A novel instrument to measure differential ablation of meteorite samples and proxies: The Meteoric Ablation Simulator (MASI)

On entering the Earth’s atmosphere, micrometeoroids partially or completely ablate, leaving behind layers of metallic atoms and ions. The relative concentration of the various metal layers is not well explained by current models of ablation. Furthermore, estimates of the total flux of cosmic dust and meteoroids entering the Earth’s atmosphere vary over two orders of magnitude. To better constrain these estimates and to better model the metal layers in the mesosphere, an experimental meteoric Ablation Simulator (MASI) has been developed. Interplanetary Dust Particle (IDP) analogs are subjected to temperature profiles simulating realistic entry heating, to ascertain the differential ablation of relevant metal species. MASI is the first ablation experiment capable of simulating detailed mass, velocity, and entry angle-specific temperature profiles whilst simultaneously tracking the resulting gas-phase ablation products in a time resolved manner. This enables the determination of elemental atmospheric entry yields which consider the mass and size distribution of IDPs. The instrument has also enabled the first direct measurements of differential ablation in a laboratory setting

Standardising terminology and notation for the analysis of demographic processes in marked populations

The development of statistical methods for the analysis of demographic processes in marked animal populations has brought with it the challenges of communication between the disciplines of statistics, ecology, evolutionary biology and computer science. In order to aid communication and comprehension, we sought to root out a number of cases of ambiguity, redundancy and inaccuracy in notation and terminology that have developed in the literature. We invited all working in this field to submit topics for resolution and to express their own views. In the ensuing discussion forum it was then possible to establish a series of general principles which were, almost without exception, unanimously accepted. Here we set out the background to the areas of confusion, how these were debated and the conclusions which were reached in each case. We hope that the resulting guidelines will be widely adopted as standard terminology in publications and in software for the analysis of demographic processes in marked animal populationspostprin

Relationship between Tibial conformation, cage size and advancement achieved in TTA procedure

Previous studies have suggested that there is a theoretical discrepancy between the cage size and the resultant tibial tuberosity advancement, with the cage size consistently providing less tibial tuberosity advancement than predicted. The purpose of this study was to test and quantify this in clinical cases. The hypothesis was that the advancement of the tibial tuberosity as measured by the widening of the proximal tibia at the tibial tuberosity level after a standard TTA, will be less than the cage sized used, with no particular cage size providing a relative smaller or higher under-advancement, and that the conformation of the proximal tibia will have an influence on the amount of advancement achieved

A bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer

© 2014 Chan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear

Patient-reported outcome and experience measures in geriatric emergency medicine

This is the author accepted manuscript. The final version is available from Springer via the DOI in this recordOlder people with frailty and health crises have complex physical and social needs. Modern emergency care systems are fast-flowing, using protocols optimised for single-problem presentations. Systems must incorporate individualised care to best serve people with multiple problems. Healthcare quality is typically appraised with service metrics, such as department length of stay and mortality. Worldwide, patient-reported outcome measures (PROM) and patient-reported experience measures (PREM) are increasingly used in research, service development and performance evaluation, paving the ground for their use to support individual clinical decision-making. The PROMs and PREMs are person-centred metrics, which inform healthcare decisions at the individual level and which at the strategic level drive improvement through comparison of interprovider effectiveness. To date, there is no PROM or PREM specifically developed for older people with frailty and emergency care needs

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak

Brensocatib in non-cystic fibrosis bronchiectasis: ASPEN protocol and baseline characteristics

\ua9 The authors 2024.Introduction Brensocatib is an investigational, oral, reversible inhibitor of dipeptidyl peptidase-1 shown to prolong time to first exacerbation in adults with bronchiectasis. Outlined here are the clinical trial design, and baseline characteristics and treatment patterns of adult patients enrolled in the phase 3 ASPEN trial (NCT04594369). Methods The ASPEN trial is a global study enrolling patients with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections), diagnosis confirmed radiologically and ⩾2 exacerbations in the prior 12 months. It was designed to evaluate the impact of two brensocatib doses (10 mg and 25 mg) on exacerbation rate over a 52-week treatment period versus placebo. Comprehensive clinical data, including demographics, disease severity, lung function, Pseudomonas aeruginosa status and quality of life, were collected at baseline. Results 1682 adults from 35 countries were randomised from December 2020 to March 2023. Mean age was 61.3 years and 64.7% were female. ∼70% had moderate-to-severe Bronchiectasis Severity Index (BSI) scores, 29.3% had ⩾3 exacerbations in the prior 12 months and 35.7% were positive for P. aeruginosa. Mean BSI scores were highest in Australia/New Zealand (8.3) and lowest in Latin America (5.9). Overall, the most common aetiology was idiopathic (58.4%). In P. aeruginosa-positive versus P. aeruginosa-negative patients, lung function was lower, with greater long-term macrolide (21.5% versus 14.0%) and inhaled corticosteroid use (63.5% versus 53.9%). There was wide regional variation in long-term antibiotic use in patients with bronchiectasis and P. aeruginosa. Discussion ASPEN baseline characteristics and treatment profiles were representative of a global bronchiectasis population

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways