Multi-stakeholder sessions on major innovation topics in rare disease clinical trials.

Background: The European Joint Programme on Rare Diseases aims to enhance the rare diseases research ecosystem by bringing together stakeholders such as research funders, institutions and patient organizations. Work Package 20 focuses on the validation, use and development of innovative methodologies for rare disease clinical trials. This paper reports on the outcomes of a retreat held in April 2023, where areas for innovation and educational needs in rare disease clinical trials were discussed in multi-stakeholder sessions.

Synchrotron-Based Phase-Contrast Micro-CT Combined With Histology to Decipher Differences Between Hereditary and Sporadic Pediatric Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a lethal variant of pulmonary hypertension. The degree of pulmonary arterial involvement varies. Here, we compare two PVOD patients who were transplanted at 8 years of age, whereof one is a homozygous mutation carrier.

Novel approaches in myelofibrosis.

Myelofibrosis (MF) is a clonal myeloid neoplasm characterized by bone marrow fibrosis, splenomegaly, and disease-associated symptoms, as well as increased mortality, due to thrombosis, severe bleeding, infections, or progression to acute leukemia. Currently, the management of MF patients is tailored according to risk scores, with higher-risk (intermediate-2 and high-risk) patients being assessed for allogeneic stem cell transplantation, which remains the only potentially curative treatment option. On the other hand, lower risk (low- and intermediate-1 risk) patients who are symptomatic may be treated with JAK inhibitors or other drugs.

Magma Chamber Response to Ice Unloading: Applications to Volcanism in the West Antarctic Rift System.

Volcanic activity has been shown to affect Earth's climate in a myriad of ways. One such example is that eruptions proximate to surface ice will promote ice melting. In turn, the crustal unloading associated with melting an ice sheet affects the internal dynamics of the underlying magma plumbing system.

Broad-scale phenotyping in Arabidopsis reveals varied involvement of RNA interference across diverse plant-microbe interactions.

RNA interference (RNAi) is a crucial mechanism in immunity against infectious microbes through the action of DICER-LIKE (DCL) and ARGONAUTE (AGO) proteins. In the case of the taxonomically diverse fungal pathogen and the oomycete , plant DCL and AGO proteins have proven roles as negative regulators of immunity, suggesting functional specialization of these proteins. To address this aspect in a broader taxonomic context, we characterized the colonization pattern of an informative set of and loss-of-function mutants in upon infection with a panel of pathogenic microbes with different lifestyles, and a fungal mutualist.

Gut microbiota research nexus: One Health relationship between human, animal, and environmental resistomes.

The emergence and rapid spread of antimicrobial resistance is of global public health concern. The gut microbiota harboring diverse commensal and opportunistic bacteria that can acquire resistance via horizontal and vertical gene transfers is considered an important reservoir and sink of antibiotic resistance genes (ARGs). In this review, we describe the reservoirs of gut ARGs and their dynamics in both animals and humans, use the One Health perspective to track the transmission of ARG-containing bacteria between humans, animals, and the environment, and assess the impact of antimicrobial resistance on human health and socioeconomic development.

Secondary Ischemia Assessment in Murine and Rat Preclinical Subarachnoid Hemorrhage Models: A Systematic Review.

Background: Delayed cerebral ischemia represents a significant contributor to death and disability following aneurysmal subarachnoid hemorrhage. Although preclinical models have shown promising results, clinical trials have consistently failed to replicate the success of therapeutic strategies. The lack of standardized experimental setups and outcome assessments, particularly regarding secondary vasospastic/ischemic events, may be partly responsible for the translational failure.

A modelling study to dissect the potential role of voltage-gated ion channels in activity-dependent conduction velocity changes as identified in small fiber neuropathy patients.

Objective: Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans.

Combined experimental and simulation study on H storage in oxygen and nitrogen co-doped activated carbon derived from biomass waste: superior pore size and surface chemistry development.

In this study, heteroatom (O, N)-doped activated carbon (AC) is produced using urea and KOH activation from abundant and cost-effective biomass waste for H storage. The O and N co-doped AC exhibits the highest specific surface area and H storage capacity (2.62 wt%), increasing by 47% from unmodified AC at -196 °C and 1 bar.

Wearable activity data can predict functional recovery after musculoskeletal injury: Feasibility of a machine learning approach.

Delayed functional recovery after injury is associated with significant personal and socioeconomic burden. Identification of patients at risk for a prolonged recovery after a musculoskeletal injury is thus of high relevance. The aim of the current study was to show the feasibility of using a machine learning assisted model to predict functional recovery based on the pre- and immediate post injury patient activity as measured with wearable systems in trauma patients.

Diagnostic efficacy of C-X-C motif chemokine receptor 4-directed PET/CT in newly diagnosed head and neck squamous cell carcinoma - a head-to-head comparison with [F]FDG.

Background: The aim of this study was to determine the read-out capabilities of the novel C-X-C motif chemokine receptor 4 (CXCR4)-targeting radiotracer [Ga]Ga-PentixaFor compared to the reference radiotracer [F]FDG in untreated individuals with head and neck squamous cell carcinoma (HNSCC).

Material And Methods: 12 patients with histologically confirmed HNSCC were scheduled for [F]FDG and [Ga]Ga-PentixaFor PET/CT. Maximum standardized uptake values (SUV) and target-to-background ratios (TBR) were applied with vena cava superior serving as reference.

Discovery of lead quinone cathode materials for Li-ion batteries.

Organic cathode materials are attractive candidates for the development of high-performance Li-ion batteries (LIBs). The chemical space of candidate molecules is too vast to be explored solely by experiments; however, it can be systematically explored by a high-throughput computational search that incorporates a spectrum of screening techniques. Here, we present a time- and resource-efficient computational scheme that incorporates machine learning and semi-empirical quantum mechanical methods to study the chemical space of approximately 200 000 quinone-based molecules for use as cathode materials in LIBs.

Polymeric materials for ultrasound imaging and therapy.

Ultrasound (US) is routinely used for diagnostic imaging and increasingly employed for therapeutic applications. Materials that act as cavitation nuclei can improve the resolution of US imaging, and facilitate therapeutic US procedures by promoting local drug delivery or allowing temporary biological barrier opening at moderate acoustic powers. Polymeric materials offer a high degree of control over physicochemical features concerning responsiveness to US, tuning chain composition, length and rigidity.

AI-based identification of therapeutic agents targeting GPCRs: introducing ligand type classifiers and systems biology.

Identifying ligands targeting G protein coupled receptors (GPCRs) with novel chemotypes other than the physiological ligands is a challenge for screening campaigns. Here we present an approach that identifies novel chemotype ligands by combining structural data with a random forest agonist/antagonist classifier and a signal-transduction kinetic model. As a test case, we apply this approach to identify novel antagonists of the human adenosine transmembrane receptor type 2A, an attractive target against Parkinson's disease and cancer.

Biomechanical evaluation of a novel biomimetic artificial intervertebral disc in canine cervical cadaveric spines.

Background Context: Cervical disc replacement (CDR) aims to restore motion of the treated level to reduce the risk of adjacent segment disease (ASD) compared with spinal fusion. However, first-generation articulating devices are unable to mimic the complex deformation kinematics of a natural disc. Thus, a biomimetic artificial intervertebral CDR (bioAID), containing a hydroxyethylmethacrylate (HEMA)-sodium methacrylate (NaMA) hydrogel core representing the nucleus pulposus, an ultra-high-molecular-weight-polyethylene fiber jacket as annulus fibrosus, and titanium endplates with pins for primary mechanical fixation, was developed.

Evaluating microbial contaminations of alternative heating oils.

Since 2008, European and German legislative initiatives for climate protection and reduced dependency on fossil resources led to the introduction of biofuels as CO-reduced alternatives in the heating oil sector. In the case of biodiesel, customers were confronted with accelerated microbial contaminations during storage. Since then, other fuel alternatives, like hydrogenated vegetable oils (HVOs), gas-to-liquid (GtL) products, or oxymethylene ether (OME) have been developed.

Impact of Covid-19 pandemic on the transnationalization of LGBT* activism in Japan and beyond.

The global Covid-19 pandemic has strongly impacted social practices, relocating communications and social networks into the digital space. Contextualized in such impact of the Covid-19 pandemic, the local LGBT* activism in Japan achieved a special momentum: both the acceleration of the socio-spatial relocation of LGBT* activism to the digital space and the postponement of the Tokyo Olympics 2020 by 1 year enabled activists to mobilize people domestically and globally. The pandemic was not the actual cause or driver of the local LGBT* activism, yet it has been an important catalyst for the transnationalization of the local movement in Japan, pushing evidently the spatial boundaries to achieve broader public outreach but in turn also receiving stronger support from the global community through transnational networks.

Recycling of NdFeB magnets employing oxidation, selective leaching, and iron precipitation in an autoclave.

The increasing production of neodymium-iron-boron (NdFeB) magnets for technological applications results in disposal problems. NdFeB magnets contain a significant quantity of rare earth elements (REEs). China is the largest REEs producer, but it applies quotas and increases the export prices of REEs.

Insights into A3(2) growth and pigment formation with high-throughput online monitoring.

species are intensively studied for their ability to produce a variety of natural products. However, conditions influencing and leading to product formation are often not completely recognized. Therefore, in this study, high-throughput online monitoring is presented as a powerful tool to gain in-depth understanding of the cultivation of the model organism A3(2).

Needle to needle robot-assisted manufacture of cell therapy products.

Advanced therapeutic medicinal products (ATMPs) have emerged as novel therapies for untreatable diseases, generating the need for large volumes of high-quality, clinically-compliant GMP cells to replace costly, high-risk and limited scale manual expansion processes. We present the design of a fully automated, robot-assisted platform incorporating the use of multiliter stirred tank bioreactors for scalable production of adherent human stem cells. The design addresses a needle-to-needle closed process incorporating automated bone marrow collection, cell isolation, expansion, and collection into cryovials for patient delivery.

Pulmonary Vascular Research Institute GoDeep: A meta-registry merging deep phenotyping datafrom international PH reference centers.

The Pulmonary Vascular Research Institute GoDeep meta-registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta-registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714).

Assessment of microbial activity by CO production during heating oil storage.

Microbial activity is the driving force of the carbon cycle, including the digestion of biomass in the soil, oceans, and oil deposits. This natural diversity of microbial carbon sources poses challenges for humans. Contamination monitoring can be difficult in oil tanks and similar settings.

Amyloidogenicity assessment of transthyretin gene variants.

Objective: Hereditary transthyretin-mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin-gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non-pathogenic is highly desirable but hampered by low frequency and penetrance.

Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function.

All irreversible Bruton tyrosine kinase (Btk) inhibitors including ibrutinib and acalabrutinib induce platelet dysfunction and increased bleeding risk. New reversible Btk inhibitors were developed, like MK-1026. The mechanism underlying increased bleeding tendency with Btk inhibitors remains unclear.