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We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.

Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.

Long Covid (LC), a multisystem disorder with persistent symptoms > 4 weeks post COVID-19, has impacted healthcare systems substantially. As information is scarce for Belgium, this study aimed to identify LC phenotypes and assess participant characteristics, healthcare use and daily life burden by phenotype. The last survey wave of COVimpact (a longitudinal online cohort study among Belgian adults recruited after SARS-CoV-2 infection) focused on LC with questions on healthcare utilization and perceived daily impact. A latent class analysis (LCA) identified phenotypes, based on symptom type, disease duration, and LC-related disability. Backward multivariable multinomial logistic regression explored predictors of LC class membership. Among 1,840 respondents self-reporting LC, four phenotypes emerged. Class 1 presented mild clinical outcomes, class 2 and 3 presented moderate clinical outcomes, differentiated by symptoms of memory problems and brain fog (class 2), and respiratory problems and muscle/joint pain (class 3), and class 4 included the most severe clinical outcomes. Compared to class 1, being older, female, lower educated, non-European, obese and experiencing moderate to severe acute COVID-19 symptoms predicted higher class severity. Diagnosis, healthcare use and support differed among adults with moderate and severe LC, many reported insufficient healthcare access and major disruption to daily life, including absenteeism from work/school. People with severe LC were the most financially impacted. By distinguishing LC phenotypes, this study enhances understanding of varying healthcare trajectories and daily life impacts. Healthcare planning and support should be more effectively tailored to the specific needs of those affected by LC.

Background The primary endpoint was to investigate the prognostic factors of acute mesenteric ischemia (AMI) in ICU patients. Methods Retrospective observational, non-interventional, monocentric study of a cohort of 214 ICU patients with a confirmed diagnosis of arterial AMI. Results We collected demographics, mortality, hospital stay, prior medical history, comorbidities, reasons for ICU admission, laboratory investigations, diagnostic procedures, therapy, severity scores. The 30-day mortality rate was 71% for the 214 patients with arterial AMI. The incidence of nonocclusive mesenteric ischemia was particularly high. AMI was a secondary diagnosis in 58% of patients. Half of the population was represented by surgical patients who mostly required an urgent procedure. The mortality rate was not different in the subgroup with aortic surgery. Three factors were associated with an increase or decrease in mortality: the maximal dose of vasopressors (VP) administered to the patient (OR = 1.20; 95%CI = 1.08–1.33; p  <  0.001), arterial change in lactate values within the first 24 h of admission (OR = 1.24; 95%CI = 1.05–1.48; p  = 0.012) and anticoagulation (OR = 0.19; 95%CI = 0.043–0.84; p  = 0.029). Conclusions Fatalities after AMI were related to a high incidence of multi-organ failure. The monitoring of arterial lactate appeared helpful to identify the patients with a poor prognosis.

Background While many studies on the determinants of post-COVID-19 conditions (PCC) have been conducted, little is known about the relationship between SARS-CoV-2 variants and PCC. This study aimed to assess the association between different SARS-CoV-2 variants and the probability of having PCC three months after the infection. Methods This study was a longitudinal cohort study conducted between April 2021 and September 2022 in Belgium. In total, 8,238 adults with a confirmed SARS-CoV-2 infection were followed up between the time of their infection and three months later. The primary outcomes were the PCC status three months post infection and seven PCC symptoms categories (neurocognitive, autonomic, gastrointestinal, respiratory, musculoskeletal, anosmia and/or dysgeusia, and other manifestations). The main exposure variable was the type of SARS-CoV-2 variants (i.e. Alpha, Delta, and Omicron), extracted from national surveillance data. The association between the different SARS-CoV-2 variants and PCC as well as PCC symptoms categories was assessed using multivariable logistic regression. Results The proportion of PCC among participants infected during the Alpha, Delta, and Omicron-dominant periods was significantly different and respectively 50%, 50%, and 37%. Participants infected during the Alpha- and Delta-dominant periods had a significantly higher odds of having PCC than those infected during the Omicron-dominant period (OR = 1.61, 95% confidence interval [CI] = 1.33–1.96 and OR = 1.73, 95%CI = 1.54–1.93, respectively). Participants infected during the Alpha and Delta-dominant periods were more likely to report neurocognitive, respiratory, and anosmia/dysgeusia symptoms of PCC. Conclusions People infected during the Alpha- and Delta-dominant periods had a higher probability of having PCC three months after infection than those infected during the Omicron-dominant period. The lower probability of PCC with the Omicron variant must also be interpreted in absolute figures. Indeed, the number of infections with the Omicron variant being higher than with the Alpha and Delta variants, it is possible that the overall prevalence of PCC in the population increases, even if the probability of having a PCC decreases.

PurposeHospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics.MethodsEligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤ 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement.ResultsThirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days.ConclusionsAdjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease, which can be primary (due to genetic mutation) or secondary to malignancy, infection and rheumatologic diseases. Data concerning Belgian patients with adult HLH are lacking. Methods: This retrospective study was performed in a teaching hospital in Belgium. All cases of adult HLH, from December 2010 to April 2022, were reviewed. Patients with more than five HLH-2004 criteria and/or HScore >80% were included in the study. The objective of our study was to describe clinical and biological characteristics of patients with HLH and attempt to look for variables associated with mortality. Results: Fifty-two patients were included in the final analysis. Mean age (SD) of patients was 48 (18) years old, and 29 patients were of male gender (56%). The underlying diseases associated with HLH were malignancy (M-HLH) in 22 patients, infection related HLH in 20 patients, rheumatologic disease related HLH in 7 patients, idiopathic in 2 patients and secondary to pregnancy in 1 patient. Overall mortality, mortality at 30 days and 90 days were 24/52 (46%), 13/52 (25%) and 4/52 (10%), respectively. In univariate analysis, malignancy, male sex, age and disseminated intravascular coagulation (DIC) were associated with mortality (p < 0.05). In multivariate analysis, only age was significantly associated with mortality (odds ratio, 1.053; 95% confidence interval, 1.016-1.092; p 0.005). Conclusion: In our study, the most frequent triggers were malignancy and infectious agent followed by rheumatologic disease. Risk factors for mortality were age, male sex, malignancy and DIC, but only age remained significant in multivariate analysis. Treatment guidelines are mainly based on pediatric patients, and it is important for physician to describe adult patients' outcome to better understand this disease and adapt treatment. Keywords: hemophagocytic lymphohistiocytosis, macrophage activation syndrome, infection, autoimmune disease, malignancy, corticosteroid, tocilizumab, ruxolitinib, mortality

