Effectiveness of nirmatrelvir-ritonavir on severe outcomes of COVID-19 in the era of vaccination and Omicron: An updated meta-analysis.

Nirmatrelvir-ritonavir (NR) was approved to treat SARS-CoV-2 positive outpatients at high risk of progression to severe disease, based on a randomized trial in unvaccinated patients. Effectiveness in vaccinated patients and against Omicron has not yet been confirmed by clinical trial data, but a recent meta-analysis suggested good real-world effectiveness based on 12 studies. We updated this meta-analysis by searching Medline and Embase databases for studies assessing effectiveness of NR on mortality, hospitalization, composite outcome of hospitalization and/or death, and progression to severe disease, published between October 1, 2022 and May 22, 2023. Random effects meta-analysis and subgroup analysis for vaccinated patients was performed. A total of 32 studies were included in the meta-analysis. Pooled RR for the effect of NR on mortality, hospitalization, hospitalization and/or mortality, and progression to severe disease were 0.36 (95% confidence interval [CI]: 0.25-0.52), 0.43 (CI: 0.37-0.51), 0.52 (CI: 0.45-0.61) and 0.54 (CI: 0.41-0.73), respectively. A subgroup analysis on vaccinated patients indicated lower effectiveness of NR on mortality (RR: 0.55, CI: 0.45-0.68), but similar effectiveness for hospitalization, hospitalization and/or mortality, or progression to severe disease (RR: 0.52, 0.58, and 0.66, respectively). This updated meta-analysis robustly confirms the protective effects of NR on severe COVID-19 outcomes.

Association between SARS-CoV-2 variants and post COVID-19 condition: findings from a longitudinal cohort study in the Belgian adult population.

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.

Survival in stage IV ovarian cancer with increased use of debulking surgery and bevacizumab.

OBJECTIVES: Advanced ovarian cancer has a poor prognosis, with a 5 year survival probability of <30%. Attempts to improve survival have focused on debulking surgery and systemic therapy. We assessed the evolution of treatment patterns and survival of patients with advanced epithelial ovarian cancer with specific attention to changes in survival after introducing bevacizumab. METHODS: Population based data from the Belgian Cancer Registry were coupled with administrative reimbursement data from the compulsory health insurance organizations and the national database where date of death is registered, based on the patient's unique national number. Patients with epithelial ovarian cancer stage IV diagnosed in 2004-17 were included. The proportion of patients who underwent debulking surgery and received bevacizumab was calculated per incidence year. Survival was compared for the three incidence periods (2004-08, 2009-13, 2014-17) and before and after the introduction of bevacizumab. RESULTS: 2034 patients with stage IV epitheial ovarian cancer were included. From 2012 onwards, uptake of bevacizumab increased, with 50% of patients with stage IV ovarian cancer diagnosed in 2017 receiving bevacizumab. The proportion of stage IV patients who underwent debulking surgery also increased over time, from 21.1% in 2004-08 to 50.4% and 45.4% in 2009-13 and 2014-17, respectively. The 3 year observed survival probability fluctuated between 27% and 42% without a trend over time. The increase in debulking surgery was associated with improved survival (hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.79 to 0.98) but the introduction of bevacizumab was not (HR 0.94, 95% CI 0.85 to 1.03). For patients diagnosed in 2004, the mean cost per patient treated with oncological drugs was about €12 500, which doubled to about €25 000 for patients diagnosed in 2014 or later. CONCLUSIONS: Despite a rise in the use of debulking surgery and the introduction of bevacizumab into clinical practice, no improvement in 3 year survival probability was observed for patients with advanced ovarian cancer in Belgium.

Improving the performance of a triage scale for chest pain patients admitted to emergency departments: combining cardiovascular risk factors and electrocardiogram.

