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Katherine B Snyder,1,2 Chase L Calkins,3 Alena Golubkova,1,2 Tyler Leiva,1,2 Camille Schlegel,1 Catherine J Hunter1,2 1Division of Pediatric Surgery, Oklahoma City, OK, 73104, USA; 2Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; 3College of Medicine, The University of Oklahoma College of Medicine, Oklahoma City, OK, 73104, USACorrespondence: Catherine J Hunter, Department of Pediatric Surgery, Oklahoma Children’s Hospital, 1200 Everett Drive, ET NP 2320, Oklahoma City, OK, 73104, USA, Email catherine-hunter@ouhsc.eduBackground: Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of death of premature neonates. NEC is associated with prematurity, a hyperinflammatory response, and dysregulation of intestinal barrier function. We hypothesize that patients with NEC will have, and continue to have after recovery, an increased hyperinflammatory intestinal response compared to those patients without NEC.Methods: Neonates with NEC, those that have recovered from NEC, and those without NEC undergoing intestinal resections had specimens collected and snap frozen or generated into enteroids. The enteroids were treated with 100ug/mL lipopolysaccharide (LPS) and subjected to 24 hr of hypoxia together, then compared with untreated controls. Expression of Tumor Necrosis Factor (TNF-α) and interleukin 8 (IL-8) were evaluated via RT-qPCR and ELISA to measure inflammatory response. ANOVA determined statistical significance (p< 0.05).Results: There was no difference in inflammatory markers in recovered NEC tissue compared to non-NEC tissue on RTqPCR (p=0.701 TNF-α and 0.861 IL-8). However, recovered NEC enteroids demonstrate elevated levels of inflammatory markers after treatment compared to non-NEC enteroids after treatment on RTqPCR (p=0.0485 TNF-α, p=0.0057 IL-8) and ELISA (p=0.0354 TNF-α, p=0.0011 IL-8). Recovered NEC enteroids that underwent treatment demonstrated increased inflammatory markers compared to recovered NEC enteroids without treatment on RTqPCR (p=0.0045 TNF-α, p=0.0002 IL-8) and ELISA (p=0.034 TNF-α, p=0.0002 IL-8) suggesting a heightened inflammatory response to a second hit.Conclusion: Intestinal tissue resected from neonates with NEC has an elevated hyperinflammatory response compared to neonates recovered from NEC and neonates without NEC. Enteroids generated from patients that have recovered from NEC have a heightened inflammatory response in response to NEC inducing stimuli compared to controls. This tendency towards an increased hyperinflammatory state may be correlated with an infant’s proclivity to develop NEC and demonstrates the significance of a second hit on this tissue creating a heightened inflammatory response. This could be correlated with the impact and trajectory of an illness post recovery from NEC.Keywords: necrotizing enterocolitis, recovery, hyperinflammatory, enteroids

Based on a growing body of evidence that a dysregulated innate immune response mediated by monocytes/macrophages plays a key role in the pathogenesis of COVID-19, a clinical trial was conducted to investigate the therapeutic potential and safety of oral macrophage activating factor (MAF) plus standard of care (SoC) in the treatment of hospitalized patients with COVID-19 pneumonia. Ninety-seven hospitalized patients with confirmed COVID-19 pneumonia were treated with oral MAF and a vitamin D3 supplement, in combination with SoC, in a single-arm, open label, multicentre, phase II clinical trial. The primary outcome measure was a reduction in an intensive care unit transfer rate below 13% after MAF administration. At the end of the study, an additional propensity score matching (PSM) analysis was performed to compare the MAF group with a control group treated with SoC alone. Out of 97 patients treated with MAF, none needed care in the ICU and/or intubation with mechanical ventilation or died during hospitalization. Oxygen therapy was discontinued after a median of nine days of MAF treatment. The median length of viral shedding and hospital stay was 14 days and 18 days, respectively. After PSM, statistically significant differences were found in all of the in-hospital outcomes between the two groups. No mild to serious adverse events were recorded during the study. Notwithstanding the limitations of a single-arm study, which prevented definitive conclusions, a 21-day course of MAF treatment plus SoC was found to be safe and promising in the treatment of hospitalized adult patients with COVID-19 pneumonia. Further research will be needed to confirm these preliminary findings.

