Data harmonization and federated learning for multi-cohort dementia research using the OMOP common data model: A Netherlands consortium of dementia cohorts case study.

BACKGROUND: Establishing collaborations between cohort studies has been fundamental for progress in health research. However, such collaborations are hampered by heterogeneous data representations across cohorts and legal constraints to data sharing. The first arises from a lack of consensus in standards of data collection and representation across cohort studies and is usually tackled by applying data harmonization processes. The second is increasingly important due to raised awareness for privacy protection and stricter regulations, such as the GDPR. Federated learning has emerged as a privacy-preserving alternative to transferring data between institutions through analyzing data in a decentralized manner. METHODS: In this study, we set up a federated learning infrastructure for a consortium of nine Dutch cohorts with appropriate data available to the etiology of dementia, including an extract, transform, and load (ETL) pipeline for data harmonization. Additionally, we assessed the challenges of transforming and standardizing cohort data using the Observational Medical Outcomes Partnership (OMOP) common data model (CDM) and evaluated our tool in one of the cohorts employing federated algorithms. RESULTS: We successfully applied our ETL tool and observed a complete coverage of the cohorts' data by the OMOP CDM. The OMOP CDM facilitated the data representation and standardization, but we identified limitations for cohort-specific data fields and in the scope of the vocabularies available. Specific challenges arise in a multi-cohort federated collaboration due to technical constraints in local environments, data heterogeneity, and lack of direct access to the data. CONCLUSION: In this article, we describe the solutions to these challenges and limitations encountered in our study. Our study shows the potential of federated learning as a privacy-preserving solution for multi-cohort studies that enhance reproducibility and reuse of both data and analyses.

Age shock index as an early predictor of cardiovascular death in acute coronary syndrome patients.

BACKGROUND: The shock index (SI), reflecting heart rate (HR) to SBP ratio, is established for predicting adverse outcomes in acute coronary syndrome (ACS) patients. Exploring the age shock index (ASI), obtained by multiplying SI with age, could offer further insights into ACS prognosis. OBJECTIVES: Assess ASI's effectiveness in predicting in-hospital death in individuals with ACS. METHODS: This study encompassed patients with acute myocardial infarction, drawn from a national registry spanning October 2010 to January 2022. The optimal ASI threshold was established using receiver operating characteristic (ROC) curve analysis. The primary outcome was in-hospital mortality. RESULTS: A total of 27 312 patients were enrolled, exhibiting a mean age of 66 ±â€…13 years, with 72.3% being male and 47.5% having ST-elevation myocardial infarction. ROC analysis yielded an area under the curve (AUC) of 0.80, identifying the optimal ASI cutoff as 44. Multivariate regression analysis, adjusting for potential confounders, established ASI ≥ 44 as an independent predictor of in-hospital death [hazard ratio: 3.09, 95% confidence interval: 2.56-3.71, P  < 0.001]. Furthermore, ASI emerged as a notably superior predictor of in-hospital death compared to the SI (AUC ASI  = 0.80 vs. AUC SI  = 0.72, P  < 0.0001), though it did not outperform the Global Registry of Acute Coronary Events (GRACE) score (AUC ASI  = 0.80 vs. AUC GRACE  = 0.85, P  < 0.001) or thrombolysis in myocardial infarction (TIMI) risk index (AUC ASI  = 0.80 vs. AUC TIMI  = 0.84, P  < 0.001). CONCLUSION: The ASI offers an expedient mean to promptly identify ACS patients at elevated risk of in-hospital death. Its simplicity and effectiveness could render it a valuable tool for early risk stratification in this population.

Image based prognosis in head and neck cancer using convolutional neural networks: a case study in reproducibility and optimization.

In the past decade, there has been a sharp increase in publications describing applications of convolutional neural networks (CNNs) in medical image analysis. However, recent reviews have warned of the lack of reproducibility of most such studies, which has impeded closer examination of the models and, in turn, their implementation in healthcare. On the other hand, the performance of these models is highly dependent on decisions on architecture and image pre-processing. In this work, we assess the reproducibility of three studies that use CNNs for head and neck cancer outcome prediction by attempting to reproduce the published results. In addition, we propose a new network structure and assess the impact of image pre-processing and model selection criteria on performance. We used two publicly available datasets: one with 298 patients for training and validation and another with 137 patients from a different institute for testing. All three studies failed to report elements required to reproduce their results thoroughly, mainly the image pre-processing steps and the random seed. Our model either outperforms or achieves similar performance to the existing models with considerably fewer parameters. We also observed that the pre-processing efforts significantly impact the model's performance and that some model selection criteria may lead to suboptimal models. Although there have been improvements in the reproducibility of deep learning models, our work suggests that wider implementation of reporting standards is required to avoid a reproducibility crisis.

Representational horizon and visual space orientation: An investigation into the role of visual contextual cues on spatial mislocalisations.

The perceived offset position of a moving target has been found to be displaced forward, in the direction of motion (Representational Momentum; RM), downward, in the direction of gravity (Representational Gravity; RG), and, recently, further displaced along the horizon implied by the visual context (Representational Horizon; RH). The latter, while still underexplored, offers the prospect to clarify the role of visual contextual cues in spatial orientation and in the perception of dynamic events. As such, the present work sets forth to ascertain the robustness of Representational Horizon across varying types of visual contexts, particularly between interior and exterior scenes, and to clarify to what degree it reflects a perceptual or response phenomenon. To that end, participants were shown targets, moving along one out of several possible trajectories, overlaid on a randomly chosen background depicting either an interior or exterior scene rotated -22.5º, 0º, or 22.5º in relation to the actual vertical. Upon the vanishing of the target, participants were required to indicate its last seen location with a computer mouse. For half the participants, the background vanished with the target while for the remaining it was kept visible until a response was provided. Spatial localisations were subjected to a discrete Fourier decomposition procedure to obtain independent estimates of RM, RG, and RH. Outcomes showed that RH's direction was biased towards the horizon implied by the visual context, but solely for exterior scenes, and irrespective of its presence or absence during the spatial localisation response, supporting its perceptual/representational nature.

Programa Nacional de Desfibrilhação Automática Externa: Impacto na recuperação de circulação espontânea das vítimas de paragem cardiorrespiratória / National Program for Automatic External Defibrillation: Impact on the recovery of spontaneous circulation in victims of cardiorespiratory arrest

Introdução: A paragem cardiorrespiratória extra-hospitalar (PCREH) é uma das principais causas de morte na Europa, apresentando custos extremamente elevados em termos de morbilidade e mortalidade, revelando-se um problema de saúde pública muito pertinente. Os países desenvolvidos têm implementado diversos sistemas de resposta comunitária para fazer face à PCREH, no entanto a sua epidemiologia e desfecho continuam a apresentar uma grande variabilidade. Em Portugal foi implementado o Programa Nacional de Desfibrilhação Automática Externa, tendo como objetivo nuclear a instalação de uma rede nacional de desfibrilhação automática externa (DAE). O presente estudo tem como objetivo determinar a taxa de recuperação de circulação espontânea (RCE) das vítimas de PCREH e identificar os fatores que a promovem. Metodologia: Através de amostragem não probabilística, intencional, constituiu-se uma amostra de 472 vítimas de PCREH do Município de Viseu, cuja sua paragem cardiorrespiratória ocorreu no período de 2016 a 2018, tendo a mesma sido inserida no Registo Nacional de Paragem Cardiorrespiratória Pré-hospitalar (RNPCR). Definiu-se como hipótese de investigação a existência de relação significativa entre a RCE das vítimas de PCREH com variáveis sociodemográficas, causa, local, circunstâncias, rapidez de atendimento, meios de resposta e manobras de reanimação cardiorrespiratória (RCR). O instrumento de colheita de dados utilizado foi a plataforma do Registo Nacional de Paragem Cardiorrespiratória Pré-hospitalar (RNPCR-PH). Na análise de dados recorreu-se a técnicas de estatística descritiva e inferencial, nomeadamente o teste t de Student, o teste de WilcoxonMann-Whitney, o teste do Qui-quadrado (χ2) de Pearson e o teste exato de Fisher, com um nível de significância de 0,05 (α = 0,05). Resultados: O estudo revelou uma taxa de RCE à entrada da vítima de PCREH na unidade de saúde de 6,8%, identificando como potenciais fatores favoráveis à RCE a ocorrência da PCREH em espaços públicos, presenciada (com maior expressividade quando ocorre perante a equipa de emergência médica extra-hospitalar (EMEH), o início imediato de manobras de Suporte Básico de Vida (SBV) e a realização de desfibrilhação precoce (quando indicada), com um impacto substancialmente mais favorável quando realizados antes da chegada da equipa de EMEH. Evidenciou ainda, como fatores potencialmente favoráveis à RCE, a chegada precoce da equipa EMEH junto da vítima de PCREH e todas as manobras realizadas pela mesma com especial relevo para as manobras de SBV. Ficou ainda evidenciado como um preditor favorável à manutenção da condição de RCE o facto da vítima, à chegada da VI equipa de EMEH, já se encontrar com circulação, ventilação ou estado de consciência recuperados. Conclusão: Embora a taxa de RCE revelada pelo estudo (6,8%) seja baixa, encontra-se enquadrada na realidade observada em outros países europeus. Apesar disso, a análise dos fatores identificados como tendo potencial impacto positivo na RCE e das caraterísticas sociodemográficas e clínicas da amostra e respetivos dados relacionados com a PCREH, permite fornecer informação que poderá servir de base para identificar variáveis modificáveis que claramente estão a contribuir para a baixa taxa de RCE das vítimas de PCREH que se verifica no Município de Viseu.

Introduction: Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death in Europe, with extremely high costs in terms of morbidity and mortality, revealing itself to be a very relevant public health problem. Developed countries have implemented several community response systems to deal with OHCA. However, its epidemiology and outcome continue to show great variability. In Portugal, the National Automated External Defibrillation Programme was implemented with the main purpose of setting up a national automatic external defibrillation (AED) network. This study aims to determine the rate of return of spontaneous circulation (ROSC) of victims of OHCA and identify the factors that potentiate it. Methodology: A sample of 472 OHCA victims from the Municipality of Viseu, whose cardiac arrest occurred between 2016 and 2018, was selected through a purposive non-probability sampling and recorded in the National Pre-hospital Cardiac Arrest Register (RNPCR). The research hypothesis was defined as the existence of a significant relationship between the ROSC of the OHCA victims with sociodemographic variables, cause, location, circumstances, response time, means of response and cardiorespiratory resuscitation (CRR) manoeuvres. The data collection tool used was the National Registry of Pre-hospital Cardiac-Respiratory Arrest (RNPCR-PH) platform. Descriptive and inferential statistical techniques were used in data analysis, namely Student's t-test, Wilcoxon-Mann-Whitney test, Pearson's chi-square (χ2) test and Fisher's exact test, with a significance level of 0.05 (α = 0.05). Results: The study revealed an ROSC rate at the OHCA victim's arrival at the health unit of 6.8%, identifying as potential favourable ROSC factors the occurrence of OHCA in public spaces, witnessed (with bigger expressiveness when it occurs in the presence of the medical emergency team), the immediate initiation of Basic Life Support (BLS) manoeuvres and the performance of early defibrillation (when indicated), with a substantially more favourable impact when performed before the arrival of the medical emergency team. The early arrival of the medical emergency team to assist the OHCA victim and all the manoeuvres performed by the team, with special emphasis on BLS manoeuvres, were also highlighted as potentially favourable factors for ROSC. It was also evidenced as a favourable predictor for the maintenance of the ROSC condition the fact that, at the arrival of the medical emergency team, the victim already had recovered one of the following: circulation, ventilation and consciousness. Conclusion: Although the OHR rate revealed by this study (6.8%) is low, it is in line with the reality observed in other European countries. Despite this, the analysis of the factors identified VIII as having a potential positive impact on ROSC, the socio-demographic and clinical sample characteristics and respective OHCA related data provide information that may serve as a basis to identify modifiable variables that clearly contribute to the low rate of ROSC in OHCA victims in the Municipality of Viseu.

Sensing a binding event through charge transport variations using an aromatic oligoamide capsule.

The selective binding properties of a 13-mer oligoamide foldamer capsule composed of 4 different aromatic subunits are reported. The capsule was designed to recognize dicarboxylic acids through multiple-point interactions owing to a combination of protonation/deprotonation events, H-bonding, and geometrical constraints imparted by the rigidity of the foldamer backbone. Compared to tartaric acid, binding of 2,2-difluorosuccinic acid or 2,2,3,3-tetrafluorosuccinic acid resulted in symmetry breaking due to deprotonation of only one of the two carboxylic acid groups of the encapsulated species as shown by NMR studies in solution and by single-crystal X-ray diffraction in the solid state. An analogous 14-mer foldamer capsule terminated with a thiol anchoring group was used to probe the complexation event in self-assembled monolayers on Au substrates. Ellipsometry and polarization-modulation infrared absorption-reflection spectroscopy studies were consistent with the formation of a single molecule layer of the foldamer capsule oriented vertically with respect to the surface. The latter underwent smooth complexation of 2,2-difluorosuccinic acid with deprotonation of one of the two carboxylic acid groups. A significant (80-fold) difference in the charge transport properties of the monolayer upon encapsulation of the dicarboxylic acid was evidenced from conducting-AFM measurements (S = 1.1 × 10-9 vs. 1.4 × 10-11 ohm-1 for the empty and complexed capsule, respectively). The modulation in conductivity was assigned to protonation of the aromatic foldamer backbone.

Large-Amplitude Conformational Changes in Self-Assembled Multi-Stranded Aromatic Sheets.

The orchestration of ever larger conformational changes is made possible by the development of increasingly complex foldamers. Aromatic sheets, a rare motif in synthetic foldamer structures, have been designed so as to form discrete stacks of intercalated aromatic strands through the self-assembly of two identical subunits. Ion-mobility ESI-MS confirms the formation of compact dimers. X-ray crystallography reveals the existence of two distinct conformational dimeric states that require large changes to interconvert. Molecular dynamics simulation validates the stability of the two conformations and the possibility of their interconversion.

Zinc(ii) and copper(ii) complexes as tools to monitor/inhibit protein phosphorylation events.

Protein phosphorylation is a key event in the signalling pathways that control most cell functions, and its deregulation is observed in many human pathologies, including inflammatory, neurodegenerative and autoimmune diseases and cancer. Compounds able to bind phosphoproteins can potentially be used as analytical tools for investigating phosphorylation-based cell signalling and/or as inhibitors of a particular signalling pathway. Metal complexes are arguably the most important class of receptors for the recognition of phosphate-containing molecules. In the last two decades the phosphate-binding ability of metal complexes has been explored for the binding and/or sensing of phosphorylated peptides and proteins. Among those we will focus this review on mono- and dinuclear copper(ii) and zinc(ii) complexes of varied ligand architectures used as binders of phosphorylated peptides and proteins and as sensors of phosphorylation reactions with fluorescence or other techniques in real-time. The cumulative information of strong and selective associations of the indicated receptors allowed selecting some of them for phosphoprotein/peptide enrichment and staining procedures, in vitro monitoring of kinase/phosphatase activity and disruption of phosphorylation-dependent protein-protein interactions. A perspective on the advance of this important area on the frontier between chemistry and biology is presented.

Selective Coordination of Cu2+ and Subsequent Anion Detection Based on a Naphthalimide-Triazine-(DPA)2 Chemosensor.

A new fluorescent chemosensor for copper (II) and subsequent anion sensing was designed and fully characterized. The sensor consisted of a 1,8-naphthalimide core, bearing two terminal dipicolylamine (DPA) receptor units for binding metal cations, and an ethoxyethanol moiety for enhanced water solubility. The DPA units are connected to position 4 of the fluorophore via a triazine-ethylenediamine spacer. Fluorescence titration studies of the chemosensor revealed a high selectivity for Cu2+ over other divalent ions, the emissions were strongly quenched upon binding, and a stability constant of 5.52 log units was obtained. Given the distance from DPA chelating units and the fluorophore, quenching from the Cu2+ complexation suggests an electron transfer or an electronic energy transfer mechanism. Furthermore, the Cu2+-sensor complex proved to be capable of sensing anionic phosphate derivatives through the displacement of the Cu2+ cation, which translated into a full recovery of the luminescence from the naphthalimide. Super-resolution fluorescence microscopy studies performed in HeLa cells showed there was a high intracellular uptake of the chemosensor. Incubation in Cu2+ spiked media revealed a strong fluorescent signal from mitochondria and cell membranes, which is consistent with a high concentration of ATP at these intracellular sites.

Impact of coronary angioplasty in elderly patients with non-ST-segment elevation myocardial infarction.

BACKGROUND: As treatment of coronary artery disease improved over the last years, management of elder patients remained a matter of debate since this age group has been underrepresented in most trials. The study aimed to evaluate a population of patients with ≥ 85 years old with non-ST-segment elevation myocardial infarction (NSTEMI) and compare the prognosis according to coronary revascularization execution. METHODS: We retrospectively studied 324 patients included in a national multicenter registry between October 2010 and October 2018, who underwent coronary angiography and had at least one stenosis ≥ 50%. RESULTS: In this population, 73.1% of the patients underwent percutaneous coronary intervention (PCI) and 26.9% of the patients underwent optimized medical treatment (OMT). The OMT group had more past history of diabetes, stroke and dementia. On coronary angiography, the PCI group used more often the femoral artery access and single-vessel lesions were also more common. Three-vessel disease was more common in the OMT group. During hospitalization, there were more major bleeding events and death in the PCI group. During the one-year follow-up, there were no significant differences in all-cause mortality rate. CONCLUSIONS: Very old patients with NSTEMI submitted to OMT had more comorbidities and more three-vessel disease, factors that could have influenced the therapeutic decision. Patients undergoing PCI had more in-hospital major bleeding events and mortality, with no significant differences after one year.

Monitoring inorganic pyrophosphatase activity with the fluorescent dizinc(ii) complex of a macrocycle bearing one dansylamidoethyl antenna.

The dizinc(ii) complexes of L were used for the recognition of anions by fluorescence spectroscopy (L is a heteroditopic hexaazamacrocycle with two diethylenetriamine coordination heads with 2-methylpyridyl and dansylamido ethyl arms, and m-xylyl spacers). The protonation of L and stability constants of its zinc(ii) complexes were determined in aqueous solution, at 298.2 ± 0.1 K and I = 0.10 ± 0.01 M in KNO3. At a 2 : 1 Zn2+/L ratio, the dinuclear complexes clearly dominate. The ligand alone does not display fluorescence changes upon increasing the pH value, but in the presence of Zn2+ the emission reaches a maximum at pH ≅ 7.5, at which 95% of the ligand is in the dinuclear complex form. The emission appears concomitantly with the [Zn2H-1L]3+ species formation, which supports that the latter complex corresponds to the metal-promoted deprotonation of dansylamide NH. The [Zn2H-1L]3+ complexes were used for the recognition of phosphate and polyphosphate anions in aqueous solution buffered at pH 7.5 with 2 mM PIPPS, at 298.2 K. The binding of anions causes a decrease of the emission. The association constant determination revealed that HPPi3- is the strongest bound anion (log Kapp = 5.57), followed by HATP3- (two times weaker), and the remaining anions show lower binding constants, with HPO42- having the weakest uptake by the receptor. The observed selectivity of the [Zn2H-1L]3+ receptor for PPi in relation to HPO42-, and the fact that the formation of the [Zn2H-1L]3+ complex is not disturbed by the presence of Mg2+, allowed monitoring of the PPi hydrolysis by using inorganic pyrophosphatase in real-time.

Evaluation of Noninvasive Prenatal Testing (NIPT) guidelines using the AGREE II instrument.

Objective: The rapid increase of cell-free fetal DNA analysis for Down syndrome screening requires evidence-based clinical practice guidelines for noninvasive prenatal testing (NIPT). Several studies show that the quality of many guidelines is low and there are still many health areas where this quality is not systematically evaluated. Given the absence of research, in the NIPT field, we used an internationally validated tool to evaluate a set of three NIPT practice guidelines and to look at dimensions that can be improved.Methods: Four appraisers, experts in prenatal screening, evaluated three main NIPT guidelines published in the last 2 years using the AGREE II (Appraisal of Guidelines for Research and Evaluation II), a tool specifically designed for guideline quality appraisal.Results: Guidelines scored higher in domains related with scope, purpose, and clarity of presentation, and lower in stakeholder involvement and rigor of development. Intradomain items evaluation showed asymmetries between guidelines. The UK-NSC was the guideline with the best scores.Discussion: Several areas of NIPT guidelines, such as stakeholders involvement, selection of supporting evidence, external reviews, updating processes, and competing interests disclosure, can be improved. Appraisers recommend modifications to all NIPT guidelines that can lead to substantial improvements in their methodological quality and subsequently make a contribution to prenatal screening improvement.

Allosteric Recognition of Homomeric and Heteromeric Pairs of Monosaccharides by a Foldamer Capsule.

The recognition of either homomeric or heteromeric pairs of pentoses in an aromatic oligoamide double helical foldamer capsule was evidenced by circular dichroism (CD), NMR spectroscopy, and X-ray crystallography. The cavity of the host was predicted to be large enough to accommodate simultaneously two xylose molecules and to form a 1:2 complex (one container, two saccharides). Solution and solid-state data revealed the selective recognition of the α-4 C1 -d-xylopyranose tautomer, which is bound at two identical sites in the foldamer cavity. A step further was achieved by sequestering a heteromeric pair of pentoses, that is, one molecule of α-4 C1 -d-xylopyranose and one molecule of ß-1 C4 -d-arabinopyranose despite the symmetrical nature of the host and despite the similarity of the guests. Subtle induced-fit and allosteric effects are responsible for the outstanding selectivities observed.

Binding of Flavylium Ions to Sulfonatocalix[4]arene and Implication in the Photorelease of Biologically Relevant Guests in Water.

The formation of host-guest complexes between seven flavylium cations and water-soluble p-sulfonatocalix[4]arene (SC4) was investigated by UV/vis absorption, fluorescence, and NMR spectroscopies. The results show the cationic guests form complexes with affinities in the submillimolar range. A representative chalcone/flavylium photoswitch was investigated in more detail regarding its pH- and light-triggered interconversion between the two forms. The dramatic affinity differentiation of the SC4 binding of the two switchable species (40 M-1 for the trans-chalcone versus 3.5 × 104 M-1 for the flavylium cation) enables the pH-gated photocontrol of the complexation process. These responsive properties were explored to demonstrate the competitive and selective release of biologically relevant guests from their supramolecular complexes with p-sulfonatocalix[4]arene (SC4), following the principle of AND logic. The guest release can be reverted by the thermally activated reaction of the flavylium ion back to the trans-chalcone.

The role of methylation in the copper(ii) coordination properties of a His-containing decapeptide.

N-Methylation of the peptide amide bond has proven to be a powerful strategy to fine-tune the conformation and properties of peptides. In this context and for the first time, we show that N-methylation can also be used to control the copper(ii) coordination properties of peptides and stabilize at high pH values the copper(ii) species lacking amidate coordination. Namely, we have prepared a derivative of the O-Asp peptide where the copper(ii) coordinating amino acids, i.e. Asp and His residues, were N-methylated (ONMe-Asp). A combined study using potentiometric and spectroscopic (UV-Vis, CD, EPR and NMR) techniques indicates the formation of the wanted major species, [CuH(ONMe-Asp)]2+, where copper(ii) is bound to His4(Nε), His7(Nε), His9(Nε) and Asp2(COO-). With respect to the parent non-methylated O-Asp peptide, [CuH(ONMe-Asp)]2+ is stable at higher pH values but has lower affinity for copper(ii). Additionally, electrochemical studies reveal a Cu(ii) ⇌ Cu(i) redox process with a larger cathodic and anodic peak separation. Species containing copper(ii) coordinating amidates were not observed for this ONMe-Asp peptide.

Association of anti-inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice.

BACKGROUND: Chronic inflammation has been implicated in cancer etiology and angiogenesis is stimulated in this disease. In prostate, the crosstalk between malignant epithelial cells and their microenvironment is an essential step of tumorigenesis during which glandular stroma undergo changes designated as reactive stroma. Thus, the aim herewith was to evaluate the effects of associating anti-inflammatory and antiangiogenic therapies on cancer progression, correlating them with steroid hormone receptor (AR and ERα), reactive stroma (vimentin, αSMA, and TGF-ß), and cell proliferation (PCNA) markers expression in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. METHODS: TRAMP mice (12-week old) were divided into the groups: Control (TRCON): received the vehicles used for drug dilution; Celecoxib (TRCEL): received oral doses of the anti-inflammatory drug celecoxib (15 mg/kg) twice daily; Nintedanib (TRNTB): received oral doses of the antiangiogenic drug nintedanib (10 mg/kg) daily; Nintedanib+Celecoxib (TRNTCEL): received the combination of drugs. After 6 weeks, mice were euthanized and ventral prostate samples were harvested for morphological, immunohistochemical, and Western blotting analyses. RESULTS: While celecoxib led to fibromuscular hypertrophy attenuation, nintedanib significantly reduced the incidence of well-differentiated adenocarcinoma (WDAC) foci in relation to controls, both when administered per se or in association to celecoxib. Furthermore, drug combination was associated with unique effects, including lower incidence of HGPIN lesions; lower AR stromal distribution; changes in ERα localization from epithelial nuclei to stroma as well as significant decrease of TGF-ß levels and associated angiogenesis. In parallel, all treatments applied resulted in reduced inflammatory marker and vimentin (VIM) expression. CONCLUSIONS: Celecoxib plus nintedanib is an effective antitumor combination against prostate cancer progression in TRAMP mice, showing remarkable efficacy in relation to isolated therapies. Importantly, this efficacy might be due to drug association effect on driving AR and mainly ERα distribution in the prostatic tissue towards benign patterns. In addition, celecoxib and nintedanib impaired the development of a stromal reaction by reducing the recruitment of reactive stroma cells and maintaining a normal smooth muscle cell-rich prostate stroma in TRAMP mice. Collectively, these findings pointed to the beneficial effects of combining anti-inflammatory and antiangiogenic strategies to prevent or delay prostatic tumorigenesis.

Left atrial volume index: Can it provide additional prognostic information in ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention?

INTRODUCTION: We sought to assess the prognostic impact of left atrial (LA) size on long-term outcomes of ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 200 consecutive patients admitted to a single center between January 2010 and December 2014 with non-fatal STEMI treated with primary percutaneous coronary intervention (pPCI) who underwent a comprehensive echocardiographic examination at discharge. LA volume was estimated by the area-length method. The left atrium was classified as normal, mildly, moderately or severely enlarged by LA volume index (LAVI). The endpoints were defined as all-cause mortality, a cardiac composite endpoint (all-cause mortality, reinfarction, unplanned revascularization and hospitalization for heart failure) and a cardiovascular composite endpoint (cardiac endpoint plus atrial fibrillation and ischemic stroke) during follow-up. RESULTS: In this STEMI population, 58% had normal LA size, 22.5% had mild LA enlargement, 10% had moderate LA enlargement and 9.5% had severe LA enlargement. During a median follow-up of 28 (IQR 21-38) months, 14 (7.0%) patients died, 53 (26.5%) had the cardiac and 58 (29%) the cardiovascular composite endpoints. There was a stepwise increase in the incidence of all-cause mortality (p=0.020) and both cardiac (p<0.001) and cardiovascular (p<0.001) endpoints with each increment of LAVI class. In multivariate analysis, severe LA enlargement by LAVI was an independent predictor of all-cause mortality (HR: 11.153; 95% CI: 1.924-64.642, p=0.007) and the cardiac (HR: 4.351; 95% CI: 1.919-9.862, p<0.001) and cardiovascular (HR: 4.351; 95% CI: 1.919-9.862, p<0.001) endpoints during follow-up. CONCLUSIONS: This contemporary study confirms the prognostic effect of LA size at discharge, applying the most recent reference values in STEMI patients treated with pPCI.

Carbohydrate binding through first- and second-sphere coordination within aromatic oligoamide metallofoldamers.

Aromatic oligoamide capsules that fold upon metal binding recognize carbohydrate guests in solution as evidenced by CD and NMR titrations. Crystallographic data reveal that, besides their structural role, metal ions also contribute to guest recognition through either first- or second-sphere coordination.

Short-term prognostic effect of prior cerebrovascular and peripheral artery disease in patients with acute coronary syndrome: Can we do better?

BACKGROUND: We sought to evaluate the impact of prior cerebrovascular and/or peripheral arterial disease (PAD) on in-hospital outcomes in patients with acute coronary syndromes. METHODS: From 1 October 2010 to 26 February 2016, 13,904 acute coronary syndrome patients were enrolled in a national multicentre registry. They were divided into four groups: prior stroke/transient ischaemic attack (stroke/TIA); prior PAD; prior stroke/TIA and PAD; none. The endpoints included in-hospital mortality and a composite endpoint of death, re-infarction and stroke during hospitalization. RESULTS: 6.3% patients had prior stroke/TIA, 4.2% prior PAD and 1.4% prior stroke/TIA and PAD. Prior stroke/TIA and/or PAD patients were less likely to receive evidence-based medical therapies (dual antiplatelet therapy: stroke/TIA= 88.6%, PAD= 86.6%, stroke/TIA+PAD= 85.7%, none= 92.2%, p<0.001; ß-blockers: stroke/TIA= 77.1%, PAD= 72.1%, stroke/TIA+PAD= 71.9%, none= 80.8%, p<0.001; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers: stroke/TIA= 86.3%, PAD= 83.6%, stroke/TIA+PAD= 83.2%, none= 87.1%, p=0.030) and to undergo percutaneous revascularization (stroke/TIA= 52.8%, PAD= 45.6%, stroke/TIA+PAD= 43.7%, none= 67.9%, p<0.001), despite more extensive coronary artery disease (three-vessel disease: stroke/TIA= 29.1%, PAD= 38.3%, stroke/TIA+PAD= 38.3%, none= 20.2%, p<0.001). In a multivariable analysis, prior stroke/TIA+PAD was a predictor of in-hospital mortality (odds ratio= 2.828, 95% confidence interval 1.001-7.990) and prior stroke/TIA (odds ratio= 1.529, 95% confidence interval 1.056-2.211), prior PAD (odds ratio= 1.618, 95% confidence interval 1.034-2.533) and both conditions (odds ratio= 3.736, 95% confidence interval 2.002-6.974) were associated with the composite endpoint. CONCLUSION: A prior history of stroke/TIA and/or PAD was associated with lower use of medical therapy and coronary revascularization and with worst short-term prognosis. An individualized management may improve their poor prognosis.

Alkali and alkaline earth metal ion binding by a foldamer capsule: selective recognition of magnesium hydrate.

Alkali and alkaline earth metal ion binding by an aromatic oligoamide foldamer was shown to induce its folding into a helical capsule. CD and NMR titrations revealed tight and selective binding of Mg2+. Crystallographic studies demonstrated that, depending on the metal, binding may involve the first or second coordination spheres of the metal hydrates.