BACKGROUND: The triage of patients presenting with chest pain on admission to the emergency department uses scales based on patient clinical presentation or an electrocardiogram (ECG). These scales have different sensitivity and specificity. Although a good sensitivity allows for the prompt identification of high-risk patients, specificity prevent ED overcrowding. Moreover, ECG at triage avoids missing ST elevation myocardial infarction, which requires urgent revascularization. Our study therefore aimed to investigate whether a scale combining ECG and cardiovascular risk factors (CVRF) improves the diagnostic performance of ED chest pain triage scale. METHODS AND RESULTS: In this prospective single-center observational study involving 505 patients, the standard ECG-based FRENCH scale was compared to a scale combining the ECG-based FRENCH scale and the patients CVRF. The new scale was called the "modified" FRENCH. The accuracy of patient CVRF collection was evaluated by comparing the results of triage nurses and ED physicians. Compared with the standard FRENCH scale, the modified FRENCH scale had an increased sensitivity (61% versus 75%) but a decrease in specificity (76% versus 64%) resulting in a similar diagnostic performance. Using CVRF collected by the ED physicians, the modified FRENCH scale had a sensitivity of 87% and a specificity of 56% with a significant improvement in his diagnostic performance compared with standard FRENCH scales. This improvement can be explained by an accurate collection of the CVRF by physicians compared with nurses, as suggested by the weak to moderate correlation between their respective data collection. CONCLUSION: In conclusion, combining ECG and accurately collected cardiovascular risks factor improves the diagnostic performance of the ECG based chest pain triage in the ED. TRIAL REGISTRATION: Trial registration number: NCT03913767 .

Difficulties encountered by long COVID patients in the Belgian health system / Difficultés rencontrées par les patients COVID long dans le système de santé belge

INTRODUCTION: After contracting COVID-19, many people have continued to experience various symptoms for several weeks and months, even after a mild acute phase. These people with ‘long COVID’ faced difficulties when confronted with the healthcare system. PURPOSE OF RESEARCH: In order to better understand their experience, we supplemented the information obtained in an online survey with a mixed qualitative approach based on 33 individual interviews and discussions with 101 participants in a forum in March 2021. RESULTS: Several shortcomings were identified in the contacts of ‘long’ COVID patients with the health care system, such as the lack of listening or empathy of some health care professionals, the lack of a systematic or proactive approach during the diagnostic assessment, or the lack of interdisciplinary coordination. Patients feel misunderstood and are forced to develop their own strategies, whether for diagnosis or treatment. Patients’ discomfort has led them to question the value of medicine and to resort to unconventional therapies to alleviate their symptoms, sometimes at great cost. CONCLUSIONS: Better informing the medical profession about the manifestation of the disease and the possible treatments, including the possibilities of reimbursement, would raise awareness and give them the tools to respond to the needs of ‘ long’ COVID patients. A comprehensive assessment of the patient through an “interdisciplinary assessment” seems necessary.

Introduction: Suite à une infection COVID-19, bon nombre de personnes ont ressenti divers symptômes pendant plusieurs semaines et mois, et ce, même après une phase aiguë légère. Ces personnes atteintes de « COVID long ¼ se sont trouvées confrontées au système de soins de santé, non sans difficultés. But de l'étude: Afin de mieux comprendre leurs expériences, nous avons complété les informations obtenues via une enquête en ligne par une approche qualitative mixte, comprenant 33 entretiens individuels et les discussions de 101 participants à un forum durant le mois de mars 2021. Résultats: Plusieurs lacunes ont été mises en évidence lors des contacts des patients « COVID long ¼ avec le système de santé, comme l'absence d'écoute ou d'empathie de certains professionnels de la santé, d'approche systématique ou proactive lors du bilan diagnostique, ou encore l'absence de coordination interdisciplinaire. Les patients se sentent incompris et se voient obligés de développer leurs propres stratégies afin d'établir un diagnostic ou un traitement. Le malaise des patients les ont amenés à remettre en question la valeur de la médecine et à recourir à des thérapies non conventionnelles afin de soulager leurs symptômes, parfois à un prix élevé. Conclusions: Mieux informer le corps médical quant à la manifestation de la maladie et aux prises en charge possibles, y compris les possibilités de remboursement, permettrait de le sensibiliser et de lui donner les outils pour répondre aux besoins des patients « COVID long ¼. Évaluer de manière globale le patient via un « bilan interdisciplinaire ¼ est nécessaire.

AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

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.

Podocyte Antigen Staining to Identify Distinct Phenotypes and Outcomes in Membranous Nephropathy: A Retrospective Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. PREDICTOR: Positive immunostaining for podocyte antigens on archived kidney biopsy samples. OUTCOMES: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. ANALYTICAL APPROACH: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. RESULTS: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R-/THSD7A-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. LIMITATIONS: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. CONCLUSIONS: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

α1AMP-Activated Protein Kinase Protects against Lipopolysaccharide-Induced Endothelial Barrier Disruption via Junctional Reinforcement and Activation of the p38 MAPK/HSP27 Pathway.

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.

Prognostic factors of acute mesenteric ischemia in ICU patients.

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.

Open Lung Biopsy in Nonresolving Acute Respiratory Distress Syndrome Commonly Identifies Corticosteroid-Sensitive Pathologies, Associated With Better Outcome.

OBJECTIVES: Approximately half of the patients undergoing lung biopsy for nonresolving acute respiratory distress syndrome exhibit another histologic pattern than diffuse alveolar damage, with some of the pathologies characterized by a potential response to corticosteroids. This study aimed to assess whether open lung biopsy performed in the ICU for nonresolving acute respiratory distress syndrome was able to identify steroid-sensitive diseases and whether patients with a steroid-sensitive pathology experienced different clinical courses and outcomes. DESIGN: Retrospective analysis. SETTING: One 22-bed mixed ICU within a tertiary medical center. PATIENTS: Patients age greater than or equal to 16 years old who met the Berlin definition for acute respiratory distress syndrome and underwent open lung biopsy from January 2007 to January 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 695 patients diagnosed with acute respiratory distress syndrome were identified, 51 (7%) of whom underwent open lung biopsy. An alternative diagnosis to diffuse alveolar damage was found in 29 patients (57%), and a steroid-sensitive pathology was identified in 19 (37%). In-hospital and 180-day mortality rates were 55% and 61%, respectively. There was a significant difference in hospital mortality and 180-day mortality rates between patients with steroid-sensitive pathology and those with steroid-resistant pathology (37% vs 65%; p < 0.045 and 37% vs 75%; p < 0.007, respectively). We did not identify any variable that could reliably predict a steroid-sensitive histologic pattern before open lung biopsy. CONCLUSIONS: Open lung biopsy was able to identify a steroid-sensitive pathology in a significant proportion of nonresolving acute respiratory distress syndrome patients. These patients had a better outcome, with lower hospital mortality and 180-day mortality.

Impact of Very Early Physical Therapy During Septic Shock on Skeletal Muscle: A Randomized Controlled Trial.

OBJECTIVES: As the catabolic state induced by septic shock together with the physical inactivity of patients lead to the rapid loss of muscle mass and impaired function, the purpose of this study was to test whether an early physical therapy during the onset of septic shock regulates catabolic signals and preserves skeletal muscle mass. DESIGN: Randomized controlled trial. SETTING: Tertiary mixed ICU. PATIENTS: Adult patients admitted for septic shock within the first 72 hours. INTERVENTIONS: Patients were assigned randomly into two groups. The control group benefited from manual mobilization once a day. The intervention group had twice daily sessions of both manual mobilization and 30-minute passive/active cycling therapy. MEASUREMENTS AND MAIN RESULTS: Skeletal muscle biopsies and electrophysiology testing were performed at day 1 and day 7. Muscle biopsies were analyzed for histology and molecular components of signaling pathways regulating protein synthesis and degradation as well as inflammation markers. Hemodynamic values and patient perception were collected during each session. Twenty-one patients were included. Three died before the second muscle biopsy. Ten patients in the control and eight in the intervention group were analyzed. Markers of the catabolic ubiquitin-proteasome pathway, muscle atrophy F-box and muscle ring finger-1 messenger RNA, were reduced at day 7 only in the intervention group, but without difference between groups (muscle atrophy F-box: -7.3% ± 138.4% in control vs -56.4% ± 37.4% in intervention group; p = 0.23 and muscle ring finger-1: -30.8% ± 66.9% in control vs -62.7% ± 45.5% in intervention group; p = 0.15). Muscle fiber cross-sectional area (µm) was preserved by exercise (-25.8% ± 21.6% in control vs 12.4% ± 22.5% in intervention group; p = 0.005). Molecular regulations suggest that the excessive activation of autophagy due to septic shock was lower in the intervention group, without being suppressed. Markers of anabolism and inflammation were not modified by the intervention, which was well tolerated by the patients. CONCLUSIONS: Early physical therapy during the first week of septic shock is safe and preserves muscle fiber cross-sectional area.

The closure of arteriovenous fistula in kidney transplant recipients is associated with an acceleration of kidney function decline.

Background: The creation of arteriovenous fistula (AVF) may retard chronic kidney disease progression in the general population. Conversely, the impact of AVF closure on renal function in kidney transplant recipients (KTRs) remains unknown. Methods: From 2007 to 2013, we retrospectively categorized 285 KTRs into three groups: no AVF (Group 0, n = 90), closed AVF (Group 1, n = 114) and left-open AVF (Group 2, n = 81). AVF closure occurred at 653 ± 441 days after kidney transplantation (KTx), with a thrombosis:ligation ratio of 19:95. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease equation. Linear mixed models calculated the slope and intercept of eGFR decline versus time, starting at 3 months post-KTx, with a median follow-up of 1807 days (95% confidence interval 1665-2028). Results: The eGFR slope was less in Group 1 (-0.081 mL/min/month) compared with Group 0 (-0.183 mL/min/month; P = 0.03) or Group 2 (-0.164 mL/min/month; P = 0.09). Still, the eGFR slope significantly deteriorated after (-0.159 mL/min/month) versus before (0.038 mL/min/month) AVF closure (P = 0.03). Study periods before versus after AVF closure were balanced to a mean of 13.5 and 12.5 months, respectively, with at least 10 observations per patient ( n = 99). Conclusions: In conclusion, a significant acceleration of eGFR decline is observed over the 12 months following the closure of a functioning AVF in KTRs.

Early hyperlactatemia predicts pancreatic fistula after surgery.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a major complication after pancreatic surgery and results from an impaired healing of the pancreatic enteric anastomosis. Whether perioperative hemodynamic fluid management aiming to provide an adequate tissue perfusion could influence the occurrence of POPF is unknown. Serum lactate level is a well-recognized marker of decreased tissue perfusion and is known to be associated with higher morbidity and mortality in various postoperative settings. We aimed to determine in a retrospective high-volume center's cohort whether postoperative hyperlactatemia could predict POPF occurrence. METHOD: We conducted a retrospective analysis of 96 consecutive patients admitted in the intensive care unit (ICU) after pancreaticoduodenectomy or distal pancreatectomy. Univariate analysis was conducted to compare lactate levels at 6 h between patients evolving with versus without POPF. A logistic regression model was developed and included potential confounding factors. RESULTS: POPF occurred in 28 patients (29 %). Serum lactate level 6 h after admission was significantly higher in the POPF group (2.8 mmol/L [95 % confidence interval (CI): 2.1-3.5] versus 1.8 mmol/L [95 % CI: 1.8-2.4], p-value = 0.04) whereas it did not differ at ICU admission or at 12 h. Despite similar cumulative fluid balance, fluid intake and vasopressor use, hyperlactatemia > 2.5 mmol/L (Odds ratio (OR): 3.58; 95 % CI: 1.22-10.48; p-value = 0.020) and red blood cells transfusion (OR: 1.24; 95 % CI: 1.03-1.49; p-value = 0.022) were found to be independent predictive factors of POPF occurrence. CONCLUSION: In patients undergoing partial pancreatectomy, hyperlactatemia measured 6 h after ICU admission is a predictive factor for the occurrence of POPF. Inflammatory changes after surgery may account for this observation and should be further evaluated.

Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKα1.

