Endotoxemia, a type of sepsis caused by gram-negative bacterial endotoxin [i.e., lipopolysaccharide (LPS)], is associated with manifestations such as cytokine storm; failure of multiple organs, including the liver; and a high mortality rate. We investigated the effect and mechanism of action of LGK974, a Wnt signaling inhibitor, in mice with LPS-induced endotoxemia, an animal model of sepsis. LGK974 significantly and dose-dependently increased the survival rate and reduced plasma cytokine levels in mice with LPS-induced endotoxemia. Transcriptome analysis of liver tissues revealed significant changes in the expression of genes associated with the Wnt pathway as well as cytokine and NF-κB signaling during endotoxemia. LGK974 treatment suppressed the activation of NF-κB signaling and cytokine expression as well as the Wnt/β-catenin pathway in the livers of endotoxemic mice. Coimmunoprecipitation of phospho-IκB and β-transducin repeat-containing protein (β-TrCP) was increased in the livers of endotoxemic mice but was reduced by LGK974 treatment. Moreover, LGK974 treatment decreased the coimmunoprecipitation and colocalization of β-catenin and NF-κB, which were elevated in the livers of endotoxemic mice. Our results reveal crosstalk between the Wnt/β-catenin and NF-κB pathways via interactions between β-TrCP and phospho-IκB and between β-catenin and NF-κB during endotoxemia. The results of this study strongly suggest that the crosstalk between the Wnt/β-catenin and NF-κB pathways contributes to the mutual activation of these two pathways during endotoxemia, which results in amplified cytokine production, liver damage and death, and that LGK974 suppresses this vicious amplification cycle by reducing the crosstalk between these two pathways.

Recruitment of microorganisms to the rhizosphere varies among plant genotypes, yet an understanding of whether the microbiome can be altered by selection on the host is relatively unknown. Here, we performed a common garden study to characterize recruitment of rhizosphere microbiome, functional groups, for 20 expired Plant Variety Protection Act maize lines spanning a chronosequence of development from 1949 to 1986. This time frame brackets a series of agronomic innovations, namely improvements in breeding and the application of synthetic nitrogenous fertilizers, technologies that define modern industrial agriculture. We assessed the impact of chronological agronomic improvements on recruitment of the rhizosphere microbiome in maize, with emphasis on nitrogen cycling functional groups. In addition, we quantified the microbial genes involved in nitrogen cycling and predicted functional pathways present in the microbiome of each genotype. Both genetic relatednesses of host plant and decade of germplasm development were significant factors in the recruitment of the rhizosphere microbiome. More recently developed germplasm recruited fewer microbial taxa with the genetic capability for sustainable nitrogen provisioning and larger populations of microorganisms that contribute to N losses. This study indicates that the development of high-yielding varieties and agronomic management approaches of industrial agriculture inadvertently modified interactions between maize and its microbiome.

Mutations in the GJB1 gene, encoding the gap junction (GJ) protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We developed a gene therapy approach for CMT1X using an AAV9 vector to deliver the GJB1/Cx32 gene under the myelin protein zero (Mpz) promoter for targeted expression in Schwann cells. Lumbar intrathecal injection of the AAV9-Mpz.GJB1 resulted in widespread biodistribution in the peripheral nervous system including lumbar roots, sciatic and femoral nerves, as well as in Cx32 expression in the paranodal non-compact myelin areas of myelinated fibers. A pre-, as well as post-onset treatment trial in Gjb1-null mice, demonstrated improved motor performance and sciatic nerve conduction velocities along with improved myelination and reduced inflammation in peripheral nerve tissues. Blood biomarker levels were also significantly ameliorated in treated mice. This study provides evidence that a clinically translatable AAV9-mediated gene therapy approach targeting Schwann cells could potentially treat CMT1X.

Osteoarthritis (OA) is a frequent cause of pain and disability, affecting half of the world's population aged 65 years or older. Due to experienced pain and limitations, OA patients generally spend most of their waking hours sedentary and fail to adhere to physical activity (PA) recommendations. As a result of living together with OA patients, their partners might adopt a sedentary lifestyle. This study investigates the change in habitual PA and sedentary behavior (SB) in patients and their partners one year after the patients' total joint replacement (arthroplasty) and inpatient rehabilitation.

Objective: To investigate variation in the characteristics of regional cerebral blood flow (rCBF), brain activity, and intrinsic functional connectivity (FC) across the Alzheimer's disease spectrum (ADS). Methods: The study recruited 20 individuals in each of the following categories: Alzheimer's disease (AD), mild cognitive impairment (MCI), subjective cognitive decline (SCD), and healthy control (HC). All participants completed the 3.0T resting-state functional MRI (rs-fMRI) and arterial spin labeling scans in addition to neuropsychological tests. Additionally, the normalized CBF, regional homogeneity (ReHo), and amplitude of low-frequency fluctuation (ALFF) of individual subjects were compared in the ADS. Moreover, the changes in intrinsic FC were investigated across the ADS using the abnormal rCBF regions as seeds and behavioral correlations. Finally, a support-vector classifier model of machine learning was used to distinguish individuals with ADS from HC. Results: Compared to the HC subjects, patients with AD showed the poorest level of rCBF in the left precuneus (LPCUN) and right middle frontal gyrus (RMFG) among all participants. In addition, there was a significant decrease in the ALFF in the bilateral posterior cingulate cortex (PCC) and ReHo in the right PCC. Moreover, RMFG- and LPCUN-based FC analysis revealed that the altered FCs were primarily located in the posterior brain regions. Finally, a combination of altered rCBF, ALFF, and ReHo in posterior cingulate cortex/precuneus (PCC/PCUN) showed a better ability to differentiate ADS from HC, AD from SCD and MCI, but not MCI from SCD. Conclusions: The study demonstrated the significance of an altered rCBF and brain activity in the early stages of ADS. These findings, therefore, present a potential diagnostic neuroimaging-based biomarker in ADS. Additionally, the study provides a better understanding of the pathophysiology of AD.

Introduction: Functional imaging studies have demonstrated the recruitment of additional neural resources as a possible mechanism to compensate for age and Alzheimer's disease (AD)-related cerebral pathology, the efficacy of which is potentially modulated by underlying structural network connectivity. Additionally, structural network efficiency (SNE) is associated with intelligence across the lifespan, which is a known factor for resilience to cognitive decline. We hypothesized that SNE may be a surrogate of the physiological basis of resilience to cognitive decline in elderly persons without dementia and with age- and AD-related cerebral pathology.Methods: We included 85 cognitively normal elderly subjects or mild cognitive impairment (MCI) patients submitted to baseline diffusion imaging, liquor specimens, amyloid-PET and longitudinal cognitive assessments. SNE was calculated from baseline MRI scans using fiber tractography and graph theory. Mixed linear effects models were estimated to investigate the association of higher resilience to cognitive decline with higher SNE and the modulation of this association by increased cerebral amyloid, liquor tau or WMHV. Results: For the majority of cognitive outcome measures, higher SNE was associated with higher resilience to cognitive decline (p-values: 0.011-0.039). Additionally, subjects with higher SNE showed more resilience to cognitive decline at higher cerebral amyloid burden (p-values: <0.001-0.036) and lower tau levels (p-values: 0.002-0.015).Conclusion: These results suggest that SNE to some extent may quantify the physiological basis of resilience to cognitive decline most effective at the earliest stages of AD, namely at increased amyloid burden and before increased tauopathy.

