Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. OBJECTIVES: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT01862237.

Right Ventriculoarterial Coupling Surrogates and Long-Term Survival in LVAD Recipients: Results of the ASSIST-ICD Multicentric Registry.

BACKGROUND: Prediction of outcomes remains an unmet need in candidates for LVADs. The development of right-heart failure portends an excess in mortality rates, but imaging parameters of right ventricular systolic function have failed to demonstrate a prognostic role. By integrating pulmonary pressure, right ventriculoarterial coupling could fill this gap. METHODS: The ASSIST-ICD registry was used to test right ventriculoarterial coupling as a surrogate parameter at implantation for the prediction of all-cause mortality. RESULTS: The ratio of the tricuspid annular-plane systolic excursion over the estimated systolic pulmonary pressure (TAPSE/sPAP) was not associated with long-term survival in univariate analysis (P = 0.89), nor was the pulmonary artery pulsatility index (PAPi) (P = 0.13). Conversely, the ratio of the right atrial pressure over the pulmonary capillary wedge pressure (RAP/PCWP) was associated with all-cause mortality (P < 0.01). After taking tricuspid regurgitation severity, LVAD indication, LVAD model, age, blood urea nitrogen levels, and pulmonary vascular resistance into account, RAP/PCWP remained associated with survival (HR 1.35 [1.10 - 1.65]; P < 0.01). CONCLUSION: Among pre-implant RVAC surrogates, only RAP/PCWP was associated with long-term all-cause mortality in LVAD recipients. This association was independent of established risk factors.

Characteristics and Outcomes of Prolonged Venoarterial Extracorporeal Membrane Oxygenation After Cardiac Surgery: The Post-Cardiotomy Extracorporeal Life Support (PELS-1) Cohort Study.

OBJECTIVES: Most post-cardiotomy (PC) extracorporeal membrane oxygenation (ECMO) runs last less than 7 days. Studies on the outcomes of longer runs have provided conflicting results. This study investigates patient characteristics and short- and long-term outcomes in relation to PC ECMO duration, with a focus on prolonged (> 7 d) ECMO. DESIGN: Retrospective observational cohort study. SETTING: Thirty-four centers from 16 countries between January 2000 and December 2020. PATIENTS: Adults requiring post PC ECMO between 2000 and 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Characteristics, in-hospital, and post-discharge outcomes were compared among patients categorized by ECMO duration. Survivors and nonsurvivors were compared in the subgroup of patients with ECMO duration greater than 7 days. The primary outcome was in-hospital mortality. Two thousand twenty-one patients were included who required PC ECMO for 0-3 days (n = 649 [32.1%]), 4-7 days (n = 776 [38.3%]), 8-10 days (n = 263 [13.0%]), and greater than 10 days (n = 333 [16.5%]). There were no major differences in the investigated preoperative and procedural characteristics among ECMO duration groups. However, the longer ECMO duration category was associated with multiple complications including bleeding, acute kidney injury, arrhythmias, and sepsis. Hospital mortality followed a U-shape curve, with lowest mortality in patients with ECMO duration of 4-7 days (n = 394, 50.8%) and highest in patients with greater than 10 days ECMO support (n = 242, 72.7%). There was no significant difference in post-discharge survival between ECMO duration groups. In patients with ECMO duration greater than 7 days, age, comorbidities, valvular diseases, and complex procedures were associated with nonsurvival. CONCLUSIONS: Nearly 30% of PC ECMO patients were supported for greater than 7 days. In-hospital mortality increased after 7 days of support, especially in patients undergoing valvular and complex surgery, or who had complications, although the long-term post-discharge prognosis was comparable to PC ECMO patients with shorter support duration.

Features and outcomes of female and male patients requiring postcardiotomy extracorporeal life support.

