B-LINES IN COVID-19: “UNSPECIFICITY” IS NOT “MEANINGLESS”Luigi Vetrugno1,2 MD, Prof, Tiziana Bove1,2 MD, Prof, Daniele Orso1 MD, Federico Barbariol2 MD, Flavio Bassi2 MD, Enrico Boero3 MD, Giovanni Ferrari4 MD, Robert Kong5MD, FRCA, EDIC,1Department of Medicine, University of Udine, ItalyAnesthesia and Intensive Care ClinicVia Colugna n° 50, 33100 Udine, Italy2University-Hospital of Udine, ItalyDepartment of Anesthesia and Intensive CareP.le S. Maria della. Misericordia n° 15, 33100 Udine, Italy3Anesthesia and Intensive Care, San Giovanni Bosco Hospital, Torino, Italy4SC Pneumologia ad Indirizzo Semi Intensivo, Azienda Ospedaliera Ordine Mauriziano. Largo Turati 62 – Torino, Italy5 Cardiac Anaesthesia & Intensive Care, Brighton & Sussex University Hospital, Brighton BN2 5BE United KingdomShort title: lung ultrasound and B-lines*Corresponding author:Prof. Luigi Vetrugno, MDDepartment of Medicine, University of Udine, ItalyAnesthesia and Intensive Care ClinicVia Colugna n° 50, 33100 Udine, ItalyPhone: +39 0432 559509Fax: +39 0432 559502Financial Support and Sponsorship: None.Conflict of Interest: Luigi Vetrugno received travel support for Congress Lecture by Cook Medical.The other authors declare no conflict of interest.Key works: Lung Ultrasound; interstitial syndrome, COVID-19, B-lines.Authors’ contributions LV and DO concept, design and drafting the manuscript. TB, FB, EB, FB, GF critical revision of the manuscript for important intellectual content. RK critical review and editing the manuscript. All authors read and approved the final manuscript.We thank Prof. Trovato and Dr Sperandeo for commenting on our article.1 We agree with them that lung ultrasound (LU) imaging is useful and our aim was to provide readers with a succinct overview of how LU was used in the care of COVID-19 patients at two centres in Italy.2 The frequent finding in COVID-19 patients of lung consolidation at the inferior and basal regions means that one of the limitations of LU, which is to perform a complete assessment of the periphery of the lungs, is mitigated, as affected regions are not obscured by the scapula. Other authors have shown that in COVID-19 patients, LU provided results similar to those of computed tomography (CT) of the lung and superior to those of standard chest x-rays.3-5 Therefore, LU provides clinicians with another mode of lung imaging that can be performed non-invasively and without the logistic challenges of obtaining CT lung scan in these patients, as is well-known to centers who have been faced with a large caseload.6 As stated in our article, we have not identified an LU finding that is pathognomonic of COVID-19.1-7 However, the presence of B lines in several different clinical situations does not decrease their significance. In medicine, many signs are frequent in various diseases, like fever, but this is not a good reason to underestimate or not consider them at all. Furthermore, emerging ultrasound image analysis based on artificial intelligence and deep learning has the potential to further enhance the utility of LU.8-9 Although caution is needed in terms of exaggerating the power of LU, we hope it will continue to be used widely after the pandemic.ReferencesSperandeo M, Trovato G. Usefulness of lung ultrasound imaging in Covid-19 pneumonia: the persisting need of safety and evidences. Echocardiography. in press (ECHO-2020-0386)Vetrugno L, Bove T, Orso D, et al. Our Italian experience using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with COVID-19. Echocardiography. 2020;37:625‐627. doi:10.1111/echo.14664Huang Y, Wang S, Liu Y. A Preliminary Study on the Ultrasonic Manifestations of Peripulmonary Lesions of Non-Critical Novel Coronavirus Pneumonia (COVID-19). SSRN. 2020. doi: 10.21203/rs.2.24369/v1Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7:4. doi: 10.1186/s40779-020-0233-6Convissar D, Gibson LE, Berra L, Bittner EA, Chang MG. Application of Lung Ultrasound during the COVID-19 Pandemic: A Narrative Review [published online ahead of print, 2020 Apr 30]. Anesth Analg. 2020;10.1213/ANE.0000000000004929. doi:10.1213/ANE.0000000000004929Wang E, Mei W, Shang Y, et al. Chinese Association of Anesthesiologists Expert Consensus on the Use of Perioperative Ultrasound in Coronavirus Disease 2019 Patients [published online ahead of print, 2020 Apr 10]. J Cardiothorac Vasc Anesth. 2020;S1053-0770(20)30325-6. doi:10.1053/j.jvca.2020.04.002Vetrugno L, Bove T, Orso D, Bassi F, Boero E, Ferrari G. Lung Ultrasound and the COVID-19 ”Pattern”: Not All That Glitters Today Is Gold Tomorrow [published online ahead of print, 2020 May 8]. J Ultrasound Med. 2020;10.1002/jum.15327. doi:10.1002/jum.15327Corradi F, Brusasco C, Vezzani A, et al. Computer-aided quantitative ultrasonography for detection of pulmonary edema in mechanically ventilated cardiac surgery patients. Chest 150:640‐651, 2016 doi:10.1016/j.chest.2016.04.013Gullett J, Donnelly JP, Sinert R, et al. Interobserver agreement in the evaluation of B-lines using bedside ultrasound. J Crit Care. 2015;30:1395-1399 doi:10.1016/j.jcrc.2015.08.021
