In this study, both laboratory experiments and numerical simulations were conducted to investigate the effect of density-driven flow on the transport of high-concentration pollutants in the hyporheic zone. The results show that the density gradient can change the flow of pore water and the strong density-driven flow can lead to an unstable flow, which increases the effect of preferential flow and thus causes the appearance of solute fingers in the hyporheic zone. Notably, these solute fingers become more obvious with the increase of depth. The appearance of solute fingers depends on the relative strength of the pumping exchange and density gradient, which are represented by the dimensionless number M* and N* respectively. Finger flows appear near the interface when M* is less than 0.5 N*. This study may contribute to better understanding the transport and destination of solutes and thus may provide some insights into the assessment on pollution incidents.

Hemophagocytic syndrome have experienced a very significant revival in recent years, we report a rare case of secondary HLH to Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection. In addition to the treatment for hepatitis the patient underwent therapy for HLH, with this treatment we obtained complete remission.

A 39 year old patient was presented with bacterial meningitis after having endoscopic surgery for removal of a benign pituitary tumor. Cerebrospinal cytology showed a marked hemophagocytic activity.

BACKGROUND Hypoalbuminemia is frequently observed in patients with SARS-CoV-2 infection although its underlying mechanism and relationship with clinical outcome still need to be clarified. METHODS We retrospectively evaluated in patients with COVID-19 hospitalized at the Fatebenefratelli-Sacco Hospital in Milan, the prevalence of hypoalbuminemia, its association with the severity of COVID-19, with the levels of C-reactive protein, d-dimer and interleukin-6 and with clinical outcome over a follow-up period of 30 days. Urinalysis was evaluated in a subgroup of patients. RESULTS Serum albumin levels < 30 g/L were found in 105/207 (50.7%) patients at hospital admission. Overall, the median albumin value was 29.5 g/L (IQR 25-32.8). A negative association was found between albumin levels and severity of COVID-19 (p<0.0001) and death (p=0.003). An inverse correlation was observed between albumin and both C-reactive protein and D-dimer at hospital admission (r = -0.487 and r = -0.479, respectively; p< 0.0001). Finally, a positive correlation was found between albumin levels and eGFR (r= 0.137; p=0.049). Proteinuria was observed in 75% of patients with available data and it did not differ between patients with hypoalbuminemia and those with albumin > 30 g/L (81% and 67%, respectively; p=0.09). CONCLUSION In patients with COVID-19 hypoalbuminemia is common and observed in quite an early stage of pulmonary disease. It is strictly associated with inflammation markers and clinical outcome. The common finding of proteinuria, even in the absence of creatinine increase, indicates protein loss as a possible biomarker of local and systemic inflammation worthwhile to evaluate disease severity in COVID-19.

The International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes and health management. Since its first edition, the ICD has maintained a framework distributing conditions according to topography, with the result that some complex conditions, such as allergies and hypersensitivity disorders (A/H) including anaphylaxis, have been poorly represented. The change in hierarchy in ICD-11 permitted the construction of the pioneer section addressed to A/H, which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019 and the implementation is ongoing worldwide. We here present the outcomes from an online survey undertaken to reach out the allergy community worldwide in order to peer review the terminology, classification and definitions of A/H introduced into ICD-11 and to support their global implementation. Data are presented here for 406 respondents from 74 countries. All of the sub-sections of the new A/H section of the ICD-11 had been considered with good accuracy by the majority of respondents. We believe that, in addition to help during the implementation phase, all the comments provided will help to improve the A/H classification and to increase awareness by different disciplines of what actions are needed to ensure more accurate epidemiological data and better clinical management of A/H patients.

Medical algorithm: Treatment of Atopic Dermatitis in Early Childhood (part II)Sherief R. Janmohamed MD PhD1, Johannes Ring MD2, Lawrence F. Eichenfield MD3, Jan Gutermuth MD11Department of Dermatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Jette, Brussels, Belgium2Department of Dermatology and Allergology Biederstein, Technical University Munich, München, Germany3Departments of Dermatology and Pediatrics, University of California, San Diego School of Medicine and Rady Children’s Hospital, San Diego CA, USA

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 protected] 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: [email protected] 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.

Water temperature is an important habitat factor in river ecosystems that exhibits the characteristics of continuous change. Dam construction disrupts the continuity of the water temperature and reset it, thus exerting range reduction and hysteresis effects on the characteristics of water temperature change. The effect of a dam on river continuity is directly related to the dam size. To explain this relationship, two rivers in China were selected: one river without reservoirs and one river with cascade reservoirs. Through the analysis of the longitudinal change of water temperature in free-flowing rivers, we found that water temperature changes continuously and uniformly in the longitudinal direction. Based on this, a temperature trend hypothesis in river was proposed, and the discontinuity of the water temperature in the reservoir section was evaluated. The result is as follows: (1) In mixed reservoirs, river water temperature remained as continuous as free-flowing rivers. However, the river water temperature had a large discontinuity in the stratified reservoir; (2) Water residence time was used as an indicator of the continuity of reservoir water temperature; (3) Selective withdrawal of stratified reservoirs in January could not remove the discontinuity caused by itself, but it worked in June.

Introduction: Patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) require chronic anticoagulation due to a high thromboembolic risk. Evidence supporting use of non-vitamin K oral anticoagulants (NOACs) in patients with HCM remains sparse, and there are no data regarding the use of NOACs in HCM patients undergoing catheter ablation of AF. Methods: Observational non-randomised study in 4 European Centres. We aimed to investigate the safety and efficacy of NOACs compared with vitamin-K antagonists (VKAs) in patients with HCM undergoing catheter ablation for AF. Results: One hundred thirty-seven HCM patients (mean age 55.0±13.4, 29.1% female) underwent 230 catheter ablations for AF (1.7±1.0 per patient). A total of 55 patients (39.4%) underwent 70 procedures (30.4%) on NOAC, while the remaining were on VKA. Warfarin (97.6%) and rivaroxaban (56.4%) were the most frequently used agents in the respective groups. No procedure-related deaths were reported. We observed no significant difference in the rate of thromboembolism (VKA 0.6%; NOAC 0%; p=1.0) or minor bleeding (VKA 0.6%; NOAC 1.4%; p=0.54). There was a non-significant trend towards a lower incidence of major bleeding (VKA 6.8%; NOAC 1.4%; p=0.09). Conclusion: These preliminary data suggest that NOACs are at least as safe and effective as VKAs in patients with HCM undergoing catheter ablation for AF.

Benzoic acid is one of the most commonly used food preservatives, but currently exclusively produced in petrochemical processes. In this study, we describe a bio-based production pathway using an engineered strain of Pseudomonas taiwanensis. In a phenylalanine-overproducing strain, we heterologously expressed bacterial, yeast, and plant genes to achieve production of benzoate via a β-oxidation pathway. Strategic disruption of the native Pseudomonas benzoate degradation pathway further allowed the production of catechol and cis,cis-muconate. Taken together, this work demonstrates new routes for the microbial production of these industrially relevant chemicals from renewable resources.

Adeno-associated viral vectors (AAV) are one of the most efficient engineered tools for delivering genetic material into host cells. The commercialization of AAV-based drugs goes hand in hand with the need to increase manufacturing capacities and to develop appropriate quality controls. In particular, accurate methods to assess the level of residual DNA in AAV vector stocks are needed, considering the potential risk of co-transferring oncogenic or immunogenic sequences with the therapeutic vectors. Our laboratory has developed an assay based on high-throughput sequencing (HTS) to exhaustively identify and quantify DNA species in recombinant AAV batches. Compiled with a computational analysis of the single nucleotide variants (SNV), Single-Stranded Virus Sequencing (SSV-Seq) also provides information regarding rAAV genome identity. In this study, we show that the PCR amplification of regions with high GC content and including mononucleotide stretches can be biased during the DNA library preparation, leading to drops in the sequencing coverage along the AAV vector genome. To circumvent this problem, we have developed a PCR-free protocol, named SSV-Seq 2.0, that is optimized for the sequencing of rAAV genomes that contain sequences with a high percentage of GC and homopolymers, such as the CAG promoter. HTS-based assays are indispensable to provide accurate data to the regulatory agencies regarding nucleic acids content in AAV vector batches and to improve the safety and efficacy of these viral vectors.

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.

CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare entity recently described. Thirteen CNS HGNET-MN1 patients were identified using genome wide methylation arrays/RT-PCR across 7 institutions and were correlated with treatment and outcome. All patients had surgery (GTR:9/STR:4) as initial management followed by radiotherapy (focal:5/craniospinal:2/CyberKnife:1) and systemic chemotherapy in 3 patients. Seven patients relapsed; 5 local and 2 metastatic despite complete resection and radiotherapy. Three patients died due to their tumor relapse after 24 months despite upfront radiotherapy. Treatment of CNS HGNET-MN1 remains a major challenge with multiple failures, despite aggressive surgical resections and upfront radiotherapy.

Redo multiple valve replacement is known to carry additional risk of morbidity and mortality. Currently, a transcatheter-based valve-in-valve approach could be useful in reducing potential serious consequences. On the other hand, this approach poses several technical challenges regarding the device and procedural aspects of the procedure. We present the case of a 78-year-old man who presented with symptoms of heart failure due to mitro-aortic bioprosthesis degenerations who was deemed to be at extremely high risk for conventional redo surgery. A two-steps single admission transcatheter-based approach was planned with a transfemoral aortic valve-in-valve procedure followed by a trans-apical mitral valve-in-valve implantation. The outcome was good and the recovery was fast.

Background and aim: The incidence of symptomatic cerebral infarction after minimally invasive cardiac surgery (MICS) with retrograde perfusion has been increasing. However, there is no report about silent brain infarction (SBI) after MICS with retrograde perfusion. Because SBI may cause delirium and decline of cognitive function, this condition is important clinically. Thus, the current study aimed to investigate the occurrence of SBI after MICS via magnetic resonance imaging (MRI). Methods: Between July 2014 and July 2018, 174 patients underwent MICS with retrograde perfusion and postoperative MRI in this study. Univariate and multivariate analyses were performed to examine the occurrence of SBI and to identify its risk factors. Results: Of 174 patients, 26 (14.9%) presented with SBI. The univariate analysis revealed that age and aortic valve stenosis (AS) are the risk factors of SBI. Meanwhile, multivariate analysis revealed AS as the only risk factor of SBI. Conclusions: At our institution, the incidence of SBI after MICS with retrograde perfusion was acceptable.

Postoperative thoracic aortic graft infection (TAGI) is a serious and potentially fatal complication. The classical approach is to replace the infected graft. However, this approach has a high mortality rate. Alternatively, treatment of TAGI without graft replacement can be performed. Herein, we present successful treatment of the case of a 72-year-old patient with mediastinitis and graft infection after type A aortic dissection operation for whom we performed omental flap coverage following vacuum-assisted wound closure therapy without graft replacement. The patient had an uneventful postoperative course and remained infection free for the last 36 months to date.

Background – The impact of post-operative complications on long-term survival is not well characterized. We sought to study the prevalence of post-operative complications after cardiac surgery and their impact on long-term survival. Methods – Operative survivors (n=26,221) who underwent coronary artery bypass grafting (CABG) (n=13054, 49.8%), valve surgery (n=8667, 33.1%) or combined CABG and valve surgery (n=4500, 17.2%) from 1993 to 2019 were included in the study. Records were reviewed for post-operative complications and long-term survival. The associations between post-operative complications and survival were assessed using a Cox-proportional model. Results – Complications occurred in 17,463 (66.6%) of 26,221 operative survivors. A total of 17 post-operative complications were analyzed. Post-operative blood product use was the commonest (n=12397, 47.3%), followed by atrial fibrillation (n=8399, 32.0%), prolonged ventilation (n=2336, 8.9%), renal failure (n=870, 3.3%), re-operation for bleeding (n=859, 3.3%) and pacemaker/ICD insertion (n=795, 3.0%). Stroke (HR 1.55, 95%CI 1.36-1.77), renal failure (HR 1.45, 95% CI 1.33-1.58) anticoagulant-related events (HR 1.26, 95%CI 1.02-1.56) and pneumonia (HR 1.23, 95%CI 1.11-1.36) had the strongest impact on long-term survival. Long-term survival decreased as the number of post-operative complications increased. Conclusions – Post-operative complications after cardiac surgery significantly impact outcomes that extend beyond the post-operative period. The presence, number and type of post-operative complications adversely impact long-term survival. Stroke, renal failure, anticoagulant-related events and pneumonia are particularly associated with poor long-term survival.