A critical appraisal of geroprotective activities of flavonoids in terms of their bio-accessibility and polypharmacology.

Flavonoids, a commonly consumed natural product, elicit health-benefits such as antioxidant, anti-inflammatory, antiviral, anti-allergic, hepatoprotective, anti-carcinogenic and neuroprotective activities. Several studies have reported the beneficial role of flavonoids in improving memory, learning, and cognition in clinical settings. Their mechanism of action is mediated through the modulation of multiple signalling cascades. This polypharmacology makes them an attractive natural scaffold for designing and developing new effective therapeutics for complex neurological disorders like Alzheimer's disease and Parkinson's disease. Flavonoids are shown to inhibit crucial targets related to neurodegenerative disorders (NDDs), including acetylcholinesterase, butyrylcholinesterase, ß-secretase, γ-secretase, α-synuclein, Aß protein aggregation and neurofibrillary tangles formation. Conserved neuro-signalling pathways related to neurotransmitter biogenesis and inactivation, ease of genetic manipulation and tractability, cost-effectiveness, and their short lifespan make Caenorhabditis elegans one of the most frequently used models in neuroscience research and high-throughput drug screening for neurodegenerative disorders. Here, we critically appraise the neuroprotective activities of different flavonoids based on clinical trials and epidemiological data. This review provides critical insights into the absorption, metabolism, and tissue distribution of various classes of flavonoids, as well as detailed mechanisms of the observed neuroprotective activities at the molecular level, to rationalize the clinical data. We further extend the review to critically evaluate the scope of flavonoids in the disease management of neurodegenerative disorders and review the suitability of C. elegans as a model organism to study the neuroprotective efficacy of flavonoids and natural products.

Bacterial endosymbionts of a nitrogen-fixing yeast Rhodotorula mucilaginosa JGTA-S1 - insights into a yet unknown micro-ecosystem.

Rhodotorula mucilaginosa JGTA-S1 is a yeast strain capable of fixing nitrogen and improving nitrogen nutrition in rice plants because of its nitrogen-fixing endobacteria, namely Stutzerimonas (Pseudomonas) stutzeri and Bradyrhizobium sp. To gain a deeper understanding of yeast endosymbionts, we conducted a whole-genome shotgun metagenomic analysis of JGTA-S1 cells grown under conditions of nitrogen sufficiency and deficiency. Our results showed that the endosymbiont population varied depending on the nitrogen regime. Upon mechanical disruption of yeast cells, we obtained endosymbionts in culturable form viz. Bacillus velezensis and Staphylococcus sp. under nitrogen-replete conditions and Lysinibacillus telephonicus., Brevibacillus sp., and Niallia circulans under nitrogen-depleted conditions. S. stutzeri and Bradyrhizobium sp. the previously reported endosymbionts remained unculturable. The culturable endosymbionts Staphylococcus sp. and Bacillus velezensis appear to possess genes for dissimilatory nitrate reduction (DNRA), an alternative pathway for ammonia synthesis. However, our findings suggest that these endosymbionts are facultative as they survive outside the host. The fitness of the yeast was not affected by curing of these microbes. Curing the yeast diazotrophic endosymbionts took a toll on its fitness. Our results also showed that the populations of S. stutzeri and B. velezensis increased significantly under nitrogen-depleted conditions compared to nitrogen-sufficient conditions. The importance of DNRA and nitrogen fixation is also reflected in the metagenomic reads of JGTA-S1.

Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis.

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC50 ∼ 1.4-6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure-activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund's adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1-100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies.

Cholesterol Allosterically Modulates the Structure and Dynamics of the Taurocholate Export Pump (ABCB11).

The BSEP/ABCB11 transmembrane protein translocates taurine- and glycine-conjugated bile salts across the hepatocyte bilayer driven by ATP-hydrolysis. Direct inhibition of BSEP/ABCB11 leads to idiosyncratic drug-induced liver injury. ABCB11 is localized within the cholesterol-enriched lipid raft, and membrane cholesterol depletion leads to impaired taurocholate transport. However, structural insight into the mechanism of the cholesterol-mediated regulation of ABCB11 activity remains elusive. We used extensive molecular dynamics simulation coupled with well-tempered metadynamics to elucidate the role of membrane cholesterol in the structure and dynamics of ABCB11. We identified specific high-residence binding sites for cholesterol within the transmembrane domain. The free-energy simulations have elucidated that the bound cholesterol stabilizes the "inward-open" conformation of the protein. Cholesterol-ABCB11 interactions trigger allosteric communications between the transmembrane and nucleotide-binding domains through the linker region. Cholesterol depletion destabilizes the allosteric network of the protein. As a result, it adopts a more collapsed form with a reduced volume of the taurocholate-binding pocket.

Antiviral Flavonoids: A Natural Scaffold with Prospects as Phytomedicines against SARS-CoV2.

Flavonoids are vital candidates to fight against a wide range of pathogenic microbial infections. Due to their therapeutic potential, many flavonoids from the herbs of traditional medicine systems are now being evaluated as lead compounds to develop potential antimicrobial hits. The emergence of SARS-CoV-2 caused one of the deadliest pandemics that has ever been known to mankind. To date, more than 600 million confirmed cases of SARS-CoV2 infection have been reported worldwide. Situations are worse due to the unavailability of therapeutics to combat the viral disease. Thus, there is an urgent need to develop drugs against SARS-CoV2 and its emerging variants. Here, we have carried out a detailed mechanistic analysis of the antiviral efficacy of flavonoids in terms of their potential targets and structural feature required for exerting their antiviral activity. A catalog of various promising flavonoid compounds has been shown to elicit inhibitory effects against SARS-CoV and MERS-CoV proteases. However, they act in the high-micromolar regime. Thus a proper leadoptimization against the various proteases of SARS-CoV2 can lead to high-affinity SARS-CoV2 protease inhibitors. To enable lead optimization, a quantitative structure-activity relationship (QSAR) analysis has been developed for the flavonoids that have shown antiviral activity against viral proteases of SARS-CoV and MERS-CoV. High sequence similarities between coronavirus proteases enable the applicability of the developed QSAR to SARS-CoV2 proteases inhibitor screening. The detailed mechanistic analysis of the antiviral flavonoids and the developed QSAR models is a step forward toward the development of flavonoid-based therapeutics or supplements to fight against COVID-19.

Clinical outcomes and the impact of valve morphology for transcatheter aortic valve replacement in bicuspid aortic valves: A systematic review and meta-analysis.

BACKGROUND: Bicuspid aortic valve (BAV) is present in approximately 0.5%-2% of the general population, causing significant aortic stenosis (AS) in 12%-37% of affected individuals. Transcatheter aortic valve replacement (TAVR) is being considered the treatment of choice in patients with symptomatic AS across all risk spectra. AIM: Aim Our study aims to compare TAVR outcomes in patients with BAV versus tricuspid aortic valves (TAV). METHODS: A comprehensive literature search was performed in PubMed, Web of Science, and Cochrane trials. Studies were included if they included BAV and TAV patients undergoing TAVR with quantitative data available for at least one of our predefined outcomes. Meta-analysis was performed by the random-effects model using Stata software. RESULTS: Fifty studies of 203,288 patients were included. BAV patients had increased 30-day all-cause mortality (odds ratio [OR] = 1.23 [1.00-1.50], p = 0.05), in-hospital stroke (OR = 1.39 [1.01-1.93], p = 0.05), in-hospital and 30-day PPI (OR = 1.13 [1.00-1.27], p = 0.04; OR = 1.16 [1.04-1.13], p = 0.01) and in-hospital, 30-day and 1-year aortic regurgitation (AR) (OR = 1.48 [1.19-1.83], p < 0.01; OR = 1.79 [1.26-2.52], p < 0.01; OR = 1.64 [1.03-2.60], p = 0.04). Subgroup analysis on new-generation valves showed a reduced 1-year all-cause mortality (OR = 0.86 [CI = 0.75-0.98], p = 0.03), despite higher in-hospital and 30-day PPI (OR = 0.1.21 [1.04-1.41], p = 0.01; OR = 1.17 [1.05-1.31], p = 0.01) and in-hospital AR (OR = 1.62 [1.14-2.31], p = 0.01) in the BAV group. The quality of included studies was moderate-to-high, and only three analyses presented high heterogeneity. CONCLUSION: TAVR is associated with comparable outcomes in patients with BAV and TAV. Careful selection of BAV cases by preprocedural assessment of valve anatomy and burden of calcification, pre- and post-procedural dilation, and implementing newer generations of valves may improve the safety and efficacy of TAVR in BAV patients.

A multi-tier computational screening framework to effectively search the mutational space of SARS-CoV-2 receptor binding motif to identify mutants with enhanced ACE2 binding abilities.

SARS-CoV-2 gained crucial mutations at the receptor binding domain (RBD) that often changed the course of the pandemic leading to new waves with increased case fatality. Variants are observed with enhanced transmission and immune invasion abilities. Thus, predicting future variants with enhanced transmission ability is a problem of utmost research interest. Here, we have developed a multi-tier exhaustive SARS-CoV-2 mutation screening platform combining MM/GBSA, extensive molecular dynamics simulations, and steered molecular dynamics to identify RBD mutants with enhanced ACE2 binding capability. We have identified four RBM mutations (F490K, S494K, G504F, and the P499L) with significantly higher ACE2 binding abilities than wild-type RBD. Compared to wild-type RBD, they all form stable complexes with more hydrogen bonds and salt-bridge interactions with ACE2. Our simulation data suggest that these mutations allosterically alter the packing of the RBM interface of the RBD-ACE2 complex. As a result, the rupture force required to break the RBD-ACE2 contacts is significantly higher for these mutants.

Preferential Ordering and Organization of Hydration Water Favor Nucleation of Ice by Ice-Nucleating Proteins over Antifreeze Proteins.

Bacteria containing ice-nucleating proteins (INPs) evolved in nature to nucleate ice at the high sub-zero ambiance. The ability of the INPs to induce order in the hydration layer and their aggregation propensity appear to be key factors of their ice nucleation abilities. However, the mechanism of the process of ice nucleation by INPs is yet to be understood clearly. Here, we have performed all-atom molecular dynamics simulations and analyzed the structure and dynamics of the hydration layer around the proposed ice-nucleating surface of a model INP. Results are compared with the hydration of a topologically similar non-ice-binding protein (non-IBP) and another ice-growth inhibitory antifreeze protein (sbwAFP). We observed that the hydration structure around the ice-nucleating surface of INP is highly ordered and the dynamics of the hydration water are slower, compared to the non-IBP. Even the ordering of the hydration layer is more evident around the ice-binding surface of INP, compared to the antifreeze protein sbwAFP. Particularly with increasing repeat units of INP, we observe an increased population of ice-like water. Interestingly, the distances between the hydroxyl groups of the threonine ladder and its associated channel water of the ice-binding surface (IBS) of INP in the X and Y direction mimic the oxygen atom distances of the basal plane of hexagonal ice. However, the structural synergies between the hydroxyl group distances of the threonine ladder and its associated channel water of the IBS of sbwAFP and oxygen atom distances of the basal plane are less evident. This difference makes the IBS of the INP a better template for ice nucleation than AFP, although both of them bind to the ice surface efficiently.

Design, synthesis and evaluation of 2-aryl quinoline derivatives against 12R-lipoxygenase (12R-LOX): Discovery of first inhibitor of 12R-LOX.

The 12R-lipoxygenase (12R-LOX), a (non-heme) iron-containing metalloenzyme belonging to the lipoxygenase (LOX) family catalyzes the conversion of arachidonic acid (AA) to its key metabolites. Studies suggested that 12R-LOX plays a critical role in immune modulation for the maintenance of skin homeostasis and therefore can be considered as a potential drug target for psoriasis and other skin related inflammatory diseases. However, unlike 12-LOX (or 12S-LOX) the enzyme 12R-LOX did not receive much attention till date. In our effort, the 2-aryl quinoline derivatives were designed, synthesized and evaluated for the identification of potential inhibitors of 12R-hLOX. The merit of selection of 2-aryl quinolines was assessed by in silico docking studies of a representative compound (4a) using the homology model of 12R-LOX. Indeed, in addition to participating in H-bonding with THR628 and LEU635 the molecule formed a hydrophobic interaction with VAL631. The desired 2-aryl quinolines were synthesized either via the Claisen-Schmidt condensation followed by one-pot reduction-cyclization or via the AlCl3 induced heteroarylation or via the O-alkylation approach in good to high (82-95%) yield. When screened against human 12R-LOX (12R-hLOX) in vitro four compounds (e.g. 4a, 4d, 4e and 7b) showed encouraging (>45%) inhibition at 100 µM among which 7b and 4a emerged as the initial hits. Both the compounds showed selectivity towards 12R-hLOX over 12S-hLOX, 15-hLOX and 15-hLOXB and concentration dependent inhibition of 12R-hLOX with IC50 = 12.48 ± 2.06 and 28.25 ± 1.63 µM, respectively. The selectivity of 4a and 7b towards 12R-LOX over 12S-LOX was rationalized with the help of molecular dynamics simulations. The SAR (Structure-Activity Relationship) within the present series of compounds suggested the need of a o-hydroxyl group on the C-2 phenyl ring for the activity. The compound 4a and 7b (at 10 and 20 µM) reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes in a concentration dependent manner. Further, both compounds decreased the protein levels of Ki67 and the mRNA expression of IL-17A in the IMQ-induced psoriatic-like keratinocytes. Notably, 4a but not 7b inhibited the production of IL-6 and TNF-α in the keratinocyte cells. In the preliminary toxicity studies (i.e. teratogenicity, hepatotoxicity and heart rate assays) in zebrafish both the compounds showed low safety (<30 µM) margin. Overall, being the first identified inhibitors of 12R-LOX both 4a and 7b deserve further investigations.

Number of Hydrogen Bonds per Unit Solvent Accessible Surface Area: A Descriptor of Functional States of Proteins.

Proteins function close to native and near-native conformations. These states are evolutionarily selected to ensure the effect of mutations is minimized. The structural organization of a protein is hierarchical and modular, which reduces the dimensionality of the configurational space of the native states. Thus, finding appropriate descriptors that define the native state among all possible states of a protein is a problem of immense interest. The present study explores the correlation between solvent accessible surface areas (SASAs) and different intraprotein as well as protein-water hydrogen bonds of 55 single-chain globular proteins from four different structural classes (all α, all ß, α+ß, and α/ß), 16 multichain proteins, and 4 macromolecular complexes. A systematic analysis of the solvent accessible surface area and intraprotein and protein-water hydrogen bonds suggests a linear relationship between SASAs and hydrogen bonds. The number of protein-water hydrogen bonds per unit SASA ranges from 3 to 4 for all the different structural protein classes. In contrast, the number of intramolecular hydrogen bonds per unit SASA, including the mainchain-mainchain, mainchain-sidechain, and sidechain-sidechain, varies between 0.75 to 2. The solvation free energy of a protein linearly decreases with SASA. Our study also shows that the solvation free energy/SASA varies from -75 to -105 kJ mol-1 nm-2 across all the native states studied here. The number conservancy of intraprotein hydrogen bonds per unit SASA possibly imparts structural stability to the native structure. On the other hand, 3-4 protein-water hydrogen bonds per unit SASA are possibly required to maintain a balance between the solubility and functionality of the native states. This study provides a basis for synthetic biologists to design new folds with improved functionality.

In silico investigation of the role of vitamins in cancer therapy through inhibition of MCM7 oncoprotein.

An overabundance of MCM7 protein, a component of the minichromosome maintenance complex that normally initiates DNA replication, has been reported to cause different types of cancers with aggressive malignancy. Inhibition of MCM7 may lead to a significant reduction in cancer-associated cell proliferation. Despite such significance of MCM7 in cancer, the protein structure is yet to be resolved experimentally. This significantly halts the structure-guided ligand designing for cancer therapy targeting the MCM7. The present study aims to resolve the tertiary structure of MCM7 and repurpose the FDA-approved clinically used drugs for cancer therapy by targeting MCM7 protein. The secondary and 3D structures of MCM7 were generated using multiple bioinformatics tools, including the Self-Optimized Prediction Method with Alignment (SOPMA), SWISS-MODEL, and I-TASSER. The reliability of the modeled structure was assessed using PROCHECK. Initially, a structure-guided virtual screening was performed on the approved drug library to identify potential hits against MCM7. The detailed molecular mechanism of receptor interactions of the identified hits was evaluated using extensive molecular dynamics simulation. The results from this study reveal an intriguing discovery of the potential of ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), ergosterol (precursor of vitamin D2) and menaquinone (vitamin K2) as oncoprotein inhibitors for cancer therapy via inhibition of MCM7.

Molecular Factors of Ice Growth Inhibition for Hyperactive and Globular Antifreeze Proteins: Insights from Molecular Dynamics Simulation.

The molecular mechanism behind the ice growth inhibition by antifreeze proteins (AFPs) is yet to be understood completely. Also, what physical parameters differentiate between the AFP and non-AFP are largely unknown. Thus, to get an atomistic overview of the differential antifreeze activities of different classes of AFPs, we have studied ice growth from different ice surfaces in the presence of a moderately active globular type III AFP and a hyperactive spruce budworm (sbw) AFP. Results are compared with the observations of ice growth simulations in the presence of topologically similar non-AFPs using all-atom molecular dynamics simulations. Simulation data suggest that the ice surface coverage is a critical factor in ice growth inhibition. Due to the presence of an ice binding surface (IBS), AFPs form a high affinity complex with ice, accompanied by a transition of hydration water around the IBS from clathrate-like to ice-like. Several residues around the periphery of the IBS anchor the AFP to the curved ice surface mediated by multiple strong hydrogen bonds, stabilizing the complex immensely. In the high surface coverage regime, the slow unbinding kinetics dominates over the ice growth kinetics and thus facilitates the ice growth inhibition. Due to the non-availability of a proper IBS, non-AFPs form a low-affinity complex with the growing ice surface. As a result, the non-AFPs are continuously repelled by the surface. If the concentration of AFPs is low, then the effective surface coverage is reduced significantly. In this low surface coverage regime, AFPs can also behave like impurities and are engulfed by the growing ice crystal.

Decoding molecular factors shaping human angiotensin converting enzyme 2 receptor usage by spike glycoprotein in lineage B beta-coronaviruses.

Acquiring the human ACE2 receptor usage trait enables the coronaviruses to spill over to humans. However, the origin of the ACE2 usage trait in coronaviruses is poorly understood. Using a multi-disciplinary approach combining evolutionary bioinformatics and molecular dynamics simulation, we decode the principal driving force behind human ACE2 receptor recognition in coronaviruses. Genomic content, evolutionary divergence, and codon usage bias analysis reveal that SARS-CoV2 is evolutionarily divergent from other human ACE2-user CoVs, indicating that SARS-CoV2 originates from a different lineage. Sequence analysis shows that all the human ACE2-user CoVs contain two insertions in the receptor-binding motif (RBM) that directly interact with ACE2. However, the insertion sequences in SARS-CoV2 are divergent from other ACE2-user CoVs, implicating their different recombination origins. The potential of mean force calculations reveals that the high binding affinity of SARS-CoV2 RBD to human ACE2 is primarily attributed to its ability to form a higher number of hydrogen bonds than the other ACE2-user CoVs. The adaptive branch-site random effects likelihood method identifies positive selection bias across the ACE2 user CoVs lineages. Recombination and selection forces shape the spike evolution in human ACE2-using beta-CoVs to optimize the interfacial hydrogen bonds between RBD and ACE2. However, these evolutionary forces work within the constraints of nucleotide composition, ensuring optimum codon adaptation of the spike (S) gene within the host cell.

Decoding the effects of spike receptor binding domain mutations on antibody escape abilities of omicron variants.

Recent times witnessed an upsurge in the number of COVID19 cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for an approved therapeutic monoclonal antibody. The Q498R RBD mutation observed across all the omicron variants can reduce ∼12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a ∼6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.

In-Hospital Outcome In Patients With Acyanotic Congenital Heart Disease Undergoing Transcatheter Aortic Valve Replacement.

The purpose of the study was to determine the in-hospital outcome and resource utilization in patients with acyanotic congenital heart disease (ACHD) undergoing transcatheter aortic valve replacement (TAVR). Current guidelines from professional societies do not support TAVR in patients with ACHD, likely from a lack of supportive evidence. Temporal trends in patients with ACHD undergoing TAVR were determined using the 2016-2018 National Inpatient Sample database appropriate ICS-10-PCS code. Stata 16.0 was used for statistical analysis. 0.87% of patients undergoing TAVR had concomitant ACHD, with ASD being the most common (78%). After matching, there was no increased risk of mortality in ACHD patients undergoing TAVR compared to patients without ACHD (OR 1.43, P = 0.59). Additionally, no difference was found in the incidence of overall cardiac complications between patients with ACHD and patients without ACHD, except STEMI (OR 4.16, 95% CI, 1.08-16.00, P = 0.038), which is likely due to more comorbidity burden in the later cohort. Complications such as acute kidney injury, ischemic stroke, and bleeding were similar. Hospital resource utilization was higher in the ACHD group in the form of increased length of stay and higher mean total cost. The comparable in-hospital all-cause mortality and complication rate in ACHD patients undergoing TAVR compared to patients without ACHD is encouraging and will be helpful to design future randomized controlled trials.

The 30-Day Readmission Rate of Same-Day Discharge Following Transcatheter Aortic Valve Implantation (from National Readmission Database 2015 to 2019).

The length of hospital stay after transcatheter aortic valve implantation (TAVI) has decreased over the years, and next-day discharge is being increasingly adopted in clinical practice. Whether further expediting discharge after TAVI by allowing same-day discharge (SDD) in selected patients is safe or derives additional benefits remains unanswered. Using the United States Nationwide Readmission Database 2015 to 2019, we identified 196,618 patients who received TAVI (mean age 79.5 8.4 years, 45.0% female). Of these, 245 patients (0.12%) were discharged on the same day they received TAVI (SDD group), and the remaining 196,373 were discharged on a different day (different-day discharge [DDD] group). A propensity score-matched analysis was done. The rate of unplanned readmission within 30 days of discharge was not significantly different between the SDD and DDD groups (11.0% vs 10.6%, hazard ratio 1.03, 95% confidence interval 0.56 to 1.90, p = 0.921). Hospitalization costs were significantly lower in the SDD group than the DDD group ($37,811 ± 18,029 vs $49,130 ± 27,007, p <0.001). In conclusion, the 30-day readmission rate was similar for patients discharged on the same day after TAVI and for patients discharged at a later time point.

Predictors and mortality risk of venous thromboembolism in patients with COVID-19: systematic review and meta-analysis of observational studies.

INTRODUCTION: Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in COVID-19 disease is associated with widespread inflammation and a prothrombotic state, resulting in frequent venous thromboembolic (VTE) events. It is currently unknown whether anticoagulation is protective for VTE events. Therefore, we conducted a systematic review to identify predictors of VTE in COVID-19. METHODS: We searched PubMed, EMBASE, Google Scholar, and Ovid databases for relevant observational studies of VTE in COVID-19 disease. The effect size for predictors of VTE was calculated using a random-effects model and presented as forest plots. Heterogeneity among studies was expressed as Q statistics and I2. Bias was assessed using the Newcastle Ottawa Scale for all identified observational studies. Publication bias was assessed with funnel plot analysis. RESULTS: We identified 28 studies involving 6053 patients with suspected or confirmed COVID-19. The overall pooled prevalence of VTE events was 20.7%. Male sex was associated with a higher risk of VTE events, whereas prior history of VTE, smoking, and cancer were not. VTE events were significantly higher in severely ill patients, mechanically ventilated patients, those requiring intensive care admission, and those with a low PaO2/FiO2 ratio (P/F ratio). Chronic comorbidities, including cardiovascular disease, heart failure, renal disease, and pulmonary disease, did not increase the risk of VTE events. Patients with VTE had higher leukocyte counts and higher levels of D-dimer, C-reactive protein, and procalcitonin. The occurrence of VTE was associated with increased length of stay but did not impact mortality. Therapeutic and prophylactic doses of anticoagulation were not protective against VTE. CONCLUSION: VTE in COVID-19 is associated with male gender and severe disease but not with traditional risk factors for VTE. The occurrence of VTE does not appear to be mitigated by either prophylactic or therapeutic anticoagulation. The occurrence of VTE in this population is associated with an increased length of stay but does not appear to impact mortality.

Impact of Pulmonary Hypertension in Patients With Hypertrophic Cardiomyopathy Presented With Cardiogenic Shock/Acute Decompensated Heart Failure.

There have been no studies focusing on how pulmonary hypertension (PH) affects inpatient outcomes in patients with hypertrophic cardiomyopathy (HCM) hospitalized for acute decompensated heart failure or cardiogenic shock. This study explores inpatient outcomes of patients with HCM, and concomitant PH compared to patients with HCM. Based on the National Inpatient Sample (NIS) 2016-2018, patients admitted with a primary diagnosis of acute decompensated heart failure or cardiogenic shock were selected. The patients diagnosed with concomitant HCM were identified and divided into 2 groups based on the presence or absence of PH. After propensity matching 1545 matched pairs were generated. Patients with PH had a higher prevalence of chronic kidney disease (P < 0.001), anemia (P < 0.001), coagulopathy (P < 0.001), atrial fibrillation (P = 0.031), and valvular disease (P < 0.001) (Table 1). The primary outcome (all-cause in-hospital mortality) occurred in 110 patients (2.6%) without PH and 95 patients (5.2%) with PH, which was not statistically significant after propensity matching (odds ratio [OR]:1.53; 95% confidence interval [CI]: 0.70-3.33; P = 0. 28) (Table 3). Patients with PH had a higher incidence of transient ischemic attack (TIA) (OR: 9.52; 95% CI: 3.38-26.78; P < 0.001)] and respiratory failure [(OR: 1.49; 95% CI:1.05-2.11; P = 0.027], although with no difference in requirement for mechanical ventilation (= 0.64), as compared to patients without PH. PH in patients with HCM is associated with increased morbidity, including increased risk of TIA and respiratory failure.

Outcomes of rotational atherectomy followed by cutting balloon versus plain balloon before drug-eluting stent implantation for calcified coronary lesions: A meta-analysis.

OBJECTIVE: The aim of this study is to compare outcomes of rotational atherectomy and cutting balloon (RACB) versus rotational atherectomy and plain balloon (RAPB) before drug-eluting stent (DES) implantation in calcified coronary lesions. METHODS: Randomized controlled trials (RCT) and observational studies comparing RACB with RAPB were identified through a systematic search of published literature across multiple databases. Random effect meta-analysis was performed to compare the outcome between the two groups. RESULTS: Four studies were included in the meta-analysis (three observational and one RCT) involving a total of 315 patients. 166 patients had RACB, and 149 patients had RAPB before DES placement with a median follow-up of 11.5 months. Compared with patients who had RAPB there was no difference in MACE (composite of death, myocardial infarction, and target vessel revascularization) (odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.25-2.18], slow flow/no reflow (OR: 0.71; 95% CI: 0.23-2.16), all-cause mortality (OR: 2.02; 95% CI: 0.28-14.60), and device success rate (OR: 1.79; 95% CI: 0.28-11.18) in the RACB approach. There was a benefit towards less target lesion revascularization in the RACB group; however, this outcome was reported in two studies (OR: 0.29; 95% CI: 0.08-0.99). On meta-regression there was no association between age, sex, diabetes, or lesion location with MACE and all-cause mortality. The studies were homogenous across all outcomes. CONCLUSION: RACB, as compared with RAPB, had a similar risk of MACE, all-cause mortality, device success, and complication, but a lower risk of target lesion revascularization.