The Activin/Follistatin Axis Is Severely Deregulated in COVID-19 and Independently Associated With In-Hospital Mortality.

BACKGROUND: Activins are members of the transforming growth factor-ß superfamily implicated in the pathogenesis of several immunoinflammatory disorders. Based on our previous studies demonstrating that overexpression of activin-A in murine lung causes pathology sharing key features of coronavirus disease 2019 (COVID-19), we hypothesized that activins and their natural inhibitor follistatin might be particularly relevant to COVID-19 pathophysiology. METHODS: Activin-A, activin-B, and follistatin were retrospectively analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in 3 independent centers, and compared with demographic, clinical, and laboratory parameters. Optimal scaling with ridge regression was used to screen variables and establish a prediction model. RESULT: The activin/follistatin axis was significantly deregulated during the course of COVID-19, correlated with severity and independently associated with mortality. FACT-CLINYCoD, a scoring system incorporating follistatin, activin-A, activin-B, C-reactive protein, lactate dehydrogenase, intensive care unit admission, neutrophil/lymphocyte ratio, age, comorbidities, and D-dimers, efficiently predicted fatal outcome (area under the curve [AUC], 0.951; 95% confidence interval, .919-.983; P <10-6). Two validation cohorts indicated similar AUC values. CONCLUSIONS: This study demonstrates a link between activin/follistatin axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that allows dynamic prediction of disease outcome, supporting clinical decision making.

Differential effects of cisplatin combined with the flavonoid apigenin on HepG2, Hep3B, and Huh7 liver cancer cell lines.

The potential of apigenin (APG) to enhance cisplatin's (CDDP) chemotherapeutic efficacy was investigated in HepG2, Hep3B, and Huh7 liver cancer cell lines. The presence of 20 µM APG sensitized all cell lines to CDDP treatment (degree of sensitization based on the MTT assay: HepG2>Huh7>Hep3B). As reflected by sister chromatid exchange levels, the degree of genetic instability as well as DNA repair by homologous recombination differed among cell lines. CDDP and 20 µM APG cotreatment exhibited a synergistic genotoxic effect on Hep3B cells and a less than additive effect on HepG2 and Huh7 cells. Cell cycle delays were noticed during the first mitotic division in Hep3B and Huh7 cells and the second mitotic division in HepG2 cells. CDDP and CDDP + APG treatments reduced the clonogenic capacity of all cell lines; however, there was a discordance in drug sensitivity compared with the MMT assay. Furthermore, a senescence-like phenotype was induced, especially in Hep3B and Huh7 cells. Unlike CDDP monotherapy, the combined treatment exhibited a significant anti-invasive and anti-migratory action in all cancer cell lines. The fact that the three liver cancer cell lines responded differently, yet positively, to CDDP + APG cotreatment could be attributed to variations they present in gene expression. Complex mechanisms seem to influence cellular responses and cell fate.

Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis.

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.

Determining rhythmicity and determinism of temperature curves in septic and non-septic critically ill patients through chronobiological and recurrence quantification analysis: a pilot study.

BACKGROUND: A few studies have demonstrated that critically ill patients exhibit circadian deregulation and reduced complexity of different time series, such as temperature. RESULTS: In this prospective study, we enrolled 21 patients divided into three groups: group A (N = 10) included subjects who had septic shock at the time of ICU entry, group B (N = 6) included patients who developed septic shock during ICU stay, and group C consisted of 5 non-septic critically ill patients. Core body temperature (CBT) was recorded for 24 h at a rate of one sample per hour (average of CBT for that hour) and during different occasions: upon ICU entry and exit in groups A and C and upon entry, septic shock development, and exit in group B. Markers of circadian rhythmicity included mean values, amplitude that is the difference between peak and mean values, and peak time. Furthermore, recurrence quantification analysis (RQA) was employed for assessing different markers of complexity of temperature signals. Patients from group C exhibited higher temperature amplitude upon entry (0.45 ± 0.19) in relation with both groups A (0.28 ± 0.18, p < 0.05) and B (0.32 ± 0.13, p < 0.05). Circadian features did not differ within all groups. Temperature amplitude in groups B and C upon entry was negatively correlated with SAPS II (r = - 0.72 and - 0.84, p < 0.003) and APACHE II scores (r = - 0.70 and - 0.63, p < 0.003), respectively, as well as duration of ICU and hospital stay in group B (r = - 0.62 and - 0.64, p < 0.003) and entry SOFA score in group C (r = - 0.82, p < 0.003). Increased periodicity of CBT was found for all patients upon exit related to entry in the ICU. Different RQA features indicating periodic patterns of change of entry CBT were negatively correlated with severity of disease and length of ICU stay for all patients. CONCLUSIONS: Increased temperature rhythmicity during ICU entry was related with lower severity of disease and better clinical outcomes, whereas the more deterministic CBT patterns were found in less critically ill patients with shorter ICU stay.

