A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).

Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations.

Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity.

Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors.

Objectives: Resistance to MET inhibition occurs inevitably in MET-dependent non-small cell lung cancer and the underlying mechanisms are insufficiently understood. We describe resistance mechanisms in patients with MET exon 14 skipping mutation (METΔ), MET amplification, and MET fusion and report treatment outcomes after switching therapy from type I to type II MET inhibitors.

Materials And Methods: Pre- and post-treatment biopsies were analysed by NGS (next generation sequencing), digital droplet PCR (polymerase chain reaction), and FISH (fluorescense in situ hybridization).

Liver cirrhosis in children - the role of imaging in the diagnostic pathway.

Liver cirrhosis in children is a rare disease with multifactorial causes that are distinct from those in adults. Underlying reasons include cholestatic, viral, autoimmune, hereditary, metabolic and cardiac disorders. Early detection of fibrosis is important as clinical stabilization or even reversal of fibrosis can be achieved in some disorders with adequate treatment.

[Transient Ischemia of One Leg in a Very Low Birthweight Infant].

Ischemias in the extremities are rather rare in the neonatal period. Both intrauterine and postnatal factors can cause ischemias. We present the diagnostic procedure and the course in a female very low birthweight (VLBW) infant with transient ischemia in the lower extremity.

Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder.

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype.

Compressed SENSE in Pediatric Brain Tumor MR Imaging : Assessment of Image Quality, Examination Time and Energy Release.

Purpose: To compare the image quality, examination time, and total energy release of a standardized pediatric brain tumor magnetic resonance imaging (MRI) protocol performed with and without compressed sensitivity encoding (C-SENSE). Recently introduced as an acceleration technique in MRI, we hypothesized that C‑SENSE would improve image quality, reduce the examination time and radiofrequency-induced energy release compared with conventional examination in a pediatric brain tumor protocol.

Methods: This retrospective study included 22 patients aged 2.

The Impact of Unilateral Y-radioembolization on Functional Changes in the Contralateral Hepatic Lobe: The Prospective, Open-label RadioEmbolization, Volumetry, and Liver FuncTion Measurements (REVoluTion) Study.

Objectives: To investigate how metabolic function of the contralateral liver lobe is affected by unilateral radioembolization (RE), and to compare the changes in volume and metabolic function.

Background: Unilateral RE induces contralateral liver hypertrophy, but it is unknown if metabolic liver function improves in line with volume increases.

Methods: This prospective open-label, nonrandomized, therapy-optimizing study included all consecutive patients undergoing right-sided or sequential Y-RE for liver malignancies without underlying liver disease or biliary obstruction at a single center in Germany.

Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM.

Fungi attacking historic wood of Fort Conger and the Peary Huts in the High Arctic.

Historic wooden structures in Polar Regions are being adversely affected by decay fungi and a warming climate will likely accelerate degradation. Fort Conger and the Peary Huts at Lady Franklin Bay in northern Ellesmere Island are important international heritage sites associated with early exploration in the High Arctic. Fort Conger, built by Adolphus Greely and expedition members during the First International Polar Year in 1881, was dismantled and used by Robert Peary and his expedition crew in the early 1900's to build several smaller shelters.

A 3D Deep Neural Network for Liver Volumetry in 3T Contrast-Enhanced MRI.

Purpose:  To create a fully automated, reliable, and fast segmentation tool for Gd-EOB-DTPA-enhanced MRI scans using deep learning.

Materials And Methods:  Datasets of Gd-EOB-DTPA-enhanced liver MR images of 100 patients were assembled. Ground truth segmentation of the hepatobiliary phase images was performed manually.

Isolation and Culture of Oculomotor, Trochlear, and Spinal Motor Neurons from Prenatal Islmn:GFP Transgenic Mice.

Oculomotor neurons (CN3s) and trochlear neurons (CN4s) exhibit remarkable resistance to degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS) when compared to spinal motor neurons (SMNs). The ability to isolate and culture primary mouse CN3s, CN4s, and SMNs would provide an approach to study mechanisms underlying this selective vulnerability. To date, most protocols use heterogeneous cell cultures, which can confound the interpretation of experimental outcomes.

MAGEL2-related disorders: A study and case series.

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them.

Phenotype delineation of ZNF462 related syndrome.

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462.

Abnormal Biodistribution on Tc-Red Blood Cell-Labeled Multigated Acquisition in the Presence of Suspected Cold Agglutinin Disease.

A Tc-red blood cell (RBC)-labeled multigated acquisition is a procedure in which the patient's RBCs are radiolabeled and imaged with electrocardiography-gated cardiac scintigraphy to assess the heart's pumping efficiency. Cold agglutinin disease, or cold antibody autoimmune hemolytic anemia, is a rare form of autoimmune hemolytic anemia in which the body's immune system attacks and destroys its own RBCs. This case addresses an altered biodistribution pattern of radiolabeled RBCs in the presence of suspected cold agglutinin disease observed during a multigated acquisition.

Washing or filtering of blood products does not improve outcome in a rat model of trauma and multiple transfusion.

Background: Transfusion is associated with organ failure and nosocomial infection in trauma patients, which may be mediated by soluble bioactive substances in blood products, including extracellular vesicles (EVs). We hypothesize that removing EVs, by washing or filtering of blood products, reduces organ failure and improves host immune response.

Materials And Methods: Blood products were prepared from syngeneic rat blood.