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Abstract A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of “interactome mapping” and illustrate by example the multiple protein–protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.

Abstract Background Over the past decade, numerous studies on potential factors contributing to ventilation-induced lung injury have been carried out. Mechanical power has been pointed out as the parameter that encloses all ventilation-induced lung injury-contributing factors. However, studies conducted to date provide data regarding mechanical power during the early hours of mechanical ventilation that may not accurately reflect the impact of power throughout the period of mechanical ventilatory support on intensive care unit mortality. Methods Retrospective observational study conducted at a single center in Spain. Patients admitted to the intensive care unit, > o = 18 years of age, and ventilated for over 24 h were included. We extracted the mechanical power values throughout the entire mechanical ventilation in controlled modes period from the clinical information system every 2 min. First, we calculate the cutoff-point for mechanical power beyond which there was a greater change in the probability of death. After, the sum of time values above the safe cut-off point was calculated to obtain the value in hours. We analyzed if the number of hours the patient was under ventilation with a mechanical power above the safe threshold was associated with intensive care unit mortality, invasive mechanical ventilation days, and intensive care unit length of stay. We repeated the analysis in different subgroups based on the degree of hypoxemia and in patients with SARS CoV-2 pneumonia. Results The cut-off point of mechanical power at with there is a higher increase in intensive care unit mortality was 18 J/min. The greater the number of hours patients were under mechanical power > 18 J/min the higher the intensive care unit mortality in all the study population, in patients with SARS CoV-2 pneumonia and in mild to moderate hypoxemic respiratory failure. The risk of death in the intensive care unit increases 0.1% for each hour with mechanical power exceeding 18 J/min. The number of hours with mechanical power > 18 J/min also affected the days of invasive mechanical ventilation and intensive care unit length of stay. Conclusions The number of hours with mechanical power > 18 J/min is associated with mortality in the intensive care unit in critically ill patients. Continuous monitoring of mechanical power in controlled modes using an automated clinical information system could alert the clinician to this risk.

Using UK data supplied by universities, this paper confirms that women academics earn less than men, even after controlling for a range of covariates. Despite narrowing after 2004/05, the observed (unconditional) pay gap was still -0.089 in 2019/20, while the conditional pay gap was relatively unchanged remaining at around -0.050 in 2019/20. The results are consistent with the literature on why pay gaps might occur, with the key disparity occurring when women face a higher cost of investment and statistical discrimination, linked to bias, to achieve promotion. That is, the results presented here suggest that earnings gaps are significantly reduced when grade-balanced gender sub-groups are compared, suggesting conditional wage differences are more likely due to bias rather than any inherent differences in (research) productivity.

Background: Complete pathological response to neoadjuvant treatment (NAT) in breast cancer is associated with prolonged survival. Compared to other breast cancer immunophenotypes, luminal tumors are the least chemosensitive with low rates of pathological response within this molecular subtype. Thus, finding predictors of response in this subset remains challenging. The emerging concept of low human epidermal growth factor receptor 2 (HER2) expression has led to a repurpose of the current prognostic system. Little is known about its correlation with response to NAT. Objectives: This study aims to evaluate predictors of response in early-stage luminal breast cancer receiving neoadjuvant chemotherapy. Design: A total of 252 luminal patients who received NAT were retrospectively assessed in this cohort study. Methods: We analyzed the correlation of ki67 and HER2 low expression with the rate of pathologic response. Using ki67 as a continuous variable and applying the receiver operating characteristic curves method. Results: We identified that in patients with a ki67 expression level >37%, the probability of having a complete pathological response was 4.80 times higher (odds ratio = 4.80, 95% confidence interval: 1.92–12.04). In Her2-low breast cancer patients, Her2 expression did not correlate with a better response rate. Conclusion: In our study, a ki67 expression value greater than 37% constitutes a predictive biomarker of pathological complete response in the subgroup of patients with luminal B tumors and could be considered, therefore, an indicator for treatment decisions in this subgroup.

Partiendo de las consideraciones de Goldstein que plantea una relación dada entre el sistema de guerra y el género, el presente artículo identifica las configuraciones de las representaciones de género en la trayectoria de vida de cuatro reincorporados/as de las FARC-EP para estudiar la forma en que se han modificado. Para las trayectorias de vida se recurrió a una metodología cualitativa a partir de la narrativa biográfica y la etnografía feminista en el AETCR Antonio Nariño ubicado en Icononzo-Tolima. El análisis de la información se llevó a cabo a partir de una tematización de las narrativas biográficas y las entrevistas para lo cual nos apoyamos en el software Citavi. Como resultado de la investigación se observa como esta guerrilla se convierte en agente de trasformación de las representaciones de género tradicionales en las zonas rurales, junto con los programas institucionales o de ONG que cuentan con una perspectiva de género y en los/as que han estado participando en su proceso de reincorporación. También se indica que a partir de las reificaciones se mantienen estáticos algunas representaciones de género a lo largo de sus vidas, lo que no nos permite hablar de cambios, sino de algunas transformaciones.

