The use of segmented regression in analysing interrupted time series studies : an example in pre-hospital ambulance care

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On the Deformation of a Hyperelastic Tube Due to Steady Viscous Flow Within

In this chapter, we analyze the steady-state microscale fluid--structure interaction (FSI) between a generalized Newtonian fluid and a hyperelastic tube. Physiological flows, especially in hemodynamics, serve as primary examples of such FSI phenomena. The small scale of the physical system renders the flow field, under the power-law rheological model, amenable to a closed-form solution using the lubrication approximation. On the other hand, negligible shear stresses on the walls of a long vessel allow the structure to be treated as a pressure vessel. The constitutive equation for the microtube is prescribed via the strain energy functional for an incompressible, isotropic Mooney--Rivlin material. We employ both the thin- and thick-walled formulations of the pressure vessel theory, and derive the static relation between the pressure load and the deformation of the structure. We harness the latter to determine the flow rate--pressure drop relationship for non-Newtonian flow in thin- and thick-walled soft hyperelastic microtubes. Through illustrative examples, we discuss how a hyperelastic tube supports the same pressure load as a linearly elastic tube with smaller deformation, thus requiring a higher pressure drop across itself to maintain a fixed flow rate.Comment: 19 pages, 3 figures, Springer book class; v2: minor revisions, final form of invited contribution to the Springer volume entitled "Dynamical Processes in Generalized Continua and Structures" (in honour of Academician D.I. Indeitsev), eds. H. Altenbach, A. Belyaev, V. A. Eremeyev, A. Krivtsov and A. V. Porubo

Functional significance may underlie the taxonomic utility of single amino acid substitutions in conserved proteins

We hypothesized that some amino acid substitutions in conserved proteins that are strongly fixed by critical functional roles would show lineage-specific distributions. As an example of an archetypal conserved eukaryotic protein we considered the active site of ß-tubulin. Our analysis identified one amino acid substitution—ß-tubulin F224—which was highly lineage specific. Investigation of ß-tubulin for other phylogenetically restricted amino acids identified several with apparent specificity for well-defined phylogenetic groups. Intriguingly, none showed specificity for “supergroups” other than the unikonts. To understand why, we analysed the ß-tubulin Neighbor-Net and demonstrated a fundamental division between core ß-tubulins (plant-like) and divergent ß-tubulins (animal and fungal). F224 was almost completely restricted to the core ß-tubulins, while divergent ß-tubulins possessed Y224. Thus, our specific example offers insight into the restrictions associated with the co-evolution of ß-tubulin during the radiation of eukaryotes, underlining a fundamental dichotomy between F-type, core ß-tubulins and Y-type, divergent ß-tubulins. More broadly our study provides proof of principle for the taxonomic utility of critical amino acids in the active sites of conserved proteins

Adherence to Tuberculosis Therapy among Patients Receiving Home-Based Directly Observed Treatment: Evidence from the United Republic of Tanzania.

\ud \ud Non-adherence to tuberculosis (TB) treatment is the leading contributor to the selection of drug-resistant strains of Mycobacterium tuberculosis and subsequent treatment failure. Tanzania introduced a TB Patient Centred Treatment (PCT) approach which gives new TB patients the choice between home-based treatment supervised by a treatment supporter of their own choice, and health facility-based treatment observed by a medical professional. The aim of this study was to assess the extent and determinants of adherence to anti-TB therapy in patients opting for home-based treatment under the novel PCT approach. In this cross-sectional study, the primary outcome was the percentage of patients adherent to TB therapy as detected by the presence of isoniazid in urine (IsoScreen assay). The primary analysis followed a non-inferiority approach in which adherence could not be lower than 75%. Logistic regression was used to examine the influence of potentially predictive factors. A total of 651 new TB patients were included. Of these, 645 (99.1%) provided urine for testing and 617 patients (95.7%; 90%CI 94.3-96.9) showed a positive result. This result was statistically non-inferior to the postulated adherence level of 75% (p<0.001). Adherence to TB therapy under home-based Directly Observed Treatment can be ensured in programmatic settings. A reliable supply of medication and the careful selection of treatment supporters, who preferably live very close to the patient, are crucial success factors. Finally, we recommend a cohort study to assess the rate of adherence throughout the full course of TB treatment

Mycobacterium tuberculosis Responds to Chloride and pH as Synergistic Cues to the Immune Status of its Host Cell

PubMed ID: 23592993This 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

Modelling and simulating change in reforesting mountain landscapes using a social-ecological framework

Natural reforestation of European mountain landscapes raises major environmental and societal issues. With local stakeholders in the Pyrenees National Park area (France), we studied agricultural landscape colonisation by ash (Fraxinus excelsior) to enlighten its impacts on biodiversity and other landscape functions of importance for the valley socio-economics. The study comprised an integrated assessment of land-use and land-cover change (LUCC) since the 1950s, and a scenario analysis of alternative future policy. We combined knowledge and methods from landscape ecology, land change and agricultural sciences, and a set of coordinated field studies to capture interactions and feedback in the local landscape/land-use system. Our results elicited the hierarchically-nested relationships between social and ecological processes. Agricultural change played a preeminent role in the spatial and temporal patterns of LUCC. Landscape colonisation by ash at the parcel level of organisation was merely controlled by grassland management, and in fact depended on the farmer's land management at the whole-farm level. LUCC patterns at the landscape level depended to a great extent on interactions between farm household behaviours and the spatial arrangement of landholdings within the landscape mosaic. Our results stressed the need to represent the local SES function at a fine scale to adequately capture scenarios of change in landscape functions. These findings orientated our modelling choices in the building an agent-based model for LUCC simulation (SMASH - Spatialized Multi-Agent System of landscape colonization by ASH). We discuss our method and results with reference to topical issues in interdisciplinary research into the sustainability of multifunctional landscapes

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

The shadow knows: using shadows to investigate the structure of the pretransitional disk of HD 100453

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.We present GPI polarized intensity imagery of HD 100453 in Y-, J-, and K1 bands which reveals an inner gap ($9 - 18$ au), an outer disk ($18-39$ au) with two prominent spiral arms, and two azimuthally-localized dark features also present in SPHERE total intensity images (Wagner 2015). SED fitting further suggests the radial gap extends to $1$ au. The narrow, wedge-like shape of the dark features appears similar to predictions of shadows cast by a inner disk which is misaligned with respect to the outer disk. Using the Monte Carlo radiative transfer code HOCHUNCK3D (Whitney 2013), we construct a model of the disk which allows us to determine its physical properties in more detail. From the angular separation of the features we measure the difference in inclination between the disks 45$^{\circ}$, and their major axes, PA = 140$^{\circ}$ east of north for the outer disk and 100$^{\circ}$for the inner disk. We find an outer disk inclination of $25 \pm 10^{\circ}$ from face-on in broad agreement with the Wagner 2015 measurement of 34$^{\circ}$. SPHERE data in J- and H-bands indicate a reddish disk which points to HD 100453 evolving into a young debris disk.Based in part on data obtained at the Gemini Observatory via the time exchange program between Gemini and the Subaru Telescope (GS-2015A-C-1). The Gemini Observatory is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the National Research Council (Canada), CONICYT (Chile), Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina), and Ministério da Ciência, Tecnologia e Inovação (Brazil). M.T. is partly supported by JSPS KAKENHI 2680016. C.A.G. is supported under NASA Origins of Solar Systems Funding via NNG16PX39P. Y.H. is supported by Jet Propulsion Laboratory, California Institute of Technology under a contract from NASA. M.S. is supported by NASA Exoplanet Research Program NNX16AJ75G. J.K. acknowledges support from Philip Leverhulme Prize (PLP-2013-110, PI: Stefan Kraus). S.K. acknowledges support from an ERC Starting Grant (Grant Agreement No. 639889). We also thank the referee for their comments and suggestions which added clarity to this paper

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

The chronic care model: Congruency and predictors among patients with cardiovascular diseases and chronic obstructive pulmonary disease in the Netherlands

Objective: The Chronic Care Model (CCM) achieved widespread acceptance and reflects the core elements of patient-centred care in chronic diseases such as CVD and COPD. Our aim is to assess the extent to which current care for CVD and COPD patients aligns with the CCM in Dutch healthcare practices in the early stages of implementing disease-management programs, thereby revealing possible predictors that tell us whether certain patients are more likel