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With global warming, extreme environmental heat is becoming a social issue of concern, which can cause adverse health results including heatstroke (HS). Severe heat stress is characterized by cell death of direct heat damage, excessive inflammatory responses, and coagulation disorders that can lead to multiple organ dysfunction (MODS) and even death. However, the significant pathophysiological mechanism and treatment of HS are still not fully clear. Various modes of cell death, including apoptosis, pyroptosis, ferroptosis, necroptosis and PANoptosis are involved in MODS induced by heatstroke. In this review, we summarized molecular mechanism, key transcriptional regulation as for HSF1, NRF2, NF-κB and PARP-1, and potential therapies of cell death resulting in CNS, liver, intestine, reproductive system and kidney injury induced by heat stress. Understanding the mechanism of cell death provides new targets to protect multi-organ function in HS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sepsis is a life-threatening condition that occurs when the body responds to an infection but subsequently triggers widespread inflammation and impaired blood flow. These pathologic responses can rapidly cause multiple organ dysfunction or failure either one by one or simultaneously. The fundamental common mechanisms involved in sepsis-induced multiple organ dysfunction remain unclear. Here, employing quantitative global and phosphoproteomics, we examine the liver's temporal proteome and phosphoproteome changes after moderate sepsis induced by cecum ligation and puncture. In total, 4593 global proteins and 1186 phosphoproteins according to 3275 phosphosites were identified. To characterize the liver-kidney comorbidity after sepsis, we developed a mathematical model and performed cross-analyses of liver and kidney proteome data obtained from the same set of mice. Beyond immune response, we showed the commonly disturbed pathways and key regulators of the liver-kidney comorbidity are linked to energy metabolism and consumption. Our data provide open resources to understand the communication between the liver and kidney as they work to fight infection and maintain homeostasis., (© 2024 Federation of American Societies for Experimental Biology.)

Sepsis is a fatal organ dysfunction caused by the host's uncontrolled response to infection, with high morbidity and mortality. Early diagnosis and intervention are the most effective methods to reduce the mortality due to sepsis. However, there is still a lack of definite biomarkers or intervention targets for the diagnosis, evaluation, prognosis, and treatment of sepsis. Long non-coding RNAs (lncRNAs) are a type of noncoding transcript with a length ranging from 200 to 100,000 nucleotides. LncRNAs mainly locate in the cytoplasm and nucleus and participate in various signaling pathways related to inflammatory reactions and organ dysfunction. Recent studies have reported that lncRNAs are involved in regulating the pathophysiological process of sepsis. Some classical lncRNAs have been confirmed as promising biomarkers to evaluate the severity and prognosis of sepsis. This review summarizes the mechanical studies on lncRNAs in sepsis-induced acute lung, kidney, myocardial, and liver injuries, analyzes the role of lncRNAs in the pathogenesis of sepsis, and explores the possibility of lncRNAs as potential biomarkers and intervention targets for sepsis-induced multiple organ dysfunction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) is the ozonation product of tire antioxidant 6-PPD. 6-PPDQ can be detected in different environments, such as roadway runoff and dust. Although 6-PPDQ toxicity has been frequently assessed in aquatic organisms, the possible toxic effects of 6-PPDQ on mammals remain largely unclear. We here aimed to perform systematic assessment to evaluate 6-PPDQ toxicity on multiple organs in mice. Male BALB/c mice were intraperitoneally injected with 6-PPDQ for two exposure modes, single intraperitoneal injection and repeated intraperitoneal injection every four days for 28 days. Serum, liver, kidney, lung, spleen, testis, brain, and heart were collected for injury evaluation by organ index, histopathology analysis and biochemical parameters. In 0.4 and 4 mg/kg 6-PPDQ single injected mice, no significant changes in organ indexes and biochemical parameters were detected, and only moderate pathological changes were observed in organs of liver, kidney, lung, and brain. Very different from this, in 0.4 and 4 mg/kg 6-PPDQ repeated injected mice, we observed the obvious increase in organ indexes of liver, kidney, lung, testis, and brain, and the decrease in spleen index. Meanwhile, the significant pathological changes were formed in liver, kidney, lung, spleen, testis, and brain in 0.4 and 4 mg/kg 6-PPDQ repeated injected mice. Biochemical parameters of liver (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)) and kidney (urea and creatinine) were all significantly upregulated by repeated injection with 0.4 and 4 mg/kg 6-PPDQ. After repeated exposure, most of 6-PPDQ was accumulated in liver and lung of mice. Therefore, our results suggested the risk of repeated exposure to 6-PPDQ in inducing toxicity on multiple organs in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The signalling mechanisms involving the kidney and heart are a niche of networks causing pathological conditions inducing inflammation, reactive oxidative species, cell apoptosis, and organ dysfunction during the onset of clinical complications. The clinical manifestation of the kidney and heart depends on various biochemical processes that influence organ dysfunction coexistence through circulatory networks, which hold utmost importance. The cells of both organs also influence remote communication, and evidence states that it may be explicitly by circulatory small noncoding RNAs, i.e. microRNAs (miRNAs). Recent developments target miRNAs as marker panels for disease diagnosis and prognosis. Circulatory miRNAs expressed in renal and cardiac disease can reveal relevant information about the niche of networks and gene transcription and regulated networks. In this review, we discuss the pertinent roles of identified circulatory miRNAs regulating signal transduction pathways critical in the onset of renal and cardiac disease, which can hold promising future targets for clinical diagnostic and prognostic purposes.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia., Competing Interests: Declaration of interests S.O. receives remuneration for scientific advisory services provided to Pfizer, AstraZeneca, Courage Therapeutics, and Third Rock Ventures. M.J.-H. has consulted for, and is a member of, the Achilles Therapeutics Scientific Advisory Board and Steering Committee, has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, and is co-inventor on a European patent application relating to methods to detect lung cancer (PCT/US2017/028013). All authors, other than J.G. and D.M., are members of the CANCAN Grand Challenge Team funded by Cancer Research UK and the National Cancer Institute. The funders had no role in writing or reviewing the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The objective of the current study was to establish a mouse model of acute radiation syndrome (ARS) after total-body irradiation with 2.5% bone marrow sparing (TBI/BM2.5) that progressed to the delayed effects of acute radiation exposure, specifically pneumonitis and/or pulmonary fibrosis (DEARE-lung), in animals surviving longer than 60 days. Two hundred age and sex matched C57L/J mice were assigned to one of six arms to receive a dose of 9.5 to 13.25 Gy of 320 kV X-ray TBI/BM2.5. A sham-irradiated cohort was included as an age- and sex-matched control. Blood was sampled from the facial vein prior to irradiation and on days 5, 10, 15, 20, 25, and 30 postirradiation for hematology. Respiratory function was monitored at regular intervals throughout the in-life phase. Animals with respiratory dysfunction were administered a single 12-day tapered regimen of dexamethasone, allometrically scaled from a similar regimen in the non-human primate. All animals were monitored daily for up to 224 days postirradiation for signs of organ dysfunction and morbidity/mortality. At euthanasia due to criteria or at the study endpoint, wet lung weights were recorded, and blood sampled for hematology and serum chemistry. The left lung, heart, spleen, small and large intestine, and kidneys were processed for histopathology. A dose-response curve with the estimated lethal dose for 10-99% of animals with 95% confidence intervals was established. The median survival time was significantly prolonged in males as compared to females across the 10.25 to 12.5 Gy dose range. Animal sex played a significant role in overall survival, with males 50% less likely to expire prior to the study endpoint compared to females. All animals developed pancytopenia within the first one- to two-weeks after TBI/BM2.5 followed by a progressive recovery through day 30. Fourteen percent of animals expired during the first 30-days postirradiation due to ARS (e.g., myelosuppression, gastrointestinal tissue abnormalities), with most deaths occurring prior to day 15. Microscopic findings show the presence of radiation pneumonitis as early as day 57. At time points later than day 70, pneumonitis was consistently present in the lungs of mice and the severity was comparable across radiation dose arms. Pulmonary fibrosis was first noted at day 64 but was not consistently present and stable in severity until after day 70. Fibrosis was comparable across radiation dose arms. In conclusion, this study established a multiple organ injury mouse model that progresses through the ARS phase to DEARE-lung, characterized by respiratory dysfunction, and microscopic abnormalities consistent with radiation pneumonitis/fibrosis. The model provides a platform for future development of medical countermeasures for approval and licensure by the U.S. Food and Drug Administration under the animal rule regulatory pathway., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

Objective: Aim: Using quantitative morphological methods to study the peculiarities of the structural reconstruction of the venous bad of the prostate at the conditions of post-resection portal hypertension., Patients and Methods: Materials and Methods: Morphologically, the venous bed of the prostate of 15 intact white rats, 30 animals with post-resection portal hypertension, 17 rats with a combination of post-resection portal hypertension with hepatargia, enteral, cardiac, and renal insufficiency was studied. Rats were slaughtered one month after the start of the experiment by bloodletting under general thiopental anesthesia. Morphometry of the venous blood vessels of the prostate gland was performed on histological specimens, during which the diameter of the postcapillary venules, the diameter of the venules, the external diameter of the venous vessels, the internal diameter of the venous vessels, the thickness of the wall of the venous vessels was determined. Also it was studied the height of endothelial cells, diameter of their nuclei, nuclear-cytoplasmic ratio in these cells, relative volume of damaged endothelial cells, density of vessels of microcirculatory bed per 1 mm² of prostate tissue., Results: Results: It was found that resection of the left and right lobes of the liver leads to the development of postresection portal hypertension and pronounced remodeling of the vessels of the venous bed of the prostate gland, which was characterized by the expansion of the capillary venules of the prostate by 36.5%, with the occurrence of multiple organ failure by 38.5% (р<0.001 ), an increase in the lumen of veins, thinning of their wall, atrophy, dystrophy, and necrobiosis of endothelial cells, disruption of structural cellular homeostasis, endothelial dysfunction, hypoxia, dystrophic-necrotic changes in cells, stromal structures, infiltration, and sclerosis. Morphological changes in the structures of the prostate dominated when post-resection portal hypertension was combined with multiple organ failure., Conclusion: Conclusions: Post-resection portal hypertension in laboratory sexually mature white male rats leads to pronounced remodeling of the venous bed of the prostate gland, which is characterized by the expansion of the lumen of the vessels, thinning of their walls, atrophic, dystrophic and necrobiotic changes in endothelial cells, a violation of structural cellular homeostasis in them, endothelial dysfunction, hypoxia, dystrophic-necrotic changes in cells, stromal structures, infiltration and sclerosis. Morphological changes in the structures of the prostate dominated when post-resection portal hypertension was combined with multiple organ failure.

Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. In this review, we have described in detail the immunopathogenesis of leptospirosis, the influence of cytokines, genetic susceptibility on the course of the disease, and the evasion of the immune response. These data are combined with information about immunological and pathomorphological changes in the kidneys, liver, and lungs, which are most affected by Weil's disease. The review also suggests a possible role of the gut microbiota in the clinical course of leptospirosis, the main mechanisms of the influence of gut dysbiosis on damage in the liver, kidneys, and lungs through several axes, i.e., gut-liver, gut-kidney, and gut-lungs. Modulation of gut microbiota by probiotics and/or fecal microbiota transplantation in leptospirosis may become an important area of scientific research.

Sepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multiorgan failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce. Here, we established a mouse model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils include upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted disease tolerance by improving tissue damage control via the suppression of neutrophils' tissue-damaging properties. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue damage control and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis., Competing Interests: RG, BM, GO, MW, AG, FQ, AF, KL, AH, AK, AA, IM, FO, FO, JB, IL, CB, SK No competing interests declared, LB is affiliated with Polypharma Biologics. The author has no financial interests to declare, (© 2022, Gawish et al.)