Since the beginning of the 21st century, three coronaviruses have crossed the species barrier and caused serious human disease: severe acute respiratory syndrome coronavirus (SARS-CoV) in November 2002 [1, 2], Middle-East respiratory syndrome coronavirus (MERS-CoV) in 2012 [3, 4], and SARS-CoV-2 in 2019 [5, 6]. SARS-CoV-2 , initially called 2019-nCoV, is the etiological agent of COVID-19, a highly contagious infectious illness that was first reported in December 2019 in Wuhan, China and subsequently spread globally . As of May 24, 2020, COVID-19 has caused >5,370,000 infections and >343,000 deaths worldwide .Unfortunately, nearly 20 years after the SARS outbreak, and despite many attempts for vaccines and therapeutic agents directed against SARS and MERS, no approved prophylactics or therapeutics exist. As a result, the management of COVID-19 largely relies on supportive care [10, 11] and on hopes surrounding compounds that appeared promising against previous coronaviruses [12, 13]. This lost opportunity, in itself, offers a valuable lesson for current and future outbreaks, and the need for new experimental rationales to accelerate discovery.The cellular entry of coronaviruses is fairly conserved across members of the Coronaviridae family and is mediated by the transmembrane spike (S) glycoprotein , a homotrimer [15, 16] that is often heavily glycosylated  and protrudes from the viral surface. Each of the three monomers of the spike glycoprotein consists of two functional subunits, S1, involved in membrane attachment, and S2, required for membrane fusion [15, 18]. In many coronaviruses, the spike glycoprotein is cleaved at the S1/S2 interface by host cell proteases . Within the S1 domain, the receptor binding domain (RBD) attaches to the cellular receptor, which in the case of both SARS-CoV and SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2) [19-21]. Another cleavage site, S2’, is located within S2 [17, 19]. The spike glycoproteins of SARS-CoV and SARS-CoV-2 share 76% identity at the amino acid level [22, 23], although biophysical assays indicate that SARS-CoV-2 binds their common receptor, ACE2, with a 10-20 fold higher affinity than SARS–CoV .As we contemplate the dynamics of COVID-19 and the development of prophylactic and therapeutic interventions, one of the key considerations is the emergence and potential relevance of viral mutations. In the short time since the pandemic started, several missense mutations have been observed in various SARS-CoV-2 isolates . One of these, the 23403A>G variant, substitutes the aspartic acid at position 614 of the viral spike glycoprotein with glycine (D614G), and is frequently documented in European countries but rarely observed in China .In the current issue of the IJCP , Becerra-Flores and Cardozo interrogate the impact of this mutation on pathogenicity and offer a structural correlate for their findings . Their analysis includes confirmed COVID-19 cases and deaths as reported by the European CDC during the first week of April 2020 and examines the viral spike genomic sequences deposited in the GISAID database over that period, correlating the prevalence of the D614G mutation with fatality rates in the same regions. The authors then use cryo-electron microscopy data andin silico mutagenesis of this key residue to predict conformational preferences of the two variants of the spike protein.The analysis indicates that viruses isolated from European patients predominantly expressed a glycine at position 614 of the spike glycoprotein, while a high percentage of the isolates collected from Far East patients favored aspartic acid at the same position. The proportion of viral isolates having a glycine at this position significantly correlated with higher average and median case fatality rates across geographic areas. Interestingly, their data also imply a rationale for divergence in the behavior of the disease between the East and West coasts of the United States, based upon the provenance of the viral ‘founders’ in these regions, from the European and Asian variants, respectively.Surprisingly, the authors’ molecular modeling indicates that the presence of a glycine at position 614 diminishes binding to the cellular receptor when replacing the aspartic acid at that residue, mainly by reducing the spike protein’s occupancy of the “up” or liganded state, when it is most amenable to receptor interaction. While seemingly counterintuitive, this finding opens at least two fascinating scenarios. As the authors hypothesize, a spike glycoprotein that harbors glycine at this position might be better protected from immune recognition, elicit the production of harmful antibodies, flood the host with ineffective antibodies, or some combination of all three. A delay in immune recognition may impact viral transmission by delaying symptomatic presentation or allowing unfettered infection without effective immune response. An aberrant response, suited to the viral conformation at large but not the infective conformation, could equally allow for an