OBJECTIVES: Although cardiogenic shock requiring extracorporeal life support after cardiac surgery is associated with high mortality, the impact of sex on outcomes of postcardiotomy extracorporeal life support remains unclear with conflicting results in the literature. We compare patient characteristics, in-hospital outcomes, and overall survival between females and males requiring postcardiotomy extracorporeal life support. METHODS: This retrospective, multicenter (34 centers), observational study included adults requiring postcardiotomy extracorporeal life support between 2000 and 2020. Preoperative, procedural, and extracorporeal life support characteristics, complications, and survival were compared between females and males. Association between sex and in-hospital survival was investigated through mixed Cox proportional hazard models. RESULTS: This analysis included 1823 patients (female: 40.8%; median age: 66.0 years [interquartile range, 56.2-73.0 years]). Females underwent more mitral valve surgery (females: 38.4%, males: 33.1%, P = .019) and tricuspid valve surgery (feamales: 18%, males: 12.4%, P < .001), whereas males underwent more coronary artery surgery (females: 45.9%, males: 52.4%, P = .007). Extracorporeal life support implantation was more common intraoperatively in feamales (females: 64.1%, females: 59.1%) and postoperatively in males (females: 35.9%, males: 40.9%, P = .036). Ventricular unloading (females: 25.1%, males: 36.2%, P < .001) and intra-aortic balloon pumps (females: 25.8%, males: 36.8%, P < .001) were most frequently used in males. Females had more postoperative right ventricular failure (females: 24.1%, males: 19.1%, P = .016) and limb ischemia (females: 12.3%, males: 8.8%, P = .23). In-hospital mortality was 64.9% in females and 61.9% in males (P = .199) with no differences in 5-year survival (females: 20%, 95% CI, 17-23; males: 24%, 95% CI, 21-28; P = .069). Crude hazard ratio for in-hospital mortality in females was 1.12 (95% CI, 0.99-1.27; P = .069) and did not change after adjustments. CONCLUSIONS: This study demonstrates that female and male patients requiring postcardiotomy extracorporeal life support have different preoperative and extracorporeal life support characteristics, as well as complications, without a statistical difference in in-hospital and 5-year survivals.

Association between pulmonary artery pulsatility and mortality after implantation of left ventricular assist device.

AIMS: Right ventricular failure after left ventricular assist device (LVAD) implantation is a major concern that remains challenging to predict. We sought to investigate the relationship between preoperative pulmonary artery pulsatility index (PAPi) and mortality after LVAD implantation. METHODS AND RESULTS: A retrospective analysis of the ASSIST-ICD multicentre registry allowed the assessment of PAPi before LVAD according to the formula [(systolic pulmonary artery pressure - diastolic pulmonary artery pressure)/central venous pressure]. The primary endpoint was survival at 3 months, according to the threshold value of PAPi determined by the receiver operating characteristic (ROC) curve. A multivariate analysis including demographic, echographic, haemodynamic, and biological variables was performed to identify predictive factors for 2 year mortality. One hundred seventeen patients were included from 2007 to 2021. The mean age was 58.45 years (±13.16), with 15.4% of women (sex ratio 5.5). A total of 53.4% were implanted as bridge to transplant and 43.1% as destination therapy. Post-operative right ventricular failure was observed in 57 patients (48.7%), with no significant difference between survivors and non-survivors at 1 month (odds ratio 1.59, P = 0.30). The median PAPi for the whole study population was 2.83 [interquartile range 1.63-4.69]. The threshold value of PAPi determined by the ROC curve was 2.84. Patients with PAPi ≥ 2.84 had a higher survival rate at 3 months [PAPi < 2.84: 58.1% [46.3-72.8%] vs. PAPi ≥ 2.84: 89.1% [81.1-97.7%], hazard ratio (HR) 0.08 [0.02-0.28], P < 0.01], with no significant difference after 3 months (HR 0.67 [0.17-2.67], P = 0.57). Other predictors of 2 year mortality were systemic hypertension (HR 4.22 [1.49-11.97], P < 0.01) and diabetes mellitus (HR 4.90 [1.83-13.14], P < 0.01). LVAD implantation as bridge to transplant (HR 0.18 [0.04-0.74], P = 0.02) and heart transplantation (HR 0.02 [0.00-0.18], P < 0.01) were associated with a higher survival rate at 2 years. CONCLUSIONS: Preoperative PAPi < 2.84 was associated with a higher risk of early mortality after LVAD implantation without impacting 2 year outcomes among survivors.

Investigating the mechanisms underlying resistance to chemoterapy and to CRISPR-Cas9 in cancer cell lines.

Cancer is one of the major causes of death worldwide and the development of multidrug resistance (MDR) in cancer cells is the principal cause of chemotherapy failure. To gain insights into the specific mechanisms of MDR in cancer cell lines, we developed a novel method for the combined analysis of recently published datasets on drug sensitivity and CRISPR loss-of-function screens for the same set of cancer cell lines. For our analysis, we first selected cell lines that consistently exhibit drug resistance across several classes of compounds. We then identified putative resistance genes for each class of compound and used inferred gene regulatory networks (GRNs) to study possible mechanisms underlying the development of MDR in the identified cancer cell lines. We show that the same method of analysis can also be used to identify cell lines that consistently exhibit resistance to the gene knockout effect of the CRISPR-Cas9 technique and to study the possible underlying mechanisms. In the GRN associated to the drug resistant cell lines, we identify genes previously associated with resistance (UHMK1, RALYL, MGST3, USP9X, and ESRG), genes for which an indirect association can be identified (SPINK13, LINC00664, MRPL38, and EMILIN3), and genes that are found to be overexpressed in non-resistant cancer cell lines (MRPL38, EMILIN3 and RALYL). In the GRNs associated to the CRISPR-Cas9 resistance mechanism, none of the identified genes has been previously reported in the admittedly sparse literature on the subject. However, some of these genes have a common role: APBB2, RUNX1T1, ZBTB7C, and ISX regulate transcription, while APBB2, BTG3, ZBTB7C, SZRD1 and LEF1 have a function in regulating proliferation, suggesting a role for these two pathways. While our results are specific for the lung cancer cell lines we selected for this work, our method of analysis can be applied to cell lines from other tissues and for which the required data is available.

Pulmonary shunt in critical care: a practical approach with clinical scenarios.

BACKGROUND: Pulmonary shunt refers to the passage of venous blood into the arterial blood system bypassing the alveoli-blood gas exchange. Pulmonary shunt is defined by a drop in the physiologic coupling of lung ventilation and lung perfusion. This may consequently lead to respiratory failure. MAIN BODY: The pulmonary shunt assessment is often neglected. From a mathematical point of view, pulmonary shunt can be assessed by estimating the degree of mixing between oxygenated and deoxygenated blood. To compute the shunt, three key components are analyzed: the oxygen (O2) content in the central venous blood before gas exchange, the calculated O2 content in the pulmonary capillaries after gas exchange, and the O2 content in the arterial system, after the mixing of shunted and non-shunted blood. Computing the pulmonary shunt becomes of further importance in patients on extracorporeal membrane oxygenation (ECMO), as arterial oxygen levels may not directly reflect the gas exchange of the native lung. CONCLUSION: In this review, the shunt analysis and its practical clinical applications in different scenarios are discussed by using an online shunt simulator.

The "ZEEP-PEEP test" to evaluate the response to positive end-expiratory pressure delivered by helmet: A prospective physiologic study.

Introduction: The improvement in oxygenation after helmet application in hypoxemic patients may be explained by the alveolar recruitment obtained with positive end expiratory pressure (PEEP) or by the administration of a more accurate inspiratory fraction of oxygen (FiO2). We have designed the "ZEEP-PEEP test", capable to distinguish between the FiO2-related or PEEP-related oxygenation improvement. Our primary aim was to describe the use of this test during helmet CPAP to assess the oxygenation improvement attributable to PEEP application. Material and methods: We performed a prospective physiological study including adult critically ill patients. Respiratory and hemodynamic parameters were recorded before helmet application (PRE step), after helmet application without PEEP (ZEEP step) and after the application of the PEEP valve (PEEP step), while maintaining a constant FiO2. We defined as "PEEP responders" patients showing a PaO2/FiO2 ratio improvement ≥10% after PEEP application. Results: 93 patients were enrolled. Compared to the PRE step, PaO2/FiO2 ratio was significantly improved during helmet CPAP both at ZEEP and PEEP step (189 ± 55, 219 ± 74 and 241 ± 82 mmHg, respectively, p < 0.01). Both PEEP responders (41%) and non-responders showed a significant improvement of PaO2/FiO2 ratio after the application of helmet at ZEEP, PEEP responders also showed a significant improvement of oxygenation after PEEP application (208 ± 70 vs 267 ± 85, p < 0.01). Conclusions: Helmet CPAP improved oxygenation. This improvement was not only due to the PEEP effect, but also to the increase of the effective inspired FiO2. Performing the ZEEP-PEEP test may help to identify patients who benefit from PEEP.

Extracorporeal cardio-pulmonary resuscitation in a patient with missed diagnosis of sodium nitrite intoxication.

INTRODUCTION: Critical poisoning with sodium nitrite (NaNO2) can present challenges in promptly identifying and managing acute methemoglobinemia. CASE REPORT: We report the case of an overt self-intoxication by an initially unknown agent, leading to cardiac arrest. Despite prodromal signs of cyanosis, coma, desaturation, and hypotension, methemoglobinemia went unrecognized during extracorporeal cardiopulmonary resuscitation (ECPR) as the point-of-care test failed to provide methemoglobin levels, leading to untreated methemoglobinemia. The blood flowing through the oxygenator notably maintained the same brown colour. Return of spontaneous circulation was never achieved, and the patient was declared dead after 60 min of unsuccessful resuscitation. Cause of death by means of NaNO2 voluntary ingestion was later clarified and confirmed by postmortem finding of elevated nitrite and nitrate concentration. CONCLUSIONS: This case highlights the risk of failure of ECPR in the context of cardiac arrest due to methemoglobinemia, emphasizing the critical need for prompt recognition of the causative agent and early administration of antidotes.

Long term outcome in patients treated with veno-venous extracorporeal membrane oxygenation: A prospective observational study.

INTRODUCTION: Over the last few decades, the use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) support for severe respiratory failure has increased. AIM: This study aimed to assess the long-term outcomes of patients treated with VV-ECMO for respiratory failure. METHODS: We performed a single-centre prospective evaluation of patients on VV-ECMO who were successfully discharged from the intensive care unit of an Italian University Hospital between January 2018 and May 2021. The enrolled patients underwent follow-up evaluations at 6 and 12 months after ICU discharge. The follow-up team performed psychological and functional assessments using the following instruments: Hospital Anxiety and Depression Scale (HADS), Post-traumatic Stress Disorder Symptom Severity Scale (PTSS-10), Euro Quality Five Domains Five Levels (EQ-5L-5D), and 6-minute walk test. RESULTS: We enrolled 33 patients who were evaluated at a follow-up clinic. The median patient age was 51 years (range: 45-58 years). The median duration of VV-ECMO support was 12 (9-19) days and the length of ICU stay was 23 (18-42) days. A HADS score higher than 14 was reported in 8 (24 %) and 7 (21 %) patients at the six- and twelve-month visit, respectively. PTSS-10 total score ≥ 35 points was present in three (9 %) and two (6 %) patients at the six- and twelve-month examination. The median EQ-5L-5D-VAS was respectively 80 (80-90) and 87.5 (70-95). The PTSS-10 score significantly decreased from six to 12 months in COVID-19 survivors (p = 0.024). CONCLUSIONS: In this cohort of patients treated with VV-ECMO, cognitive and psychological outcomes were good and comparable to those of patients with Adult Respiratory Distress Syndrome (ARDS) managed without ECMO. IMPLICATIONS FOR CLINICAL PRACTICE: The findings of this study confirm the need for long-term follow-up and rehabilitation programs for every ICU survivor after discharge. COVID-19 survivors treated with VV-ECMO had outcomes comparable to those reported in non-COVID patients.

Ultra-High-Resolution and K-Edge Imaging of Prosthetic Heart Valves With Spectral Photon-Counting CT: A Phantom Study.

BACKGROUND AND PURPOSE: The contribution of cardiac computed tomography (CT) for the detection and characterization of prosthetic heart valve (PHV) complications is still limited due mainly to artifacts. Computed tomography systems equipped with photon-counting detectors (PCDs) have the potential to overcome these limitations. Therefore, the aim of the study was to compare image quality of PHV with PCD-CT and dual-energy dual-layer CT (DEDL-CT). MATERIALS AND METHODS: Two metallic and 3 biological PHVs were placed in a tube containing diluted iodinated contrast inside a thoracic phantom and scanned repeatedly at different angles on a DEDL-CT and PCD-CT. Two small lesions (~2 mm thickness; containing muscle and fat, respectively) were attached to the structure of 4 valves, placed inside the thoracic phantom, with and without an extension ring, and scanned again. Acquisition parameters were matched for the 2 CT systems and used for all scans. Metallic valves were scanned again with parameters adapted for tungsten K-edge imaging. For all valves, different metallic parts were measured on conventional images to assess their thickness and blooming artifacts. In addition, 6 parallelepipeds per metallic valve were drawn, and all voxels with density <3 times the standard deviation of the contrast media were recorded as an estimate of streak artifacts. For subjective analysis, 3 expert readers assessed conventional images of the valves, with and without lesions, and tungsten K-edge images. Conspicuity and sharpness of the different parts of the valve, the lesions, metallic, and blooming artifacts were scored on a 4-point scale. Measurements and scores were compared with the paired t test or Wilcoxon test. RESULTS: The objective analysis showed that, with PCD-CT, valvular metallic structures were thinner and presented less blooming artifacts. Metallic artifacts were also reduced with PCD-CT (11 [interquartile (IQ) = 6] vs 40 [IQ = 13] % of voxels). Subjective analysis allowed noticing that some structures were visible or clearly visible only with PCD-CT. In addition, PCD-CT yielded better scores for the conspicuity and for the sharpness of all structures (all P s < 0.006), except for the conspicuity of the leaflets of the mechanical valves, which were well visible with either technique (4 [IQ = 3] for both). Both blooming and streak artifacts were reduced with PCD-CT ( P ≤ 0.01). Overall, the use of PCD-CT resulted in better conspicuity and sharpness of the lesions compared with DEDL-CT (both P s < 0.02). In addition, only with PCD-CT some differences between the 2 lesions were detectable. Adding the extension ring resulted in reduced conspicuity and sharpness with DEDL-CT ( P = 0.04 and P = 0.02, respectively) and only in reduced sharpness with PCD-CT ( P = 0.04). Tungsten K-edge imaging allowed for the visualization of the only dense structure containing it, the leaflets, and it resulted in images judged having less blooming and metallic artifacts as compared with conventional PCD-CT images ( P < 0.01). CONCLUSIONS: With PCD-CT, objective and subjective image quality of metallic and biological PHVs is improved compared with DEDL-CT. Notwithstanding the improvements in image quality, millimetric lesions attached to the structure of the valves remain a challenge for PCD-CT. Tungsten K-edge imaging allows for even further reduction of artifacts.

Electrophysiological neuromuscular alterations and severe fatigue predict long-term muscle weakness in survivors of COVID-19 acute respiratory distress syndrome.

Introduction: Long-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits. Methods: Muscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control. Results: MVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT. Discussion: Electrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.

