Aberrant mitochondrial dynamics contributes to diaphragmatic weakness induced by mechanical ventilation.

In critical care patients, the “”temporary inactivity of the diaphragm caused by mechanical ventilation (MV) triggers a series of events leading to diaphragmatic dysfunction and atrophy, commonly known as ventilator-induced diaphragm dysfunction (VIDD). While mitochondrial dysfunction related to oxidative stress is recognized as a crucial factor in VIDD, the exact molecular mechanism remains poorly understood. In this study, we observe that 6 h of MV triggers aberrant mitochondrial dynamics, resulting in a reduction in mitochondrial size and interaction, associated with increased expression of dynamin-related protein 1 (DRP1). This effect can be prevented by P110, a molecule that inhibits the recruitment of DRP1 to the mitochondrial membrane. Furthermore, isolated mitochondria from the diaphragms of ventilated patients exhibited increased production of reactive oxygen species (ROS). These mitochondrial changes were associated with the rapid oxidation of type 1 ryanodine receptor (RyR1) and a decrease in the stabilizing subunit calstabin 1. Subsequently, we observed that the sarcoplasmic reticulum (SR) in the ventilated diaphragms showed increased calcium leakage and reduced contractile function. Importantly, the mitochondrial fission inhibitor P110 effectively prevented all of these alterations. Taken together, the results of our study illustrate that MV leads, in the diaphragm, to both mitochondrial fragmentation and dysfunction, linked to the up-/down-regulation of 320 proteins, as assessed through global comprehensive quantitative proteomics analysis, primarily associated with mitochondrial function. These outcomes underscore the significance of developing compounds aimed at modulating the balance between mitochondrial fission and fusion as potential interventions to mitigate VIDD in human patients

Optimising respiratory support for early COVID-19 pneumonia : a computational modelling study

Optimal respiratory support in early COVID-19 pneumonia is controversial and remains unclear. Using computational modelling, we examined whether lung injury might be exacerbated in early COVID-19 by assessing the impact of conventional oxygen therapy (COT), high-flow nasal oxygen therapy (HFNOT), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV). Using an established multi-compartmental cardiopulmonary simulator, we first modelled COT at a fixed FiO (0.6) with elevated respiratory effort for 30 min in 120 spontaneously breathing patients, before initiating HFNOT, CPAP, or NIV. Respiratory effort was then reduced progressively over 30-min intervals. Oxygenation, respiratory effort, and lung stress/strain were quantified. Lung-protective mechanical ventilation was also simulated in the same cohort. HFNOT, CPAP, and NIV improved oxygenation compared with conventional therapy, but also initially increased total lung stress and strain. Improved oxygenation with CPAP reduced respiratory effort but lung stress/strain remained elevated for CPAP >5 cm H O. With reduced respiratory effort, HFNOT maintained better oxygenation and reduced total lung stress, with no increase in total lung strain. Compared with 10 cm H O PEEP, 4 cm H O PEEP in NIV reduced total lung stress, but high total lung strain persisted even with less respiratory effort. Lung-protective mechanical ventilation improved oxygenation while minimising lung injury. The failure of noninvasive ventilatory support to reduce respiratory effort may exacerbate pulmonary injury in patients with early COVID-19 pneumonia. HFNOT reduces lung strain and achieves similar oxygenation to CPAP/NIV. Invasive mechanical ventilation may be less injurious than noninvasive support in patients with high respiratory effort

High risk of patient self-inflicted lung injury in COVID-19 with frequently encountered spontaneous breathing patterns: a computational modelling study

Background: There is ongoing controversy regarding the potential for increased respiratory effort to generate patient self-inflicted lung injury (P-SILI) in spontaneously breathing patients with COVID-19 acute hypoxaemic respiratory failure. However, direct clinical evidence linking increased inspiratory effort to lung injury is scarce. We adapted a computational simulator of cardiopulmonary pathophysiology to quantify the mechanical forces that could lead to P-SILI at different levels of respiratory effort. In accordance with recent data, the simulator parameters were manually adjusted to generate a population of 10 patients that recapitulate clinical features exhibited by certain COVID-19 patients, i.e. severe hypoxaemia combined with relatively well-preserved lung mechanics, being treated with supplemental oxygen. Results: Simulations were conducted at tidal volumes (VT) and respiratory rates (RR) of 7 ml/kg and 14 breaths/min (representing normal respiratory effort) and at VT/RR of 7/20, 7/30, 10/14, 10/20 and 10/30 ml/kg / breaths/min. While oxygenation improved with higher respiratory efforts, significant increases in multiple indicators of the potential for lung injury were observed at all higher VT/RR combinations tested. Pleural pressure swing increased from 12.0±0.3 cmH 2 O at baseline to 33.8±0.4 cmH 2 O at VT/RR of 7 ml/kg/30 breaths/min and to 46.2±0.5 cmH 2 O at 10 ml/kg/30 breaths/min. Transpulmonary pressure swing increased from 4.7±0.1 cmH 2 O at baseline to 17.9±0.3 cmH 2 O at VT/RR of 7 ml/kg/30 breaths/min and to 24.2±0.3 cmH 2 O at 10 ml/kg/30 breaths/min. Total lung strain increased from 0.29±0.006 at baseline to 0.65±0.016 at 10 ml/kg/30 breaths/min. Mechanical power increased from 1.6±0.1 J/min at baseline to 12.9±0.2 J/min at VT/RR of 7 ml/kg/30 breaths/min, and to 24.9±0.3 J/min at 10 ml/kg/30 breaths/min. Driving pressure increased from 7.7±0.2 cmH 2 O at baseline to 19.6±0.2 cmH 2 O at VT/RR of 7 ml/kg/30 breaths/min, and to 26.9±0.3 cmH 2 O at 10 ml/kg/30 breaths/min. Conclusions: Our results suggest that the forces generated by increased inspiratory effort commonly seen in COVID-19 acute hypoxaemic respiratory failure are comparable with those that have been associated with ventilator-induced lung injury during mechanical ventilation. Respiratory efforts in these patients should be carefully monitored and controlled to minimise the risk of lung injury

Validation of at-the-bedside formulae for estimating ventilator driving pressure during airway pressure release ventilation using computer simulation

Background: Airway pressure release ventilation (APRV) is widely available on mechanical ventilators and has been proposed as an early intervention to prevent lung injury or as a rescue therapy in the management of refractory hypoxemia. Driving pressure (ΔP) has been identified in numerous studies as a key indicator of ventilator-induced-lung-injury that needs to be carefully controlled. ΔP delivered by the ventilator in APRV is not directly measurable in dynamic conditions, and there is no “gold standard” method for its estimation. Methods: We used a computational simulator matched to data from 90 patients with acute respiratory distress syndrome (ARDS) to evaluate the accuracy of three “at-the-bedside” methods for estimating ventilator ΔP during APRV. Results: Levels of ΔP delivered by the ventilator in APRV were generally within safe limits, but in some cases exceeded levels specified by protective ventilation strategies. A formula based on estimating the intrinsic positive end expiratory pressure present at the end of the APRV release provided the most accurate estimates of ΔP. A second formula based on assuming that expiratory flow, volume and pressure decay mono-exponentially, and a third method that requires temporarily switching to volume-controlled ventilation, also provided accurate estimates of true ΔP. Conclusions: Levels of ΔP delivered by the ventilator during APRV can potentially exceed levels specified by standard protective ventilation strategies, highlighting the need for careful monitoring. Our results show that ΔP delivered by the ventilator during APRV can be accurately estimated at the bedside using simple formulae that are based on readily available measurements

Correction to: Two years later: Is the SARS-CoV-2 pandemic still having an impact on emergency surgery? An international cross-sectional survey among WSES members

Background: The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. Methods: A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. Results: 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. Conclusions: The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years

Key Attack Strategies Against Black-Box DNNs

International audienceIn this paper, we examined to what extent and under what settings the confidentiality and integrity of black-box DNNs—which are the most challenging setup of DNNs—can be threatened. In this way, we proposed a comprehensive taxonomy of the key strategies developed in the literature to attack black-box DNNs.We believe that a coherent classification incorporating all key aspects is needed to organise the body of knowledge on research and methodologies for understanding and securing black-box DNNs

Key Attack Strategies Against Black-Box DNNs

International audienceIn this paper, we examined to what extent and under what settings the confidentiality and integrity of black-box DNNs—which are the most challenging setup of DNNs—can be threatened. In this way, we proposed a comprehensive taxonomy of the key strategies developed in the literature to attack black-box DNNs.We believe that a coherent classification incorporating all key aspects is needed to organise the body of knowledge on research and methodologies for understanding and securing black-box DNNs

Key Attack Strategies Against Black-Box DNNs

International audienceIn this paper, we examined to what extent and under what settings the confidentiality and integrity of black-box DNNs—which are the most challenging setup of DNNs—can be threatened. In this way, we proposed a comprehensive taxonomy of the key strategies developed in the literature to attack black-box DNNs.We believe that a coherent classification incorporating all key aspects is needed to organise the body of knowledge on research and methodologies for understanding and securing black-box DNNs

Key Attack Strategies Against Black-Box DNNs

International audienceIn this paper, we examined to what extent and under what settings the confidentiality and integrity of black-box DNNs—which are the most challenging setup of DNNs—can be threatened. In this way, we proposed a comprehensive taxonomy of the key strategies developed in the literature to attack black-box DNNs.We believe that a coherent classification incorporating all key aspects is needed to organise the body of knowledge on research and methodologies for understanding and securing black-box DNNs

Hyperglycemia triggers RyR2-dependent alterations of mitochondrial calcium homeostasis in response to cardiac ischemia-reperfusion: Key role of DRP1 activation

Hyperglycemia increases the heart sensitivity to ischemia-reperfusion (IR), but the underlying cellular mechanisms remain unclear. Mitochondrial dynamics (the processes that govern mitochondrial morphology and their interactions with other organelles, such as the reticulum), has emerged as a key factor in the heart vulnerability to IR. However, it is unknown whether mitochondrial dynamics contributes to hyperglycemia deleterious effect during IR. We hypothesized that (i) the higher heart vulnerability to IR in hyperglycemic conditions could be explained by hyperglycemia effect on the complex interplay between mitochondrial dynamics, Ca2+ homeostasis, and reactive oxygen species (ROS) production; and (ii) the activation of DRP1, a key regulator of mitochondrial dynamics, could play a central role. Using transmission electron microscopy and proteomic analysis, we showed that the interactions between sarcoplasmic reticulum and mitochondria and mitochondrial fission were increased during IR in isolated rat hearts perfused with a hyperglycemic buffer compared with hearts perfused with a normoglycemic buffer. In isolated mitochondria and cardiomyocytes, hyperglycemia increased mitochondrial ROS production and Ca2+ uptake. This was associated with higher RyR2 instability. These results could contribute to explain the early mPTP activation in mitochondria from isolated hearts perfused with a hyperglycemic buffer and in hearts from streptozotocin-treated rats (to increase the blood glucose). DRP1 inhibition by Mdivi-1 during the hyperglycemic phase and before IR induction, normalized Ca2+ homeostasis, ROS production, mPTP activation, and reduced the heart sensitivity to IR in streptozotocin-treated rats. In conclusion, hyperglycemia-dependent DRP1 activation results in higher reticulum-mitochondria calcium exchange that contribute to the higher heart vulnerability to IR