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Introduction and Objectives: Subjects without cardiovascular (CV) disease (CVD) may suffer from subclinical atherosclerosis, and are at increased risk for atherosclerotic CV events (ASCVE). The ESC/EAS risk SCORE was updated by SCORE2, which estimates 10-year risk of fatal and non-fatal CVD in European populations aged 40-69 years without established CVD or diabetes. Our aim was to compare the two ESC/EAS risk scores and to validate SCORE2 in our population., Methods: A total of 1071 individuals (age 57.2±6.1 years; 75.2% male) without CVD or diabetes, from GENEMACOR study controls, were analyzed over 5.4±3.9 years. The population was stratified into risk categories according to the two scores, and the area under the ROC curve (AUC) and Harrell's C-index assessed the scores' performance. Calibration was performed using the goodness-of-fit test, and occurrence of the first event assessed by Cox regression. Kaplan-Meier analysis estimated SCORE2 survival., Results: SCORE stratified subjects into four risk categories: low (7.4%), moderate (46.5%), high (25.3%) and very high (20.8%), and SCORE2 into three: low-to-moderate (24.7%), high (59.0%) and very high (16.2%). SCORE presented good discrimination for CV mortality (AUC=0.838; C-index=0.834, 95% CI: 0.728-0.940), as did SCORE2 for total CV events (AUC=0.744; C-index=0.728, 95% CI: 0.648-0.808). Calibration did not show a disparity between observed and expected ASCVE. The probability of ASCVE was eight times higher in very-high-risk SCORE2 (p=0.001), and three times in the high-risk group (p=0.049). Event-free survival was 99%, 90% and 72% in the low-to-moderate, high and very-high-risk categories, respectively (p<0.0001)., Conclusions: SCORE2 improved population stratification by identifying higher-risk patients, enabling early preventive measures. It showed good discriminative ability for all ASCVE., (Copyright © 2024 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Aims: Coronary artery calcium score (CACS) and polygenic risk score have been used as novel markers to predict cardiovascular (CV) events of asymptomatic individuals compared with traditional scores. No previous studies have directly compared the additive capacity of these two markers relative to conventional scores. The aim of the study was to evaluate the change in CV risk prediction ability when CACS, genetic risk score (GRS), or both are added to Systematic Coronary Risk Evaluation 2 (SCORE2)., Methods and Results: In a prospective, observational population-based study, 1002 asymptomatic subjects (mean age 53.1 ± 6.8 years, 73.8% male), free of clinical coronary disease and diabetes, were selected from GENEMACOR-study controls. SCORE2, CACS, and GRS were estimated to evaluate CV events' predictive and discriminative ability through Harrell's C-statistics. Net reclassification improvement (NRI) and integrated discrimination index were used to reclassify the population. Multivariable Cox proportional hazard ratio (HR) analysis assessed the variables independently associated with CV events. C-statistic demonstrated that the discriminative value for CV event occurrence was 0.608 for SCORE2, increasing to 0.749 (P = 0.001) when CACS was added, and improved to 0.802 (P = 0.0008) with GRS, showing a better discriminative capacity for CV events. Continuous NRI reclassified >70% of the population. Cox proportional analysis showed that the highest categories of SCORE2, CACS, and GRS remained in the equation with an HR of 2.9 (P = 0.003), 5.0 (P < 0.0001), and 3.2 (P = 0.003), respectively, when compared with the lowest categories., Conclusion: In our population, CACS added to SCORE2 had better ability than GRS in CV event risk prediction, discrimination, and reclassification. However, adding the three scores can become clinically relevant, especially in intermediate-risk persons., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Conflict of interest: None declared.

Introduction and Objectives: Transcription factor 21 (TCF21) is a member of the basic helix-loop-helix (bHLH) transcription factor family, and is critical for embryogenesis of the heart. It regulates differentiation of epicardium-derived cells into smooth muscle cell (SMC) and fibroblast lineages. The biological role of TCF21 in the progression of atherosclerosis is the subject of debate. The aim of this study was to investigate the impact of the TCF21 rs12190287 gene variant on the prognosis of coronary artery disease (CAD) in a Portuguese population from Madeira island., Methods: We analyzed major adverse cardiovascular events (MACE) in 1713 CAD patients, mean age 53.3±7.8, 78.7% male, for 5.0±4.3 years. Genotype and allele distribution between groups with and without MACE was determined. The dominant genetic model (heterozygous GC plus homozygous CC) was used and compared with the wild GG to assess survival probability. Cox regression with risk factors and genetic models assessed variables associated with MACE. Kaplan-Meier analysis was used to estimate survival., Results: The wild homozygous GG, heterozygous GC and risk CC genotypes were found in 9.5%, 43.2% and 47.3% of the population, respectively. The dominant genetic model remained in the equation as an independent risk factor for MACE (HR 1.41; p=0.033), together with multivessel disease, chronic kidney disease, low physical activity and type 2 diabetes. The C allele in the dominant genetic model showed worse survival (22.5% vs. 44.3%) at 15 years of follow-up., Conclusion: The TCF21 rs12190287 variant is a risk factor for CAD events. This gene may influence fundamental SMC processes in response to vascular stress, accelerating atherosclerosis progression, and may represent a target for future therapies., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

Introduction: Coronary artery disease (CAD), characterized by an atherogenic process in the coronary arteries, is one of the leading causes of death in Madeira. The GENEMACOR (GENEs in MAdeira and CORonary Disease) study sought to investigate the main risk factors - environmental and genetic - and estimate whether a genetic risk score (GRS) improves CAD prediction, discrimination and reclassification., Methods: Traditional risk factors and 33 CAD genetic variants were considered in a case-control study with 3139 individuals (1723 patients and 1416 controls). The multivariate analysis assessed the likelihood of CAD. A multiplicative GRS (mGRS) was created, and two models (with and without mGRS) were prepared. Two areas under receiver operating characteristic curve (area under curve (AUC)) were analyzed and compared to discriminate CAD likelihood. Net reclassification improvement (NRI) and integrated discrimination index (IDI) were used to reclassify the population., Results: All traditional risk factors were strong and independent predictors of CAD, with smoking being the most significant (OR 3.25; p<0.0001). LPA rs3798220 showed a higher CAD likelihood (odds ratio 1.45; p<0.0001). Individuals in the fourth mGRS quartile had an increased CAD probability of 136% (p<0.0001). A traditional risk factor-based model estimated an AUC of 0.73, rising to 0.75 after mGRS inclusion (p<0.0001), revealing a better fit. Continuous NRI better reclassified 28.1% of the population, and categorical NRI mainly improved the reclassification of the intermediate risk group., Conclusions: CAD likelihood was influenced by traditional risk factors and genetic variants. Incorporating GRS into the traditional model improved CAD predictive capacity, discrimination and reclassification. These approaches may provide helpful diagnostic and therapeutic advances, especially in the intermediate risk group., (Copyright © 2022 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.repc.2022.10.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal., (Copyright © 2022. Publicado por Elsevier España, S.L.U.)

The inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies.

A novel solvent controlled precipitation (SCP) process based on microfluidization was assessed to produce solid dispersions of carbamazepine, a poorly water-soluble drug with dissolution-rate limited absorption. A half-factorial design (2(3-1)+2 central points) was conducted to study the effect of different formulation variables (viz. polymer type, drug load, and feed solids' concentration) on the particle size and morphology, drug's solid state and drug's molecular distribution within the carrier of the co-precipitated materials produced. Co-precipitated powders were isolated via spray drying (SD). Nano-composite aggregated particles were obtained among all the tests. The particle size of the aggregates was dependent on the feed solids' concentration, while the level of aggregation between nanoparticles was dependent on the drug-polymer ratio. Both amorphous and crystalline nano-solid dispersions were produced using the proposed SCP process. The solid dispersion produced was dependent on both the type of polymeric stabilizer chosen and the drug load. Controls of amorphous and crystalline nano-solid dispersions produced by SCP and an amorphous micro-solid dispersion produced by SD were tested for: in vitro dissolution, in vivo pharmacokinetics in mice, and long-term storage physical stability. Both nano-amorphous and nano-crystalline presented faster dissolution rates and enhanced bioavailabilities than the micro-sized amorphous powder. The reduction of particle size to the nano-scale was found to be more important than the amorphization of the drug. The long-term physical stability of the amorphous nano-solid dispersion and the amorphous micro-solid dispersion were comparable., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Pharmaceutical cocrystals are used as a strategy to overcome poor physicochemical properties of drugs. The use of cocrystals in the pharmaceutical industry remains to be fully exploited due, in part, to the scarcity of suitable large-scale production methods and lack of robust and cost-effective processes. To overcome these challenges, spray congealing was used for the first time in the preparation of cocrystals. The work considered a feasibility study, followed by a design of experiments to assess the impact of varying atomization and cooling-related process parameters on cocrystal formation, purity, particle size, shape and bulk powder flow properties. It was demonstrated that spray congealing could be used to produce cocrystals. The thermal analysis and X-ray results of the spray-congealed products were different from the pure components or physical mixtures and were aligned with those reported for the same cocrystals systems produced by other techniques. Cocrystal particles were compact and spherical consisting of aggregates of individual cocrystals entangled or adhered with each other. From the design of experiments, the results demonstrated that varying the process parameters did not influence cocrystal formation, but had an impact on cocrystal purity. Moreover, it was demonstrated that cocrystal particle properties can be adjusted, in situ, by varying atomization and cooling efficiency, in order to produce particles more suited for incorporation in final dosage forms such as tablets., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The data presented in this article are related to the production of 1:1 Caffeine:Glutaric Acid cocrystals as part of the research article entitled "Green production of cocrystals using a new solvent-free approach by spray congealing" (Duarte et al., 2016) [1]. More specifically, here we present the thermal analysis and the X-ray powder diffraction data for pure Glutaric Acid, used as a raw material in [1]. We also include the X-ray powder diffraction and electron microscopy data obtained for the 1:1 Caffeine:Glutaric Acid cocrystal (form II) produced using the cooling crystallization method reported in "Operating Regions in Cooling Cocrystallization of Caffeine and Glutaric Acid in Acetonitrile" (Yu et al., 2010) [2]. Lastly, we show the X-ray powder diffraction data obtained for assessing the purity of the 1:1 Caffeine:Glutaric cocrystals produced in [1].

Purpose: To present a new screening methodology intended to be used in the early development of spray-dried amorphous solid dispersions., Methods: A model that combines thermodynamic, kinetic and manufacturing considerations was implemented to obtain estimates of the miscibility and phase behavior of different itraconazole-based solid dispersions. Additionally, a small-scale solvent casting protocol was developed to enable a fast assessment on the amorphous stability of the different drug-polymer systems. Then, solid dispersions at predefined drug loads were produced in a lab-scale spray dryer for powder characterization and comparison of the results generated by the model and solvent cast samples., Results: The results obtained with the model enabled the ranking of the polymers from a miscibility standpoint. Such ranking was consistent with the experimental data obtained by solvent casting and spray drying. Moreover, the range of optimal drug load determined by the model was as well consistent with the experimental results., Conclusions: The screening methodology presented in this work showed that a set of amorphous formulation candidates can be assessed in a computer model, enabling not only the determination of the most suitable polymers, but also of the optimal drug load range to be tested in laboratory experiments. The set of formulation candidates can then be further fine-tuned with solvent casting experiments using a small amount of API, which will then provide the decision for the final candidate formulations to be assessed in spray drying experiments.

Differently shaped polymeric matrices were efficiently coated with stimuli-responsive hydrogels for a wide range of applications using a new methodology. By combining plasma surface activation and polymerization in supercritical media at mild conditions, we report the direct smart coating of microcarriers and membranes in gram-scale quantities with a scalable, green, and low-cost approach.

Molecularly imprinted polymers (MIPs) of poly(ethylene glycol dimethacrylate) and poly(N-isopropylacrylamide-co-ethylene glycol dimethacrylate) were synthesized for the first time in supercritical carbon dioxide (scCO(2)), using Boc-L-tryptophan as template. Supercritical fluid technology provides a clean and one-step synthetic route for the preparation of affinity polymeric materials with sensing capability for specific molecules. The polymeric materials were tested as stationary HPLC phases for the enantiomeric separation of L- and D-tryptophan. HPLC results prove that the synthesized MIPs are able to recognize the template molecule towards its enantiomer which opens up potential applications in chromatographic chiral separation., ((c) 2009 Elsevier B.V. All rights reserved.)

Cyclodextrin-containing polymers have proved themselves to be useful for controlled release. Herein we describe the preparation of membranes of poly(methylmethacrylate) (PMMA) containing hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) using a supercritical CO(2)-assisted phase inversion method, for potential application as drug delivery devices. Results are reported on the membrane preparation, physical properties, and drug elution profile of a model drug. The polymeric membranes were obtained with HP-beta-CD contents ranging from 0 to 33.4 wt%, by changing the composition of the casting solution, and were further impregnated with ibuprofen using supercritical carbon dioxide (scCO(2)) in batch mode. The influence of the membrane functionalization in the controlled release of ibuprofen was studied by performing in vitro experiments in buffer solution pH at 7.4. The release of the anti-inflammatory drug could be tuned by varying the cyclodextrin content on the membranes.

Cyclodextrins are used in many drug formulations since their cavities provide microenvironments where drug molecules can enter and form inclusion complexes for controlled drug delivery. Supercritical carbon dioxide (scCO(2)) is an alternative to organic solvents and a very attractive medium for the preparation of these inclusion complexes. The potential ability of triacetyl-beta-cyclodextrin (TA-beta-CD) to form inclusion complexes in addition to its high miscibility in liquid and scCO(2) could offer a chance for an economical and environmental friendly chemical processing. In this work, high-pressure NMR studies were performed in order to obtain information on the molecular structure and dynamics of TA-beta-CD in scCO(2) at 313.15 K and 20 MPa and its ability to form inclusion complexes under these conditions was studied. The influence of scCO(2) on a number of NMR spectral parameters, such as chemical shifts, spin-spin coupling constants, nuclear Overhauser effect (NOE) and spin-lattice relaxation (T(1)) has been studied. We unequivocally show for the first time structural changes of TA-beta-CD in scCO(2), like acetyl chain orientation and overall shape distortions that can affect its inclusion capability in this medium. The possibility of cavity self-closure is discussed and the results of two inclusion studies that support cavity self-closure, with the angiotensin-converting enzyme inhibitor, captopril, and the nonsteroid anti-inflammatory drug, flufenamic acid, are presented., (2008 John Wiley & Sons, Ltd.)

The carbon and fluorine chemical shifts of mixtures of carbon dioxide and Krytox, a carboxylic acid end-capped perfluorinated polyether used as stabilizer for the dispersion polymerization of methyl methacrylate, have been studied using high-pressure, high-resolution nuclear magnetic resonance. 13C and 19F spectra were measured in the density region between 0.54 and 0.73 g.cm(-3) at 334 K for different solutions of Krytox in scCO2 (0.22, 1.13 and 1.72 w/w %). An in-house developed high-pressure apparatus with the capability to change in situ the sample composition was used for this purpose using a 10 mm polyether ketone NMR tube. The nature of CO2-Krytox interaction was assessed both by comparing the CO2 deltaC variation of neat CO2 with that of mixtures with increasing surfactant composition and by the analysis of Krytox 19F corrected chemical shifts in terms of medium magnetic susceptibility. Ab initio calculations, at the second-order Møller-Plesset level of theory to include the effects of electron correlation, were performed to access and compare the nature of the interactions between CO2 and perfluorinated and nonfluorinated analogue model molecules. Both experimental 13C and 19F HP-NMR results and molecular modeling studies support a F...CO2 site-specific Lewis acid-Lewis base interaction model. A positive entropic variation for the formation of CO2-fluorinated solute complex is advanced as an explanation for the higher solubility of perfluorinated molecules when compared to the nonfluorinated analogues.