Analysis of clinical benefit, harms, and cost-effectiveness of screening women for abdominal aortic aneurysm.

BACKGROUND: A third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study. METHODS: We developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs. FINDINGS: AAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000-87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500-71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life. INTERPRETATION: By UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options. FUNDING: UK National Institute for Health Research Health Technology Assessment programme

Discrete Event Simulation for Decision Modeling in Health Care: Lessons from Abdominal Aortic Aneurysm Screening.

Markov models are often used to evaluate the cost-effectiveness of new healthcare interventions but they are sometimes not flexible enough to allow accurate modeling or investigation of alternative scenarios and policies. A Markov model previously demonstrated that a one-off invitation to screening for abdominal aortic aneurysm (AAA) for men aged 65 y in the UK and subsequent follow-up of identified AAAs was likely to be highly cost-effective at thresholds commonly adopted in the UK (£20,000 to £30,000 per quality adjusted life-year). However, new evidence has emerged and the decision problem has evolved to include exploration of the circumstances under which AAA screening may be cost-effective, which the Markov model is not easily able to address. A new model to handle this more complex decision problem was needed, and the case of AAA screening thus provides an illustration of the relative merits of Markov models and discrete event simulation (DES) models. An individual-level DES model was built using the R programming language to reflect possible events and pathways of individuals invited to screening v. those not invited. The model was validated against key events and cost-effectiveness, as observed in a large, randomized trial. Different screening protocol scenarios were investigated to demonstrate the flexibility of the DES. The case of AAA screening highlights the benefits of DES, particularly in the context of screening studies

Effects of Varying the Three-Body Molecular Hydrogen Formation Rate in Primordial Star Formation

The transformation of atomic hydrogen to molecular hydrogen through three-body reactions is a crucial stage in the collapse of primordial, metal-free halos, where the first generation of stars (Population III stars) in the Universe are formed. However, in the published literature, the rate coefficient for this reaction is uncertain by nearly an order of magnitude. We report on the results of both adaptive mesh refinement (AMR) and smoothed particle hydrodynamics (SPH) simulations of the collapse of metal-free halos as a function of the value of this rate coefficient. For each simulation method, we have simulated a single halo three times, using three different values of the rate coefficient. We find that while variation between halo realizations may be greater than that caused by the three-body rate coefficient being used, both the accretion physics onto Population III protostars as well as the long-term stability of the disk and any potential fragmentation may depend strongly on this rate coefficient.Comment: 29 pages, 7 figures; Accepted for publication in The Astrophysical Journa

EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing: a NICE medical technology guidance

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article has been made available through the Brunel Open Access Publishing Fund.A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC’s findings, and the final NICE guidance issued.The Birmingham and Brunel Consortium is funded by NICE to act as an External Assessment Centre for the Medical Technologies Evaluation Programme

A Database of Alkaline-Earth-Coordinated Peptide Cross Sections: Insight into General Aspects of Structure

Abstract. A database of 1470 collision cross sections (666 doubly-and 804 triplycharged) of alkaline-earth-coordinated tryptic peptide ions [where the cation (M 2+ ) correspond to Mg 2+ , Ca 2+ , or Ba 2+ ] is presented. The utility of such an extensive set of measurements is illustrated by extraction of general properties of M 2+ -coordinated peptide structures. Specifically, we derive sets of intrinsic size parameters (ISPs) for individual amino acid residues for M 2+ -coordinated peptides. Comparison of these parameters with existing ISPs for protonated peptides suggests that M 2+ binding occurs primarily through interactions with specific polar aliphatic residues (Asp, Ser, and Thr) and the peptide backbone. A comparison of binding interactions for these alkaline-earth metals with interactions reported previously for alkali metals is provided. Finally, we describe a new analysis in which ISPs are used as probes for assessing peptide structure based on amino acid composition

