Hairy Cell Leukemia in a Filipino Male during the COVID-19 Pandemic - Report of a Rare Case

Hairy cell leukemia (HCL) is a rare, chronic, mature B-cell lymphoproliferative disorder accounting for 2% of all leukemias. In this paper, we would like to present our experience in the management of HCL in a financially limited setting where other diagnostic tests and chemotherapy are unavailable. The case report aims to emphasize the recognition of the distinctive morphology of hairy cells in the peripheral blood in the consideration of the initial diagnosis. A 60-year-old Filipino male was incidentally found to have anemia, thrombocytopenia and an absolute neutrophilic count below 1,000 in a pre-operative clearance for elective herniorrhaphy. Blood smear revealed atypical lymphocytes with hair like cytoplasmic projections. CT-scan of the abdomen showed splenomegaly and prominent paraaortic nodes. Flow cytometry of the bone marrow aspirate was consistent with an involvement of a Mature B cell neoplasm markers CD19, CD20, CD22 and surface immunoglobulin lambda and hairy cell leukemia markers CD11c, CD103 and CD25. He responded to six-weekly sessions of Cladribine with remission of the bone marrow and hematologic parameters. HCL is a rare type of a mature B cell neoplasm characterized by pancytopenia, splenomegaly, bone marrow fibrosis and the presence of atypical lymphoid cells with hairy projections in blood, bone marrow and spleen. Immunophenotyping express CD11c, CD103, CD123, and CD25. BRAF V600E mutation is the disease defining genetic event. Cladribine and Pentostatin are the first line of treatment. Cases of leukemia can be easily overlooked because of the mild derangement in the complete blood count. A meticulous differential review of the atypical lymphocyte, is the first step in the diagnosis of this rare disease.Copyright © 2022, Philippine College of Physicians. All rights reserved.

The abundance of Interleukin-22, 37, and 38 post-vaccination and following COVID-19 recuperation

The SARS-CoV-2 virus causes a contagious disease known as Coronavirus Disease 2019 (COVID-19). It began spreading globally in 2019 and is still producing pandemics today. Different COVID-19 vaccinations offer protection against this illness. Pfizer-BioNTech and Sinopharm were the two vaccine manufacturers with the highest usage in Iraq. Both vaccines use a different method to activate the immune system. This study seeks to compare the IL-22, IL-37, and IL-38 levels in those who received either the Sinopharm or the Pfizer-BioNTech COVID-19 vaccination. IL-22, IL-37, IL-38 levels have been shown to be upregulated in COVID-19 patients. In this study, IL-22, IL-37, and IL-38 levels were tested in 80 healthy controls and 100 COVID-19 patients 14-21 days after recovery. Additionally, people who received the Sinopharm or Pfizer-BioNTech vaccine (50 each) were monitored 21 days after the first dosage and 21 days after the second dose. In comparison to controls, serum levels were noticeably higher in recovered patients. Except for the first dosage of Pfizer BioNTech, the first and second doses of Sinopharm and Pfizer BioNTech were linked to considerably higher levels of IL-22, IL-37, and IL-38 compared to controls or recovered patients. where IL-22, IL-37, and IL-38 levels did not show significant differences compared to recovered patients. In conclusion, lower IL-37 and IL-38 molecule levels were linked to recovery from COVID-19, although these levels remained considerably greater in recovered patients compared to uninfected controls. Vaccination with Sinopharm or Pfizer-BioNTech confirmed the up-regulating effects of SARS-CoV-2 on IL-22, IL-37, and IL-38 levels.Copyright © 2023, Codon Publications. All rights reserved.

COVID-19 Anxiety and Washing Obsessive-compulsive Symptoms: Stress Coping Styles as a Mediator

Background: The COVID-19 pandemic has significantly impacted people's psychological functioning, including how they cope with anxiety. This study aimed to assess the role of coping styles in the relationship between COVID-19 anxiety and Washing ObsessiveCompulsive Disorder (W-OCD) symptoms. Methods: A cross-sectional study was performed on 420 people living in Kashan city (Iran) from March to April, 2020. Participants were selected by the convenience sampling method due to the difficulties brought about by COVID-19 and completed the contamination subscale of the Padua Inventory, COVID-19 anxiety inventory, and coping strategies scale. Data were analyzed by structural equation modeling (SEM) using AMOS-22. Results: The results revealed that emotion-focused, somatization and social support coping strategies were significantly associated with W-OCD symptoms. Also, there was a significant correlation between COVID-19 anxiety and the W-OCD symptoms. SEM results revealed that emotion-focused and somatization coping strategies positively mediated the relationship between COVID-19 and W-OCD symptoms. Conclusion: Emotion-focused and somatization coping strategies increase W-OCD symptoms following COVID-19 anxiety. Psychoeducation interventions addressing COVID-19's physical and psychological impacts on health, discriminating the rational and adaptive behavior and obsessive and compulsive behaviors, and restricting the information gathering from numerous sources, which may lead to increased negative emotions, might be helpful. © 2023 Bentham Science Publishers.

Impact of the COVID-19 Pandemic on Middle-Aged and Older Patients With Adolescent Idiopathic Scoliosis Who Underwent Spinal Fusion: A Questionnaire-Based Survey.

Purpose To investigate the impact of the COVID-19 pandemic on middle-aged and older patients with adolescent idiopathic scoliosis (AIS) who underwent spinal fusion. Methods The subjects were 252 AIS patients who underwent spinal fusion between 1968 and 1988. The surveys were performed before the COVID-19 pandemic (a primary survey in 2014) and during the pandemic (a secondary survey in 2022). The self-administered questionnaires were mailed to the patients. We analyzed 35 patients (33 females and two males) who replied to both surveys. Results The pandemic had low impacts on 11 patients (31.4%). Two patients reported refraining from seeing a doctor because they were concerned about going to the clinic or hospital, eight reported that the pandemic impacted their work, and five reported fewer opportunities to go out (based on multiple-choice answers). Twenty-four patients reported that their lives were unaffected by the pandemic. No significant differences were detected between both surveys for Scoliosis Research Society-22 (SRS-22) in any domains (function, pain, self-image, mental, or satisfaction). The Oswestry Disability Index (ODI) questionnaires revealed a significant worsening of the survey during the pandemic compared with the survey before the pandemic. There was no significant difference in the impact of the pandemic between the ODI deterioration group (27.8%) and the ODI stable group (35.3%). Conclusion The COVID-19 pandemic had a low impact on 31.4% of middle-aged and older patients with AIS who underwent spinal fusion. The impact of the pandemic did not significantly differ between the groups with ODI deteriorations and the groups with stable ODI. The pandemic had a smaller impact on AIS patients at a minimum of 33 years after surgery.

Predictive Value of Specific Cytokines for Lethal Covid-19 Outcome

In our study, we aimed to evaluate the significance of specific cytokines in blood plasma as predictive markers of COVID-associated mortality. Materials and methods. In plasma samples of 29 patients with PCR-confirmed COVID-19 we measured the concentrations of 47 molecules. These molecules included: interleukins and selected pro-inflammatory cytokines (IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IL-17-E/IL-25, IL-17F, IL-18, IL-22, IL-27, IFNalpha2, IFNgamma, TNFalpha, TNFbeta/Lymphotoxin-alpha(LTA));chemokines (CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROalpha, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine);anti-inflammatory cytokines (IL-1Ra, IL-10);growth factors (EGF, FGF-2/FGF-basic, Flt-3 Ligand, G-CSF, M-CSF, GM-CSF, PDGF-AA, PDGFAB/BB, TGFalpha, VEGF-A);and sCD40L. We used multiplex analysis based on xMAP technology (Luminex, USA) using Luminex MagPix. As controls, we used plasma samples of 20 healthy individuals. Based on the results, we applied Receiver Operating Characteristic (ROC) analysis and Area Under Curve (AUC) values to compare two different predictive tests and to choose the optimal division point for disease outcome (survivors/non-survivors). To find optimal biomarker combinations, we as used cytokines concentrations as dependent variables to grow a regression tree using JMP 16 Software.Results. Out of 47 studied cytokines/chemokines/growth factors, we picked four pro-inflammatory cytokines as having high significance in evaluation of COVID-19 outcome: IL-6, IL-8, IL-15, and IL-18. Based on the results received, we assume that the highest significance in terms of predicting the outcome of acute COVID-19 belongs to IL-6 and IL-18. Conclusion. Analyzing concentrations of IL-6 and IL-18 before administering treatment may prove valuable in terms of outcome prognosis. Copyright © Arsentieva N.A. et al., 2022.

