk of postoperative complications in this population. Similarly, repeat testing is important for monitoring patients for concomitant infections. Alongside changes to hospital protocol, service delivery will inevitably shift. The successful application of telemedicine during the pandemic has already been reported in the delivery of oncology services.15 Moreover, the benefits of telecardiology outside of the COVID-19 era have been previously reported, and cardiology services will likely embrace the utilisation of telemedicine for managing outpatient consultations.16 Units will also have to address the vast backlog of surgeries caused by cancellation of elective cardiac operations in a sustainable manner, with adequate hospital space and personal protective equipment availability.17 In order to resume success services, planning for this eventuality should begin now and patients at significant mortality risk due to delayed surgery need to be prioritised.Ultimately, clear guidelines should be implemented to ensure safe resumption of surgical services, whilst also reassuring patients concerned about safety.3 Whilst the future trajectory of this pandemic is uncertain, the insights from the impact of COVID-19 on cardiac surgery will undoubtedly shape the future delivery of cardiac surgery.

Mirror syndrome is a rare disease associated with a high fetal mortality of up to 67.2%. It is thought to be underdiagnosed and is often mistaken for preeclampsia. Mirror syndrome is characterized by ‘triple edema’: generalized maternal, placental, and fetal edema. A comprehensive search of several databaseswas conducted. Mirror syndrome is associated with high fetal morbidity and mortality; it is an important differential diagnosis with pre-eclampsia and thought to be currently underdiagnosed. Minimal is known about its pathogenesis. Maternal symptoms usually regress with resolution of pregnancy and management is dependent on the cause of fetal hydrops.

Objective To explore the effect of different delivery modes, vaginal delivery compared to caesarean section with or without initiation of labour, on the immune system and brain of the infants. Further, we aimed to elucidate gender and gestational ages’ effect on these biomarkers. Design Retrospective case control study Setting Dried blood spots from new-born screening biobank drawn 2-4 days after birth Population or Sample Mature new-borns divided into delivery by pre-labour (n=714), in-labour caesarean section (n=655), and vaginally (n=5897). Method The samples were analysed for inflammatory markers (IL-18, MCP-1, CRP, sTNF RI), stress- (HSP-70), growth- (EGF, VEGF-A), and neurotrophic factors (BDNF, NT-3, S100B). Main Outcome Measures Delivery by caesarean section with or without initiation of labour Results The neonatal levels of inflammatory and stress-markers were significantly lower, while the levels of growth factors were higher after pre-labour caesarean section compared to vaginal delivery. The biomarker levels were similar after in-labour caesarean section and vaginal delivery. Males had generally higher levels of inflammation and lower levels of growth and neurotrophic factors. Overall, the levels of inflammatory markers increased, and the growth factors decreased with increasing gestational age. Conclusion The biomarker levels indicates that the labour process has an important effect on the foetal immune system and level of stress, regardless if the delivery ends with caesarean section or vaginal birth. Funding ”Læge Sofus Carl Emil Friis og hustru Olga Doris Friis’ legat” and ”Fonden til Lægevidenskabens Fremme”. Keywords Inflammation; brain; CODIBINE; caesarean section; dried blood spot samples

Objectives Otorhinolaryngology trainees in the United Kingdom are required to perform ten septorhinoplasty procedures as the main operating surgeon in order to achieve a certificate of completion of training (CCT). The COVID-19 pandemic has profoundly reduced operative opportunities for surgical trainees around the world. Our aim was to assess UK otorhinolaryngology trainees’ perceptions of their septorhinoplasty training in the pre-COVID-19 era and frame this within the current training environment brought about by the COVID-19 pandemic. Design Cross-sectional survey. Setting United Kingdom. Participants UK otorhinolaryngology trainees. Main outcome measures Information on trainees’ previous operative experience, courses attended, learning materials used and challenges faced gaining septorhinoplasty training was collected. Results 64 trainees responded. All Deaneries and Local Education and Training Boards were represented. 63/64 (98.4%) trainees had operative exposure septorhinoplasty. 60/64 (93.8%) trainees were currently at a trust where septorhinoplasty was performed. A variety of challenges regarding septorhinoplasty training were highlighted, the most common problem being the low number of cases being performed. Nearly one-third (8/25) of ST7-8 trainees in this sample had still not yet performed a septorhinoplasty on at least one occasion even though they were into the final third of their training. Conclusions The COVID-19 pandemic is a new and additional threat to septorhinoplasty training for otorhinolaryngology trainees, particularly those in the final third of the programme. In the short term, clarification is required on what level of operative proficiency is required for a CCT. Longer-term, threats to training can be mitigated by providing cadaveric courses, embracing simulation and considering private sector placements in areas of low NHS volume.

Rationale, aims, and objectives An inefficient health system wastes scarce resources even if it makes considerable gains in accountability and equity. Such a system is expected to perform better. Therefore, it is vital to examine the current performance of health systems and their constituents as well as assess how to reach their full potential. The aim of this study was to evaluate the technical and economic efficiency of medical diagnostic laboratories in hospitals affiliated with Urmia Medical Sciences University (UMSU) in 2016. Methods In this descriptive-analytical study, the data of all diagnostic laboratories of the hospitals of UMSU were inputted into Frontier 4.1 software after taking the logarithm. Then, the technical and economic efficiency of the laboratories were obtained by estimating the production and cost function using the stochastic frontier analysis method, assuming input minimization for 2016. Results The average technical and economic efficiency of the diagnostic laboratories was obtained as 0.931±0.34 and 0.519±0.33, respectively. These laboratories must reduce their inputs and costs to achieve full efficiency without changing the amount of their output. Conclusion Although the average economic efficiency of the diagnostic laboratories of the studied hospitals was high, there is still an increase in the efficiency of these units given the cost of inputs at the time of allocating resources. In addition, it is possible to improve the technical efficiency of the clinical laboratories of hospitals affiliated with UMSU by 48.1% by applying the same level of inputs and without increasing the costs.