Background: Secondary haemophagocytic lymphohistiocytosis (sHLH) is characterised by a hyper activation of immune system that leads to multiorgan failure. It is suggested that excessive immune response in patients with COVID-19 could mimic this syndrome. Some COVID-19 autopsy studies have revealed the presence of haemophagocytosis images in bone marrow, raising the possibility, along with HScore parameters, of sHLH., Aim: Our objective is to ascertain the existence of sHLH in some patients with severe COVID-19., Methods: We report the autopsy histological findings of 16 patients with COVID-19, focusing on the presence of haemophagocytosis in bone marrow, obtained from rib squeeze and integrating these findings with HScore parameters. CD68 immunohistochemical stains were used to highlight histiocytes and haemophagocytic cells. Clinical evolution and laboratory parameters of patients were collected from electronic clinical records., Results: Eleven patients (68.7%) displayed moderate histiocytic hyperplasia with haemophagocytosis (HHH) in bone marrow, three patients (18.7%) displayed severe HHH and the remainder were mild. All HScore parameters were collected in 10 patients (62.5%). Among the patients in which all parameters were evaluable, eight patients (80%) had an HScore >169. sHLH was not clinically suspected in any case., Conclusions: Our results support the recommendation of some authors to use the HScore in patients with severe COVID-19 in order to identify those who could benefit from immunosuppressive therapies. The presence of haemophagocytosis in bone marrow tissue, despite not being a specific finding, has proved to be a very useful tool in our study to identify these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Pulmonary fibrosis induced by silica particles is defined as silicosis, which is an incurable disease. The pathogenesis of silicosis is not completely clear, but it's certain that immune system dysfunction is closely related to it. Immune checkpoint inhibitors (ICIs) are emerging immunotherapeutic agents that mainly target adaptive immune cells, and there is abundant evidence that ICIs are of great value in cancer treatment. However, whether these attractive agents can be implemented in silicosis treatment is unclear. In this study, we explored the efficacy of small molecule inhibitors targeted PD-1/PD-L1 and CTLA-4 on silica-induced pulmonary fibrosis in mice. ICIs were injected intraperitoneally into mice that received silica instillation twice a week. The mice were sacrificed 7 and 28 days after the injection. The lungs, spleen, hilar lymph nodes, thymus, and peripheral blood of mice were collected and subjected to histological examination, flow cytometry analysis, and mRNA and protein quantification. Our results demonstrated that silica exposure caused damage to multiple immune organs in mice, leading to an imbalance in systemic immune homeostasis. Specifically, proportions and subtypes of T and B cells were significantly altered, and the expressions of PD-1, PD-L1 and CTLA-4 were abnormal on these cells. Both PD-1/PD-L1 and CTLA-4 inhibitor administration modulated silica-induced immune system disruption, however, only PD-1/PD-L1 signaling inhibition showed significant amelioration of silicosis. Our findings confirmed for the first time the potential value of ICIs for the treatment of silica-induced pulmonary fibrosis, and this may provide new ideas for the treatment of other fibrosis-related diseases., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is present in almost all cells and regulates the activity of innate immune responses in both intracellular and extracellular settings. Current evidence suggests that HMGB1 plays a pivotal role in human pathological and pathophysiological processes such as the inflammatory response, immune reactions, cell migration, aging, and cell death. Sepsis is a systemic inflammatory response syndrome (SIRS) that occurs in hosts in response to microbial infections with a proven or suspected infectious etiology and is the leading cause of death in intensive care units worldwide, particularly in the aging population. Dysregulated systemic inflammation is a classic characteristic of sepsis, and suppression of HMGB1 may ameliorate inflammation and improve patient outcomes. Here, we focus on the latest breakthroughs regarding the roles of HMGB1 in sepsis and sepsis-related organ injury, the ways by which HMGB1 are released, and the signaling pathways and therapeutics associated with HMGB1. This review highlights recent advances related to HMGB1: the regulation of HMBG1 might be helpful for both basic research and drug development for the treatment of sepsis and sepsis-related organ injury., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Cancer is the second most common cause of death in the United States and is a challenging disease to treat. The treatment options for various cancers include but are not limited to surgery, radiation, and chemotherapy. The mechanism behind chemotherapy is intended to promote cellular damage to cells that are proliferating uncontrollably. Unfortunately for the recipients, most chemotherapeutic agents cannot differentiate between malignant cells and healthy cells and tissues. Thus, chemotherapy-induced toxicities are often observed in once-healthy organs. These effects can be acute and self-limiting or chronic, appearing long after chemotherapy is completed. Cancer survivors can then present for non-cancer related surgeries later in life, due to this toxicity. Furthermore, the administration of chemotherapeutic agents can profoundly impact the anesthetic management of patients who are undergoing surgery. This review discusses how chemotherapy-induced organ toxicity can occur in multiple organ systems and what drugs should be avoided if prior toxicity exists in these organ systems., (Published by Elsevier Masson SAS.)

Background: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO-VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology., Methods: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22-89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ2 and Mann-Whitney U tests., Results: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either., Conclusions: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO-VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Multi-organ failure is one of the common causes of fatal outcome in COVID-19 patients. However, the pathogenetic association of the SARS-CoV-2 viral load (VL) level with fatal dysfunctions of the lungs, liver, kidneys, heart, spleen and brain, as well as with the risk of death in COVID-19 patients remains poorly understood. SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: N SARS-CoV-2 /N ABL1 × 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The "pulmonary factors" of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart-56.5%, spleen-52.2%, liver-47.8%, kidney-26%, and brain-13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment., (© 2021 by The American Society of Hematology.)

The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people worldwide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the crucial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1 β levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utilization of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection.

We hypothesized that the composition of sepsis-inducing bacterial flora influences the course of fecal peritonitis in rodents. Saline or fecal suspensions with a standardized dose range of bacterial colony-forming units (CFUs) were injected intraperitoneally into Sprague-Dawley rats. The qualitative composition of the initial inoculum and the ascites was analyzed separately by MALDI-TOF mass spectrometry. Invasive monitoring was conducted in separate anesthetized groups (n = 12-13/group) after 12, 24, 48 and 72 h to determine rat-specific organ failure assessment (ROFA) scores. Death and ROFA scores peaked at 24 h. At this time, 20% mortality occurred in animals receiving a monomicrobial E. coli suspension, and ROFA scores were significantly higher in the monomicrobial subgroup than in the polymicrobial one (median 6.5; 5.0-7.0 and 5.0; 4.75-5.0, respectively). ROFA scores dropped after 48 h, accompanied by a steady decrease in ascites CFUs and a shift towards intra-abdominal monomicrobial E. coli cultures. Furthermore, we found a relationship between ascites CFUs and the evolving change in ROFA scores throughout the study. Hence, quantitatively identical bacterial loads with mono- or polymicrobial dominance lead to a different degree of sepsis severity and divergent outcomes. Initial and intraperitoneal microbiological testing should be used to improve translational research success., (© 2021. The Author(s).)