Individual response in patient's effort and driving pressure to variations in assistance during pressure support ventilation.

BACKGROUND: During Pressure Support Ventilation (PSV) an inspiratory hold allows to measure plateau pressure (Pplat), driving pressure (∆P), respiratory system compliance (Crs) and pressure-muscle-index (PMI), an index of inspiratory effort. This study aims [1] to assess systematically how patient's effort (estimated with PMI), ∆P and tidal volume (Vt) change in response to variations in PSV and [2] to confirm the robustness of Crs measurement during PSV. METHODS: 18 patients recovering from acute respiratory failure and ventilated by PSV were cross-randomized to four steps of assistance above (+ 3 and + 6 cmH2O) and below (-3 and -6 cmH2O) clinically set PS. Inspiratory and expiratory holds were performed to measure Pplat, PMI, ∆P, Vt, Crs, P0.1 and occluded inspiratory airway pressure (Pocc). Electromyography of respiratory muscles was monitored noninvasively from body surface (sEMG). RESULTS: As PSV was decreased, Pplat (from 20.5 ± 3.3 cmH2O to 16.7 ± 2.9, P < 0.001) and ∆P (from 12.5 ± 2.3 to 8.6 ± 2.3 cmH2O, P < 0.001) decreased much less than peak airway pressure did (from 21.7 ± 3.8 to 9.7 ± 3.8 cmH2O, P < 0.001), given the progressive increase of patient's effort (PMI from -1.2 ± 2.3 to 6.4 ± 3.2 cmH2O) in line with sEMG of the diaphragm (r = 0.614; P < 0.001). As ∆P increased linearly with Vt, Crs did not change through steps (P = 0.119). CONCLUSION: Patients react to a decrease in PSV by increasing inspiratory effort-as estimated by PMI-keeping Vt and ∆P on a desired value, therefore, limiting the clinician's ability to modulate them. PMI appears a valuable index to assess the point of ventilatory overassistance when patients lose control over Vt like in a pressure-control mode. The measurement of Crs in PSV is constant-likely suggesting reliability-independently from the level of assistance and patient's effort.

Impact of COVID-19 on incidence and outcomes of post-infarction mechanical complications in Europe.

OBJECTIVES: Post-acute myocardial infarction mechanical complications (post-AMI MCs) represent rare but life-threatening conditions, including free-wall rupture, ventricular septal rupture and papillary muscle rupture. During the coronavirus disease-19 (COVID-19) pandemic, an overwhelming pressure on healthcare systems led to delayed and potentially suboptimal treatments for time-dependent conditions. As AMI-related hospitalizations decreased, limited information is available whether higher rates of post-AMI MCs and related deaths occurred in this setting. This study was aimed to assess how COVID-19 in Europe has impacted the incidence, treatment and outcome of MCs. METHODS: The CAUTION-COVID19 study is a multicentre retrospective study collecting 175 patients with post-AMI MCs in 18 centres from 6 European countries, aimed to compare the incidence of such events, related patients' characteristics, and outcomes, between the first year of pandemic and the 2 previous years. RESULTS: A non-significant increase in MCs was observed [odds ratio (OR) = 1.15, 95% confidence interval (CI) 0.85-1.57; P = 0.364], with stronger growth in ventricular septal rupture diagnoses (OR = 1.43, 95% CI 0.95-2.18; P = 0.090). No significant differences in treatment types and mortality were found between the 2 periods. In-hospital mortality was 50.9% and was higher for conservatively managed cases (90.9%) and lower for surgical patients (44.0%). Patients admitted during COVID-19 more frequently had late-presenting infarction (OR = 2.47, 95% CI 1.24-4.92; P = 0.010), more stable conditions (OR = 2.61, 95% CI 1.27-5.35; P = 0.009) and higher EuroSCORE II (OR = 1.04, 95% CI 1.01-1.06; P = 0.006). CONCLUSIONS: A non-significant increase in MCs incidence occurred during the first year of COVID-19, characterized by a significantly higher rate of late-presenting infarction, stable conditions and EuroSCORE-II if compared to pre-pandemic data, without affecting treatment and mortality.