ObjectivesSince the onset of the COVID-19 pandemic, most research has focused on its acute pathophysiology, yet some people tend to experience persisting symptoms beyond the acute phase of infection, referred to as post COVID-19 condition (PCC). However, evidence on PCC is still scarce. This study aimed to assess the distribution, classification of symptoms and associated factors of PCC in adults.DesignLongitudinal online cohort study.SettingNational study in Belgium.ParticipantsParticipants were Belgian adults with a recent SARS-CoV-2 infection and were recruited when called up for contact tracing. A total of 3039 participants were included and completed an online questionnaire at the time of their infection and again 3 months later.Outcome measuresThe baseline questionnaire assessed the initial health status of the participants and their status during the acute phase of the infection. The follow-up questionnaire assessed their PCC status 3 months after infection. A latent class analysis (LCA) was performed to assess whether there are different classes of individuals with a similar set of self-reported PCC symptoms.ResultsHalf of the participants reported PCC 3 months after infection (47%). The most frequent symptoms were fatigue (21%), headache (11%) and memory problems (10%). The LCA highlighted three different classes of PCC symptoms with different risk factors: (1) a combination of loss of smell and taste, (2) a combination of neurological symptoms and (3) other heterogeneous symptoms.ConclusionsWith the increasing number of people who underwent COVID-19, PCC has become an important but complex public health problem due to the heterogeneity of its symptoms. The classification of symptoms performed in this study can help give insight into different aetiologies of PCC and better plan care according to the symptoms and needs of those affected.

The neutrophil-to-lymphocyte ratio (NLR) could be a predictive factor of severe COVID-19. However, most relevant studies are retrospective, and the optimal NLR cut-off point has not been determined. The objective of our research was identification and validation of the best NLR cut-off value on admission that could predict high in-hospital mortality in COVID-19 patients. Medical files of all patients admitted for COVID-19 pneumonia in our dedicated COVID-units between March and April 2020 (derivation cohort) and between October and December 2020 (validation cohort) were reviewed. Two hundred ninety-nine patients were included in the study (198 in the derivation and 101 in the validation cohort, respectively). Youden's J statistic in the derivation cohort determined the optimal cut-off value for the performance of NLR at admission to predict mortality in hospitalized patients with COVID-19. The NLR cut-off value of 5.94 had a sensitivity of 62% and specificity of 64%. In ROC curve analysis, the AUC was 0.665 [95% CI 0.530-0.801, p= 0.025]. In the validation cohort, the best predictive cut-off value of NLR was 6.4, which corresponded to a sensitivity of 63% and a specificity of 64% with AUC 0.766 [95% CI 0.651-0.881, p <0.001]. When the NLR cut-off value of 5.94 was applied in the validation cohort, there was no significant difference in death and survival in comparison with the derivation NLR cut-off. Net reclassification improvement (NRI) analysis showed no significant classification change in outcome between both NLR cut-off values (NRI:0.012, p=0.31). In prospective analysis, an NLR value of 5.94 predicted high in-hospital mortality upon admission in patients hospitalized for COVID-19 pneumonia.

Vascular hyperpermeability is a determinant factor in the pathophysiology of sepsis. While, AMP-activated protein kinase (AMPK) is known to play a role in maintaining endothelial barrier function in this condition. Therefore, we investigated the underlying molecular mechanisms of this protective effect. α1AMPK expression and/or activity was modulated in human dermal microvascular endothelial cells using either α1AMPK-targeting small interfering RNA or the direct pharmacological AMPK activator 991, prior to lipopolysaccharide (LPS) treatment. Western blotting was used to analyze the expression and/or phosphorylation of proteins that compose cellular junctions (zonula occludens-1 (ZO-1), vascular endothelial cadherin (VE-Cad), connexin 43 (Cx43)) or that regulate actin cytoskeleton (p38 MAPK; heat shock protein 27 (HSP27)). Functional endothelial permeability was assessed by in vitro Transwell assays, and quantification of cellular junctions in the plasma membrane was assessed by immunofluorescence. Actin cytoskeleton remodeling was evaluated through actin fluorescent staining. We consequently demonstrate that α1AMPK deficiency is associated with reduced expression of CX43, ZO-1, and VE-Cad, and that the drastic loss of CX43 is likely responsible for the subsequent decreased expression and localization of ZO-1 and VE-Cad in the plasma membrane. Moreover, α1AMPK activation by 991 protects against LPS-induced endothelial barrier disruption by reinforcing cortical actin cytoskeleton. This is due to a mechanism that involves the phosphorylation of p38 MAPK and HSP27, which is nonetheless independent of the small GTPase Rac1. This results in a drastic decrease of LPS-induced hyperpermeability. We conclude that α1AMPK activators that are suitable for clinical use may provide a specific therapeutic intervention that limits sepsis-induced vascular leakage.