Rationale: Studies have previously reported misidentifying Caltha palustris (C. palustris) as Ligularia fischeri and its subsequent ingestion leading to abdominal pain and gastrointestinal symptoms, which are alleviated immediately. Bradycardia and hypotension may persist for several days, and an infusion of dopamine can restore a healthy state without complications. We report a case of C. palustris poisoning with protein-losing enteropathy that has not been reported previously. The patient died of multiple organ failure, and exhibited more severe clinical deterioration than previous cases due to prolonged shock., Patient Concerns: A 70-year-old woman was admitted to the emergency department (ED) with complaints of epigastric pain, vomiting, and diarrhea after ingestion of a poisonous plant presumed to be C. palustris. The patient presented with bradycardia and hypotension after ED admission, and vasopressor infusion improved bradycardia but not hypotension, while the patient complained of severe epigastric pain., Diagnoses: Abdominal computed tomography showed luminal distention and edematous thickening of the entire stomach lining, as well as small and large intestinal wall edema, indicating severe gastritis and enterocolitis. The laboratory test results suggested severe hypoalbuminemia, while the arterial blood gas analyses showed a continuous increase in metabolic acidosis., Interventions: As plant poisoning was suspected, activated charcoal was administered to the patient, followed by administration of vasopressors and other conservative therapies. Continuous renal replacement therapy (CRRT) was used for metabolic acidosis of increasing severity., Outcomes: Despite the administration of vasopressors and other conservative therapies, the state of shock persisted, and metabolic acidosis did not improve even after CRRT. Ultimately, the patient died of multiple organ failure., Lessons: For many poisonous wild plants, the precise profile of toxic compounds and mechanisms of action remain to be identified; when there is insufficient literature reporting on suspected plant poisoning, the medical personnel providing the treatment should consider the various side effects that differ from the reported ones and the possibility of more severe clinical progress and poor prognosis., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Sepsis is a life-threatening organ dysfunction syndrome arising from infection-induced uncontrolled systemic inflammatory responses. Patients surviving severe sepsis also exhibit increased mortality due to enhanced vulnerability to infections. In this study, we examined whether (R)-ketamine could prevent against lethal sepsis-induced systemic inflammation and inflammatory organ injury., Main Methods: Septic model was induced by cecal ligation and puncture (CLP) surgery on adult mice. (R)-ketamine (10 or 15 mg/kg) was administrated intraperitoneally (i.p.) 24 h before and/or immediately after CLP., Key Findings: Combined prophylactic and therapeutic use of (R)-ketamine (10 mg/kg), as well as either prophylactic or therapeutic use of (R)-ketamine at a single dose of 15 mg/kg did not reduce 14-day mortality after CLP. However, combined prophylactic and therapeutic use of (R)-ketamine (15 mg/kg) significantly increased 14-day survival rate, attenuated sepsis-induced marked drop in the rectal temperature and increase in the plasma levels of inflammatory cytokines [i.e., interleukin (IL)-6, IL-17A, tumor necrosis factor (TNF)-α, IL-1β, and IL-10] 12 h after CLP. Furthermore, (R)-ketamine alleviated sepsis-induced increase in the organ injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), myocardial kinase (CK-MB), and creatinine 24 h after CLP. Moreover, the increased lung wet/dry weight ratio, pulmonary morphological injury and the pulmonary levels of inflammatory cytokines were also attenuated by (R)-ketamine., Significance: Combined prophylactic and therapeutic use of (R)-ketamine could attenuate systemic inflammation and inflammatory multi-organ injury in mice after CLP-induced lethal sepsis. Therefore, (R)-ketamine would be a potential prophylactic and therapeutic drug for patients prone to sepsis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The regulation of intracellular calcium (Ca 2+ ) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca 2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients' cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient's genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics., (© 2021. The Author(s).)

Background: Inflammatory lipid mediators in mesenteric lymph (ML), including arachidonic acid (AA), are considered to play an important role in the pathogenesis of multiple-organ dysfunction after hemorrhagic shock. A previous study suggested that vagus nerve stimulation (VNS) could relieve shock-induced gut injury and abrogate ML toxicity, resulting in the prevention of multiple-organ dysfunction. However, the detailed mechanism of VNS in lymph toxicity remains unclear. The study aimed to investigate the relationship between VNS and inflammatory lipid mediators in ML., Methods: Male Sprague-Dawley rats underwent laparotomy and superior mesenteric artery obstruction (SMAO) for 60 minutes to induce intestinal ischemia followed by reperfusion and observation. The ML duct was cannulated, and ML samples were obtained both before and after SMAO. The distal ileum was removed at the end of the observation period. In one group of animals, VNS was performed from 10 minutes before 10 minutes after SMAO (5 V, 0.5 Hz). Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of AA was performed for each ML sample. The biological activity of ML was examined using a monocyte nuclear factor κ-light-chain-enhancer of activated B cells activation assay. Western blotting of phospholipase A2 group IIA (PLA2-IIA) was also performed for ML and ileum samples., Results: Vagus nerve stimulation relieved the SMAO-induced histological gut injury. The concentration of AA and level of nuclear factor κ-light-chain-enhancer of activated B cells activation in ML increased significantly after SMAO, whereas VNS prevented these responses. Western blotting showed PLA2-IIA expression in the ML and ileum after SMAO; however, the appearance of PLA2-IIA band was remarkably decreased in the samples from VNS-treated animals., Conclusion: The results suggested that VNS could relieve gut injury induced by SMAO and decrease the production of AA in ML by altering PLA2-IIA expression in the gut and ML., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain., 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 Tan, Komarasamy and RMT Balasubramaniam.)

