Traceability and comparability through crosswalks with the NeuroMET Memory Metric.

Accurate assessment of memory ability for persons on the continuum of Alzheimer's disease (AD) is vital for early diagnosis, monitoring of disease progression and evaluation of new therapies. However, currently available neuropsychological tests suffer from a lack of standardization and metrological quality assurance. Improved metrics of memory can be created by carefully combining selected items from legacy short-term memory tests, whilst at the same time retaining validity, and reducing patient burden. In psychometrics, this is known as "crosswalks" to link items empirically. The aim of this paper is to link items from different types of memory tests. Memory test data were collected from the European EMPIR NeuroMET and the SmartAge studies recruited at Charité Hospital (Healthy controls n = 92; Subjective cognitive decline n = 160; Mild cognitive impairment n = 50; and AD n = 58; age range 55-87). A bank of items (n = 57) was developed based on legacy short-term memory items (i.e., Corsi Block Test, Digit Span Test, Rey's Auditory Verbal Learning Test, Word Learning Lists from the CERAD test battery and Mini Mental State Examination; MMSE). The NeuroMET Memory Metric (NMM) is a composite metric that comprises 57 dichotomous items (right/wrong). We previously reported on a preliminary item bank to assess memory based on immediate recall, and have now demonstrated direct comparability of measurements generated from the different legacy tests. We created crosswalks between the NMM and the legacy tests and between the NMM and the full MMSE using Rasch analysis (RUMM2030) and produced two conversion tables. Measurement uncertainties for estimates of person memory ability with the NMM across the full span were smaller than all individual legacy tests, which demonstrates the added value of the NMM. Comparisons with one (MMSE) of the legacy tests showed however higher measurement uncertainties of the NMM for people with a very low memory ability (raw score ≤ 19). The conversion tables developed through crosswalks in this paper provide clinicians and researchers with a practical tool to: (i) compensate for ordinality in raw scores, (ii) ensure traceability to make reliable and valid comparisons when measuring person ability, and (iii) enable comparability between test results from different legacy tests.

Theranostic SPECT reconstruction for improved resolution: application to radionuclide therapy dosimetry.

BACKGROUND: SPECT-derived dose estimates in tissues of diameter less than 3× system resolution are subject to significant losses due to the limited spatial resolution of the gamma camera. Incorporating resolution modelling (RM) into the SPECT reconstruction has been proposed as a possible solution; however, the images produced are prone to noise amplification and Gibbs artefacts. We propose a novel approach to SPECT reconstruction in a theranostic setting, which we term SPECTRE (single photon emission computed theranostic reconstruction); using a diagnostic PET image, with its superior resolution, to guide the SPECT reconstruction of the therapeutic equivalent. This report demonstrates a proof in principle of this approach. METHODS: We have employed the hybrid kernelised expectation maximisation (HKEM) algorithm implemented in STIR, with the aim of producing SPECT images with PET-equivalent resolution. We demonstrate its application in both a dual 68Ga/177Lu IEC phantom study and a clinical example using 64Cu/67Cu. RESULTS: SPECTRE is shown to produce images comparable in accuracy and recovery to PET with minimal introduction of artefacts and amplification of noise. CONCLUSION: The SPECTRE approach to image reconstruction shows improved quantitative accuracy with a reduction in noise amplification. SPECTRE shows great promise as a method of improving SPECT radioactivity concentrations, directly leading to more accurate dosimetry estimates in small structures and target lesions. Further investigation and optimisation of the algorithm parameters is needed before this reconstruction method can be utilised in a clinical setting.

Biomarker-guided trials: Challenges in practice.

Biomarker-guided trials have drawn considerable attention as they promise to lead to improvements in the benefit-risk ratio of treatments and enhanced opportunities for drug development. A variety of such designs have been proposed in the literature, many of which have been adopted in practice. Implementing such trial designs in practice can be challenging, and identifying those challenges was the main objective of a workshop organised by the MRC Hubs for Trials Methodology Research Network's Stratified Medicine Working Group in March 2017. Participants reflected on completed and ongoing biomarker-guided trials to identify the practical challenges encountered. Here, the key challenges identified during the workshop including those related to funding, ethical and regulatory issues, recruitment, monitoring of samples and laboratories, biomarker assessment, and data sharing and resources, are discussed. Despite the complexities often associated with biomarker-guided trials, the workshop concluded that they can play an important role in advancing the field of personalised medicine. Therefore, it is important that the practical challenges surrounding their implementation are acknowledged and addressed.

Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria.

BACKGROUND: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). OBJECTIVES: To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. METHODS: Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). RESULTS: Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1 ) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1 . CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.

Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry.

BACKGROUND: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited. AIMS: To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. METHODS: A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. RESULTS: Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 ≥ 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). CONCLUSION: Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.

Third-order thermo-mechanical properties for packs of Platonic solids using statistical micromechanics.

Obtaining an accurate higher order statistical description of heterogeneous materials and using this information to predict effective material behaviour with high fidelity has remained an outstanding problem for many years. In a recent letter, Gillman & Matous (2014 Phys. Lett. A 378, 3070-3073. ()) accurately evaluated the three-point microstructural parameter that arises in third-order theories and predicted with high accuracy the effective thermal conductivity of highly packed material systems. Expanding this work here, we predict for the first time effective thermo-mechanical properties of granular Platonic solid packs using third-order statistical micromechanics. Systems of impenetrable and penetrable spheres are considered to verify adaptive methods for computing n-point probability functions directly from three-dimensional microstructures, and excellent agreement is shown with simulation. Moreover, a significant shape effect is discovered for the effective thermal conductivity of highly packed composites, whereas a moderate shape effect is exhibited for the elastic constants.

Microstructure-statistics-property relations of anisotropic polydisperse particulate composites using tomography.

In this paper, a systematic method is presented for developing microstructure-statistics-property relations of anisotropic polydisperse particulate composites using microcomputer tomography (micro-CT). Micro-CT is used to obtain a detailed three-dimensional representation of polydisperse microstructures, and an image processing pipeline is developed for identifying particles. In this work, particles are modeled as idealized shapes in order to guide the image processing steps and to provide a description of the discrete micro-CT data set in continuous Euclidean space. n-point probability functions used to describe the morphology of mixtures are calculated directly from real microstructures. The statistical descriptors are employed in the Hashin-Shtrikman variational principle to compute overall anisotropic bounds and self-consistent estimates of the thermal-conductivity tensor. We make no assumptions of statistical isotropy nor ellipsoidal symmetry, and the statistical description is obtained directly from micro-CT data. Various mixtures consisting of polydisperse ellipsoidal and spherical particles are prepared and studied to show how the morphology impacts the overall anisotropic thermal-conductivity tensor.

What do asthmatics have to fear from food and additive allergy?

International studies report marked increases in the prevalence of food allergy, along with increases in hospital admissions and emergency presentations for severe allergic reactions due to foods. The prevalence of self-reported food allergy is common, but generally exceeds that which can be verified from challenge studies, although nut allergies appear to be an important exception to this rule. Studies examining food allergy deaths suggest that those who die of food allergy usually have co-existent asthma. Adolescents and young adults are at most risk, and adrenaline auto-injectors are sub-optimally used. Food chemical sensitivity is very commonly reported but not usually verified by challenge testing. However, the exception to this is sulphite sensitivity, which can elicit reproducible reactions in some. The increasing prevalence of severe food allergies and awareness of its risk in those with asthma demands an especially rigorous approach to the diagnosis and management of co-existent food allergy and asthma, especially in young people who appear to be at most risk from death from severe food allergy.

Sarcoidosis in Australia.

BACKGROUND: The incidence of sarcoidosis in Australia is unknown. The clinical features, diagnostic strategy and treatment of sarcoidosis in Australia have been poorly documented. METHODS: We analysed the medical records of 122 patients with sarcoidosis presenting to a respiratory service, between 1995 and 2005, which serves a regional southeastern Australian population of approximately 200,000. RESULTS: The incidence of sarcoidosis from 2000 to 2005 remained static and ranged from 4.4 to 6.3 patients per 100,000 population. The data showed that 55% were women and 28% were current smokers. Systems involved included lung parenchyma (66%), thoracic adenopathy (58%), skin (22%), ocular (18%), joint (11%), gastrointestinal tract (5%), central nervous system (3%) and hypercalcaemia (3%). Fifty-one per cent of patients had an increased serum angiotensin-converting enzyme level. The diagnosis was secured based on histological confirmation in 69%. Forty-three per cent of the patients were treated with oral corticosteroids and 10% with inhaled steroids. CONCLUSION: Sarcoidosis in Australia is a multi-system disease of unknown aetiology. This is the first reported incidence of sarcoidosis in Australia. The incidence is similar to another US-based epidemiological study of a predominately white population. The development of a larger multicentre database would assist in the identification, clinical description and treatment of sarcoidosis.