Methodological Insights on Biomarker-Based Patient Selection: A Review of Scientific Advice Procedures at the European Medicines Agency.

Biomarkers play a pivotal role in the selection and enrollment of trial participants. Particularly, predictive biomarkers help tailor medical care to individual patients; however, also prognostic biomarkers require consideration at the design stage. At the time of initiating a clinical trial, there may be uncertainty about whether a biomarker is predictive or prognostic, and the trial design may need to account for this.

Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.

Naturally russeted and wound russeted skins of mango (cv. 'Apple') show no differences in anatomy, chemical composition or gene expression.

The mango cultivar 'Apple' is commercially important in Kenya but highly susceptible to russeting. Russeting refers to an area of fruit skin where the primary (epidermal) surface has been replaced by a secondary (peridermal) surface. The objective was to establish histologies, gene expressions and chemical compositions of a natural periderm, a wound-induced periderm and of cuticles of an un-russeted skin.

AN IMMUNOHISTOCHEMICAL AND MOLECULAR GENETIC STUDY OF 60 COLORECTAL CARCINOMA BRAIN METASTASES IN PURSUIT OF PREDICTIVE BIOMARKERS FOR CANCER THERAPY.

Colorectal carcinoma brain metastases (n=60) were studied using next-generation sequencing and immunohistochemistry. RAS and BRAF mutations were detected in 58.2% and 7.

Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy.

Regulatory workshop on standardisation of clinical procedures, endpoints and data robustness of human challenge studies - A stakeholder meeting report.

Inno4Vac, a public-private partnership funded by the IMI2/EU/EFPIA Joint Undertaking (IMI2 JU), brings together academic institutions, SMEs, and pharmaceutical companies to accelerate and de-risk vaccine development. The project has made significant strides in the selection and production of challenge agents for influenza, respiratory syncytial virus (RSV), and toxigenic Clostridioides difficile for controlled human infection model studies (CHIMs). A regulatory workshop held on March 20, 2024, addressed the standardisation of clinical procedures, ethical considerations, endpoints, and data integrity, highlighting the ongoing initiatives related to these CHIMs.

Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation.

Feasibility of very low iodine dose aortoiliac CT angiography using dual-source photon-counting detector CT.

Purpose: To evaluate the feasibility of aortoiliac CT-Angiography (CTA) using dual-source photon-counting detector (PCD)-CT with minimal iodine dose.

Methods: This IRB-approved, single-center prospective study enrolled patients with indications for aortoiliac CTA from December 2022 to March 2023. All scans were performed using a first-generation dual-source PCD-CT.

Prediction of microbial crude protein flow from the rumen of dairy cattle by means of dietary characteristics - a meta-analysis.

Protein supply to ruminants relies mainly on the flow of microbial crude protein (MCP) from the rumen, which is commonly assumed to primarily depend on energy supply. This study evaluated this assumption with recent data and tested if ruminally fermented organic matter (FOM) was a better predictor of MCP flow than total-tract digestible organic matter (DOM) and if more variables could improve the prediction of MCP flow. A previously published data set was extended by additional studies resulting in a data set of 139 studies including 407 treatment means, typical to Central European rations.

A highly magnetized long-period radio transient exhibiting unusual emission features.

Long-period radio transients are a new class of astrophysical objects that exhibit periodic radio emission on timescales of tens of minutes. Their true nature remains unknown; possibilities include magnetic white dwarfs, binary systems, or long-period magnetars; the latter class is predicted to produce fast radio bursts (FRBs). Using the MeerKAT radio telescope, we conducted follow-up observations of the long-period radio transient GPM J1839-10.

Rationalizing Predictions of Isoform-Selective Phosphoinositide 3-Kinase Inhibitors Using MolAnchor Analysis.

Explaining the predictions of machine learning models is of critical importance for integrating predictive modeling in drug discovery projects. We have generated a test system for predicting isoform selectivity of phosphoinositide 3-kinase (PI3K) inhibitors and systematically analyzed correct predictions of selective inhibitors using a new methodology termed MolAnchor, which is based on the "anchors" concept from explainable artificial intelligence. The approach is designed to generate chemically intuitive explanations of compound predictions.

Illuminating the dark mess of fibers: Application of circular cross polarized light in unravelling the bone tissue structure of the dermal pectoral girdle of Metoposaurus krasiejowensis.

Current understanding of the histology of the dermoskeleton of tetrapods comes from fossilized and recent remains of skulls, osteoderms, carapace, plastron and other postcranial material which were always investigated using linear cross polarized light (LCPL) microscopy. The pectoral girdle of vast majority of non-amniote tetrapods, including temnospondyls evolved large ventrally located dermal bones- the interclavicle and a pair of clavicles. Despite that, there is a lack of information about the bone tissue structure from these postcranial dermal bones.

