Patients with atrial fibrillation and common exclusion criteria from clinical trials are at high risk of clinical events: the Murcia AF Project II (MAFP-II) cohort study.

BACKGROUND: Some clinical characteristics and comorbidities in atrial fibrillation (AF) patients are exclusion criteria in randomized clinical trials (RCTs) investigating oral anticoagulants (OAC). However, these conditions are present also in everyday clinical practice patients. We compared the risk of adverse clinical outcomes between patients with and without RCT exclusion criteria. METHODS: The Murcia AF Project II was an observational cohort study including AF outpatients starting vitamin K antagonists (VKAs) from July 2016 to June 2018. For the selection of the exclusion criteria, the four pivotal RCTs of direct-acting OAC (DOACs) were used as reference. During 2 years, all ischemic strokes/transient ischemic attacks, major adverse cardiovascular events (MACEs), major bleeds, and all-cause deaths were recorded. RESULTS: 1050 patients (51.5% female, median age 77 years) were included, of whom 368 (35%) met at least one exclusion criterion for RCTs. During follow-up, the incidence rate ratios for major bleeding, MACE and all-cause mortality were higher among patients with exclusion criteria (all p < 0.001). Patients fulfilling at least one exclusion criterion had increased risks of major bleeding (aHR 1.48; 95% CI 1.22-1.81; p < 0.001), MACE (aHR 1.51, 95% CI 1.10-2.09, p = 0.012), and mortality (aHR 3.22, 95% CI 2.32-4.48, p < 0.001), as well as a lower event-free survival (all log-rank p < 0.001). CONCLUSIONS: In this AF cohort taking VKAs, more than one-third had at least one RCT exclusion criteria, which translates into higher risk of major bleeding, MACE, and death. These observations should be considered when translating RCTs results to AF patients for a proper and a more patient-centered management.

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy.

BACKGROUND: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. METHODS: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. RESULTS: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. CONCLUSIONS: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Unlocking the effective alliance of ß-lapachone and hydroxytyrosol against triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is characterised by its aggressiveness and resistance to chemotherapy, demanding the development of effective strategies against its unique characteristics. Derived from lapacho tree bark, ß-lapachone (ß-LP) selectively targets cancer cells with elevated levels of the detoxifying enzyme NQO1. Hydroxytyrosol (HT) is a phenolic compound derived from olive trees with important anticancer properties that include the inhibition of cancer stem cells (CSCs) and metastatic features in TNBC, as well as relevant antioxidant activities by mechanisms such as the induction of NQO1. We aimed to study whether these compounds could have synergistic anticancer activity in TNBC cells and the possible role of NQO1. For this pourpose, we assessed the impact of ß-LP (0.5 or 1.5 µM) and HT (50 and 100 µM) on five TNBC cell lines. We demonstrated that the combination of ß-LP and HT exhibits anti-proliferative, pro-apoptotic, and cell cycle arrest effects in several TNBC cells, including docetaxel-resistant TNBC cells. Additionally, it effectively inhibits the self-renewal and clonogenicity of CSCs, modifying their aggressive phenotype. However, the notable impact of the ß-LP-HT combination does not appear to be solely associated with the levels of the NQO1 protein and ROS. RNA-Seq analysis revealed that the combination's anticancer activity is linked to a strong induction of endoplasmic reticulum stress and apoptosis through the unfolded protein response. In conclusion, in this study, we demonstrated how the combination of ß-LP and HT could offer an affordable, safe, and effective approach against TNBC.

Suspensión de antibióticos a través de un programa de optimización de tratamiento antibiótico en pacientes atendidos en Urgencias con baja sospecha de infección / Antibiotic discontinuation through an antibiotic treatment optimization program in emergency department patients with low suspicion of infection