Background: Necrotizing enterocolitis (NEC) is a devastating disease of premature neonates with substantial morbidity and mortality. Necrotizing enterocolitis is associated with prematurity, a hyperinflammatory response, and dysregulation of intestinal barrier function. We hypothesize that patients with NEC will have an increased hyperinflammatory intestinal response compared with those without NEC. Patients and Methods: Enteroids were generated from intestinal tissue from neonates undergoing resection. They were treated with 100 mcg/mL lipopolysaccharide (LPS), subjected to 24 hours of hypoxia inducing experimental NEC, then compared with untreated controls. Expression of tumor necrosis factor (TNF-α) and interleukin 8 (IL-8) were evaluated via reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure inflammatory response. Analysis of variance (ANOVA) determined statistical significance (p < 0.05). Results: Treated NEC-derived enteroids expressed significantly higher levels of IL-8 (RT-qPCR, p = 0.003; ELISA, p = 0.0002) compared with untreated NEC-derived enteroids with an increase in inflammatory marker concentration in those with a greater degree of prematurity (ELISA, p = 0.0015). A higher level of IL-8 was seen in NEC-derived enteroids compared with control after treatment (RT-qPCR, p = 0.024). Tumor necrosis factor-α levels were elevated in treated NEC-derived enteroids compared with untreated NEC-derived enteroids (RT-qPCR, p = 0.006; ELISA, p = 0.002) and compared with treated non-NEC–derived enteroids (RT-qPCR, p = 0.025; ELISA, p < 0.0001). Conclusions: Enteroids generated from neonates with NEC have an elevated hyperinflammatory response in response to NEC-inducing stimuli compared with controls. Enteroids generated from neonates with NEC with a greater degree of prematurity have a larger increase in inflammatory markers. This tendency toward a hyperinflammatory state may be correlated with an infant's proclivity to develop NEC and further demonstrates the hyperinflammatory state of prematurity. [ABSTRACT FROM AUTHOR]