increased—but poorly targeted—inflammatory cascade. The possibility of a harmful immune response is particularly thought provoking, as antibody-dependent enhancement, the phenomenon by which antibodies facilitate viral entry into host cells that do not necessarily have viral receptors [27, 28], has been reported for many viruses, including coronaviruses [27, 29], dengue virus [30, 31], feline infectious peritonitis virus  , Ebola virus , and HIV . Another possibility, not mutually exclusive, is that the D614G mutation creates or exposes a novel cleavage site in the spike glycoprotein.Delving into these molecular mechanisms with confirmatory in vitro studies will hopefully reap the benefits of decades of scientific strides while simultaneously highlighting deficiencies in key areas that can guide our approach to the current pandemic. One of the immediate questions involves the impact of this and other mutations on vaccine efficiency and the potential need to develop multiple candidate vaccines that cover a range of epitopes and their variants. In all likelihood, there is a lengthy and tortuous road ahead, but characterizing significant variants will allow us to better understand many elusive aspects of this virus’ success – the latent/incubation period, immune evasion and hyper-response, variable receptor binding, replication dynamics, and organ-specific pathogenesis—and discover host vulnerabilities that mutations such as D614G seem to exploit.The D614G mutation appears to become more common as the pandemic unfolds . That this phenomenon is simply the result of a founder effect is possible but unlikely, and rather may be explained by this variant’s selective advantage allowing more efficient spread. Whether this advantage is conferred by infectivity, immune evasion, or pathogenicity—or some combination of these—is yet to be understood. Interestingly, this mutation is now known to travel simultaneously with other mutations, including one that affects the RNA-dependent RNA polymerase, with implications for proofreading, replication efficiency (and thus viral titer), and the emergence of drug-resistant viral phenotypes .Addressing these molecular questions relies heavily on widespread efforts to assemble accurate and comprehensive data on population infection rates and mortality, and frequent sampling of the genotypes of circulating isolates on a global basis. So far, this feat has been challenging and continued deficiencies will translate into missed singular opportunities to link molecular findings with population-level consequences, ultimately leaving us less prepared to address both this and future pandemics.The valuable and timely experimental strategy used by Becerra-Flores and Cardozo serves as an important analytic model that should be employed routinely to understand the ‘molecular strategy’ of this virus in the context of the evolving pandemic. This approach will also prove to be an indispensable instrument if also employed routinely at the onset of future outbreaks, which are all but guaranteed in the coming years, given the only recently appreciated ease of global spread of viruses in the modern world. In summary, this set of tools allows us to perform active surveillance, monitor the emergence of deleterious mutations prior to their widespread distribution, and use informed in silico and structural data to make informed decisions guiding molecular research and epidemic preparedness.
Combined use of hydroxychloroquine and azithromycin was globally adopted, in part due to paucity and high cost of alternative therapies. However the utility of these medications has been questioned; and thus safety becomes a major concern given clinical equipoise regarding efficacy. Both hydroxychloroquine and azithromycin continue to be administered in US clinical trials examining their potential role in prevention of infection, treatment of mild infection in ambulatory patients, and in combination with other medical regimens in treatment of patients with severe disease. These drugs also continue to be clinically utilized in hospitalized patients around the globe, often without continuous telemetry due to lack of resources. Concern regarding use of hydroxychloroquine without adequate rhythm monitoring in clinical trials has been recently expressed.1 A review of clinicaltrials.gov at the time of submission of this correspondence reveals actively recruiting trials of combined hydroxychloroquine/azithromycin with or without additional COVID-19 therapies, for both ambulatory and hospitalized patients within and outside the US. The potential for hydroxychloroquine and azithromycin to cause QT prolongation is counterbalanced by very low risk of pro-arrhythmia in the general population, and emerging evidence of relatively low risk of Torsades de Pointes (TdP) in COVID-19 patients.2,3,4,5 Thus delineation of the determinants of significant QTc prolongation and pro-arrhythmic risk for hydroxychloroquine/azithromycin is very important, especially given mounting evidence of inefficacy in COVID-19 treatment.
Dear Editor,We would like to comment on the systematic review by Li et al.(1)The use of steroid hormones in the first trimester is a serious issue as organogenesis takes place at this time and therefore there is the possibility of harm from not only congenital anomalies, but also long-term, and even inter-generational effects. Anyone investigating the use of steroid hormones in the first trimester should remember the diethylstilbestrol legacy of devastating harm. Oestrogen (C18H24O2) and diethylstilbestrol (C18H20O2) have similar molecular composition, but their effects are poles apart. In this review, the authors have combined progesterone with progestogens; however they are not the same, in the same way that oestrogen and diethylstilbestrol are not the same. Vaginal micronized progesterone, which we used in our large and high-quality trials (the PROMISE (2) and PRISM (3) trials), has identical molecular structure to natural progesterone, but the other drugs included in this review do not (Table 1). We chose to study vaginal micronized progesterone, as it is identical in structure to natural progesterone, and the available evidence and expert opinion suggested that this is least likely to cause harm. It is important to note that there is evidence of potential harm from dydrogesterone, particularly congenital heart disease.(4)The authors make a bold statement in the abstract about the effects of dydrogesterone on live birth rate. However, they don’t fully address the weaknesses in the evidence. Therefore, we wish to highlight the significant deficiencies in the two trials that contributed live birth data that led to the assertion of beneficial effects from dydrogesterone. Both studies were single centre, open-label studies without placebo control. El-Zibdeh et al did not randomise participants, but instead allocated patients to dydrogesterone on Saturdays, Mondays and Wednesdays, and to no treatment on Sundays, Tuesdays and Thursdays. The trial by Pandian RU was not just a single-centre, but also a single-author study, with insufficient details of the methods to assess its quality. Thus, the effectiveness evidence from these trials cannot be considered reliable.Approximately 80% (4038 of 5056) of the data used in this systematic review come from our PRISM trial.(3) The PRISM trial is a prospectively-registered, randomised, placebo-controlled, multi-centre trial conducted to the highest standards in the UK. The trial found a 3% increase in live birth rate, but with borderline statistical significance (RR, 1.03; 95% CI, 1.00 to 1.07; P=0.08). A pre-specified subgroup analysis in women with the dual risk factors of current pregnancy bleeding and one or more previous miscarriages found a 5% increase in live birth rate (RR, 1.09; 95% CI, 1.03-1.15; P=0.003). In those with three or more previous miscarriages, a 15% increase in live birth rate was observed (RR, 1.28; 95% CI, 1.08 to 1.51; P=0.004).(3, 5) No short-term safety concerns were identified. Based on these data, our recommendation is to consider vaginal micronized progesterone for women with early pregnancy bleeding and one or more previous miscarriages. As for the role of dydrogesterone, we need not only high-quality, randomised trial evidence of its effects but also credible evidence of its safety. As dydrogesterone is a synthetic progesterone-like drug, i.e. a progestogen but not progesterone, the burden of proof to demonstrate short- and long-term safety rests on those promoting this drug.
Dear EditorBirth Trauma organisations advocate on behalf of women and babies who have experienced adverse outcomes and naturally they will take a risk-averse perspective on birth-related care. The latest version of the Assisted Vaginal Birth (AVB) RCOG Guideline (previously called Operative Vaginal Delivery) has focussed specifically on revisions designed to minimise the risk of traumatic injuries for the mother and baby.1 The landmark Montgomery ruling that raised the bar on the standard required for informed consent has been embraced and endorsed within the guideline. 2 It is disappointing to read that Hull et al have concluded that “Montgomery is missing from RCOG’s Assisted Vaginal Birth guideline”.3Hull et al have acknowledged the important counselling advice that has been recommended – antenatal discussion about AVB when planning birth in the third trimester (especially for first-time mothers), review of birth preferences when conducting routine labour ward rounds, and in depth counselling, where circumstances allow, if complications arise during the course of labour particularly during the second stage. However, the guideline apparently falls short of the Montgomery ruling in that we have not recommended “planned caesarean” as an option to prevent assisted vaginal birth.The AVB guideline went through an extensive scoping process. The agreed scope was to address all key questions that arise in relation to labouring women who may require obstetric assistance in the second stage of labour - the assumption being that these women have the intention to labour and deliver vaginally. A guideline addressing maternal request “planned” caesarean section is an entirely different guideline. It is also incorrect to state that the RCOG have provided no direct guidance on this (see Choosing to have a Caesarean section , RCOG Patient Information (2015) based on NICE Clinical Guideline Caesarean Section (2011)).4 The issue of pelvic floor morbidity was included in the literature search and has been discussed in detail.The Montgomery ruling related to a woman with diabetes in pregnancy and a large for gestational age fetus who experienced shoulder dystocia resulting in her baby developing cerebral palsy. The importance of outlining, in advance, the birth options for this woman is clear, given the specific known risks associated with labour in her circumstances. Hull et al suggest on the same basis that all women should be advised that a planned caesarean section is an option to prevent assisted vaginal birth. If taken one step further the Montgomery ruling could be cited to support the argument that all women should be advised that the best way to avoid pregnancy-related complications is to avoid getting pregnant. Common sense would infer that this was not the intention of the Montgomery ruling.Where this RCOG guideline is likely to be consistent with Birth Trauma organisations is in the recommendations on careful assessment, supervision and decision-making; clear communication and transparent consent procedures; and an overall approach that places safety as the first priority when deciding when and when not to attempt a vacuum or forceps assisted delivery, and when to discontinue any such attempt. It is hoped that all relevant health professionals will review and implement the evidence-based, peer-reviewed recommendations within this guideline. They are designed to support women in achieving safe and joyful births, even when obstetric assistance is required.Deirdre J Murphy,1 Rachna Bahl,2Bryony Strachan21) Coombe Women & Infants University HospitalCork St, Dublin 8, Republic of Ireland2) St Michael’s Hospital, Bristol
