Biomarkers in congenital adrenal hyperplasia

Monitoring of hormone replacement therapy represents a major challenge in the management of congenital adrenal hyperplasia (CAH). In the absence of clear guidance and standardised monitoring strategies, there is no consensus among clinicians regarding the relevance of various biochemical markers used in practice, leading to wide variability in their application and interpretation. In this review, we summarise the published evidence on biochemical monitoring of CAH. We discuss temporal variations of the most commonly measured biomarkers throughout the day, the interrelationship between different biomarkers, as well as their relationship with different glucocorticoid and mineralocorticoid treatment regimens and clinical outcomes. Our review highlights significant heterogeneity across studies in both aims and methodology. However, we identified key messages for the management of patients with CAH. The approach to hormone replacement therapy should be individualised, based on the individual hormonal profile throughout the day in relation to medication. There are limitations to using 17-hydroxyprogesterone, androstenedione and testosterone, and the role of additional biomarkers such 11-oxygenated androgens which are more disease specific should be further established. Noninvasive monitoring via salivary and urinary steroid measurements is becoming increasingly available and should be considered, especially in the management of children with CAH. Additionally, this review indicates the need for large scale longitudinal studies analysing the interrelation between different monitoring strategies used in clinical practice and health outcomes in children and adults with CAH

LEAP2 changes with body mass and food intake in humans and mice

Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state-dependence of ghrelin’s metabolic actions. Here, we hypothesized that LEAP2 (liver enriched antimicrobial peptide-2), a recently-characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and post-prandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increase with body mass and blood glucose, and decrease with fasting, RYGB, and in post-prandial states following VSG. These changes were mostly opposite to those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2:acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose

Design, Commissioning and Performance of the PIBETA Detector at PSI

We describe the design, construction and performance of the PIBETA detector built for the precise measurement of the branching ratio of pion beta decay, pi+ -> pi0 e+ nu, at the Paul Scherrer Institute. The central part of the detector is a 240-module spherical pure CsI calorimeter covering 3*pi sr solid angle. The calorimeter is supplemented with an active collimator/beam degrader system, an active segmented plastic target, a pair of low-mass cylindrical wire chambers and a 20-element cylindrical plastic scintillator hodoscope. The whole detector system is housed inside a temperature-controlled lead brick enclosure which in turn is lined with cosmic muon plastic veto counters. Commissioning and calibration data were taken during two three-month beam periods in 1999/2000 with pi+ stopping rates between 1.3*E3 pi+/s and 1.3*E6 pi+/s. We examine the timing, energy and angular detector resolution for photons, positrons and protons in the energy range of 5-150 MeV, as well as the response of the detector to cosmic muons. We illustrate the detector signatures for the assorted rare pion and muon decays and their associated backgrounds.Comment: 117 pages, 48 Postscript figures, 5 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth.

Ultrahigh-Q Resonance in Bound States in the Continuum–Enabled Plasmonic Terahertz Metasurface

The study of optical resonators is of significant importance in terms of their ability to confine light in optical devices. A major drawback of optical resonators is the phenomenon of light emission due to their limited capacity for light confinement. Bound states in the continuum are gaining significant attention in the realization of optical devices due to their unique ability for reducing light scattering via interference mechanisms. This process can potentially suppress scattering, leading to improved optical performance. Using this concept, a metasurface having two elliptical silicon (Si) resonators nonidentically angled to create an outof-plane asymmetry is studied. Various parameters are optimized by employing a genetic algorithm (GA) to subsequently achieve a high-Q factor at terahertz frequencies. Herein, the device is fabricated using a novel method, and a thick high-index resonator is achieved. Terahertz measurements are carried out to validate the results. It is indicated in the experimental results that plasmons appear at the top surface of the metasurface and create strong sharp resonances that are sensitive to the external environment. Owing to strong field confinement ability, and high-Q factor, the metasurface is sensitive to its surrounding environment and can be essentially employed in terahertz sensing applications.Md Saiful Islam, Aditi Upadhyay, Rajour Tanyi Ako, Nicholas P. Lawrence, Jakeya Sultana, Abhishek Ranjan, Brian Wai-Him Ng, Nelson Tansu, Madhu Bhaskaran, Sharath Sriram, and Derek Abbot

Quantifying stratospheric biases and identifying their potential sources in subseasonal forecast systems

The stratosphere can be a source of predictability for surface weather on timescales of several weeks to months. However, the potential predictive skill gained from stratospheric variability can be limited by biases in the representation of stratospheric processes and the coupling of the stratosphere with surface climate in forecast systems. This study provides a first systematic identification of model biases in the stratosphere across a wide range of subseasonal forecast systems. It is found that many of the forecast systems considered exhibit warm global-mean temperature biases from the lower to middle stratosphere, too strong/cold wintertime polar vortices, and too cold extratropical upper-troposphere/lowerstratosphere regions. Furthermore, tropical stratospheric anomalies associated with the Quasi-Biennial Oscillation tend to decay toward each system¿s climatology with lead time. In the Northern Hemisphere (NH), most systems do not capture the seasonal cycle of extreme-vortex-event probabilities, with an underestimation of sudden stratospheric warming events and an overestimation of strong vortex events in January. In the Southern Hemisphere (SH), springtime interannual variability in the polar vortex is generally underestimated, but the timing of the final breakdown of the polar vortex often happens too early in many of the prediction systems. These stratospheric biases tend to be considerably worse in systems with lower model lid heights. In both hemispheres, most systems with low-top atmospheric models also consistently underestimate the upward wave driving that affects the strength of the stratospheric polar vortex. We expect that the biases identified here will help guide model development for subseasonal-to-seasonal forecast systems and further our understanding of the role of the stratosphere in predictive skill in the troposphere.This work uses S2S Project data. S2S is a joint initiative of the World Weather Research Programme (WWRP) and the World Climate Research Programme (WCRP). This work was initiated by the Stratospheric Network for the Assessment of Predictability (SNAP), a joint activity of SPARC (WCRP) and the S2S Project (WWRP–WCRP). The work of Rachel W.-Y. Wu is funded through ETH grant ETH-05 19-1. Support from the Swiss National Science Foundation through projects PP00P2_170523 and PP00P2_198896 to Daniela I. V. Domeisen is gratefully acknowledged. Chaim I. Garfinkel and Chen Schwartz are supported by the ISF–NSFC joint research program (grant no. 3259/19). The work of Marisol Osman was supported by UBACyT20020170100428BA and PICT-2018-03046 projects. The work of Alvaro de la Cámara is funded by the Spanish Ministry of Science and Innovation through project PID2019-109107GB-I00. Blanca Ayarzagüena and Natalia Calvo acknowledge the support of the Spanish Ministry of Science and Innovation through the JeDiS (RTI2018-096402-B-I00) project. Froila M. Palmeiro and Javier García-Serrano have been partially supported by the Spanish ATLANTE project (PID2019-110234RB-C21) and Ramón y Cajal program (RYC-2016-21181), respectively. Neil P. Hindley and Corwin J. Wright are supported by UK Natural Environment Research Council (NERC), grant number NE/S00985X/1. Corwin J. Wright is also supported by a Royal Society University Research Fellowship UF160545. Seok-Woo Son and Hera Kim are supported by the Basic Science Research Program through the National Research Foundation of Korea (2017R1E1A1A01074889). This material is based upon work supported by the US Department of Energy, Office of Science, Office of Biological and Environmental Research (BER), Regional and Global Model Analysis (RGMA) component of the Earth and Environmental System Modeling program under award no. DE-SC0022070 and National Science Foundation (NSF) IA 1947282. This work was also supported by the National Center for Atmospheric Research (NCAR), which is a major facility sponsored by the NSF under cooperative agreement no. 1852977. Pu Lin is supported by award NA18OAR4320123 from the National Oceanic and Atmospheric Administration (NOAA), U.S. Department of Commerce. Zachary D. Lawrence was partially supported under NOAA award NA20NWS4680051; Zachary D. Lawrence and Judith Perlwitz also acknowledge support from US federally appropriated funds

Health status of children and young persons with congenital adrenal hyperplasia in the UK (CAH-UK): a cross-sectional multi-centre study

Objective There is limited knowledge on the onset of comorbidities in congenital adrenal hyperplasia (CAH) during childhood. We aimed to establish the health status of children with CAH in the UK. Design and methods This cross-sectional multicentre study involved 14 tertiary endocrine UK units, recruiting 101 patients aged 8–18 years with classic 21-hydroxylase deficiency and 83 controls. We analysed demographic, clinical and metabolic data, as well as psychological questionnaires (Strengths and Difficulties (SDQ), Paediatric Quality of Life (PedsQL)). Results Patient height SDS in relation to mid-parental height decreased with age, indicating the discrepancy between height achieved and genetic potential height. Bone age was advanced in 40.5% patients, with a mean difference from the chronological age of 1.8 (±2.3) years. Patients were more frequently overweight (27%) or obese (22%) compared to controls (10.8% and 10.8%, respectively, P < 0.001). No consistent relationship between glucocorticoid dose and anthropometric measurements or hormonal biomarkers was detected. A small number of patients had raised total cholesterol (3.0%), low HDL (3.0%), raised LDL (7.0%) and triglycerides (5.0%). SDQ scores were within the ‘high’ and ‘very high’ categories of concern for 16.3% of patients. ‘School functioning’ was the lowest PedsQL scoring dimension with a median (interquartile range) of 70 (55–80), followed by ‘emotional functioning’ with a median of 75 (65–85). Conclusions Our results show an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life. This highlights the urgent need to optimise management and monitoring strategies to improve long-term health outcomes

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types