Isoflavones are major neuroprotective components of a medicinal herb Astragali Radix, against cerebral ischemia-reperfusion injury but the mechanisms of neuroprotection remain unclear. Calycosin and formononetin are two major AR isoflavones while daidzein is the metabolite of formononetin after absorption. Herein, we aim to investigate the synergistic neuroprotective effects of those isoflavones of Astragali Radix against cerebral ischemia-reperfusion injury. Calycosin, formononetin and daidzein were organized with different combinations whose effects observed in both in vitro and in vivo experimental models. In the in vitro study, primary cultured neurons were subjected to oxygen-glucose deprivation plus reoxygenation (OGD/RO) or l-glutamate treatment. In the in vivo study, rats were subjected to middle cerebral artery occlusion to induce cerebral ischemia and reperfusion. All three isoflavones pre-treatment alone decreased brain infarct volume and improved neurological deficits in rats, and dose-dependently attenuated neural death induced by l-glutamate treatment and OGD/RO in cultured neurons. Interestingly, the combined formulas of those isoflavones revealed synergistically activated estrogen receptor (estrogen receptors)-PI3K-Akt signaling pathway. Using ER antagonist and phosphatidylinositol 3-kinase (PI3K) inhibitor blocked the neuroprotective effects of those isoflavones. In conclusion, isoflavones could synergistically alleviate cerebral ischemia-reperfusion injury via activating ER-PI3K-Akt pathway.

Background: The process of brain death (BD) leads to a pro-inflammatory state of the donor lung, which deteriorates its quality. In an attempt to preserve lung quality, methylprednisolone is widely recommended in donor lung management. However, clinical treatment doses vary and the dose-effect relation of methylprednisolone on BD-induced lung inflammation remains unknown. The aim of this study was to investigate the effect of three different doses methylprednisolone on the BD-induced inflammatory response. Methods: BD was induced in rats by inflation of a Fogarty balloon catheter in the epidural space. After 60 min of BD, saline or methylprednisolone (low dose (5 mg/kg), intermediate dose (12.5 mg/kg) or high dose (22.5 mg/kg)) was administered intravenously. The lungs were procured and processed after 4 h of BD. Inflammatory gene expressions were analyzed by RT-qPCR and influx of neutrophils and macrophages were quantified with immunohistochemical staining. Results: Methylprednisolone treatment reduced neutrophil chemotaxis as demonstrated by lower IL-8-like CINC-1 and E-selectin levels, which was most evident in rats treated with intermediate and high doses methylprednisolone. Macrophage chemotaxis was attenuated in all methylprednisolone treated rats, as corroborated by lower MCP-1 levels compared to saline treated rats. Thereby, all doses methylprednisolone reduced TNF-α, IL-6 and IL-1β tissue levels. In addition, intermediate and high doses methylprednisolone induced a protective anti-inflammatory response, as reflected by upregulated IL-10 expression when compared to saline treated brain-dead rats. Conclusion: We showed that intermediate and high doses methylprednisolone share most potential to target BD-induced lung inflammation in rats. Considering possible side effects of high doses methylprednisolone, we conclude from this study that an intermediate dose of 12.5 mg/kg methylprednisolone is the optimal treatment dose for BD-induced lung inflammation in rats, which reduces the pro-inflammatory state and additionally promotes a protective, anti-inflammatory response.

Background: Patients experience moderate-high intensity postoperative pain after cesarean section (CS). The aim of this study was to investigate the optimal concentrations of ropivacaine and sufentanil for use in controlling pain after CS. Methods: One hundred and seventy-four women undergoing elective CS were randomly allocated to four groups. Epidural analgesia was administered with 0.1% ropivacaine in the R1 group, 0.15% ropivacaine in the R2 group, a combination of 0.1% ropivacaine and 0.5 μg/ml of sufentanil in the R1S group, and a combination of 0.15% ropivacaine and 0.5 μg/ml of sufentanil in the R2S group (at a basal rate of 4 ml/h, bolus dose of 4 ml/20 min as needed). Pain scores (numerical rating scale [NRS]: 0-10 cm) at rest (NRS-R), during movement (NRS-M), and when massaging the uterus (NRS-U) were documented at 6 and 24 h. We also recorded patient satisfaction scores, time to first flatus, motor deficits, and adverse drug reactions. Results: NRS (NRS-R, NRS-M, NRS-U) scores in the R2S group (2 [1-3], 4 [3-5], 6 [5-6], respectively) were lower than in the R1 group (3 [3-4], 5 [4-6], 7 [6-8], respectively) (p < 0.001, p < 0.05, p < 0.01, respectively) at 6 h; and patient satisfaction (9 [8-10]) was improved compared to the R1 group (8 [6-8]) (p < 0.01). The time to first flatus (18.7 ± 11.8 h) was reduced relative to the R1 group (25.9 ± 12.0 h) (p < 0.05). The time to first ambulation was not delayed (p > 0.05). However, the incidence of pruritus (4 [9.3%]) was increased compared to the R2 group (0 [0]) (p < 0.05) at 6 h, and the incidence of numbness (23 [53.5%], 23 [53.5%]) was increased compared to the R1 group (10 [23.3%], 10 [23.3%]) (all p < 0.01) at both 6 and 24 h. Conclusions: Although we observed a higher incidence of pruritus and numbness, co-administration of 0.15% ropivacaine and 0.5 μg/ml of sufentanil administered epidurally optimized pain relief after CS, with treated subjects exhibiting lower NRS scores, shorter time to first flatus, and higher patient-satisfaction scores.