Working from home for good? Lessons learned from the COVID-19 pandemic and what this means for the future of work

In the wake of the COVID-19 pandemic, more firms than ever before have enabled their employees to work from home. Based on a representative firm survey in Germany, surveying 2.000 firms per month throughout the course of the pandemic (October 2020 until June 2022), this paper provides suggestive evidence concerning the effects of working from home (WFH) at different points in time during the pandemic and discusses implications for the future of work. We assess the potential of WFH in Germany to be 25–30% of private-sector employees. On the firm side, we find that higher WFH use is positively related to business success during the crisis, with increased employee productivity and employees working more hours when remote being possible mechanisms. Larger firms in particular are open towards expanding their WFH offerings in the future. During the pandemic, firms have experienced that WFH has worked well in many respects (e.g., productivity of employees, quality of work performed) and, for the future, they are willing to facilitate WFH in order to give their employees more flexibility, and to be considered an attractive employer. However, working on site brings advantages (e.g., communication, cooperation and onboarding of new employees) firms will not want to sacrifice, pointing towards a hybrid model of work.

Leucemia Aguda De Fenotipo Misto - Apresentacao Inicial Atipica - Um Relato De Caso

Introducao: Com desafiador tratamento e de diagnostico criterioso, a leucemia aguda de fenotipo misto (LAFM) e uma entidade rara dentro do espectro das leucemias agudas. Requer a presenca imunofenotipica de marcadores de linhagem B (CD19, CD22, CD79a), T (CD3) em conjunto com a linhagem mieloide (mieloperoxidase e diferenciacao monocitica - CD11c, CD14, CD64 ou lisozima). Relato de caso: Paciente masculino, 30 anos, obeso e diabetico tipo 2, hipertrigliceridemia, inicia com febre (38C), dor abdominal em hipocondrio direito e fadiga. Com dois dias de sintomas procura atendimento sendo liberado com sintomaticos. No quarto dia de sintomas houve piora da febre (39degreeC) e da dor, surgindo maculas hiperemiadas pruriginosas pelo corpo, ictericia e coluria. Retornou ao hospital de sua cidade sendo prescrito azitromicina e liberado com suspeita de influenza. No sexto dia de sintomas notou piora da ictericia, procurando, novamente, atendimento. Encaminhado, entao ao servico de referencia da regiao. Interna inicialmente na equipe da gastroenterologia como suspeita de hepatite viral. Na chegada: Hb 14,9, leucocitos 6140 com 2793 neutrofilos, 442 monocitos e 2812 linfocitos, 53 mil plaquetas;AST 57, ALT 733, hiperbilirrubinemia as custas de bilirrubina direta. Com todos os marcadores virais negativos, prosseguiu a investigacao de hepatite. No dia em que realiza ressonancia magnetica, que indicava processo infiltrativo/inflamatorio em figado e rim esquerdo, alem de testar positivo para COVID-19, ha evolucao no hemograma: Hb 10,7, leucocitos 7450 com 1192 blastos, 60 neutrofilos, 2012 monocitos e 4187 linfocitos, 23 mil plaquetas. Com o aparecimento de blastos, piora dos niveis de bilirrubinas e das lesoes de pele, foi realizado imunofenotipagem de sangue periferico que indicava leucemia monocitica aguda. Transferido a equipe da hematologia, sendo realizada biopsia de medula e iniciado protocolo 7 + 3 com substituicao das antraciclinas em falta no mercado por doxorrubicina 45 mg/m2. No terceiro dia da inducao, foi liberado o resultado da imunofenotipagem que confirmava o diagnostico de leucemia aguda de fenotipo misto B/mieloide, marcando CD19, CD22 e CD79a, com diferenciacao monocitica (CD14 e CD64). Cariotipo nao houve crescimento e PCR BCR/ABL negativo. Optado por seguir tratamento com 7 + 3, apresentando medula no D14 aplasiada e medula no D28 com doenca residual minima (DRM) negativa. Realiza tres consolidacoes com altas doses de citarabina (3g/m2). Paciente sustenta DRM negativa, estando em remissao completa. Iniciado manutencao com vincristina, mercaptopurina, metotrexato e prednisona. Aguarda transplante de celulas tronco hematopoieticas (TCTH). Discussao: Com o diagnostico de LAFM, o tratamento requer o maior numero de quimioterapicos, sendo sugerido o uso de protocolos para leucemia linfoblastica aguda. Como ja havia sido instituido o tratamento com doxorrubicina e citarabina, foi optado por seguir protocolo e, na manutencao da remissao completa, terminar as consolidacoes e iniciar a manutencao prevista pelo protocolo HyperCVAD. Devido a ser uma leucemia de alto risco, a realizacao do TCTH e necessaria e, neste caso relatado, a manutencao sera mantida ate a realizacao do transplante. Conclusao: Contudo, por se tratar de doenca rara e com poucos estudos publicados, requer compartilhamento de conhecimentos e condutas para melhora da abordagem. Copyright © 2022

