Search

Summary: Background: The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. Methods: We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. Findings: By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients’ subgroups. Interpretation: An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. Funding: German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.

The aim of this work is to present a methodology for the reconstruction of missing fracture density within highly fractured intervals, which can represent preferential fluid flow pathways. The lack of record can be very common due to the intense presence of fractures, dissolution processes, or data acquisition issues. The superposition of numerous fractures makes the definition of fracture surfaces impossible, as a consequence, modeling such zones is challenging. In order to address this issue, the usage of direct sampling multiple-point statistics to perform gap filling in well logs is demonstrated as an alternative to other techniques. It reproduces data patterns and provides several models representing uncertainty. The method was tested in intervals from a highly fractured well, by removing previously known fracture density data, and simulating different scenarios with direct sampling. Simulation results are compared to the observed data using cross-validation and continuous rank probability score. The reference scenario training data set consists in one well and two variables: fracture density and fracture occurrence. A sensitivity analysis is carried out considering additional variables, additional wells, different intervals, resampling with extremes, and other gap filling techniques. The auxiliary variable plays an important role in pattern matching, but adding wells and logs increases the complexity of the method without improving pattern retrieval. Best results are obtained applying extreme values theory for stochastic process with the enrichment of the fracture density data at the tail region, followed by resampling of the new values. The enriched data is used for the gap filling resulting in lower continuous rank probability score, and the achievement of extreme fracture density values.

Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2 . More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.

Abstract The identification of gene fusions has become an integral part of soft tissue and bone tumour diagnosis. We investigated the added value of targeted RNA‐based sequencing (targeted RNA‐seq, Archer FusionPlex) to our current molecular diagnostic workflow of these tumours, which is based on fluorescence in situ hybridisation (FISH) for the detection of gene fusions using 25 probes. In a series of 131 diagnostic samples targeted RNA‐seq identified a gene fusion, BCOR internal tandem duplication or ALK deletion in 47 cases (35.9%). For 74 cases, encompassing 137 FISH analyses, concordance between FISH and targeted RNA‐seq was evaluated. A positive or negative FISH result was confirmed by targeted RNA‐seq in 27 out of 49 (55.1%) and 81 out of 88 (92.0%) analyses, respectively. While negative concordance was high, targeted RNA‐seq identified a canonical gene fusion in seven cases despite a negative FISH result. The 22 discordant FISH‐positive analyses showed a lower percentage of rearrangement‐positive nuclei (range 15–41%) compared to the concordant FISH‐positive analyses (>41% of nuclei in 88.9% of cases). Six FISH analyses (in four cases) were finally considered false positive based on histological and targeted RNA‐seq findings. For the EWSR1 FISH probe, we observed a gene‐dependent disparity (p = 0.0020), with 8 out of 35 cases showing a discordance between FISH and targeted RNA‐seq (22.9%). This study demonstrates an added value of targeted RNA‐seq to our current diagnostic workflow of soft tissue and bone tumours in 19 out of 131 cases (14.5%), which we categorised as altered diagnosis (3 cases), added precision (6 cases), or augmented spectrum (10 cases). In the latter subgroup, four novel fusion transcripts were found for which the clinical relevance remains unclear: NAB2::NCOA2, YAP1::NUTM2B, HSPA8::BRAF, and PDE2A::PLAG1. Overall, targeted RNA‐seq has proven extremely valuable in the diagnostic workflow of soft tissue and bone tumours.

Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that the neural circuits underlying the regulation and expression of social behaviors are highly overlapped with those targeted by psychostimulants, which in most cases have strong rewarding and, consequently, addictive properties. In the present work, we provide an overview regarding the effects of illicit and prescription psychostimulants, such as cocaine, amphetamine-type stimulants, methylphenidate or modafinil, upon social behaviors such as social play, maternal behavior, aggression, pair bonding and social cognition and how psychostimulants in both animals and humans alter them. Finally, we discuss why these effects can vary depending on numerous variables such as the type of drug considered, acute versus long-term use, clinical versus recreational consumption, or the presence or absence of concomitant risk factors.

RÉSUMÉLa quantification des incertitudes des données hydrométriques (mesure de débit des cours d’eau) est reconnue comme indispensable mais sa mise en œuvre pratique nécessite un ensemble d’outils adaptés au traitement des mesures sur l’ensemble d’une chaîne complexe allant des mesures de terrain (jaugeages, limnigrammes) aux hydrogrammes, en passant par les courbes de tarage. Nous présentons plusieurs méthodes et outils logiciels développés ces vingt dernières années et intégrés dans les pratiques des hydromètres en France. L’incertitude plus forte des débits de crue est un des défis à relever. Outre la poursuite des développements méthodologiques, une réflexion sur la communication et la bancarisation des incertitudes est à entreprendre.

Introduction: Obesity is a chronic disease that increases cardiovascular and metabolic morbidity and mortality, decreases quality of life, and increases health care costs. While the role of lifestyle behavioral factors in the development of obesity is well established, the role of traumatic life events, including abuse, is unclear. To describe situations of violence and hardship reported by patients undergoing a bariatric surgery program, with a particular focus on sexual violence and its clinical correlates Methods: In this cross-sectional study, patients with grade II or III obesity, admitted to our digestive surgery department for bariatric surgery from 01/08/2019 to 31/12/2020, underwent a structured interview by a trained psychologist to describe the history of distressing life events self-reported by the patients. The primary endpoint was the presence of a history of sexual abuse. Multivariate logistic regressions were applied to identify independent risk factors for sexual violence (SV). Results: Of the 408 patients interviewed, 87.1% reported at least one distressing life event and 33.1% reported having had an SV in the past. Female gender (aOR =7.44, 95% CI: 3.85 - 15.73; p

Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the Initiative for the Critical Assessment of Metagenome Interpretation (CAMI). The CAMI II challenge engaged the community to assess methods on realistic and complex datasets with long- and short-read sequences, created computationally from around 1,700 new and known genomes, as well as 600 new plasmids and viruses. Here we analyze 5,002 results by 76 program versions. Substantial improvements were seen in assembly, some due to long-read data. Related strains still were challenging for assembly and genome recovery through binning, as was assembly quality for the latter. Profilers markedly matured, with taxon profilers and binners excelling at higher bacterial ranks, but underperforming for viruses and Archaea. Clinical pathogen detection results revealed a need to improve reproducibility. Runtime and memory usage analyses identified efficient programs, including top performers with other metrics. The results identify challenges and guide researchers in selecting methods for analyses.

Abstract Decades of theory and scholarship on the concept of human well‐being have informed a proliferation of approaches to assess well‐being and support public policy aimed at sustainability and improving quality of life. Human well‐being is multidimensional, and well‐being emerges when the dimensions and interrelationships interact as a system. In this paper, we illuminate two crucial components of well‐being that are often excluded from policy because of their relative difficulty to measure and manage: equity and interrelationships between humans and the environment. We use a mixed‐methods approach to review and summarize progress to date in developing well‐being constructs (including frameworks and methods) that address these two components. Well‐being frameworks that do not consider the environment, or interrelationships between people and their environment, are not truly measuring well‐being in all its dimensions. Use of equity lenses to assess well‐being frameworks aligns with increasing efforts to more holistically characterize well‐being and to guide sustainability management in ethical and equitable ways. Based on the findings of our review, we identify several pathways forward for the development and implementation of well‐being frameworks that can inform efforts to leverage well‐being for public policy.

Abstract Background A worldwide increased incidence of HM has been marked in recent decades. Therefore, to update epidemiological characteristics of HM in a French West Indies territory, we have performed analysis through Martinique's population-based cancer registry database. Methods We included cancer case data, from 2009–2018, coded in strict compliance with international standards set by International Agency for Research on Cancer. We calculated standardized incidence rates, cumulative rate (ages 0–74), and temporal trends for cases and deaths using the global population standard, by sex and five age group. Mortality rates were obtained from the French Epidemiology Center on Medical Causes of Death (CépiDc). Results One thousand forty seven new cases and 674 deaths from HM were recorded, of which 501 MM (47.8%), 377 LMNH (36%), 123 LAM (11.8%), and 46 LH (4.4%) were reported in both sexes. MM is one of the hematological malignancies with the highest incidence in Martinique among men. Temporal trends of incidence rates for all HM decreased overall in both sexes, except for MM in men. There is significant variability in mortality rates for both sexes. In addition, over the period, the temporal trends of mortality rates for all HMs has decreased overall. Gender-specific rates, between 2009 and 2018, showed that all lymphoid HM have a multimodal distribution curve that increased with age. Conclusions Characteristics of HM in Martinique over the reporting periods differ from mainland France. Higher incidences have been observed, particularly for MM, and non-significant sub-mortality is observed compared to mainland France. Moreover, temporal distribution of mortality and incidence trends had decreased over the reporting periods except for MM. Our results showed similarities with African-Americans groups in United States and in particular an equivalence in the frequency distribution of diagnosed HM. However, SMR remains lower compared to US black ethnic groups. Our results contributed to expanding knowledge on the epidemiology of HM with Caribbean data.

Reconstructing the geologic history of a karst area can advance understanding of the system's present-day hydrogeologic functioning and help predict the location of unexplored conduits. This study tests competing hypotheses describing past conditions controlling cave formation in an alpine karst catchment, by comparing an ensemble of modeled networks to the observed network map. The catchment, the Gottesacker karst system (Germany and Austria), is drained by three major springs and a paleo-spring and includes the partially explored Hölloch cave, which consists of an active section whose formation is well-understood and an inactive section whose formation is the subject of debate. Two hypotheses for the formation of the inactive section are the following: (1) glaciation obscured the three present-day springs, leaving only the paleo-spring, or (2) the lowest of the three major springs (Sägebach) is comparatively young, so its subcatchment previously drained to the paleo-spring. These hypotheses were tested using the pyKasso Python library (built on anisotropic fast-marching methods) to generate two ensembles of networks, one representing each scenario. Each ensemble was then compared to the known cave map. The simulated networks generated under hypothesis 2 match the observed cave map more closely than those generated under hypothesis 1. This supports the conclusion that the Sägebach spring is young, and it suggests that the cave likely continues southwards. Finally, this study extends the applicability of model ensemble methods from situations where the geologic setting is known but the network is unknown to situations where the network is known but the geologic evolution is not.

Abstract Determining how fracture network development leads to macroscopic failure in heterogeneous materials may help estimate the timing of failure in rocks in the upper crust as well as in engineered structures. The proportion of extensile and shear deformation produced by fracture development indicates the appropriate failure criteria to apply, and thus is a key constraint in such an effort. Here, we measure the volume proportion of extensile and shear fractures using the orientation of the fractures that develop in triaxial compression experiments in which fractures are identified using dynamic in situ synchrotron X-ray imaging. The fracture orientations transition from shear to extensile approaching macroscopic, system-size failure. Numerical models suggest that this transition occurs because the fracture networks evolve in order to optimize the total mechanical efficiency of the system. Our results provide a physical interpretation of the empirical internal friction coefficient in rocks.

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients who misuse alcohol, especially in the context of comorbid depressive symptoms. Deficits in impulse control and decision-making are linked to routine alcohol consumption and alcohol dependence. The goal of this study was to determine the effects of a single dose of citalopram on measures of impulsivity, decision-making, and/or brain dopamine receptor availability in alcohol-dependent individuals. A double-blind, placebo-controlled, within-subject, outpatient study was conducted with active alcohol-dependent (DSM-IV-TR criteria) participants (n = 12) and matched healthy controls (n = 13). Serial doses of both citalopram (40 mg) and saline were administered intravenously before laboratory tests of decision-making (Balloon Analogue Risk Task, delay discounting task, and Loss Aversion Gambling Task) and positron emission tomography with [18F]-fallypride to measure dopamine D2/3 receptor availability, separated by at least one week. Alcohol-dependent participants demonstrated greater loss aversion than healthy controls, but there were no group differences in risk taking on the Balloon Analogue Risk Task. Citalopram increased delay discounting across groups, with no group difference in the effect. There were no effects of citalopram on risk taking on the Balloon Analogue Risk Task. PET showed a negative correlation between thalamic dopamine D2/3 receptor availability and loss aversion across groups. The effect of citalopram to decrease the valuation of monetary reward as a function of delay raises the possibility that SSRIs can influence risky decision-making in clinical populations. In addition, these results suggest that altered thalamic dopamine signaling may play an important role in disproportionately valuing losses in patients with Alcohol Use Disorder. This trial is registered under ClinicalTrials.gov registration NCT01657760.

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics.

A high level of transparency in reported research is critical for several reasons, such as ensuring an acceptable level of trustworthiness and enabling replication. Transparency in qualitative research permits the identification of specific circumstances which are associated with findings and observations. Thus, transparency is important for the repeatability of original studies and for explorations of the transferability of original findings. There has been no investigation into levels of transparency in reported technology education research to date. With a position that increasing transparency would be beneficial, this article presents an analysis of levels of transparency in contemporary technology education research studies which employed interviews within their methodologies, and which were published within the "International Journal of Technology and Design Education and Design and Technology Education: An International Journal" (n = 38). The results indicate room for improvement, especially in terms of documenting researcher positionality, determinations of data saturation, and how power imbalances were managed. A discussion is presented on why it is important to improve levels of transparency in reported studies, and a guide on areas to make transparent is presented for qualitative and quantitative research.

Abstract Background Ventilator-free days (VFDs) are a composite endpoint increasingly used as the primary outcome in critical care trials. However, because of the skewed distribution and competitive risk between components, sample size estimation remains challenging. This systematic review was conducted to systematically assess whether the sample size was congruent, as calculated to evaluate VFDs in trials, with VFDs’ distribution and the impact of alternative methods on sample size estimation. Methods A systematic literature search was conducted within the PubMed and Embase databases for randomized clinical trials in adults with VFDs as the primary outcome until December 2021. We focused on peer-reviewed journals with 2021 impact factors greater than five. After reviewing definitions of VFDs, we extracted the sample size and methods used for its estimation. The data were collected by two independent investigators and recorded in a standardized, pilot-tested forms tool. Sample sizes were calculated using alternative statistical approaches, and risks of bias were assessed with the Cochrane risk-of-bias tool. Results Of the 26 clinical trials included, 19 (73%) raised “some concerns” when assessing risks of bias. Twenty-four (92%) trials were two-arm superiority trials, and 23 (89%) were conducted at multiple sites. Almost all the trials (96%) were unable to consider the unique distribution of VFDs and death as a competitive risk. Moreover, significant heterogeneity was found in the definitions of VFDs, especially regarding varying start time and type of respiratory support. Methods for sample size estimation were also heterogeneous, and simple models, such as the Mann–Whitney–Wilcoxon rank-sum test, were used in 14 (54%) trials. Finally, the sample sizes calculated varied by a factor of 1.6 to 17.4. Conclusions A standardized definition and methodology for VFDs, including the use of a core outcome set, seems to be required. Indeed, this could facilitate the interpretation of findings in clinical trials, as well as their construction, especially the sample size estimation which is a trade-off between cost, ethics, and statistical power. Systematic review registration PROSPERO ID: CRD42021282304. Registered 15 December 2021 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021282304 ).

ABSTRACTBacterial plasmids play a major role in the spread of antibiotic resistance genes. However, their characterization via DNA sequencing suffers from the low abundance of plasmid DNA in those samples. Although sample preparation methods can enrich the proportion of plasmid DNA before sequencing, these methods are expensive and laborious, and they might introduce a bias by enriching only for specific plasmid DNA sequences. Nanopore adaptive sampling could overcome these issues by rejecting uninteresting DNA molecules during the sequencing process. In this study, we assess the application of adaptive sampling for the enrichment of low-abundant plasmids in known bacterial isolates using two different adaptive sampling tools. We show that a significant enrichment can be achieved even on expired flow cells. By applying adaptive sampling, we also improve the quality of de novo plasmid assemblies and reduce the sequencing time. However, our experiments also highlight issues with adaptive sampling if target and non-target sequences span similar regions.IMPORTANCEAntimicrobial resistance causes millions of deaths every year. Mobile genetic elements like bacterial plasmids are key drivers for the dissemination of antimicrobial resistance genes. This makes the characterization of plasmids via DNA sequencing an important tool for clinical microbiologists. Since plasmids are often underrepresented in bacterial samples, plasmid sequencing can be challenging and laborious. To accelerate the sequencing process, we evaluate nanopore adaptive sampling as an in silico method for the enrichment of low-abundant plasmids. Our results show the potential of this cost-efficient method for future plasmid research but also indicate issues that arise from using reference sequences.

Background: In recent times there has been a surge in innovative techniques concerning complex abdominal wall surgery. The availability of simulation models for comprehensive training and skill set development remains limited.Methods: Cadaveric dissections of the porcine abdominal wall were conducted to assess the suitability of anesthetized porcine models for training in both minimally invasive and open surgical procedures.Results: The panniculus carnosus, a typical muscular layer in mammals, is the outermost layer covering the anterolateral abdominal wall. Beneath it, there are four main pairs of abdominal wall muscles, mirroring the human anatomy. The rectus abdominis muscle runs straight along the linea alba and is surrounded by the rectus sheath, which is formed by the fusion of the lateral abdominal wall muscles and differs along the different regions of abdominal wall. The orientation of the muscle fibers in the lateral abdominal wall muscles, i.e., musculus obliquus externus, internus and transversus, is comparable to human anatomy. Although the transition lines between their muscular and aponeurotic part differ to some extent. Relevant for the adoption of surgical techniques, the transversus abdominis muscle is well-developed and resembles a bell curve shape as it transitions from its muscular to aponeurotic part.Conclusion: Despite minor differences in abdominal wall anatomy between pigs and humans, the porcine model provides a high level of fidelity in terms of both anatomical features and the development of skill sets relevant to hernia surgery.

Not available.

In the context of current climate change, municipalities tend to plant more trees in order to benefit from services they provide in urban areas, such as reducing heat islands. However, in cities, trees are subject to severe abiotic constraints, the main ones being soil contamination and the lack of water due to soil compaction and droughts. This can negatively impact the ecological services provided by trees. Our study aims to help managers in monitoring the phytosanitary status of trees in order to be able to react promptly. In a controlled condition experiment, different plant compounds were analyzed (proline, malondialdehyde-MDA, photosynthetic pigments) in the leaves of young linden trees conventionally grown for planting by the City of Paris, France. They were grown on a trace element (TE) contamination soil gradient, and under different water regimes (well-hydrated/no water stress (Ct), dehydration (Dh), rehydration (Rh)) to see if tested compounds could be early stress markers in trees. Chlorophylls (Chl) could be considered as water and TE-mediated stress markers. Indeed Chl a and b concentrations significantly decreased with dehydration (e.g. respectively −34 % and −24 %) and increasing lead concentration in leaves (respectively, correlation coefficients were −1.08; −0.64 (p