The frail patient undergoing cardiac surgery: lessons learned and future perspectives.

Frailty is a geriatric condition characterized by the reduction of the individual's homeostatic reserves. It determines an increased vulnerability to endogenous and exogenous stressors and can lead to poor outcomes. It is an emerging concept in perioperative medicine, since an increasing number of patients undergoing surgical interventions are older and the traditional models of care seem to be inadequate to satisfy these patients' emerging clinical needs. Nowadays, the progressive technical and clinical improvements allow to offer cardiac operations to an older, sicker and frail population. For these reasons, a multidisciplinary team involving cardiac surgeons, clinical cardiologists, anesthesiologists, and geriatricians, is often needed to assess, select and provide tailored care to these high-risk frail patients to optimize clinical outcomes. There is unanimous agreement that frailty assessment may capture the individual's biological decline and the heterogeneity in risk profile for poor health-related outcomes among people of the same age. However, since commonly used preoperative scores for cardiac surgery fail to capture frailty, a specific preoperative assessment with dedicated tools is warranted to correctly recognize, measure and quantify frailty in these patients. On the contrary, pre-operative and post-operative interventions can reduce the risk of complications and support patient recovery promoting surgical resilience. Minimally invasive cardiac procedures aim to reduce surgical trauma and may be associated with better clinical outcome in this specific sub-group of high-risk patients. Among postoperative adverse events, the occurrence of delirium represents a risk factor for several unfavorable outcomes including mortality and subsequent cognitive decline. Its presence should be carefully recognized, triggering an adequate, evidence based, treatment. There is evidence, from several cross-section and longitudinal studies, that frailty and delirium may frequently overlap, with frailty serving both as a predisposing factor and as an outcome of delirium and delirium being a marker of a latent condition of frailty. In conclusion, frail patients are at increased risk to experience poor outcome after cardiac surgery. A multidisciplinary approach aimed to recognize more vulnerable individuals, optimize pre-operative conditions, reduce surgical invasivity and improve post-operative recovery is required to obtain optimal long-term outcome.

Endoscopy-based IBD identification by a quantized deep learning pipeline.

BACKGROUND: Discrimination between patients affected by inflammatory bowel diseases and healthy controls on the basis of endoscopic imaging is an challenging problem for machine learning models. Such task is used here as the testbed for a novel deep learning classification pipeline, powered by a set of solutions enhancing characterising elements such as reproducibility, interpretability, reduced computational workload, bias-free modeling and careful image preprocessing. RESULTS: First, an automatic preprocessing procedure is devised, aimed to remove artifacts from clinical data, feeding then the resulting images to an aggregated per-patient model to mimic the clinicians decision process. The predictions are based on multiple snapshots obtained through resampling, reducing the risk of misleading outcomes by removing the low confidence predictions. Each patient's outcome is explained by returning the images the prediction is based upon, supporting clinicians in verifying diagnoses without the need for evaluating the full set of endoscopic images. As a major theoretical contribution, quantization is employed to reduce the complexity and the computational cost of the model, allowing its deployment on small power devices with an almost negligible 3% performance degradation. Such quantization procedure holds relevance not only in the context of per-patient models but also for assessing its feasibility in providing real-time support to clinicians even in low-resources environments. The pipeline is demonstrated on a private dataset of endoscopic images of 758 IBD patients and 601 healthy controls, achieving Matthews Correlation Coefficient 0.9 as top performance on test set. CONCLUSION: We highlighted how a comprehensive pre-processing pipeline plays a crucial role in identifying and removing artifacts from data, solving one of the principal challenges encountered when working with clinical data. Furthermore, we constructively showed how it is possible to emulate clinicians decision process and how it offers significant advantages, particularly in terms of explainability and trust within the healthcare context. Last but not least, we proved that quantization can be a useful tool to reduce the time and resources consumption with an acceptable degradation of the model performs. The quantization study proposed in this work points up the potential development of real-time quantized algorithms as valuable tools to support clinicians during endoscopy procedures.

Cutting-edge technology and automation in the pathology laboratory.

One of the goals of pathology is to standardize laboratory practices to increase the precision and effectiveness of diagnostic testing, which will ultimately enhance patient care and results. Standardization is crucial in the domains of tissue processing, analysis, and reporting. To enhance diagnostic testing, innovative technologies are also being created and put into use. Furthermore, although problems like algorithm training and data privacy issues still need to be resolved, digital pathology and artificial intelligence are emerging in a structured manner. Overall, for the field of pathology to advance and for patient care to be improved, standard laboratory practices and innovative technologies must be adopted. In this paper, we describe the state-of-the-art of automation in pathology laboratories in order to lead technological progress and evolution. By anticipating laboratory needs and demands, the aim is to inspire innovation tools and processes as positively transformative support for operators, organizations, and patients.

Airway Closure in Patients With Cardiogenic Pulmonary Edema as a Cause of Driving Pressure Overestimation: The "Uncorking Effect".

Airway closure is an underestimated phenomenon reported in hypoxemic respiratory failure under mechanical ventilation, during cardiac arrest, and in patients who are obese. Because airway and alveolar pressure are not communicating, it leads to an overestimation of driving pressure and an underestimation of respiratory system compliance. Airway closure also favors denitrogenation atelectasis. To date, it has been described mainly in patients with ARDS and those with obesity. We describe three cases of airway closure in patients with hydrostatic pulmonary edema caused by cardiogenic shock, highlighting its resolution in a limited period of time (24 h) as pulmonary edema resolved. The waveforms show a biphasic reopening that we refer to as the "uncorking effect". The detection of airway closure may require setting positive end-expiratory pressure at or above the airway opening pressure to avoid the overestimation of driving pressure.

Safety of inter-facility transport strategies for patients referred for severe acute respiratory distress syndrome.

BACKGROUND: Inter-facility transport of patients with acute respiratory distress syndrome (ARDS) in the prone position (PP) is a high-risk situation, compared to other strategies. We aimed to quantify the prevalence of complications during transport in PP, compared to transports with veno-venous extracorporeal membrane oxygenation (VV-ECMO) or in the supine position (SP). METHODS: We performed a retrospective, single center cohort study in Lyon university hospital, France. We included patients ≥ 16 years with ARDS (Berlin definition) transported to an ARDS referral center between 01/12/2016 and 31/12/2021. We compared patients transported in PP, to those transported in SP without VV-ECMO, and those transported with VV-ECMO (in SP), by a multidisciplinary and specialized medical transport team, including an emergency physician and an intensivist. The primary outcome was the rate of transport-related complications (hypoxemia, hypotension, cardiac arrest, cannula or tube dislodgement) in each study groups, compared using a Fisher test. RESULTS: One hundred thirty-four patients were enrolled (median PaO2/FiO2 70 [58-82] mmHg), of which 11 (8%) were transported in PP, 44 (33%) with VV-ECMO, and 79 (59%) in SP. The most frequent risk factor for ARDS in the PP group was bacterial pneumonitis, and viral pneumonitis in the other 2 groups. Transport-related complications occurred in 36% (n = 4) of transports in PP, compared to 39% (n = 30) in SP and 14% (n = 6) with VV-ECMO, respectively (p = 0.33). VV-ECMO implantation after transport was not different between SP and PP patients (n = 7, 64% vs. n = 31, 39%, p = 0.19). CONCLUSIONS: In the context of a specialized multi-disciplinary ARDS transport team, transport-related complication rates were similar between patients transported in PP and SP, while there was a trend of lower rates in patients transported with VV-ECMO.