The OpenMolcas Web: A Community-Driven Approach to Advancing Computational Chemistry.

The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations.

Identification of a Novel Score for Adherence to the Mediterranean Diet That Is Inversely Associated with Visceral Adiposity and Cardiovascular Risk: The Chrono Med Diet Score (CMDS).

Adherence to the Mediterranean diet (MedDiet) leads to reduction of mortality from all causes, especially in subjects with cardiovascular disease, obesity, and diabetes. Numerous scores have been proposed to evaluate the adherence to MedDiet, mainly focused on eating habits. In this study, we verified whether existing validated MedDiet scores, namely, MEDI-LITE and the Mediterranean Diet Score (MDS), could be associated with visceral adiposity. Failing to find a significant association with adiposity, we proposed the validation of a new, easy-to-use adherence questionnaire, the Chrono Med-Diet score (CMDS). CMDS contains eleven food categories, including chronobiology of dietary habits and physical activity. Compared to the MEDI-LITE score and MDS, low values of CMDS are linked to increased waist circumference (WC) and dysmetabolic conditions. CMDS was also inversely correlated with cardiovascular risk (CVR), as well as Fatty Liver Index (FLI). In conclusion, the CMDS is a novel questionnaire to study the adherence to the MedDiet that, focusing on type and timing of carbohydrates intake, has the peculiar capability of capturing subjects with abdominal obesity, thus being an easy-to-use instrument of personalized medicine.

Adverse Maternal Outcomes in Pregnant Women Affected by Severe-Critical COVID-19 Illness: Correlation with Vaccination Status in the Time of Different Viral Strains' Dominancy.

This is a monocentric and cross-sectional study conducted at the COVID-19 Division of the Obstetrical and Gynecological Unit and Intensive Care Units (ICUs) of Policlinico di Bari, in Bari, Italy, between September 2020 and April 2022. This study aimed to identify the prevalence of severe-critical COVID-19 illness requiring access to the Intensive Care Unit (ICU) among 287 pregnant patients, and possible correlations between the SARS-CoV-2 variants, the specific pandemic wave (dominated by wild, Alpha, Delta, and Omicron strains), and severe-critical adverse maternal outcomes. The prevalence of severe-critical COVID-19 illness was 2.8% (8/287), reaching 4.9% (8/163) excluding the 4th wave (Omicron dominant). The Delta variant determined the highest risk ratio and odds for access to the ICU due to severe-critical COVID-19-related symptoms compared to the other variants (wild, Alpha, Omicron). During the third wave (Delta), the ICU cases underwent a higher rate of hyperimmune plasma infusion (75%), antibiotic therapy (75%), and remdesivir (33%); all of the patients were intubated. During the Omicron wave, the patients were asymptomatic or with few symptoms: most of them (70%) were vaccinated with a median of two doses. The maternal outcome worsened in the case of Alpha and, especially, Delta variants for severe-critical COVID-19-related symptoms and ICU access.

Liver Fibrosis Indices Predict the Severity of SARS-CoV-2 Infection.

Discovering novel risk and prognostic factors for COVID-19 may help not only in reducing severity and mortality but also in creating targeted therapies considering patients' individual features. Liver fibrosis is considered a complication in Non-alcoholic Fatty Liver Disease (NAFLD), it is a feature of steatohepatitis (NASH), and it has already been related to an increased risk for a wide range of diseases. Here, we aimed to define if any parameter assessing metabolic status has predictive power in identifying inpatients at risk for poorer prognosis and an increased mortality from COVID-19. This retrospective study was conducted at the Sub-Intensive Medicine Care Unit of the Presidio Maxi-Emergenze Fiera del Levante, Azienda Ospedaliero-Universitaria Policlinico di Bari, Italy. We evaluated 271 inpatients with moderate-to-severe SARS-CoV-2-related respiratory failure by comparing biochemical features and non-invasive liver fibrosis scores among discharged, transferred to Intensive Care Units (ICU) and non-survivor patients. Moreover, by performing ROC curves, we defined cut-off values to predict mortality and disease severity for each score. We found that non-invasive scores of liver fibrosis, obtained at day of admission, such as AAR (p < 0.001), FIB-4 and mFIB-4, FORNS, and AARPRI (p < 0.05) strongly predict not only in-hospital mortality but also the length of hospitalization and eventual admission to ICU. FIB-4 was the best score to identify non-survivor patients (sensitivity of 80% and specificity of 63%) and predict the need for ICU or mortality (71% of sensitivity and 65% of specificity), with a cut-off value of 1.94. Therefore, we present the predictive power and the cut-off values of several liver fibrosis scores here for disease severity and mortality in SARS-CoV-2 in-patients and we proposed the use of the present scores to identify ab initio the clinical therapeutic and diagnostic protocols for high-risk patients.