Letter to the EditorCoronavirus disease COVID-19 has deeply modified national health services with a profound impact on hospital and in particular emergency and intensive care units (ICU) activities. As recently reported in Italy pediatric emergency accesses substantially decreased likely due to the instructions to prevent overcrowding in emergency rooms and spread of SARS-CoV-2 infection and to fear of the infection.1 At the Santobono-Pausilipon Hospital (Neaples), pediatric emergency accesses in March 2020 were only one fifth of those registered in 2019 in the same period. Likewhise a marked reduction of consultations occurred also in family pediatricians clinics.2We report here 3 children who arrived at hospital in life-threatening conditions at the onset of Acute Lymphoblastic Leukemia (ALL) between March 14 and April 10, 2020.First case: a 2-year-old-child arrived at the emergency department with a 15 days history of fatigue, pallor and dyspnea, in a comatose state, with severe anemia, respiratory distress, hematemesis and metabolic acidosis. Chest X-ray showed interstitial pneumonia. Blood tests showed: hemoglobin 2.7 gr/dL, WBC count 185.000/μl, platelets (PTL) 10.000/μl, LDH 3609 U/L. Peripheral blood was diagnostic for CD10, CD19 and CD58 positive ALL (B-lineage ALL). The patient, admitted at the ICU, intubated, transfused with RBC, PTL and plasma, died 12 hours after arrival at the hospital due to progressive worsening of clinical conditions. The nasal swab was negative for SARS-CoV-2 and positive for adenovirus.Second case: a 5-year-old-child arrived at the emergency department with a one month history of respiratory distress. Imaging showed a mediastinal mass compressing the brachiocephalic vein, the aorta, the pulmonary trunk and the left pulmonary artery, tracheal deviation, compression of the left main bronchus, left lung atelectasis and pleural effusion. Blood tests showed: hemoglobin 14.5 gr/dL, WBC count 37.000/μl, PTL 294.000/μl, LDH 6153 U/L, creatinine 1.9 mg/dl. Peripheral blood was diagnostic for CD5, CD7, CyCD3 and CD8 positive ALL (T-ALL). Steroid treatment was started. Clinical conditions deteriorated rapidly with cardiac and renal failure. The patient, admitted to ICU 2 hours after arrival at the hospital and intubated, died 24h later. The nasal swab was negative for SARS-CoV-2.Third Case: a 4-year-old child arrived at the hospital with one month history of fever, cough and shortness of breath treated at home with antibiotics and steroids without improvement. Imaging showed a mediastinal mass compressing the left brachiocephalic, azygos and superior cava veins, and right pulmonary artery and vein; mild tracheal deviation, compression of the left main bronchus; pericardial and pleural effusion; nephro-hepato-splenomegaly and ascites. Due to signs of cardiac tamponade, pericardiac and pleural drainage were placed and the patient was admitted at ICU and intubated. Blood tests showed: normal hemoglobin, WBC and PTL counts; LDH 2732 U/L, creatinine 2.98 mg/dl, K 8 mEq/L, Ca 5.4 mEq/L. Bone marrow was diagnostic for CD2, CD5, CD7, CD99 and CyCD3 positive ALL (T-ALL). Treatment with steroids was started. Due to progressive renal failure hemodialysis was performed for 9 days. Clinical conditions improved with rapid shrinking of mediastinal masses and resolution of pericardial and pleural effusion. The patient was thus extubated and treatment for ALL was instituted with good response to induction therapy. The nasal swab was negative for SARS-CoV-2.The 3 cases of ALL here described, 2 of them fatal, arrived at the hospital in critical conditions, most likely as a consequence of fear of COVID-19. Delay in diagnosis of neoplastic disease is a well-known problem in low-middle income countries (LMIC), but is quite rare in high-income countries (HIC). Actually, this combination of events never occurred in the past at the Santobono-Pausilipon Hospital, where, at the time of writing, no SARS-CoV-2 positive cases have been identified among children treated for cancer.Considering low prevalence of virus spreading in children and that SARS-CoV-2 positive children are generally asymptomatic or have a very mild course of the disease there is a substantial risk that collateral effects of COVID-19 pandemic, i.e. delays in diagnosis, chemotherapeutic treatments and treatment of chemotherapy complications, may be worse than those posed by the disease itself.3,4,7 Recently the major pediatric cancer scientific associations have expressed great concern on the risk that fear to access to medical care raised by Covid-19 may cause these delays not only in LMIC but also in HIC with dramatic consequences we are not used to face.5-6 Our experience confirms the occurrence of these collateral effects, indicating that there is a need of awareness of this risk and careful medical attention to assure timely diagnoses and adequate treatment adherence in childhood cancer.
Double-outlet left ventricle (DOLV) is a rare congenital cardiac anomaly. The aorta and the main pulmonary arterial trunk arises predominantly from the left ventricle(LV) and is associated with a malaligned ventricular septal defect(VSD), various degrees of hypoplasia of the right ventricle, and presence or absence of pulmonary stenosis. Bi-ventricular repair is the preferred treatment option whenever possible. Various techniques for bi-ventricular repair have been described. The best option for DOLV correction is by translocating the pulmonary root to the right ventricle(RV). In this series, we report four patients who underwent biventricular repair of DOLV in our institute with excellent outcomes. All patient details were collected from the institute patient record system. Echocardiographic data were obtained from the records. Intraoperative charts were reviewed for further information on the surgical procedure and cardiopulmonary bypass. Postoperative data included survival, functional status and followup echocardiography. Of the four children, three underwent pulmonary root translocation and one child underwent Reparation al etage Ventriculaire(REV) procedure. There was no mortality and all children are in stable clinical condition in the recent follow-up and no re-operations or interventions were required following primary surgical correction. Thus DOLV is anatomically and surgically a challenging subset. Pulmonary root translocation in this anatomy is technically challenging but safe and superior option when compared to other alternative surgical procedures and it can be performed with excellent results, even in infants.
While there is significant awareness regarding droplet and contact transmission, aerosols are generally underestimated as a potential mode of transmission of SARS-Cov-2 infection. With the gradual resumption of cardiac surgical activities, the cardiac surgical operating room will become an important potential source of infection to the cardiac surgeon and other healthcare workers participating in the operation. There is also diminished awareness about the different aerosol generating procedures (AGP) in the cardiac surgical operating room. In this mini-review we intend to highlight the various aerosol generating procedures that are common in cardiac surgery. This will help increase the awareness among surgeons to AGP. A practical approach to taking preventive measures have also been discussed.
Objectives The impact of the COVID 19 pandemic on the treatment of patient with aortic valve stenosis is unknown and there is uncertainty on the optimal strategies in managing these patients. Methods This study is supported and endorsed by the Asia Pacific Society of Interventional Cardiology. Due to the inability to have face to face discussions during the pandemic, an online survey was performed by inviting key opinion leaders ( cardiac surgeon/interventional cardiologist/echocardiologist) in the field of transcatheter aortic valve implantation (TAVI) in Asia to participate. The answers to a series of questions pertaining to the impact of COVID-19 on TAVI were collected and analyzed. These led subsequently to an expert consensus recommendations on the conduct of TAVI during the pandemic Results The COVID 19 pandemic had resulted in a 25% (10-80) reduction of case volume and 53% of operators required triaging to manage their patients with severe aortic stenosis. The two most important parameters used to triage were symptoms and valve area. Periprocedural changes included the introduction of teleconsultation, pre-procedure COVD 19 testing, optimization of pre-tests and catheterization laboratory set up. In addition, length of stay was reduced from a mean of 4.4 to 4 days. Conclusion The COVID-19 pandemic has impacted on the delivery of TAVI services to patients in Asia. This expert recommendations on best practices may be a useful to guide to help TAVI teams during this period until a COVID 19 vaccine becomes widely available
After its first description in Wuhan (China), SARS-CoV-2 the agent of coronavirus disease 2019 (COVID-19) rapidly spread worldwide. Previous studies suggested that pets could be susceptible to SARS-CoV-2. Here, we investigated the putative infection of SARS-CoV-2 in 22 cats and 11 dogs from owners previously infected or suspected of being infected by SARS-CoV-2. For each animal, rectal, nasopharyngeal swabs and serum were taken. Swabs were submitted to RT-qPCR assays targeting 2 genes of SARS-CoV-2. All dogs were tested SARS-CoV-2 negative. One cat was tested positive by RT-qPCR on rectal swab. Nasopharyngeal swabs from this animal were tested negative. This cat showed mild respiratory and digestive signs. Serological analysis confirm the presence of antibodies against the SARS-CoV-2 in the two serum samples taken 10 days apart. Genome sequence analysis revealed that the cat SARS-CoV-2 belongs to the phylogenetic clade A2a like most of the French human SARS-CoV-2. This study reports for the first time the natural infection of a cat in France (near Paris) probably through their owners. There is currently no evidence that cats can spread COVID-19 and owners should not abandon their pets or compromise their welfare.
Are all Non-sustained Ventricular Tachycardia the Same in Hypertrophic Cardiomyopathy Risk Stratification for Sudden Cardiac Death?Mohamad Khaled Sabeh MD1, Marwan M. Refaat MD21Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts - USA2Division of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center Beirut, LebanonRunning Title: NSVT in HCM SCD Risk StratificationWords (excluding references): 664Disclosures: NoneFunding: NoneKeywords: Hypertrophic Cardiomyopathy, Non-sustained Ventricular Tachycardia, Cardiac Arrhythmias, Cardiovascular DiseasesCorrespondence:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FRCPAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonFax: +961-1-370814Clinic: +961-1-350000/+961-1-374374 Extension 5800Office: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: email@example.comCardiomyopathies with reduced systolic function predispose to sudden cardiac death (SCD) and many studies helped in decreasing that risk by Implantable Cardioverter Defibrillator (ICD) implantation and pharmacologic management (1-4). Many types of cardiomyopathies with preserved systolic function, including hypertrophic cardiomyopathy (HCM), can predispose to malignant ventricular arrhythmias and SCD. HCM is the most common inherited cardiac disease that affects 1 in 200 live births (5,6). SCD remains one of the main causes of death in HCM and the SCD rate peaks in early adulthood (7-14). Data from ICDs suggest that SCD in HCM is most commonly caused by ventricular fibrillation (VF) (15). One major clinical challenge is identifying patients at risk for SCD. Multiple studies showed that non-sustained ventricular tachycardia (NSVT) is a risk actor for SCD (16,17). However the strength of the data was variable across these studies due to difference in populations and the low sensitivity of Holter ECG. Moreover, other studies looked at the rate and duration of the ventricular arrhythmias and their relationship to SCD in HCM (17-19) yet the effect of the morphology of NSVT on SCD has not been well investigated.In this single center study Adduci et al . explore the prognostic impact of different NSVT morphologies in a cohort of 109 consecutive HCM patients. The study included patients who had an ICD implanted in the authors’ institution from January 2001 to December 2018. The ICDs were mostly implanted for primary prevention in HCM patient with 1) one or more risk factor including maximal LV thickness ≥30 mm, family history of SD in at least 1 first-degree relative <50 years of age, non-sustained ventricular tachycardia (NSVT), recent (≤ 6 months) unexplained syncope, 2) hypotensive blood pressure during exercise with at least one additional major risk factor for SD 3) end-stage HCM regardless of other established risk markers of SCD. Devices were interrogated on evaluation every 3 to 6 months and the data was assessed for appropriate or inappropriate ICD therapies. Two independent electrophysiologists analyzed the ICD near field and far field EGMs from the ventricular tachycardia runs. They classified the VTs as either monomorphic (MMVT) or polymorphic (PMVT).During a mean follow up of 71+/- 48 months, 377 NSVT episodes of NSVT were retrieved from ICD memory in 46 patients; of these episodes, 7(2%) were polymorphic and 370 (98%) were monomorphic (MM). The mean HR of The MM NSVT had an average HR of 171+/- 32 BPM and lasted for 17 +/- 12 beats while the PMVT were faster at 241BPM +/- and longer at 28+/- 16 beats. The appropriate intervention rate was 5.1% per year and interestingly NSVT did not predict the occurrence of ICD therapy. However patients with polymorphic NSVT had a statistically higher risk for ICD intervention as compared to monomorphic NSVT. Further analysis noted a trend for increased risk of ICD therapy with patients with >1 NSVT morphology. Moreover 75% of the treated VTs had been previously observed as NSVT.Risk stratification is very important in this young patient population; decreasing the risk threshold for ICD implants leads to missed arrhythmias and bad outcomes while increasing it increases the risk for complications from unnecessarily implanted devices. There are several types of ICDs: Transvenous ICD, Subcutaneous ICD and Extravascular ICD. The results of this study suggest that the risk of SCD in patients with PMVT and/or NSVT with multiple morphologies is different from that of patients with a MMVT, and that the presence of short MMVT doe not predict the future ICD therapies. As such, one may consider a conservative approach in low-risk patients with short bursts of slow MM NSVT, and a more aggressive approach in patients with frequent, rapid rate burst of PMVT. Although this study suggests that different NSVT morphologies affect the prognosis in HCM patients, the low number of events lacked the statistical power to redefine ICD candidacy. Larger multicenter studies are needed to confirm these findings and to help delineate the “at risk patients” who would truly benefit from ICDs.
A Cardiac Sodium Channel Mutation Associated with Epinephrine-Induced Marked QT-ProlongationMohamad N. El Moheb MD1, Marwan M. Refaat MD21Division of Trauma Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Boston, Massachusetts - USA2Division of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center Beirut, LebanonRunning Title: SCN5A mutation associated with epinephrine-induced LQTSWords (excluding references): 746Disclosures: NoneFunding: NoneKeywords: Long QT Syndrome, Genetics, Variants, Cardiac Arrhythmias, Cardiovascular DiseasesCorrespondence:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FRCPAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonFax: +961-1-370814Clinic: +961-1-350000/+961-1-374374 Extension 5800Office: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: firstname.lastname@example.orgThe hereditary long QT syndrome (LQTS) is an important cause of polymorphous ventricular tachycardia (torsades de pointes) and sudden cardiac death in otherwise young and healthy individuals. Clinically, this condition is caused by delayed ventricular repolarization and manifests as an abnormally prolonged QT interval on the electrocardiogram (ECG). The most common subtypes of LQTS are LQT1, LQT2, and LQT3 (1-10). The life-threatening arrhythmias occur most frequently during exercise in LQT1, upon auditory stimulation or emotional stress in LQT2, and at rest or during sleep in LQT3 (11). Patients with LQT1 have a mutation in the KCNQ1 gene which codes for the subunit of the slow outward potassium current channel (IKs) while patients with LQT3 have a mutation in the SCN5A gene, which codes for the cardiac voltage-dependent sodium channel (INa) (12). LQT1-affected individuals are more vulnerable to β-adrenergic modulation than LQT3-affected individuals. Exercise and epinephrine-infusion ECG tests are therefore useful in differentiating between the LQTS subtypes and optimizing therapeutic strategies in order to prevent sudden cardiac death. While beta-blockers have been established as the standard of care for the treatment of the LQT1 and LQT2 subtypes, their use in LQT3 remains controversial (13, 14). A new missense mutation has been recently identified in the SCN5A-encoding INA channels and was found to be associated with sinus node dysfunction and epinephrine-induced QT prolongation (1). This atypical phenotype of LQT3 has so far been observed in only one patient. Whether other mutations exist that can cause a similar manifestation has yet to determined.In the current issue of the Journal of Cardiovascular Electrophysiology, Nakajima et al. describe a family with LQT3 that exhibited epinephrine-induced marked QT prolongation. The SCN5A V1667I mutation was found to be responsible for this atypical phenotype which resulted in prolongation of the QT interval in the proband as well as in family members carrying the mutation. The SCN5A V1667I mutation is a gain of function mutation located in domain IV-segment 5 (DIV-S5) of the sodium channel encoding SCN5A gene. To elucidate the pathophysiology of the disease, the authors transfected a human kidney cell line (tsA-201) to induce expression of wild-type and mutated sodium channels and measured the membrane sodium currents (INA). They showed that SCN5A V1667I mutation was associated with larger INA peak density, depolarizing shift in steady-state inactivation (SSI) leading to increased window current, and accelerated recovery from depolarization. Additionally, an increased hump in the INA of V1667I mutant cells (V1667I-INA) was observed during a ramp pulse protocol consistent with increased window current. There was no difference in fast inactivation rate and steady-state activation between the V1667I-INA and wild-type INA(WT-INA). The authors further examined the effects of protein kinase A (PKA) activation on V1667I-INA to mimic the effect of epinephrine. PKA activation resulted in a less significant hyperpolarizing shift in SSI in V1667I-INA compared to WT-INA leading to increased window current. Additionally, V1667I mutation was found to be associated with accelerated recovery from depolarization, and increased hump during ramp pulse protocol in the setting of PKA activation. Chen et al. have also reported the case of an individual with a mutation in SCN5A who exhibited marked QT-prolongation after epinephrine infusion (1). However, contrary to the SCN5A V1667I mutation described by Nakajima et al, the SCN5A V2016M defect was a loss of function mutation causing a decrease in INA peak density. The clinical manifestations of the SCN5A mutations described by Chen et al. and Nakajima et al. are more comparable to individuals with the LQT1 subtype than those with the LQT3 subtype. Therefore, it should be considered whether certain patients with SCN5A would benefit from beta-blocker therapy.Overall, the authors should be commended on their efforts to describe for the first time a family with the SCN5A V1667I mutation and show that this mutation is associated with epinephrine-induced marked QT prolongation. The authors have also provided important insight into the electrophysiological properties of the mutant channels and the structure-function relationship of SCN5A. Further studies are needed to elucidate the precise molecular mechanisms of PKA activation on WT-INa and V1667I-INa. The results of this study have important clinical implications. The efficacy of beta-blockers for the treatment of LQTS has so far only been proven for the LQT1 and LQT2 subtypes, with conflicting results for the LQT3 subtype (13, 14). Given the marked QT prolongation in response to epinephrine infusion in carriers of the SCN5A V1667I mutation, certain LQT3 patients may benefit from beta-blocker therapy. Future studies should clarify whether beta-blockers are effective in these patients.
On March 11, 2020, the World Health Organization (WHO) declared the SARS-CoV-2 outbreak a pandemic: it took a toll of more than 300.000 deaths and more than 4.5 million cases, worldwide. The initial data pointed out the tight bond between cardiovascular diseases and worse outcomes in COVID19-patients. Epidemiologically speaking, there is an overlap between the age-groups more affected by COVID-related death and the age-groups in which Cardiac Surgery has its usual base of patients. The Cardiac Surgery Departments have to think to a new normal: since the virus will remain endemic in the society, dedicated pathways or even dedicated Teams are pivotal to treat safely the patients, in respect of the safety of the health care workers. Moreover, we need a keen eye on deciding which pathologies have to be treated with priority: Coronary Artery Disease (CAD) showed a higher mortality rate in patients affected by COVID19, but it’s however reasonable to think that all the cardiac pathologies affecting the lung circulation - such as symptomatic severe mitral diseases or aortic stenosis - might deserve a priority access to treatment, in order to increase the survival rate in case of an acquired-Coronavirus infection later on.
The nano/microelectromechanical systems (N/MEMS) have been caught much attention in the past few decades for their attractive properties such as small size, high reliability, batch fabrication, and low power consumption. The dynamic oscillatory behavior of these systems is very complex due to strong nonlinearities in these systems. The basic aim of this manuscript is to investigate the nonlinear vibration property of N/MEMS oscillators by the homotopy perturbation method coupled with Laplace transform (also called as He-Laplace method in literature). A generalized N/MEMS oscillator is systematically studied, and a fairly accurate analytic solution is obtained. Three special cases for electrically actuated MEMS, multi-walled Carbon nanotubes-based MEMS, and MEMS subjected to van der Waals attraction are considered for comparison, and a good agreement with exact solutions is observed.