The outbreak of a new coronavirus (SARS-CoV-2), which is responsible for the COVID-19 disease and is spreading rapidly around the world, urgently requires effective therapeutic treatments. In this context, drug repurposing represents a valuable strategy, as it enables accelerating the identification of drug candidates with already known safety profiles, possibly aiding in the late stages of clinical evaluation. Moreover, therapeutic treatments based on drugs with beneficial multi-target activities (polypharmacology) may show an increased antiviral activity or help to counteract severe complications concurrently affecting COVID-19 patients. In this study, we present the results of a computational drug repurposing campaign that aimed at identifying potential inhibitors of the main protease (Mpro) of the SARS-CoV-2. The performed in silico screening allowed the identification of 22 candidates with putative SARS-CoV-2 Mpro inhibitory activity. Interestingly, some of the identified compounds have recently entered clinical trials for COVID-19 treatment, albeit not being assayed for their SARS-CoV-2 antiviral activity. Some candidates present a polypharmacology profile that may be beneficial for COVID-19 treatment and, to the best of our knowledge, have never been considered in clinical trials. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.

The female menstrual cycle (MC) is characterized by hormonal fluctuations throughout its different phases. However, research regarding its effect on athletic performance in high level athletes is sparse. The aim of this study was to (i) investigate the female MCs effect on strength and power performance in highly trained female team athletes throughout the MC and (ii) examine whether eumenorrheic participants with natural hormonal fluctuations displayed enhanced performance in the follicular phase (FP) versus the luteal phase (LP), compared to controls using hormonal contraceptives.

The prevalence of non-alcoholic steatohepatitis (NASH) rapidly increases with associated metabolic disorders such as dyslipidemia; therefore, NASH is now considered an independent risk factor of cardiovascular diseases. NASH displays sex-linked epidemiological, phenotypical, and molecular differences; however, little is known about the background of these sex-specific differences on the molecular level.