ObjectiveIdiopathic central precocious puberty (CPP) precipitates epiphyseal fusion of growth plates in long bones, leading to reduced adult stature. Gonadotropin-releasing hormone analogues (GnRHa) are the treatment of choice for idiopathic CPP, but their benefit on height gain is unclear. We aimed to elucidate the effects of GnRHa treatment on adult height in girls with idiopathic CPP.DesignThis prospective observational descriptive study analyzed data of girls with idiopathic CPP diagnosed at 55 centers in Spain between January 1, 1998 and December 31, 2012 included in the Spanish Society for Pediatric Endocrinology’s national registry.MethodsWe included girls with idiopathic CPP (thelarche < 8 years, positive LHRH stimulation test, bone age > 1 year older than chronological age, and normal brain imaging) treated with triptorelin (3.75 mg monthly, adjusted according to LHRH test results and clinical findings). We assessed weight, height, BMI, and secondary sexual characteristics every 6 months and bone age every 12 months until adult height (AH) was attained. The primary outcome was the difference between AH and target height (TH).ResultsA total of 465 girls (18.90% adopted) were included; we analyzed data recorded at treatment end in 358 girls and at AH in 216. Mean difference between AH and TH was -1.5 (95%CI: -2.56− -0.45) cm and between AH and PAH 2,57 (95%CI:-3.56− -1.58) cm.ConclusionsGnRHa treatment helps preserve genetic growth potential in girls with idiopathic CPP.

The aim of this paper is to analyse the main demographic and socio-economic conditions of the primary caregivers of Alzheimer's and dementia sufferers, and their relationship to the employment situation of the caregiver. Material and Methods: Empirical analysis of the data obtained from surveys of 694 primary caregivers of Alzheimer's and dementia sufferers through the Andalusian Associations of Relatives of Alzheimer’s Patients. The sampling procedure was selective non-probabilistic sampling. The SPSS 19 statistical software package was used to process the data. The verification of the hypothesis of independence of variables was performed using the chi square test under the usual parameters. Results: The employment rate of working-age caregivers is much lower than that of the general population, especially in older women with low levels of education who live with the patient. The data revealed that caregiving which takes place in the home represents the main restriction preventing access to the labour market, i.e. living with the patient is an additional handicap, and an even greater one for women. Conclusions: Those who care for dementia patients have greater limitations in accessing the labour market than the rest of the population, and this limitation is significantly greater when care is provided in the home. As such, health and social policy, with a view towards encouraging employment, needs to take into account the option of boosting available resources outside of family care.

Introduction: Nephroblastoma, or Wilms’ tumor, is a malignant renal neoplasm commonly found in children, is extremely rare in adults representing only 0.5% of all renal neoplasms. Adult Wilms tumor is rare, to our knowledge fewer than 300 cases have been reported in the English literature to date. However, in older adults after 60 years of age, only less than 45 cases have been reported. For this reason, treatment guidelines in adults still are lacking. Prognosis in nephroblastoma for adult patients is found to be worse than in children. Case Presentation: We report the case of a 65-year-old female with lumbar fossa mass, flank pain and hematuria, and pathologic diagnosis of Wilms tumor. We performed nephrectomy. No adjuvant treatment was given. Our patient remains asymptomatic and without evidence of recurrence 12 months after the surgery. Conclusion: Nephroblastoma in the elderly presents different clinical behavior and prognosis compared to nephroblastoma in children.

La obra aforística de Juan Varo Zafra es una de las más originales del panorama del género en España en el siglo XXI. Por su calidad intrínseca, a partir de sus características formales, discursivas y temáticas, pero además por lo que implica para la comprensión del género. Varo Zafra ha desarrollado una genuina poética y retórica del aforismo desde el aforismo mismo. También ha reflexionado sobre él desde el punto de vista teórico. Con este trabajo, pretendemos estudiar la teoría y retórica del aforismo de este autor, y reivindicarlo como una de sus figuras destacadas de la actualidad. Por otro, añadir, en la medida de lo posible, un hito teórico y crítico más en la indagación general acerca de ese objeto textual tan difícil de definir, acotar y de clasificar.