Recently, a new pattern of multisystem inflammatory syndrome following an infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged globally. The initial cases were described in the adult population followed by sporadic cases in the pediatric population also. By the end of 2020, similar reports were recognised in the neonatal age group. The purpose of this study was to systematically review clinical characteristics, laboratory parameters, treatment, and outcomes of neonates with multisystem inflammatory syndrome in neonates (MIS-N). A systematic review was conducted after registering with PROSPERO and electronic databases including MEDLINE, EMBASE, PubMed, SCOPUS, Google Scholar, and Web of Science were searched from January 1st 2020 till September 30th 2022. A total of 27 studies describing 104 neonates were analysed. The mean gestation age and birth weight was 35.9 ± 3.3 weeks and 2255.7 ± 783.7 g respectively. A large proportion (91.3%) of the reported cases belonged to the South-East Asian region. The median age of presentation was 2 days (range: 1–28 days) with cardiovascular system being the predominant system involved in 83.65% followed by respiratory (64.42%). Fever was noted in only 20.2%. Commonly elevated inflammatory markers were IL-6 in 86.7% and D-dimer in 81.1%. Echocardiographic evaluation suggested ventricular dysfunction in 35.8% and dilated coronary arteries in 28.3%. Evidence of SARS-CoV-2 antibodies (IgG or IgM) was seen in 95.9% neonates and evidence of maternal SARS-CoV-2 infection, either as history of COVID infection or positive antigen or antibody test, was noted in 100% of the cases. Early MIS-N was reported in 58 (55.8%) cases, late MIS-N in 28 (26.9%), and 18 cases (17.3%) did not report the timing of presentation. There was a statistically increased proportion of preterm infants (67.2%, p < 0.001), and a trend towards increased low birth weight infants, in the early MIS-N group when compared to the infants with late MIS-N. Fever (39.3%), central nervous system (50%), and gastrointestinal manifestations (57.1%) were significantly higher in the late MIS-N group (p = 0.03, 0.02, 0.01 respectively). The anti-inflammatory agents used for the treatment of MIS-N included steroids 80.8% which were given for a median of 10 (range 3–35) days and IVIg in 79.2% with a median of 2 (range 1–5) doses. The outcomes were available for 98 cases, of whom 8 (8.2%) died during treatment in hospital and 90 (91.8%) were successfully discharged home. Conclusion: MIS-N has a predilection for late preterm males with predominant cardiovascular involvement. The diagnosis is challenging in neonatal period due to overlap with neonatal morbidities and a high risk of suspicion is warranted, especially in presence of supportive maternal and neonatal clinical history. The major limitation of the review was inclusion of case reports and case series, and highlights need of global registries for MIS-N. What is Known: • A new pattern of multisystem inflammatory syndrome following SARS-CoV-2 infection has emerged in adult population with sporadic cases now being reported in neonates. What is New: • MIS-N is an emerging condition with a heterogeneous spectrum and has a predilection for late preterm male infants. Cardiovascular system is the predominant system involved followed by respiratory, however fever remains an uncommon presentation unlike other age-groups. There are two subtypes based on timing of presentation, with early MIS-N being reported more in preterm and low-birth weight infants. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by ineffective hematopoiesis and dysplasia of the myeloid cell lineage and are characterized by peripheral blood cytopenia and an increased risk of transformation to acute myeloid leukemia (AML). Approximately half of the patients with MDS have somatic mutations in the spliceosome gene. Splicing Factor 3B Subunit 1A (SF3B1), the most frequently occurring splicing factor mutation in MDS is significantly associated with the MDS-RS subtype. SF3B1 mutations are intimately involved in the MDS regulation of various pathophysiological processes, including impaired erythropoiesis, dysregulated iron metabolism homeostasis, hyperinflammatory features, and R-loop accumulation. In the fifth edition of the World Health Organization (WHO) classification criteria for MDS, MDS with SF3B1 mutations has been classified as an independent subtype, which plays a crucial role in identifying the disease phenotype, promoting tumor development, determining clinical features, and influencing tumor prognosis. Given that SF3B1 has demonstrated therapeutic vulnerability both in early MDS drivers and downstream events, therapy based on spliceosome-associated mutations is considered a novel strategy worth exploring in the future. [ABSTRACT FROM AUTHOR]

IL-6 receptor antagonist tocilizumab (TCZ) has been used in several reported studies in the treatment of COVID-19 pneumonia and pieces of evidence are still emerging. All patients with COVID-19 pneumonia showing features of hyperinflammatory syndrome receiving TCZ at a tertiary care center in India were included in the study and a retrospective descriptive analysis was done. Between May 2020 to August 2020, 21 patients received TCZ out of which 13 survived and 8 died. All non-survivors had longer duration (median 12 days, minimum 9, maximum 15 days compared to median 6 days, minimum 3 and maximum 14 days in survivors) of symptoms and severe disease requiring mechanical ventilation at the time of TCZ administration. Among survivors, 8 patients had severe disease, 3 had moderate disease, and 2 patients had mild disease. Six out of 8 (75%) among non-survivors and 8 out of 13 (62%) among survivors had preexisting medical comorbidities. The non-survivors had higher baseline neutrophil-to-leukocyte ratio (10.5 vs 8.8), serum ferritin (960 ng/ml vs 611 ng/ml), lactate dehydrogenase (795 IU/L vs 954 IU/L), and D-dimer (5900 μg/ml vs 1485 mg/ml) levels. No drug-related serious adverse effect was noted among the patients. In a scenario of emerging evidence for the role of TCZ in the management of severe COVID-19, our study provides useful data on its use in the Indian scenario. Deliberate patient selection and timing initiation of TCZ at a crucial stage of the disease may be beneficial in COVID-19 pneumonia with good safety returns. [ABSTRACT FROM AUTHOR]

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study. [ABSTRACT FROM AUTHOR]

