CytoSorb on the Septic Shock

Background: Septic shock, defined as organ dysfunction caused by a dysregulated host response to infection, is a condition associated with high morbidity and mortality. One of the hallmarks of sepsis is the excessive release of cytokines and other inflammatory mediators that cause septic shock and multi-organ failure (MOF). New adsorbents are now available as adjuvant therapy aimed at modulating the cytokine "storm" in sepsis. They are thought to be useful if adopted early (within 8-24 hours of the diagnosis of septic shock) in patients who are unresponsive to standard therapy. Here we report our experience with CytoSorb. Method(s): From January 2021 to May 2022, 46 patients with septic shock were treated with continuous renal replacement therapy (CRRT) associated with hemoadsorption with CytoSorb. All cases presented organ failure including AKI. Surgical patients (n = 13) were treated with surgery, COVID patients (n = 15) and medical patients (n = 16) with medical therapy;all surgery cases were operated on before starting the haemadsorption and in some cases reoperation with the need to suspend the adsorption. The mean age was 69 +/- 17 years (SD). On admission the mean SAPSII score was 50 +/- 11 (SD). CRRT as hemodiafiltration (CVVHDF) was performed. All patients received at least one CytoSorb treatment and additional treatments (up to 21 filters in a Covid patient) according to our indication. The CytoSorb cartridge was installed in series to the high cut-off filter;blood flow rates were maintained between 120 and 150 mL/min while dialysis doses from 18 to 45 mL/kg/hour. CytoSorb was renewed every 24 hours. We evaluated the impact of CytoSorb on 30-day survival, haemodynamics and relevant outcomes. Result(s): The 30-day survival was 30%. During treatment with CytoSorb, patients had a hemodynamic stabilization with a significant improvement in MAP, a reduction in amines and a decrease in PCR and PCT (Figure 1). Mortality at 30 days among medical patients was almost comparable to that of COVID patients and higher than that of surgical patients (70%, 69% and 61%, respectively). It should be noted that almost half of the deceased patients arrived late in the hospital, thus leading to a late start of treatment. Conclusion(s): We confirm the efficacy and usefulness of the CytoSorb if adopted early in patients who do not respond to standard therapy. CytoSorb treatment was safe and well tolerated with no device-related adverse events during or after treatment sessions.

Predictors of poor outcomes in patients with pandemic viral infections (influenza AH1N1pdm09, COVID-19) on a ventilator.

Considering the commonality of the pathogenetic links of the critical forms of COVID-19 and influenza AH1N1pdm09 (cytokine over-release syndrome), the question arises: will the predictors of an unfavorable outcome in patients on mechanical ventilation and, accordingly, the universal tactics of respiratory support in these diseases be identical? Objective. In a comparative aspect, to characterize patients with influenza AH1N1pdm09 and COVID-19 who were on mechanical ventilation, to identify additional clinical and laboratory risk factors for death, to determine the degree of influence of respiratory support (RP) tactics on an unfavorable outcome in the studied category of patients. Patients and methods. Patients treated on the basis of resuscitation and intensive care departments of the State Budgetary Healthcare Institution "SKIB" in Krasnodar and the State Budgetary Healthcare Institution "IB No 2" in Sochi were studied: group 1 - 31 people with influenza AH1N1pdm09 (21 people died - subgroup 1A;10 people survived - subgroup 1B) and group 2 - 50 people with COVID-19 (29 patients died - subgroup 2A;21 people survived - subgroup 2B). All patients developed hypoxemic ARF. All patients received step-by-step tactics of respiratory support, starting with oxygen therapy and ending with the use of "traditional" mechanical ventilation. Continuous variables were compared in subgroups of deceased and surviving patients for both nosologies at the stages: hospital admission;registration of hypoxemia and the use of various methods of respiratory therapy;development of multiple organ dysfunctions. With regard to the criteria for which a statistically significant difference was found (p < 0.05), we calculated a simple correlation, the relative risk of an event (RR [CI 25-75%]), the cut-off point, which corresponded to the best combination of sensitivity and specificity. Results. Risk factors for death of patients with influenza AH1N1pdm09 on mechanical ventilation: admission to the hospital later than the 8th day of illness;the fact of transfer from another hospital;leukocytosis >=10.0 x 109/l, granulocytosis >=5.5 x 109/l and LDH level >=700.0 U/l at admission;transfer of patients to mechanical ventilation on the 9th day of illness and later;SOFA score >=8;the need for pressor amines and replacement of kidney function. Predictors of poor outcome in ventilated COVID-19 patients: platelet count <=210 x 109/L on admission;the duration of oxygen therapy for more than 4.5 days;the use of HPNO and NIV as the 2nd step of RP for more than 2 days;transfer of patients to mechanical ventilation on the 14th day of illness and later;oxygenation index <=80;the need for pressors;SOFA score >=8. Conclusion. When comparing the identified predictors of death for patients with influenza and COVID-19 who needed mechanical ventilation, there are both some commonality and differences due to the peculiarities of the course of the disease. A step-by-step approach to the application of respiratory support methods is effective both in the case of patients with influenza AH1N1pdm09 and patients with COVID-19, provided that the respiratory support method used is consistent with the current state of the patient and his respiratory system, timely identification of markers of ineffectiveness of the respiratory support stage being carried out and determining the optimal moment escalation of respiratory therapy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Clinical Features, Laboratory Findings Outcomes in Multisystem Inflammatory Syndrome (Mis-C) Following Covid-19 Infection - a Multicenter, Observational, Ambidirectional Cohort Study in Rio De Janeiro State, Brazil

