Inhibition of circulating dipeptidyl-peptidase 3 by procizumab in experimental septic shock reduces catecholamine exposure and myocardial injury.

BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. METHODS: In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65-75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin-angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. RESULTS: PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. CONCLUSIONS: In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.

Incidence of acute kidney injury and attributive mortality in acute respiratory distress syndrome randomized trials.

PURPOSE: The development of acute kidney injury (AKI) after the acute respiratory distress syndrome (ARDS) reduces the chance of organ recovery and survival. The purpose of this study was to examine the AKI rate and attributable mortality in ARDS patients. METHODS: We performed an individual patient-data analysis including 10 multicenter randomized controlled trials conducted over 20 years. We employed a Super Learner ensemble technique, including a time-dependent analysis, to estimate the adjusted risk of AKI. We calculated the mortality attributable to AKI using an inverse probability of treatment weighting estimator integrated with the Super Learner. RESULTS: There were 5148 patients included in this study. The overall incidence of AKI was 43.7% (n = 2251). The adjusted risk of AKI ranged from 38.8% (95% confidence interval [CI], 35.7 to 41.9%) in ARMA, to 55.8% in ROSE (95% CI, 51.9 to 59.6%). 37.1% recovered rapidly from AKI, with a significantly lower recovery rate in recent trials (P < 0.001). The 90-day excess in mortality attributable to AKI was 15.4% (95% CI, 12.8 to 17.9%). It decreased from 25.4% in ARMA (95% CI, 18.7 to 32%), to 11.8% in FACTT (95% CI, 5.5 to 18%) and then remained rather stable over time. The 90-day overall excess in mortality attributable to acute kidney disease was 28.4% (95% CI, 25.3 to 31.5%). CONCLUSIONS: The incidence of AKI appears to be stable over time in patients with ARDS enrolled in randomized trials. The development of AKI remains a significant contributing factor to mortality. These estimates are essential for designing future clinical trials for AKI prevention or treatment.

Impaired angiotensin II signaling in septic shock.

Recent years have seen a resurgence of interest for the renin-angiotensin-aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II-angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin-angiotensin-aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin-angiotensin-aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin-angiotensin-aldosterone system alterations in septic shock should help to decipher patients' phenotypes and to implement targeted interventions.

Specific and Non-specific Aspects and Future Challenges of ICU Care Among COVID-19 Patients with Obesity: A Narrative Review.

PURPOSE OF REVIEW: Since the end of 2019, the coronavirus disease 2019 (COVID-19) pandemic has infected nearly 800 million people and caused almost seven million deaths. Obesity was quickly identified as a risk factor for severe COVID-19, ICU admission, acute respiratory distress syndrome, organ support including mechanical ventilation and prolonged length of stay. The relationship among obesity; COVID-19; and respiratory, thrombotic, and renal complications upon admission to the ICU is unclear. RECENT FINDINGS: The predominant effect of a hyperinflammatory status or a cytokine storm has been suggested in patients with obesity, but more recent studies have challenged this hypothesis. Numerous studies have also shown increased mortality among critically ill patients with obesity and COVID-19, casting doubt on the obesity paradox, with survival advantages with overweight and mild obesity being reported in other ICU syndromes. Finally, it is now clear that the increase in the global prevalence of overweight and obesity is a major public health issue that must be accompanied by a transformation of our ICUs, both in terms of equipment and human resources. Research must also focus more on these patients to improve their care. In this review, we focused on the central role of obesity in critically ill patients during this pandemic, highlighting its specificities during their stay in the ICU, identifying the lessons we have learned, and identifying areas for future research as well as the future challenges for ICU activity.

VirtualPain. Preliminary findings from a group-based digital therapeutics intervention for fibromyalgia.

Introduction: Fibromyalgia (FM) is a disorder characterized by chronic pain, with significant medical, psychological, and socio-economic implications. Although there is limited evidence, cognitive-behavioral therapy (CBT) has shown to be effective in improving FM symptoms. An alternative to enhance CBT effectiveness is to incorporate digital therapeutics (DTx). Aim: We conducted a pilot study to investigate whether the addition of a DTx intervention (VirtualPain) to cognitive-behavioral group therapy (CBGT) can reduce pain perception and associated symptoms in patients with FM. Method: Ten patients with FM were initially recruited from a public hospital in Barcelona. The treatment consisted of 6 weeks of VirtualPain group sessions and 16 weeks of CBGT. Measures of catastrophizing, self-efficacy, and coping were recorded before, during, and after the protocol. In the DTx sessions, pain intensity was recorded before and after each session. Results: The program (DTx and CBGT) showed a significant improvement in pain-related self-efficacy and relaxation measures. Improvement in pain perception was observed only after the DTx intervention. Conclusions: This study provides preliminary results regarding the added value of DTx (VirtualPain) as part of a CBGT for FM. The use of the program has facilitated a significant reduction in pain perception in each of the VirtualPain sessions, which provides further evidence of how this technology can be beneficial for improving FM treatments.

Exploring Attentional Bias toward Alcohol Content: Insights from Eye-Movement Activity.

INTRODUCTION: Attentional bias (AB) is an implicit selective attention toward processing disorder-significant information while neglecting other environmental cues. Considerable empirical evidence highlights the clinical implication of AB in the onset and maintenance of substance use disorder. An innovative method to explore direct measures of AB relies on the eye-movement activity using technologies like eye-tracking (ET). Despite the growing interest regarding the clinical relevance of AB in the spectrum of alcohol consumption, more research is needed to fully determine the AB patterns and its transfer from experimental to clinical applications. The current study consisted of three consecutive experiments. The first experiment aimed to design an ad-hoc visual attention task (VAT) consisting of alcohol-related and neutral images using a nonclinical sample (n = 15). The objective of the second and third experiments was to analyze whether the effect of type of image (alcohol-related vs. neutral images) on AB toward alcohol content using the VAT developed in the first experiment was different for type of drinker (light vs. heavy drinker in the second experiment [n = 30], and occasional social drinkers versus alcohol use disorder (AUD) patients in the third experiment [n = 48]). METHODS: Areas of interest (AOIs) within each type of image (neutral and alcohol-related) were designed and raw ET-based data were subsequently extracted through specific software analyses. For experiment 1, attention maps were created and processed for each image. For experiments 2 and 3, data on ET variables were gathered and subsequently analyzed through a two-way ANOVA with the aim of examining the effects of the type of image and drinker on eye-movement activity. RESULTS: There was a statistically significant interaction effect between type of image and type of drinker (light vs. heavy drinker in experiment 2, F(1, 56) = 13.578, p < 0.001, partial η2 = 0.195, and occasional social drinker versus AUD patients in the experiment 3, F(1, 92) = 35.806, p < 0.001, partial η2 = 0.280) for "first fixation" with large effect sizes, but not for "number of fixations" and "dwell time." The simple main effect of type of image on mean "first fixation" score for AUD patients was not statistically significant. CONCLUSION: The data derived from the experiments indicated the importance of AB in sub-clinical populations: heavy drinkers displayed an implicit preference for alcohol-related images compared to light drinkers. Nevertheless, AB fluctuations in patients with AUD compared to the control group were found. AUD patients displayed an early interest in alcohol images, followed by an avoidance attentional processing of alcohol-related images. The results are discussed in light of recent literature in the field.

Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock.

BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-ß-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65-75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70-90] mmHg for early treatment, 57 [70-90] mmHg for late treatment, and 55 [49-60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials.

The alternative renin-angiotensin system in critically ill patients: pathophysiology and therapeutic implications.

The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure and the cardio-renal system. The classical RAS, mainly mediated by angiotensin I, angiotensin-converting enzyme, and angiotensin II, has been reported to be altered in critically ill patients, such as those in vasodilatory shock. However, recent research has highlighted the role of some components of the counterregulatory axis of the classical RAS, termed the alternative RAS, such as angiotensin-converting Enzyme 2 (ACE2) and angiotensin-(1-7), or peptidases which can modulate the RAS like dipeptidyl-peptidase 3, in many critical situations. In cases of shock, dipeptidyl-peptidase 3, an enzyme involved in the degradation of angiotensin and opioid peptides, has been associated with acute kidney injury and mortality and preclinical studies have tested its neutralization. Angiotensin-(1-7) has been shown to prevent septic shock development and improve outcomes in experimental models of sepsis. In the context of experimental acute lung injury, ACE2 activity has demonstrated a protective role, and its inactivation has been associated with worsened lung function, leading to the use of active recombinant human ACE2, in preclinical and human studies. Angiotensin-(1-7) has been tested in experimental models of acute lung injury and in a recent randomized controlled trial for patients with COVID-19 related hypoxemia. Overall, the alternative RAS appears to have a role in the pathogenesis of disease in critically ill patients, and modulation of the alternative RAS may improve outcomes. Here, we review the available evidence regarding the methods of analysis of the RAS, pathophysiological disturbances of this system, and discuss how therapeutic manipulation may improve outcomes in the critically ill.

The role of renin-angiotensin system in sepsis-associated acute kidney injury: mechanisms and therapeutic implications.

PURPOSE OF REVIEW: This review aims to explore the relationship between the renin angiotensin system (RAS) and sepsis-associated acute kidney injury (SA-AKI), a common complication in critically ill patients associated with mortality, morbidity, and long-term cardiovascular complications. Additionally, this review aims to identify potential therapeutic approaches to intervene with the RAS and prevent the development of AKI. RECENT FINDINGS: Recent studies have provided increasing evidence of RAS alteration during sepsis, with systemic and local RAS disturbance, which can contribute to SA-AKI. Angiotensin II was recently approved for catecholamine resistant vasodilatory shock and has been associated with improved outcomes in selected patients. SUMMARY: SA-AKI is a common condition that can involve disturbances in the RAS, particularly the canonical angiotensin-converting enzyme (ACE) angiotensin-II (Ang II)/angiotensin II receptor 1 (AT-1R) axis. Increased renin levels, a key enzyme in the RAS, have been shown to be associated with AKI and may also guide vasopressor therapy in shock. In patients with high renin levels, angiotensin II administration may reduce renin concentration, improve intra-renal hemodynamics, and enhance signaling through the angiotensin II receptor 1. Further studies are needed to explore the role of the RAS in SA-AKI and the potential for targeted therapies.

Development of quantitative detection method for mass spectrometry coupled to an infrared laser spectroscope (Picarro) to monitor in nitrogen matrix a complex gas mixture of H2 , He, CO, N2 , Ne, O2 , Ar, CO2 , H2 S, CH4 , C2 H4 , C2 H6 , C3 H6 , C3 H8 , i-C4 H10 , n-C4 H10 , and C5 H12.

RATIONALE: The deep geological repository is considered the international reference for radioactive waste management. All gas exchanges must be understood in the context of the feasibility of such a repository. The technological challenge is to continuously monitor a wide range of gaseous molecules at low concentrations in confined spaces. METHODS: A gas monitoring station, composed of two complementary analyzers, was developed: an electron impact quadrupole mass spectrometer (HPR-20 R&D Hiden Analytical) and an infrared laser spectroscope (Picarro). The spectrometer was calibrated using simple mixtures (i.e., C2 H6 in N2 ) and multiple mixtures (i.e., H2 , He, CO2 , CH4 , and O2 in N2 ) at different concentrations to correct interferences. A matrix calculation is proposed to calculate the relative concentrations. RESULTS: The method developed allows the measurement of gaseous species: light hydrocarbons, noble gases, sulfides, greenhouse gases, oxygen, hydrogen, and nitrogen in the same mixture. For each gas, the SDs and the limits of detection and quantification were calculated. The method was validated by comparing the concentrations of the measured gas species with the reference values of two standard gas cylinders. CONCLUSIONS: Calibration of a complex gas mixture remains a challenge because fragmentation of molecules, especially hydrocarbons, reduces the sensitivity of the method. The method developed is suitable for continuous gas monitoring in a confined environment and can be implemented to perform experiments in underground structures: galleries, microtunnels (cells), and boreholes.

Body Dissatisfaction and Body-Related Attentional Bias: Is There a Causal Relationship?

Previous research has shown an association between body dissatisfaction and attentional biases toward the body, but the nature of this relationship is not clear. It is possible that dissatisfaction causes attentional bias or that dissatisfaction is a result of such bias. To clarify the causal relationship between these two variables, this study manipulated dissatisfaction in a sample of healthy women by exposing them to images of "ideal" bodies and observed whether this manipulation increased attentional biases toward different body parts. Fifty-seven women took part in a pre-post experimental design in which they observed an avatar representing themselves in a virtual mirror before and after being exposed to "thin ideal" photographs. Eye-tracking technology was employed to quantify the frequency and duration of fixations on weight-related and weight-unrelated body parts. The outcomes revealed a successful induction of body dissatisfaction, leading participants to display a heightened number of fixations and prolonged fixation durations on unrelated-weight body parts. These findings remained significant after controlling for the effects of trait body dissatisfaction and body mass index. The results imply that heightened body dissatisfaction fosters the aversion of attention from weight-related body parts, which may function as a protective mechanism for preserving self-esteem and promoting psychological well-being.

Attentional Bias Modification Training Based on Virtual Reality and Eye Tracking in Anorexia Nervosa Patients.

Anorexia nervosa (AN) patients exhibit attentional bias (AB) related to the body, which is the tendency to pay greater attention to weight-related body areas compared to non-weight-related ones. This phenomenon has been linked to elevated levels of body dissatisfaction (BD) and may potentially reduce the effectiveness of body exposure therapy. The purpose of this pilot study is to assess the efficacy of a single session of a new body-related AB modification task (ABMT) that combines virtual reality with eye tracking in patients with AN. The goals of the ABMT are to reduce body-related AB by balancing attention between weight and non-weight-related body areas and to reduce BD levels. Twenty-three adolescent patients with AN were embodied in a virtual avatar and immersed in a virtual environment where they completed the ABMT. Body-related AB measures and BD levels were assessed before and after the training. A paired samples t-test showed statistically significant differences between pre-assessment and post-assessment; the complete fixation time on weight-related body parts was reduced and BD levels decreased. The initial evidence of the efficacy of this ABMT has important clinical implications, since AB and BD are considered risk factors for developing and maintaining eating disorder symptomatology among patients with AN.

Modification of Body-Related Attentional Bias through Virtual Reality and Eye-Tracking in Healthy Participants: Implications for Anorexia Nervosa Treatments.

Cognitive biases have a significant impact on the etiology and treatment of eating disorders (EDs). These biases, including selective attentional bias (AB) to disliked body parts, may reinforce concerns about body shape, fear of gaining weight and body image disturbances and may contribute to dietary restriction and restraint. Decreasing AB could reduce core symptoms in anorexia nervosa (AN). This study represents a preliminary exploration aiming to assess whether AB towards weight-related (WR) and non-weight-related (NW) body parts could be reduced through an AB modification task in a virtual reality (VR) environment in healthy participants. A total of 54 female participants, aged 22.98 ± 1.89, were recruited. The task consisted of directing the participants' attention towards all body parts equally in a VR setting. Eye-tracking (ET) measurements (complete fixation time [CFT] and number of fixations [NF]) were made before and after the task. The results showed a significant reduction of the AB in the two groups with an initial AB towards WR body parts or towards NW body parts. Participants showed a tendency to more balanced (non-biased) attention after the intervention. This study provides evidence of the usefulness of AB modification tasks in a non-clinical sample.

Hypertonic sodium lactate infusion reduces vasopressor requirements and biomarkers of brain and cardiac injury after experimental cardiac arrest.

INTRODUCTION: Prognosis after resuscitation from cardiac arrest (CA) remains poor, with high morbidity and mortality as a result of extensive cardiac and brain injury and lack of effective treatments. Hypertonic sodium lactate (HSL) may be beneficial after CA by buffering severe metabolic acidosis, increasing brain perfusion and cardiac performance, reducing cerebral swelling, and serving as an alternative energetic cellular substrate. The aim of this study was to test the effects of HSL infusion on brain and cardiac injury in an experimental model of CA. METHODS: After a 10-min electrically induced CA followed by 5 min of cardiopulmonary resuscitation maneuvers, adult swine (n = 35) were randomly assigned to receive either balanced crystalloid (controls, n = 11) or HSL infusion started during cardiopulmonary resuscitation (CPR, Intra-arrest, n = 12) or after return of spontaneous circulation (Post-ROSC, n = 11) for the subsequent 12 h. In all animals, extensive multimodal neurological and cardiovascular monitoring was implemented. All animals were treated with targeted temperature management at 34 °C. RESULTS: Thirty-four of the 35 (97.1%) animals achieved ROSC; one animal in the Intra-arrest group died before completing the observation period. Arterial pH, lactate and sodium concentrations, and plasma osmolarity were higher in HSL-treated animals than in controls (p < 0.001), whereas potassium concentrations were lower (p = 0.004). Intra-arrest and Post-ROSC HSL infusion improved hemodynamic status compared to controls, as shown by reduced vasopressor requirements to maintain a mean arterial pressure target > 65 mmHg (p = 0.005 for interaction; p = 0.01 for groups). Moreover, plasma troponin I and glial fibrillary acid protein (GFAP) concentrations were lower in HSL-treated groups at several time-points than in controls. CONCLUSIONS: In this experimental CA model, HSL infusion was associated with reduced vasopressor requirements and decreased plasma concentrations of measured biomarkers of cardiac and cerebral injury.

A Self-Help Virtual Therapeutic Experience Intervention for Overcoming Psychological Distress Related to the COVID-19 Pandemic: Results From the European Multicentric COVID Feel Good Trial.

OBJECTIVE: The general objective of the current study was to investigate the efficacy of a novel self-help virtual therapeutic experience (specifically, the COVID Feel Good intervention) in lowering the psychological burden experienced during the COVID-19 lockdowns in four European countries. METHODS: We focused on participants recruited from June 2020 to May 2021 in the context of a European multicenter project including four university/academic sites. The total number of participants in the longitudinal studies was 107 (study 1, N = 40; study 2, N = 29; study 3, N = 38). The randomized controlled trial (study 4) included 31 participants in total, 16 in the intervention group and 15 in the control group. Primary outcome measures were depression, anxiety, stress symptoms, perceived stress level, and perceived hopelessness. The secondary outcome was experienced social connectedness. RESULTS: Using separate linear mixed-effects models, the most consistent result across countries was a reduction in perceived stress after the participation in the COVID Feel Good intervention. By pooling the results of the models using a random-effects meta-analysis, we found that after the COVID Feel Good intervention, participants reported a decrease in perceived general distress (mean standardized effect size for general distress in the treatment groups compared with the control conditions was -0.52 [ p = .008, 95% confidence interval = -0.89 to -0.14]) and an increase in the perceived social connection (mean standardized effect size for social connection using COVID Feel Good compared with the control conditions was 0.50 [ p ≤ .001, 95% confidence interval = 0.25 to 0.76]). CONCLUSIONS: Findings of this study indicate that a virtual self-help intervention is effective in reducing psychological distress. These results contribute to the growing literature supporting the use of digital psychological therapies to relieve psychological distress among the general population during the COVID-19 pandemic.Trial Registration : ISRCTN63887521.

An Attentional Bias Modification Task, through Virtual Reality and Eye-Tracking Technologies, to Enhance the Treatment of Anorexia Nervosa.

Mirror exposure therapies (METs) have been shown to be effective in reducing body image disturbances through the habituation process. Virtual reality (VR) combined with eye-tracking techniques can provide innovative solutions to some of METs' limitations reported with patients with anorexia nervosa (AN), especially the negative influence of body-related attentional bias (AB). This pilot study aimed to assess the preliminary efficacy of a new VR-based AB modification task (ABMT) among healthy women and the procedure's user experience. AB levels towards weight- and non-weight-related body parts, using complete fixation time (CFT) and number of fixations (NF), were assessed throughout the ABMT procedure (300 trials). The user experience was evaluated at the end of the procedure. The results showed that VR-based ABMT was effective in reducing AB significantly after 150 trials for both CFT- and NF-based measures, although 225 trials were necessary to get the same result for women with an NF initially more oriented towards weight-related body parts. Overall, the software received a "C-rating" on a scale from "A" (most usable) to "F" (least usable). These results provide evidence of the opportunity to use a VR-based ABMT procedure to reduce AB and improve existing treatments for AN.

Latest-iteration balloon- and self-expandable transcatheter valves for severe bicuspid aortic stenosis: the TRITON study.

INTRODUCTION AND OBJECTIVES: No comparisons have been published yet regarding the newest iteration of balloon- and self-expandable transcatheter heart valves for the treatment of bicuspid aortic valve (BAV) stenosis. METHODS: Multicenter registry of consecutive patients with severe BAV stenosis treated with balloon-expandable transcatheter heart valves (Myval and SAPIEN 3 Ultra, S3U) or self-expanding Evolut PRO+(EP+). TriMatch analysis was carried out to minimize the impact of baseline differences. The primary endpoint of the study was 30-day device success, and the secondary endpoints were the composite and individual components of early safety at 30 days. RESULTS: A total of 360 patients (age 76.6±7.6 years, 71.9% males) were included: 122 Myval (33.9%), 129 S3U (35.8%), and 109 EP+(30.3%). The mean STS score was 3.6±1.9%. There were no cases of coronary artery occlusion, annulus rupture, aortic dissection, or procedural death. The primary endpoint of device success at 30 days was significantly higher in the Myval group (Myval: 100%; S3U: 87.5%; and EP+: 81.3%), mainly due to higher residual aortic gradients with S3U and greater≥moderate aortic regurgitation (AR) with EP+. No significant differences were found in the unadjusted rate of pacemaker implantation. CONCLUSIONS: In patients with BAV stenosis deemed unsuitable for surgery, Myval, S3U and EP+showed similar safety but balloon-expandable Myval had better gradients than S3U, and both balloon-expandable devices had lower residual AR than EP+, suggesting that, taking into consideration the patient-specific risks, any of these devices can be selected with optimal outcomes.

Angiotensin 1-7 in an experimental septic shock model.

BACKGROUND: Alterations in the renin-angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1-7 (Ang-(1-7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1-7) infusion on the development and severity of septic shock. METHODS: This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1-7) (n = 7) or placebo (n = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. RESULTS: There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1-7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 µg/kg/min in the Ang-(1-7) group compared to 4.3 µg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1-7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO2/FiO2 ratio were higher in the Ang-(1-7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1-7) group compared to 7.4 mmol/L in the control group. CONCLUSIONS: In this experimental septic shock model, early Ang-(1-7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.