Recent studies have shown that several children diagnosed with COVID-19 have developed Kawasaki Disease (KD)-like symptoms. This systematic review aims to assess the demographic, laboratory, and clinical characteristics of children with KD-like syndrome during the COVID-19 pandemic and evaluate efficacy of treatments and patients' outcome. A comprehensive search was carried out systematically through PubMed, Scopus, and Web of Science (WoS), medRxiv, and bioRxiv by two reviewers independently for all studies or preprints data on the demographic, laboratory, and clinical characteristics of children with K.D-like signs during the COVID-19 outbreak. Overall, 378 studies were identified by the systematic search, of which 25 studies were included in the study. The included studies involved 599 patients in total. Thirteen studies (52%) were case reports or case series, and the rest (48%) were cohort studies. In 19 studies, patients were diagnosed with Multisystem inflammatory syndrome in children (MIS-C). In 16 studies COVID-19 was diagnosed in all patients based on their polymerase chain reaction result, serological findings, and computed tomography results. Higher C-reactive protein and erythrocyte sedimentation rate level were the most prevalent laboratory findings. In most studies, patients had leucopenia with marked lymphopenia, hypoalbuminemia, and increased ferritin, as well as hyponatremia. Abnormal echocardiography and respiratory outcomes were the most common clinical outcomes. In 11 studies, all patients required intensive care unit admission. Findings of the present systematic review show that the incidence of KD-like syndrome in the COVID-19 pandemic increased significantly. Moreover, this study offers new insights in the KD-like syndrome pathogenesis and clinical spectrum during COVID-19 pandemic.

Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARS-CoV-2 spike (S) protein-ACE-2 interface; Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (Mpro). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-Mpro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of Mpro with DMO and, thus, its inhibition. The docking predicted IC50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and Mpro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection.

In this period of global pandemic caused by SARS-Cov-2, it is of paramount importance to recognize all risk factors that may increase the likelihood of infection. In addition to the risk factors known as pre-existing diseases and old age, risk factors could be drug treatments for chronic diseases, such as immunomodulating drugs that can alter immune defences and response to infectious agents. Antibodies that inhibit tumor necrosis factor (TNF) such as adalimumab infliximab etanercept and golimumab have been used for over 20 years in severe cases of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease or ankylosing spondylitis. Due to their mechanism of action they reduce inflammation and can stop the progression of the disease by inhibiting a key factor of inflammation such as TNF. In this article we want to examine the possible correlation between therapy with TNF inhibitors and the increased risk of SARS-CoV-2 infection, and the possible paradoxical therapeutic efficacy in patients with ongoing infection, especially in phase two and three. We express our opinion on this very complex and sensitive topic which is the subject of discussion among physicians and experts, based on current knowledge of the literature.

Based on a growing body of evidence that a dysregulated innate immune response mediated by monocytes/macrophages plays a key role in the pathogenesis of COVID-19, a clinical trial was conducted to investigate the therapeutic potential and safety of oral macrophage activating factor (MAF) plus standard of care (SoC) in the treatment of hospitalized patients with COVID-19 pneumonia. Ninety-seven hospitalized patients with confirmed COVID-19 pneumonia were treated with oral MAF and a vitamin D3 supplement, in combination with SoC, in a single-arm, open label, multicentre, phase II clinical trial. The primary outcome measure was a reduction in an intensive care unit transfer rate below 13% after MAF administration. At the end of the study, an additional propensity score matching (PSM) analysis was performed to compare the MAF group with a control group treated with SoC alone. Out of 97 patients treated with MAF, none needed care in the ICU and/or intubation with mechanical ventilation or died during hospitalization. Oxygen therapy was discontinued after a median of nine days of MAF treatment. The median length of viral shedding and hospital stay was 14 days and 18 days, respectively. After PSM, statistically significant differences were found in all of the in-hospital outcomes between the two groups. No mild to serious adverse events were recorded during the study. Notwithstanding the limitations of a single-arm study, which prevented definitive conclusions, a 21-day course of MAF treatment plus SoC was found to be safe and promising in the treatment of hospitalized adult patients with COVID-19 pneumonia. Further research will be needed to confirm these preliminary findings. [Display omitted] [ABSTRACT FROM AUTHOR]