Objectives: As of March 5th, 2022, around 1.585 cases of MIS-C and 98 deaths (6,4%) were reported in Brazil. The state of Rio de Janeiro State (RJ) having 94 cases (5,9%) and 4 deaths (4,2%)1.Our aim was to evaluate clinical and laboratory features, and management of MIS-C in seven pediatric hospitals in RJ, Brazil. Method(s): Multicenter, observational, ambidirectional cohort study in seven tertiary hospitals in RJ(Brazil), assessing medical charts of pediatric inpatients (0-18 years) diagnosed with MIS-C according to WHO/CDC criteria, from August, 2020 to February, 2022. Descriptive statistics were used to analyze distributions of continuous variables, frequencies, and proportions. Result(s): A total of 112 cases of MIS-C were enrolled. The mean age was 4.2 years and thre was male predominance (59,8%). All cases had a SARS-CoV-2 contact (29.5% close contact;31.3%:positive PCR;serology:43.8%).Only 12.5% had comorbidities. Length of stay (LOS) was 7 days.Median duration of fever was 8 days. Most common symptoms were: rash(67%);gastrointestinal (67%);conjunctivitis (42%);neurological(39.6%);cardiovascular(37.5%);cervical lymphadenopathy (36.6%), and shock/hypotension(28.6%).Co-infection occurred in 3 patients. Forty-four patients fulfilled criteria for Kawasaki disease. Most patients were admitted to PICU(12;62,5%) for amedian of 2 days. Respiratory distress was seen in 18,7%;hypotension:28,6%, and shock in 23,2%. Main laboratory findings were: high C-reactive protein in 95%;D-dimer:77%, anemia:77%, thrombocytosis:63%;transaminitis:43.8%, lymphopenia:38%;hypoalbuminemia:34%;thrombocytopenia: 29%;hypertriglyceridemia:28%, and high pro-BNP in 27%. Echocardiogram was performed in 91/112 patients;abnormal in 70,3%;exhibiting myocardial dysfunction( 25%);pericardial effusion(21%);coronary dilation/aneurysms(11%) and, valvulitis (14.5%). IVIG+corticosteroids (CTC) were administered in 59.8%(67/ 112);18.6%(18/112) IVIG only;10.7%(12/112) CTC only;3.4%(4/112)biologics, and 15(13.3%) received no treatment. ASA low dose in 77.7% (87/112) and moderate/high dose in 34.8%. Oxygen support was needed in 27,7%;vasoactive amines:18,7%;dialysis:5,3%, and transfusion:18,7%.One patient died from a cytokine storm syndrome. Conclusion(s): Our study reports a higher number of MIS-C cases in RJ than the number reported to Brazilian authorities, highlighting underreporting. Our patients were younger, had fewer comorbidities, cardiovascular/gastrointestinal/renal involvement, shortest LOS in ICU, and a higher frequency of myopericarditis.

Predictors of poor outcomes in patients with pandemic viral infections (influenza AH1N1pdm09, COVID-19) on a ventilator.

Considering the commonality of the pathogenetic links of the critical forms of COVID-19 and influenza AH1N1pdm09 (cytokine over-release syndrome), the question arises: will the predictors of an unfavorable outcome in patients on mechanical ventilation and, accordingly, the universal tactics of respiratory support in these diseases be identical? Objective. In a comparative aspect, to characterize patients with influenza AH1N1pdm09 and COVID-19 who were on mechanical ventilation, to identify additional clinical and laboratory risk factors for death, to determine the degree of influence of respiratory support (RP) tactics on an unfavorable outcome in the studied category of patients. Patients and methods. Patients treated on the basis of resuscitation and intensive care departments of the State Budgetary Healthcare Institution "SKIB" in Krasnodar and the State Budgetary Healthcare Institution "IB No 2" in Sochi were studied: group 1 - 31 people with influenza AH1N1pdm09 (21 people died - subgroup 1A;10 people survived - subgroup 1B) and group 2 - 50 people with COVID-19 (29 patients died - subgroup 2A;21 people survived - subgroup 2B). All patients developed hypoxemic ARF. All patients received step-by-step tactics of respiratory support, starting with oxygen therapy and ending with the use of "traditional" mechanical ventilation. Continuous variables were compared in subgroups of deceased and surviving patients for both nosologies at the stages: hospital admission;registration of hypoxemia and the use of various methods of respiratory therapy;development of multiple organ dysfunctions. With regard to the criteria for which a statistically significant difference was found (p < 0.05), we calculated a simple correlation, the relative risk of an event (RR [CI 25-75%]), the cut-off point, which corresponded to the best combination of sensitivity and specificity. Results. Risk factors for death of patients with influenza AH1N1pdm09 on mechanical ventilation: admission to the hospital later than the 8th day of illness;the fact of transfer from another hospital;leukocytosis >=10.0 x 109/l, granulocytosis >=5.5 x 109/l and LDH level >=700.0 U/l at admission;transfer of patients to mechanical ventilation on the 9th day of illness and later;SOFA score >=8;the need for pressor amines and replacement of kidney function. Predictors of poor outcome in ventilated COVID-19 patients: platelet count <=210 x 109/L on admission;the duration of oxygen therapy for more than 4.5 days;the use of HPNO and NIV as the 2nd step of RP for more than 2 days;transfer of patients to mechanical ventilation on the 14th day of illness and later;oxygenation index <=80;the need for pressors;SOFA score >=8. Conclusion. When comparing the identified predictors of death for patients with influenza and COVID-19 who needed mechanical ventilation, there are both some commonality and differences due to the peculiarities of the course of the disease. A step-by-step approach to the application of respiratory support methods is effective both in the case of patients with influenza AH1N1pdm09 and patients with COVID-19, provided that the respiratory support method used is consistent with the current state of the patient and his respiratory system, timely identification of markers of ineffectiveness of the respiratory support stage being carried out and determining the optimal moment escalation of respiratory therapy.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Aggressive behavior in Italian children with ADHD in the middle of COVID-19 pandemic: Preliminary data on MAOA gene polymorphisms involvement

