Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.

Background: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program.

Assessing the Impact of COVID-19 on Amateur Runners' Performance: An Analysis through Monitoring Devices.

This retrospective study aimed to analyze the return to running of non-professional runners after experiencing asymptomatic or mild COVID-19. Participants aged 18-55 years who maintained a training load of ≥10 km/week for at least three months prior to diagnosis and utilized Garmin/Polar apps were included. From these devices, parameters such as pace, distance, total running time, cadence, and heart rate were collected at three intervals: pre-COVID, immediately post-COVID, and three months after diagnosis.

variants in the non-coding spliceosomal snRNA gene are a frequent cause of syndromic neurodevelopmental disorders.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA as a novel syndromic NDD gene.

MOGS-CDG: Quantitative analysis of the diagnostic Glc Man tetrasaccharide and clinical spectrum of six new cases.

Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogeneous subgroup of inherited metabolic disorders. Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS-CDG can be challenging.

Comprehensive Multidimensional Liquid Chromatography-Mass Spectrometry for the Characterization of Charge Variants of a Bispecific Antibody.

Identification and further characterization of antibody charge variants is a crucial step during biopharmaceutical drug development, particularly with regard to the increasing complexity of novel antibody formats. As a standard analytical approach, manual offline fractionation of charge variants by cation-exchange chromatography followed by comprehensive analytical testing is applied. These conventional workflows are time-consuming and labor-intensive and overall reach their limits in terms of chromatographic separation of enhanced structural heterogeneities raised from new antibody formats.

Constraining neutron-star matter with microscopic and macroscopic collisions.

Interpreting high-energy, astrophysical phenomena, such as supernova explosions or neutron-star collisions, requires a robust understanding of matter at supranuclear densities. However, our knowledge about dense matter explored in the cores of neutron stars remains limited. Fortunately, dense matter is not probed only in astrophysical observations, but also in terrestrial heavy-ion collision experiments.

Contraception use and knowledge related to pregnancy in diabetic women.

Background: Diabetes mellitus prevalence is increasing among women of child-bearing age. Diabetic pregnancy is associated with major maternal and fetal risks, and these can be reduced by preconception care. Pregnancy can be planned using appropriate effective contraception.

Biallelic Variants in Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (; previously called ) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in identified by genome sequencing in a patient with suspected mitochondrial disease.

Quantifying methionine sulfoxide in therapeutic protein formulation excipients as sensitive oxidation marker.

Methionine is a common excipient used in therapeutic protein liquid formulations as stabilizer and antioxidant. The oxidation of methionine to methionine sulfoxide can be regarded as a sensitive marker of oxidative stress for drug product storage conditions. In this study, a sensitive HPLC method for the quantification of methionine sulfoxide in formulated protein product was developed and qualified according to regulatory requirements using a SIELC® Primesep 100 column with UV detection.

Premorbid aspirin use is not associated with lower mortality in older inpatients with SARS-CoV-2 pneumonia.

Platelet aggregation has been associated with COVID-19 pathogenesis. In older patients hospitalized for SARS-CoV-2 pneumonia, we aimed to investigate the association between aspirin use before admission and the risk of in-hospital all-cause mortality. We performed a retrospective international cohort study in five COVID-19 geriatric units in France and Switzerland.

Extended disorder at the cell surface: The conformational landscape of the ectodomains of syndecans.

Syndecans are membrane proteoglycans regulating extracellular matrix assembly, cell adhesion and signaling. Their ectodomains can be shed from the cell surface, and act as paracrine and autocrine effectors or as competitors of full-length syndecans. We report the first biophysical characterization of the recombinant ectodomains of the four human syndecans using biophysical techniques, and show that they behave like flexible random-coil intrinsically disordered proteins, and adopt several conformation ensembles in solution.

Association Between Early Antibiotic Therapy and In-Hospital Mortality Among Older Patients With SARS-CoV-2 Pneumonia.

Background: It is uncertain whether antibiotic therapy should be started in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. We aimed to investigate the association between early antibiotic therapy and the risk of in-hospital mortality in older patients.

Methods: We performed a retrospective international cohort study (ANTIBIOVID) in 5 coronavirus disease 2019 geriatric units in France and Switzerland.

Exploring Conformational Landscapes Using Trap and Release Tandem Ion Mobility Spectrometry.

The dynamics and thermodynamics of structural changes in isolated glu-fibrinopeptide B (GluFib) were investigated by tandem ion mobility spectrometry (IMS). Doubly protonated GluFib ions were first selected by IMS and then stored for a controlled duration in a thermalized ion trap. Temperature-induced conformational changes were finally monitored by IMS as a function of trapping time.

A 3D Human Liver Model of Nonalcoholic Steatohepatitis.

To better understand nonalcoholic steatohepatitis (NASH) disease progression and to evaluate drug targets and compound activity, we undertook the development of an 3D model to mimic liver architecture and the NASH environment. We have developed an preclinical 3D NASH model by coculturing primary human hepatocytes, human stellate cells, liver endothelial cells and Kupffer cells embedded in a hydrogel of rat collagen on a 96-well plate. A NASH-like environment was induced by addition of medium containing free fatty acids and tumor necrosis factor-α.

Evolution of macroprolactinomas during pregnancy: A cohort study of 85 pregnancies.

Objective: Pregnancy in patients with macroprolactinomas has been associated with a higher risk of pituitary tumour growth. However, the incidence and risk factors remain unclear. We aimed to evaluate the evolution of macroprolactinomas during pregnancy and to identify potential risk factors.

Compound heterozygous Pkd1l1 variants in a family with two fetuses affected by heterotaxy and complex Chd.

Heterotaxy and congenital heart defects associated with pathogenic variants in the PKD1L1 gene (autosomal visceral heterotaxy type 8, MIM 617205) has been reported in only four individuals from three unrelated families. We describe a further family with two affected fetuses and novel compound heterozygous pathogenic variants in PKD1L1. PKD1L1 has been shown to function in the ciliary sensation of nodal flow at the embryo primitive node and in the restriction of NODAL signalling to the left lateral.

Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome.

Study Question: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)?

Summary Answer: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS.

What Is Known Already: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS.

Elevated Serum Tissue Transglutaminase Antibodies in Children With Eosinophilic Esophagitis.

Objectives: This study compared the clinical and histopathological characteristics of children with eosinophilic esophagitis (EoE) and elevated anti-transglutaminase (TTG Ab) with those with EoE and normal TTG Ab titres.

Methods: Single-center chart and blinded histopathological review of patients diagnosed with EoE for a 4-year period, who had esophageal and duodenal biopsies taken at time of endoscopy, and TTG Ab measured within 6 months of biopsy. Patients with histology-proven CD were excluded.

Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature.

Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11-q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11-q13 imprinting defect on the maternal allele.

TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis.

Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels.

Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency.

Context: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder.