Background/Objectives: Flavonoids are low-molecular-weight polyphenolic compounds that are universally distributed in plants. They are a chemically varied group of secondary metabolites with a broad range of biological activity. The use of flavonoids is known to decrease the risk of many chronic diseases due to their radical scavenging, antioxidant, anti-inflammatory, anticarcinogenic, and antimutagenic properties. Limitations in the use of flavonoids include their low water solubility and poor stability, and therefore their low bioavailability. The encapsulation of flavonoids in different nanocarriers has helped to overcome this limitation. Taking this into account, in this work, the encapsulation of four flavones with several therapeutic applications—7-hydroxyflavone, 7,8-dihydroxyflavone, baicalein, and luteolin—in poly(lactic-co-glycolic) acid (PLGA)-derived polymeric nanoparticles (NPs) has been investigated. Methods: A physicochemical characterization of the NPs has been carried out using different techniques, including the evaluation of antioxidant and antimicrobial activities. Results: In all cases, the encapsulation efficiency of the four flavones in the prepared NPs was high (>90%), the zeta potential was about −31 mV, and the size was nanometric (~450 nm). The drug release from the nanoparticles was also studied, showing first-order kinetics. Statistical tools were applied to the release rate constants. The antioxidant activity and the in vitro antimicrobial activity of the free and flavone-loaded NPs were investigated, in the case of the latter using Gram-positive and Gram-negative bacteria. Results show that when the flavones are encapsulated, they retain their therapeutic properties. Conclusions: In summary, PLGA-based NPs not only prevent flavone degradation but also significantly boost solubility, ultimately optimizing bioavailability. Our results underscore these NPs as a promising platform for efficient flavone delivery.

The overuse of antibiotics over decades has led to a multi-resistance of bacteria that today poses a serious threat to human health. (3-lactam antibiotics are one of the most prescribed drugs against bacterial infectious diseases, which has conducted to increased resistance. The short half-life of these drugs results in low bioavailability, which limits their clinical use and requires continuous administration by infusion. Encapsulation of these antibiotics in nanocarriers would improve their biopharmaceutical properties by protecting them. With this in mind, single- and multi-walled carbon nanotubes (SWCNTs and MWCNTs, respectively) were used here as nanocarriers for the antibiotics Meropenem and Cefepime. The adsorption process of these antibiotics in the carbon nanotubes (CNTs) was optimized to obtain a high encapsulation efficiency. The complexes CNT/drug prepared were characterized by dynamic light scattering and spectroscopic measurements. The growth of Escherichia coli and Staphylococcus aureus bacteria was analyzed in the presence of the CNT/drug complexes to evaluate the pharmacological properties of the encapsulated antibiotics. Results showed lower minimum inhibitory concentration (MIC) values of the CNT/drug complexes compared to free drugs. This indicates the preservation of the pharmacological properties of the encapsulated antibiotics. In addition, the stability of the encapsulated antibiotics was observed to last at least 24 h, which was a great improvement compared to the free drugs.

Flavonoids are secondary plant metabolites with a wide range of pharmacological effects. Among others, their antioxidant, anti-inflammatory and vasoprotective actions are noteworthy. However, the low bioavailability of flavonoids limits their direct clinical use. Nanoencapsulation of flavonoids is an effective tool to improve their biopharmaceutical characteristics, as the drug is protected inside the nanocarrier and specifically released into the therapeutic target. Bearing this in mind, pristine single- and multi-walled carbon nanotubes have been studied in this work as nanocarriers of 7,8-dihydroxyflavone, 7,8-DHF. Flavone encapsulation is optimized according to the influence of pH, the type of CNTs and their concentration on the association process. The equilibrium binding constants of 7,8-DHF to the CNTs are determined by measuring the variation observed in the flavone absorbance when the concentration of carbon nanotubes increases. CNTs/flavone complexes are characterized by particle size distribution and Z-potential measurements, as well as Transmission Electron Microscopy. The antioxidant capacity of free 7,8-DHF and the CNTs/7,8-DHF complexes are estimated by using the DPPH & sdot;, 2,2-diphenyl-1-picrylhydrazyl radical scavenging method. The results show that the encapsulation of the flavone in the CNTs results in a preservation of its pharmacological properties and provides stability to the encapsulated drug.

