Mechanical power normalized to aerated lung predicts noninvasive ventilation failure and death and contributes to the benefits of proning in COVID-19 hypoxemic respiratory failure.

Background: Concern exists that noninvasive ventilation (NIV) may promote ventilation-induced lung injury(VILI) and worsen outcome in acute hypoxemic respiratory failure (AHRF). Different individual ventilatory variables have been proposed to predict clinical outcomes, with inconsistent results.Mechanical power (MP), a measure of the energy transfer rate from the ventilator to the respiratory system during mechanical ventilation, might provide solutions for this issue in the framework of predictive, preventive and personalized medicine (PPPM). We explored (1) the impact of ventilator-delivered MP normalized to well-aerated lung (MPWAL) on physio-anatomical and clinical responses to NIV in COVID-19-related AHRF and (2) the effect of prone position(PP) on MPWAL. Methods: We analyzed 216 noninvasively ventilated COVID-19 patients (108 patients receiving PP + NIV and 108 propensity score-matched patients receiving supine NIV) with moderate-to-severe(paO2/FiO2 ratio < 200) AHRF enrolled in the PRO-NIV controlled non-randomized study (ISRCTN23016116).Quantification of differentially aerated lung volumes by lung ultrasonography (LUS) was validated against CT scans. Respiratory parameters were hourly recorded, ABG were performed 1 h after each postural change. Time-weighed average values of ventilatory variables, including MPWAL, and gas exchange parameters (paO2/FiO2 ratio, dead space indices) were calculated for each ventilatory session. LUS and circulating biomarkers were assessed daily. Results: Compared with supine position, PP was associated with a 34% MPWAL reduction, attributable largely to an absolute MP reduction and secondly to an enhanced lung reaeration.Patients receiving a high MPWAL during the 1st 24 h of NIV [MPWAL(day 1)] had higher 28-d NIV failure (HR = 4.33,95%CI:3.09 - 5.98) and death (HR = 5.17,95%CI: 3.01 - 7.35) risks than those receiving a low MPWAL(day 1).In Cox multivariate analyses, MPWAL(day 1) remained independently associated with 28-d NIV failure (HR = 1.68,95%CI:1.15-2.41) and death (HR = 1.69,95%CI:1.22-2.32).MPWAL(day 1) outperformed other power measures and ventilatory variables as predictor of 28-d NIV failure (AUROC = 0.89;95%CI:0.85-0.93) and death (AUROC = 0.89;95%CI:0.85-0.94).MPWAL(day 1) predicted also gas exchange, ultrasonographic and inflammatory biomarker responses, as markers of VILI, on linear multivariate analysis. Conclusions: In the framework of PPPM, early bedside MPWAL calculation may provide added value to predict response to NIV and guide subsequent therapeutic choices i.e. prone position adoption during NIV or upgrading to invasive ventilation, to reduce hazardous MPWAL delivery, prevent VILI progression and improve clinical outcomes in COVID-19-related AHRF. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00325-5.

Mechanical Power Delivered by Noninvasive Ventilation Contributes to Physio-Anatomical and Clinical Responses to Early Versus Late Proning in COVID-19 Pneumonia.

OBJECTIVES: To study: 1) the effect of prone position (PP) on noninvasive ventilation (NIV)-delivered mechanical power (MP) and 2) the impact of MP on physio-anatomical and clinical responses to early versus late PP in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. DESIGN: Nonrandomized trial with inverse probability of treatment weighted-matched groups. SETTING: HUMANITAS Gradenigo Sub-ICU. PATIENTS: One hundred thirty-eight SARS-CoV-2 pneumonia patients with moderate-to-severe acute hypoxemic respiratory failure (Pa o2 /F io2 ratio < 200 mm Hg) receiving NIV from September 1, 2020, to February 28, 2021 (Ethics approval: ISRCTN23016116). INTERVENTIONS: Early PP or late PP or supine position. MEASUREMENTS AND MAIN RESULTS: Respiratory parameters were hourly recorded. Time-weighted average MP values were calculated for each ventilatory session. Gas exchange parameters and ventilatory ratio (VR) were measured 1 hour after each postural change. Lung ultrasonographic scores and circulating biomarkers were assessed daily. MP delivered during the initial 24 hours of NIV (MP [first 24 hr]) was the primary exposure variable. Primary outcomes: 28-day endotracheal intubation and death. Secondary outcomes: oxygen-response, C o2 -response, ultrasonographic, and systemic inflammatory biomarker responses after 24 hours of NIV. Fifty-eight patients received early PP + NIV, 26 late PP + NIV, and 54 supine NIV. Early PP group had lower 28-day intubation and death than late PP (hazard ratio [HR], 0.35; 95% CI, 0.19-0.69 and HR, 0.26; 95% CI, 0.07-0.67, respectively) and supine group. In Cox multivariate analysis, (MP [first 24 hr]) predicted 28-day intubation (HR, 1.70; 95% CI, 1.25-2.09; p = 0.009) and death (HR, 1.51; 95% CI, 1.19-1.91; p = 0.007). Compared with supine position, PP was associated with a 35% MP reduction. VR, ultrasonographic scores, and inflammatory biomarkers improved after 24 hours of NIV in the early PP, but not in late PP or supine group. A MP (first 24 hr) greater than or equal to 17.9 J/min was associated with 28-day death (area under the curve, 0.92; 95% CI, 0.88-0.96; p < 0.001); cumulative hours of MP greater than or equal to 17.9 J/min delivered before PP initiation attenuated VR, ultrasonographic, and biomarker responses to PP. CONCLUSIONS: MP delivered by NIV during initial 24 hours predicts clinical outcomes. PP curtails MP, but cumulative hours of NIV with MP greater than or equal to 17.9 J/min delivered before PP initiation attenuate the benefits of PP.