Cardiac fibroblasts (CF) are crucial in left ventricular (LV) healing and remodeling after myocardial infarction (MI). They are typically activated into myofibroblasts that express alpha-smooth muscle actin (α-SMA) microfilaments and contribute to the formation of contractile and mature collagen scars that minimize the adverse dilatation of infarcted areas. CF predominantly express the α1 catalytic subunit of AMP-activated protein kinase (AMPKα1), while AMPKα2 is the major catalytic isoform in cardiomyocytes. AMPKα2 is known to protect the heart by preserving the energy charge of cardiac myocytes during injury, but whether AMPKα1 interferes with maladaptative heart responses remains unexplored. In this study, we investigated the role of AMPKα1 in modulating LV dilatation and CF fibrosis during post-MI remodeling. AMPKα1 knockout (KO) and wild type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery. The absence of AMPKα1 was associated with increased CF proliferation in infarcted areas, while expression of the myodifferentiation marker α-SMA was decreased. Faulty maturation of myofibroblasts might derive from severe down-regulation of the non-canonical transforming growth factor-beta1/p38 mitogen-activated protein kinase (TGF-ß1/p38 MAPK) pathway in KO infarcts. In addition, lysyl oxidase (LOX) protein expression was dramatically reduced in the scar of KO hearts. Although infarct size was similar in AMPK-KO and WT hearts subjected to MI, these changes resulted in compromised scar contractility, defective scar collagen maturation, and exacerbated adverse remodeling, as indicated by increased LV diastolic dimension 30days after MI. Our data genetically demonstrate the centrality of AMPKα1 in post-MI scar formation and highlight the specificity of this catalytic isoform in cardiac fibroblast/myofibroblast biology.

AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes.

Exposure of cardiomyocytes to high glucose concentrations (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase (NOX2). NOX2 activation is triggered by enhanced glucose transport through a sodium-glucose cotransporter (SGLT) but not by a stimulation of glucose metabolism. The aim of this work was to identify potential therapeutic approaches to counteract this glucotoxicity. In cultured adult rat cardiomyocytes incubated with 21 mM glucose (HG), AMP-activated protein kinase (AMPK) activation by A769662 or phenformin nearly suppressed ROS production. Interestingly, glucagon-like peptide 1 (GLP-1), a new antidiabetic drug, concomitantly induced AMPK activation and prevented the HG-mediated ROS production (maximal effect at 100 nM). α2-AMPK, the major isoform expressed in cardiomyocytes (but not α1-AMPK), was activated in response to GLP-1. Anti-ROS properties of AMPK activators were not related to changes in glucose uptake or glycolysis. Using in situ proximity ligation assay, we demonstrated that AMPK activation prevented the HG-induced p47phox translocation to caveolae, whatever the AMPK activators used. NOX2 activation by either α-methyl-d-glucopyranoside, a glucose analog transported through SGLT, or angiotensin II was also counteracted by GLP-1. The crucial role of AMPK in limiting HG-mediated NOX2 activation was demonstrated by overexpressing a constitutively active form of α2-AMPK using adenoviral infection. This overexpression prevented NOX2 activation in response to HG, whereas GLP-1 lost its protective action in α2-AMPK-deficient mouse cardiomyocytes. Under HG, the GLP-1/AMPK pathway inhibited PKC-ß2 phosphorylation, a key element mediating p47phox translocation. In conclusion, GLP-1 induces α2-AMPK activation and blocks HG-induced p47phox translocation to the plasma membrane, thereby preventing glucotoxicity.

Survival of patients with unfavorable prognosis cutaneous melanoma with increased use of immunotherapy agents: a population-based study in Belgium.

BACKGROUND: Although metastatic cutaneous melanoma is associated with an unfavorable prognosis, innovative therapies including immunomodulating agents and targeted therapies have shown survival benefits in clinical trials. We assessed the impact of the introduction of innovative drugs into clinical practice on the survival of patients with metastatic cutaneous melanoma during the period 2004-2017, in Belgium. The evolution of associated expenses was also analyzed. METHODS: This is a retrospective population-based study using data from the national Belgian Cancer Registry, compulsory health insurance, and administrative survival data. The immunomodulating drugs were ipilimumab, nivolumab and pembrolizumab, while targeted therapies included vemurafenib, dabrafenib and trametinib. RESULTS: We did not identify a trend for improvement over time. Median survival (years) was 1.5 (95% CI: 1.1-1.8) in 2004-2008, 1.1 (95% CI: 0.8-1.5) in 2009-2013, and 1.6 (95% CI: 1.3-2.4) in 2014-2017, respectively. In contrast, survival improved in those with unknown primary tumor localization. In this group, median survival time was 2.0 (95% CI: 1.4-2.9) in the most recent period, while it was 1.1 (95% CI: 0.7-1.3) in 2009-2013, and 0.9 (95% CI: 0.6-1.2) in 2004-2008. The uptake of innovative drugs remained modest, with no drug being used by more than 30% of patients. Yearly expenditure was almost non-existent, and gradually increased, reaching several million euros in 2014-2017. CONCLUSION: Patients with metastatic cutaneous melanoma who were diagnosed between 2004 and 2017 showed no apparent improvement in survival. In contrast, increased survival was observed in the subgroup of patients with unknown primary tumor localization.