The article presents Diagnostic value of plasma viscosity testing for patients with COVID-19. Topics discussed include unusual cluster of patients suffering from a pneumonia-inducing condition was first reported within Wuhan, Hubei Province, China, in late December 2019; and it was determined that the causative pathogen was a novel coronavirus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by ineffective hematopoiesis and dysplasia of the myeloid cell lineage and are characterized by peripheral blood cytopenia and an increased risk of transformation to acute myeloid leukemia (AML). Approximately half of the patients with MDS have somatic mutations in the spliceosome gene. Splicing Factor 3B Subunit 1A (SF3B1), the most frequently occurring splicing factor mutation in MDS is significantly associated with the MDS-RS subtype. SF3B1 mutations are intimately involved in the MDS regulation of various pathophysiological processes, including impaired erythropoiesis, dysregulated iron metabolism homeostasis, hyperinflammatory features, and R-loop accumulation. In the fifth edition of the World Health Organization (WHO) classification criteria for MDS, MDS with SF3B1 mutations has been classified as an independent subtype, which plays a crucial role in identifying the disease phenotype, promoting tumor development, determining clinical features, and influencing tumor prognosis. Given that SF3B1 has demonstrated therapeutic vulnerability both in early MDS drivers and downstream events, therapy based on spliceosome-associated mutations is considered a novel strategy worth exploring in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiang, Chen, Liu, Jin, Yang and Zhang.)

In this period of global pandemic caused by SARS-Cov-2, it is of paramount importance to recognize all risk factors that may increase the likelihood of infection. In addition to the risk factors known as pre-existing diseases and old age, risk factors could be drug treatments for chronic diseases, such as immunomodulating drugs that can alter immune defences and response to infectious agents. Antibodies that inhibit tumor necrosis factor (TNF) such as adalimumab infliximab etanercept and golimumab have been used for over 20 years in severe cases of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease or ankylosing spondylitis. Due to their mechanism of action they reduce inflammation and can stop the progression of the disease by inhibiting a key factor of inflammation such as TNF. In this article we want to examine the possible correlation between therapy with TNF inhibitors and the increased risk of SARS-CoV-2 infection, and the possible paradoxical therapeutic efficacy in patients with ongoing infection, especially in phase two and three. We express our opinion on this very complex and sensitive topic which is the subject of discussion among physicians and experts, based on current knowledge of the literature. [ABSTRACT FROM AUTHOR]

