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Background: Age-related remodelling has the potential to affect the microvascular response to hyperemic stimuli. However, its precise effects on the vasodilatory response to adenosine and contrast medium, as well as its influence on fractional flow reserve (FFR) and contrast fractional flow reserve (cFFR), have not been previously investigated. We investigate the impact of age on these indices., Methods: We extrapolated data from the post-revascularization optimization and physiological evaluation of intermediate lesions using fractional flow reserve (PROPHET-FFR) and The Multi-center Evaluation of the Accuracy of the Contrast MEdium INduced Pd/Pa RaTiO in Predicting (MEMENTO) studies. Only lesions with a relevant vasodilatory response to adenosine and contrast medium were considered of interest. A total of 2080 patients, accounting for 2294 pressure recordings were available for analysis. The cohort was stratified into three age terciles. Age-dependent correlations with FFR, cFFR, distal pressure/aortic pressure (Pd/Pa) and instantaneous wave-free ratio (iFR) were calculated. The vasodilatory response was calculated in 1619 lesions (with both FFR and cFFR) as the difference between resting and hyperaemic pressure ratios and correlated with aging. The prevalence of FFR-cFFR discordance was assessed., Results: Age correlated positively to FFR (r = 0.062, p = 0.006), but not with cFFR (r = 0.024, p = 0.298), Pd/Pa (r = -0.015, p = 0.481) and iFR (r = -0.026, p = 0.648). The hyperemic response to adenosine (r = -0.102, p ≤ 0.0001) and to contrast medium (r = -0.076, p = 0.0023) showed a negative correlation with age. When adjusted for potential confounders, adenosine induced hyperaemia was negatively associated with age ( p = 0.04 vs p = 0.08 for cFFR). Discordance decreased across age terciles (14.64% vs 12.72% vs 10.12%, p = 0.032)., Conclusions: As compared to adenosine, contrast induced hyperaemia appeared to be less affected by age. cFFR may be considered a more stable and reproducible tool to assess epicardial stenosis in elderly patients., Clinical Trial Registration: PROPHET-FFR STUDY, Clinicaltrials.gov (NCT05056662)., Competing Interests: AML. received speaking honoraria from Abbott, Menarini, Bruno, Bayer, Medtronic and Daiichi Sankyo; CT, FB. received speaker’s fees from Abbott, Medtronic, and Abiomed. SBB has received investigation grants and consulting honoraria from Abbott and investigation grants from Volcano/Philips. NA has received consulting honoraria from Abbott, Boston Scientific and Shockwave Medical. LR has received investigation speaker fees from Boston Scientific, Abbott vascular, Philips/Volvano. Antonio Maria Leone is serving as one of the Editorial Board members and Guest Editors of this journal. We declare that Antonio Maria Leone had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Ezra Abraham Amsterdam. The other authors have no conflicts of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Alpha-glucosidase inhibitors play an important role in Diabetes Mellitus (DM) treatment since they prevent postprandial hyperglycemia. The Glycoside Hydrolase family 13 (GH13) is the major family of enzymes acting on substrates containing α-glucoside linkages, such as maltose and amylose/amylopectin chains in starch. Previously, our group identified glycoconjugate 1H-1,2,3-triazoles (GCTs) inhibiting two GH13 α-glycosidases: yeast maltase (MAL12) and porcine pancreatic amylase (PPA). Here, we combined kinetic studies and computational methods on nine GCTs to characterize their inhibitory mechanism. They all behaved as reversible inhibitors, and kinetic models encompassed noncompetitive and various mechanisms of mixed-type inhibition for both enzymes. Most potent inhibitors displayed K i values of 30 μM for MAL12 (GPESB16) and 37 μM for PPA (GPESB15). Molecular dynamics and docking simulations indicated that on MAL12, GPESB15 and GPESB16 bind in a cavity adjacent to the active site, while on the PPA, GPESB15 was predicted to bind at the entrance of the catalytic site. Notably, despite its putative location within the active site, the binding of GPESB15 does not obstruct the substrate's access to the cleavage site. Our study contributes to paving the way for developing novel therapeutic strategies for managing DM-2 through GH13 α-glycosidases inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible for causing diseases in humans, like the West Nile virus (WNV) and the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the mechanisms behind blocking viral protease's function is pivotal for the development of new antiviral drugs and therapeutical strategies. Apart from directly inhibiting the target protease, usually by targeting its active site, several new pathways have been explored to impair its activity, such as inducing protein aggregation, targeting allosteric sites or by inducing protein degradation by cellular proteasomes, which can be extremely valuable when considering the emerging drug-resistant strains. In this review, we aim to discuss the recent advances on a broad range of viral proteases inhibitors, therapies and molecular approaches for protein inactivation or degradation, giving an insight on different possible strategies against this important class of antiviral target.

Introduction: Clinical events may occur after percutaneous coronary intervention (PCI), particularly in complex lesions and complex patients. The optimization of PCI result, using pressure guidewire and intracoronary imaging techniques, may reduce the risk of these events. The hypothesis of the present study is that the clinical outcome of patients with indication of PCI and coronary stent implantation that are at high risk of events can be improved with an unrestricted use of intracoronary tools that allow PCI optimization., Methods and Analysis: Observational prospective multicenter international study, with a follow-up of 12 months, including 1064 patients treated with a cobalt‑chromium everolimus-eluting stent. Inclusion criteria include any of the following: Lesion length > 28 mm; Reference vessel diameter < 2.5 mm or > 4.25 mm; Chronic total occlusion; Bifurcation with side branch ≥2.0 mm;Ostial lesion; Left main lesion; In-stent restenosis; >2 lesions stented in the same vessel; Treatment of >2 vessels; Acute myocardial infarction; Renal insufficiency; Left ventricular ejection fraction <30 %; Staged procedure. The control group will be comprised by a similar number of matched patients included in the "extended risk" cohort of the XIENCE V USA study. The primary endpoint will be the 1-year rate of target lesion failure (TLF) (composite of ischemia-driven TLR, myocardial infarction (MI) related to the target vessel, or cardiac death related to the target vessel). Secondary endpoints will include overall mortality, cardiovascular mortality, acute myocardial infarction, TVR, TLR, target vessel failure, and definitive or probable stent thrombosis at 1 year., Implications: The ongoing OPTI-XIENCE study will contribute to the growing evidence supporting the use of intra-coronary imaging techniques for stent optimization in patients with complex coronary lesions., Competing Interests: Declaration of competing interest The following authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The rest of the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Antibiotic resistance continues to be an ominous threat facing human health globally and urgent action is required to limit the loss of human life. The pollution of antibiotics into the environment is one of the drivers behind the crisis. With this in mind, we have developed novel photodecomposable antimicrobial agents based on an ethanolamine scaffold, which upon photoirradiation decomposes into two major inactive fragments. Herein we describe our further work on the synthesis of novel ethanolamines with a particular focus on structure activity relationship, resulting in four new active compounds which photodecomposed into inactive fragments., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

