The index of rural access: an innovative integrated approach for measuring primary care access

<p>Abstract</p> <p>Background</p> <p>The problem of access to health care is of growing concern for rural and remote populations. Many Australian rural health funding programs currently use simplistic rurality or remoteness classifications as proxy measures of access. This paper outlines the development of an alternative method for the measurement of access to primary care, based on combining the three key access elements of spatial accessibility (availability and proximity), population health needs and mobility.</p> <p>Methods</p> <p>The recently developed two-step floating catchment area (2SFCA) method provides a basis for measuring primary care access in rural populations. In this paper, a number of improvements are added to the 2SFCA method in order to overcome limitations associated with its current restriction to a single catchment size and the omission of any distance decay function. Additionally, small-area measures for the two additional elements, health needs and mobility are developed. By utilising this improved 2SFCA method, the three access elements are integrated into a single measure of access. This index has been developed within the state of Victoria, Australia.</p> <p>Results</p> <p>The resultant index, the Index of Rural Access, provides a more sensitive and appropriate measure of access compared to existing classifications which currently underpin policy measures designed to overcome problems of limited access to health services. The most powerful aspect of this new index is its ability to identify access differences within rural populations at a much finer geographical scale. This index highlights that many rural areas of Victoria have been incorrectly classified by existing measures as homogenous in regards to their access.</p> <p>Conclusion</p> <p>The Index of Rural Access provides the first truly integrated index of access to primary care. This new index can be used to better target the distribution of limited government health care funding allocated to address problems of poor access to primary health care services in rural areas.</p

An Overview of the 2014 ALMA Long Baseline Campaign

A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from September to late November 2014, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy.Comment: 11 pages, 7 figures, 2 tables; accepted for publication in the Astrophysical Journal Letters; this version with small changes to affiliation

The 2014 ALMA Long Baseline Campaign: An Overview

A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from September to late November 2014, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy

Label-Free Bottom-Up Proteomic Workflow for Simultaneously Assessing the Target Specificity of Covalent Drug Candidates and Their Off-Target Reactivity to Selected Proteins

Although designed covalent inhibitors as drug candidates offer several unique advantages over conventional reversible inhibitors, including high potency and the potential for less frequent dosing, there is a general tendency to avoid the covalent mode of action in drug discovery programs due to concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. Therefore, the ability to assess off-target reactivity relative to target specificity is desirable for optimizing covalent drug candidates in the early discovery stage. One concern with current surrogate nucleophile trapping approaches is that they employ a simplistic model nucleophile such as glutathione, which may not reliably reflect the covalent interactions with cellular or extracellular proteins. One way to get a more relevant reactivity assessment is to directly measure the ability of an inhibitor to covalently modify nucelophilic amino acids on biologically relevant proteins, both on- and off-target. In this article, we describe a label-free bottom-up proteomic workflow for simultaneous evaluation of target binding and off-target reactivity of covalent drug candidates to selected proteins at the peptide level. Ibrutinib, a covalent drug targeting the active site of BTK protein, was used as a model compound to demonstrate the feasibility of the workflow. The compound was incubated with a mixture of target protein, Bruton’s tyrosine kinase (BTK), and two abundant proteins in blood, hemoglobin (Hb) and human serum albumin (HSA), and then the ibrutinib modification sites were determined utilizing a bottom-up proteomic approach. A non-BTK specific model compound (<b>1</b>) known to modify cysteine residues was also included. By comparing the extent of off-target modifications to the targeted BTK C481 binding in a wide compound concentration range, we were able to determine the concentration where maximum target binding was achieved with minimal off-target reactivity. The generic label-free bottom-up proteomics workflow described in this article should be useful in the rank order assessment of off-target reactivity vs on-target reactivity of covalent drug candidates in the early drug discovery stage

Label-Free Bottom-Up Proteomic Workflow for Simultaneously Assessing the Target Specificity of Covalent Drug Candidates and Their Off-Target Reactivity to Selected Proteins

Although designed covalent inhibitors as drug candidates offer several unique advantages over conventional reversible inhibitors, including high potency and the potential for less frequent dosing, there is a general tendency to avoid the covalent mode of action in drug discovery programs due to concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. Therefore, the ability to assess off-target reactivity relative to target specificity is desirable for optimizing covalent drug candidates in the early discovery stage. One concern with current surrogate nucleophile trapping approaches is that they employ a simplistic model nucleophile such as glutathione, which may not reliably reflect the covalent interactions with cellular or extracellular proteins. One way to get a more relevant reactivity assessment is to directly measure the ability of an inhibitor to covalently modify nucelophilic amino acids on biologically relevant proteins, both on- and off-target. In this article, we describe a label-free bottom-up proteomic workflow for simultaneous evaluation of target binding and off-target reactivity of covalent drug candidates to selected proteins at the peptide level. Ibrutinib, a covalent drug targeting the active site of BTK protein, was used as a model compound to demonstrate the feasibility of the workflow. The compound was incubated with a mixture of target protein, Bruton’s tyrosine kinase (BTK), and two abundant proteins in blood, hemoglobin (Hb) and human serum albumin (HSA), and then the ibrutinib modification sites were determined utilizing a bottom-up proteomic approach. A non-BTK specific model compound (<b>1</b>) known to modify cysteine residues was also included. By comparing the extent of off-target modifications to the targeted BTK C481 binding in a wide compound concentration range, we were able to determine the concentration where maximum target binding was achieved with minimal off-target reactivity. The generic label-free bottom-up proteomics workflow described in this article should be useful in the rank order assessment of off-target reactivity vs on-target reactivity of covalent drug candidates in the early drug discovery stage