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.

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.

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.

Inhaled drug delivery: a randomized study in intubated patients with healthy lungs.

BACKGROUND: The administration technique for inhaled drug delivery during invasive ventilation remains debated. This study aimed to compare in vivo and in vitro the deposition of a radiolabeled aerosol generated through four configurations during invasive ventilation, including setups optimizing drug delivery. METHODS: Thirty-one intubated postoperative neurosurgery patients with healthy lungs were randomly assigned to four configurations of aerosol delivery using a vibrating-mesh nebulizer and specific ventilator settings: (1) a specific circuit for aerosol therapy (SCAT) with the nebulizer placed at 30 cm of the wye, (2) a heated-humidified circuit switched off 30 min before the nebulization or (3) left on with the nebulizer at the inlet of the heated-humidifier, (4) a conventional circuit with the nebulizer placed between the heat and moisture exchanger filter and the endotracheal tube. Aerosol deposition was analyzed using planar scintigraphy. RESULTS: A two to three times greater lung delivery was measured in the SCAT group, reaching 19.7% (14.0-24.5) of the nominal dose in comparison to the three other groups (p < 0.01). Around 50 to 60% of lung doses reached the outer region of both lungs in all groups. Drug doses in inner and outer lung regions were significantly increased in the SCAT group (p < 0.01), except for the outer right lung region in the fourth group due to preferential drug trickling from the endotracheal tube and the trachea to the right bronchi. Similar lung delivery was observed whether the heated humidifier was switched off or left on. Inhaled doses measured in vitro correlated with lung doses (R = 0.768, p < 0.001). CONCLUSION: Optimizing the administration technique enables a significant increase in inhaled drug delivery to the lungs, including peripheral airways. Before adapting mechanical ventilation, studies are required to continue this optimization and to assess its impact on drug delivery and patient outcome in comparison to more usual settings.

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.

Classification of post COVID-19 condition symptoms: a longitudinal study in the Belgian population.

OBJECTIVES: Since 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. DESIGN: Longitudinal online cohort study. SETTING: National study in Belgium. PARTICIPANTS: Participants 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 MEASURES: The 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. RESULTS: Half 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. CONCLUSIONS: With 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.

Improving Safety in Living Liver Donation: Lessons From Intraoperative Adverse Events in 438 Donors Undergoing a Left Liver Resection.

Background: Donor safety is paramount in living organ donation. Left liver resections are considered safer than right lobe hepatectomies. However, unexpected intraoperative adverse events (iAEs), defined as any deviation from the ideal intraoperative course, can also occur during left liver resections and may be life threatening or lead to postoperative complication or permanent harm to the donor and recipient. Methods: Records of 438 liver living donors (LDs) who underwent 393 left lateral sectionectomies (LLSs) and 45 left hepatectomies (LHs) between July 1993 and December 2018 in a pediatric living-donor liver transplantation center were reviewed for the appearance of iAEs that could have influenced the donor morbidity and mortality and that could have contributed to the improvement of the LD surgical protocol. Results: Clinical characteristics of LLS and LH groups were comparable. Nine iAEs were identified, an incidence of 2%, all of them occurring in the LLS group. Seven of them were related to a surgical maneuver (5 associated with vascular management and 2 with the biliary tree approach). One iAE was associated with an incomplete donor workup and the last with drug administration. Each iAE resulted in subsequent changes in the surgical protocol. Donor outcome was at risk by 5 iAEs classed as type a, recipient outcome by 2 iAEs (type b) and both by 2 iAEs (type c). Postoperative complications occurred in 87 LDs (19.9%), with no differences between the LLS and LH groups (P = 0.227). No Clavien-Dindo class IVa or b complications or donor mortality (Clavien-Dindo class V) were observed. Conclusions: iAEs debriefings induced changes in our LD protocol and may have contributed to reduced morbidity and zero mortality. iAEs analysis can be used as a quality and safety improvement tool in the context of LD procedures, which may include right liver donation, laparoscopic, and robotic living liver graft procurement.

Belgian observational survival data (incidence years 2004-2017) and expenditure for innovative oncology drugs in twelve cancer indications.

BACKGROUND: The Food and Drug Administration and European Medicines Agency typically approve market access for cancer drugs based on surrogate end-points, which do not always translate into substantiated improvements in outcomes that matter the most to patients, i.e. survival and quality of life. These drugs often, also, have a high price tag. We assessed whether there was an increase in cancer drug expenditure for a broad selection of indications, and whether this correlates with increased overall survival. METHODS: This cohort study used Belgian Cancer Registry data from 125,692 patients (12 cancer indications, incidence period 2004-2017), which was linked to reimbursement and survival data. This reliably represents the Belgian situation. One-to-five year observed survival probability, median survival time, oncology drug expenditure and mean oncology drug cost per patient were reviewed. FINDINGS: In almost all indications, total expenditure and average treatment cost for oncology drugs increased over the years (2004-2017). In contrast, mixed findings are observed for the evolution in overall survival probability and median survival time. While an absolute improvement in the 3-year survival probability of about 10% is noticed in non-small-cell lung cancer and chronic myeloid leukaemia, improvements in about half of the other indications are limited or even absent. INTERPRETATION: The Belgian observational data indicate that assuming 'innovative' oncology drugs always add value in terms of improved survival is often unjustified. The literature also highlights the problem of using surrogate end-points, and the lack of comparative evidence showing an added value of oncology drugs for both survival and quality of life at market approval or during the post-marketing phase. Comparative studies should be conducted in the pre-marketing phase that are suitable for registration purposes, aid reimbursement decisions and support physicians and patients when making treatment decisions.

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.

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.

Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Study in a Belgian Teaching Hospital.

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.

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 .

Validation of Neutrophil-to-Lymphocyte Ratio Cut-off Value Associated with High In-Hospital Mortality in COVID-19 Patients.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSION: In prospective analysis, an NLR value of 5.94 predicted high in-hospital mortality upon admission in patients hospitalized for COVID-19 pneumonia.

Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK.

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.

Prone Positioning in Spontaneously Breathing Subjects With Moderate or Severe ARDS During Invasive Ventilation.

BACKGROUND: Prone positioning (PP) during invasive mechanical ventilation improves outcomes of patients with severe ARDS. Recent studies suggest that PP in spontaneously breathing, nonintubated patients with acute respiratory failure is well tolerated and improves oxygenation. However, little is known regarding patient triggered ventilation in intubated patients with ARDS undergoing PP. We conducted a retrospective review of our experience with placing patients in the prone position in 2 cohorts of subjects with moderate and severe ARDS (ie, one cohort with ARDS related to COVID-19, the other with ARDS unrelated to COVID-19), many of whom were receiving pressure support ventilation (PSV). METHODS: We conducted a retrospective analysis in a single 22-bed mixed ICU. The subjects included in the analysis were ≥ 18 y old, met the Berlin definition for moderate or severe ARDS (whether related COVID-19 or not), and underwent PP during invasive ventilation. RESULTS: 39 subjects were included in the analysis: 20 subjects had ARDS related to COVID-19, while 19 had ARDS related to other etiologies. A total of 113 PP episodes were analyzed: 84 during PSV and 29 during volume control continuous mandatory ventilation. PP during PSV was well tolerated and was effective in improving arterial oxygenation (ie, an increase of median [Formula: see text] from 100 mm Hg [interquartile range 75-120] before PP to 135 mm Hg [interquartile range 111-161] at the end of the PP session, P < .0001). No significant difference between continuous mandatory ventilation and PSV was noted regarding arterial oxygenation during PP. Compared with continuous mandatory ventilation mode, PP during PSV was associated with a significant decrease in the use of neuromuscular blocking agents (4% vs 69% of subjects, P < .001), while sedative requirements remained unchanged. CONCLUSIONS: In a retrospective analysis of consecutive intubated subjects with moderate or severe ARDS, related or not to COVID-19, spontaneous breathing during PP was well tolerated and achieved significant improvement in arterial oxygenation.

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.

Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study.

Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1ß and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.

Acute Effects of Sitting Out of Bed and Exercise on Lung Aeration and Oxygenation in Critically Ill Subjects.

BACKGROUND: Early mobilization during critical illness is safe and has beneficial effects on functional outcomes. However, its impact on pulmonary function has not been thoroughly explored. We hypothesized that a sitting position out of bed coupled with exercise could result in an improvement in oxygenation and lung aeration. METHODS: The study was conducted on a cohort of adult subjects within a week of their admission to an ICU. Subjects were transferred to a chair and undertook a 15-min session of exercise, either active or passive. Subjects in the control group were only transferred to a chair. Electrical impedance tomography, a reliable bedside technique monitoring regional lung aeration and the distribution of ventilation, was continuously performed, and blood gases were assessed at baseline and 20 min post-exercise. RESULTS: The cohort included 40 subjects, 17 of whom were mechanically ventilated and 23 spontaneously breathing. The control group for each modality consisted of 5 mechanically ventilated or 5 spontaneously breathing subjects. Mild hypoxemia was present in 45% of the spontaneously breathing cohort, whereas the mechanically ventilated subjects demonstrated moderate (50%) or severe (12%) hypoxemia. Compared with the control group, early mobilization induced a significant increase in lung aeration. In mechanically ventilated subjects, lung aeration increased, especially in the anterior lung regions (mean impedance [95% CI]: T1 (baseline in bed) = 1,265 [691-1,839]; T2 (chair sitting) = 2,003 [1,042-2,963]; T3 (exercise) = 1,619 [810 2,427]; T4 (post exercise in chair) = 2,320 [1,186-3,455]). In spontaneously breathing subjects, lung aeration increased mainly in the posterior lung regions (mean impedance [95% CI]: T1 = 380 [124-637]; T2 = 655 [226-1,084]; T3 = 621 [335-906]; T4 = 600 [340-860]). [Formula: see text] increased, especially in subjects with lower [Formula: see text] at baseline (< 200) (133 ± 31 to 158 ± 48, P = .041). CONCLUSIONS: For critically ill subjects, a sitting position and exercise increased lung aeration and were associated with an improvement in [Formula: see text] in the more severely hypoxemic subjects.