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Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institutions experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan-Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10-6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10-6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p

In recent years, some models for binary and graded format responses have been proposed to assess unipolar variables or "quasi-traits." These studies have mainly focused on clinical variables that have traditionally been treated as bipolar traits. In the present study, we have made a proposal for unipolar traits measured with continuous response items. The proposed log-logistic continuous unipolar model (LL-C) is remarkably simple and is more similar to the original binary formulation than the graded extensions, which is an advantage. Furthermore, considering that irrational, extreme, or polarizing beliefs could be another domain of unipolar variables, we have applied this proposal to an empirical example of superstitious beliefs. The results suggest that, in certain cases, the standard linear model can be a good approximation to the LL-C model in terms of parameter estimation and goodness of fit, but not trait estimates and their accuracy. The results also show the importance of considering the unipolar nature of this kind of trait when predicting criterion variables, since the validity results were clearly different.

A frequent criticism of exploratory factor analysis (EFA) is that it does not allow correlated residuals to be modelled, while they can be routinely specified in the confirmatory (CFA) model. In this article, we propose an EFA approach in which both the common factor solution and the residual matrix are unrestricted (i.e., the correlated residuals need not be specified a priori). The estimation procedures are two-stage and based on the unweighted least squares principle. Procedures for judging the solution appropriateness (including goodness of fit) are also proposed. The simulation studies and illustrative example suggest that the approach works quite well Although the proposal is based on existing results, most of the developments can be considered to be new contributions, and are expected to be particularly useful in the earlier stages of item calibration. The whole procedure has been implemented in both R language and a well-known non-commercial EFA program.

Climate change poses significant risks to health and health systems, with the greatest impacts in low- and middle-income countries--which are least responsible for greenhouse gas emissions. The Conference of Parties 28 at the 2023 United Nations Climate Change Conference led to agreement on the need for holistic and equitable financing approaches to address the climate and health crisis. This paper provides an overview of existing climate finance mechanisms--that is, multilateral funds, voluntary market-based mechanisms, taxes, microlevies and adaptive social protection. We discuss these approaches' potential use to promote health, generate additional health sector resources and enhance health system sustainability and resilience, and also explore implementation challenges. We suggest that public health practitioners, policy-makers and researchers seize the opportunity to leverage climate funding for better health and sustainable, climate-resilient health systems. Emphasizing the wider benefits of investing in health for the economy can help prioritize health within climate finance initiatives. Meaningful progress will require the global community acknowledging the underlying political economy challenges that have so far limited the potential of climate finance to address health goals. To address these challenges, we need to restructure financing institutions to empower communities at the frontline of the climate and health crisis and ensure their needs are met. Efforts from global and national level stakeholders should focus on mobilizing a wide range of funding sources, prioritizing co-design and accessibility of financing arrangements. These stakeholders should also invest in rigorous monitoring and evaluation of initiatives to ensure relevant health and well-being outcomes are addressed. [phrase omitted] Le changement climatique fait peser des risques considerables sur la sante et les systemes de sante, affectant principalement les pays a revenu faible et intermediaire--alors qu'ils contribuent le moins aux emissions de gaz a effet de serre. Lors de la Conference des Nations Unies sur le changement climatique de 2023, la 28e Conference des Parties a abouti a un accord sur la necessite d'adopter des approches de financement equitables et holistiques pour resoudre la crise climatique et sanitaire. Le present document offre un apercu des dispositifs de financement climatique existants--a savoir des fonds multilateraux, des mecanismes de marche volontaires, des micro-taxes et une protection sociale adaptative. Nous evoquons la possibilite de recourir a ces approches en vue de promouvoir la sante, de generer des ressources supplementaires pour le secteur de la sante et de renforcer la viabilite et la resilience des systemes de sante; nous nous interessons egalement aux defis que represente leur mise en reuvre. Nous suggerons que les professionnels de la sante publique, les responsables politiques et les chercheurs profitent de cette occasion pour obtenir des fonds climatiques afin d'ameliorer la sante et de developper des systemes de sante durables et adaptes au changement climatique. Souligner tout l'interet, pour l'economie, d'investir dans la sante peut aider a inscrire la sante en priorite dans les initiatives de financement climatique. Realiser des progres significatifs implique que la communaute internationale prenne conscience des enjeux sous-jacents en matiere d'economie politique, enjeux qui ont jusqu'a present limite le potentiel du financement climatique dans l'atteinte des objectifs de sante. Pour y remedier, nous devons restructurer les institutions financieres afin d'accroitre l'autonomie des communautes en premiere ligne face a la crise climatique et sanitaire, et de faire en sorte que leurs besoins soient satisfaits. Les efforts des parties prenantes a l'echelle nationale et mondiale doivent porter sur la mobilisation d'un large eventail de sources de financement, en mettant l'accent sur la conception conjointe et l'accessibilite des modalites financieres. Ces parties prenantes doivent en outre investir dans un suivi etroit et une evaluation rigoureuse des initiatives pour veiller a obtenir des resultats pertinents en termes de sante et de bien-etre. [phrase omitted] El cambio climatico plantea riesgos importantes para la salud y los sistemas sanitarios, con mayores impactos en los paises de ingresos bajos y medios, que son los menos responsables de las emisiones de gases de efecto invernadero. La 28.a Conferencia de las Partes en la Conferencia de las Naciones Unidas sobre el Cambio Climatico de 2023 condujo a un acuerdo sobre la necesidad de enfoques de financiacion holisticos y equitativos para abordar la crisis climatica y sanitaria. Este documento ofrece una vision general de los mecanismos de financiacion climatica existentes, es decir, los fondos multilaterales, los mecanismos voluntarios basados en el mercado, los impuestos, los microimpuestos y la proteccion social adaptable. Analizamos el uso potencial de estos enfoques para promover la salud, generar recursos adicionales para el sector sanitario y mejorar la sostenibilidad y la resiliencia de los sistemas sanitarios. Sugerimos que los profesionales de la salud publica, los responsables de formular las politicas y los investigadores aprovechen la oportunidad de utilizar la financiacion climatica para mejorar la salud y los sistemas sanitarios sostenibles y resilientes al cambio climatico. Destacar los beneficios mas amplios de invertir en salud para la economia puede ayudar a priorizar la salud dentro de las iniciativas de financiacion climatica. Para lograr avances significativos sera necesario que la comunidad mundial reconozca los problemas de economia politica subyacentes que hasta ahora han limitado el potencial de la financiacion para abordar los objetivos de salud. Para superar estos desafios, necesitamos reestructurar las instituciones financieras para empoderar a las comunidades que se encuentran en primera linea de la crisis climatica y sanitaria y asegurar que se satisfacen sus necesidades. Los esfuerzos de las partes interesadas a nivel mundial y nacional deben centrarse en movilizar una gran variedad de fuentes de financiacion y priorizar el diseno conjunto y la accesibilidad de los acuerdos de financiacion. Estas partes interesadas tambien deben invertir en la supervision y evaluacion rigurosas de las iniciativas para garantizar que se abordan los resultados pertinentes en materia de salud y bienestar., Introduction An estimated 3.6 billion people worldwide are highly vulnerable to climate change and therefore exposed to additional health risks. Climate change is expected to contribute 250 000 additional deaths [...]

Abstract The druggable proteome refers to proteins that can bind to small molecules with appropriate chemical affinity, inducing a favorable clinical response. Predicting druggable proteins through screening and in silico modeling is imperative for drug design. To contribute to this field, we developed an accurate predictive classifier for druggable cancer-driving proteins using amino acid composition descriptors of protein sequences and 13 machine learning linear and non-linear classifiers. The optimal classifier was achieved with the support vector machine method, utilizing 200 tri-amino acid composition descriptors. The high performance of the model is evident from an area under the receiver operating characteristics (AUROC) of 0.975 ± 0.003 and an accuracy of 0.929 ± 0.006 (threefold cross-validation). The machine learning prediction model was enhanced with multi-omics approaches, including the target-disease evidence score, the shortest pathways to cancer hallmarks, structure-based ligandability assessment, unfavorable prognostic protein analysis, and the oncogenic variome. Additionally, we performed a drug repurposing analysis to identify drugs with the highest affinity capable of targeting the best predicted proteins. As a result, we identified 79 key druggable cancer-driving proteins with the highest ligandability, and 23 of them demonstrated unfavorable prognostic significance across 16 TCGA PanCancer types: CDKN2A, BCL10, ACVR1, CASP8, JAG1, TSC1, NBN, PREX2, PPP2R1A, DNM2, VAV1, ASXL1, TPR, HRAS, BUB1B, ATG7, MARK3, SETD2, CCNE1, MUTYH, CDKN2C, RB1, and SMARCA4. Moreover, we prioritized 11 clinically relevant drugs targeting these proteins. This strategy effectively predicts and prioritizes biomarkers, therapeutic targets, and drugs for in-depth studies in clinical trials. Scripts are available at https://github.com/muntisa/machine-learning-for-druggable-proteins .

Abstract Minimal residual disease (MRD) assessment is a known surrogate marker for survival in multiple myeloma (MM). Here, we present a single institution’s experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients; 482 MM patients at the University of California, San Francisco (UCSF) diagnosed from 2008 to 2020 were analyzed retrospectively. MRD assessment was performed by NGS. PFS curves were plotted by the Kaplan–Meier method. In the newly diagnosed group, 119 of 304, achieved MRD negativity at the level of 10−6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD positive at different levels (p > 0.0001). In the relapsed disease group, 64 of 178 achieved MRD negativity at 10−6, and PFS was prolonged versus patients who remained MRD positive (p = 0.03). Three categories of MRD dynamics were defined by artificial intelligence: (A) patients with ≥3 consistently MRD negative samples, (B) patients with continuously declining but detectable clones, and (C) patients with either increasing or a stable number of clones. Groups A and B had a more prolonged PFS than group C (p

Transferring a pedagogical proposal from a face-to-face environment to a virtual one is not an automatic conversion. It requires a thorough instructional design and the appropriate methodology. The main purpose of this study is to analyze the variables that influence the selection of an active methodology mediated by information and communication technologies for the design of a didactic sequence developed in a digital environment. We have worked with a sample of teachers who have participated in a training experience in which they have built a didactic proposal for a digital environment, selecting an active methodology from a reflective dynamic based on objective criteria. The study shows that there is a positive association between the year the course was taken, the sex of the participants and the stage where the participants work, and the chosen methodology. Finally, the area of knowledge taught is not a determining factor. It is concluded that regardless of the methodological selection, teachers tend to value the didactic component training over the instrumental one, although it is decisive that the training deals with technology, but from a techno pedagogical perspective.

Machine Learning (ML) has extended its use in several domains to support complex analyses of data. The medical field, in which significant quantities of data are continuously generated, is one of the domains that can benefit from the application of ML pipelines to solve specific problems such as diagnosis, classification, disease detection, segmentation, assessment of organ functions, etc. However, while health professionals are experts in their domain, they can lack programming and theoretical skills regarding ML applications. Therefore, it is necessary to train health professionals in using these paradigms to get the most out of the application of ML algorithms to their data. In this work, we present a platform to assist non-expert users in defining ML pipelines in the health domain. The system’s design focuses on providing an educational experience to understand how ML algorithms work and how to interpret their outcomes and on fostering a flexible architecture to allow the evolution of the available components, algorithms, and heuristics.

Background: There are evidence indicating that some metabolites of arachidonic acid produced by cytochromes P450 (CYP) and epoxide hydroxylase (EPHX2), such as hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) or dihydroxyeicosatrienoic acids (DHETEs), play an important role in blood pressure regulation and they could contribute to the development of hypertension (HT) and kidney damage. Therefore, the main aim of the study was to evaluate whether the genetic polymorphisms of CYP2C8, CYP2C9, CYP2J2, CYP4F2, CYP4F11 and EPHX2, responsible for the formation of HETEs, EETs and DHETEs, are related to the progression of impaired renal function in a group of patients with hypertension. Methods: 151HT patients from a hospital nephrology service were included in the study. Additionally, a group of 87 normotensive subjects were involved in the study as control group. For HT patients, a general biochemistry analysis, estimated glomerular filtration rate and genotyping for different CYPs and EPHX2 variant alleles was performed. Results: CYP4A11 rs3890011, rs9332982 and EPHX2 rs41507953 polymorphisms, according to the dominant model, presented a high risk of impaired kidney function, with odds ratios (OR) of 2.07 (1.00–4.32; P = 0.049) 3.02 (1.11–8.23; P = 0.030) and 3.59 (1.37–9.41; P = 0.009), respectively, and the EPHX2 rs1042032 polymorphism a greater risk according to the recessive model (OR = 6.23; 95% CI = 1.50−25.95; P = 0.007). However, no significant differences in allele frequencies between HT patients and in normotensive subjects for any of the SNP analysed. In addition, the patients with diagnosis of dyslipidemia (n = 90) presented higher frequencies of EPHX2 K55R (rs41507953) and *35A>G (rs1042032) variants than patients without dyslipidemia, 4% vs. 14% (P = 0.005) and 16 vs. 27% (P =0.02), respectively. Conclusions: In this study has been found higher odds of impaired renal function progression associated with rs3890011 and rs9332982 (CYP4A11) and rs41507953 and rs1042032 (EPHX2) polymorphisms, which may serve as biomarkers for improve clinical interventions aimed at avoiding or delaying, in chronic kidney disease patients, progress to end-stage kidney disease needing dialysis or kidney transplant. Resumen: Antecedentes: Existen evidencias que muestran que algunos metabolitos del ácido araquidónico producidos por los citocromos P450 (CYP) y por la enzima epóxido hidroxilasa (EPHX2), tales como los ácidos hidroxieicosatetraenoicos (HETEs), ácidos epoxieicosatrienoicos (EETs) o ácidos dihidroxieicosatrienoicos (DHETEs), juegan un papel importante en la regulación de la presión arterial y, por tanto, podrían contribuir al desarrollo de hipertensión y daño renal. Por ello, el objetivo del estudio fue evaluar si los polimorfismos de los genes CYP2C8, CYP2C9, CYP2J2, CYP4F2, CYP4F11 y EPHX2, responsables de la formación de HETEs, EETs y DHETEs, están relacionados con la progresión de la función renal en un grupo de pacientes con hipertensión arterial (HT). Métodos: Se incluyeron en el estudio 151 pacientes de un servicio hospitalario de nefrología con diagnóstico de HT. Además, un grupo de 87 sujetos normotensos participó en el estudio como grupo de control. A los pacientes con HT se les realizó un análisis de bioquímica general, se calculó la tasa estimada de filtración glomerular y se analizaron los genotipos de los diferentes genes CYPs y EPHX2 incluidos en el estudio. Resultados: Los polimorfismos rs3890011, rs9332982 del gen CYP4A11 y rs41507953 del gen EPHX2 presentaron un alto riesgo de alteración de la función renal con unos odds ratios (OR) de 2,07 (1,00–4,32; P = 0,049) 3,02 (1,11−8,23; P = 0,030) y 3,59 (1,37−9,41; P = 0,009), respectivamente, así como el polimorfismo rs1042032 del gen EPHX2 presentó también un mayor riesgo (OR = 6,23; IC 95% = 1,50−25,95; P = 0,007). Sin embargo, no se observaron diferencias significativas en las frecuencias alélicas entre pacientes con HT y sujetos normotensos para ninguno de los polimorfismos analizados. Además, los pacientes con dislipidemia (n = 90) presentaron una mayor frecuencia de las variantes EPHX2 K55R (rs41507953) y *35A > G (rs1042032) que los pacientes sin dislipidemia, 4% vs. 14% (P = 0,005) y 16 vs. 27% (P = 0.02), respectivamente. Conclusiones: En este estudio se han encontrado mayores probabilidades de progresión de la función renal asociadas a los polimorfismos rs3890011 y rs9332982 del gen CYP4A11 y rs41507953 y rs1042032 del gen EPHX2, que podrían servir como biomarcadores para mejorar las intervenciones clínicas destinadas a evitar o retrasar, en pacientes con enfermedad renal crónica, el avance de la enfermedad renal hacia la etapa terminal en la que necesitarían diálisis o trasplante de riñón.

In recent years we have witnessed a series of changes that make it both necessary and urgent to redefine the limits of the architectural discipline, and in particular those of its teaching. The traditional profile of the architect as a builder has been radically transformed and has evolved towards other scenarios. The traditional teaching tools and procedures do not offer a response to the professional reality that the architect must assume in the face of the new approaches, services and considerations that contemporary society demands for this century. The aim of this article is to offer a reflection, from an educational perspective, on the challenges that the teaching of architectural project must face in order to provide future architects with the tools that will allow them to both approach new professional scenarios and respond to untested problems and unforeseen situations in a complex world. Training professionals to think for themselves with a critical and innovative spirit, encouraging the practice of creative and flexible thinking that enables them to define proposals and make imaginative decisions, developing work skills in co-production and co-creation environments or incorporating digital technology in the training of professionals are some of the challenges that this research addresses.

Context: Epilepsy is a neurological disease that affects more than 50 million people worldwide, causing recurrent seizures, with a significant impact on patients' quality of life due to abnormally synchronized neuronal activity. Method: This article discusses three methods used for signal analysis in patients diagnosed with epilepsy. Conventional signal decomposition methods, such as the fast Fourier transform, widely used in signal analysis based on time series techniques, have some issues when analyzing nonlinear and non-stationary signals, in addition to difficulties in detecting low-order frequencies. Results: To overcome these limitations, alternatives such as empirical mode decomposition and one of its variants, called ensemble empirical mode decomposition, have been developed. These techniques allow observing different oscillation modes through intrinsic mode functions and instantaneous frequencies. Conclusions: In this study, the results obtained through the aforementioned techniques were compared, revealing the impact of nonlinear methods on the reconstruction of brain activity.

Presentamos una revisión de los “ídolos placa” del Sureste de la península ibérica tras los nuevos hallazgos del Polideportivo de Martos (Jaén) y Los Millares (Almería). El análisis estilístico y contextual ha permitido diferentes valoraciones. Así, se observa una relación entre la variedad formal y la localización geográfica respecto a la distancia a la necrópolis millarense. Igualmente, se aprecia la conexión de las similitudes con contactos entre grupos sociales. Con todo, se plantea el rol que la circulación de personas, especialmente de determinadas mujeres, tuvo en la configuración de una ideología relativamente común en el sur de la península ibérica. Las “placas” desempeñaron un papel trascendente en la conexión de determinadas personas con los ancestros (genéricos o particulares) sea por su integración en el ritual funerario, sea por su (re)uso como reliquia-ornamento, o por su movilización en ceremoniales de regeneración agraria. Su uso se desarrolló desde mediados del IV milenio cal AC.