Attention Deficit Hyperactivity Disorder (ADHD) is characterized by oppositional, defiant, disobedient, disruptive and also aggressive behavior. Many genes are involved in its onset, particularly dopaminergic pathway genes. Moreover, genetic predisposition to aggression appears affected by the polymorphic genetic variants of the serotoninergic system, among which, functional polymorphisms in monoamine oxidase A (MAOA). The risk of contracting coronavirus infection may arouse in some people severe emotional distress characterized by symptoms of fatigue, guilt, and aggression. A survey on the psychological impact of COVID-19 pandemic in Italian families of children with neurodevelopmental disorders such as ADHD showed how children have been particularly affected by the emergency. The aim of this study was to determine whether polymorphisms at the MAOA gene are associated with increased or reduced susceptibility to develop ADHD. Therefore, the variants rs6323, rs587777457 and rs1137070 of the MAOA gene were evaluated by SBT in 35 children (mean age 10.257 range 6-16) with ADHD and 27 healthy individuals. Our analysis allowed us to identify the G/G genotype of the variant rs6323 (Arg297Arg) was significantly associated with an increased risk of ADHD (p = 0.015). Allele G indicates higher levels of the enzyme, while the T allele indicates lower levels of enzyme production. When compared in patients, the G allele was associated with higher anger (p-value = 0.01) and might cause aggressive behavior in males. Our study shows that defining a genetic profile of ADHD can provide important information on the etiopathogenesis of the disease and help identify the best therapeutic option for patients with this disorder.

COVID-19: How Nuclear Medicine Can Provide A Differential Diagnosis In A Very Dubious Case

Background: We present the case of a 55-year-old woman, admitted to the Infectious Disease Department of Policlinico Umberto I, Rome, in mid-March 2020, with suspicion of COVID-19 infection. Objective(s): The rRT-PCR was negative, and the following CT scan, performed to exclude false-neg-ative results and help diagnosis, was inconclusive. Method(s): It was decided to submit the patient to a 99mTc-HMPAO-labelled leukocyte scan. Result(s): This exam led to the diagnosis of infective endocarditis. Conclusion(s): In the present pandemic scenario, 99mTc-HMPAO-labelled leukocyte scan represents a reliable imaging technique for differential diagnosis with COVID-19 in patients with confusing clinical signs, possible false-negative rRT-PCR results, and inconclusive CT scan.Copyright © 2021 Bentham Science Publishers.

Coronavirus (COVID-19) and Employee Health

Background: The coronavirus, which is now spreading around the world as a pandemic has caused more than 30 million cases and nearly 1000,000 deaths worldwide. No vaccine has been used against the virus so far, and there are no specific drugs to cure the patients. This paper ex-amines the impact of the COVID-19 pandemic on employees' health, either in the governmental or private sector. The aim of this study was to protect the staff against the disease in pandemic conditions by identifying the main ways to keep employees healthy during the COVID-19 pandemic in different scenarios. Method(s): This paper is a perspective article, and different scenarios were assessed for the consider-ation of employee health. Result(s): Two scenarios could be considered first, when the vaccine against COVID-19 is not available for the prevention and the second scenario is that the vaccine is available for all in the world. In both cases, maintaining the health of the staff will be different. If the coronavirus disease will continue to occur in humans till the access to a safe vaccine is not possible, emphasis on maintaining health standards, keeping a social distance, and wearing the mask are the only ways to deal with this life threatening disease. Even after the preparation of the vaccine, maintaining health stan-dards, keeping a social distancing, and wearing the mask must be continued. Conclusion(s): The high level of health for the employee must be considered by governments in dif-.Copyright © 2021 Bentham Science Publishers.

What is the role of brown adipose tissue in metabolic health: lessons learned and future perspectives in the long COVID?