Revision of the millipede family Dalodesmidae in Madagascar, with descriptions of two new Malagasy species of Cook, 1896 (Diplopoda, Polydesmida).

The family Dalodesmidae Cook, 1896 in the fauna of Madagascar is reviewed and shown to presently encompass eight species in three genera: Cook, 1896 (six species), Brölemann, 1916 (one species), and de Saussure & Zehntner, 1897 (one species). These genera are diagnosed, and their respective species keyed, all being endemic to Madagascar proper and/or the immediately adjacent islets of Nosy Be and/or Nosy Sakatia. currently contains six species, including two new, all supplied either with brief descriptive notes and available iconography or extensive descriptions and new illustrations, as follows: (Brandt, 1841), from an unspecified locality in Madagascar, now redescribed from a male specimen from Makira, northeastern Madagascar; (Attems, 1898), from Nosy Be Isle; Hoffman, 1974, from Ambohimitombo, central Madagascar; Cook, 1896 (= (de Saussure & Zehntner, 1897), ), originally described from an unspecified locality in central Madagascar, with a male type and additional males identified as recorded from the Andasibe National Park (= Périnet) in east-central Madagascar.

Idecabtagene vicleucel or ciltacabtagene autoleucel for relapsed or refractory multiple myeloma: An international multicenter study.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel ( = 162) versus cilta-cel ( = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS).

Fatty-acid amide hydrolase inhibition mitigates Alzheimer's disease progression in mouse models of amyloidosis.

The endocannabinoid N-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer's disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis (APP/PS1 and Tg2576). Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice.

Effects of Webcam Access to Preterm Infants in NICUs on Parental Psychological Strain.

Aim: To investigate whether webcam access for parents of infants in neonatal intensive care units influences parental postpartum depression and stress experiences.

Methods: Parents whose infants had a birth weight below 1500 g and who were admitted to one of the four participating tertiary care hospitals were eligible to participate in the study. The study followed the structure of a multi-centre cross-over pragmatic randomised controlled trial.

German evidence- and consensus-based guideline on the management of penile urethritis.

Urethritis is a common condition predominantly caused by sexually transmitted pathogens such as Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium. It is not possible to differentiate with certainty between pathogens on the basis of clinical characteristics alone. However, empirical antibiotic therapy is often initiated in clinical practice.

Huge extrahepatic gallstone on percutaneous transhepatic biliary drainage tip-a pediatric case report.

Biliary strictures, which are common in the first year after pediatric liver transplantation, are diagnosed and managed with percutaneous transhepatic cholangiography. In children undergoing percutaneous transhepatic cholangiography, early cholangitis is the most common complication while typical catheter-related complications are obstruction, dislodgement, kinking, or fracture. This case report discusses the unique presentation and management of a 5-year-old girl with an incidental percutaneous transhepatic biliary drainage-associated extrahepatic gallstone formation following treatment of biliary stricture after pediatric liver transplantation.

Resetting of the Human Circadian Melatonin Rhythm by Ambient Hypoxia.

Circadian clocks in the body drive daily cycles in physiology and behavior. A master clock in the brain maintains synchrony with the environmental day-night cycle and uses internal signals to keep clocks in other tissues aligned. Work in cell cultures uncovered cyclic changes in tissue oxygenation that may serve to reset and synchronize circadian clocks.

Psychological safety, Job satisfaction, and the Intention to Leave among German early-career physicians.

Background: Healthcare systems worldwide experience shortages of healthcare professionals. Retention of physicians is becoming an increasing problem. The psychological safety among physicians affects not only performance, but also their emotional well-being and job satisfaction.

Removal of dissolved organic carbon in the West Pacific hadal zones.

The deep oceans are environments of complex carbon dynamics that have the potential to significantly impact the global carbon cycle. However, the role of hadal zones, particularly hadal trenches (water depth > 6 km), in the oceanic dissolved organic carbon (DOC) cycle is not thoroughly investigated. Here we report distinct DOC signatures in the Japan Trench bottom water.

Borderline Findings in -(2-[F]-Fluoroethyl)-l-Tyrosine PET of Patients with Suspected Glioma Relapse: Role in Clinical Practice.

One of the most common clinical indications for amino acid PET using the tracer -(2-[F]-fluoroethyl)-l-tyrosine (F-FET) is the differentiation of tumor relapse from treatment-related changes in patients with gliomas. A subset of patients may present with an uptake of F-FET close to recommended threshold values. The goal of this study was to investigate the frequency of borderline cases and the role of quantitative F-FET PET parameters in this situation.

Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Typhimurium (.