Mesenchymal Stem Cell-Derived Extracellular Vesicles Protect Human Corneal Endothelial Cells from Endoplasmic Reticulum Stress-Mediated Apoptosis.

Corneal endothelial dystrophy is a relevant cause of vision loss and corneal transplantation worldwide. In the present study, we analyzed the effect of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in an in vitro model of corneal dystrophy, characterized by endoplasmic reticulum stress. The effects of MSC-EVs were compared with those of serum-derived EVs, reported to display a pro-angiogenic activity. MSC-EVs were able to induce a significant down-regulation of the large majority of endoplasmic reticulum stress-related genes in human corneal endothelial cells after exposure to serum deprivation and tunicamycin. In parallel, they upregulated the Akt pathway and limited caspase-3 activation and apoptosis. At variance, the effect of the serum EVs was mainly limited to Akt phosphorylation, with minimal or absent effects on endoplasmic reticulum stress modulation and apoptosis prevention. The effects of MSC-EVs were correlated to the transfer of numerous endoplasmic reticulum (ER)-stress targeting miRNAs to corneal endothelial cells. These data suggest a potential therapeutic effect of MSC-EVs for corneal endothelial endoplasmic reticulum stress, a major player in corneal endothelial dystrophy.

Effect of Stem Cell-Derived Extracellular Vesicles on Damaged Human Corneal Endothelial Cells.

PURPOSE: Human corneal endothelial cells (HCECs) are essential to visual function; however, since they have limited proliferative capacity in vivo, they are prone to corneal endothelial dysfunction. At present, the only treatment is a corneal transplantation from donor cadavers. Also, due to a global shortage of donor corneas, it is important to find alternative strategies. Recent studies highlight that stem cell-derived extracellular vesicles (EVs) play a relevant role in stem cell-induced regeneration by reprogramming injured cells and inducing proregenerative pathways. The aim of this work is to evaluate whether EVs derived from mesenchymal stem cells (MSC-EVs) are able to promote regeneration of damaged HCECs. METHODS: We isolated HCECs from discarded corneas in patients undergoing corneal transplantation or enucleation (N = 23 patients). Bone marrow mesenchymal stem cells (MSCs) were obtained from Lonza, cultured, and characterized. MSC-EVs were obtained from supernatants of MSCs. In order to establish a valid in vitro damage model to test the regenerative potential of EVs on HCECs, we evaluated the proliferation rate and the apoptosis after exposing the cells to serum-deprived medium at different concentrations for 24 hours. We then evaluated the HCEC migration through a wound healing assay. RESULTS: In the selected serum deprivation damage conditions, the treatment with different doses of MSC-EVs resulted in a significantly higher proliferation rate of HCECs at all the tested concentrations of EVs (5-20 × 103 MSC-EV/cell). MSC-EVs/cell induced a significant decrease in number of total apoptotic cells after 24 hours of serum deprivation. Finally, the wound healing assay showed a significantly faster repair of the wound after HCEC treatment with MSC-EVs. CONCLUSIONS: Results highlight the already well-known proregenerative potential of MSC-EVs in a totally new biological model, the endothelium of the cornea. MSC-EVs, indeed, induced proliferation and survival of HCECs, promoting the migration of HCECs in vitro.

Tuning of the spin distribution between ligand- and metal-based spin: electron paramagnetic resonance of mixed-ligand molybdenum tris(dithiolene) complex anions.

