Mortality impact of low CAC density predominantly occurs in early atherosclerosis: explainable ML in the CAC consortium.

BACKGROUND: Machine learning (ML) models of risk prediction with coronary artery calcium (CAC) and CAC characteristics exhibit high performance, but are not inherently interpretable. OBJECTIVES: To determine the direction and magnitude of impact of CAC characteristics on 10-year all-cause mortality (ACM) with explainable ML. METHODS: We analyzed asymptomatic subjects in the CAC consortium. We trained ML models on 80% and tested on 20% of the data with XGBoost, using clinical characteristics â€‹+ â€‹CAC (ML 1) and additional CAC characteristics of CAC density and number of calcified vessels (ML 2). We applied SHAP, an explainable ML tool, to explore the relationship of CAC and CAC characteristics with 10-year all-cause and CV mortality. RESULTS: 2376 deaths occurred among 63,215 patients [68% male, median age 54 (IQR 47-61), CAC 3 (IQR 0-94.3)]. ML2 was similar to ML1 to predict all-cause mortality (Area Under the Curve (AUC) 0.819 vs 0.821, p â€‹= â€‹0.23), but superior for CV mortality (0.847 vs 0.845, p â€‹= â€‹0.03). Low CAC density increased mortality impact, particularly ≤0.75. Very low CAC density ≤0.75 was present in only 4.3% of the patients with measurable density, and 75% occurred in CAC1-100. The number of diseased vessels did not increase mortality overall when simultaneously accounting for CAC and CAC density. CONCLUSION: CAC density contributes to mortality risk primarily when it is very low ≤0.75, which is primarily observed in CAC 1-100. CAC and CAC density are more important for mortality prediction than the number of diseased vessels, and improve prediction of CV but not all-cause mortality. Explainable ML techniques are useful to describe granular relationships in otherwise opaque prediction models.

Vulnerability and Well-Being Decades After Leaving Care.

One of the most important goals of out of home placements is to reduce vulnerability and to enable well-being in the long term. This article hermeneutically reconstructs biographies decades after leaving-care to understand the impact of residential care experiences on selected dimensions of care-leavers' well-being, that were discovered in the data material. For this article three analytic areas were selected from the core of the narratives of former care leavers: Social networks, parenthood and state interventions. The selected findings on long-term outcomes presented here are based on a qualitative research project funded by the Swiss National Science Foundation on life trajectories after residential care (1950-1990). The authors have conducted 37 biographical narrative interviews with former children placed in residential care between 1950 and 1990 in the Canton of Zurich, Switzerland. The analysis of these narrative interviews was structured by the inductive procedures of Grounded Theory. Its foundation is the conceptualisation and dimensionalisation of data through inductive coding within the narratives. Research question: We mainly were interested in aspects of transitions exclusively relevant from the actors' point of view. The objective of this paper is to learn for the future by taking biographical experiences and long-term outcome in account. As we know residential care facilities have changed in last decades, but structurally some key figures are still continuing. They still interrupt the life course two times: when you start to the live in the institution and when you leave. One main question is how young people manage to integrate residential experiences through their life course and where they keep on struggling until the end of their lives. From a life-course perspective, the impact of social service intention on individual life courses, behind sending the individuals to such facilities, are important to investigate. They implicate relevant information concerning current practice and impact of placing children in residential care. Social networks and experiences of parenthood show why we must frame and accompany transitions out of care.

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia.

Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC-derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as ß-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.

chemalot and chemalot_knime: Command line programs as workflow tools for drug discovery.

BACKGROUND: Analyzing files containing chemical information is at the core of cheminformatics. Each analysis may require a unique workflow. This paper describes the chemalot and chemalot_knime open source packages. Chemalot is a set of command line programs with a wide range of functionalities for cheminformatics. The chemalot_knime package allows command line programs that read and write SD files from stdin and to stdout to be wrapped into KNIME nodes. The combination of chemalot and chemalot_knime not only facilitates the compilation and maintenance of sequences of command line programs but also allows KNIME workflows to take advantage of the compute power of a LINUX cluster. RESULTS: Use of the command line programs is demonstrated in three different workflow examples: (1) A workflow to create a data file with project-relevant data for structure-activity or property analysis and other type of investigations, (2) The creation of a quantitative structure-property-relationship model using the command line programs via KNIME nodes, and (3) The analysis of strain energy in small molecule ligand conformations from the Protein Data Bank database. CONCLUSIONS: The chemalot and chemalot_knime packages provide lightweight and powerful tools for many tasks in cheminformatics. They are easily integrated with other open source and commercial command line tools and can be combined to build new and even more powerful tools. The chemalot_knime package facilitates the generation and maintenance of user-defined command line workflows, taking advantage of the graphical design capabilities in KNIME. Graphical abstract Example KNIME workflow with chemalot nodes and the corresponding command line pipe.

Out of home care in France and Switzerland / Las medidas de protección a la infancia con separación familiar en Francia y Suiza

Este artículo se centra en las semejanzas y diferencias entre los sistemas de protección a la infancia de Francia y Suiza, de acuerdo con la evolución del último decenio. La falta de un sistema integrado, holístico, y la enorme diversidad de prácticas entre territorios en ambos países crea una realidad que plantea un desafío tanto para la investigación como para los profesionales. Además, la legislación y Francia y en Suiza es bastante parecida en el hecho de que no hay un apoyo definido ni un cuerpo de legislación sobre el bienestar en niños y jóvenes. En ambos países es la necesidad de una mejor comprensión de esta realidad lo que impulsa el desarrollo de mejores procesos de recogida de datos y una nueva investigación en profundidad en este campo (AU)

This article focuses on the structural similarities and dissimilarities that exist between child protection systems in France and Switzerland, as exemplified by the evolutions of the last decade. The absence of an integrated holistic system and the great diversity of practices between territories in both countries creates a reality that is a challenge for research and practitioners alike. Furthermore, legislation in France and Switzerland is quite similar in that there is no single defined support or welfare body of legislation for children and youth. In both countries, the need for a better understanding of this reality drives the development of better data collection processes and of new in-depth research on these issues (AU)

A new kinetic framework for synaptic vesicle trafficking tested in synapsin knock-outs.

At least two rate-limiting mechanisms in vesicle trafficking operate at mouse Schaffer collateral synapses, but their molecular/physical identities are unknown. The first mechanism determines the baseline rate at which reserve vesicles are supplied to a readily releasable pool. The second causes the supply rate to depress threefold when synaptic transmission is driven hard for extended periods. Previous models invoked depletion of a reserve vesicle pool to explain the reductions in the supply rate, but the mass-action assumption at their core is not compatible with kinetic measurements of neurotransmission under maximal-use conditions. Here we develop a new theoretical model of rate-limiting steps in vesicle trafficking that is compatible with previous and new measurements. A physical interpretation is proposed where local reserve pools consisting of four vesicles are tethered to individual release sites and are replenished stochastically in an all-or-none fashion. We then show that the supply rate depresses more rapidly in synapsin knock-outs and that the phenotype can be fully explained by changing the value of the single parameter in the model that would specify the size of the local reserve pools. Vesicle-trafficking rates between pools were not affected. Finally, optical imaging experiments argue against alternative interpretations of the theoretical model where vesicle trafficking is inhibited without reserve pool depletion. This new conceptual framework will be useful for distinguishing which of the multiple molecular and cell biological mechanisms involved in vesicle trafficking are rate limiting at different levels of synaptic throughput and are thus candidates for physiological and pharmacological modulation.

Incidencia de Huesos Suturales en Cráneos de Changos del Norte de Chile, Región de Antofagasta / Incidence of sutural bones in a population of chango? skulls of Northern Chile, Antofagasta

La presencia de huesos suturales es producto de alteraciones en la formación de los huesos anchos del cráneo, considerándose también, variables étnicas, siendo de interés para la anatomía humana, antropología física, imagenología y medicina legal. Con la finalidad de contribuir al conocimiento de los huesos suturales y su incidencia en individuos originarios, se analizó su presencia en 23 cráneos de changos del Norte de Chile quienes se encuentran clasificados y pertenecen a la colección del Museo Regional de Antofagasta. Se comprobó la presencia de suturales en el 43,5% de los casos, con un rango de 1 a 9, siendo bilaterales en el 60%. Predominan los huesos en el lado izquierdo (64,9%) y en cráneos braquicefálicos (IC=96,8). Se identificó el hueso lambda o interparietal en el 13,04% de los cráneos. Los datos obtenidos se corresponden con los descritos en la literatura.

The presence of sutural bones is a product of alterations in the formation of the wide bones of the skull, in addition to ethnic variables, being of interest in human anatomy, physical anthropology, imagenology and legal medicine. With the purpose of contributing to the knowledge of the sutural bones and its incidence in original individuals, its presence in 23 skulls of changos of the North of Chile was analyzed that are classified and that they belong to the collection of the Regional Museum of Antofagasta. The presence of sutural bones in 43.5% of the cases with a rank from 1 to 9 was verified, being bilateral in 60%. The bones in the left side (64,9%) and in brachicephalic skulls predominate (IC=96,8). The lambda or interparietal bone was identified in 13.04% of the skulls. The collected data correspond with the described ones by Literature.

Dynamical basis of irregular spiking in NMDA-driven prefrontal cortex neurons.

Slow N-Methyl-D-aspartic acid (NMDA) synaptic currents are assumed to strongly contribute to the persistently elevated firing rates observed in prefrontal cortex (PFC) during working memory. During persistent activity, spiking of many neurons is highly irregular. Here we report that highly irregular firing can be induced through a combination of NMDA- and dopamine D1 receptor agonists applied to adult PFC neurons in vitro. The highest interspike-interval (ISI) variability occurred in a transition regime where the subthreshold membrane potential distribution shifts from mono- to bimodality, while neurons with clearly mono- or bimodal distributions fired much more regularly. Predictability within irregular ISI series was significantly higher than expected from a noise-driven linear process, indicating that it might best be described through complex (potentially chaotic) nonlinear deterministic processes. Accordingly, the phenomena observed in vitro could be reproduced in purely deterministic biophysical model neurons. High spiking irregularity in these models emerged within a chaotic, close-to-bifurcation regime characterized by a shift of the membrane potential distribution from mono- to bimodality and by similar ISI return maps as observed in vitro. The nonlinearity of NMDA conductances was crucial for inducing this regime. NMDA-induced irregular dynamics may have important implications for computational processes during working memory and neural coding.

Quantification of Mg2+ extrusion and cytosolic Mg2+-buffering in Xenopus oocytes.

Intracellular Mg(2+) buffering and Mg(2+) extrusion were investigated in Xenopus laevis oocytes. Mg(2+) or EDTA were pressure injected and the resulting changes in the intracellular Mg(2+) concentration were measured simultaneously with Mg(2+)-selective microelectrodes. In the presence of extracellular Na(+), injected Mg(2+) was extruded from the oocytes with an estimated v(max) and K(M) of 74 pmol cm(-2)s(-1) and 1.28 mM, respectively. To investigate genuine cytosolic Mg(2+) buffering, measurements were carried out in the nominal absence of extracellular Na(+) to block Mg(2+) extrusion, and during the application of CCCP (inhibiting mitochondrial uptake). Under these conditions, Mg(2+) buffering calculated after both MgCl(2) and EDTA injections could be described by a buffer equivalent with a concentration of 9.8mM and an apparent dissociation constant, K(d-app), of 0.6mM together with an [ATP](i) of 0.9 mM with a K(d-app) 0.12 mM. Xenopus oocytes thus possess highly efficient mechanisms to maintain their intracellular Mg(2+) concentration.