"Particle Informatics": Advancing Our Understanding of Particle Properties through Digital Design

We introduce a combination of existing and novel approaches to the assessment and prediction of particle properties intrinsic to the formulation and manufacture of pharmaceuticals. Naturally following on from established solid form informatics methods, we return to the drug lamotrigine, re-evaluating its context in the Cambridge Structural Database (CSD). We then apply predictive digital design tools built around the CSD-System suite of software, including Synthonic Engineering methods that focus on intermolecular interaction energies, to analyze and understand important particle properties and their effects on several key stages of pharmaceutical manufacturing. We present a new, robust workflow that brings these approaches together to build on the knowledge gained from each step and explain how this knowledge can be combined to provide resolutions at decision points encountered during formulation design and manufacturing processes

A modified echocardiographic protocol with intrinsic plausibility control to determine intraventricular asynchrony based on TDI and TSI

<p>Abstract</p> <p>Background</p> <p>Established methods to determine asynchrony suffer from high intra- and interobserver variability and failed to improve patient selection for cardiac resynchronization therapy (CRT). Thus, there is a need for easy and robust approaches to reliably assess cardiac asynchrony.</p> <p>Methods and Results</p> <p>We performed echocardiography in 100 healthy subjects and 33 patients with left bundle branch block (LBBB). To detect intraventricular asynchrony, we combined two established methods, i.e., tissue synchronization imaging (TSI) and tissue Doppler imaging (TDI). The time intervals from the onset of aortic valve opening (AVO) to the peak systolic velocity (S') were measured separately in six basal segments in the apical four-, two-, and three-chamber view. Color-coded TSI served as an intrinsic plausibility control and helped to identify the correct S' measuring point in the TDI curves. Next, we identified the segment with the shortest AVO-S' interval. Since this segment most likely represents vital and intact myocardium it served as a reference for other segments. Segments were considered asynchronous when the delay between the segment in question and the reference segment was above the upper limit of normal delays derived from the control population. Intra- and interobserver variability were 7.0% and 7.7%, respectively.</p> <p>Conclusion</p> <p>Our results suggest that combination of TDI and TSI with intrinsic plausibility control improves intra- and interobserver variability and allows easy and reliable assessment of cardiac asynchrony.</p

Multivariate relationships among morphology, fitness and motor coordination in prepubertal girls

Motor coordination and physical fitness are multidimensional concepts which cannot be reduced to a single variable. This study evaluated multivariate relationships among morphology, physical fitness and motor coordination in 74 pre-pubertal girls 8.0-8.9 years of age. Data included body dimensions, eight fitness items and four motor coordination tasks (KTK battery). Maturity status was estimated as percentage of predicted mature stature attained at the time of observation. Canonical correlation analysis was used to examine the relationships between multivariate domains. Significant pairs of linear functions between indicators of morphology and fitness (r(c) = 0.778, Wilks' Lambda = 0.175), and between fitness and motor coordination (r(c) = 0.765, Wilks' Lambda = 0.289) were identified. Girls who were lighter and had a lower waist-to-stature ratio and % fat mass attained better scores in the endurance run, sit-ups and standing long jump tests, but poorer performances in hand grip strength and 2-kg ball throw. Better fitness test scores were also associated with better motor coordination scores. Relationships between body size and estimated fatness with motor fitness suggested an inverse relationship that was particularly evident in performance items that required the displacement of the body through space, while motor coordination was more closely related with fitness than with somatic variables

Information transmission in oscillatory neural activity

Periodic neural activity not locked to the stimulus or to motor responses is usually ignored. Here, we present new tools for modeling and quantifying the information transmission based on periodic neural activity that occurs with quasi-random phase relative to the stimulus. We propose a model to reproduce characteristic features of oscillatory spike trains, such as histograms of inter-spike intervals and phase locking of spikes to an oscillatory influence. The proposed model is based on an inhomogeneous Gamma process governed by a density function that is a product of the usual stimulus-dependent rate and a quasi-periodic function. Further, we present an analysis method generalizing the direct method (Rieke et al, 1999; Brenner et al, 2000) to assess the information content in such data. We demonstrate these tools on recordings from relay cells in the lateral geniculate nucleus of the cat.Comment: 18 pages, 8 figures, to appear in Biological Cybernetic