Sepsis, an inflammation-related clinical syndrome, is characterized by disrupted immune homeostasis accompanied by infection and multiple organ dysfunction as determined by the Sequential Organ Failure Assessment (SOFA). Substantial evidence has recently suggested that lncRNAs orchestrate various biological processes in diseases, and lncRNAs play special roles in the diagnosis and management of sepsis. To date, very few reviews have provided clear and comprehensive clues to demonstrate the roles of lncRNAs in the pathogenesis of sepsis. Based on previously published studies, in this review, we summarize the different functions of lncRNAs in sepsis-induced cellular disorders and sepsis-induced organ failure to show the potential roles of lncRNAs in the diagnosis and management of sepsis. We further depict the function of some lncRNAs known to be pivotal regulators in the pathogenesis of sepsis to discuss the underlying molecular events. Additionally, we list and discuss several hotspots in research on lncRNAs, which may be conducive to future lncRNA-targeted therapeutic approaches for sepsis treatment., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We investigated the impact of aerobic exercise (AE) on multiple organ dysfunction syndrome (MODS), aortic injury, pathoglycemia, and death during sepsis. ICR mice were randomized into four groups: Control (Con), Lipopolysaccharide (LPS), Exercise (Ex), and Exercise + LPS (Ex + LPS) groups. Mice were trained with low-intensity for 4 weeks. LPS and Ex + LPS mice received 5 mg/kg LPS intraperitoneally for induction of sepsis. Histopathological micrographs showed the organ morphology and damage. This study examined the effects of AE on LPS-induced changes in systemic inflammation, pulmonary inflammation, lung permeability, and bronchoalveolar lavage fluid (BALF) cell count, oxidative stress-related indicators in the lung, blood glucose levels, plasma lactate levels, serum insulin levels, plasma high-mobility group box 1 (HMGB1) levels, glucose transporter 1 (Glut1) and HMGB1, silent information regulator 1 (Sirt-1), and nuclear factor erythroid 2-related factor 2 (Nrf-2) mRNA expression levels in lung tissue. AE improved sepsis-associated multiple organ dysfunction syndrome (MODS), aortic injury, hypoglycemia, and death. AE prominently decreased pulmonary inflammation, pulmonary edema, and modulated redox balance during sepsis. AE prominently decreased neutrophil content in organ. AE prominently downregulated CXCL-1, CXCL-8, IL-6, TNF-α, Glu1, and HMGB1 mRNA expression but activated IL-1RN, IL-10, Sirt-1, and Nrf-2 mRNA expression in the lung during sepsis. AE decreased the serum levels of lactate and HMGB1 but increased blood glucose levels and serum insulin levels during sepsis. A 4-week AE improves sepsis-associated MODS, aortic injury, pathoglycemia, and death. AE impairs LPS-induced lactate and HMGB1 release partly because AE increases serum insulin levels and decreases the levels of Glut1. AE is a novel therapeutic strategy for sepsis targeting aerobic glycolysis., (© 2021. The Author(s).)

Acute pancreatitis (AP) is a common pancreatic inflammation associated with substantial morbidity and mortality. AP may be mild or severe which can spread systemically causing multiple organs failure (MOF) and even death. In the current study, protocatechuic acid (PCA), a natural phenolic acid, was investigated for its possible protective potential against L-arginine induced AP and multiple organs injury (MOI) in rats. AP was induced by L-arginine (500 mg/100 g, ip). Two dose levels of PCA were tested (50 and 100 mg/kg, oral, 10 days before L-arginine injection). PCA successfully protected against L-arginine induced AP and MOI that was manifested by normalizing pancreatic, hepatic, pulmonary, and renal tissue architecture and restoring the normal values of pancreatic enzymes (amylase and lipase), serum total protein, liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) and kidney function biomarkers (blood urea nitrogen (BUN) and serum creatinine (Cr)) that were significantly elevated upon L-arginine administration. Additionally, PCA restored balanced oxidant/antioxidants status that was disrupted by L-arginine and normalized pancreatic levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content. Moreover, PCA significantly decreased L-arginine induced elevation in pancreatic high motility group box protein 1 (HMGB1), toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) expression. PCA significantly ameliorated L-arginine-induced AP and MOI through its anti-inflammatory and antioxidant effects. HMGB1/TLR4/NF-κB was the major pathway involved in the observed protective potential., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: We aimed to analyze risk factors related to the development of delirium, aiming for early intervention in patients with greater risk., Material and Methods: Observational study, including prospectively collected patients treated in a single general ICU. These were classified into two groups, according to whether they developed delirium or not (screening performed using CAM-ICU tool). Demographics and clinical data were analyzed. Multivariate logistic regression analyses were performed to quantify existing associations., Results: 1462 patients were included. 93 developed delirium (incidence: 6.3%). These were older, scored higher on the Clinical Frailty Scale, on the risk scores on admission (SAPS-3 and SOFA), and had a greater number of organ failures (OF). We observed more incidence of delirium in patients who (a) presented more than two OF (20.4%; OR 4.9; CI95%: 2.9-8.2), and (b) were more than 74 years old albeit having <2 OF (8.6%; OR 2.1; CI95%: 1.3-3.5). Patients who developed delirium had longer ICU and hospital length-of-stays and a higher rate of readmission., Conclusions: The highest risk observed for developing delirium clustered in patients who presented more than 2 OF and patients over 74 years old. The detection of patients at high risk for developing delirium could imply a change in management and improved quality of care., Competing Interests: The authors have declared that no competing interests exist.

Uricase-deficient rats could be one of the optimal model animals to study hyperuricemia. The present study aimed to find the biological differences between uricase-deficient (Kunming-DY rats) and wild-type male rats. Uricase-deficient rats and wild-type rats were commonly bred. Their body weight, water and food consumption, 24-h urine and feces, uric acid in serum and organs, and serum indexes were recorded or assayed. Organs, including the heart, liver, spleen, lung, kidney, thymus, stomach, duodenum, and ileum, were examined using a routine hematoxylin-eosin staining assay. We found that the growth of male uricase-deficient rats was retarded. These rats excreted more urine than the wild-type rats. Their organ indexes (organ weight body weight ratio), of the heart, liver, kidney, and thymus significantly increased, while those of the stomach and small intestine significantly decreased. The uricase-deficient rats had a significantly higher level of serum uric acid and excreted more uric acid via urine at a higher concentration. Except for the liver, uric acid increased in organs and intestinal juice of uricase-deficient rats. Histological examination of the uricase-deficient rats showed mild injuries to the heart, liver, spleen, lung, kidney, thymus, stomach, duodenum, and ileum. Our results suggest that uricase-deficient rats have a different biological pattern from the wild-type rats. Uricase deficiency causes growth retardation of young male rats and the subsequent increase in serum uric acid results in mild organs injuries, especially in the kidney and liver., Competing Interests: The authors have declared that no competing interests exist.

