THE CRITICAL ROLE OF CYTOKINE DYSREGULATION IN ACUTE KIDNEY INJURY DEVELOPMENT IN PATIENTS WITH COVID-19

BACKGROUND AND AIMS: One of the complications described in critically ill patients in intensive care units with severe COVID-19 was acute kidney injury (AKI). The pathophysiology of AKI in patients with COVID-19 is multifactorial. In addition to the direct virulence of SARS-CoV-2 in renal cells, the tissue inflammation and local immune cell infiltration, cytokine storm, secondary infections and nephrotoxicity associated drugs may contribute to AKI [1]. Mounting evidence throughout the pandemic suggests that patients with severe COVID-19 may have a cytokine storm syndrome, one of the possible causes of AKI in these patients [2]. The present prospective cohort study analysed the correlation between circulating cytokine profile and estimated glomerular filtration rate (eGFR) in patients with COVID-19. METHOD: After signing the informed consent, patients positive for SARS-CoV- 2 infection (n = 74) had blood samples (n = 139) collected at hospital admission until the day of the outcome. ELISA measured the cytokines IL-10, IL-4, L-6, TNF- α and IFN-γ , and the eGFR was calculated by the CKD-EPI Cystatin C equation. Statistics description: Continuous variables were checked for normality and presented as mean ± standard deviation or median and interquartile range. The association between continuous variables is shown in scatterplots, and a predicted response with 95% confidence interval (95% CI) is plotted using fractional polynomials. For linear correlations, we obtained P-values using Pearson's correlation coefficient. RESULTS: There is a more significant distribution of eGFR below 90 mL/min in the population studied, associated with older patients. Glomerular filtration rates were negatively correlated with age as expected (-0.60;P < 0.0001). Lower eGFR was correlated with levels of proinflammatory cytokines such as IL-6 (-0.33;P < .0007) and TNF- α (-0.21;P < .03);but without positive correlation with IL-10 (0.04;P < 0.68) or IFN-γ (-0.14;P < .16), even though higher IFN-γ levels have been linked to a worse prognosis in patients with severe COVID-19 [3]. Curiously, a positive correlation was observed between lower eGFR and IL-4 levels. CONCLUSION: These results demonstrate that a shift in the immune response profile, cytokines with a Th2 profile such as IL-4, and cytokines with systemic functions such as IL-6 and TNF-α can be related to renal failure. The elucidation of the potential pathophysiological mechanisms of AKI associated with COVID-19 as well as monitoring of cytokine levels can (a) help to identify patients with severe COVID-19 at risk of loss of renal function, (b) provide information on specific therapeutic strategies. (Figure Presented).

LEUCEMIA MIELOÓIDE AGUDA COM ACOMETIMENTO EXTRAMEDULAR

Introdução: De acordo com o Instituto Nacional de Câncer (INCA) para cada ano, entre 2020 e 2022, são diagnosticados 10.810 novos casos de leucemias no Brasil. A leucemia mieloide aguda é um dos tipos mais comuns de leucemia em adultos, mas mesmo assim é bem rara. A leucemia mieloide aguda (LMA) é uma doença caracterizada pela expansão clonal, heterogênea e progressiva, com proliferação anormal de células progenitoras da linhagem mieloide, associada à perda da capacidade de diferenciação, ocasionando produção insuficiente de células sanguíneas maduras normais, com consequente substituição do tecido normal. Acomete frequentemente idosos acima de 60 anos de idade e é rara em menores de 45 anos, representando cerca de 15% a 20% das leucemias agudas na infância e 80% nos adultos. A doença também pode ser manifestar com formas extramedulares, onde células leucêmicas saem da medula e se infiltram em outros tecidos, como a pele, gânglios e sistema nervoso, levando a um aumento da gravidade. Relato de caso: Paciente, 14 anos, masculino, foi diagnosticado com LMA com acometimento extramedular. Iniciou quadro com mialgia intensa em MMII, progredindo com paraparesia, sensibilidade tátil, térmica e dolorosa preservadas, além de retenção urinária, conferindo uma mielite torácica. RM de coluna evidenciou lesões expansivas extramedulares e extradurais desde o nível T3 até o nível T9. Hemograma apresentava anemia (Hb 9,9g/dl), leucócitos totais 26.700, segmentados 500, linfócitos 3200, blastos 76% e plaquetas 120.000. Realizado estudo de medula óssea que diagnosticou a leucemia mieloide aguda. O cariótipo era 45, X, -Y, t (8:21) (q22;q22), 9qh+c [18], 9qh+c [2]. Paciente realizou radioterapia em região de coluna torácica e quimioterapia de indução “3+7”com remissão completa e DRM negativa. Sem doadores compatíveis na família, foi inscrito no REREME e seguiu com consolidação com ARA-C altas doses. Após o 4°ciclo de consolidação, paciente evoluiu com neutropenia febril secundária e pneumonia por COVID-19. Ficou internado por mais de 30 dias na UTI com piora do status performance e dificuldade de seguir tratamento da leucemia pela complicação clínica, apresentando recidiva da doença extra e intra-medular, evoluindo para óbito. Discussão: Neste caso o paciente abriu o quadro clínico com sintomas neurológicos sugestivos de mielite de causa desconhecida, após realização de RNM foi identificado lesão expansiva comprimido coluna torácica. Assim, feito o diagnóstico de LMA com acometimento extramedular pelo hemograma e estudo de medula óssea. LMA com sarcoma granulocítico é uma doença de pior prognóstico, com necessidade de tratamento intensivo e transplante de medula óssea alogênico. Nosso paciente acabou recidivando a doença antes do transplante devido complicação infecciosa por neutropenia febril secundária a pneumonia viral (COVID), evoluindo para óbito.

Impact of cultural behavior on the bullwhip effect in the COVID-19 pandemic

With the broadening of interconnection between national borders, it is paramount to take into account different cultural behavior to enhance the visibility and integration among supply chain partners with the aim to improve organizational performance. There are a few studies exploring the role of culture in supply chain coordination and buyer-supplier relationships that results in the Bullwhip Effect, but they consider simulation environments or real-life scenarios with minor perturbation. Therefore, this study complements the literature by analyzing how the perception of large disruptions in supply chain coordination varies between cultures. More specifically, this paper will investigate the behavioral causes of Bullwhip Effect during the COVID-19 pandemic to illustrate how these disruptions affect the supply chain coordination. The Hofstede’s Cultural Dimensions Theory and other three studies were considered when elaborating and applying a multiple-case study approach with semi-structured interviews and podcasts as the main source of data. The results provided a framework of the relation between cultural differences and the Bullwhip Effect in large disruptions, with the confirmation of a few tendencies that were observed from previous studies, and elaboration of propositions and managerial applications. © IEOM Society International.

An educational intervention to increase advance care planning activities among emergency medicine providers during the covid-19 pandemic

Background: Coronavirus Disease 2019 (COVID-19) has heightened the importance of emergency department (ED) providers in initiating advance care planning (ACP) conversations. Clarifying ACP helps ensure care is aligned with patients' wishes and can avoid unnecessary suffering. The objective was to determine the effect of a training for emergency providers on ACP conversations in the ED during the COVID-19 pandemic. We hypothesized that the intervention would increase the documentation of advance care planning in the emergency department. Methods: This was an observational pre-/post-interventional study at a southeastern academic emergency department. Palliative care physicians carried out a three-fold educational intervention for emergency medicine providers on April 1, 2020 including: (1) an evidence-based guide to COVID-19 risk stratification, (2) education on language to initiate ACP conversations, and (3) instructions on how to document ACP preferences in the electronic health record. A medical student was trained on manual chart review of COVID-infected patients. Data was then abstracted on patient demographics, placement of code status orders, documentation of a healthcare decision maker (HCDM), and documentation of ACP. Results: In total, 143 charts of confirmed COVID-19 patients were reviewed between March 26, 2020 and May 25, 2020. There were 28 patients in the pre-intervention period and 115 post-intervention. There was a roughly ∼25% increase in ACP-related activities among emergency providers in the post-intervention period (25.0% v 49.6% ACP activities noted in the pre-and post-intervention subjects, respectively ;p < 0.03). After adjustment for patient demographics, a non-significant trend towards increased ACP activity was observed (OR = 2.54, p = 0.08). Conclusion: We present preliminary evidence that a simple physician-facing educational intervention can improve ED-based goals of care conversation and documentation for patients infected with COVID-19.

The role of miR-193B-5P in virus induced ARDS

Introduction: The avian influenza virus (IAV) commonly cause acute respiratory distress syndrome (ARDS), shock and death. Unlike the current coronavirus outbreak, IAV does not grab the same level of public attention, although its clinical implications remain dire. As of 2019, a recorded 10,000 patients have died and 180,000 were hospitalized according to CDC. ARDS leads to a surge in the use of mechanical ventilators for life support. Host-derived cellular microRNAs (miRs) play a critical role in ARDS dependent lung injury, alveolar-capillary membrane integrity, and host responses to viral infections. We hypothesize that increased miR193b-5p upon IAV infection, downregulates occludin expression, and is associated with increased inflammation and injury in experimental models of pneumonia. Methods: Wild type mice (C57Bl/6J, 10 -14 weeks) were randomized to infection with H1N1 virus (A/PR/8/34) treated a miR193b-5p inhibitor (INH) versus placebo delivered on day 4 post-infection. On day 8, lung injury was assessed using histology, bronchoalveolar lavage fluid cell counts and differential, membrane permeability, and viral load. In vitro, Beas2b cells were infected with H1N1 and treated with or without miR- 193b-5p inhibitor (INH) or mimic, and occludin was knocked down. Transcript expression levels were determined by qRT-PCR. Beas2b cells were treated with IFNb and qRT-PCR and digital droplet PCR was used to assess targets. Results: Intranasal infection of IAV increased pulmonary inflammation, lung edema, increased levels of miR193b-5p (20- fold) and decreased expression of occludin (>50%) that peak at day 5 days post-infection. Reporter construct demonstrates miR-193b-5p binds specifically to the 3'UTR of occludin. Inhibition of miR193b- 5p mitigates H1N1-induced lung injury, edema formation, viral load, and anti-viral Interferon b (IFNb) and Interferon Regulated Genes expression. In vitro, silencing of occludin results in increased viral load and dysregulation of the host antiviral response. miR193b-5p is IFNb responsive confirmed by qRT-PCR and ddPCR. Conclusions: We demonstrate the role of miR193b-5p in barrier function, viral infection and host anti-viral responses in a murine model of H1N1. IFNb, a natural host antiviral response, promotes miR193b upregulation. The upregulation of miR-193b-5p downregulates occludin. And the inhibition of miR-193b-5p results in decreased lung injury, inflammation, and viral load.