• GQP inhibited thrombi in the lung, liver, and tail and augmented the tail blood flow in mice. • GQP reduced the plasma TNF-α and diminished the expression of HMGB1in mice lung tissue. • GQP reduced inflammation-induced thrombosis by inhibiting HMGB1/NFκB/NLRP3 signaling The high incidence of thrombotic events is one of the clinical characteristics of coronavirus disease of 2019 (COVID-19), due to a hyperinflammatory response caused by the virus. Gegen Qinlian Pills (GQP) is a Traditional Chinese Medicine that is included in the Chinese Pharmacopoeia and played an important role in the clinical fight against COVID-19. Although GQP has shown the potential to treat thrombosis, there is no relevant research on its treatment of thrombosis so far. We hypothesized that GQP may be capable inhibit inflammation-induced thrombosis. We tested our hypothesis in a carrageenan-induced thrombosis mouse model in vivo and lipopolysaccharide (LPS)-induced human endothelial cells (HUVECs) in vitro. We used a carrageenan-induced mouse thrombus model to confirm the inhibitory effect of GQP on inflammation-induced thrombus. In vitro, studies in human umbilical vein endothelial cells (HUVECs) and in silico network pharmacology analyses were performed to reveal the underlying mechanisms of GQP and determine the main components, targets, and pathways of GQP, respectively. Oral administration of 227.5 mg/kg, 445 mg/kg and 910 mg/kg of GQP significantly inhibited thrombi in the lung, liver, and tail and augmented tail blood flow of carrageenan-induced mice with reduced plasma tumor necrosis factor α (TNF-α) and diminished expression of high mobility group box 1 (HMGB1) in lung tissues. GQP ethanol extract (1, 2, or 5 μg/ml) also reduced the adhesion of platelets to LPS stimulated HUVECs. The TNF-α and the expression of HMGB1, nuclear factor kappa B (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) in LPS stimulated HUVECs were also attenuated. Moreover, we analyzed the components of GQP and inferred the main targets, biological processes, and pathways of GQP in the treatment of inflammation-induced thrombosis through network pharmacology. Overall, we demonstrated that GQP could reduce inflammation-induced thrombosis by inhibiting HMGB1/NFκB/NLRP3 signaling and provided an accurate explanation for the multi-target, multi-function mechanism of GQP in the treatment of thromboinflammation, and provides a reference for the clinical usage of GQP. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis is defined as a dysregulated host-response to infection, across all ages and pathogens. What defines a dysregulated state remains intensively researched but incompletely understood. Here, we dissect the meaning of this definition and its importance for the diagnosis and management of sepsis. We deliberate on pathophysiological features and dogmas that range from cytokine storms and immune paralysis to dormancy and altered homeostasis setpoints. Mathematical reasoning, used to test for plausibility, reveals three interlinked cardinal rules governing host-response trajectories in sepsis. Rule one highlights that the amplitude of the immune response while important is not sufficient and is strictly dependent on rule two, specifying bioenergetic capacity and are together dynamically driven by rule three, delineating stability and alterations in setpoints. We consider these rules and associated pathophysiological parameters for guiding data-science and artificial intelligence mining of multi-omics and big-data for improving the precision of diagnostic and therapeutic approaches to sepsis. FUNDING: PG funded by the European Regional Development Fund and Welsh Government (Ser Cymru programme - Project Sepsis)., Competing Interests: Declaration of interests None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: The systemic inflammatory response syndrome (SIRS) is the body''s response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an “inflammatory” response, it actually has pro- and anti-inflammatory components. This review outlines the pathophysiology of SIRS and highlights potential targets for future therapeutic intervention in patients with this complex entity. [Copyright &y& Elsevier]

Little is known about the arterial complications and hypercoagulability associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We sought to characterize our experience with arterial thromboembolic complications in patients with hospitalized for coronavirus disease 2019 (COVID-19). All patients admitted from March 1 to April 20, 2020, and who underwent carotid, upper, lower and aortoiliac arterial duplex, computed tomography angiogram or magnetic resonance angiography for suspected arterial thrombosis were included. A retrospective case control study design was used to identify, characterize and evaluate potential risk factors for arterial thromboembolic disease in SARS-CoV-2 positive patients. Demographics, characteristics, and laboratory values were abstracted and analyzed. During the study period, 424 patients underwent 499 arterial duplex, computed tomography angiogram, or magnetic resonance angiography imaging studies with an overall 9.4% positive rate for arterial thromboembolism. Of the 40 patients with arterial thromboembolism, 25 (62.5%) were SARS-CoV-2 negative or admitted for unrelated reasons and 15 (37.5%) were SARS-CoV-2 positive. The odds ratio for arterial thrombosis in COVID-19 was 3.37 (95% confidence interval, 1.68-6.78; P =.001). Although not statistically significant, in patients with arterial thromboembolism, patients who were SARS-CoV-2 positive compared with those testing negative or not tested tended to be male (66.7% vs 40.0%; P =.191), have a less frequent history of former or active smoking (42.9% vs 68.0%; P =.233) and have a higher white blood cell count (14.5 vs 9.9; P =.208). Although the SARS-CoV-2 positive patients trended toward a higher the neutrophil-to-lymphocyte ratio (8.9 vs 4.1; P =.134), creatinine phosphokinase level (359.0 vs 144.5; P =.667), C-reactive protein level (24.2 vs 13.8; P =.627), lactate dehydrogenase level (576.5 vs 338.0; P =.313), and ferritin level (974.0 vs 412.0; P =.47), these differences did not reach statistical significance. Patients with arterial thromboembolic complications and SARS-CoV-2 positive when compared with SARS-CoV-2 negative or admitted for unrelated reasons were younger (64 vs 70 years; P =.027), had a significantly higher body mass index (32.6 vs 25.5; P =.012), a higher d -dimer at the time of imaging (17.3 vs 1.8; P =.038), a higher average in hospital d -dimer (8.5 vs 2.0; P =.038), a greater distribution of patients with clot in the aortoiliac location (5 vs 1; P =.040), less prior use of any antiplatelet medication (21.4% vs 62.5%; P =.035), and a higher mortality rate (40.0% vs 8.0%; P =.041). Treatment of arterial thromboembolic disease in COVID-19 positive patients included open thromboembolectomy in six patients (40%), anticoagulation alone in four (26.7%), and five (33.3%) did not require or their overall illness severity precluded additional treatment. Patients with SARS-CoV-2 are at risk for acute arterial thromboembolic complications despite a lack of conventional risk factors. A hyperinflammatory state may be responsible for this phenomenon with a preponderance for aortoiliac involvement. These findings provide an early characterization of arterial thromboembolic disease in SARS-CoV-2 patients. [ABSTRACT FROM AUTHOR]

Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARS-CoV-2 spike (S) protein-ACE-2 interface; Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (M pro ). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-M pro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of M pro with DMO and, thus, its inhibition. The docking predicted IC 50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and M pro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thangavel, Al Bratty, Al Hazmi, Najmi and Ali Alaqi.)

Following its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused what rapidly became a global pandemic. The precise origin and subsequent path of transmission have not yet been established-but like the other novel coronaviruses that it closely resembles, it appears to have evolved naturally in a bat host. The disease caused by SARS-CoV-2 infection, designated as coronavirus disease 2019 (COVID-19), ranges from asymptomatic, to mild self-limited illness, to progressive pneumonia, respiratory compromise, multiorgan failure, and death. In addition, a hyperinflammatory disease state occurs in a subset of patients, and may be seen either during acute infection or following recovery. The search for effective pharmacological management of COVID-19 continues, but several promising candidates have been identified, including the viral nucleoside analog remdesivir. However, despite the existence of literally thousands of clinical trials, the management of COVID-19 remains challenging, and the development of an optimal, evidence-based therapeutic approach is ongoing. The impact of SARS-CoV-2 and COVID-19 on the biobanking world is evolving and profound-in particular, it is likely that many of mysteries surrounding COVID-19 will be solved via the availability of high-quality, large-scale collection, storage, and analysis of patient specimens. The purpose of this review article is therefore to provide a rapid, comprehensive, and relevant overview and primer on SARS-CoV-2 and COVID-19, with attention to the epidemiology, virology, transmission, clinical features, and major therapeutic options currently existent.

The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 presents with a spectrum of clinical manifestations from asymptomatic or mild, self-limited constitutional symptoms to a hyperinflammatory state ("cytokine storm") followed by acute respiratory distress syndrome and death. The objective of this study was to provide an evidence-based review of the associated pathways and potential treatment of the hyperinflammatory state associated with severe acute respiratory syndrome coronavirus 2 infection. Dysregulated immune responses have been reported to occur in a smaller subset of those infected with severe acute respiratory syndrome coronavirus 2, leading to clinical deterioration 7 to 10 days after initial presentation. A hyperinflammatory state referred to as cytokine storm in its severest form has been marked by elevation of IL-6, IL-10, TNF-α, and other cytokines and severe CD4 + and CD8 + T-cell lymphopenia and coagulopathy. Recognition of at-risk patients could permit early institution of aggressive intensive care and antiviral and immune treatment to reduce the complications related to this proinflammatory state. Several reports and ongoing clinical trials provide hope that available immunomodulatory therapies could have therapeutic potential in these severe cases. This review highlights our current state of knowledge of immune mechanisms and targeted immunomodulatory treatment options for the current coronavirus disease 2019 pandemic., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)