Explainable Machine Learning Model to Preoperatively Predict Postoperative Complications in Inpatients With Cancer Undergoing Major Operations.

PURPOSE: Preoperative prediction of postoperative complications (PCs) in inpatients with cancer is challenging. We developed an explainable machine learning (ML) model to predict PCs in a heterogenous population of inpatients with cancer undergoing same-hospitalization major operations. METHODS: Consecutive inpatients who underwent same-hospitalization operations from December 2017 to June 2021 at a single institution were retrospectively reviewed. The ML model was developed and tested using electronic health record (EHR) data to predict 30-day PCs for patients with Clavien-Dindo grade 3 or higher (CD 3+) per the CD classification system. Model performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), and calibration plots. Model explanation was performed using the Shapley additive explanations (SHAP) method at cohort and individual operation levels. RESULTS: A total of 988 operations in 827 inpatients were included. The ML model was trained using 788 operations and tested using a holdout set of 200 operations. The CD 3+ complication rates were 28.6% and 27.5% in the training and holdout test sets, respectively. Training and holdout test sets' model performance in predicting CD 3+ complications yielded an AUROC of 0.77 and 0.73 and an AUPRC of 0.56 and 0.52, respectively. Calibration plots demonstrated good reliability. The SHAP method identified features and the contributions of the features to the risk of PCs. CONCLUSION: We trained and tested an explainable ML model to predict the risk of developing PCs in patients with cancer. Using patient-specific EHR data, the ML model accurately discriminated the risk of developing CD 3+ complications and displayed top features at the individual operation and cohort level.

"Every Cloud Has a Silver Lining": How Three Rare Diseases Defend Themselves from COVID-19 and What We Have Learnt from It.

The process of SARS-CoV-2 infection, responsible for the COVID-19 pandemic, is carried out through different steps, with the interaction between ACE2 and Spike protein (S) being crucial. Besides of that, the acidic environment of endosomes seems to play a relevant role in the virus uptake into cells and its intracellular replication. Patients affected by two rare genetic tubulopathies, Gitelman's and Bartter's Syndromes, and a rare genetic metabolic disease, Fabry Disease, have shown intrinsic protection from SARS-CoV-2 infection and COVID-19 on account of specific intrinsic features that interfere with the virus uptake into cells and its intracellular replication, which will be reported and discussed in this paper, providing interesting insights for present and future research.

Unlocking mechanosensitivity: integrins in neural adaptation.

Mechanosensitivity extends beyond sensory cells to encompass most neurons in the brain. Here, we explore recent research on the role of integrins, a diverse family of adhesion molecules, as crucial biomechanical sensors translating mechanical forces into biochemical and electrical signals in the brain. The varied biomechanical properties of neuronal integrins, including their force-dependent conformational states and ligand interactions, dictate their specific functions. We discuss new findings on how integrins regulate filopodia and dendritic spines, shedding light on their contributions to synaptic plasticity, and explore recent discoveries on how they engage with metabotropic receptors and ion channels, highlighting their direct participation in electromechanical transduction. Finally, to facilitate a deeper understanding of these developments, we present molecular and biophysical models of mechanotransduction.

Hydrogen sulfide dysfunction in metabolic syndrome-associated vascular complications involves cGMP regulation through soluble guanylyl cyclase persulfidation.

Here, by using in vitro and ex vivo approaches, we elucidate the impairment of the hydrogen sulfide (H2S) pathway in vascular complications associated with metabolic syndrome (MetS). In the in vitro model simulating hyperlipidemic/hyperglycemic conditions, we observe significant hallmarks of endothelial dysfunction, including eNOS/NO signaling impairment, ROS overproduction, and a reduction in CSE-derived H2S. Transitioning to an ex vivo model using db/db mice, a genetic MetS model, we identify a downregulation of CBS and CSE expression in aorta, coupled with a diminished L-cysteine-induced vasorelaxation. Molecular mechanisms of eNOS/NO signaling impairment, dissected using pharmacological and molecular approaches, indicate an altered eNOS/Cav-1 ratio, along with reduced Ach- and Iso-induced vasorelaxation and increased L-NIO-induced contraction. In vivo treatment with the H2S donor Erucin ameliorates vascular dysfunction observed in db/db mice without impacting eNOS, further highlighting a specific action on smooth muscle component rather than the endothelium. Analyzing the NO signaling pathway in db/db mice aortas, reduced cGMP levels were detected, implicating a defective sGC/cGMP signaling. In vivo Erucin administration restores cGMP content. This beneficial effect involves an increased sGC activity, due to enzyme persulfidation observed in sGC overexpressed cells, coupled with PDE5 inhibition. In conclusion, our study demonstrates a pivotal role of reduced cGMP levels in impaired vasorelaxation in a murine model of MetS involving an impairment of both H2S and NO signaling. Exogenous H2S supplementation through Erucin represents a promising alternative in MetS therapy, targeting smooth muscle cells and supporting the importance of lifestyle and nutrition in managing MetS.

Effect of Kinesio taping on wrist proprioception in healthy subjects: A randomized clinical trial.

BACKGROUND: Although the use of KT has increased considerably in the clinical practice in the last years, there is limited evidence about the effects of its application in proprioception. PURPOSE: The aim of this study was to determine the effect of KT on joint position sense and force sense on the wrist of healthy subjects. METHODS: Fifty-four subjects were analyzed in a randomized, crossover, single-blind study design. To determine the force sense, the subjects had to reach 50% of their maximum grip force. Wrist joint position sense was assessed during active repositioning tests at the target angles of 30° flexion and extension of wrist. A digital dynamometer was used to determine the sense of force and a digital goniometer was used to determine the joint position sense. Subjects were evaluated with KT (I- strip on ventral aspect of forearms from origin to insertion) and placebo (an inelastic tape was applied following the same procedure as KT). RESULTS: No significant differences have been found in the force sense, neither in the comparisons between control and interventions (p=0.286), nor between pre and post-intervention (p=0.111). For wrist joint position sense, a statistically significant effect (p< 0.05) was found at 30º of extension between the control and experimental group in favor of the control group. CONCLUSIONS: The application of KT did not produce changes in FS and only caused a significant improvement in JPS in extension (30º). The results appear to indicate that the application of KT to improve proprioception in healthy subjects should be reconsidered.

The Ultrasound Renal Stress Test for the Assessment of Functional Renal Reserve in Kidney Transplantation: A Pilot Study in Living Donors.

In the evolving landscape of nephrology and kidney transplants, assessing renal functional reserve (RFR) in living kidney donors is essential for ensuring donor safety and successful transplantation. This study explores the use of the Intra-Parenchymal Renal Resistive Index Variation (IRRIV) test, a novel non-invasive method, to measure RFR in living donors. Our observational study included 11 participants undergoing living kidney donations, evaluated using the IRRIV-based Renal Stress Test (RST) before and 12 months post-nephrectomy. The study demonstrated significant changes in creatinine and eGFR CKD-EPI levels post-donation, with an average creatinine rise from 69 to 97 µmol/L and a reduction in eGFR from 104 to 66 mL/min/1.73 m2. These variations align with the expected halving of nephron mass post-nephrectomy and the consequent recruitment of RFR and hyperfiltration in the remaining nephrons. This pilot study suggests that the IRRIV-based RST is a practical, safe, and reproducible tool, potentially revolutionizing the assessment of RFR in living kidney donors, with implications for broader clinical practice in donor eligibility evaluation, even in borderline renal cases. Furthermore, it confirms the feasibility of RST in living kidney donors and allows us to assess the sample size in 48 donors for a future study.

Identification of compounds present in lipophilic extracts from Brachystola magna (Girard): substances with potential healing properties.

Insects from the Orthoptera order possess important biological activities such as wound healing and represent a therapeutic resource in traditional medicine worldwide. Hence, this study addressed the characterisation of lipophilic extracts from Brachystola magna (Girard), identifying compounds with potential healing properties. For that, four extracts were obtained from sample 1 (head-legs) and sample 2 (abdomen): extract A (hexane/sample 1), extract B (hexane/sample 2), extract C (ethyl acetate/sample 1) and extract D (ethyl acetate/sample 2). All extracts were analysed by Gas Chromatography-Mass Spectrometry (GC-MS), Gas Chromatography-Flame Ionization Detection (GC-FID) and Fourier-Transform Infrared Spectroscopy (FTIR). Compounds identified were squalene, cholesterol and fatty acids, having a higher concentration of linolenic acid in extracts A and B, while extracts C and D had a higher content of palmitic acid. Additionally, FTIR detected characteristic peaks of lipids and triglycerides. Components of the lipophilic extracts suggested that this product could be used for skin illnesses treatment.

Indirect cardiac output assessment in a swine pediatric acute respiratory distress syndrome model.

PURPOSE: To investigate the correlation between volume of carbon dioxide elimination (V̇CO2) and end-tidal carbon dioxide (PETCO2) with cardiac output (CO) in a swine pediatric acute respiratory distress syndrome (ARDS) model. METHODS: Respiratory and hemodynamic variables were collected from twenty-six mechanically ventilated juvenile pigs under general anesthesia before and after inducing ARDS, using oleic acid infusion. RESULTS: Prior to ARDS induction, mean (SD) CO, V̇CO2, PETCO2, and dead space to tidal volume ratio (Vd/Vt) were 4.16 (1.10) L/min, 103.69 (18.06) ml/min, 40.72 (3.88) mmHg and 0.25 (0.09) respectively. Partial correlation coefficients between average CO, V̇CO2, and PETCO2 were 0.44 (95% confidence interval: 0.18-0.69) and 0.50 (0.18-0.74), respectively. After ARDS induction, mean CO, V̇CO2, PETCO2, and Vd/Vt were 3.33 (0.97) L/min, 113.71 (22.97) ml/min, 50.17 (9.73) mmHg and 0.40 (0.08). Partial correlations between CO and V̇CO2 was 0.01 (-0.31 to 0.37) and between CO and PETCO2 was 0.35 (-0.002 to 0.65). CONCLUSION: ARDS may limit the utility of volumetric capnography to monitor CO.

Spin-Vibronic Dynamics in Open-Shell Systems beyond the Spin Hamiltonian Formalism.

Vibronic coupling has a dramatic influence over a large number of molecular processes, ranging from photochemistry to spin relaxation and electronic transport. The simulation of vibronic coupling with multireference wave function methods has been largely applied to organic compounds, and only early efforts are available for open-shell systems such as transition metal and lanthanide complexes. In this work, we derive a numerical strategy to differentiate the molecular electronic Hamiltonian in the context of multireference ab initio methods and inclusive of spin-orbit coupling effects. We then provide a formulation of open quantum system dynamics able to predict the time evolution of the electron density matrix under the influence of a Markovian phonon bath up to fourth-order perturbation theory. We apply our method to Co(II) and Dy(III) molecular complexes exhibiting long spin relaxation times and successfully validate our strategy against the use of an effective spin Hamiltonian. Our study sheds light on the nature of vibronic coupling, the importance of electronic excited states in spin relaxation, and the need for high-level computational chemistry to quantify it.

EBV Reactivation in Transplant Recipients following SARS-CoV-2 Infection: A Retrospective Study.

Reactivation and primary infection with a high Epstein Barr Virus (EBV) DNA level in kidney transplant patients could cause severe complications, including the development of Post-Transplantation Lymphoproliferative Disease (PTLD). While in the general population the reactivation of EBV after SARS-CoV-2 infection has been reported, very few data are available in transplant recipients. Our retrospective study aimed to evaluate a possible EBV reactivation in kidney transplant patients following SARS-CoV-2 infection and a possible impairment of the immune system. In addition, the effects of changes in immunosuppressive therapy on EBV DNA reactivation and vaccination were also evaluated. A total of 166 kidney transplant patients followed at the Kidney-Pancreas Transplant Ambulatory Nephrology Unit at Padova University Hospital were retrospectively considered for an observation period of 6 months from January 2020 to April 2023. EBV DNA level was measured by Rt-PCR and evaluated 6 months before and after SARS-CoV-2 infection. Patients' serological states were established via quantification of anti-VCA and anti-EBNA (chemiluminescence). Patients' immune systems were characterized by CD4+/CD8+ lymphocyte ratio (flow cytometry). EBV DNA was reactivated in 50% of the 166 patients with COVID-19 who completed the study. Older patients with more severe forms of COVID-19 had higher EBV reactivation (p < 0.05). EBV reactivation significantly increased in patients with severe SARS-CoV-2 infection requiring hospitalization compared to patients managed at home (p < 0.001). CD4+/CD8+ lymphocyte ratio was reduced in patients with a younger age of transplant (p < 0.01) and on a higher dose of steroids (p < 0.01). The results of our study confirm the role of immunodepression, especially in recent transplant patients and those on high steroids, in EBV reactivation. These results combined with the few available in the literature might contribute to providing an optimal management of immunosuppressive treatment for these patients in order to obtain an immune state unfavorable to the activation of latent viruses, including EBV.

Varicella Zoster vaccination in hemodialysis patients: The state of the art.

Varicella Zoster Virus (VZV) infection is a common childhood exanthematous disease, which in adults and immunocompromised people may result in severe neurologic complications. Up to one-third of infected subjects may have VZV clinical reactivation particularly if immunocompromised. Patients affected by end-stage renal disease on hemodialysis present immunodepression that contributes to their higher incidence of VZV infections and reactivation. While antiviral treatment in these patients shows low efficacy, the prevention of VZV through vaccination avoids the primary infection and the risk of reactivation. Two VZV vaccines are currently available: the live attenuate Zoster Vaccine (LZV) and a Recombinant Zoster Vaccine (RZV), with the latter appearing to provide greater efficacy. Given the higher incidence of VZV infection and reactivation, the lesser response to antivirals and the lower impact of VZ vaccine in hemodialysis patients in terms of side effects, a higher diffusion of VZV vaccination should be promoted by nephrologists in these patients in particular in those with future transplant opportunities.

The RAAS Goodfellas in Cardiovascular System.

In the last two decades, the study of the renin-angiotensin-aldosterone system (RAAS) has revealed a counterregulatory protective axis. This protective arm is characterized by ACE2/Ang 1-7/MasR and Ang 1-9 that largely counteracts the classic arm of the RAAS mediated by ACE/Ang II/AT1R/aldosterone and plays an important role in the prevention of inflammation, oxidative stress, hypertension, and cardiovascular remodeling. A growing body of evidence suggests that enhancement of this counterregulatory arm of RAAS represents an important therapeutic approach to facing cardiovascular comorbidities. In this review, we provide an overview of the beneficial effects of ACE2, Ang 1-7/MasR, and Ang 1-9 in the context of oxidative stress, vascular dysfunction, and organ damage.

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Nanoscale organization of CaV2.1 splice isoforms at presynaptic terminals: implications for synaptic vesicle release and synaptic facilitation.

The distance between CaV2.1 voltage-gated Ca2+ channels and the Ca2+ sensor responsible for vesicle release at presynaptic terminals is critical for determining synaptic strength. Yet, the molecular mechanisms responsible for a loose coupling configuration of CaV2.1 in certain synapses or developmental periods and a tight one in others remain unknown. Here, we examine the nanoscale organization of two CaV2.1 splice isoforms (CaV2.1[EFa] and CaV2.1[EFb]) at presynaptic terminals by superresolution structured illumination microscopy. We find that CaV2.1[EFa] is more tightly co-localized with presynaptic markers than CaV2.1[EFb], suggesting that alternative splicing plays a crucial role in the synaptic organization of CaV2.1 channels.

Bioelectrical impedance analysis in patients with posterior vitreous detachment.

OBJECTIVE: The purpose of the study is to assess body hydration in patients with posterior vitreous detachment (PVD) by bioelectrical impedance analysis (BIA). PVD, one of the most common eye diseases, is associated in both research and the collective image with reduced daily water intake, but this finding is not supported by strong evidence in the literature. PATIENTS AND METHODS: Based on Spectral Domain Optical Coherence Tomography (SD-OCT) evaluation, different PVD stages are identified: absent posterior vitreous detachment, partial posterior vitreous detachment (P-PVD), or complete posterior vitreous detachment (C-PVD). BIA is a simple, non-invasive bedside method used to assess body composition. Patients underwent BIA and completed a floaters symptoms. 30 patients were enrolled and divided into two groups according to the degree of vitreous detachment, in P-PVD (n=12) and C-PVD (n=18). Patients underwent BIA and completed a floaters symptoms questionnaire. BIA measured the Resistance (R), Reactance (Xc), Phase Angle (PhA), Total Body Water (TBW), Extracellular Water (ECW), Fat Mass (FM), Fat-Free Mass (FFM), and Body Cell Mass Index (BCMI). Finally, patients received a test to assess adherence to the Mediterranean diet (Mediterranean Diet Test Score, MDTS) with the addition of daily water intake. RESULTS: Relevant data were obtained from the BIA evaluation: the values of R and Xc were lower in the P-PVD group than C-PVD group (respectively 417.08±58.12 Ω vs. 476.94±51.29 Ω p=0.006 and 41.33±8.23 Ω vs. 50.61±7.98 Ω p=0.004). Instead, patients in the P-PVD group reported higher values of TBW and ECW than C-PVD group (respectively 44.13±7.57 L vs. 37.96±6.27 L p=0.021 and 21.03±4.06 L vs. 17.24±2.63 L p=0.004). CONCLUSIONS: In the present study, we reported a significant correlation between vitreous pathology and anthropometric and BIA measurements.

Safety profile and SARS-CoV-2 breakthrough infections among HCWs receiving anti-SARS-CoV-2 and influenza vaccines simultaneously: an Italian observational study.

In October/December 2021, World Health Organization and other international agencies recommended the offer of the third dose of anti-SARS-CoV-2 vaccine. In this period, the routine offer of seasonal influenza vaccination was also guaranteed and simultaneous administration of the two vaccines was encouraged. This study aims to evaluate the safety profile and to estimate the incidence of SARS-CoV-2 breakthrough infections in subjects receiving the anti-SARS-CoV-2 and influenza vaccines simultaneously. The study population was represented by healthcare workers (HCWs) of Bari Policlinico General Hospital who received the influenza (Flucelvax Tetra®) and/or anti-SARS-CoV-2 vaccination (BNT162b2 mRNA COVID-19 vaccine, Comirnaty®) either in coadministration or separately in October 2021. Reports of adverse events following immunization (AEFIs) were investigated to study the safety of both vaccines in coadministration and in separate-instance administration. Post-vaccination SARS-CoV-2 breakthrough infection was also studied. 942 HCWs accepted to join our study. 610/942 received both vaccines simultaneously. 25.26 % subjects (238/942) were only vaccinated against SARS-CoV-2, while the remaining 94 HCWs received the influenza vaccination first and subsequently received the anti-SARS-CoV2 booster dose. 717 HCWs reported AEFIs (Reporting Rate 76.1 per 100 subjects). Simultaneous administration of the two vaccines was not related with an increase of the rate of AEFIs compared to the single administration of SARS-CoV-2 vaccine, but the AEFIs' rate was lower among subjects who received only influenza vaccine. Post-vaccination SARS-CoV-2 infections were notified for 41.5 % of enrolled subjects (391/942). Incidence of breakthrough infection and symptomatic disease was not significantly different between the simultaneous administration group and other subjects. Our data suggests that simultaneous administration of a quadrivalent influenza vaccine and an mRNA anti-SARS-CoV-2 vaccine neither affected the safety of said products nor was associated with a higher risk of SARS-CoV-2 breakthrough infection.

Base metal complexes featuring a new pyrazole-derived PCP pincer ligand.

A new pyrazole-derived PCP pincer ligand featuring a 1-methylpyrazole backbone tethered to two di(isopropyl)phosphine moieties via phenylene spacers (P(CH)P-iPr) was prepared. When reacting the ligand with group six carbonyl complexes [M(CO)6] (M = Cr, Mo, W) at 130 °C, complexes of the type [M(κ2PN-PCP-iPr)(CO)4] were obtained featuring a κ2P,N-bound ligand with a pendant phosphine arm. Upon an increase of the reaction temperature to 150 °C, in the case of molybdenum, the formation of the complex [Mo(κ3PCP-PCP-iPr)(CO)3] was observed featuring a weak Mo-C bond. DFT calculations reveal that there is no agostic η2-C-H interaction. Treatment of [Mn2(CO)10], [Fe2(CO)9], [Co2(CO)8] and [Ni(COD)2] afforded complexes [Mn(κ3PCP-PCP-iPr)(CO)3], [Fe(κ3PCP-PCP-iPr)(H)(CO)2], [Co(κ3PCP-PCP-iPr)(CO)2] and [Ni(κ3PCP-PCP-iPr)(H)], respectively, where the PCP ligand is coordinated in the typical meridional κ3-fashion. Postfunctionalization of the anionic PCP pincer ligand was possible via N-methylation of the second nitrogen atom of the pyrazole unit with the oxonium salt [Me3O]BF4. Treatment of [Mn(κ3PCP-PCP-iPr)(CO)3] and [Fe(κ3PCP-PCP-iPr)(H)(CO)2] with [Me3O]BF4 resulted in the formation of the cationic complexes [Mn(κ3PCP-PCPMe-iPr)(CO)3]+ and [Fe(κ3PCP-PCPMe-iPr)(Cl)(CO)2]+. In the case of the latter, the chloride ligand seems to originate from the solvent CH2Cl2 undergoing a hydride chloride exchange. All complexes were characterized by means of 1H, 13C{1H}, and 31P{1H} NMR spectroscopy, IR spectroscopy and HR-MS. In addition, the structures of representative complexes were determined by X-ray crystallography.