The HIV attacks the immune system provoking an infection that is considered a global health challenge. Despite antiretroviral treatments being effective in reducing the plasma viral load in the blood to undetectable levels in people living with HIV (PLWH), the disease is not cured and has become chronic. This happens because of the existence of anatomical and cellular viral reservoirs, mainly located in the lymph nodes and gastrointestinal tract, which are composed of infected CD4+ T cells with a resting memory phenotype and inaccessible to antiretroviral therapy. Herein, a new therapeutic strategy based on nanotechnology is presented. Different combinations of antiretroviral drugs (bictegravir/tenofovir/emtricitabine and nevirapine/tenofovir/emtricitabine) and toll-like receptor agonists were encapsulated into metal-organic frameworks (MOFs) PCN-224 and ZIF-8. The encapsulation efficiencies of all the drugs, as well as their release rate from the carriers, were measured. In vitro studies about the cell viability, the hemocompatibility, and the platelet aggregation of the MOFs were carried out. Epifluorescence microscopy assays confirmed the ability of ZIF-8 to target a carboxyfluorescein probe inside HeLa cell lines and PBMCs. These results pave the way for the use of these structures to eliminate latent HIV reservoirs from anatomical compartments through the activation of innate immune cells, and a higher efficacy of the triplet combinations of antiretroviral drugs.

The goal of this work is to investigate if the synergistic antifungal activity between cyclosporine A, CsA, and voriconazole, VRZ, increases when both drugs are encapsulated in a nanocarrier as compared when they are free. The preparation and characterization of blank and VRZ and CsA loaded polymeric based PLGA nanoparticles (PLGA, PLGA-PEG, and PLGA+PEG) was a necessary previous step. Using the more suitable NPs, those of PLGA, the antifungal susceptibility tests performed with VRZ-loaded PLGA NPs, show no significant increase of the antifungal activity in comparison to that of free VRZ. However, the synergistic behavior found for the (VRZ+CsA)-loaded PLGA NPs was fourfold stronger than that observed for the two free drugs together. On the other hand, the investigation into the suppression of C. albicans biofilm formation showed that blank PLGA NPs inhibit the biofilm formation at high NPs concentrations. However, a minor effect or even a slight biofilm increase formation was observed at low and moderate NPs concentrations. Therefore, the enhancement of the biofilm inhibition found for the three tested treatments (CsA alone, VRZ alone, and VRZ+CsA) when comparing free and encapsulated drugs, within the therapeutic window, can be attributed to the drug encapsulation approach. Indeed, polymeric PLGA NPs loaded with CsA, VRZ, or VRZ+CsA are more effective at inhibiting the C. albicans biofilm growth than their free counterparts.

BACKGROUND:Aortic stenosis is the most common valvulopathy in Western countries. The treatment of choice had been surgery aortic valve replacement (SAVR), but the improvement in endovascular approaches as transcatheter aortic valve implantation (TAVI), initially reserved for patients with very high surgical risk, has been extended to high and intermediate, and recently also to low-risk patients. Stroke and vascular cognitive impairment are the most important complications. It is not entirely clear which technique is best to avoid these complications as well as their impact. Our goal is to evaluate changes in cognitive performance in the early (1-month) and late (1-year) postoperative period in patients undergoing SAVR or TAVI, by extensive neuropsychological study (NRP) and advanced Magnetic Resonance Imaging (MRI). Specifically, to compare early and late cognitive changes after the intervention between both groups, the occurrence of stroke during follow-up and to compare the appearance of silent vascular lesions and changes in brain activity and functional connectivity with functional MRI during follow-up between both groups.METHODS/DESIGN:Prospective longitudinal cohort study. A non-selected representative sample of 80 subjects, 40 SAVR and 40 TAVI to obtain a final sample of 36 eligible subjects in each group, ranging from 70 to 85 years old, with indication for aortic replacement and intermediate or high surgical risk will be studied. At baseline, within one month before the treatment, all individuals will undergo an extensive NRP and advanced MRI study. These studies will also be performed 1-month and 1-year after treatment, to assess the appearance of new vascular lesions, as well as changes in cognitive performance with respect to baseline.DISCUSSION:This study aims to evaluate changes in cognitive performance as well as both clinical and silent vascular events occurring in the early (1-month) and late (1-year) periods after SAVR and TAVI. We will also analyze the correlation between neuropsychological and neuroimaging approaches in order to evaluate cognition. Therefore, it may provide high-quality data of cognitive changes and vascular events for both techniques, and be useful to tailor interventions to individual characteristics and ultimately aiding in decision-making.TRIAL REGISTRATION:This study is register in Clinicaltrials.gov (NCT05235529) on 11th February 2022.

Gene therapy is a technique that is currently under expansion and development. Recent advances in genetic medicine have paved the way for a broader range of therapies and laid the groundwork for next-generation technologies. A terminally substituted difluorene-diester Schiff Base calix[4]arene has been studied in this work as possible nanovector to be used in gene therapy. Changes to luminescent behavior of the calixarene macrocycle are reported in the presence of ct-DNA. The calixarene macrocycle interacts with calf thymus DNA (ct-DNA), generating changes in its conformation. Partial double-strand denaturation is induced at low concentrations of the calixarene, resulting in compaction of the ct-DNA. However, interaction between calixarene molecules themselves takes place at high calixarene concentrations, favoring the decompaction of the polynucleotide. Based on cytotoxicity studies, the calixarene macrocycle investigated has the potential to be used as a nanovehicle and improve the therapeutic efficacy of pharmacological agents against tumors.

Gene therapy is a technique to treat or prevent diseases through the use of therapeutic genetic material. Viral or non-viral vectors are needed to deliver genes into cells. Even if viral vectors show several advantages (long-term gene expression and/or high transfection efficiency), their use could produce side effects in the patients. Therefore, non-viral vectors (with a large-scale production and a low immunogenicity) have been shown to be a good choice as nanovehicles of DNA or RNA. Cationic surfactants form organized structures (liposomes, micelles vesicles, or nanoparticles) that can act as non-viral vectors. Both electrostatic and hydrophobic interactions with the nucleic acids produce a conformational change in their doubled helical structure. This new cationic complex (surfactant-based nanostructures + DNA) crosses the lipid bilayer of the cells and delivers the genetic material into the cytosol. In the last years, nanostructures containing cationic metallosurfactants have been successfully used as non-viral vectors. These surfactants contain metal ions incorporated into their structure, generally in their hydrophilic head groups. Redox properties of these metals could be utilized to optimize the transfection process through their self-assembly. The hydrophobic nature of the surfactants also influences the gene delivery. Metallosurfactants can also participate in biological processes such as metabolisms involving enzymes or the production of radical species with antimicrobial properties.

The research on flavonoids has exponentially grown since their first therapeutic evidence, in 1937. They are effective in vitro in a wide range of human diseases, particularly those mediated by free radicals, such as cancer, atherosclerosis, AIDS, or neuronal diseases. However, their applications have been reduced due to their low solubility, poor absorption, and rapid metabolism. Flavonoid encapsulation in nanocarriers significantly improves their oral absorption, protects the drug against degradation, decreases the first-pass hepatic effect, and makes absorption through the lymphatic system easier. In this work, carbon nanotubes were used as nanocarriers of 7-hydroxyflavone, 7-HF. The encapsulation of 7-HF into pristine single- and multi-walled carbon nanotubes, and into -COOH functionalized single-walled carbon nanotubes has been investigated. The equilibrium association constants were estimated. The structural backbone of 7-HF, two benzene rings linked through three carbon atoms that form a pyran heterocyclic ring containing a keto group, seems to play a key role in the 7-HF/CNT interactions, although other types of interactions are also at work. The in vitro release of 7-HF was studied at three pHs, 2.0, 7.4, and 9.2, mimicking the different biological barriers of the human organism.

The interaction (adsorption process) of commercial ionic surfactants with non-functionalized and functionalized carbon nanotubes (CNTs) has been studied by potentiometric measurements based on the use of ion-selective electrodes. The goal of this work was to investigate the role of the CNTs’ charge and structure in the CNT/surfactant interactions. Non-functionalized single- (SWCNT) and multi-walled carbon nanotubes (MWCNT), and amine functionalized SWCNT were used. The influence of the surfactant architecture on the CNT/surfactant interactions was also studied. Surfactants with different charge and hydrophobic tail length (sodium dodecyl sulfate (SDS), octyltrimethyl ammonium bromide (OTAB), dodecyltrimethyl ammonium bromide (DoTAB) and hexadecyltrimethyl ammonium bromide (CTAB)) were studied. According to the results, the adsorption process shows a cooperative character, with the hydrophobic interaction contribution playing a key role. This is made evident by the correlation between the free surfactant concentration (at a fixed [CNT]) and the critical micellar concentration, cmc, found for all the CNTs and surfactants investigated. The electrostatic interactions mainly determine the CNT dispersion, although hydrophobic interactions also contribute to this process.

The formation of calixarene-based liposomes was investigated, and the characterization of these nanostructures was carried out using several techniques. Four amphiphilic calixarenes were used. The length of the hydrophobic chains attached to the lower rim as well as the nature of the polar group present in the upper rim of the calixarenes were varied. The lipid bilayer was formed with one calixarene and with the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, DOPE. The cytotoxicity of the liposomes for various cell lines was also studied. From the results obtained, the liposomes formed with the least cytotoxic calixarene, (TEAC12)4, were used as nanocarriers of both nucleic acids and the antineoplastic drug doxorubicin, DOX. Results showed that (TEAC12)4/DOPE/p-EGFP-C1 lipoplexes, of a given composition, can transfect the genetic material, although the transfection efficiency substantially increases in the presence of an additional amount of DOPE as coadjuvant. On the other hand, the (TEAC12)4/DOPE liposomes present a high doxorubicin encapsulation efficiency, and a slow controlled release, which could diminish the side effects of the drug.

Background The clinical significance of conduction disturbances after transcatheter aortic valve implantation has been described; however, little is known about the influence of baseline ECGs in the prognosis of these patients. Our aim was to study the influence of baseline ECG parameters, including interatrial block (IAB), in the prognosis of patients treated with transcatheter aortic valve implantation. Methods and Results The BIT (Baseline Interatrial Block and Transcatheter Aortic Valve Implantation) registry included 2527 patients with aortic stenosis treated with transcatheter aortic valve implantation. A centralized analysis of baseline ECGs was performed. Patients were divided into 4 groups: normal P wave duration (<120 ms); partial IAB (P wave duration ≥120 ms, positive in the inferior leads); advanced IAB (P wave duration ≥120 ms, biphasic [+/–] morphology in the inferior leads); and nonsinus rhythm (atrial fibrillation/flutter and paced rhythm). The mean age of patients was 82.6±9.8 years and 1397 (55.3%) were women. A total of 960 patients (38.0%) had a normal P wave, 582 (23.0%) had partial IAB, 300 (11.9%) had advanced IAB, and 685 (27.1%) presented with nonsinus rhythm. Mean follow‐up duration was 465±171 days. Advanced IAB was the only independent predictor of all‐cause mortality (hazard ratio [HR], 1.48; 95% CI, 1.10–1.98 [P=0.010]) and of the composite end point (death/stroke/new atrial fibrillation) (HR, 1.51; 95% CI, 1.17–1.94 [P=0.001]). Conclusions Baseline ECG characteristics influence the prognosis of patients with aortic stenosis treated with transcatheter aortic valve implantation. Advanced IAB is present in about an eighth of patients and is associated with all‐cause death and the composite end point of death, stroke, and new atrial fibrillation during follow‐up.

Servicio de Cardiologı́a, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain Servicio de Cardiologı́a, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain Servicio de Cardiologı́a, Hospital Universitario de La Princesa, Madrid, Spain Servicio de Cardiologı́a, Hospital Moisès Broggi, Sant Joan Despı́, Barcelona, Spain Servicio de Cardiologı́a, Hospital General Universitario Gregorio Marañón, CIBERCV, Universidad Complutense, Universidad Europea, Madrid, Spain

Background: Aortic stenosis (AS) is currently the most frequent heart valve disease. Symptomatic severe AS has a poor prognosis and transcatheter aortic valve implantation (TAVI) is becoming the therapy of choice in these patients. Changes in the conduction tissue after the procedure constitute one of the main limitations of TAVI, with a frequent need for a definitive pacemaker. Interatrial block (IAB) is defined as a prolonged P-wave duration and is related with atrial fibrosis. The presence of IAB could be a marker of conduction tissue abnormalities at other levels. No study has specifically analyzed the role of IAB as a predictor of the need for permanent pacemaker in patients with AS undergoing TAVI. Methods: The Baseline Interatrial block and Transcatheter aortic valve implantation (BIT) registry will be performed in approximately 3000 patients with severe AS treated with TAVI. A centralized analysis of baseline ECGs will study the presence and type of IAB and other ECG data (rhythm, P-wave duration, PR and QRS intervals/intraventricular conduction disorders). Clinical follow-up will be carried out by local researchers. The primary endpoint will be the requirement of permanent pacemaker during post-TAVI hospitalization. As secondary objectives, the incidence of new onset AF, stroke, or mortality during follow-up will be analyzed. Secondary endpoints will include the incidence of new onset AF, stroke, or mortality during follow-up. Conclusion: The BIT registry will study, for the first time, the influence of previous IAB in the need of permanent pacemaker after TAVI: This large registry will also provide information regarding the association of this and other ECG parameters with prognosis. (C) 2019 Elsevier Inc. All rights reserved.

OBJECTIVES:No previous studies have assessed the role of the FRAIL scale in predicting long-term outcomes in older patients with acute coronary syndromes (ACS). DESIGN, SETTING AND PARTICIPANTS:The multicenter observational LONGEVO-SCA registry included unselected patients ≥80 years of age with ACS from 44 centers. A comprehensive geriatric assessment was performed during hospitalization. MEASURES:Frailty was measured by the FRAIL scale. For the purpose of this study, main outcome measured was mortality or readmission at 24 months. RESULTS:A total of 498 patients were included. Mean age was 84.3 years. A total of 198 patients (33.1%) were prefrail and 135 (27.1%) frail. Patients who were prefrail and frail had a higher degree of comorbidities, and higher prevalence of disability, cognitive impairment, and nutritional risk. A total of 165 out of 498 patients (33.1%) died, and 331 patients (66.7%) died or were readmitted at 24 months. Both prefrailty and frailty were associated with a higher mortality compared with robust patients (P < .001). The incidence of mortality or readmission was also higher in patients who were prefrail or frail (P < .001). After adjusting for potential confounders, the association between frailty and mortality or readmission remained significant (hazard ratio 1.28 for prefrailty and hazard ratio 1.96 for frailty, P < .001). The FRAIL scale showed an optimal ability for predicting mortality or readmission (area under the receiver operating characteristics curve 0.86, 95% confidence interval 0.83‒0.89). The area under the receiver operating characteristics curve from the Global Registry of Acute Coronary Events risk score was 0.89. No significant differences were observed between both AUC values (P = .163). CONCLUSIONS AND IMPLICATIONS:The FRAIL scale independently predicted long-term outcomes in older patients with ACS. The predictive ability of this scale was comparable to the strongly recommended Global Registry of Acute Coronary Events risk score. Frailty assessment is mandatory for improving risk prediction in these complex patients.

In this work, poly(lactic-co-glycolic acid) (PLGA) and chitosan (CS) nanoparticles were synthesized with the purpose of encapsulating levofloxacin (LEV). A thorough study has been carried out in order to optimize the preparation of LEV-loaded polymeric nanoparticles (NPs) suitable for parenteral administration. Changes in the preparation method, in the organic solvent nature, in the pH of the aqueous phase, or in the temperature were investigated. To the authors´ knowledge, a systematic study in order to improve the LEV nanocarrier characteristics and the yield of drug encapsulation has not been carried out to date. The physicochemical characterization of the NPs, their encapsulation efficiency (EE), and the in vitro release of LEV revealed that the best formulation was the emulsion-solvent evaporation method using dichloromethane as organic solvent, which renders suitable LEV loaded PLGA NPs. The morphology of these NPs was investigated using TEM. Their antimicrobial activities against several microorganisms were determined in vitro measuring the minimum inhibitory concentration (MIC). The results show that the use of these loaded LEV PLGA nanoparticles has the advantage of the slow release of the antibiotic, which would permit an increase in the time period between administrations as well as to decrease the side effects of the drug.

Background The number of nonagenarian patients with aortic stenosis will likely increase due to the ageing population. We assessed the clinical characteristics, management, and outcomes of nonagenarian patients with severe aortic stenosis. Methods A total of 177 (117 females and 60 males) consecutive nonagenarian patients from two large contemporary registries were included in this study. Clinical characteristics, comorbidity as assessed by the Charlson Index, clinical management, and outcomes were recorded. The main outcome measure was 1-year mortality. Results The mean patient age was 91.1 years, and 56 patients (31.6%) had a Charlson Index <3. A strong association between comorbidity and 1-year overall mortality was observed, with higher 1-year mortality in patients with Charlson Index >= 3 (66.4% vs. 32.1%, p < 0.001). A total of 150 patients (84.7%) were managed conservatively, and 27 (15.3%) underwent transcatheter aortic valve implantation (TAVI). Predictors of a conservative management were treatment out of TAVI centres, lower mean aortic gradient and better functional class. Clinical management was not significantly different with different degrees of comorbidity. A trend toward higher mortality in patients undergoing conservative management was observed (58% vs. 40.7%, p = 0.097). Independent predictors of mortality were higher Charlson Index, lower creatinine clearance, lower mean aortic gradient, poorer left ventricular ejection fraction, significant mitral regurgitation and conservative management. Conclusions About one third of nonagenarians with severe aortic stenosis have few comorbidities. The clinical management was similar irrespective of the Charlson Index. Both higher Charlson Index values and a conservative management were independently associated with a higher mortality.

The authors regret the change in affiliations for Dr. Eva Bernal. The current affiliations of Dr. Eva Bernal are: Eva Bernala,b a Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain b Universitat Autònoma de Barcelona, Spain The second affiliation should be changed to a Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain b Departament de Medicina, Universitat Autònoma de Barcelona, Spain The authors would like to apologise for any inconvenience caused. Conservative management in very elderly patients with severe aortic stenosis: Time to change?Journal of CardiologyVol. 69Issue 6PreviewDespite current recommendations, a high percentage of patients with severe symptomatic aortic stenosis are managed conservatively. The aim of this study was to study symptomatic patients undergoing conservative management from the IDEAS registry, describing their baseline clinical characteristics, mortality, and the causes according to the reason for conservative management. Full-Text PDF Open Archive