Melatonin and cortisol exhibit different circadian rhythm profiles during septic shock depending on timing of onset: a prospective observational study.

BACKGROUND: Septic shock has been found to disrupt circadian rhythms. Moreover, timing of onset has been associated with different circadian profiles in experimental studies. RESULTS: In this prospective study, we enrolled 26 patients divided into two groups: Group A (N = 15) included subjects who had septic shock at the time of ICU admission and Group B (N = 11) included patients who developed septic shock during ICU admission. 6-Sulfatoxymelatonin (aMT6s) and cortisol levels were measured in urine samples every 4 h over a 24-h period. Two sets of samples were taken from Group A (entry/septic shock and exit) and three sets from Group B (entry, septic shock and exit). Mean, amplitude that is the difference between peak and mean values, as well as peak time, were estimated for both aMT6s and cortisol. In Group A, amplitude of aMT6s upon entry (septic shock) was reduced in relation to exit (437.2 ± 309.2 vs. 674.1 ± 657.6 ng/4 h, p < 0.05). Peak time occurred earlier (10:00 p.m. vs. 07:00 a.m, p < 0.05) and correlated with higher APACHE II score and longer ICU stay. In Group B, aMT6s mean values were significantly increased during septic shock (2492.2 ± 1709.1 ng/4 h) compared to both entry (895.4 ± 715.5 ng/4 h) and exit (1308.6 ± 1214.4 ng/4 h, p < 0.05 for all comparisons). Amplitude of aMT6s was also elevated during septic shock (794.8 ± 431.8 ng/4 h) in relation to entry (293.1 ± 275.9 ng/4 h, p < 0.05). Regarding cortisol rhythm in Group A, during septic shock amplitude was increased compared to exit (13.3 ± 31 ng/4 h vs. 8.7 ± 21.2 ng/4 h p < 0.05) and correlated with reduced hospital length of stay. In Group B, cortisol mean values and amplitude during septic shock (10 ± 5.3 and 3 ± 1.8 ng/4 h, respectively) were significantly reduced compared to both entry (30 ± 57.9 and 12.3 ± 27.3 ng/4 h) and exit (14.4 ± 20.7 and 6.6 ± 8.7 ng/4 h, p < 0.05 for all comparisons) and correlated with higher SOFA score and longer ICU and hospital stay. CONCLUSIONS: Septic shock induced inverse changes of aMT6s and cortisol circadian rhythm profiles both within and between different groups of patients, depending on timing of onset. Reduced rhythmicity was correlated with severity of disease and longer ICU stay.

Gut failure in critical care: old school versus new school.

The concept of bacterial translocation and gut-origin sepsis as causes of systemic infectious complications and multiple organ deficiency syndrome in surgical and critically ill patients has been a recurring issue over the last decades attracting the scientific interest. Although gastrointestinal dysfunction seemingly arises frequently in intensive care unit patients, it is usually underdiagnosed or underestimated, because the pathophysiology involved is incompletely understood and its exact clinical relevance still remains controversial with an unknown yet probably adverse impact on the patients' outcome. The purpose of this review is to define gut-origin sepsis and related terms, to describe the mechanisms leading to gut-derived complications, and to illustrate the therapeutic options to prevent or limit these untoward processes.

Traumatic asphyxia due to blunt chest trauma: a case report and literature review.

INTRODUCTION: Crush asphyxia is different from positional asphyxia, as respiratory compromise in the latter is caused by splinting of the chest and/or diaphragm, thus preventing normal chest expansion. There are only a few cases or small case series of crush asphyxia in the literature, reporting usually poor outcomes. CASE PRESENTATION: We present the case of a 44-year-old Caucasian man who developed traumatic asphyxia with severe thoracic injury and mild brain edema after being crushed under heavy auto vehicle mechanical parts. He remained unconscious for an unknown time. The treatment included oropharyngeal intubation and mechanical ventilation, bilateral chest tube thoracostomies, treatment of brain edema and other supportive measures. Our patient's outcome was good. Traumatic asphyxia is generally under-reported and most authors apply supportive measures, while the final outcome seems to be dependent on the length of time of the chest compression and on the associated injuries. CONCLUSION: Treatment for traumatic asphyxia is mainly supportive with special attention to the re-establishment of adequate oxygenation and perfusion; treatment of the concomitant injuries might also affect the final outcome.