Regularized CASPT2: an Intruder-State-Free Approach.

In this work we present a new approach to fix the intruder-state problem (ISP) in CASPT2 based on σp regularization. The resulting σp-CASPT2 method is compared to previous techniques, namely, the real and imaginary level shifts, on a theoretical basis and by performing a series of systematic calculations. The analysis is focused on two aspects, the effectiveness of σp-CASPT2 in removing the ISP and the sensitivity of the approach with respect to the input parameter. We found that σp-CASPT2 compares favorably with respect to previous approaches and that different versions, σ1-CASPT2 and σ2-CASPT2, have different potential application domains. This analysis also reveals the unsuitability of the real level shift technique as a general way to avoid the intruder-state problem.

Analytic First-Order Derivatives of (X)MS, XDW, and RMS Variants of the CASPT2 and RASPT2 Methods.

Crossings between states involve complex electronic structures, making the accurate characterization of the crossing point difficult. In this study, the analytic derivatives of three complete active space second-order perturbation theory (CASPT2) variants as well as an extension of the restricted active space (RASPT2) are developed. These variants are applied to locating minimum energy conical intersections. Our results demonstrate that the three CASPT2 variants predict qualitatively similar results, but a recently developed variant, the rotated multistate CASPT2 (RMS-CASPT2), is least sensitive to the number of states considered in the calculation. We demonstrate that CASPT2 and the reference self-consistent field calculations predict qualitatively different energetics and bond lengths.

Monocyte-to-HDL Ratio (MHR) Predicts Vitamin D Deficiency in Healthy and Metabolic Women: A Cross-Sectional Study in 1048 Subjects.

Vitamin D deficiency is often linked with Metabolic Syndrome, both being more frequent with ageing and associated with an increase inflammatory state. Recently, monocytes-to-high density lipoprotein (HDL) ratio (MHR) has emerged as a powerful index to predict systemic inflammation. In this cross-sectional study, we investigated the association between circulating vitamin D level (25-OH vitamin D) and inflammatory status in a population of 1048 adult individuals. Our study reveals an inverse association between 25-OH vitamin D levels and MHR in the overall population. When the population is stratified by gender, waist circumference, and body mass index (BMI), we observed that while in men this relation is strongly significative only in condition of central obesity, in women a lifelong negative correlation exists between circulating 25-OH vitamin D and MHR and it is independent of the metabolic status. These observations underscore the relevance of circulating biomarkers such as MHR in the prediction of systemic inflammatory conditions sustained by vitamin D deficiency also in healthy and young women.

Toward a Generalized Hückel Rule: The Electronic Structure of Carbon Nanocones.

In this work, we investigate a particular class of carbon nanocones, which we name graphannulenes, and present a generalized Hückel rule (GHR) that predicts the character of their ground state based on simply the three topological indices that uniquely define them. Importantly, this rule applies to both flat and curved systems, encompassing a wide variety of known structures that do not satisfy the "classic" 4n + 2 rule such as coronene, corannulene, and Kekulene. We test this rule at the Hückel level of theory for a large number of systems, including structures that are convex and flat, with a saddle-like geometry, and at the CASSCF level of theory for a selected representative subset. All the performed calculations support the GHR that we propose in this work.

Prolonged Active Prone Positioning in Spontaneously Breathing Non-intubated Patients With COVID-19-Associated Hypoxemic Acute Respiratory Failure With PaO2/FiO2 >150.

Background: The COVID-19 pandemic has led to new approaches to manage patients outside the ICU, including prone positioning in non-intubated patients. Objectives: To report the use of prolonged active prone positioning in spontaneously breathing patients with COVID-19-associated acute respiratory failure. Spontaneously breathing vs non-invasive respiratory support for COVID19 associated acute respiratory failure. Methods: Patients with PaO2/FiO2 > 150, with lung posterior consolidations as assessed by means of lung ultrasound, and chest x-ray were studied. Under continuous pulse oximetry (SpO2) monitoring, patients maintained active prone position. A PaO2/FiO2 < 150 was considered as treatment failure and patients had to be switched to non-invasive respiratory support. Retrospectively, data of 16 patients undergoing who refused proning and underwent non-invasive respiratory support were used as controls. The primary outcome was the proportion of patients maintaining prolonged prone position and discharged home. Secondary outcomes included improvement in oxygenation, hospital length of stay, and 6-month survival. Results: Three out of 16 (18.7%) patients did not tolerate the procedure. Three more patients showed a worsening in PaO2/FiO2 to <150 and required non-invasive support, two of whom finally needing endotracheal intubation. After 72 h, 10 out of 16 (62.5%) patients improved oxygenation [PaO2/FiO2: from 194.6 (42.1) to 304.7 (79.3.2) (p < 0.001)] and were discharged home. In the control group, three out of 16 failed, required invasive ventilatory support, and died within 1 month in ICU. Thirteen were successful and discharged home. Conclusion: In non-intubated spontaneously breathing COVID-19 patients with PaO2/FiO2 >150, active prolonged prone positioning was feasible and tolerated with significant improvement in oxygenation.

AST to Platelet Ratio Index (APRI) is an easy-to-use predictor score for cardiovascular risk in metabolic subjects.

Visceral obesity is characterized by a low-grade inflammatory systemic state that contributes to the genesis of non-alcoholic fatty liver disease (NAFLD), frequently associated with liver fibrosis. Non-invasive serum markers have recently emerged as reliable, easy-to-use scores to predict liver fibrosis. NAFLD is often linked to metabolic and cardiovascular risk. Thus, in this cross-sectional study, we investigated in a population of 1225 subjects if AST to Platelet Ratio Index (APRI), one of the non-invasive liver fibrosis serum markers, can predict cardiovascular risk (CVR). APRI has been previously validated as an efficient score to predict liver fibrosis in viral hepatitis patients with a cut-off of 0.5 for fibrosis and 1.5 for cirrhosis. Our study showed that APRI significantly correlates with CVR and determines, when elevated, a significant increase in CVR for both genders, especially females. This spike in CVR, observed when APRI is elevated, is relatively high in patients in the age of 51-65 years, but it is significantly higher in younger and premenopausal women, approaching risk values usually typical of men at the same age. Taken together, our data highlighted the role of APRI as a reliable predictor easy-to-use score for CVR in metabolic patients.

Uridine and pyruvate protect T cells' proliferative capacity from mitochondrial toxic antibiotics: a clinical pilot study.

Antibiotics that inhibit bacterial protein or nucleic acid synthesis and function can exert an off-target action on mitochondria (mitotoxic antibiotics), making actively dividing mammalian cells dependent on uridine and pyruvate supplementation. Based on this rationale, we carried out, for the first time, a randomized pilot study in 55 patients with asymptomatic bacteriuria or positive sperm culture, each treated with a single mitotoxic antibiotic with or without oral supplementation of uridine + pyruvate (Uripyr, Mitobiotix, Italy). The in vivo and ex vivo data show a a 3.4-fold higher value in the differential (before and after the antibiotic treatment) lymphocytes count and a 3.7-fold increase in the percentage of dividing T cells, respectively, in the Uripyr vs the control group. Our findings lay the groundwork to enhance the synergy between antibiotics and the immune system in order to optimize the administration protocols and widen the application potentials of antibiotic therapies as well as to re-evaluate old "forgotten" molecules to fight bacterial infections in the antibiotics resistance era.

Intracoronary monocyte expression pattern and HDL subfractions after non-ST elevation myocardial infarction.

AIMS: Coronary artery disease (CAD) is described as a range of clinical conditions including myocardial infarction (MI) and unstable angina. Lipid and apolipoprotein profiles together with the study of cholesterol deposit and efflux serve to identify novel pre and post infarct scenarios for the treatment of these patients. In (non-ST elevation myocardial infarction) NSTEMI patients, we analysed both systemic and intracoronary serum ability to accept cholesterol as well as cholesterol efflux capacity (CEC) of monocytes in terms of expression of genes involved in the reverse cholesterol transport (RCT). METHODS AND RESULTS: While HDL-C quantity was similar between systemic and coronary arterial blood, in 21 NSTEMI patients we observed a significant reduction of the preß-HDL fraction and the levels of Apolipoproteins AI, AII, B and E in coronary versus systemic serum. These data are complemented with the observed reduction of CEC. On the contrary, compared to systemic arterial monocytes, in coronary microenvironment of NSTEMI patients after myocardial infarction, the monocytes exhibited a higher mRNA expression of nuclear receptor LXRα and its targets ABCA1 and APOE, which drive cholesterol efflux capacity. CONCLUSION: In this cross-sectional study we observe that in the immediate post infarction period, there is a spontaneous bona fide ligand-induced activation of the LXR driven cholesterol efflux capacity of intracoronary monocytes to overcome the reduced serum ability to accept cholesterol and to inhibit the post-infarction pro-inflammatory local microenvironment.

On the role of symmetry in XDW-CASPT2.

Herewith, we propose two new exponents for the recently introduced XDW-CASPT2 method [S. Battaglia and R. Lindh, J. Chem. Theory Comput. 16, 1555-1567 (2020)], which fix one of the largest issues hindering this approach. By using the first-order effective Hamiltonian coupling elements, the weighting scheme implicitly takes into account the symmetry of the states, thereby averaging Fock operators only if the zeroth-order wave functions interact with each other. The use of Hamiltonian couplings also provides a physically sounder approach to quantitate the relative weights; however, it introduces new difficulties when these rapidly die off to zero. The improved XDW-CASPT2 method is critically tested on several systems of photochemical relevance, and it is shown that it succeeds in its original intent of maintaining MS-CASPT2 accuracy for the evaluation of transition energies and at the same time providing smooth potential energy surfaces around near-degenerate points akin to XMS-CASPT2.

P,N-Chelated Gold(III) Complexes: Structure and Reactivity.

Gold(III) complexes are versatile catalysts offering a growing number of new synthetic transformations. Our current understanding of the mechanism of homogeneous gold(III) catalysis is, however, limited, with that of phosphorus-containing complexes being hitherto underexplored. The ease of phosphorus oxidation by gold(III) has so far hindered the use of phosphorus ligands in the context of gold(III) catalysis. We present a method for the generation of P,N-chelated gold(III) complexes that circumvents ligand oxidation and offers full counterion control, avoiding the unwanted formation of AuCl4-. On the basis of NMR spectroscopic, X-ray crystallographic, and density functional theory analyses, we assess the mechanism of formation of the active catalyst and of gold(III)-mediated styrene cyclopropanation with propargyl ester and intramolecular alkoxycyclization of 1,6-enyne. P,N-chelated gold(III) complexes are demonstrated to be straightforward to generate and be catalytically active in synthetically useful transformations of complex molecules.

Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase(SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

The importance of maintaining the same order of performance of lung function and SNIP tests in patients with amyotrophic lateral sclerosis.

Objective: Sniff nasal inspiratory pressure (SNIP), a useful tool for the assessment of diaphragm function in patients with Amyotrophic Lateral Sclerosis (ALS), is usually performed together with lung function tests. The aim of this study was to evaluate whether SNIP results are influenced by the order of performance of the tests. Methods: 103 consecutive patients (65% males, 80% spinal onset) were recruited. The highest value of up to 10 sniffs, was recorded before (SNIPT0) and after (SNIPT1) the assessment of lung function, peak cough (PCF), and peak expiratory flow (PEF). Results: Mean and median values were respectively 31.10 and 26.00 cm H2O for SNIPT0 and 28.93 and 25.00 cm H2O for SNIPT1 (p < 0.001). The median value of (SNIPT1 - SNIPT0)/SNIPT0% was -7.10. Patients showing post lung function SNIP values above the median were included in Group 1 (51%), the others in group 2 (49%). Group 2 showed more severe baseline ventilatory restriction and reduction in PCF than Group 1. Positive direct relationships were found between SNIPT0 and SNIPT1 (coefficient ß = 0.95, p < 0.001), and forced vital capacity and forced expiratory volume at one second. Conclusions: 50/103(49%) patients with ALS show a significant reduction in SNIP when assessed shortly after the performance of lung function tests. These patients suffer from more severe ventilatory restriction than patients not showing the reduction. Our findings suggest standardizing the order of respiratory tests during the follow up in order to avoid to misestimate the real strength of inspiratory muscles.

Modern quantum chemistry with [Open]Molcas.