Metabolic physiology plays a key role in maintaining our health and resilience. Metabolic disorders can lead to serious illnesses, including obesity. The pathogenesis of the new long COVID syndrome in individuals with long-term recovery after SARS-Co-2 infection is still incomplete. Thus there is growing attention in the study of adipose tissue activities, especially brown adipose tissue (BAT) and associated resilience which plays a crucial role in different types of obesity as potential targets for pharmacologic and nutritional interventions in the context of obesity and long COVID. The number of studies examining mechanisms underlying BAT has grown rapidly in the last 10 years despite of role of BAT in individuals with COVID-19 and long COVID is modest. Therefore, this review aims to sum up data examining BAT activities, its resilience in health, obesity, and the possible link to long COVID. The search was conducted on studies published in English mostly between 2004 and 2022 in adult humans and animal models. Database searches were conducted using PubMed, Scopus, and Google Scholar for key terms including adipose tissue, BAT, adipokines, obesity, VPF/VEGF, and pathogenesis. From the initial search through the database were identified relevant articles that met inclusion and exclusion criteria and our data regarding adipose tissues were presented in this review. It will discuss adiposity tissue activities. Current literature suggests that there are BAT integral effects to whitening and browning fat phenomena which reflect the homeostatic metabolic adaptive ability for environmental demand or survival/adaptive mechanisms. We also review neural and vascular impacts in BAT that play a role in resilience and obesity. Finally, we discuss the role of BAT in the context of long COVID in basic research and clinical research.

Mechanism-based approaches of 1,3,4 thiadiazole scaffolds as potent enzyme inhibitors for cytotoxicity and antiviral activity

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)

Vascular adhesion protein-1 (VAP-1) in vascular inflammatory diseases.

Vascular adhesion protein-1 (VAP-1) also known as amino oxidase copper containing 3 (AOC3) is a pro-inflammatory and versatile molecule with adhesive and enzymatic properties. VAP-1 is a primary amine oxidase belonging to the semicarbazide-sensitive amine oxidase (SSAO) family, which catalyzes the oxidation of primary amines leading to the production of ammonium, formaldehyde, methylglyoxal, and hydrogen peroxide. VAP-1 is mainly expressed by endothelial cells, smooth muscle cells, adipocytes and pericytes. It is involved in a repertoire of biological functions, e.g., immune cell extravasation, angiogenesis, and vascularization. Research into VAP-1 has intensified within the last decade on its role as a novel clinical biomarker and as a potential therapeutic target of vascular inflammatory disorders such as atherosclerosis, stroke, diabetes, neurovascular disorders (e.g., Alzheimer's Disease), hepatic disease (e.g., non-alcoholic steatohepatitis), and skin conditions (e.g., psoriasis). This is the most up-to-date and comprehensive review on VAP-1 focusing on the translational aspects of VAP-1. Compared to recent reviews, our review provides novel insights on VAP-1 and heart failure, stroke and frailty, diabetes, endometriosis, osteoarthritis, COVID-19, conjunctivitis associated systemic lupus erythematosus, hematopoietic stem cells, gliomas, treatment of colorectal cancer with a novel VAP-1 inhibitor (U-V269), promoting recovery of motor functions and habit learning with a novel VAP-1 inhibitor (PXS-4681A), and 68Ga-DOTA-Siglec-9, a labelled peptide of Siglec-9 (a VAP-1 ligand), which appears to be a safe PET tracer for inflammation in rheumatoid arthritis. Finally, we present the emerging role of VAP-1 in pregnancy as a gatekeeper of immune cells, which are critical for spiral arterial remodeling, the deficiency of which could lead to vascular disorders of pregnancy such as preeclampsia. Future research should prioritize clinical trials on VAP-1 small-molecule inhibitors and monoclonal antibodies, thus, maximizing the potential of VAP-1 targeted therapy as well as research into sVAP-1 as a clinical biomarker of diseases and its prognosis.

Amine-Functionalized Silver Nanoparticles: A Potential Antiviral-Coating Material with Trap and Kill Efficiency to Combat Viral Dissemination (COVID-19).

The outbreak of COVID-19 has drastically affected the daily lifestyles of people globally where specific Coronavirus-2 transmits primarily by respiratory droplets. Structurally, the SARS-CoV-2 virus is made up of four types of proteins in which S-protein is indispensable among them, as it causes rapid replication in the host body. Therefore, the glycine and alanine composed of HR1 of S-protein is the ideal target for antiviral action. Different forms of surface-active PPEs can efficiently prevent this transmission in this circumstance. However, the virus can survive on the conventional PPEs for a long time. Hence, the nanotechnological approaches based on engineered nanomaterials coating on medical equipments can potentially prevent the dissemination of infections in public. Silver nanoparticles with tuneable physicochemical properties and versatile chemical functionalization provide an excellent platform to combat the disease. The coating of amine-functionalized silver nanoparticle (especially amine linked to aliphatic chain and trialkoxysilane) in its nanostructured form enables cloths trap and kill efficient. PPEs are a primary and reliable preventive measure, although they are not 100% effective against viral infections. So, developing and commercializing surface-active PPEs with trap and kill efficacy is highly needed to cope with current and future viral infections. This review article discusses the COVID-19 morphology, antiviral mechanism of Ag-NPs against SARS-CoV-2 virus, surface factors that influence viral persistence on fomites, the necessity of antiviral PPEs, and the potential application of amine-functionalized silver nanoparticles as a coating material for the development of trap and kill-efficient face masks and PPE kits.