We aimed to determine disseminated intravascular coagulation (DIC)-associated organ failure and underlying diseases based on data from three ICU wards in tertiary hospitals in China from 2008 to 2016. The diagnosis of DIC was confirmed by an International Society of Thrombosis and Hemostasis score greater than or equal to 5. The maternal outcomes included the changes in organ function 24 h after ICU admission. The durations of hospital stay and ICU stay were recorded as secondary outcomes. Among 297 ICU admissions (median Sequential Organ Failure Assessment score, 4) for obstetric diseases, there were 87 DIC cases, with an estimated DIC incidence of 87 per 87,580 deliveries. Postpartum hemorrhage was the leading disease associated with DIC (71, 81.6%), followed by hypertensive disorders (27, 31.0%), sepsis (15, 17.2%), acute fatty liver of pregnancy (11, 12.6%) and amniotic fluid embolism (10, 11.5%). Compared with patients without DIC, those with DIC had higher rates of multiple organ dysfunction syndrome/death (27.6% vs 4.8%, p = 0.000), organ failure (36.8% vs 24.3%, p = 0.029), among which organ failure included acute renal failure (32.2% vs 10.0%, p = 0.000), respiratory failure (16.1% vs 8.6%, p = 0.057), disturbance of consciousness (12.6% vs 2.4%, p = 0.000) and DIC group also had higher rates of massive transfusion (52.9% vs 21.9%, p = 0.000), hysterectomy (32.2% vs 15.7%, p = 0.001), longer ICU (4 days vs 2 days, p = 0.000) and hospital stays (14 days vs 11 days, p = 0.005). DIC and amniotic fluid embolism were independent risk factors for organ failure in patients admitted to the ICU. Postpartum hemorrhage was the leading cause of DIC associated organ failure in obstetrics admitted to the ICU. The control of obstetric bleeding in a timely manner may improve obstetric prognoses., (© 2021. The Author(s).)

Levels of circulating cell-free hemoglobin are elevated during hemolytic and inflammatory diseases and contribute to organ dysfunction and severity of illness. Though several studies have investigated the contribution of hemoglobin to tissue injury, the precise signaling mechanisms of hemoglobin-mediated endothelial dysfunction in the lung and other organs are not yet completely understood. The purpose of this review is to highlight the knowledge gained thus far and the need for further investigation regarding hemoglobin-mediated endothelial inflammation and injury to develop novel therapeutic strategies targeting the damaging effects of cell-free hemoglobin.

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment., (© 2021. The Author(s).)

Purpose: To explore the clinical features and immunological mechanisms of Castleman disease (CD) complicated with autoimmune diseases (AID)., Methods: We explored the prevalence and clinical manifestations of CD complicated with AID by reviewing clinical, pathological, and laboratory data of 40 CD patients retrospectively, and then explored abnormal immune mechanisms in the co-existence of the two entities by monitoring lymphocyte subsets in peripheral blood., Results: Paraneoplastic pemphigus, autoimmune hemolytic anemia, Sjogren's syndrome, myasthenia gravis, and psoriasis were found to be coexisted with CD in 9/40 (22.5%) patients with different sequence of onset. No bias in the clinical and histological type of CD was observed for the occurrence of AID. CD patients with AID were more likely to have skin and/or mucous membrane damage and pulmonary complications, and presented elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and positive autoantibodies than those without AID (p < 0.05). Deregulated cellular and innate immune responses as indicated by decreased CD3 + T cells and increased natural killer cells were observed in peripheral blood of CD patients with AID (p < 0.05). UCD patients with AID were successfully treated with surgery and immunosuppressive therapy. MCD complicated by AID relieved with immunosuppressors, cytotoxic chemotherapy, and rituximab., Conclusion: Systemic inflammation/immunological abnormalities and organ dysfunction were associated with the occurrence of AID in CD. Impairment of cellular and innate immunity may be a candidate etiology for the coexistence of the two entities.

Sepsis is described as a systemic immune response of the body to an infectious process that might result in dysfunctional organs that may lead to death. In clinical practice, sepsis is considered a medical emergency. The initial event in sepsis caused by a deregulated host response towards harmful microorganisms that leads to an aggravated systemic inflammatory response syndrome (SIRS) to tackle with pathogen invasion and a compensatory anti-inflammatory response syndrome (CARS) that lasts for several days. The inflammatory response and the cellular damage as well as the risk of an organ dysfunction are in direct proportion. Even though, the pathogenesis of sepsis remains unclear, many studies have shown evidence of role of oxidants and antioxidants in sepsis. The altered innate and adaptive immune cell and upregulated production and release of cytokines and chemokines most probably due to involvement of JAK-STAT pathway, disturbance in redox homeostasis due to low clearance of lactate and other oxidative stressors, contributes to sepsis process to organ dysfunction which contribute to increase rates of mortality among these patients. Hence, the treatment strategies for sepsis include antibiotics, ventilator and blood glucose management and other strategies for resuscitation are rapidly progressing. In the current review, we mainly concentrate on throwing light on the main molecular aspects and chemico-biological interactions that shows involvement in pathways manipulating alteration in physiology of immune cells (innate and adaptive) that change the bioenergetics/cellular metabolism to organ dysfunction and correlation of these altered pathway, improve the understating for new therapeutic target for sepsis.

A novel infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in December 2019 and declared as a global pandemic by the World Health. Approximately 15% of patients with COVID-19 progress to severe pneumonia and eventually develop acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure with high morbidity and mortality. Evidence points towards a determinant pathogenic role of members of the renin-angiotensin system (RAS) in mediating the susceptibility, infection, inflammatory response and parenchymal injury in lungs and other organs of COVID-19 patients. The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, has important roles in pulmonary pathological states, including fibrosis, pneumonia and ARDS. RAGE overexpression/hyperactivation is essential to the deleterious effects of RAS in several pathological processes, including hypertension, chronic kidney and cardiovascular diseases, and diabetes, all of which are major comorbidities of SARS-CoV-2 infection. We propose RAGE as an additional molecular target in COVID-19 patients for ameliorating the multi-organ pathology induced by the virus and improving survival, also in the perspective of future infections by other coronaviruses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To investigate the relationship between smoking history and pack-year exposure on the rate of end-organ damage in systemic lupus erythematosus (SLE)., Methods: The SLE incident cohort included patients who met American College of Rheumatology (ACR) 1997 or SLE International Collaborating Clinics (SLICC) 2012 SLE criteria and had rheumatology encounters at a US academic institution (2008-16). The primary outcome was median time to SLICC/ACR damage index (SLICC/ACR-DI) increase or death. Main explanatory variables were smoking status and pack-years. Covariates included age, sex, race, ethnicity, receipt of Medicaid, neighborhood area deprivation index, and baseline SLE damage. Damage increase-free survival was evaluated by smoking status and pack-years using Kaplan-Meier and Cox proportional hazards methods., Results: Patients of Black race and Medicaid recipients were more commonly current smokers ( p 's < 0.05). Former smokers were older and more likely to have late-onset SLE (54% versus 33% of never and 29% of current smokers, p  = 0.001). Median time to SLICC/ACR-DI increase or death was earlier in current or former compared to never smokers (4.5 and 3.4 versus 9.0 yrs; p  = 0.002). In multivariable models, the rate of damage accumulation was twice as fast in current smokers (HR 2.18; 1.33, 3.57) and smokers with a >10 pack-year history (HR 2.35; 1.15, 3.64) versus never smokers., Conclusions: In this incident SLE cohort, past or current smoking predicted new SLE damage 4-5 years earlier. After adjustment, current smokers and patients with a pack-year history of >10 years accumulated damage at twice the rate of never smokers.

Objective: To test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions., Methods: We conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes., Results: Forty-three decedents (n = 13 female, median age 47 years) received autopsies after undergoing ECMO for acute respiratory distress syndrome (n = 14), cardiogenic shock (n = 14), and cardiac arrest (n = 15). Median duration of ECMO was 140 hours, most decedents (n = 40) received anticoagulants; 60% (n = 26) underwent venoarterial ECMO, and 40% (n = 17) underwent venovenous ECMO. Neuropathology was found in 35 decedents (81%), including microhemorrhages (37%), macrohemorrhages (35%), infarctions (47%), and hypoxic-ischemic brain injury (n = 17, 40%). Most pathology occurred in frontal neocortices (n = 43 occurrences), basal ganglia (n = 33), and cerebellum (n = 26). Decedents with hemorrhage were older (median age 57 vs 38 years, p = 0.01); those with hypoxic brain injury had higher Sequential Organ Failure Assessment scores (8.0 vs 2.0, p = 0.04); and those with infarction had lower peak Paco 2 (53 vs 61 mm Hg, p = 0.04). Six of 9 patients with normal neuroimaging results were found to have pathology on autopsy. The majority underwent withdrawal of life-sustaining therapy (n = 32, 74%), and 2 of 8 patients with normal brain autopsy underwent withdrawal of life-sustaining therapy for suspected neurologic injury., Conclusion: Neuropathological findings after ECMO are common, varied, and associated with various clinical factors. Further study on underlying mechanisms is warranted and may guide ECMO management., (© 2021 American Academy of Neurology.)

Abstract: Intermediate care units (ImCUs) have been shown as appropriate units for the management of selected septic patients. Developing specific protocols for residents in training may be useful for their medical performance. The objective of this study was to analyze whether a simulation-based learning bundle is useful for residents while acquiring competencies in the management of sepsis during their internship in an ImCU.A prospective study, set in a tertiary-care academic medical center was performed enrolling residents who performed their internship in an ImCU from 2014 to 2017. The pillars of the simulation-based learning bundle were sepsis scenario in the simulation center, instructional material, and sepsis lecture, and management of septic patients admitted in the ImCU. Each resident was evaluated in the beginning and at the end of their internship displaying a sepsis-case scenario in the simulation center. The authors developed a sepsis-checklist that residents must fulfill during their performance which included 5 areas: hemodynamics (0-10), oxygenation (0-5), antibiotic therapy (0-9), organic injury (0-5), and miscellaneous (0-4).Thirty-four residents from different years of residency and specialties were evaluated. The total median score (interquartile range) increased significantly after training: 12 (25) vs 23 (16), P = .001. First-year residents scored significantly lower than older residents at baseline: 10 (14) vs 14.5 (19), P = .024. However, the performance at the end of the training period was similar in both groups: 21.5 (11) vs 23 (16), P = 1.000. Internal Medicine residents scored significantly higher than residents from other specialties: 18 (17) vs 10.5 (21), P = .007. Nonetheless, the performance at the end of the training period was similar in both groups: 24.5 (9) vs 22 (13), P = 1.000.Combining medical simulation with didactic lectures and a rotation in an ImCU staffed by hospitalists seems to be useful in acquiring competencies to manage critically ill patients with sepsis. We designed a checklist to assure an objective evaluation of the performance of the residents and to identify those aspects that could be potentially improved., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Recent studies using genetically manipulated mouse models have shown the pivotal role of O-linked N-acetylglucosamine modification (O-GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O-GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O-GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O-GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β-cells. Furthermore, we discuss the importance of O-GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown. Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury. Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence. Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues. Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

We describe the case of a 36-year-old male who presented to hospital with acute respiratory distress, and hemoptysis after intravenously injecting 20 milliliters of pure gasoline. Despite maximum supportive care he died without a definitive diagnosis 4 hours after presentation to the hospital. Postmortem examination confirmed diffuse pulmonary hemorrhage as a cause of death. Our case highlights the key clinical, and pathological features of this very rare poisoning with a volatile substance and reminds clinicians to consider it as a potential cause of hemoptysis and pulmonary hemorrhage.

The precise mechanisms of pathology in severe COVID-19 remains elusive. Current evidence suggests that inflammatory mediators are responsible for the manifestation of clinical symptoms that precedes a fatal response to infection. This review examines the nature of platelet activating factor and emphasizes the similarities between the physiological effects of platelet activating factor and the clinical complications of severe COVID-19.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in December 2019 form Wuhan, China leads to coronavirus disease 2019 (COVID-19) pandemic. While the common cold symptoms are observed in mild cases, COVID-19 is accompanied by multiorgan failure in severe patients. The involvement of different organs in severe patients results in lengthening the hospitalization duration and increasing the mortality rate. In this review, we aimed to investigate the involvement of different organs in COVID-19 patients, particularly in severe cases. Also, we tried to define the potential underlying mechanisms of SARS-CoV2 induced multiorgan failure. The multi-organ dysfunction is characterized by acute lung failure, acute liver failure, acute kidney injury, cardiovascular disease, and as well as a wide spectrum of hematological abnormalities and neurological disorders. The most important mechanisms are related to the direct and indirect pathogenic features of SARS-CoV2. Although the presence of angiotensin-converting enzyme 2, a receptor of SARS-CoV2 in the lung, heart, kidney, testis, liver, lymphocytes, and nervous system was confirmed, there are controversial findings to about the observation of SARS-CoV2 RNA in these organs. Moreover, the organ failure may be induced by the cytokine storm, a result of increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs. Therefore, further investigations are needed to detect the exact mechanisms of pathogenesis. Since the involvement of several organs in COVID-19 patients is important for clinicians, increasing their knowledge may help to improve the outcomes and decrease the rate of mortality and morbidity.

During hyperinflammatory conditions that can occur in acute critical illness, such as shock or hypoperfusion, inflammatory mediators activate the endothelium, fueling a proinflammatory host-response as well as procoagulant processes. These changes result in shedding of the glycocalyx, endothelial hyperpermeability, edema formation, and lead to disturbed microcirculatory perfusion and organ failure. Different fluid strategies that are used in shock may have differential effects on endothelial integrity. Collectively, low protein content fluids seem to have negative effects on the endothelial glycocalyx, aggravating endothelial hyperpermeability, whereas fluids containing albumin or plasma proteins may be superior to normal saline in protecting the glycocalyx and endothelial barrier function. Targeting the endothelium may be a therapeutic strategy to limit organ failure, which hitherto has not received much attention. Treatment targets aimed at restoring the endothelium should focus on maintaining glycocalyx function and/or targeting coagulation pathways or specific endothelial receptors. Potential treatments could be supplementing glycocalyx constituents or inhibiting glycocalyx breakdown. In this review, we summarize mechanisms of endothelial dysfunction during acute critical illness, such as the systemic inflammatory response, shedding of the glycocalyx, endothelial activation, and activation of coagulation. In addition, this review focuses on the effects of different fluid strategies on endothelial permeability. Also, potential mechanisms for treatment options to reduce endothelial hyperpermeability with ensuing organ failure are evaluated. Future research is needed to elucidate these pathways and to translate these data to the first human safety and feasibility trials.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which rapidly became a pandemic of global proportions. Sepsis is commonly present with high lethality in the severe forms of the disease. The virus-induced cytokine storm puts the immune system in overdrive at the expense of the pathogen-specific immune response and is likely to underlie the most advanced COVID-19 clinical features, including sepsis-related multiple organ dysfunction as well as the pathophysiological changes found in the lungs. We review the major therapeutic strategies that have been considered for sepsis and might be amenable to repurposing for COVID-19. We also discuss two different immunization strategies that have the potential to confer antiviral heterologous protection: innate-induced trained immunity and adaptive-induced immune response resetting., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Coronavirus disease 2019 (COVID-19), like cancer, is a complex disease with clinical phases of progression. Initially conceptualized as a respiratory disease, COVID-19 is increasingly recognized as a multi-organ and heterogeneous illness. Disease staging is a method for measuring the progression and severity of an illness using objective clinical and molecular criteria. Integral to cancer staging is "metastasis," defined as the spread of a disease-producing agent, including neoplastic cells and pathogens such as certain viruses, from the primary site to distinct anatomic locations. Staging provides valuable frameworks and benchmarks for clinical decision-making in patient management, improved prognostication, and evidence-based treatment selection., Competing Interests: Declaration of Interests C.C.-C., A.F.-B., F.K., and V.S., as part of Mount Sinai, report that the institution has licensed SARS-CoV-2 serological assays to commercial entities and have filed for patent protection for serological assays. R.S. reports to be associated with SEMA4. P.S.-S. is the chief executive officer and majority shareholder of both ImmunityBio, Inc., and NantKwest, Inc., and is developing a qLAMP assay., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Kidney failure occurs frequently and is associated with high mortality during sepsis. Proenkephalin (PENK) is an emerging biomarker of kidney function. We explored whether PENK levels could predict severity, organ failure, and mortality in septic patients., Methods: We measured the PENK level in the plasma of 215 septic patients using the sphingotest penKid assay (Sphingotec GmbH, Hennigsdorf, Germany). This was analyzed in terms of sepsis severity, vasopressor use, 30-day mortality, sequential organ failure assessment (SOFA) renal subscore, the Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (CKD-EPI eGFR) categories, and renal replacement therapy (RRT) requirement., Results: The PENK levels were significantly higher in patients with septic shock, vasopressor use, and non-survivors than in patients with solitary sepsis, no vasopressor use, and survivors, respectively (P=0.02, P=0.007, P<0.001, respectively). The PENK levels were significantly associated with SOFA renal subscore and CKD-EPI eGFR categories (both P<0.001). The distribution of lower eGFR (<60 mL/min/1.73 m 2 ), RRT requirement, SOFA renal subscore, and the number of organ failures differed significantly according to the PENK quartile (P for trend<0.001 or 0.017). The 30-day mortality rate also differed significantly according to the PENK quartile (P for trend<0.001)., Conclusions: PENK could be an objective and reliable marker to predict severity, organ failure, and 30-day mortality in septic patients.