SARS-CoV-2 is the causative agent of COVID-19 and is responsible for the current global pandemic. The viral genome contains 5 major open reading frames of which the largest ORF1ab codes for two polyproteins, pp1ab and pp1a, which are subsequently cleaved into 16 nonstructural proteins (nsp) by two viral cysteine proteases encoded within the polyproteins. The main protease (Mpro, nsp5) cleaves the majority of the nsp's, making it essential for viral replication and has been successfully targeted for the development of antivirals. The first oral Mpro inhibitor, nirmatrelvir, was approved for treatment of COVID-19 in late December 2021 in combination with ritonavir as Paxlovid. Increasing the arsenal of antivirals and development of protease inhibitors and other antivirals with a varied mode of action remains a priority to reduce the likelihood for resistance emerging. Here, we report results from an artificial intelligence-driven approach followed by in vitro validation, allowing the identification of five fragment-like Mpro inhibitors with IC 50 values ranging from 1.5 to 241 μM. The three most potent molecules (compounds 818, 737, and 183) were tested against SARS-CoV-2 by in vitro replication in Vero E6 and Calu-3 cells. Compound 818 was active in both cell models with an EC 50 value comparable to its measured IC 50 value. On the other hand, compounds 737 and 183 were only active in Calu-3, a preclinical model of respiratory cells, showing selective indexes twice as high as those for compound 818. We also show that our in silico methodology was successful in identifying both reversible and covalent inhibitors. For instance, compound 818 is a reversible chloromethylamide analogue of 8-methyl-γ-carboline, while compound 737 is an N -pyridyl-isatin that covalently inhibits Mpro. Given the small molecular weights of these fragments, their high binding efficiency in vitro and efficacy in blocking viral replication, these compounds represent good starting points for the development of potent lead molecules targeting the Mpro of SARS-CoV-2.

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC 50 = 7-50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.

Background: Patients undergoing heart valve surgery are routinely evaluated for the presence of coronary artery disease (CAD). Currently, concomitant valve intervention and surgical revascularization is recommended when there is obstructive CAD. The aim of our study was to evaluate the prevalence of CAD, its treatment strategies, and their prognostic implications in a contemporary population of patients with valvular heart disease (VHD) referred for valve surgery (HVS)., Methods: In a multicenter registry, consecutive patients with formal indication for HVS referred for a preoperative routine invasive coronary angiogram (ICA) were analyzed. Baseline characteristics, CAD prevalence and revascularization patterns, as well as their impact on short and mid-term all-cause mortality, were assessed., Results: Overall, 1133 patients were included; most had aortic stenosis (69%) and obstructive CAD was present in 307 (27.1%). HVS was ultimately performed in 82.3%. In patients with CAD, 53.4% were revascularized. After a mean follow-up time of 29.06±18.46 months, all-cause mortality rate was 12.9%. In multivariate analysis, not having HVS (HR 6.845, 95% CI=4.281-10.947, P<0.001), obstructive CAD (HR 2.762, 95% CI=1.764-4.326, P<0.01), COPD (HR 2.043, 95% CI=1.014-4.197, P=0.022), and age (HR 1.030, 95% CI=1.009-1.063, P=0.047), were independent predictors of all-cause mortality. In patients with obstructive CAD who underwent HVS, revascularization was not significantly associated with survival (HR 2.127, 95% CI=0.0-4.494, P=0.048; log rank P=0.042)., Conclusions: In a contemporary cohort of patients with VHD and surgical indication, overall obstructive CAD prevalence was 27%. CAD presence and severity were associated with higher mortality. However, revascularization was not associated with a survival benefit, except in patients with left anterior descending artery disease.

Snakebite envenoming is a health concern and has been a neglected tropical disease since 2017, according to the World Health Organization. In this study, we evaluated the ability of ten 1,2,3-triazole derivatives AM001 to AM010 to inhibit pertinent in vitro (coagulant, hemolytic, and proteolytic) and in vivo (hemorrhagic, edematogenic, and lethal) activities of Bothrops jararaca venom. The derivatives were synthesized, and had their molecular structures fully characterized by CHN element analysis, Fourier-transform infrared spectroscopy and Nuclear magnetic resonance. The derivatives were incubated with the  B. jararaca venom (incubation protocol) or administered before (prevention protocol) or after (treatment protocol) the injection of B. jararaca venom into the animals. Briefly, the derivatives were able to inhibit the main toxic effects triggered by B. jararaca venom, though with varying efficacies, and they were devoid of toxicity through in vivo , in silico or in vitro analyses. However, it seemed that the derivatives AM006 or AM010 inhibited more efficiently hemorrhage or lethality, respectively. The derivatives were nontoxic. Therefore, the 1,2,3-triazole derivatives may be useful as an adjuvant to more efficiently treat the local toxic effects caused by B. jararaca envenoming., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The use of innate products for the fast and efficient promotion of healing process has been one of the biomedical sector's main bets for lesion treatment modernization process. The aim of this study was to develop and characterize bacterial cellulose-based (BC) wound dressings incorporated with green and red propolis extract (2 to 4%) and the active compounds p -coumaric acid and biochanin A (8 to 16 mg). The characterization of the nine developed samples (one control and eight active wound dressings) evidenced that the mechanics, physics, morphological, and barrier properties depended not only on the type of active principle incorporated onto the cellulosic matrix, but also on its concentration. Of note were the results found for transparency (28.59-110.62T 600 mm -1 ), thickness (0.023-0.046 mm), swelling index (48.93-405.55%), water vapor permeability rate (7.86-38.11 g m 2 day -1 ), elongation (99.13-262.39%), and antioxidant capacity (21.23-86.76 μg mL -1 ). The wound dressing based on BC and red propolis was the only one that presented antimicrobial activity. The permeation and retention test revealed that the wound dressing containing propolis extract presented the most corneal stratum when compared with viable skin. Overall, the developed wound dressing showed potential to be used for treatment against different types of dermal lesions, according to its determined proprieties.