Lipid Nanoparticles With Low Immunogenicity For Nucleic Acid Delivery

Purpose/Objectives: The delivery of nucleic acids to cells has revolutionized medicine and enabled new technologies such as mRNA vaccines and stem cell therapies. These recent advances rely on delivery vehicles to stabilize the genetic payload and increase cellular transfection. While engineered viruses are efficient vectors for ex vivo cellular reprogramming, they are not ideal for in vivo gene therapies as repeated dosing leads to anti-vector immunity. Lipid nanoparticles have thus emerged as the best alternative to viral vectors for in vivo nucleic acid delivery. However, all FDA-approved lipid nanoparticles have been linked to inflammatory responses, undesirable for regenerative medicine applications that require precise immunomodulation. Thus, non-immunogenic delivery materials must be developed to fulfill the immense potential of gene therapy in regenerative medicine. Lipid nanoparticles typically comprise 4 different lipids, with the ionizable amino lipid being the main driver of potency and immunogenicity. A way to reduce immunogenicity is to develop lipid nanoparticles that minimize the amount of lipids per gram of nucleic acids. To do so, we developed a novel class of ionizable amino lipids with high charge density. Our primary objective is to design a lipid nanoparticle that maximizes RNA delivery and minimizes immunogenicity. Methodology: We designed a library of proprietary ionizable lipids based on the structure of a poly(amido amine) dendron. The structure is modular, which allowed us to systematically vary molecular motifs to optimize important physiochemical parameters: Lipid-to-RNA ratio;apparent pKa;surface zeta potential;size distribution;and RNA encapsulation These structures are also designed to include a higher number of amines compared to current ionizable lipids. This improves ionization charge density of the lipid and lowers the amount of lipid required to encapsulate RNA. In this study, lipid nanoparticles contain an ionizable lipid selected from our library, cholesterol, a phospholipid, and a PEG-lipid. The lipids and formulation conditions were selected to mimic Moderna's COVID-19 vaccine (SpikeVax), albeit with different lipid-to-RNA ratios. C57BL/6 mice were injected intramuscularly with nanoparticles co-formulated with a firefly luciferase mRNA and ovalbumin mRNA to simultaneously study transfection efficiency and antigen-specific immune responses. Nanoparticles that comprise SM-102, the ionizable lipid used in SpikeVax, were used as a comparative control due to their high potency and immunogenicity. Luciferase activity was detected using an IVIS Spectrum, and key organs were harvested for immune phenotyping. Results: We have so far determined the effect of hydrophobic motifs on apparent pKa and RNA encapsulation. Our best lipids with optimized tails did not induce IFN-I responses in vitro and demonstrated comparable in vivo efficacy to SM-102. We are currently in the process of collecting immunogenicity data which we expect to complete prior to the conference. Conclusion/Significance: We have produced a novel set of lipid nanoparticles that efficiently transfect cells in vivo. These new particles deliver RNA with half of the lipid mass used in SpikeVax, which can reduce the amount of material-induced immunogenicity. This result opens the door to developing mRNA vaccines with fewer side effects and equitable gene therapies for untreatable diseases such as inflammatory and autoimmune disorders.

Clinical features and treatment of mixed cardiogenic and distributive shock in patients with multisystem inflammatory syndrome in children (MIS-C)

Background and Aim: Mixed shock in multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 is con-sequence of acute heart failure, inflammation-induced vasodilation and potential volume loss. Method(s): Retrospective analysis included 25 patients (7 girls) with MIS-C-related combined shock, treated in period from April 2020 to December 2021. Result(s): Mean age of patients was 12.6 +/- 4.0 years. Admission was 6.1 +/- 1.6 days after symptoms onset. Systemic inflammatory response was manifested with neutrophilia (10.7 +/- 4.2 x109/), lymphopenia (1.1 +/- 0.7 x109/L), elevated CRP (220.9 +/- 86.1 mg/L), ferritin (684.5 +/- 549.5 mug/L) and D-dimer (1528 +/- 1254 ng/mL). One third of patients had acute kidney injury with glomerular filtration rate of 64 +/- 22 mL/min/1.73 m2 and urea level of 16.0 +/- 8.4 mmol/L. All patients had acute heart failure with ejection fraction 47.2% +/- 7.7% and fractional shortening 23.6% +/- 4.9%, 92% of patients had NTproBNP gt;1500 pg/mL and 58% had elevated troponin I (1.34 +/- 1.47 ng/mL). Z-scores for end-diastolic left ventricle, interventricular septum and pos-terior wall diameters were 0.7 +/- 1.1, 1.7 +/- 1.3 and 0.6 +/- 0.7 respectively. All patients had mild/moderate mitral regurgitation, and 60% had mild pericardial effusion. Inotropes, administered during first 3.7 +/- 1.6 days, were divided in three groups: 1) dop-amine (n = 14), 2) dobutamine + dopamine (n = 5), 3) milrinone +/- dopamine (n = 6). Additional treatment included diuretics and captopril. Total fluid balance (including insensible loss of 300 mL/m2/day) through days 1-7 was +860 mL/m2, +128 mL/m2,-108 mL/m2,-36 mL/m2,-306 mL/m2,-335 ml/m2,-298 ml/m2 (total-95 ml/m2). Methylprednisolone/intravenous immuno-globulin and low-molecular-weight heparin/acetylsalicylic acid were administered and fever persisted 1.2 days averagely. Oxygen supplementation was needed in 71% of patients. Transitory bradycardia was noticed and there was no difference in heart rate between treatment groups. Profound hypotension was revealed on admission and correction differed regarding treat-ment (p lt;0.05) (Figure 1). All patient survived with clinical improvement (one had mechanical ventilation, and one had stroke). Conclusion(s): Mixed shock is the most severe manifestation of MIS-C, and treatment of heart failure should be combined with cau-tious fluid resuscitation.

