Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (&gt;20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.</p

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells

Mechanical loading and inflammation interact to cause degenerative disc disease and low back pain (LBP). However, the underlying mechanosensing and mechanotransductive pathways are poorly understood. This results in untargeted pharmacological treatments that do not take the mechanical aspect of LBP into account. We investigated the role of the mechanosensitive ion channel TRPV4 in stretch-induced inflammation in human annulus fibrosus (AF) cells. The cells were cyclically stretched to 20% hyperphysiological strain. TRPV4 was either inhibited with the selective TRPV4 antagonist GSK2193874 or knocked out (KO) via CRISPR-Cas9 gene editing. The gene expression, inflammatory mediator release and MAPK pathway activation were analyzed. Hyperphysiological cyclic stretching significantly increased the IL6, IL8, and COX2 mRNA, PGE2 release, and activated p38 MAPK. The TRPV4 pharmacological inhibition significantly attenuated these effects. TRPV4 KO further prevented the stretch-induced upregulation of IL8 mRNA and reduced IL6 and IL8 release, thus supporting the inhibition data. We provide novel evidence that TRPV4 transduces hyperphysiological mechanical signals into inflammatory responses in human AF cells, possibly via p38. Additionally, we show for the first time the successful gene editing of human AF cells via CRISPR-Cas9. The pharmacological inhibition or CRISPR-based targeting of TRPV4 may constitute a potential therapeutic strategy to tackle discogenic LBP in patients with AF injury

Visualizing reaction fronts and transport limitations in solid-state Li-S batteries via operando neutron imaging

The exploitation of high-capacity conversion-type materials such as sulfur in solid-state secondary batteries is a dream combination for achieving improved battery safety and high energy density in the push towards a sustainable future. Yet, the exact rate-limiting step, bottlenecking further development of solid-state lithium-sulfur batteries, has not been determined. Here, we directly visualize the spatial distribution of lithium via neutron imaging during operation and show that sluggish macroscopic ion transport within the composite cathode is rate-limiting. Observing a reaction front propagating from the separator side towards the current collector confirms detrimental influences of a low effective ionic conductivity. Furthermore, irreversibly concentrated lithium in the vicinity of the current collector, revealed via state-of-charge-dependent tomography, highlights a hitherto-overlooked loss mechanism triggered by sluggish effective ionic transport within a composite cathode. This discovery will be a cornerstone for future research on solid-state batteries, irrespective of the type of active material

Interfacial Processes and Influence of Composite Cathode Microstructure Controlling the Performance of All Solid State Lithium Batteries

All solid state lithium ion batteries have the potential to become an important class of next generation electrochemical energy storage devices. However, for achieving competitive performance, a better understanding of the interfacial processes at the electrodes is necessary for optimized electrode compositions to be developed. In this work, the interfacial processes between the solid electrolyte Li10GeP2S12 and the electrode materials In InLi and LixCoO2 are monitored using impedance spectroscopy and galvanostatic cycling, showing a large resistance contribution and kinetic hindrance at the metal anode. The effect of different fractions of the solid electrolyte in the composite cathodes on the rate performance is tested. The results demonstrate the necessity of a carefully designed composite microstructure depending on the desired applications of an all solid state battery. While a relatively low mass fraction of solid electrolyte is sufficient for high energy density, a higher fraction of solid electrolyte is required for high power density