MOLCAS/OpenMolcas is an ab initio electronic structure program providing a large set of computational methods from Hartree-Fock and density functional theory to various implementations of multiconfigurational theory. This article provides a comprehensive overview of the main features of the code, specifically reviewing the use of the code in previously reported chemical applications as well as more recent applications including the calculation of magnetic properties from optimized density matrix renormalization group wave functions.

Gender, BMI and fasting hyperglycaemia influence Monocyte to-HDL ratio (MHR) index in metabolic subjects.

Metabolic Syndrome (MS) is characterized by a low-grade inflammatory state causing an alteration of non-invasive indexes derived from blood count, namely monocyte-to-HDL ratio (MHR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR). We analyse a population of 771 subjects (394 controls and 377 MS patients) to evaluate the best predictive index of MS. The diagnosis of MS was made according to the 2006 criteria of the International Diabetes Federation (IDF). We performed ROC curve analyses to evaluate the best predictor index of MS. MHR cut-off value was used to classify the population in two different groups and to create the outcome variable of the Recursive Partitioning and Amalgamation (RECPAM) analysis. This method is a tree-structured approach that defines "risk profiles" for each group of dichotomous variables. We showed that MHR index is significantly linked to body mass index (BMI), waist circumference, creatinine, C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR). ROC curve defined an MHR cut-off value of 6.4, which was able to identify two patient groups with significant differences in waist circumference, blood pressure, creatinine, estimated glomerular filtration rate and fasting plasma glucose. RECPAM analysis demonstrated that gender, BMI categorization and hyperglycaemia were the most important risk determinants of increased MHR index that can be considered bona fide a useful and easily obtainable tool to suggest the presence of peculiar metabolic features that predict MS.

Extended Dynamically Weighted CASPT2: The Best of Two Worlds.

We introduce a new variant of the complete active space second-order perturbation theory (CASPT2) method that performs similarly to multistate CASPT2 (MS-CASPT2) in regions of the potential energy surface where the electronic states are energetically well separated and is akin to extended MS-CASPT2 (XMS-CASPT2) in case the underlying zeroth-order references are near-degenerate. Our approach follows a recipe analogous to that of XMS-CASPT2 to ensure approximate invariance under unitary transformations of the model states and a dynamic weighting scheme to smoothly interpolate the Fock operator between state-specific and state-average regimes. The resulting extended dynamically weighted CASPT2 (XDW-CASPT2) methodology possesses the most desirable features of both MS-CASPT2 and XMS-CASPT2, that is, the ability to provide accurate transition energies and correctly describe avoided crossings and conical intersections. The reliability of XDW-CASPT2 is assessed on a number of molecular systems. First, we consider the dissociation of lithium fluoride, highlighting the distinctive characteristics of the new approach. Second, the invariance of the theory is investigated by studying the conical intersection of the distorted allene molecule. Finally, the relative accuracy in the calculation of vertical excitation energies is benchmarked on a set of 26 organic compounds. We found that XDW-CASPT2, albeit being only approximately invariant, produces smooth potential energy surfaces around conical intersections and avoided crossings, performing equally well to the strictly invariant XMS-CASPT2 method. The accuracy of vertical transition energies is almost identical to MS-CASPT2, with a mean absolute deviation of 0.01-0.02 eV, in contrast to 0.12 eV for XMS-CASPT2.

Symmetry of three-center, four-electron bonds.

Three-center, four-electron bonds provide unusually strong interactions; however, their nature remains ununderstood. Investigations of the strength, symmetry and the covalent versus electrostatic character of three-center hydrogen bonds have vastly contributed to the understanding of chemical bonding, whereas the assessments of the analogous three-center halogen, chalcogen, tetrel and metallic [small sigma, Greek, circumflex]-type long bonding are still lagging behind. Herein, we disclose the X-ray crystallographic, NMR spectroscopic and computational investigation of three-center, four-electron [D-X-D]+ bonding for a variety of cations (X+ = H+, Li+, Na+, F+, Cl+, Br+, I+, Ag+ and Au+) using a benchmark bidentate model system. Formation of a three-center bond, [D-X-D]+ is accompanied by an at least 30% shortening of the D-X bonds. We introduce a numerical index that correlates symmetry to the ionic size and the electron affinity of the central cation, X+. Providing an improved understanding of the fundamental factors determining bond symmetry on a comprehensive level is expected to facilitate future developments and applications of secondary bonding and hypervalent chemistry.