Resumen: Introducción y objetivos: el mareo, abarcando el vértigo, el desequilibrio y el presíncope, afecta al 15–20% de los adultos, aumentando el riesgo de caídas, especialmente en ancianos. La interacción entre señales del sistema vestibular periférico, los núcleos vestibulares y el sistema nervioso central, modulada por neurotransmisores como glutamato, acetilcolina y glicina, junto con histamina, adrenalina y noradrenalina, es crucial para el equilibrio. El mareo surge cuando la información vestibular no coincide con otras fuentes y puede asociarse con diversas condiciones neurológicas, psiquiátricas, respiratorias o infecciosas. El tratamiento actual se basa en reposo, maniobras de reposición de partículas y medicamentos como betahistina y sedantes; pero la combinación fija de cinarizina y dimenhidrinato ha demostrado eficacia en ensayos clínicos, tratando eficazmente el vértigo de varios orígenes, actuando en sistemas vestibulares periféricos y centrales. Pacientes: presentamos 7 casos clínicos en los que hemos utilizado el mismo tratamiento con cinarizina y dimenhidrato a dosis de 20/40 mg. Resultados: la combinación de cinarizina y dimenhidrinato demostró ser efectiva en el manejo de una variedad de trastornos vestibulares, incluyendo vértigo posicional paroxístico benigno recurrente, migraña vestibular, síndrome de Ménière y presbivestibulopatía. Los pacientes experimentaron mejoría en los síntomas vestibulares como mareos, vértigo y desequilibrio, siendo un fármaco seguro y eficaz, demostrando en algunos casos la resolución de los síntomas en pacientes previamente tratados con otras terapias. Conclusión: la versatilidad de la combinación permite su uso en el tratamiento de vértigos de origen diverso, lo que lo convierte en una opción integral y valiosa para situaciones donde el diagnóstico preciso de las causas del vértigo no está claro. Abstract: Introduction and objectives: Dizziness, including vertigo, imbalance, and presyncope, affects 15–20% of adults, increasing the risk of falls, especially in the elderly. The interaction between signals from the peripheral vestibular system, vestibular nuclei, and the central nervous system, modulated by neurotransmitters such as glutamate, acetylcholine, and glycine, along with histamine, adrenaline, and noradrenaline, is crucial for balance. Dizziness arises when vestibular information does not match other sources and can be associated with various neurological, psychiatric, respiratory, or infectious conditions. Current treatment is based on rest, particle replacement maneuvers and medications such as betahistine and sedatives, but the fixed combination of cinnarizine and dimenhydrinate has proven effective in clinical trials, effectively treating vertigo of various origins by acting on peripheral and central vestibular systems. Patients: We present 7 clinical cases, in which we have used the same treatment with cinnarizine and dimenhydrate at fixed doses of 20/40 mg. Results: The combination of cinnarizine and dimenhydrinate proved effective in managing a variety of vestibular disorders, including recurrent benign paroxysmal positional vertigo, vestibular migraine, Meniere's syndrome, and presbivestibulopathy. Patients experienced improvement in vestibular symptoms, such as dizziness, vertigo, and imbalance, proving to be a safe and effective drug, demonstrating in some cases the resolution of symptoms in patients previously treated with other therapies. Conclusion: The versatility of the combination allows its use in the treatment of vertigo of various origins, making it a comprehensive and valuable option for situations where the precise diagnosis of the causes of vertigo is not clear.

Energy needs in the buildings sector accounts for 40 % of global energy demand. Therefore, the implementation of several renewable energy sources is necessary to reduce this demand. The design stage of a decentralized generation project requires quantifying the power to be installed and the energy forecast for each source throughout the useful life of the building. This study develops a novel optimization algorithm for a long-term economic function based on mixed-integer disciplined convex programming (MIDCP) which guarantees the sustainability of the building and its energy systems. The robust algorithm integrates risk management of intermittent sources, technical and economic parameters of selected technologies, and life cycle analysis (LCA) of different energy systems, including storage. Furthermore, the penetration of green hydrogen into the distributed generation mix is evaluated as an important contribution. Meteorological and energy demand variables of two antagonistic scenarios were also used as inputs to the algorithm. As a result, the optimal energy supply sizing for tertiary buildings in the two defined locations was obtained. The results of the simulations have achieved an optimal convergence of 100 % in the proposed scenarios, with a resolution time of 14 s and using a memory of about 183 MB. The simulations suggest a higher penetration of green hydrogen in scenarios where supply and investment costs decrease to gray hydrogen supply levels, reaching up to 81 % coverage of the thermal demand of the building. Hybrid energy systems under favorable conditions show a penetration of about 92 % within the distributed generation mix. The developed tool could enable decision-makers to optimally plan distributed generation projects in buildings based on economic, policy, and geographic conditions.

Resumen: Objetivo: Estimar el flujo sanguíneo en intestino delgado e hígado mediante la administración de microesferas coloreadas en la aurícula izquierda, comparando dicha estimación con flujo continuo y flujo pulsátil, para confirmar o rechazar como causa del síndrome de Heyde la hipoperfusión e hipoxia en estos órganos atribuidos a la pérdida de la amplitud del pulso arterial. Material y método: Se utilizaron 22 cerdos minipig de ambos sexos con un peso 29,5 ± 9,6 kg, implantándose 11 asistencias mecánicas circulatorias de flujo continuo y 11 de flujo pulsátil, monitorizados hemodinámica y analíticamente. La perfusión sanguínea en hígado e íleon terminal fue estimada mediante la administración de microesferas coloreadas en situación basal, a los 30 min de asistencia total y a los 30 min de asistencia parcial. Resultados: Los datos fueron referidos en tanto por ciento de la perfusión de estos órganos estimada en situación basal. Se realizó el estudio estadístico mediante el análisis de la varianza para medidas repetidas con una significación α de 0,05. En el hígado, el tipo asistencia (total o parcial), el tipo de bomba (continua o pulsátil) y la interacción entre ambas, arrojó la siguiente significación estadística: 0,518, 0,364 y 0,237, respectivamente. En el íleon terminal los resultados fueron: 0,264, 0,193 y 0,141.Analíticamente se observaron diferencias significativas en el nivel de bilirrubina relacionadas con la bomba de flujo continuo, así como pH y urea. Conclusiones: No observamos diferencias significativas en la estimación de la perfusión en íleon ni hígado cuando comparamos asistencia mecánica circulatoria de flujo continuo y flujo pulsátil. Abstract: Objective: To estimate blood flow in the small intestine and liver by administration of coloured microspheres in the left atrium, comparing this estimate with continuous flow perfusion and pulsatile flow, in order to confirm or reject hypoperfusion and hypoxia in these organs attributed to loss of pulse amplitude as the cause of Heyde's syndrome. Material and method: Twenty-two minipig pigs of both sexes weighing 29.5 ± 9.6 kg were implanted with 11 continuous and 11 pulsatile mechanical circulatory assist devices were implanted in 22 minipig. Haemodynamic and analytic parameter were measured. Liver and terminal ileum blood perfusión was estimated by administration of stained microspheres previus to circulatory support, at 30 minutes of full assist and at 30 minutes of partial assist. Results: Data were reported as percent of estimated perfusion at baseline. The study was performed by analysis of variance for repeated measures with a significance α of 0.05. In the liver, type of assistance (total or partial), type of pump (continuous or pulsatile) and the interaction between the 2 had the following statistical significance: 0.518. 0.364 and 0.237 respectively. In the terminal ileum the results were: 0.264. 0.193 and 0.141.Analytically significant differences were observed in bilirubin level related to the continuous flow pump, as well as pH and urea. Conclusions: We observed no significant differences in the estimation of perfusion in ileum and liver when comparing continuous flow and pulsatile flow CMA.

RESUMEN En este artículo analizamos la tentativa que realizó la joven Simone Weil por pensar el tiempo y el cambio, y por descifrar la participación que el mundo y la mente puedan tener en su configuración. Para lograrlo, nos propusimos elucidar dos conceptos que creemos sintetizan su acercamiento: el primero es el del asombro, entendido tanto en su calidad de intuición incesante que revela la impotencia humana para comprender el presente, como en su calidad de instancia mediadora entre ignorancia y ciencia humana aproximativa del ámbito fenoménico. El segundo concepto que analizamos es el de tiempo dirigido, significativo de la primera filosofía weiliana por cuanto patentiza la subyugación del hombre al presente, único tiempo tangible. Determinación que permite entender el sentido del pasado como existencia abolida, y el futuro como núcleo virtual de posibilidades hacia el cual el ser humano prepara su acción y trabajo gracias a su facultad para idear proyectos. En fin, en este artículo tratamos de evidenciar la tensión problemática que discernía la joven Weil entre la ley de la inmediatez del mundo y la ley del tiempo que impone pasos intermedios a la realización de toda actividad humana.

Abstract Substantial global attention is focused on how to reduce the risk of future pandemics. Reducing this risk requires investment in prevention, preparedness, and response. Although preparedness and response have received significant focus, prevention, especially the prevention of zoonotic spillover, remains largely absent from global conversations. This oversight is due in part to the lack of a clear definition of prevention and lack of guidance on how to achieve it. To address this gap, we elucidate the mechanisms linking environmental change and zoonotic spillover using spillover of viruses from bats as a case study. We identify ecological interventions that can disrupt these spillover mechanisms and propose policy frameworks for their implementation. Recognizing that pandemics originate in ecological systems, we advocate for integrating ecological approaches alongside biomedical approaches in a comprehensive and balanced pandemic prevention strategy.

Background and Objectives: Venous thromboembolism (VTE) can be the first manifestation of an underlying cancer. This study aimed to develop a predictive model to assess the risk of occult cancer between 30 days and 24 months after a venous thrombotic event using machine learning (ML). Materials and Methods: We designed a case–control study nested in a cohort of patients with VTE included in a prospective registry from two Spanish hospitals between 2005 and 2021. Both clinically and ML-driven feature selection were performed to identify predictors for occult cancer. XGBoost, LightGBM, and CatBoost algorithms were used to train different prediction models, which were subsequently validated in a hold-out dataset. Results: A total of 815 patients with VTE were included (51.5% male and median age of 59). During follow-up, 56 patients (6.9%) were diagnosed with cancer. One hundred and twenty-one variables were explored for the predictive analysis. CatBoost obtained better performance metrics among the ML models analyzed. The final CatBoost model included, among the top 15 variables to predict hidden malignancy, age, gender, systolic blood pressure, heart rate, weight, chronic lung disease, D-dimer, alanine aminotransferase, hemoglobin, serum creatinine, cholesterol, platelets, triglycerides, leukocyte count and previous VTE. The model had an ROC-AUC of 0.86 (95% CI, 0.83–0.87) in the test set. Sensitivity, specificity, and negative and positive predictive values were 62%, 94%, 93% and 75%, respectively. Conclusions: This is the first risk score developed for identifying patients with VTE who are at increased risk of occult cancer using ML tools, obtaining a remarkably high diagnostic accuracy. This study’s limitations include potential information bias from electronic health records and a small cancer sample size. In addition, variability in detection protocols and evolving clinical practices may affect model accuracy. Our score needs external validation.

Finding the balance between CO2 concentration and thermal comfort is very important during the heating season in a daycare classroom due to the impact it has on children’s health. Air treatment systems together with outdoor hygrothermal conditions are decisive in finding this balance. The objective of this work is to evaluate the impact that three air treatment systems, ventilation, conditioning, and air cleaning, have on thermal comfort and CO2 concentration in the two breathing planes defined by the occupants of a daycare classroom. Eight experimental tests were carried out, using different combinations of air systems. Temperature, relative humidity, and CO2 concentration are measured at eight points in the classroom: four in the children’s breathing plane (0.75 m) and the other four in that of an adult (1.7 m). The results show, on the one hand, that the ventilation or conditioning systems improve the indoor CO2 concentration in the two planes, equalizing it in the two planes and, on the other hand, that the sensation of cold is greater in the children’s breathing plane than in the adult’s breathing plane in all the experimental tests studied.