The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.

Background: The influence of age-dependent changes on fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) and the response to pharmacological hyperaemia has not been investigated., Aims: We investigated the impact of age on these indices., Methods: This is a post hoc analysis of the ADVISE II trial, including a total of 690 pressure recordings (in 591 patients). Age-dependent correlations with FFR and iFR were calculated and adjusted for stenosis severity. Patients were stratified into three age terciles. The hyperaemic response to adenosine, calculated as the difference between resting and hyperaemic pressure ratios, and the prevalence of FFR-iFR discordance were assessed., Results: Age correlated positively with FFR (r=0.08, 95% CI: 0.01 to 0.15, p=0.015), but not with iFR (r=-0.03, 95% CI: -0.11 to 0.04, p=0.411). The hyperaemic response to adenosine decreased with patient age (0.12±0.07, 0.11±0.06, 0.09±0.05, for the 1st [33-58 years], 2nd [59-69 years] and 3rd [70-94 years] age tertiles, respectively, p<0.001) and showed significant correlation with age (r=-0.14, 95% CI: -0.21 to -0.06, p<0.001). The proportion of patients with FFR ≤0.80+iFR >0.89 discordance doubled in the first age tercile (14.1% vs 7.1% vs 7.0%, p=0.005)., Conclusions: The hyperaemic response of the microcirculation to adenosine administration is age dependent. FFR values increase with patient age, while iFR values remain constant across the age spectrum. These findings contribute to explaining differences observed in functional stenosis classification with hyperaemic and non-hyperaemic coronary indices.

Introduction and Objectives: Use of invasive physiological assessment in patients with coronary artery disease varies widely and is perceived to be low. We aimed to examine adoption rates as well as patterns and determinants of use in an unselected population undergoing invasive coronary angiography over a long time frame., Methods: We retrospectively determined the per-procedure prevalence of physiological assessment in 40821 coronary cases performed between 2007 and 2018 in two large-volume centers. Adoption was examined according to procedure type and patient- and operator-related variables. Its association with relevant scientific landmarks, such as the release of clinical trial results and practice guidelines, was also assessed., Results: Overall adoption was low, ranging from 0.6% in patients undergoing invasive coronary angiography due to underlying valve disease, to 6% in the setting of stable coronary artery disease (CAD); it was 3.1% in patients sustaining an acute coronary syndrome. Of scientific landmarks, FAME 1, the long-term results of FAME 2 and the 2014 European myocardial revascularization guidelines were associated with changes in practice. Publication of instantaneous wave-free ratio (iFR) trials had no influence on adoption rates, except for a higher proportion of iFR use. In 42.9% of stable CAD patients undergoing percutaneous coronary intervention there was no objective non-invasive evidence of ischemia, nor was physiological assessment performed. Younger operator age (4.5% vs. 4.0% vs. 0.9% for ages <40, 40-55 and >55 years, respectively; p<0.001) and later time of procedure during the day (2.9% between 6 and 8 p.m. vs. 4.4% at other times) were independent correlates of use of invasive physiology., Conclusions: Our study confirms the low use of invasive physiology in routine practice. The availability of resting indices did not increase adoption. Strategies are warranted to promote guideline implementation and to improve patient care and clinical outcomes., (Copyright © 2021 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. All rights reserved.)

We have used the Cu(i)-catalyzed azide-alkyne Huisgen cycloaddition reaction to obtain two families of bivalent heterodimers where tacrine is connected to an azasugar or iminosugar, respectively, via linkers of variable length. The heterodimers were investigated as cholinesterase inhibitors and it was found that their activity increased with the length of the linker. Two of the heterodimers were significantly stronger acetylcholinesterase inhibitors than the monomeric tacrine. Molecular modelling indicated that the longer heterodimers fitted better into the active gorge of acetylcholinesterase than the shorter counterparts and the former provided more efficient simultaneous interaction with the tryptophan residues in the catalytic anionic binding site (CAS) and the peripheral anionic binding site (PAS).

One of the major benefits of biomedicine is the use of biocomposites as wound dressings to help improve the treatment of injuries. Therefore, the main objective of this study was to develop and characterize biocomposites based on bacterial cellulose (BC) with different concentrations of collagen and starch and characterize their thermal, morphological, mechanical, physical, and barrier properties. In total, nine samples were produced with fixed amounts of glycerol and BC and variations in the amount of collagen and starch. The water activity (0.400-0.480), water solubility (12.94-69.7%), moisture (10.75-20.60%), thickness (0.04-0.11 mm), water vapor permeability (5.59-14.06 × 10 -8 g·mm/m 2 ·h·Pa), grammage (8.91-39.58 g·cm -2 ), opacity (8.37-36.67 Abs 600 nm·mm -1 ), elongation (4.81-169.54%), and tensile strength (0.99-16.32 MPa) were evaluated and defined. In addition, scanning electron microscopy showed that adding biopolymers in the cellulose matrix made the surface compact, which also influenced the visual appearance. Thus, the performance of the biocomposites was directly influenced by their composition. The performance of the different samples obtained resulted in them having different potentials for application considering the injury type. This provides a solution for the ineffectiveness of traditional dressings, which is one of the great problems of the biomedical sector.