Interactive deciphering electron-shuttling characteristics of Coffea arabica leaves and potential bioenergy-steered anti-SARS-CoV-2 RdRp inhibitor via microbial fuel cells.

Due to the pandemics of COVID-19, herbal medicine has recently been explored for possible antiviral treatment and prevention via novel platform of microbial fuel cells. It was revealed that Coffea arabica leaves was very appropriate for anti-COVID-19 drug development. Antioxidant and anti-inflammatory tests exhibited the most promising activities for C. arabica ethanol extracts and drying approaches were implemented on the leaf samples prior to ethanol extraction. Ethanol extracts of C. arabica leaves were applied to bioenergy evaluation via DC-MFCs, clearly revealing that air-dried leaves (CA-A-EtOH) exhibited the highest bioenergy-stimulating capabilities (ca. 2.72 fold of power amplification to the blank). Furthermore, molecular docking analysis was implemented to decipher the potential of C. arabica leaves metabolites. Chlorogenic acid (-6.5 kcal/mol) owned the highest binding affinity with RdRp of SARS-CoV-2, showing a much lower average RMSF value than an apoprotein. This study suggested C. arabica leaves as an encouraging medicinal herb against SARS-CoV-2.

IS PSORIATIC ARTHRITIS A RISK FACTOR for SEVERE COVID-19 INFECTION? DATA from the ARGENTINIAN REGISTRY SAR-COVID

Background: Comorbidities, particularly cardio-metabolic disorders, are highly prevalent in patients with psoriatic arthritis (PsA) and they were associated with an increased risk of atherosclerotic cardiovascular disease, which have been associated with higher morbidity and mortality. Whether PsA enhances the risk of SARS-CoV-2 infection or affects the disease outcome remains to be ascertained. Objectives: To describe the sociodemographic, clinical and treatment characteristics of patients with PsA with confrmed SARS-CoV-2 infection from the SAR-COVID registry and to identify the variables associated with poor COVID-19 outcomes, comparing them with those with rheumatoid arthritis (RA). Methods: Cross-sectional observational study including patients ≥18 years old, with diagnosis of PsA (CASPAR criteria) and RA (ACR/EULAR 2010 criteria), who had confrmed SARS-CoV-2 infection (RT-PCR or serology) from the SAR-COVID registry. Recruitment period was between August 13, 2020 and July 31, 2021. Sociodemographic variables, comorbidities, and treatments were analyzed. To assess the severity of the infection, the ordinal scale of the National Institute of Allergy and Infectious Diseases (NIAID)1 was used, and it was considered that a patient met the primary outcome, if they presented criteria of categories 5 or higher on the severity scale. For this analysis, Chi2 test, Fisher's test, Student's test or Wilcoxon test, and binomial logistic regression using NIAID>=5 as dependent variable were performed. Results: A total of 129 PsA patients and 808 with RA were included. Clinical characteristics are shown in Table 1. Regarding PsA treatment, 12.4% of PsA were receiving IL-17 inhibitors, 5.4% IL12-23 inhibitors, one patient apremilast and one abatacept. The frequency of NIAID≥5 was comparable between groups (PsA 19.5% vs RA 20.1%;p=0.976). (Figure 1). PsA patients with NIAID≥5 in comparison with NIAID<5 were older (58.6±11.4 vs 50±12.5;p=0.002), had more frequently hypertension (52.2% vs 23%;p=0.011) and dyslipidemia (39.1% vs 15%;p=0.017). In the multivariate analysis, age (OR 1.06;95% CI 1.02-1.11) was associated with a worse outcome of the COVID-19 (NIAID≥5) in patients with PsA, while those who received methotrexate (OR 0.34;95% CI 0.11-0.92) and biological DMARDs (OR 0.28;95% CI 0.09-0.78) had a better outcome. Conclusion: Although PsA patients have a higher frequency of cardiovascular and metabolic comorbidities than those with RA, the COVID-19 severity was similar. Most of the patients had mild SARS-CoV-2 infection and a low death rate.

MACROGLOBULINEMIA DE WALDENSTRÖM: RELATO DE CASO

Introdução: A macroglobulinemia de Waldenstrom (MW) é uma patologia linfoproliferativa neoplásica maligna das células plasmáticas e linfócitos B, normalmente responsável pela síntese das cadeias pesadas de imunoglobulinas. Diferente da leucemia linfoblástica aguda, os linfócitos mantêm a capacidade de se diferenciar e amadurecer em células plasmáticas. A MW possui características que variam de células linfoides maduras a plasmócitos. Imunofenotipagem de células obtidas a partir da medula óssea, dos linfonodos ou do sangue periférico de pacientes com essa doença mostram IgM citoplasmática detectável em células plasmáticas e imunoglobulina superficial na maioria dos linfócitos. Objetivo: Apresentar um caso de MW. Material e métodos: Revisão de prontuáriros médicos e literatura. Descrição do caso: Paciente do sexo masculino, 61 anos, apresentou epistaxe de grande volume com repetição, fadiga e astenia, além de perda de 15 quilos em 6 meses. Na admissão hospitalar apresentava os seguintes exames: anemia com hemoglobina 5,4 g/dL, hemácias de 1,45 milhão/mm3, plaquetopenia (87.000/mm3), presença de esplenomegalia importante, roleaux eritrocitário, esplenomegalia e linfonodomegalia abdominal. Solicitada avaliação com hematologista por paciente referir repetidas anemias ao longo da vida e histórico de transfusões de repetição. Seguem os resultados da investigação com especialisgta: Mielograma apresentou células linfoides de tamanho pequeno e aspecto maduro, algumas apresentando aspecto plasmocitoide. Imunofenotipagem de sangue periférico com CD20/CD38, CD38, CD200, CD19/CD200 positivo fraco;CD19, CD45, CD45/CD22, KAPPA, CD20: positivo de alta intensidade;KAPPA cito- plasmático e CD43 positivo. Dosagem de Imunoglobulinas: IgM 10.100 mg/dL, IgG 242 mg/dL e IgA 91,5 mg/dL. Pico monoclonal IgM/Lambda na imunofixação sérica. Exame de Coombs direto negativo. Como terapêutica, iniciou-se Ciclofosfamida associado a Rituximabe. O paciente evoluiu ao óbito devido ao Covid-19 durante a internação. Discussão: A MW é uma neoplasia rara, sendo que o paciente deste relato enquadra-se na idade média do diagnóstico de MW, que ocorre em torno dos 60 anos, maioria do sexo masculino. Grande parte dos pacientes apresenta sintomas como fadiga, fraqueza e sangramento (principalmente epistaxe). Outras manifestações como perda de peso, distúrbios visuais e fenômeno de Raynaud são menos comuns. Ao exame físico, encontra-se rotineiramente hepatoesplenomegalia e linfadenopatia. Proteinúria de Bence Jones está presente em um quarto de todos os pacientes com MW, devido a uma lesão predominantemente glomerular com depósitos de IgM e material amiloide. A função plaquetária está prejudicada pelo revestimento de plaquetas com IgM, e alguns pacientes podem apresentar defeitos da cascata de coagulação. Os níveis de IgM são marcadamente aumentados, e a crioglobulina pode ser detectada em alguns pacientes. O tratamento deve ser individualizado de acordo com as manifestações clínicas de cada paciente e seu curso clínico é variável. Causas de morte relacionam-se geralmente a hiperviscosidade, anemia, hemorragia, trombose e infecções, sendo que neste caso a infecção por Covid-19 atuou como fator definidor. Conclusão: É oportuno o relato de um caso de MW devido a raridade de seu diagnóstico e importância de estabelecer diagnóstico diferencial com doenças de maior prevalência.

Kombucha - An ancient fermented beverage with desired bioactivities: A narrowed review.

Kombucha, originated in China 2000  years ago, is a sour and sweet-tasted drink, prepared traditionally through fermentation of black tea. During the fermentation of kombucha, consisting of mainly acidic compounds, microorganisms, and a tiny amount of alcohol, a biofilm called SCOBY forms. The bacteria in kombucha has been generally identified as Acetobacteraceae. Kombucha is a noteworthy source of B complex vitamins, polyphenols, and organic acids (mainly acetic acid). Nowadays, kombucha is tended to be prepared with some other plant species, which, therefore, lead to variations in its composition. Pre-clinical studies conducted on kombucha revealed that it has desired bioactivities such as antimicrobial, antioxidant, hepatoprotective, anti-hypercholestorelomic, anticancer, anti-inflammatory, etc. Only a few clinical studies have been also reported. In the current review, we aimed to overhaul pre-clinical bioactivities reported on kombucha as well as its brief compositional chemistry. The literature data indicate that kombucha has valuable biological effects on human health.

Distribution of COVID-19 government support and its consequences for firm liquidity and solvency.

We utilize several unique firm-level datasets in order to assess the efficiency and effectiveness of the government support aiming to curb the economic consequences of the coronavirus pandemic. The results, drawing on the experience of a small open European country, suggest the distributed COVID-19 subsidies save non-negligible number of jobs and sustain economic activity during the first wave of the pandemic. General distribution rules designed on the fly may bring close to optimal results in terms of the support allocation, as relatively more productive, privately owned, foreign-demand oriented firms are prioritized and firms with a high environmental footprint or zombie firms record a relatively lower chance of obtaining government funding. By assuming constant cost elasticities to sales, we show that the pandemic deteriorates strongly firm profits and increases significantly the share of illiquid and insolvent firms. Government wage subsidies somewhat mitigate firm losses and have statistically significant effect, but relatively mild compared to the size of the economic shock. Our estimates also confirm that larger firms, receiving smaller relative size of the support, have more space to cover their additional liquidity needs by increasing trade liabilities or liabilities to affiliated entities, while SMEs face higher risk of insolvencies.

The COVOSMIA-19 trial: Preliminary application of the Singapore smell and taste test to objectively measure smell and taste function with COVID-19.

Sudden loss of smell and/or taste has been identified as an early symptom of SARS-CoV-2 2019 (COVID-19) infection, and presents an effective target for prompt self-isolation and reducing community spread. The current study sought to develop and test a novel, rapid, self-administered test to objectively measure smell and taste losses associated with COVID-19, and administered self-report questionnaires to characterise symptoms associated with COVID-19 in Singapore. Participants (N = 99) completed questionnaires to record recent changes in smell and taste ability. This was followed by the 'Singapore Smell and Taste Test' (SSTT), a personal, objective testing kit for daily self-assessment of smell and taste function at their place of residence. Seventy-two recruited participants were confirmed as COVID-19 positive at baseline, of which 58 completed the SSTT at home. Of these, 36.2% had objectively measured smell and/or taste loss. The SSTT measures of smell and taste function were positively associated with participants' self-reported smell and taste acuity, and rated smell intensity of 6 common household items. This study presents the first application of the SSTT as a rapid, cost-effective, objective tool to self-monitor smell and taste function in a residential setting, and ensures comparability across individuals through the use of standardised stimuli. The SSTT has potential for future application in populations with limited access to formal COVID-19 testing as a self-administered objective method to monitor sudden changes in smell and taste, and to prompt early self-isolation, in order to reduce community transmission of COVID-19.

Adoptive Immune Responses to Sars-Cov2 Vaccination in CART19 Treated Patients

Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. [Formula presented] Disclosures: Frey: Novartis: Research Funding;Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria;CRISPR Therapeutics: Research Funding;GlaxoSmithKline: Honoraria;Janssen: Honoraria, Research Funding;Novartis: Research Funding;Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;ASH: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy;Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company;Novartis: Patents & Royalties.

The potential of BEN815 as an anti-inflammatory, antiviral and antioxidant agent for the treatment of COVID-19.

Background: The corona virus disease 2019 (COVID-19) pandemic has highlighted the fact that there are few effective antiviral agents for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Although the very recent development of vaccines is an extremely important breakthrough, it remains unclear how long-lived such vaccines will be. The development of new agents therefore remains an important goal. Purpose: Given the multifaceted pathology of COVID-19, a combinatorial formulation may provide an effective treatment. BEN815, a natural nutraceutical composed of extracts from guava leaves (Psidium guajava), green tea leaves (Camellia sinensis), and rose petals (Rosa hybrida), had previously shown to have a therapeutic effect on allergic rhinitis. We investigated whether BEN815 possesses anti-inflammatory, antiviral and antioxidant activities, since the combination of these effects could be useful for the treatment of COVID-19. Study design: We examined the anti-inflammatory effects of BEN815 and its principal active components quercetin and epigallocatechin gallate (EGCG) in lipopolysaccharide (LPS)-induced RAW264.7 cells and in an LPS-challenged mouse model of endotoxemia. We also assessed the antioxidant activity, and antiviral effect of BEN815, quercetin, and EGCG in SARS-CoV-2-infected Vero cells. Methods: The principal active ingredients in BEN815 were determined and quantified using HPLC. Changes in the levels of LPS-induced pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured by ELISA. Changes in the expression levels of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) were analyzed using western blotting. Antioxidant assay was performed using DPPH and ABTS assay. SARS-CoV-2 replication was measured by immunofluorescence staining. Results: BEN815 significantly suppressed the induction of IL-6 and TNF-α as well as COX-2 and iNOS in LPS-induced RAW264.7 cells. In addition, BEN815 protected against LPS-challenged endotoxic shock in mice. Two major constituents of BEN815, quercetin and EGCG, reduced the induction of IL-6 and TNF-α as well as COX-2 and iNOS synthase in LPS-induced RAW264.7 cells. BEN815, quercetin, and EGCG were also found to have antioxidant effects. Importantly, BEN815 and EGCG could inhibit SARS-CoV-2 replications in Vero cells. Conclusion: BEN815 is an anti-inflammatory, antiviral, and antioxidant natural agent that can be used to prevent and improve inflammation-related diseases, COVID-19.

Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways.

Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.