Hierarchical patterning modes orchestrate hair follicle morphogenesis

Two theories address the origin of repeating patterns, such as hair follicles, limb digits, and intestinal villi, during development. The Turing reaction–diffusion system posits that interacting diffusible signals produced by static cells first define a prepattern that then induces cell rearrangements to produce an anatomical structure. The second theory, that of mesenchymal self-organisation, proposes that mobile cells can form periodic patterns of cell aggregates directly, without reference to any prepattern. Early hair follicle development is characterised by the rapid appearance of periodic arrangements of altered gene expression in the epidermis and prominent clustering of the adjacent dermal mesenchymal cells. We assess the contributions and interplay between reaction–diffusion and mesenchymal self-organisation processes in hair follicle patterning, identifying a network of fibroblast growth factor (FGF), wingless-related integration site (WNT), and bone morphogenetic protein (BMP) signalling interactions capable of spontaneously producing a periodic pattern. Using time-lapse imaging, we find that mesenchymal cell condensation at hair follicles is locally directed by an epidermal prepattern. However, imposing this prepattern’s condition of high FGF and low BMP activity across the entire skin reveals a latent dermal capacity to undergo spatially patterned self-organisation in the absence of epithelial direction. This mesenchymal self-organisation relies on restricted transforming growth factor (TGF) β signalling, which serves to drive chemotactic mesenchymal patterning when reaction–diffusion patterning is suppressed, but, in normal conditions, facilitates cell movement to locally prepatterned sources of FGF. This work illustrates a hierarchy of periodic patterning modes operating in organogenesis

Screening women aged 65 years or over for abdominal aortic aneurysm: a modelling study and health economic evaluation.

BACKGROUND: Abdominal aortic aneurysm (AAA) screening programmes have been established for men in the UK to reduce deaths from AAA rupture. Whether or not screening should be extended to women is uncertain. OBJECTIVE: To evaluate the cost-effectiveness of population screening for AAAs in women and compare a range of screening options. DESIGN: A discrete event simulation (DES) model was developed to provide a clinically realistic model of screening, surveillance, and elective and emergency AAA repair operations. Input parameters specifically for women were employed. The model was run for 10 million women, with parameter uncertainty addressed by probabilistic and deterministic sensitivity analyses. SETTING: Population screening in the UK. PARTICIPANTS: Women aged ≥ 65 years, followed up to the age of 95 years. INTERVENTIONS: Invitation to ultrasound screening, followed by surveillance for small AAAs and elective surgical repair for large AAAs. MAIN OUTCOME MEASURES: Number of operations undertaken, AAA-related mortality, quality-adjusted life-years (QALYs), NHS costs and cost-effectiveness with annual discounting. DATA SOURCES: AAA surveillance data, National Vascular Registry, Hospital Episode Statistics, trials of elective and emergency AAA surgery, and the NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP). REVIEW METHODS: Systematic reviews of AAA prevalence and, for elective operations, suitability for endovascular aneurysm repair, non-intervention rates, operative mortality and literature reviews for other parameters. RESULTS: The prevalence of AAAs (aortic diameter of ≥ 3.0 cm) was estimated as 0.43% in women aged 65 years and 1.15% at age 75 years. The corresponding attendance rates following invitation to screening were estimated as 73% and 62%, respectively. The base-case model adopted the same age at screening (65 years), definition of an AAA (diameter of ≥ 3.0 cm), surveillance intervals (1 year for AAAs with diameter of 3.0-4.4 cm, 3 months for AAAs with diameter of 4.5-5.4 cm) and AAA diameter for consideration of surgery (5.5 cm) as in NAAASP for men. Per woman invited to screening, the estimated gain in QALYs was 0.00110, and the incremental cost was £33.99. This gave an incremental cost-effectiveness ratio (ICER) of £31,000 per QALY gained. The corresponding incremental net monetary benefit at a threshold of £20,000 per QALY gained was -£12.03 (95% uncertainty interval -£27.88 to £22.12). Almost no sensitivity analyses brought the ICER below £20,000 per QALY gained; an exception was doubling the AAA prevalence to 0.86%, which resulted in an ICER of £13,000. Alternative screening options (increasing the screening age to 70 years, lowering the threshold for considering surgery to diameters of 5.0 cm or 4.5 cm, lowering the diameter defining an AAA in women to 2.5 cm and lengthening the surveillance intervals for the smallest AAAs) did not bring the ICER below £20,000 per QALY gained when considered either singly or in combination. LIMITATIONS: The model for women was not directly validated against empirical data. Some parameters were poorly estimated, potentially lacking relevance or unavailable for women. CONCLUSION: The accepted criteria for a population-based AAA screening programme in women are not currently met. FUTURE WORK: A large-scale study is needed of the exact aortic size distribution for women screened at relevant ages. The DES model can be adapted to evaluate screening options in men. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020444 and CRD42016043227. FUNDING: The National Institute for Health Research Health Technology Assessment programme

A new generation of magnetoencephalography: room temperature measurements using optically-pumped magnetometers

Advances in the field of quantum sensing mean that magnetic field sensors, operating at room temperature, are now able to achieve sensitivity similar to that of cryogenically cooled devices (SQUIDs). This means that room temperature magnetoencephalography (MEG), with a greatly increased flexibility of sensor placement can now be considered. Further, these new sensors can be placed directly on the scalp surface giving, theoretically, a large increase in the magnitude of the measured signal. Here, we present recordings made using a single optically-pumped magnetometer (OPM) in combination with a 3D-printed head-cast designed to accurately locate and orient the sensor relative to brain anatomy. Since our OPM is configured as a magnetometer it is highly sensitive to environmental interference. However, we show that this problem can be ameliorated via the use of simultaneous reference sensor recordings. Using median nerve stimulation, we show that the OPM can detect both evoked (phase-locked) and induced (non-phase-locked oscillatory) changes when placed over sensory cortex, with signals ~4 times larger than equivalent SQUID measurements. Using source modelling, we show that our system allows localisation of the evoked response to somatosensory cortex. Further, source-space modelling shows that, with 13 sequential OPM measurements, source-space signal-to-noise ratio (SNR) is comparable to that from a 271-channel SQUID system. Our results highlight the opportunity presented by OPMs to generate uncooled, potentially low-cost, high SNR MEG systems

The Birth of a Galaxy: Primordial Metal Enrichment and Stellar Populations

By definition, Population III stars are metal-free, and their protostellar collapse is driven by molecular hydrogen cooling in the gas-phase, leading to large characteristic masses. Population II stars with lower characteristic masses form when the star-forming gas reaches a critical metallicity of 10^{-6} - 10^{-3.5} Z_\odot. We present an adaptive mesh refinement radiation hydrodynamics simulation that follows the transition from Population III to II star formation. The maximum spatial resolution of 1 comoving parsec allows for individual molecular clouds to be well-resolved and their stellar associations to be studied in detail. We model stellar radiative feedback with adaptive ray tracing. A top-heavy initial mass function for the Population III stars is considered, resulting in a plausible distribution of pair-instability supernovae and associated metal enrichment. We find that the gas fraction recovers from 5 percent to nearly the cosmic fraction in halos with merger histories rich in halos above 10^7 solar masses. A single pair-instability supernova is sufficient to enrich the host halo to a metallicity floor of 10^{-3} Z_\odot and to transition to Population II star formation. This provides a natural explanation for the observed floor on damped Lyman alpha (DLA) systems metallicities reported in the literature, which is of this order. We find that stellar metallicities do not necessarily trace stellar ages, as mergers of halos with established stellar populations can create superpositions of t-Z evolutionary tracks. A bimodal metallicity distribution is created after a starburst occurs when the halo can cool efficiently through atomic line cooling.Comment: 11 pages, 7 figures; replaced with accepted version to ApJ; additional movies and images can be found at http://www.astro.princeton.edu/~jwise/research/GalaxyBirth.htm

A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO)

Rationale Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. Objectives To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. Measurements and methods This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5–<30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6 weeks of treatment with three nonadjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. Main results 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20 000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39 800/QALY. Conclusions Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective