Nedosiran in pediatric patients with PH1 and relatively preserved kidney function, a phase 2 study (PHYOX8).

Background: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder with dysregulated glyoxylate metabolism in the liver. Oxalate over-production leads to renal stones, progressive kidney damage and renal failure, with potentially life-threatening systemic oxalosis. Nedosiran is a synthetic RNA interference therapy, designed to reduce hepatic lactate dehydrogenase (LDH) to decrease oxalate burden in PH.

Efficacy of innovative systemic treatments in combination with radiotherapy for bone metastases: a GEMO (the European Study Group of Bone Metastases) state of the art.

The management of bone metastases (BoM) requires a multidisciplinary approach to prevent complications, necessitating updated knowledge in light of the rapid advancements in systemic treatments and surgical, interventional radiology or radiation techniques. This review aims to discuss efficacy of new systemic treatments on BoM, the benefits of radiotherapy adjunction, and the optimal methods for combining them. Preliminary evidence suggesting reduced efficacy of immune checkpoint inhibitors (ICI), and several multi-kinase inhibitors regarding BoM may encourage early use of radiotherapy (RT).

Benefits of HIV-1 transmission cluster surveillance: a French retrospective observational study of the molecular and epidemiological co-evolution of recent circulating recombinant forms 94 and 132.

Introduction: Molecular surveillance is an important tool for detecting chains of transmission and controlling the HIV epidemic. This can also improve our knowledge of molecular and epidemiological factors for the optimization of prevention. Our objective was to illustrate this by studying the molecular and epidemiological evolution of the cluster including the new circulating recombinant form (CRF) 94_cpx of HIV-1, detected in 2017 and targeted by preventive actions in 2018.

Impact of Rule 11 on the European Medical Software Landscape: Analysis of EUDAMED and Further Databases Three Years After MDR Implementation.

Medicine is increasingly supported by software, with digital health technologies offering innovative ways to capture insights and drive therapies. Globally, medical device software must follow regulatory processes based on risk classification. The introduction of MDR represents a significant shift in risk-based classification for Medical Devices in Europe, including classification Rule 11 for software, which has caused significant discussions among European regulators.

Pediatric eosinophilic fasciitis: similarities and differences with adult forms.

The purpose of this study was to identify pediatric eosinophilic fasciitis, which is an extremely rare condition, in order to describe their clinical, paraclinical, and therapeutic characteristics. We made a call for observations via societies for pediatric rheumatology in France and surrounding countries and collected clinical and paraclinical data of the cases fulfilling the diagnostic criteria. Eight patients under 18 years of age with confirmed eosinophilic fasciitis followed between April 2004 and July 2022 in France, Germany, Italy, and Spain were included.

fMRI data acquisition and analysis for task-free, anesthetized rats.

Templates for the acquisition of large datasets such as the Human Connectome Project guide the neuroimaging community to reproducible data acquisition and scientific rigor. By contrast, small animal neuroimaging often relies on laboratory-specific protocols, which limit cross-study comparisons. The establishment of broadly validated protocols may facilitate the acquisition of large datasets, which are essential for uncovering potentially small effects often seen in functional MRI (fMRI) studies.

Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type.

To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53-mediated gene expression.

The architecture of the human default mode network explored through cytoarchitecture, wiring and signal flow.

The default mode network (DMN) is implicated in many aspects of complex thought and behavior. Here, we leverage postmortem histology and in vivo neuroimaging to characterize the anatomy of the DMN to better understand its role in information processing and cortical communication. Our results show that the DMN is cytoarchitecturally heterogenous, containing cytoarchitectural types that are variably specialized for unimodal, heteromodal and memory-related processing.

Chromatin environment-dependent effects of DOT1L on gene expression in male germ cells.

The H3K79 methyltransferase DOT1L is essential for multiple aspects of mammalian development where it has been shown to regulate gene expression. Here, by producing and integrating epigenomic and spike-in RNA-seq data, we decipher the molecular role of DOT1L during mouse spermatogenesis and show that it has opposite effects on gene expression depending on chromatin environment. On one hand, DOT1L represses autosomal genes that are devoid of H3K79me2 at their bodies and located in H3K27me3-rich/H3K27ac-poor environments.

Semi-mechanistic efficacy model for PARP + ATR inhibitors-application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs.

Background: Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges.

Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination.

TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations.

Evaluation of ampicillin plus ceftobiprole combination therapy in treating Enterococcus faecalis infective endocarditis and bloodstream infection.

Enterococcus faecalis is responsible for numerous serious infections, and treatment options often include ampicillin combined with an aminoglycoside or dual beta-lactam therapy with ampicillin and a third-generation cephalosporin. The mechanism of dual beta-lactam therapy relies on the saturation of penicillin-binding proteins (PBPs). Ceftobiprole exhibits high affinity binding to nearly all E.

Meta-analysis of RNA-Seq datasets allows a better understanding of P. tricornutum cellular biology, a requirement to improve the production of Biologics.

The marine diatom Phaeodactylum tricornutum is currently used for various industrial applications, including the pharmaceutical industry as a cost-effective cell biofactory to produce Biologics. Recent studies demonstrated that P. tricornutum can produce functional monoclonal antibodies, such application is currently limited by the production yield that hinders industrialization.

Radon on Mars and the Moon derived from Martian and lunar meteorites.

The radioactive gas radon-222, a fluid and aerosol tracer in Earth's lithosphere and atmosphere, can also reveal subtle rock physics processes in extraterrestrial environments, such as those involving water, but remains poorly constrained in planetary bodies due to the limited number of samples available. Here we measure the effective radium-226 concentration (EC) of six Martian and nine lunar meteorites to derive radon source terms for Martian and lunar rocks. EC values are 0.

A guide for active learning in synergistic drug discovery.

Synergistic drug combination screening is a promising strategy in drug discovery, but it involves navigating a costly and complex search space. While AI, particularly deep learning, has advanced synergy predictions, its effectiveness is limited by the low occurrence of synergistic drug pairs. Active learning, which integrates experimental testing into the learning process, has been proposed to address this challenge.

Neural circuits underlying context-dependent competition between defensive actions in Drosophila larvae.

To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine learning-based behavioral detection, electron microscopy (EM) connectomics and calcium imaging in Drosophila larvae, we map second-order interneurons that are differentially involved in the competition between defensive actions in response to competing aversive cues.

A catalogue of land-based adaptation and mitigation solutions to tackle climate change.

Informing and engaging all actors in the land sector, including land-owners and managers, researchers, policy-makers and citizens, on the most effective sustainable land-based solutions and behavioural changes is a key strategy for achieving climate change adaptation and mitigation targets at the global as well as at EU and local level. One requisite to support actors in the land sector is to provide them publicly available, reliable and ready-to-use information related to the implementation of Land-based Adaptation and Mitigation Solutions (LAMS). Here we introduce a LAMS catalogue, a collection of meaningful quantitative and qualitative information on 60 solutions characterised according to a set of specifications (e.

Can a single coastal tide gauge help predict internal solitary wave activity offshore.

Internal solitary waves (ISWs) propagate in stratified waters, enhancing diapycnal mixing, sediment and mass transport on shelves. They have typical wavelengths of hundreds of meters and tens of minutes periods, requiring high resolution and high frequency measurements for their sampling. But such in-situ measurements are scarce and ISWs remain largely unpredictable.

High-rate quantum LDPC codes for long-range-connected neutral atom registers.

High-rate quantum error correcting (QEC) codes with moderate overheads in qubit number and control complexity are highly desirable for achieving fault-tolerant quantum computing. Recently, quantum error correction has experienced significant progress both in code development and experimental realizations, with neutral atom qubit architecture rapidly establishing itself as a leading platform in the field. Scalable quantum computing will require processing with QEC codes that have low qubit overhead and large error suppression, and while such codes do exist, they involve a degree of non-locality that has yet to be integrated into experimental platforms.

Scottish Open Fractures of Tibia (SOFT) audit; a multi-centre retrospective review of ortho-plastic management of tibial shaft fractures at major trauma centres (MTCs) in Scotland.

Aims: Open fractures of the tibia are associated with significant complications, for which attempts have been made to standardise and optimise their management. In the UK, this standard is the British Orthopaedic Association Standards for Trauma (BOAST) guidelines. The Scottish Open Fracture of Tibia (SOFT) Audit is a national review of open tibial shaft fractures across all four Scottish Trauma Networks, which aims to provide a definite review of ortho-plastic care for open tibial shaft fractures in Scotland.