Accuracy of Malaria Rapid Diagnostic Tests in Community Studies and their Impact on Treatment of Malaria in an Area with Declining Malaria Burden in North-Eastern Tanzania.

Despite some problems related to accuracy and applicability of malaria rapid diagnostic tests (RDTs), they are currently the best option in areas with limited laboratory services for improving case management through parasitological diagnosis and reducing over-treatment. This study was conducted in areas with declining malaria burden to assess; 1) the accuracy of RDTs when used at different community settings, 2) the impact of using RDTs on anti-malarial dispensing by community-owned resource persons (CORPs) and 3) adherence of CORPs to treatment guidelines by providing treatment based on RDT results. Data were obtained from: 1) a longitudinal study of passive case detection of fevers using CORPs in six villages in Korogwe; and 2) cross-sectional surveys (CSS) in six villages of Korogwe and Muheza districts, north-eastern, Tanzania. Performance of RDTs was compared with microscopy as a gold standard, and factors affecting their accuracy were explored using a multivariate logistic regression model. Overall sensitivity and specificity of RDTs in the longitudinal study (of 23,793 febrile cases; 18,154 with microscopy and RDTs results) were 88.6% and 88.2%, respectively. In the CSS, the sensitivity was significantly lower (63.4%; χ2=367.7, p<0.001), while the specificity was significantly higher (94.3%; χ2=143.1, p<0.001) when compared to the longitudinal study. As determinants of sensitivity of RDTs in both studies, parasite density of<200 asexual parasites/μl was significantly associated with high risk of false negative RDTs (OR≥16.60, p<0.001), while the risk of false negative test was significantly lower among cases with fever (axillary temperature ≥37.5 °C) (OR≤0.63, p≤0.027). The risk of false positive RDT (as a determinant of specificity) was significantly higher in cases with fever compared to afebrile cases (OR≥2.40, p<0.001). Using RDTs reduced anti-malarials dispensing from 98.9% to 32.1% in cases aged ≥5 years. Although RDTs had low sensitivity and specificity, which varied widely depending on fever and parasite density, using RDTs reduced over-treatment with anti-malarials significantly. Thus, with declining malaria prevalence, RDTs will potentially identify majority of febrile cases with parasites and lead to improved management of malaria and non-malaria fevers

Generating real-world evidence on the quality use, benefits and safety of medicines in australia: History, challenges and a roadmap for the future

Australia spends more than $20 billion annually on medicines, delivering significant health benefits for the population. However, inappropriate prescribing and medicine use also result in harm to individuals and populations, and waste of precious health resources. Medication data linked with other routine collections enable evidence generation in pharmacoepidemiology; the science of quantifying the use, effectiveness and safety of medicines in real-world clinical practice. This review details the history of medicines policy and data access in Australia, the strengths of existing data sources, and the infrastructure and governance enabling and impeding evidence generation in the field. Currently, substantial gaps persist with respect to cohesive, contemporary linked data sources supporting quality use of medicines, effectiveness and safety research; exemplified by Aus-tralia’s limited capacity to contribute to the global effort in real-world studies of vaccine and dis-ease-modifying treatments for COVID-19. We propose a roadmap to bolster the discipline, and population health more broadly, underpinned by a distinct capability governing and streamlining access to linked data assets for accredited researchers. Robust real-world evidence generation requires current data roadblocks to be remedied as a matter of urgency to deliver efficient and equitable health care and improve the health and well-being of all Australians

First results from the Solar Orbiter Heavy Ion Sensor

Context. Aims. Solar Orbiter launched in February 2020 with the goal of revealing the connections between the Sun’s interior, atmosphere, and the heliosphere. The Solar Orbiter Heavy Ion Sensor (HIS) is a time-of-flight ion mass spectrometer dedicated to measuring heavy ions in the solar wind. Methods. We present an overview of the first measurements of heavy ion composition from HIS, reviewing the methods used to transform the spectra obtained on board into scientific data products and examining two solar wind case studies as well as the statistical properties of the heavy ion composition observed by HIS. We also carried out a comparison with prior measurements of heavy ions at L1. Results. The HIS data set provides the first mass- and charge-resolved heavy ion measurements in the inner heliosphere. Conclusions. These high temporal resolution data have the potential to transform our understanding of the connections between the solar wind and its origin at the Sun, as well as the interaction between the solar wind and the environment around planets, comets, and in the interstellar medium

Strengthening confidence in climate change impact science

Aim: To assess confidence in conclusions about climate-driven biological change through time, and identify approaches for strengthening confidence scientific conclusions about ecological impacts of climate change. Location: Global. Methods: We outlined a framework for strengthening confidence in inferences drawn from biological climate impact studies through the systematic integration of prior expectations, long-term data and quantitative statistical procedures. We then developed a numerical confidence index (Cindex) and used it to evaluate current practices in 208 studies of marine climate impacts comprising 1735 biological time series. Results: Confidence scores for inferred climate impacts varied widely from 1 to 16 (very low to high confidence). Approximately 35% of analyses were not associated with clearly stated prior expectations and 65% of analyses did not test putative non-climate drivers of biological change. Among the highest-scoring studies, 91% tested prior expectations, 86% formulated expectations for alternative drivers but only 63% statistically tested them. Higher confidence scores observed in studies that did not detect a change or tracked multiple species suggest publication bias favouring impact studies that are consistent with climate change. The number of time series showing climate impacts was a poor predictor of average confidence scores for a given group, reinforcing that vote-counting methodology is not appropriate for determining overall confidence in inferences. Main conclusions: Climate impacts research is expected to attribute biological change to climate change with measurable confidence. Studies with long-term, high-resolution data, appropriate statistics and tests of alternative drivers earn higher Cindex scores, suggesting these should be given greater weight in impact assessments. Together with our proposed framework, the results of our Cindex analysis indicate how the science of detecting and attributing biological impacts to climate change can be strengthened through the use of evidence-based prior expectations and thorough statistical analyses, even when data are limited, maximizing the impact of the diverse and growing climate change ecology literature

Generating Real-World Evidence on the Quality Use, Benefits and Safety of Medicines in Australia: History, Challenges and a Roadmap for the Future.

Australia spends more than $20 billion annually on medicines, delivering significant health benefits for the population. However, inappropriate prescribing and medicine use also result in harm to individuals and populations, and waste of precious health resources. Medication data linked with other routine collections enable evidence generation in pharmacoepidemiology; the science of quantifying the use, effectiveness and safety of medicines in real-world clinical practice. This review details the history of medicines policy and data access in Australia, the strengths of existing data sources, and the infrastructure and governance enabling and impeding evidence generation in the field. Currently, substantial gaps persist with respect to cohesive, contemporary linked data sources supporting quality use of medicines, effectiveness and safety research; exemplified by Australia's limited capacity to contribute to the global effort in real-world studies of vaccine and disease-modifying treatments for COVID-19. We propose a roadmap to bolster the discipline, and population health more broadly, underpinned by a distinct capability governing and streamlining access to linked data assets for accredited researchers. Robust real-world evidence generation requires current data roadblocks to be remedied as a matter of urgency to deliver efficient and equitable health care and improve the health and well-being of all Australians

Assessing Communities of Practice in health policy : A conceptual framework as a first step towards empirical research

Peer reviewe