Electron paramagnetic resonance spectra of homoleptic and mixed-ligand molybdenum tris(dithiolene) complex anions [Mo(tfd)(m)(bdt)(n)](-) (n + m = 3; bdt = S(2)C(6)H(4); tfd = S(2)C(2)(CF(3))(2)) reveal that the spin density has mixed metal-ligand character with more ligand-based spin for [Mo(tfd)(3)](-) and a higher degree of metal-based spin for [Mo(bdt)(3)](-): the magnitude of the isotropic (95,97)Mo hyperfine interaction increases continuously, by a factor of 2.5, on going from the former to the latter. The mixed complexes fall in between, and the metal character of the spin increases with the bdt content. The experiments were corroborated by density functional theory computations, which reproduce this steady increase in metal-based character.

Kinetic hydrogen/deuterium effects in the direct hydrogenation of ketones catalyzed by a well-defined ruthenium diphosphine diamine complex.

The trans-dihydride complex trans-RuH(2)(NH(2)CMe(2)CMe(2)NH(2))((R)-binap) (1) is an active catalyst for the homogeneous hydrogenation of ketones in benzene under pressure of H(2) gas. The mechanism of the catalysis is proposed to occur through a rapid transfer of a hydride from the ruthenium and a proton from the amine on 1 to the carbonyl of the ketone to give the product alcohol and a hydrido-amido intermediate RuH(NHCMe(2)CMe(2)NH(2))((R)-binap) (2). The dihydride is then regenerated by the turnover-limiting heterolytic splitting of dihydrogen by complex 2. In this work the kinetic isotope effect (KIE) is measured to be 2.0 (+/-0.1) for the reduction of acetophenone to 1-phenylethanol catalyzed by 1 using 8.0 atm of H(2) versus D(2) gas. DFT calculations predict a KIE of 2.1 for the described mechanism using the simplified catalyst RuH(NHCH(2)CH(2)NH(2))(PH(3))(2) with H(2) or the catalyst RuD(NDCH(2)CH(2)ND(2))(PH(3))(2) with D(2). This supports the observation that deuterium scrambles into the catalyst when a pressure of D(2) is used. We discuss the significance of these results relative to the KIE of 2 that was reported by Sandoval et al. (J. Am. Chem. Soc. 2003 125, 13490) for the hydrogenation/deuteriation of acetophenone catalyzed by trans-RuH(eta(1)-BH(4))((S)-tolbinap)((S,S)-dpen) in basic isopropanol/isopropanol-d(8).

Synthesis and characterization of iron(II) complexes with tetradentate diiminodiphosphine or diaminodiphosphine ligands as precatalysts for the hydrogenation of acetophenone.

Six complexes of the type trans-[Fe(NCMe)2(P-N-N-P)]X2 (X = BF4(-), B{Ar(f)}4(-)) (Ar(f) = 3,5-(CF3)2C6H3) containing diiminodiphosphine ligands and the complexes trans-[Fe(NCMe)2(P-NH-NH-P)][BF4]2 with a diaminodiphosphine ligand were obtained by the reaction of Fe(II) salts with achiral and chiral P-N-N-P or P-NH-NH-P ligands, respectively, in acetonitrile at ambient temperature. The P-N-N-P ligands are derived from reaction of ortho-diphenylphosphinobenzaldehyde with the diamines 1,2-ethylenediamine, 1,3-propylenediamine, (S,S)-1,2-disopropyl-1,2-diaminoethane, and (R,R)-1,2-diphenyl-1,2-diaminoethane. Some complexes could also be obtained for the first time in a one-pot template synthesis under mild reaction conditions. Single crystal X-ray diffraction studies of the complexes revealed a trans distorted octahedral structure around the iron. The iPr or Ph substituents on the diamine were found to be axial in the five-membered Fe-N-CHR-CHR-N- ring of the chiral P-N-N-P ligands. A steric clash between the imine hydrogen and the substituent probably determines this stereochemistry. The diaminodiphosphine complex has longer Fe-N and Fe-P bonds than the analogous diiminodiphosphine complex. The new iron compounds were used as precatalysts for the hydrogenation of acetophenone. The complexes without axial substituents on the diamine had moderate catalytic activity while that with axial Ph substituents had low activity but fair (61%) enantioselectivity for the asymmetric hydrogenation of acetophenone. The fact that the diaminodiphosphine complex has a slightly higher activity than the corresponding diiminodiphosphine complex suggests that hydrogenation of the imine groups in the P-N-N-P ligand may be important for catalyst activation. Evidence is provided, including the first density-functional theory calculations on iron-catalyzed outer-sphere ketone hydrogenation, that the mechanism is similar to that of ruthenium analogues.