Introduction: Recent randomised clinical trials showed benefit of non-culprit lesion revascularisation in ST-elevation myocardial infarction (STEMI) patients. However, it remains unclear whether revascularisation should be performed at the index procedure or at a later stage., Methods and Analysis: The instantaneous wave-free ratio (iFR) Guided Multivessel Revascularisation During Percutaneous Coronary Intervention for Acute Myocardial Infarction trial is a multicentre, randomised controlled prospective open-label trial with blinded evaluation of endpoints. After successful primary percutaneous coronary intervention (PCI), eligible STEMI patients with residual non-culprit lesions are randomised, to instantaneous wave-free ratio guided treatment of non-culprit lesions during the index procedure versus deferred cardiac MR-guided management within 4 days to 6 weeks. The primary endpoint of the study is the combined occurrence of all-cause death, recurrent myocardial infarction and hospitalisation for heart failure at 12 months follow-up. Clinical follow-up includes questionnaires at 3 months and outpatient visits at 6 months and 12 months after primary PCI. Furthermore, a cost-effectiveness analysis will be performed., Ethics and Dissemination: Permission to conduct this trial has been granted by the Medical Ethical Committee of the Amsterdam University Medical Centres (loc. VUmc, ID NL60107.029.16). The primary results of this trial will be shared in a main article and subgroup analyses or spin-off studies will be shared in secondary papers., Trial Registration Number: NCT03298659., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ethical issues that arise during the care of a pregnant woman with cancer are challenging to physicians, policymakers, lawyers, and the bioethics community. The main purpose of this scoping review is to summarize existing literature regarding the bioethical dilemmas when a conflict arises in the maternal-fetus dyad, like the one related to cancer and pregnancy outcomes. Moreover, we illustrate the decision-making process of real-life case reports. Published data were searched through the PubMed and Google Scholar databases, as well as in grey literature, using appropriate controlled keywords in English and Portuguese. After identification, screening, eligibility and data extraction from the articles, a total of 50 was selected. There are several established ethical frameworks for conflict resolution and decision-making. Pragmatic theoretical approaches include case-based analysis, the ethics of care, feminist theory, and traditional ethical principlism that scrutinizes the framework of autonomy, justice, beneficence, and non-maleficence. In addition, society and practitioner values could mediate this complex ethical interplay. The physician must balance autonomy and beneficence-based obligations to the pregnant woman with cancer, along with beneficence-based obligations to the fetus. Ethical challenges have received less attention in the literature, particularly before the third trimester of pregnancy. Best, unbiased and balanced information must be granted both to the patient and to the family, regarding the benefits and harms for the woman herself as well as for the fetal outcome. Based on a previously validated method for analyzing and working up clinical ethical problems, we suggest an adaptation of an algorithm for biomedical decision-making in cancer during pregnancy, including recommendations that can facilitate counseling and help reduce the suffering of the patient and her family., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Alpuim Costa, Nobre, de Almeida, Ferreira, Gonçalves, Braga and Pais.)

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

Introduction and Objectives: Recent randomized controlled trials have evaluated the benefit of extended antithrombotic therapy in secondary prevention of acute coronary syndrome (ACS). However, the numerous and strict enrollment criteria may limit the validity and reproducibility of the published results in clinical practice. Our goal was to estimate the eligibility for participation in two randomized clinical trials in a group of patients followed for ACS., Methods: We applied the enrollment criteria of two randomized clinical trials (PEGASUS and COMPASS) to consecutive patients who underwent percutaneous coronary intervention in an ACS registry between January 2016 and June 2017., Results: A total of 780 patients were included in the final analysis. The proportion of patients fulfilling the trial enrollment criteria was 35.9% for PEGASUS and 32.1% for COMPASS. The proportion of patients eligible for both trials was 17.7% and 49.7% of patients were eligible for at least one trial. The need for anticoagulant therapy was the most common reason for exclusion on the PEGASUS criteria (46.2%) and the presence of high bleeding risk was the most common reason for exclusion on the COMPASS criteria (61.5%)., Conclusions: Approximately 50% of real-world patients are not eligible for the antithrombotic strategies applied in these trials. Since this non-eligible population is at greater risk of events, further studies are needed to confirm the applicability of these strategies., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: To evaluate agreement between instantaneous wave free ratio (iFR) and fractional flow reserve (FFR) for the functional assessment of nonculprit coronary stenoses at staged follow-up after ST-segment elevation myocardial infarction (STEMI)., Results: We measured iFR and FFR at staged follow-up in 112 STEMI patients with 146 nonculprit stenoses. Median interval between STEMI and follow-up was 16 (interquartile range 5-32) days. Agreement between iFR and FFR was 77% < 5 days after STEMI and 86% after ≥ 5 days (p = 0.19). Among cases with disagreement, the proportion of cases with hemodynamically significant iFR and non-significant FFR were different when assessed < 5 days (5 in 8, 63%) versus ≥ 5 days (3 in 15, 20%) after STEMI (p = 0.04). Overall classification agreement between iFR and FFR was comparable to that observed in stable patients. Time interval between STEMI and follow-up evaluation may impact agreement between iFR and FFR.

Background: Intracoronary physiology is increasingly used in nonculprit stenoses of patients with acute coronary syndromes (ACS). However, evidence regarding the safety of fractional flow reserve-based deferral in patients with ACS, compared with patients with stable angina pectoris (SAP), is scarce., Objectives: The aim of this study was to evaluate the safety of revascularization deferral on the basis of fractional flow reserve interrogation of nonculprit lesions in patients with ACS., Methods: A pooled analysis was performed of individual patient data included in 5 large international published studies on physiology-guided revascularization. The primary endpoint was major adverse cardiac events (MACE) (a composite of death, nonfatal myocardial infarction, or unplanned revascularization) at 1-year follow-up. Clinical outcomes of patients with ACS and SAP were compared in both the deferred and the revascularized groups., Results: A total of 8,579 patients were included in the analysis, 6,461 with SAP and 2,118 with ACS and nonculprit stenoses. Using fractional flow reserve, revascularization was deferred in 5,129 patients (59.8%) and performed in 3,450 patients (40.2%). In the deferred ACS group, a higher MACE rate was observed compared with the deferred SAP group (4.46% vs. 2.83%; adjusted hazard ratio [HR]: 1.72; 95% confidence interval [CI]: 1.17 to 2.53; p < 0.01). In particular, early unplanned revascularization (3.34% and 2.04% in ACS and SAP; adjusted HR: 1.81; 95% CI: 1.09 to 3.00; p = 0.02) contributed to this excess in MACE but the difference between the ACS and SAP groups did not reach statistical significance. On the contrary, no differences in outcomes linked to clinical presentation were found in treated patients (MACE rate 6.51% vs. 6.20%; adjusted HR: 1.21; 95% CI: 0.88 to 1.26; p = 0.24)., Conclusions: Patients with ACS in whom revascularization of nonculprit lesions was deferred on the basis of fractional flow reserve have more MACE at 1 year compared with patients with SAP with deferred revascularization. Unplanned revascularization mainly contributed to this excess of MACE., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The instantaneous wave-free ratio cutoff value of <0.90 for hemodynamic significance of coronary stenoses has been validated in stable patients. We examined different cutoff values in the evaluation of nonculprit stenoses in patients with ST-segment elevation myocardial infarction., Methods: We measured instantaneous wave-free ratio across nonculprit stenoses in the acute setting and at follow-up in 120 patients with ST-segment elevation myocardial infarction and 157 nonculprit stenoses, of which, 113 patients with 147 nonculprit stenoses completed follow-up., Methods: The prevalence of nonculprit stenosis hemodynamic significance was 52% in the acute setting and 41% at follow-up. With follow-up, instantaneous wave-free ratio as reference, acute instantaneous wave-free ratio >0.90 had a negative predictive value of 89%. Acute instantaneous wave-free ratio <0.90 had a positive predictive value of 68%. Acute instantaneous wave-free ratio >0.93 had a negative predictive value of 100%. Acute instantaneous wave-free ratio <0.86 and <0.83 had positive predictive values of 71 and 77%. Using acute instantaneous wave-free ratio <0.90 as cutoff for hemodynamic significance yielded the highest degree of classification agreement between acute and follow-up instantaneous wave-free ratio., Conclusions: In patients with ST-segment elevation myocardial infarction, acute instantaneous wave-free ratio with the cutoff values <0.90 for hemodynamic significance appears optimal in the evaluation of nonculprit stenoses and has a high negative predictive value and a moderate positive predictive value.

Nonculprit lesions are frequently observed in patients with ST-segment elevation myocardial infarction. Results from recent randomized clinical trials suggest that complete revascularization after ST-segment elevation myocardial infarction improves outcomes. In this state-of-the-art paper, the authors review these trials and consider how best to determine which nonculprit lesions require revascularization and when this should be performed., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumor. Pharmacological treatment of this malignance is limited by the selective permeability of the blood-brain barrier (BBB) and relies on a single drug, temozolomide (TMZ), thus making the discovery of new compounds challenging and urgent. Therefore, aiming to discover new anti-glioma drugs, we developed robust machine learning models for predicting anti-glioma activity and BBB penetration ability of new compounds. Using these models, we prioritized 41 compounds from our in-house library of compounds, for further in vitro testing against three glioma cell lines and astrocytes. Subsequently, the most potent and selective compounds were resynthesized and tested in vivo using an orthotopic glioma model. This approach revealed two lead candidates, 4m and 4n, which efficiently decreased malignant glioma development in mice, probably by inhibiting thioredoxin reductase activity, as shown by our enzymological assays. Moreover, these two compounds did not promote body weight reduction, death of animals, or altered hematological and toxicological markers, making then good candidates for lead optimization as anti-glioma drug candidates., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2019. Published by Elsevier Masson SAS.)

Importance: Approximately one-third of patients considered for coronary revascularization have diabetes, which is a major determinant of clinical outcomes, often influencing the choice of the revascularization strategy. The usefulness of fractional flow reserve (FFR) to guide treatment in this population is understudied and has been questioned., Objective: To evaluate the usefulness and rate of major adverse cardiovascular events (MACE) of integrating FFR in management decisions for patients with diabetes who undergo coronary angiography., Design, Setting, and Participants: This cross-sectional study used data from the PRIME-FFR study derived from the merger of the POST-IT study (Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease [March 2012-November 2013]) and R3F study (French Study of FFR Integrated Multicenter Registries Implementation of FFR in Routine Practice [October 2008-June 2010]), 2 prospective multicenter registries that shared a common design. A population of all-comers for whom angiography disclosed ambiguous lesions was analyzed for rates, patterns, and outcomes associated with management reclassification, including revascularization deferral, in patients with vs without diabetes. Data analysis was performed from June to August 2018., Main Outcomes and Measures: Death from any cause, myocardial infarction, or unplanned revascularization (MACE) at 1 year., Results: Among 1983 patients (1503 [77%] male; mean [SD] age, 65 [10] years), 701 had diabetes, and FFR was performed for 1.4 lesions per patient (58.2% of lesions in the left anterior descending artery; mean [SD] stenosis, 56% [11%]; mean [SD] FFR, 0.81 [0.01]). Reclassification by FFR was high and similar in patients with and without diabetes (41.2% vs 37.5%, P = .13), but reclassification from medical treatment to revascularization was more frequent in the former (142 of 342 [41.5%] vs 230 of 730 [31.5%], P = .001). There was no statistical difference between the 1-year rates of MACE in reclassified (9.7%) and nonreclassified patients (12.0%) (P = .37). Among patients with diabetes, FFR-based deferral identified patients with a lower risk of MACE at 12 months (25 of 296 [8.4%]) compared with those undergoing revascularization (47 of 257 [13.1%]) (P = .04), and the rate was of the same magnitude of the observed rate among deferred patients without diabetes (7.9%, P = .87). Status of insulin treatment had no association with outcomes. Patients (6.6% of the population) in whom FFR was disregarded had the highest MACE rates regardless of diabetes status., Conclusions and Relevance: Routine integration of FFR for the management of coronary artery disease in patients with diabetes may be associated with a high rate of treatment reclassification. Management strategies guided by FFR, including revascularization deferral, may be useful for patients with diabetes.

Bacterial cellulose (BC) has received considerable attention due to its unique properties, including an ultrafine network structure with high purity, mechanical strength, inherent biodegradability, biocompatibility, high water-holding capacity and high crystallinity. These properties allow BC to be used in biomedical and industrial applications, such as medical product. This research investigated the production of BC by Gluconacetobacter hansenii ATCC 23769 using different carbon sources (glucose, mannitol, sucrose and xylose) at two different concentrations (25 and 50 g∙L -1 ). The BC produced was used to develop a biocomposite with montmorillonite (MMT), a clay mineral that possesses interesting characteristics for enhancing BC physical-chemical properties, at 0.5, 1, 2 and 3% concentrations. The resulting biocomposites were characterized in terms of their physical and barrier properties, morphologies, water-uptake capacities, and thermal stabilities. Our results show that bacteria presented higher BC yields in media with higher glucose concentrations (50 g∙L -1 ) after a 14-day incubation period. Additionally, the incorporation of MMT significantly improved the mechanical and thermal properties of the BC membranes. The degradation temperature of the composites was extended, and a decrease in the water holding capacity (WHC) and an improvement in the water release rate (WRR) were noted. Determining a cost-effective medium for the production of BC and the characterization of the produced composites are extremely important for the biomedical applications of BC, such as in wound dressing materials.

Introduction : The timely identification biologically active chemicals, in disease relevant screening assays, is a major endeavor in drug discovery. The existence of frequent hitters (FHs) in non-related assays poses a formidable challenge in terms of whether to consider these molecules as chemical gold or promiscuous non-selective reactive trash (also known as PAINS - pan assay interference compounds). Areas covered : In this review, the authors bring together expertize in synthetic chemistry, cheminformatics and biochemistry, three key areas for dealing with FHs. They discuss synthetic methods facilitating preparation of chemically diverse molecular libraries, while favoring activity in the biological space. They also survey and discuss recent computational advances in the prediction of PAINS from chemical structures. Finally, they review experimental approaches for the validation of the biological activity of screening hits and discuss alternatives for exploiting promiscuity and chemical reactivity. Expert opinion : It's essential to develop more efficient computational methods to reliably recognize PAINS in distinct molecular environments. Accordingly, advances in synthetic chemistry hold the promise to provide a better quality of chemical matter for drug discovery. Medicinal chemists should be more open to screening for hits showing biologically complex mechanisms of action rather than discarding molecules that may prove valuable as innovative disease treatments.

Objectives: This study sought to evaluate sex differences in procedural characteristics and clinical outcomes of instantaneous wave-free ratio (iFR)- and fractional flow reserve (FFR)-guided revascularization strategies., Background: An iFR-guided strategy has shown a lower revascularization rate than an FFR-guided strategy, without differences in clinical outcomes., Methods: This is a post hoc analysis of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate stenosis to guide Revascularization) study, in which 601 women and 1,891 men were randomized to iFR- or FFR-guided strategy. The primary endpoint was 1-year major adverse cardiac events (MACE), a composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization., Results: Among the entire population, women had a lower number of functionally significant lesions per patient (0.31 ± 0.51 vs. 0.43 ± 0.59; p < 0.001) and less frequently underwent revascularization than men (42.1% vs. 53.1%; p < 0.001). There was no difference in mean iFR value according to sex (0.91 ± 0.09 vs. 0.91 ± 0.10; p = 0.442). However, the mean FFR value was lower in men than in women (0.83 ± 0.09 vs. 0.85 ± 0.10; p = 0.001). In men, an FFR-guided strategy was associated with a higher rate of revascularization than an iFR-guided strategy (57.1% vs. 49.3%; p = 0.001), but this difference was not observed in women (41.4% vs. 42.6%; p = 0.757). There was no difference in MACE rates between iFR- and FFR-guided strategies in both women (5.4% vs. 5.6%, adjusted hazard ratio: 1.10; 95% confidence interval: 0.50 to 2.43; p = 0.805) and men (6.6% vs. 7.0%, adjusted hazard ratio: 0.98; 95% confidence interval: 0.66 to 1.46; p = 0.919)., Conclusions: An FFR-guided strategy was associated with a higher rate of revascularization than iFR-guided strategy in men, but not in women. However, iFR- and FFR-guided strategies showed comparable clinical outcomes, regardless of sex. (Functional Lesion Assessment of Intermediate Stenosis to guide Revascularization [DEFINE-FLAIR]; NCT02053038)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To identify clinical, angiographic and hemodynamic predictors of discordance between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR)., Background: The iFR was found to be non-inferior to the gold-standard FFR for guiding coronary revascularization, although it is discordant with FFR in 20% of cases. A better understanding of the causes of discordance may enhance application of these indices., Methods: Both FFR and iFR were measured in the prospective multicenter CONTRAST study. Clinical, angiographic and hemodynamic variables were compared between patients with concordant values of FFR and iFR (cutoff ≤0.80 and ≤0.89, respectively)., Results: Out of the 587 patients included, in 466 patients (79.4%) FFR and iFR agreed: both negative, n = 244 (41.6%), or positive, n = 222 (37.8%). Compared with FFR, iFR was negative discordant (FFR+/iFR-) in 69 (11.8%) patients and positive discordant (FFR-/iFR+) in 52 (8.9%) patients. On multivariate regression, stenosis location (left main or proximal left anterior descending) (OR: 3.30[1.68;6.47]), more severe stenosis (OR: 1.77[1.35;2.30]), younger age (OR: 0.93[0.90;0.97]), and slower heart rate (OR: 0.59[0.42;0.75]) were predictors of a negative discordant iFR. Absence of a beta-blocker (OR: 0.41[0.22;0.78]), older age (OR: 1.04[1.00;1.07]), and less severe stenosis (OR: 0.69[0.53;0.89]) were predictors of a positive discordant iFR., Conclusions: During iFR acquisition, stenosis location, stenosis degree, heart rate, age and use of beta blockers influence concordance with FFR and should be taken into account when interpreting iFR., (© 2019 Wiley Periodicals, Inc.)

Importance: Invasive physiologic indices such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are used in clinical practice. Nevertheless, comparative prognostic outcomes of iFR-guided and FFR-guided treatment in patients with type 2 diabetes have not yet been fully investigated., Objective: To compare 1-year clinical outcomes of iFR-guided or FFR-guided treatment in patients with and without diabetes in the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization (DEFINE-FLAIR) trial., Design, Setting, and Participants: The DEFINE-FLAIR trial is a multicenter, international, randomized, double-blinded trial that randomly assigned 2492 patients in a 1:1 ratio to undergo either iFR-guided or FFR-guided coronary revascularization. Patients were eligible for trial inclusion if they had intermediate coronary artery disease (40%-70% diameter stenosis) in at least 1 native coronary artery. Data were analyzed between January 2014 and December 2015., Interventions: According to the study protocol, iFR of 0.89 or less and FFR of 0.80 or less were used as criteria for revascularization. When iFR or FFR was higher than the prespecified threshold, revascularization was deferred., Main Outcomes and Measures: The primary end point was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. The incidence of MACE was compared according to the presence of diabetes in iFR-guided and FFR-guided groups., Results: Among the total trial population (2492 patients), 758 patients (30.4%) had diabetes. Mean age of the patients was 66 years, 76% were men (1868 of 2465), and 80% of patients presented with stable angina (1983 of 2465). In the nondiabetes population (68.5%; 1707 patients), iFR guidance was associated with a significantly higher rate of deferral of revascularization than the FFR-guided group (56.5% [n = 477 of 844] vs 46.6% [n = 402 of 863]; P < .001). However, it was not different between the 2 groups in the diabetes population (42.1% [n = 161 of 382] vs 47.1% [n = 177 of 376]; P = .15). At 1 year, the diabetes population showed a significantly higher rate of MACE than the nondiabetes population (8.6% vs 5.6%; adjusted hazard ratio [HR], 1.88; 95% CI, 1.28-2.64; P < .001). However, there was no significant difference in MACE rates between iFR-guided and FFR-guided groups in both the diabetes (10.0% vs 7.2%; adjusted HR, 1.33; 95% CI, 0.78-2.25; P = .30) and nondiabetes population (4.7% vs 6.4%; HR, 0.83; 95% CI, 0.51-1.35; P = .45) (interaction P = .25)., Conclusions and Relevance: The diabetes population showed significantly higher risk of MACE than the nondiabetes population, even with the iFR-guided or FFR-guided treatment. The iFR-guided and FFR-guided treatment showed comparable risk of MACE and provided equal safety in selecting revascularization target among patients with diabetes., Trial Registration: ClinicalTrials.gov identifier: NCT02053038.

Cancer is one of the leading causes of death around the world and although the different clinical approaches have helped to increase survival rates, incidence is still high and so its mortality. Chemotherapy is the only approach which is systemic, reaching cancer cells in all body tissues and the search for new potent and selective drugs is still an attractive field within cancer research. Naphthoquinones, natural and synthetic, have garnered much attention in the scientific community due to their pharmacological properties, among them anticancer action, and potential therapeutic significance. Many mechanisms of action have been reported which also depend on structural differences among them. Here, we describe some of the most relevant mechanisms of action reported so far for naphthoquinones and highlight novel targets which are being described in the literature. Furthermore, we gather some of the most impressive efforts done by researchers to harness the anticancer properties of these compounds through specifically designed structural modifications., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR)., Objectives: The purpose of this study was to establish the safety of deferring treatment in the LAD using FFR or iFR within the DEFINE-FLAIR trial., Methods: MACE rates at 1 year were compared between groups (iFR and FFR) in patients whose physiological assessment led to LAD lesions being deferred. MACE was defined as a composite of cardiovascular death, myocardial infarction (MI), and unplanned revascularization at 1 year. Patients, and staff performing follow-up, were blinded to whether the decision was made with FFR or iFR. Outcomes were adjusted for age and sex., Results: A total of 872 patients had lesions deferred in the LAD (421 guided by FFR, 451 guided by iFR). The event rate with iFR was significantly lower than with FFR (2.44% vs. 5.26%; adjusted HR: 0.46; 95% confidence interval [CI]: 0.22 to 0.95; p = 0.04). This was driven by significantly lower unplanned revascularization with iFR and numerically lower MI (unplanned revascularization: 2.22% iFR vs. 4.99% FFR; adjusted HR: 0.44; 95% CI: 0.21 to 0.93; p = 0.03; MI: 0.44% iFR vs. 2.14% FFR; adjusted HR: 0.23; 95% CI: 0.05 to 1.07; p = 0.06)., Conclusions: iFR-guided deferral appears to be safe for patients with LAD lesions. Patients in whom iFR-guided deferral was performed had statistically significantly lower event rates than those with FFR-guided deferral., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS)., Background: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization., Methods: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year., Results: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04)., Conclusions: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to examine the level of agreement between acute instantaneous wave-free ratio (iFR) measured across nonculprit stenoses in patients with ST-segment elevation myocardial infarction (STEMI) and iFR measured at a staged follow-up procedure., Background: Acute full revascularization of nonculprit stenoses in STEMI is debated and currently guided by angiography. Acute functional assessment of nonculprit stenoses may be considered., Methods: Immediately after successful primary culprit intervention for STEMI, nonculprit coronary stenoses were evaluated with iFR and left untreated. Follow-up evaluation with iFR was performed at a later stage. iFR <0.90 was considered hemodynamically significant., Results: One hundred twenty patients with 157 nonculprit lesions were included. Median acute iFR was 0.89 (interquartile range [IQR]: 0.82 to 0.94; n = 156), and median follow-up iFR was 0.91 (interquartile range: 0.86 to 0.96; n = 147). Classification agreement was 78% between acute and follow-up iFR. The negative predictive value of acute iFR was 89%. Median time from acute to follow-up evaluation was 16 days (IQR: 5 to 32 days). With follow-up within 5 days after STEMI, no difference was observed between acute and follow-up iFR, and classification agreement was 89%. With follow-up ≥16 days after STEMI, acute iFR was lower than follow-up iFR, and classification agreement was 70%., Conclusions: Acute iFR evaluation appeared valid for ruling out significant nonculprit stenoses in patients with STEMI undergoing primary percutaneous coronary intervention. The time interval from acute to follow-up iFR influenced classification agreement, suggesting that inherent physiological disarrangements during STEMI may contribute to classification disagreement., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The new European guidelines on diabetes mellitus and cardiovascular diseases propose that the FINnish Diabetes RIsk SCore should be used to evaluate the risk of diabetes mellitus and that diabetes mellitus screening in coronary artery disease patients should be based on fasting glucose and HbA1c. The 2 hour oral glucose tolerance test, recommended for all pts in the previous guidelines, is now only recommended for 'inconclusive' cases. We aimed to evaluate this new strategy., Material and Methods: Fasting glucose, HbA1c and glucose tolerance test (75 g, 2h) were prospectively evaluated in a consecutive group of pts with coronary artery disease. ADA criteria (both glucose tolerance test and HbA1c) were used to define diabetes mellitus and pre-diabetes mellitus. Diabetes mellitus risk was evaluated according to the FINnish Diabetes RIsk SCore., Results: A total of 135 patients were included (mean age 62.3 +/- 13.1 years, 99 males). Glucose tolerance test and HbA1c together diagnosed 18 (13.3%) new cases of diabetes mellitus and 77 (57.0%) patients with pre-diabetes mellitus. Fasting glucose + HbA1c (guidelines strategy) identified 12/18 patients with diabetes mellitus (Sens 66.7%; negative predictive value 95.1%; Kappa 0.78; p < 0.0001) and 83/95 patients with glucose anomalies (pre- diabetes mellitus + diabetes mellitus) (Sens 87.4%; negative predictive value 76.9%). Performing glucose tolerance test in the 29 patients with an elevated FINnish Diabetes RIsk SCore would allow identifying 15/18 patients with diabetes mellitus (Sens 83.3%; negative predictive value 97.5%; Kappa 0.85; p < 0.0001) and 86/95 patients with glucose anomalies (Sens 90.5%; negative predictive value 81.6%)., Discussion: Although this strategy improved the screening accuracy, one in each six patients with diabetes mellitus would still remain undiagnosed, as compared to measuring HbA1c and performing an glucose tolerance test in all patients., Conclusion: Using the FINnish Diabetes RIsk SCore to select candidates to additional glucose tolerance test improves the accuracy for identifying diabetic patients, as compared with fasting glucose + HbA1c alone. However, 1/6 patients diabetes mellitus is still left undiagnosed with this strategy proposed by the current guidelines.

Background: Fractional flow reserve (FFR) is not firmly established as a guide to treatment in patients with acute coronary syndromes (ACS). Primary goals were to evaluate the impact of integrating FFR on management decisions and on clinical outcome of patients with ACS undergoing coronary angiography, as compared with patients with stable coronary artery disease., Methods and Results: R3F (French FFR Registry) and POST-IT (Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease), sharing a common design, were pooled as PRIME-FFR (Insights From the POST-IT and R3F Integrated Multicenter Registries - Implementation of FFR in Routine Practice). Investigators prospectively defined management strategy based on angiography before performing FFR. Final decision after FFR and 1-year clinical outcome were recorded. From 1983 patients, in whom FFR was prospectively used to guide treatment, 533 sustained ACS (excluding acute ST-segment-elevation myocardial infarction). In ACS, FFR was performed in 1.4 lesions per patient, mostly in left anterior descending (58%), with a mean percent stenosis of 58±12% and a mean FFR of 0.82±0.09. In patients with ACS, reclassification by FFR was high and similar to those with non-ACS (38% versus 39%; P =NS). The pattern of reclassification was different, however, with less patients with ACS reclassified from revascularization to medical treatment compared with those with non-ACS ( P =0.01). In ACS, 1-year outcome of patients reclassified based on FFR (FFR against angiography) was as good as that of nonreclassified patients (FFR concordant with angiography), with no difference in major cardiovascular event (8.0% versus 11.6%; P =0.20) or symptoms (92.3% versus 94.8% angina free; P =0.25). Moreover, FFR-based deferral to medical treatment was as safe in patients with ACS as in patients with non-ACS (major cardiovascular event, 8.0% versus 8.5%; P =0.83; revascularization, 3.8% versus 5.9%; P =0.24; and freedom from angina, 93.6% versus 90.2%; P =0.35). These findings were confirmed in ACS explored at the culprit lesion. In patients (6%) in whom the information derived from FFR was disregarded, a dire outcome was observed., Conclusions: Routine integration of FFR into the decision-making process of ACS patients with obstructive coronary artery disease is associated with a high reclassification rate of treatment (38%). A management strategy guided by FFR, divergent from that suggested by angiography, including revascularization deferral, is safe in ACS., (© 2017 American Heart Association, Inc.)