A Comparison Study of Lymph Node Tuberculosis and Sarcoidosis Involvement to Facilitate Differential Diagnosis and to Establish a Predictive Score for Tuberculosis.

Background: Tuberculosis (TB) and sarcoidosis are two common granulomatous diseases involving lymph nodes. Differential diagnosis is not always easy because pathogen demonstration in tuberculosis is not always possible and both diseases share clinical, radiological and histological patterns. The aim of our study was to identify factors associated with each diagnosis and set up a predictive score for TB. Methods: All cases of lymph node tuberculosis and sarcoidosis were retrospectively reviewed. Demographics, clinical characteristics, laboratory and imaging data, and microbiological and histological results were collected and compared. Results: Among 441 patients screened, 192 patients were included in the final analysis. The multivariate analysis showed that weight loss, necrotic granuloma, normal serum lysozyme level and hypergammaglobulinemia were significantly associated with TB. A risk score of TB was built based on these variables and was able to discriminate TB versus sarcoidosis with an AUC of 0.85 (95% CI: 0.79-0.91). Using the Youden's J statistic, its most discriminant value (-0.36) was associated with a sensitivity of 80% and a specificity of 75%. Conclusions: We developed a score based on weight loss, necrotic granuloma, normal serum lysozyme level and hypergammaglobulinemia with an excellent capacity to discriminate TB versus sarcoidosis. This score needs still to be validated in a multicentric prospective study.

Connection between cardiac vascular permeability, myocardial edema, and inflammation during sepsis: role of the α1AMP-activated protein kinase isoform.

OBJECTIVE: As adenosine monophosphate (AMP)-activated protein kinase both controls cytoskeleton organization in endothelial cells and exerts anti-inflammatory effects, we here postulated that it could influence vascular permeability and inflammation, thereby counteracting cardiac wall edema during sepsis. DESIGN: Controlled animal study. SETTINGS: University research laboratory. SUBJECTS: C57BL/6J, α1AMPK, and α1AMPK mice. INTERVENTION: Sepsis was triggered in vivo using a sublethal injection of lipopolysaccharide (O55B5, 10 mg/kg), inducing systolic left ventricular dysfunction. Left ventricular function, edema, vascular permeability, and inflammation were assessed in vivo in both wild-type mice (α1AMPK) and α1AMP-activated protein kinase-deficient mice (α1AMPK). The 5-aminoimidazole-4-carboxamide riboside served to study the impact of AMP-activated protein kinase activation on vascular permeability in vivo. The integrity of endothelial cell monolayers was also examined in vitro after lipopolysaccharide challenge in the presence of aminoimidazole-4-carboxamide riboside and/or after α1AMP-activated protein kinase silencing. MEASUREMENTS AND MAIN RESULTS: α1AMP-activated protein kinase deficiency dramatically impaired tolerance to lipopolysaccharide challenge. Indeed, α1AMPK exhibited heightened cardiac vascular permeability after lipopolysaccharide challenge compared with α1AMPK. Consequently, an increase in left ventricular mass corresponding to exaggerated wall edema occurred in α1AMPK, without any further decrease in systolic function. Mechanistically, the lipopolysaccharide-induced α1AMPK cardiac phenotype could not be attributed to major changes in the systemic inflammatory response but was due to an increased disruption of interendothelial tight junctions. Accordingly, AMP-activated protein kinase activation by aminoimidazole-4-carboxamide riboside counteracted lipopolysaccharide-induced hyperpermeability in wild-type mice in vivo as well as in endothelial cells in vitro. This effect was associated with a potent protection of zonula occludens-1 linear border pattern in endothelial cells. CONCLUSIONS: Our results demonstrate for the first time the involvement of a signaling pathway in the control of left ventricular wall edema during sepsis. AMP-activated protein kinase exerts a protective action through the preservation of interendothelial tight junctions. Interestingly, exaggerated left ventricular wall edema was not coupled with aggravated systolic dysfunction. However, it could contribute to diastolic dysfunction in patients with sepsis.