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Abstract There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn’s disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56–87), P

This study analyzes the effect of spatial competition on public schools' efficiency in Chile, an extreme case of market-oriented reforms in the educational sector. To address this issue, we use a measure of competition that captures three major characteristics of market competition in a spatial context: the number of competitors, based on distance buffers; the size of competitors, measured by the enrollment of voucher schools; and the geographical distance among public schools and their competitors. To control for the potential endogeneity of our measure of spatial competition on public schools' efficiency, we use an instrumental variable based on the discontinuites generated by admissions municipality boundaries . We do not find evidence that public schools' efficiency increases or decreases as the result of the increment of voucher schools located near to public schools, an increase in the enrollment of existing voucher schools, or both factors simultaneously. This result is robust to: (1) the limit of education market or other measures of spatial competition; (2) the methodology used to compute the efficiency measures; and (3) whether we explain efficiency or educational performance.

(1) Background: Liver metastases (LM) are the leading cause of death in colorectal cancer (CRC) patients. Despite advancements, relapse rates remain high and current prognostic nomograms lack accuracy. Our objective is to develop an interpretable neoadjuvant algorithm based on mathematical models to accurately predict individual risk, ensuring mathematical transparency and auditability. (2) Methods: We retrospectively evaluated 86 CRC patients with LM treated with neoadjuvant systemic therapy followed by complete surgical resection. A comprehensive analysis of 155 individual patient variables was performed. Logistic regression (LR) was utilized to develop the predictive model for relapse risk through significance testing and ANOVA analysis. Due to data limitations, gradient boosting machine (GBM) and synthetic data were also used. (3) Results: The model was based on data from 74 patients (12 were excluded). After a median follow-up of 58 months, 5-year relapse-free survival (RFS) rate was 33% and 5-year overall survival (OS) rate was 60.7%. Fifteen key variables were used to train the GBM model, which showed promising accuracy (0.82), sensitivity (0.59), and specificity (0.96) in predicting relapse. Similar results were obtained when external validation was performed as well. (4) Conclusions: This model offers an alternative for predicting individual relapse risk, aiding in personalized adjuvant therapy and follow-up strategies.

Abstract There is an increasing demand to enhance infrastructure asset management within the drinking water sector. A key factor for achieving this is improving the accuracy of pipe failure prediction models. Machine learning-based models have emerged as a powerful tool in enhancing the predictive capabilities of water distribution network models. Extensive research has been conducted to explore the role of explanatory variables in optimizing model outputs. However, the underlying mechanisms of incorporating explanatory variable data into the models still need to be better understood. This review aims to expand our understanding of explanatory variables and their relationship with existing models through a comprehensive investigation of the explanatory variables employed in models over the past 15 years. The review underscores the importance of obtaining a substantial and reliable dataset directly from Water Utilities databases. Only with a sizeable dataset containing high-quality data can we better understand how all the variables interact, a crucial prerequisite before assessing the performance of pipe failure rate prediction models.

The forms of citizen participation have been reconfigured in recent years. The presence of social networks and digital media in general have favored multiple modes of access to information, expression of ideas and social participation. A necessary reflection to think about a sustainable future requires an assessment of communicative practices in digital media and the challenges in citizen education that globalization entails. This research focused on the analysis of citizen participation practices of university students in digital media and its implications for global citizenship. A mixed investigation with a quantitative-qualitative sequence was proposed. In the first phase, a cross-sectional descriptive study was developed with 740 students from a Colombian university, to whom an electronic questionnaire was applied. In the second qualitative phase, discussion groups were held with 42 students, with the purpose of discussing the findings of the questionnaire from the perspective of the participants. It was found that the practices conducted by the students focus mostly on basic and intermediate levels of citizenship represented in the consultation of online information and expression of the ideological positions in social networks, with high limitations towards higher levels of citizenship referred to concrete actions to impact reality. It is evident that this difficulty in contributing to social changes in the world is due to the lack of education for critical global citizenship. Therefore, critical literacy for the use of digital media is proposed as a citizen educational strategy, considering that it contributes to the construction of a more hopeful vision of the future.

Se analiza el control biopolítico al solicitante de asilo en la UE que efectúan tres mecanismos jurídicos: Frontex, Eurodac y Reglamento Dublín, y las prácticas de resistencia de los inmigrantes ante este control. Metodológicamente se implementó una revisión documental teórica sobre biopolítica y una encuesta a 1 478 solicitantes de asilo en España entre 2021 y 2023. Se concluye que esta población reúne los elementos que caracterizan al Homo sacer y que, en respuesta a esto, profanan los dispositivos de control estudiados, lo que genera una forma-de-vida en comunidad que extrapola sus propias reglas a la ley, como plantea Agamben. Sin embargo, se demuestra que esta vida extralegal es transitoria y por lo tanto no coincide con el ideal de altísima pobreza agambeniano, sino que deja ver sus dificultades prácticas. Se proponen las bases de una ética de la acción ajustada a la realidad del inmigrante, que va más allá de la forma-de-vida agambeniana.

BackgroundUp to one-fifth of patients continue to have poor quality of life after transcatheter aortic valve implantation (TAVI), with an additional similar proportion not surviving 1 year after the procedure. We aimed to assess the value of a new method based on an integrated analysis of left ventricular outflow tract flow velocity and aortic pressure to predict objective functional improvement and prognosis after TAVI.MethodsIn a cohort of consecutive patients undergoing TAVI, flow velocity–pressure integrated analysis was obtained from simultaneous pressure recordings in the ascending aorta and flow velocity recordings in the left ventricular outflow tract by echocardiography. Objective functional improvement 6 months after TAVI was assessed through changes in a 6-min walk test and NT-proBNP levels. A clinical follow-up was conducted at 2 years.ResultsOf the 102 patients studied, 82 (80.4%) showed objective functional improvement. The 2-year mortality of these patients was significantly lower (9% vs. 44%, p = 0.001). In multivariate analysis, parameter “(Pressure at Vmax − Pressure at Vo)/Vmax” was found to be an independent predictor for objective improvement. The C-statistic was 0.70 in the overall population and 0.78 in the low-gradient subgroup. All echocardiographic parameters and the valvuloarterial impedance showed a C-statistic of

Introduction: Understanding alterations to brain anatomy and cognitive function associated with neurodegenerative diseases remains a challenge for neuroscience today. In experimental neuroscience, several computerised tests have been developed to contribute to our understanding of neural networks involved in cognition. The Attention Network Test (ANT) enables us to measure the activity of 3 attentional networks (alertness, orienting, and executive function). Objectives: The main aim of this review is to describe all the anatomical and functional alterations found in diverse neurological diseases using the ANT. Material and methods: We collected studies published since 2010 in the PubMed database that employed the ANT in different neurological diseases. Thirty-two articles were obtained, addressing multiple sclerosis, epilepsy, and Parkinson’s disease, among other disorders. Conclusions: Some of the anatomical structures proposed in the 3 attentional networks model were confirmed. The most relevant structures in the alertness network are the prefrontal cortex, parietal region, thalamus, and cerebellum. The thalamus is also relevant in the orienting network, together with posterior parietal regions. The executive network does not depend exclusively on the prefrontal cortex and anterior cingulate cortex, but also involves such subcortical structures as the basal ganglia and cerebellum and their projections towards the entire cortex. Resumen: Introducción: Comprender las alteraciones en la anatomía y función del cerebro en los procesos cognitivos para las enfermedades neurodegenerativas es aún un desafío para la neurociencia actual. Desde la neurociencia experimental, algunos tests computarizados han sido desarrollados para mejorar nuestro conocimiento de las redes neurales involucradas en la cognición. El Attention Network Test (ANT) permite medir la activad de las tres redes atencionales (alerta, orientación y función ejecutiva). Objetivos: El principal objetivo de esta revisión fue describir todas las alteraciones anatómicas y funcionales encontradas en diversas enfermedades neurológicas usando el ANT. Material y métodos: Un protocolo de revisión fue aplicado seleccionando estudios desde 2010 en la base de datos PubMed que involucraban al Attention Network Test en diferentes enfermedades neurológicas. Se obtuvieron treinta y dos artículos para esclerosis múltiple, epilepsia o Parkinson entre otras patologías. Conclusiones: Se confirman algunas de las estructuras anatómicas propuestas para el modelo de tres grandes redes atencionales. Las estructuras más relevantes para la red de alerta son la corteza prefrontal, regiones parietales, tálamo y el cerebelo. El tálamo es también relevante para la red de orientación, junto a regiones parietales posteriores. Respecto a la red ejecutiva, no depende exclusivamente de la corteza prefrontal y corteza cingulada anterior, sino también de estructuras subcorticales como los ganglios basales y el cerebelo y sus proyecciones hacia toda la corteza.

Despite the huge availability of software to estimate cross-sectional spatial models, there are only few functions to estimate models dealing with spatial limited dependent variable. This paper fills this gap introducing the new R package spldv. The package is based on generalized methods of moment (GMM) estimators and includes a series of one- and two-step estimators based on different choices of the weighting matrix for the moments conditions in the first step, and different estimators for the variance-covariance matrix of the estimated coefficients. An important feature of spldv is that users can estimate the spatial Durbin model and compute the direct, indirect, and total effects in a friendly and flexible way.

Background and objectivesIntermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson’s disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity.MethodsA total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS.DiscussionThe findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Motivation: For a number of neurological diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribute to the lifecycle of drug development.Results: To this end, we introduce VariantSurvival, a tool that identifies changes in survival relative to structural variants within target genes. VariantSurvival matches annotated structural variants with genes that are clinically relevant to neurological diseases. A Cox regression model determines the change in survival between the placebo and clinical trial groups with respect to the number of structural variants in the drug target genes. We demonstrate the functionality of our approach with the exemplary case of the SETX gene. VariantSurvival has a user-friendly and lightweight graphical user interface built on the shiny web application package.

Abstract Recent studies have suggested that nonphase-locked activity can reveal cognitive mechanisms that cannot be observed in phase-locked activity. In fact, we describe a concomitant decrease in nonphase-locked alpha activity (desynchronization) when stimuli were processed (alpha phase-locked modulation). This desynchronization may represent a reduction in “background activity” in the visual cortex that facilitates stimulus processing. Alternatively, nonphase-locked gamma activity has been hypothesized to be an index of shifts in attentional focus. In this study, our main aim was to confirm these potential roles for nonphase-locked alpha and gamma activities with a lateralized Go/NoGo paradigm. The results showed that nonphase-locked alpha modulation is bilaterally represented in the scalp compared to the contralateral distribution of the phase-locked response. This finding suggests that the decrease in background activity is not limited to neural areas directly involved in the visual processing of stimuli. Additionally, gamma activity showed a higher desynchronization of nonphase-locked activity in the ipsilateral hemisphere, where the phase-locked activity reached the minimum amplitude. This finding suggests that the possible functions of nonphase-locked gamma activity extend beyond shifts in attentional focus and could represent an attentional filter reducing the gamma representation in the visual area irrelevant to the task.

Summary: Background: Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. Methods: Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. Findings: Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel–Cox) test p = 0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. Interpretation: CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. Funding: For a full list of funding bodies, please see the Acknowledgements.