METABOLOMIC PROFILING AND PROGNOSTICATION IN COVID-19-RELATED ARDS

SESSION TITLE: Late Breaking Posters in Critical Care SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: The majority of deaths in COVID-19 are due to acute respiratory distress syndrome (ARDS). We recently identified two subphenotypes among patients with COVID-19 related ARDS (C-ARDS) with divergent outcomes and responses to therapies. However, the precise biological processes that distinguish the subphenotypes, remain to be fully elucidated. High-resolution profiling of the metabolome can be used to gain precise insights into disease pathogenesis. The purpose of this study was to use precise, metabolomic profiling at the onset of C-ARDS to identify metabolic alterations and predict hospital mortality. METHODS: This was a retrospective, matched cohort study. Participants were adults with COVID-19 who met Berlin criteria for ARDS on the initial day of mechanical ventilation. All participants had prospectively banked plasma samples collected within one week of intubation. Twenty-five survivors to 90-days were matched on age, sex, and ethnicity to 25 patients who died within 28 days of intubation. Untargeted and targeted metabolomic analysis was performed using mass spectrometry and compared between survivors and non-survivors. Statistical analyses were performed with conditional logistic regression modeling with Bayesian inference. Compounds associated with mortality were identified using a cut-off of Bayes Factor (BF) > 3. Biological clustering analysis was performed using ChemRICH. Competitive modeling by four machine learning models—LASSO, adaptive LASSO, Random Forest, and XGBoost—was used to predict mortality. Three sets of predictors were explored: all metabolites, metabolites with BF > 1, and metabolites with BF > 3. RESULTS: Targeted and untargeted metabolomics of metabolic analytes yielded data for 30 bile acids, 340 biogenic amines, 522 complex lipids, 83 oxylipins, and 133 primary metabolites. Twenty-five compounds were identified with significant differences between survivors and non-survivors. Five compounds had increased levels associated with mortality, and 20 had decreased levels associated with mortality. Biological clustering analysis on these compounds identified four key clusters of compounds—unsaturated and saturated lysophosphatidylcholines, plasmalogens, and saturated ceramides—that were decreased amongst non-survivors. A machine learning-derived signature reflecting these metabolites showed excellent discrimination in predicting mortality, with the best model demonstrating area-under-the-receiver-operating-characteristic curve of 0.91. CONCLUSIONS: Metabolomic analysis identified differential enrichment of lipid metabolites in C-ARDS survivors compared to non-survivors. A machine learning model was able to accurately predict mortality from C-ARDS based on metabolomic profiles. CLINICAL IMPLICATIONS: Improved characterization of the metabolomic derangements in COVID-19 ARDS may lead to an enhanced understanding of drivers of mortality and improve prognostication and precision therapy. DISCLOSURES: No relevant relationships by Thomas Briese No relevant relationships by Xiaoyu Che No relevant relationships by Matthew Cummings No relevant relationships by Oliver Fiehn No relevant relationships by David Furfaro No relevant relationships by Wenhao Gou no disclosure on file for Walter Lipkin;no disclosure on file for Nischay Mishra;No relevant relationships by Max O'Donnell

The 43rd Annual Meeting of the Canadian College of Neuropsychopharmacology November 4, 2021

OVERVIEW OF EVENTS 10:30 am Opening of Meeting 10:45 am Opening Remarks - Dr. Jeff Daskalakis, CCNP President 10:50 am Introduction - Dr. Cecilia Flores, CCNP Vice-President 11:00 am CCNP 2020 Young Investigator Award Presentation Caroline Ménard, PhD, Department of Psychiatry & Neuroscience, Université Laval: "Sex-specific vascular alterations and biomarkers underlie stress responses in mice mirrored in human depression" 11:50 am CCNP Next Generation Awardee Andrea H. Pantoja Urban, MSc, Integrated Program in Neuroscience, McGill University: "Short and long-term effects of social defeat stress in adolescent female mice" 12:05 pm CCNP Next Generation Awardee Orna Issler, PhD, Department of Neuroscience, Mount Sinai:"The sex-specific role for long noncoding RNAs in depression: from genome-wide patterns to behavioral readout" 12:20 pm Lunch/Break 12:50 pm CCNP 2020 Heinz Lehmann Award Presentation Martin Alda, MD, FRCPC, Department of Psychiatry, Dalhousie University: "Personalized long-term treatment of bipolar disorder" 1:40 pm CCNP Next Generation Awardee Mikaela K Dimick, BA, Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health: "Cerebral blood flow and core mood symptoms in youth bipolar disorder: evidence for region-symptom specificity" 1:55 pm CCNP Next Generation Awardee Sneha Chenji, PhD, Department of Psychiatry & Pediatrics, University of Calgary: "The effect of rTMS treatment on cortico-striatal-thalamo-cortical (CSTC) circuit connectivity in Tourette's syndrome: a pilot study" 2:10 pm Break 2:20 pm CCNP 2020 Innovations in Neuropsychopharmacology Award Presentation Jeffrey Meyer, MD, PhD, FRCPC, Department of Psychiatry, University of Toronto: "Imaging markers of gliosis and monoamine oxidase in major depressive disorder: implications for personalized prevention and treatment" 3:10 pm CCNP Next Generation Awardee Jasmine D. Cakmak, MSc, Neuroscience, Western University: "The functional and structural consequences of aberrant microglial activity in major depressive disorder" 3:25 pm CCNP Next Generation Awardee Kayla D. Stone, PhD, Department of Psychiatry, University of Calgary: "Dorsolateral prefrontal cortex neurometabolite concentrations in pediatric mild traumatic brain injury" 3:40 pm Break 3:50 pm Keynote Speaker Rémi Quirion, OC, CQ, PhD, FRSC, Chief Scientist of Quebec, Ministry of Economy & Innovation: "A less well travelled road: from neuroscientist to chief scientist and then came COVID-19" 4:50 pm Closing Remarks - Dr. Cecilia Flores, CCNP Vice President Acknowledgments: In keeping with CMA guidelines, program content and selection of speakers are the responsibility of the planning committee. Methods: Here, we characterized the enduring changes in histone modifications in the NAcc of mice exposed to chronic social defeat stress (CSDS), a validated model for the study of depression-like behaviours that separates mouse populations into susceptible (SUS) and resilient (RES) based on a social interaction test (SIT). Tissue from the NAcc of control, SUS, and RES mice was collected either 24 hours or 4 weeks after the SIT and processed for histone profiling via mass spectrometry. From the Department of Psychiatry, University of Alberta, Edmonton, AB, Canada (Yap, Luki, S. Hanstock, Lirette, Zhaoa, Aitchison, Le Melledo);the Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada (Aitchison);the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada (Aitchison);the Edmonton Mood and Anxiety Disorders Program, University of Alberta Hospital, Edmonton, AB, Canada (Aitchison);the Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada (C. Hanstock, Seres);and the Royal Alexandra Hospital, Edmonton, AB, Canada (Shandro).

Severe COVID-19 Is Characterised by Perturbations in Plasma Amines Correlated with Immune Response Markers, and Linked to Inflammation and Oxidative Stress.

The COVID-19 pandemic raised a need to characterise the biochemical response to SARS-CoV-2 infection and find biological markers to identify therapeutic targets. In support of these aims, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The first publication in a series reports the results of quantitative LC-MS/MS profiling of 56 amino acids and derivatives. A comparison between samples taken from ICU and ward patients revealed a notable increase in ten post-translationally modified amino acids that correlated with markers indicative of an excessive immune response: TNF-alpha, neutrophils, markers for macrophage, and leukocyte activation. Severe patients also had increased kynurenine, positively correlated with CRP and cytokines that induce its production. ICU and ward patients with high IL-6 showed decreased levels of 22 immune-supporting and anti-oxidative amino acids and derivatives (e.g., glutathione, GABA). These negatively correlated with CRP and IL-6 and positively correlated with markers indicative of adaptive immune activation. Including corresponding alterations in convalescing ward patients, the overall metabolic picture of severe COVID-19 reflected enhanced metabolic demands to maintain cell proliferation and redox balance, alongside increased inflammation and oxidative stress.

A scalable process for the synthesis of key intermediates novoldiamine & hydroxynovaldiamine and their utility in chloroquine, hydroxychloroquine and mepacrine synthesis

A highly efficient and scalable process for the synthesis of novoldiamine and hydroxynovaldiamine is accomplished from levulinic acid, which is easily accessible from the natural feedstock. These diamines are used as the key intermediates for the synthesis of chloroquine, hydroxychloroquine and mepacrine. The key steps involved in this process are the coupling of levulinic acid with secondary amine assisted by 1, 1'-carbonyldiimidazole and one-pot reduction of oxime-amide functional groups to get the corresponding diamine.

Development of novel effective agents from 1H-indolylammonium trifluoroacetates effective against conditionally pathogenic microorganisms

Introduction: The problem of antibiotic resistance of microorganisms is becoming more urgent in the twenty-first century. More and more pathogenic microbes are becoming resistant to two or more antibiotics. This problem has become worse into the COVID-19 pandemic. The search for new compounds with antimicrobial activity is one of the principles for overcoming the antibiotic resistance of microorganisms. Materials and methods: Methods for the preparation, isolation, and identification of salts of 2,3,5-trimethyl-, 1,2,3,5-tetramethyl-, 2,3-dimethyl-5-methoxy-, 5-methoxy-1,2,3-trimethyl-1H-indole-6-amines and trifluoroacetic acid were developed and laboratory microbiological studies of them for antimicrobial activity were carried out. Sensitivity of the test-strains of microorganisms to the new compounds was studied. A method of serial dilutions to determine the minimal inhibitory concentration (MIC) of the compounds under study was used in the study. Results and discussion: The compounds 5-8 showed a pronounced antibacterial activity against the test strains of microorganisms in vitro with MIC from 0.98 μg/mL to 125.0 μg/mL. The prospects for targeted synthesis of biologically active compounds which are derivatives of 1H-indolylamines with a trifluoromethyl group in the molecule were determined, and after additional studies, the compounds 5-8 may find application as water-soluble synthetic antimicrobial agents. Conclusion: The laboratory microbiological screening of showed that they have an antimicrobial effect that exceeds the activity of the reference drug, dioxidine. The presence of molecular mechanisms predicted in silico in the spectrum of biological activity of the studied compounds, such as Pseudolysin inhibitor, Omptin inhibitor, Undecaprenyldiphospho-muramoylpentapeptide beta-N-acetylglucosaminyltransferase inhibitor, UDP-epimerase inhibitor, Bacterial efflux pump inhibitor, suggests the presence of antimicrobial activity against gram-positive and gram-negative microorganisms. Trifluoroacetates 2,3,5-trimethyl-1H-indole-6-ammonium (5), 1,2,3,5-tetramethyl-1H-indole-6-ammonium (6), 2,3-dimethyl-5-methoxy-1H-indole-6-ammonium (7), 1,2,3-trimethyl-5-methoxy-1H-indole-6-ammonium (8), after additional studies, may find application as water-soluble synthetic antimicrobial agents.

Wang-OSO3H catalyzed green synthesis of bioactive isoindolo 2,1-a quinazoline-5,11-dione derivatives: An unexpected observation

The sulphonic acid-functionalized Wang resin (Wang-OSO3H) was explored as a polymeric and recov-erable acidic catalyst for the synthesis of isoindolo[2,1-alpha]quinazoline-5,11-dione derivatives under green conditions. Thus the Wang-OSO3H catalyzed MCR of isatoic anhydride, 2-formylbenzoic acid and vari-ous amines in pure water afforded a range of desired product in good to excellent (86-94%) yield. The methodology can be performed under open air and is amenable for scale-up synthesis. The catalyst can be recovered and recycled for several times without significant loss of its catalytic activity. The unex-pected formation of 2-(1-hydroxy-3-oxoisoindolin-2-yl)benzamide derivative as observed in one case may allow the access of this class of heterocycles from the same MCR by using an appropriate amine. In silico assessment suggested that the compound 4j , a known inhibitor of TNF-alpha could be a potential ligand for SARS-CoV-2 with which it formed H-bonds through its OMe and two C = O groups. (C) 2021 Elsevier B.V. All rights reserved.

The unexpected decrease of Kawasaki syndrome during the second COVID-19 wave: the report from the COVASAKI survey

Introduction: During the first pandemic wave, Tuscany reported the fifth Italian highest number of COVID-19 cases in Italy even if this prevalence was lower if compared to other high-prevalence regions in the North of Italy. From September 2020, Tuscany situation has deeply changed with a significant increase of SARS CoV-2 positive cases, currently standing almost 234,000. Objectives: The Pediatric Tuscany Network continued the COVASAKI survey with the aim to track children who received a Kawasaki Syndrome (KS) or Multisystem Infalmmatory syndrome (MIS-C) diagnosis during the second vawe of COVID-19 pandemic. Methods: We retrospectively collected demographics, clinical findings, treatment and outcome of KS and MIS-C children between November 1st, 2020 to April 30th,2021 and compared the number of KS cases during this period to the number of reported KS children in the first pandemic vawe and in the previous five years in the same region. Results: 14 MIS-C children were admitted to 5 Paediatric Units (incidence 2.3/month), 10 boys and 4 girls (mean age of 9.6 years [IQR] 8.8-12). 11/14 patients required intensive care unit admission: 10 needed amines and 3 underwent mechanical ventilation. Echocardiography revealed a reduced left ventricular ejection fraction in 8/14. A diffuse coronary artery ectasia was found in 1. All children completely recovered with a timely immunomodulatory treatment with intravenous immunoglobulins, steroids and, in case of severe cardiac involvement, anakinra. Nasopharyngeal swabs and serological test for SARS CoV-2 resulted positive in 5/13 and 14/14 respectively. The MIS-C incidence rate, adjusted for the 5,170 children hospitalized, resulted 0.27% and represented the 13.9 % of paediatric COVID 19- related hospital admissions in Tuscany. Conversely, the number of observed KS significantly reduced comparing to the first six months of COVASAKI survey: 3 cases, 0.5 incidence/month vs 11 cases, 1.8 incidence/ month (p <0.03, RR 0.27, 95% CI 0.06 to 0.92). Comparing the 2.7 incidence/month of the 165 diagnosed KS from 1st January 2015 to 31th January 2020, a statistically significant difference has been detected (p <0.0005, RR 0.24, 95% CI 0.07 to 0.59). The same result has been found limiting the analysis to the 92 children with KS diagnosed during the same corresponding 6 months of the last 5 years: 3.0 versus 0.7 incidence/month (p <0.0002, RR 0.21, 95% CI 0.06 to 0.53). Conclusion: Our results seem in accordance with the hypothesis of an infectious trigger in KS pathogenesis. The stay-home imposed by pandemic and the extensive adoption of barrier protection devices have concomitantly reduced the incidence of respiratory infections among general and paediatric population. At this regard, the massive drop in the number of influenza and Syncytial Virus infections during the winter months results emblematic. From this point of view, it could be hypothesized that, in contrast to what had been previously reported in the early stages of its outbreak, the SARS CoV-2 pandemic could lead to a reduction rather than a substantial increase in the number of KS cases. Although indirectly, the behavioural measures adopted to contain the contagion or maybe further mechanisms not yet identified might be the reason.