Planning ability is important in everyday functioning, and a key measure to assess the preparation and execution of plans is the Tower of London (ToL) task. Previous studies indicate that older adults are often less accurate than the young on the ToL and that there may be cultural differences in performance on the task. However, potential interactions between age and culture have not previously been explored. In the current study we examined the effects of age on ToL performance in an Asian culture (Malaysia) and a Western culture (British) (n = 191). We also explored whether working memory, age, education, and socioeconomic status explained variance in ToL performance across these two cultures. Results indicated that age effects on ToL performance were greater in the Malaysian sample. Subsequent moderated mediation analysis revealed differences between the two cultures (British vs Malaysians), in that the age-related variance in ToL accuracy was accounted for by WM capacity at low and medium education levels only in the Malaysian sample. Demographic variables could not explain additional variance in ToL speed or accuracy. These results may reflect cultural differences in the familiarity and cognitive load of carrying out complex planning tasks.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune-related neurological disorder of the central nervous system. Most patients with NMOSD have serum anti-aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). In addition to optic neuritis and myelitis, other insidious symptoms such as depressive state and chronic fatigue in NMOSD are gradually being recognized. Methods: To elucidate the impact of low- to medium-dose oral prednisolone (PSL) as a relapse prevention therapy for psychiatric disturbances and chronic fatigue in NMOSD, we evaluated clinical data from 39 patients with AQP4-IgG-positive NMOSD, along with the details of present and cumulative oral PSL dosage. Results: Thirty-six of the 39 patients were treated with low- to medium-dose oral PSL, and the mean and standard deviation of the present daily dose of oral PSL were 7.9 ± 4.0 mg/day. None of the patients were treated with a daily PSL dose of >15 mg. As a result, the disease duration and the untreated period before starting oral PSL showed weak to moderate correlations with the subsequent severities of psychiatric disturbance and fatigue level. Meanwhile, none of the other treatment-related variables evaluated, such as the present oral PSL daily dose, cumulative PSL dose, months of oral PSL administration, previous courses of steroid pulse therapy, and coadministered immunosuppressants, were correlated with these insidious symptoms. Conclusion: Our results suggest that the use of long-term low- to medium-dose oral PSL ≤15 mg daily for relapse prevention in AQP4-IgG-positive NMOSD would not aggravate the psychiatric and fatigue conditions. On the contrary, early initiation of oral PSL for relapse prevention, together with significantly decreased relapse rate, alleviated the subsequent depressive state and fatigue from the disease.

Tree species identity is one of the key factors driving ectomycorrhizal (EcM) fungal richness and community composition in boreal and temperate forest ecosystems, but little is known about the influence of tree species combinations and their neighborhood effects on EcM communities. To advance our understanding of host plant effects on EcM fungi, the roots of silver birch, Scots pine, and Norway spruce were analyzed using high-throughput sequencing across mature boreal forest exploratory plots of monocultures and two- and three-species mixtures in Finland. Our analyses revealed that tree species identity was an important determinant of EcM fungal community composition, but tree species richness had no significant influence on EcM fungal richness and community composition. We found that EcM fungal community composition associated with spruce depends on neighboring tree species. Our study suggests that at a regional-scale tree species identity is the primary factor determining community composition of root-associated EcM fungi alongside with tree species composition effects on EcM fungal community of spruce in mixed stands.

Antimicrobial peptides (AMPs) or host defense peptides protect the host against various pathogens such as yeast, fungi, viruses and bacteria. AMPs also display immunomodulatory properties ranging from the modulation of inflammatory responses to the promotion of wound healing. More interestingly, AMPs cause cell disruption through non-specific interactions with the membrane surface of pathogens. This is most likely responsible for the low or limited emergence of bacterial resistance against many AMPs. Despite the increasing number of antibiotic-resistant bacteria and the potency of novel AMPs to combat such pathogens, only a few AMPs are in clinical use. Therefore, the current review describes (i) the potential of AMPs as alternatives to antibiotics, (ii) the challenges toward clinical implementation of AMPs and (iii) strategies to improve the success rate of AMPs in clinical trials, emphasizing the lessons we could learn from these trials.

A Gram-staining-negative, non-spore-forming, short, straight rod, non-motile, and obligate anaerobic bacterial strain, AF73-05CM02T, was isolated from a fecal sample of a 30 years old healthy male living in Shenzhen, China. Colonies were approximately 0.2 mm in diameter, beige, and circular after 4 days of incubation on PYG agar under anaerobic conditions at 37°C. Strain AF73-05CM02T grew in a temperature range between 30 and 42°C and a pH range from 6.0 to 8.5, with optimum growth at 37-42°C and pH 7.0. 16S rRNA gene sequence analysis demonstrated that strain AF73-05CM02T belongs to the genus Christensenella and showed the highest level of sequence similarity (98.68%) with Christensenella minuta DSM 22607T. The predominant fatty acids of strain AF73-05CM02T were C10 : 0 (7.5%), iso-C11 : 0 (5.6%), C12 : 0 (7.2%), C14 : 0 (46.6%), iso-C15 : 0 (7.4%), C16 : 0 (9.7%), and C18 : 1 ω9c (6.9%). Acetic acid, formic acid, butyric acid, and lactic acid were the end products of glucose fermentation. The strain was negative for catalase, indole production, and hydrolysis of gelatin. Genomic relatedness analyses based on average nucleotide identity (ANI) indicated that strain AF73-05CM02T significantly differed from other species of the genus Christensenella, showing ANI values less than 82.89% with the phylogenetically closest species. The G + C content of the genomic DNA was 52.07 mol% from the genome sequence, which differs from that of Christensenella minuta. Several physiological, biochemical, and genotypic properties differentiated the novel bacterial strain from the related species, indicating that the strain represents a new species of the genus Christensenella for which the name Christensenella intestinihominis sp. nov. is proposed, with strain AF73-05CM02T ( = CGMCC 1.5207T = DSM 103477T ) being the type strain. The following study explored the cholesterol-lowering function of strains AF73-05CM02T and Christensenella minuta DSM 22067T and revealed that the two strains exhibit the capacity for removing cholesterol with efficiency rates of 36.6 and 54.3% and produce exopolysaccharide of 234 and 271 mg/L, respectively.

The C3a receptor (C3aR) is a seven trans-membrane domain G-protein coupled receptor with a range of immune modulatory functions. C3aR is activated by the third complement component (C3) activation derived peptide C3a and a neuropeptide TLQP-21. In the central nervous system (CNS), C3aR is expressed by neural progenitors, neurons as well as glial cells. The non-immune functions of C3aR in the adult CNS include regulation of basal neurogenesis, injury-induced neural plasticity, and modulation of glial cell activation. In the developing brain, C3aR and C3 have been shown to play a role in neural progenitor cell proliferation and neuronal migration with potential implications for autism spectrum disorder, and adult C3aR deficient (C3aR-/-) mice were reported to exhibit subtle deficit in recall memory. Here, we subjected 3 months old male C3aR-/- mice to a battery of behavioral tests and examined their brain morphology. We found that the C3aR-/- mice exhibit a short-term memory deficit and increased locomotor activity, but do not show any signs of autistic behavior as assessed by self-grooming behavior. We also found regional differences between the C3aR-/- and wild-type (WT) mice in the morphology of motor and somatosensory cortex, as well as amygdala and hippocampus. In summary, constitutive absence of C3aR signaling in mice leads to neurodevelopmental abnormalities that persist into adulthood and are associated with locomotive hyperactivity and altered cognitive functions.

Genetic and epigenetic factors are considered to be critical for host-parasite interactions. There are limited data on the role of such factors during human infections with Ascaris lumbricoides. Here, we describe the potential role of genetic factors as determinants of the Th2 immune response to A. lumbricoides in Brazilian children. Stool samples were collected from the children to detect A. lumbricoides by microscopy and peripheral blood leukocytes (PBLs) were cultured in whole blood cultures for detection of cytokines (IL-5, IL-10, and IL-13) in vitro. Levels of anti-A. lumbricoides IgE and IgG4 were measured in plasma. DNA was extracted from PBLs and genotyped using Illumina 2.5 Human Omni Beadchip. Candidate genes associated with A. lumbricoides responses were identified and SNVs in these selected genes associated with the Th2 immune response to A. lumbricoides. Haplotype, gene expression, and epigenetic analyses were done to identify potential associations with Th2 immune responses. GWAS on samples from 1,189 children identified WSB1 as a candidate gene, and IL-21R was selected as a biologically relevant linked gene for further analysis. Variants in WSB1 and IL21R were associated with markers of Th2 immune responses: increased A. lumbricoides-specific IgE and IL-5/IL-13 by PBLs from infected compared to uninfected individuals. In infected children, WSB1 but not IL21R gene expression was suppressed and increased methylation was observed in the WSB1 promoter region. This is the first study to show an association between genetic variants in WSB1 and IL21R and Th2 immune responses during A. lumbricoides infections in children. WSB1/IL21R pathways could provide a potential target for the treatment of Th2-mediated diseases.

An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.