Introducción: Una de las estrategias más importantes de los PROA en los Servicios de Urgencias (SU) es el diagnóstico adecuado de infección para evitar la prescripción inadecuada. Nuestro objetivo es evaluar a los pacientes que reciben antibiótico a pesar de no tener datos objetivos de infección. Métodos: Realizamos un estudio transversal de los pacientes ingresados en el SU del Hospital Universitario Fundación Alcorcón durante 2 meses (mayo del 2019 y marzo del 2021) en los que se recomendó suspender el antibiótico a través del PROA. Se analizaron las características clínicas y epidemiológicas, y el seguimiento a 30 días para valorar los reingresos y la mortalidad. Resultados: Se analizaron 145 pacientes. Se recomendó suspender el antibiótico en 25. El 44% de ellos tenían diagnóstico de infección urinaria. La recomendación de suspensión se aceptó en el 88%. Ningún paciente falleció y uno reingresó. Conclusiones: Un porcentaje importante de pacientes tenían prescrito antibiótico a pesar de no tener criterios de infección, siendo la evolución clínica tras la de prescripción favorable.(AU)

Introduction: One of the most important strategies of PROA in the Emergency Department (ED) is the accurate diagnosis of infection to avoid inappropriate prescription. Our objective is to evaluate patients who receive antibiotics despite not having objective data of infection. Methods: We carried out a cross-sectional study of patients admitted to the ED of the Hospital Universitario Fundación Alcorcón in which it was recommended to suspend the antibiotic through the PROA. Clinical and epidemiological characteristics and 30-day follow-up were analyzed to assess readmissions and mortality. Results: 145 patients were analyzed. It was recommended to suspend the antibiotic in 25. 44% of them had a diagnosis of urinary infection. The suspension recommendation was accepted by 88%. No patient died and one was readmitted. Conclusions: An important percentage of patients are prescribed antibiotics despite not having infection criteria, the clinical evolution after suspension of antibiotics was favorable.(AU)

Clinical Evaluation of Nontuberculous Mycobacteria (NTM) Elite Agar, a New Medium for the Isolation of NTM: a Multicenter Study.

Nontuberculous mycobacteria (NTM) are gaining interest with the increased number of infected patients. NTM Elite agar is designed specifically for the isolation of NTM without the decontamination step. We assessed the clinical performance of this medium combined with Vitek mass spectrometry (MS) matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) technology for the isolation and identification of NTM in a prospective multicenter study, including 15 laboratories (24 hospitals). A total of 2,567 samples from patients with suspected NTM infection were analyzed (1,782 sputa, 434 bronchial aspirates, 200 bronchoalveolar lavage samples, 34 bronchial lavage samples, and 117 other samples). A total of 220 samples (8.6%) were positive with existing laboratory methods against 330 with NTM Elite agar (12.8%). Using the combination of both methods, 437 isolates of NTM were detected in 400 positive samples (15.6% of samples). In total, 140 samples of the standard procedures (SP) and 98 of the NTM Elite agar were contaminated. NTM Elite agar showed a higher performance for rapidly growing mycobacteria (RGM) species than SP (7% versus 3%, P < 0.001). A trend has been noted for the Mycobacterium avium complex (4% with SP versus 3% with NTM Elite agar, P = 0.06). The time to positivity was similar (P = 0.13) between groups. However, the time to positivity was significantly shorter for the RGM in subgroup analysis (7 days with NTM and 6 days with SP, P = 0.01). NTM Elite agar has been shown to be useful for the recovery of NTM species, especially for the RGM. Using NTM Elite agar + Vitek MS system in combination with SP increases the number of NTM isolated from clinical samples.

TGFß Governs the Pleiotropic Activity of NDRG1 in Triple-Negative Breast Cancer Progression.

In triple-negative breast cancer (TNBC), the pleiotropic NDRG1 (N-Myc downstream regulated gene 1) promotes progression and worse survival, yet contradictory results were documented, and the mechanisms remain unknown. Phosphorylation and localization could drive NDRG1 pleiotropy, nonetheless, their role in TNBC progression and clinical outcome was not investigated. We found enhanced p-NDRG1 (Thr346) by TGFß1 and explored whether it drives NDRG1 pleiotropy and TNBC progression. In tissue microarrays of 81 TNBC patients, we identified that staining and localization of NDRG1 and p-NDRG1 (Thr346) are biomarkers and risk factors associated with shorter overall survival. We found that TGFß1 leads NDRG1, downstream of GSK3ß, and upstream of NF-κB, to differentially regulate migration, invasion, epithelial-mesenchymal transition, tumor initiation, and maintenance of different populations of cancer stem cells (CSCs), depending on the progression stage of tumor cells, and the combination of TGFß and GSK3ß inhibitors impaired CSCs. The present study revealed the striking importance to assess both total NDRG1 and p-NDRG1 (Thr346) positiveness and subcellular localization to evaluate patient prognosis and their stratification. NDRG1 pleiotropy is driven by TGFß to differentially promote metastasis and/or maintenance of CSCs at different stages of tumor progression, which could be abrogated by the inhibition of TGFß and GSK3ß.

Antibiotic discontinuation through an antibiotic treatment optimization program in emergency department patients with low suspicion of infection.

INTRODUCTION: One of the most important strategies of PROA in the Emergency Department (ED) is the accurate diagnosis of infection to avoid inappropriate prescription. Our objective is to evaluate patients who receive antibiotics despite not having objective data of infection. METHODS: We carried out a cross-sectional study of patients admitted to the ED of the Hospital Universitario Fundación Alcorcón in which it was recommended to suspend the antibiotic through the PROA. Clinical and epidemiological characteristics and 30-day follow-up were analyzed to assess readmissions and mortality. RESULTS: 145 patients were analyzed. It was recommended to suspend the antibiotic in 25. 44% of them had a diagnosis of urinary infection. The suspension recommendation was accepted by 88%. No patient died and one was readmitted. CONCLUSIONS: An important percentage of patients are prescribed antibiotics despite not having infection criteria, the clinical evolution after suspension of antibiotics was favorable.

On the proper periodic Ricker model.

The periodic Ricker equation has been studied by several authors, including the present one. However, the periodic model derived from the original one has not been studied in detail. We show that the model often taken as a periodic Ricker model is a particular case of the original one and compare their dynamics. In particular, we characterize the parameter region where the model has a periodic point of period two, which is globally stable. We also compute the parameter regions where complex behavior is exhibited.

Nanomedicine as a Promising Tool to Overcome Immune Escape in Breast Cancer.

Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-based strategies targeting cancer immune evasion and modulating the immunosuppressive tumor microenvironment, including the inhibition of immunosuppressive cells in the tumor area, the activation of dendritic cells and the stimulation of the specific antitumor T-cell response.

The dynamics of a four-step feedback procedure to control chaos.

In this paper, we describe the dynamics of a four-step procedure to control the dynamics of the logistic map fµ(x)=µx(1-x). First, we calculate topological entropy with given accuracy through massive computations. Second, we find the parameter regions where the model has complicated dynamical behavior. Finally, to avoid undesirable dynamics, our computations also show that we should take into account Parrondo's paradox "simple+simple=complex."

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

Antioxidants for the Treatment of Breast Cancer: Are We There Yet?

Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on "redoxidomics" or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.

Drug Repurposing for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.

Using Permutations for Hierarchical Clustering of Time Series.

Two distances based on permutations are considered to measure the similarity of two time series according to their strength of dependency. The distance measures are used together with different linkages to get hierarchical clustering methods of time series by dependency. We apply these distances to both simulated theoretical and real data series. For simulated time series the distances show good clustering results, both in the case of linear and non-linear dependencies. The effect of the embedding dimension and the linkage method are also analyzed. Finally, several real data series are properly clustered using the proposed method.

Food poisoning caused by scombroids: A case-control study.

The aim of this study is to report the epidemiological characteristics of a food poisoning outbreak due to scombroid fish in a hospital. A case-control study (1:4) was conducted. Patients either symptomatic of food poisoning (cases) or asymptomatic (controls) eating at the hospital cafeteria were included. To identify the source of the outbreak, sanitary control factors were assessed. Microbiological studies and the mast cell tryptase test were performed. All cases and controls received a questionnaire enquiring about symptoms and foods consumed. The odds ratios (OR) for all risk factors and their 95% confidence intervals (CI) were assessed. In total, 20 individuals (90% female) were included in the study: four cases and 16 controls. The overall mean age was 43 years (SD: 10.2). The most frequent symptom observed was facial and neck erythaema (100%). Microbiological cultures were negative, the mast cell tryptase test was normal and breakdown of the cold chain did not occur. The most likely source of the outbreak was fried anchovies (OR: 34.7; 95% CI: 1.50-809.6; p=0.02). Methods suitable to the rapid assessment of the outbreak allowed us to establish prompt preventive measures and identify the likely aetiology.

Publisher Correction: IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A.

In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.

IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A.

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1α is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1α expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1α also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1α in cell migration, whereby filamin A operates as an interphase between the UPR and the actin cytoskeleton.

The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol.

Alcohol and ketogenic diets increase water consumption. Here, we show that the hormone FGF21 is required for this drinking response in mice. Circulating levels of FGF21 are increased by alcohol consumption in humans and by both alcohol and ketogenic diets in mice. Pharmacologic administration of FGF21 stimulates water drinking behavior in mice within 2 hr. Concordantly, mice lacking FGF21 fail to increase water intake in response to either alcohol or a ketogenic diet. The effect of FGF21 on drinking is mediated in part by SIM1-positive neurons of the hypothalamus and is inhibited by ß-adrenergic receptor antagonists. Given that FGF21 also is known to suppress alcohol intake in favor of pure water, this work identifies FGF21 as a fundamental neurotropic hormone that governs water balance in response to specific nutrient stresses that can cause dehydration.

Antibioterapia profiláctica en la artroplastia de cadera. Estudio de cohorts / Prophylactic antibiotherapy in hip arthroplasty. Cohort study

Introducción: La infección de herida quirúrgica (IHQ) es la principal causa de infección nosocomial en pacientes quirúrgicos, siendo la profilaxis antibiótica uno de los factores más importantes para su prevención. En este trabajo se evaluó la adecuación de la profilaxis antibiótica en la artroplastia de cadera de acuerdo a la pauta establecida en nuestro centro y el efecto en la IHQ. Material y métodos. Se realizó un estudio de cohortes prospectivo entre enero de 2011 y diciembre de 2016. Se evaluó el grado de adecuación de la profilaxis antibiótica en cirugía de artroplastia de cadera. Se estudió la incidencia de IHQ tras un periodo máximo de 90 días. El efecto de la inadecuación de la profilaxis antibiótica en la incidencia de IHQ se evaluó con el riesgo relativo (RR) ajustado mediante un modelo de regresión logística. Resultados. Se incluyeron un total de 681 pacientes. La incidencia global de IHQ fue del 4% (IC 95%: 2,5-5,5). La profilaxis antibiótica se administró en el 99% de los casos, con una adecuación al protocolo del 74%. La causa más frecuente de inadecuación fue la duración de la profilaxis, con un 22,2% (149 pacientes). El efecto de la inadecuación de la profilaxis sobre la incidencia de infección fue de RR ajustado =0,47; IC95%: 0,19-1,17) (p>0,05). Conclusiones. La adecuación de la profilaxis antibiótica fue alta. No se encontró asociación entre adecuación de la profilaxis y la incidencia de infección en artroplastia de cadera. La vigilancia de la infección quirúrgica permite medir su incidencia y evaluar sus factores de riesgo

Introduction. The surgical site infection is the main cause of nosocomial infection in surgical patients, being antibiotic prophylaxis one of the most important factors for preventing it. This study evaluates adequacy of antibiotic prophylaxis in hip arthroplasty surgery as well as its effect on preventing surgical site infection. Material and methods. A prospective cohort study was carried out from January 2011 to December 2016. We assessed the degree of adequacy of antibiotic prophylaxis in hip arthroplasty. Incidence of surgical site infection was studied after a maximum incubation period of 90 days. In order to assess the effect of inadequate prophylaxis on surgical site infection we used the relative risk adjusted with a logistic regression model. Results. We studied 681 patients. Incidence of surgical site infection was 4% (95% CI 2.5-5.5). Antibiotic prophylaxis was administered in 99% of cases, with an overall protocol adequacy of 74%. The main cause of non-compliance was the length of prescription (22.2%; 149 patients). The effect of inadequate prophylaxis on surgical site infection was RR adjusted =0.47; 95%CI 0.19-1.17, (p>0.05). Conclusions. Adequacy of antibiotic prophylaxis was high. No relationship between prophylaxis adequacy and incidence of surgical site infection was founded. Surveillance allows us to assess surgical site infection and risk factors