This study evaluates the mycoremediation potential of wild mushroom species from Chiapas, Mexico, specifically for high copper concentrations. Nine fungal carpophores were collected from tropical forests near coffee plantations. The morphological characteristics of the fungal strains and fruiting bodies were analyzed. Each specimen was identified through sequencing using the ITS1 and ITS4 primers. The ability to tolerate different concentrations of copper was evaluated by determining the fungal mycelial growth inhibition potential. Copper bioaccumulation by the fungi was quantified using biosorption assays with atomic absorption spectrophotometry. The enzymatic activity of laccase, lignin peroxidase, and manganese peroxidase from the fungal species was also determined in the presence of copper. Phylogenetic analysis identified the fungal species as Agaricus bisporus, A. subrufescens, Calvatia fragilis, Ganoderma coffeatum, G. lucidum, Pleurotus djmor, P. floridanus, Trametes elegans, and T. versicolor, all classified within the Agaromycetes class. The nine fungal species exhibited varying abilities to tolerate Cu2+ concentrations from 30 to 100 mg L−1. At 30 and 60 mg L−1 Cu2+, the G. lucidum H14-35 strain demonstrated the highest biosorption capacity, reaching 76.97%. Overall, the mushrooms in this study showed strong Cu2⁺ tolerance and biosorption, making them promising biomaterials for remediating copper-contaminated soils.

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1–2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0–1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.

Introduction: Firearm injury is a leading cause of death among Americans. Because the right to bear arms is protected by the Second Amendment, policymakers must consider the impact of legislation on both firearm ownership and firearm harms. The current state of knowledge in firearm research majorly examines the impact of firearm legislation on firearm injuries and fatalities alone, and it relies on correlational analyses. The few studies that consider causal effects employ counterfactual-based inference. This study introduces information-theoretic tools to explore the role of firearm laws in mitigating firearm harms while maintaining citizens’ right to bear arms. Methods: The authors study monthly time series from January 2000 to October 2019 for the implementation of firearm laws from RAND's State Firearm Law Database, firearm deaths by intent from the Centers for Disease Control and Prevention databases, and firearm ownership from an econometric model. The authors employ transfer entropy, an information-theoretic method that relies on Granger causality, to infer relationships from time series. Specifically, the authors examine transfer entropy from firearm restrictiveness to deaths per firearm owner, firearm ownership, and firearm deaths, independently. Results: On a national level, the authors uncover a negative association from firearm restrictiveness to deaths per firearm owner and a positive association from firearm restrictiveness to firearm ownership. On a regional level, the authors identify a negative association from firearm restrictiveness to deaths per firearm owner in the Northeast, a negative association from firearm restrictiveness to firearm ownership in the Midwest, and a negative association from firearm restrictiveness to firearm suicides in the South. Conclusions: The authors present an information-theoretic approach to study relationships in firearm research. This method provides preliminary evidence for the role of restrictive legislation in promoting safe firearm ownership. The authors find that firearm acquisition considerably increases after the implementation of restrictive firearm laws, and simultaneously, firearm deaths decrease. These effects vary with respect to death by intent and the geographic region the laws were implemented in.

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances. A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology. It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress. Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Increasing the productivity of crops in water deficit circumstances is of great significance in order to face the challenge of securing global food production. Nowadays, the use of biochar (BC) and arbuscular mycorrhizal fungi (AMF) are considered as one of the most effective methods for empowering plants to deal with drought stress. However, the literature regarding the effects of the simultaneous use of AMF+BC on plants under drought stress is scarce. Hence, the present study was conducted to consider the combined application of AMF and biochar on the physiological and biochemical properties of lavender under various levels of irrigation. The first factor includes three irrigation regimes of 90 % field capacity (FC), 60 % FC, and 30 % FC, respectively, corresponding to normal irrigation, mild and severe drought stress. The second factor included a fertilizer or microbial inoculant source, which were respectively: no inoculation (control), inoculation with AMF, BC, and co-application of AMF along with BC. The highest nutrient, chlorophyll and carotenoid content, and fresh, and dry weight of lavender were recorded under normal irrigation conditions with combined application of AMF+BC. The combined application of AMF+BC was significantly effective in increasing the activity of antioxidant enzymes against oxidative damage caused by drought stress and in reducing the accumulation of proline and malondialdehyde. An increase in phenolic, flavonoid, and concentration of essential oil was observed under mild stress and using AMF+BC, while the highest essential oil yield was recorded under a normal irrigation regime and treated with AMF+BC. The highest content of linalool, camphor, borneol, and linalyl acetate was obtained in mild stress by adding AMF+BC. It can be concluded that the use of AMF+BC combination treatment may be a useful strategy to improve the quantity and quality of lavender EO in drought-stress circumstances.

Background and Objectives: To evaluate the effectiveness of an integral HAMMAM experience, a 4-week therapeutic program that combined hydrotherapy and Swedish massage, applied in a multisensorial immersive environment, on pain, well-being and quality of life (QoL) in women with endometriosis-related chronic pelvic pain that is unresponsive to conventional treatment. Materials and Methods: This randomized controlled trial included 44 women with endometriosis. They were randomly allocated to either the ‘HAMMAM’ group (n = 21) or to a control group (n = 23). The primary outcome, pain intensity, was evaluated using numeric rating scales (NRSs). The secondary outcomes were pain interference, pain-related catastrophic thoughts, pressure pain thresholds (PPTs), subjective well-being, functional capacity and QoL, which were evaluated using the brief pain inventory (BPI), the pain catastrophizing scale (PCS), algometry, the subjective well-being scale-20 (EBS-20), the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) and the Endometriosis Health Profile-30 Questionnaire (EHP-30), respectively. The primary and secondary outcomes were measured at the baseline and after the intervention. The statistical (between-group analyses of covariance) and clinical effects were analyzed by the intention to treat. Results: The adherence rate was 100.0% and the mean (± standard deviation) satisfaction was 9.71 ± 0.46 out of 10. No remarkable health problems were reported during the trial. The ‘HAMMAM’ intervention improved dysmenorrhea and dyspareunia after the intervention with large and moderate effect sizes, respectively. Improvements in pain interference during sleep and PPTs in the pelvic region were also observed in women allocated to the ‘HAMMAM’ group. No effects were observed in catastrophizing thoughts, well-being nor QoL, except for the sleep subscale. Conclusions: A 4-week program of an integral ‘HAMMAM’ experience combining hydrotherapy and massage in a multisensorial immersive environment is a feasible and effective intervention to alleviate pain during menstruation and sexual intercourse as well as pain interference with sleep in women with endometriosis.

Increasing crop yield with low-N supplies has become one of the main aims of current agriculture to reduce the excessive use of chemical fertilizers. A sustainable strategy to improve crop productivity, N assimilation, and N Use Efficiency (NUE) under limit-N growth conditions is the application of biostimulants, such as humic substances (HS). Here, we evaluated the effectiveness of an HS-based biostimulant, BLACKJAK®, in improving lettuce growth and NUE under N-deficit conditions. Thus, BLACKJAK® was applied radicularly (R) and foliarly (F) at the following doses: R-HS 0.40 mL/L, R-HS 0.60 mL/L, F-HS 7.50 mL/L, and F-HS 10.00 mL/L. Three N levels were applied: optimal (7 mM) and N-deficit (3 mM and 1 mM). The results showed that shoot dry weight (DW) was reduced at 3 mM N (−32%) and 1 mM N (−42%). However, R and F BLACKJAK® enhanced plant growth at all three N levels, especially with F-HS at 10.00 mL/L, which showed an increase of 43% in shoot DW at 3 and 1 mM N, compared to plants not treated with HS. BLAKCJAK® also improved photosynthesis, NO3− and organic N accumulation, the activity of N assimilation enzymes, and the concentration of amino acids and proteins, regardless of the N level. In addition, HS enhanced NUE parameters under all N conditions, except for R-HS 0.60 mL/L at 1 mM N. Hence, our study suggests that the HS-based product BLACKJAK® could be a good candidate for reducing chemical fertilizer use and improving lettuce growth and NUE under low N conditions, although further research is required.

Abstract Both myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) and long COVID (LC) are characterized by similar immunological alterations, persistence of chronic viral infection, autoimmunity, chronic inflammatory state, viral reactivation, hypocortisolism, and microclot formation. They also present with similar symptoms such as asthenia, exercise intolerance, sleep disorders, cognitive dysfunction, and neurological and gastrointestinal complaints. In addition, both pathologies present Epstein–Barr virus (EBV) reactivation, indicating the possibility of this virus being the link between both pathologies. Therefore, we propose that latency and recurrent EBV reactivation could generate an acquired immunodeficiency syndrome in three steps: first, an acquired EBV immunodeficiency develops in individuals with “weak” EBV HLA-II haplotypes, which prevents the control of latency I cells. Second, ectopic lymphoid structures with EBV latency form in different tissues (including the CNS), promoting inflammatory responses and further impairment of cell-mediated immunity. Finally, immune exhaustion occurs due to chronic exposure to viral antigens, with consolidation of the disease. In the case of LC, prior to the first step, there is the possibility of previous SARS-CoV-2 infection in individuals with “weak” HLA-II haplotypes against this virus and/or EBV.

Summary: Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2−/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2−/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose

BackgroundCancer is a global health problem accounting for nearly one in six deaths worldwide. Conventional treatments together with new therapies have increased survival to this devastating disease. However, the persistent challenges of treatment resistance and the limited therapeutic arsenal available for specific cancer types still make research in new therapeutic strategies an urgent need.MethodsChloroquine was tested in combination with different drugs (Panobinostat, KU-57788 and NU-7026) in 8 human-derived cancer cells lines (colorectal: HCT116 and HT29; breast: MDA-MB-231 and HCC1937; glioblastoma: A-172 and LN-18; head and neck: CAL-33 and 32816). Drug´s effect on proliferation was tested by MTT assays and cell death was assessed by Anexin V-PI apoptosis assays. The presence of DNA double-strand breaks was analyzed by phospho-H2AX fluorescent staining. To measure homologous recombination efficiency the HR-GFP reporter was used, which allows flow cytometry-based detection of HR stimulated by I-SceI endonuclease-induced DSBs.ResultsThe combination of chloroquine with any of the drugs employed displayed potent synergistic effects on apoptosis induction, with particularly pronounced efficacy observed in glioblastoma and head and neck cancer cell lines. We found that chloroquine produced DNA double strand breaks that depended on reactive oxygen species formation, whereas Panobinostat inhibited DNA double-strand breaks repair by homologous recombination. Cell death caused by chloroquine/Panobinostat combination were significantly reduced by N-Acetylcysteine, a reactive oxygen species scavenger, underscoring the pivotal role of DSB generation in CQ/LBH-induced lethality. Based on these data, we also explored the combination of CQ with KU-57788 and NU-7026, two inhibitors of the other main DSB repair pathway, nonhomologous end joining (NHEJ), and again synergistic effects on apoptosis induction were observed.ConclusionOur data provide a rationale for the clinical investigation of CQ in combination with DSB inhibitors for the treatment of different solid tumors.

The world’s largest extant carnivorous marsupial, the Tasmanian devil, is challenged by Devil Facial Tumor Disease (DFTD), a fatal, clonally transmitted cancer. In two decades, DFTD has spread across 95% of the species distributional range. A previous study has shown that factors such as season, geographic location, and infection with DFTD can impact the expression of immune genes in Tasmanian devils. To date, no study has investigated within-individual immune gene expression changes prior to and throughout the course of DFTD infection. To explore possible changes in immune response, we investigated four locations across Tasmania that differed in DFTD exposure history, ranging between 2 and >30 years. Our study demonstrated considerable complexity in the immune responses to DFTD. The same factors (sex, age, season, location and DFTD infection) affected immune gene expression both across and within devils, although seasonal and location specific variations were diminished in DFTD affected devils. We also found that expression of both adaptive and innate immune genes starts to alter early in DFTD infection and continues to change as DFTD progresses. A novel finding was that the lower expression of immune genes MHC-II, NKG2D and CD8 may predict susceptibility to earlier DFTD infection. A case study of a single devil with regressed tumor showed opposite/contrasting immune gene expression patterns compared to the general trends observed across devils with DFTD infection. Our study highlights the complexity of DFTD’s interactions with the host immune system and the need for long-term studies to fully understand how DFTD alters the evolutionary trajectory of devil immunity.

Studies of the virome of olive trees with symptoms of leaf mottling by high-throughput sequencing (HTS) revealed the presence of a new virus. Full coding genome sequences of two isolates were determined and consisted of a single RNA segment of 16,516 nt and 16,489, respectively. The genomic organization contained 10 open reading frames (ORFs) from 5′ to 3′: ORF1a, ORF1b (RdRp), ORF2 (p22), ORF3 (p7), ORF4 (HSP70h), ORF5 (HSP90h), ORF6 (CP), ORF7 (p19), ORF8 (p12), ORF9 (p23) and ORF10 (p9). Phylogenetic analyses clustered this virus in the genus Olivavirus, family Closteroviridae, with the closest species being Olivavirus flaviolae, commonly named olive leaf yellowing-associated virus (OLYaV). However, amino acid sequences of all taxonomically relevant proteins showed, in all cases, a divergence higher than 25% between OLYaV and the new virus, indicating that it represents a new species in the genus Olivavirus for which the common name of olive leaf mottling virus (OLMV) is proposed. This study represents an advance in the genus Olivavirus and provides new insights into the olive virome.

Background: Preclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human epidermal growth factor 2-negative (ER+/HER2–) breast cancer. The noncomparative phase 1b/2 CheckMate 7A8 study (NCT04075604) evaluated neoadjuvant treatment with nivolumab, palbociclib, and anastrozole in patients with ER+/HER2− breast cancer. Here, we report outcomes from the safety run-in phase. Methods: Patients with histologically confirmed, untreated ER+/HER2− breast cancer, primary tumour ≥2 cm, ECOG performance status ≤1, and eligible for post-treatment surgery received nivolumab 480 mg intravenously every 4 weeks, palbociclib 125 mg or 100 mg orally once daily for 3 weeks per cycle, and anastrozole 1 mg orally once daily for five 4-week cycles, or until disease progression. The primary endpoint was the proportion of patients with dose-limiting toxicities (DLTs) within 4 weeks of treatment initiation. Results: At safety data review, 21 patients were treated (palbociclib 125-mg group: n = 9; palbociclib 100-mg group: n = 12). DLTs were reported in 2 (22.2%) and 0 patients in the palbociclib 125-mg and 100-mg groups, respectively. Across both groups, 9 patients discontinued treatment due to toxicity (grade 3/4 hepatic adverse events [n = 6], grade 3 febrile neutropaenia [n = 1], grade 1 pneumonitis [n = 1], and grade 3 rash and grade 2 immune-mediated pneumonitis [n = 1]). Consequently, the study was closed early. Conclusions: Neoadjuvant treatment with nivolumab, palbociclib, and anastrozole showed a high incidence of grade 3/4 hepatotoxicity and treatment discontinuation, indicating that this combination should not be further pursued for treatment of primary ER+/HER2− breast cancer.

The monocytes are key components of innate immunity, as they can differentiate into phagocytic cells or macrophages with proinflammatory or anti-inflammatory phenotypes. The gamma-aminobutyric acid (GABA) and adenosine triphosphate (ATP), two known neurotransmitters, are two environmental signals that contribute to the differentiation of monocytes into macrophages and their subsequent polarization into proinflammatory M1 and anti-inflammatory M2 macrophages. Although monocytes and macrophages express proteins related to GABA and ATP-mediated response (GABAergic and purinergic systems, respectively), it is unknown whether changes in their expression occur during monocyte activation or their differentiation and polarization into macrophages. Therefore, we evaluated the expression levels of GABAergic and purinergic signaling components in the THP-1 monocyte cell line and their changes during monocyte activation, differentiation, and polarization to M1 proinflammatory macrophages. Our results showed that activated monocytes are characterized by increased expression of two GABAergic components, the GABA transporter 2 (GAT-2) and the glutamic acid decarboxylase (GAD)-67, an enzyme involved in GABA synthesis. Also, monocytes showed a pronounced expression of the purinergic receptors P2X4 and P2X7. Interestingly, during differentiation, monocytes increased the expression of the β2 subunit of GABA A-type receptor (GABA-AR), while the purinergic receptors P2X1 and P2X1del were reduced. In contrast, proinflammatory M1 macrophages showed a reduced expression in the α4 subunit of GABA-AR and GAD67, while P2X4 and P2X7 were overexpressed. These results indicate that dynamical changes in the GABAergic and purinergic components occur during the transition from monocytes to macrophages. Since GABA and ATP are two neurotransmitters, our results suggest that monocytes and macrophages respond to neurotransmitter-induced stimulation and may represent a path of interaction between the nervous and immune systems during peripheral inflammation and neuroinflammation development.

En el campo de los accionamientos eléctricos de velocidad variable ha aparecido recientemente el método predictivo basado en vectores virtuales de tensión. Este método permite reducir la contribuci´on del voltaje en el subespacio x-y, en el cual no se produce par, sino pérdidas. De este modo no sólo se limitan las pérdidas sino que se reduce la complejidad de sintonía del controlador predictivo. Los vectores virtuales de tensión se obtienen mediante combinación de vectores de tensión pertenencientes a distintas coronas pequeña, media y grande además de los vectores nulos. En una aplicación típica se elige en primer lugar la(s) corona(s) a usar y después se desarrollan los vectores virtuales. El controlador predictivo usa en cada periodo de muestreo el vector virtual más adecuado. En este trabajo se propone el uso de varios conjuntos de vectores virtuales provenientes de diferentes combinaciones de coronas. Para cada punto de operación del accionamiento eléctrico se utiliza el conjunto que proporciona mejores valores de cierto criterio de bondad. El método propuesto es validado experimentalmente usando una máquina de inducción de seis fases.

La interpasividad es la estructura inversa de la interactividad y ha sido analizada como comportamiento cultural por los filósofos Robert Pfaller y Slavoj Zizek. La interpasividad es pasividad delegada, se es pasivo por medio del otro mientras se hace algo de forma activa, lo que permite esquivar la identificación y la subjetivación. ¿Podríamos hablar de arte interpasivo? ¿Qué vínculos establecería con el arte interactivo? ¿Cuáles serían sus características y condiciones? Se plantea una traslación del concepto de interpasividad desde el campo de la filosofía hacia el espacio de la recepción del arte, aporte original de esta investigación. Se ha empleado una metodología basada en la literatura comparada, aplicando la exégesis (interactividad-interpasividad) y la eiségesis (arte interpasivo) como métodos. Se concluye que todo arte es interactivo y que la interactividad como falsa actividad en la obra de arte ejerce como acto ritual sustitutivo para el espectador. La paradoja fundamental reside en que la interactividad, al diluir la distancia y el disenso en la recepción del arte, se convierte en un medio interpasivo que dificulta los procesos de subjetivación propios de la experiencia estética. La interactividad permite un arte interpasivo. Lo que hoy se denomina arte interactivo es verdaderamente un arte interpasivo.

Under stress or in optimum conditions, plants foster a specific guild of symbiotic microbes to strengthen pivotal functions including metabolic regulation. Despite that the role of the plant genotype in microbial selection is well documented, the potential of this genotype-specific microbial assembly in maintaining the host homeostasis remains insufficiently investigated. In this study, we aimed to assess the specificity of the foliar metabolic response of contrasting olive genotypes to microbial inoculation with wet-adapted consortia of plant-growth-promoting rhizobacteria (PGPR), to see if previously inoculated plants with indigenous or exogenous microbes would display any change in their leaf metabolome once being subjected to drought stress. Two Tunisian elite varieties, Chetoui (drought-sensitive) and Chemleli (drought-tolerant), were tested under controlled and stressed conditions. Leaf samples were analyzed by gas chromatography–mass spectrometry (GC-TOFMS) to identify untargeted metabolites. Root and soil samples were used to extract microbial genomic DNA destined for bacterial community profiling using 16S rRNA amplicon sequencing. Respectively, the score plot analysis, cluster analysis, heat map, Venn diagrams, and Krona charts were applied to metabolic and microbial data. Results demonstrated dynamic changes in the leaf metabolome of the Chetoui variety in both stress and inoculation conditions. Under the optimum state, the PGPR consortia induced noteworthy alterations in metabolic patterns of the sensitive variety, aligning with the phytochemistry observed in drought-tolerant cultivars. These variations involved fatty acids, tocopherols, phenols, methoxyphenols, stilbenoids, triterpenes, and sugars. On the other hand, the Chemleli variety displaying comparable metabolic profiles appeared unaffected by stress and inoculation probably owing to its tolerance capacity. The distribution of microbial species among treatments was distinctly uneven. The tested seedlings followed variety-specific strategies in selecting beneficial soil bacteria to alleviate stress. A highly abundant species of the wet-adapted inoculum was detected only under optimum conditions for both cultivars, which makes the moisture history of the plant genotype a selective driver shaping microbial community and thereby a useful tool to predict microbial activity in large ecosystems.