A methodology for identifying high-need, high-cost patient personas for international comparisons.

ObjectiveTo establish a methodological approach to compare two high-need, high-cost (HNHC) patient personas internationally.Data sourcesLinked individual-level administrative data from the inpatient and outpatient sectors compiled by the International Collaborative on Costs, Outcomes, and Needs in Care (ICCONIC) across 11 countries: Australia, Canada, England, France, Germany, the Netherlands, New Zealand, Spain, Sweden, Switzerland, and the United States.Study designWe outline a methodological approach to identify HNHC patient types for international comparisons that reflect complex, priority populations defined by the National Academy of Medicine. We define two patient profiles using accessible patient-level datasets linked across different domains of care-hospital care, primary care, outpatient specialty care, post-acute rehabilitative care, long-term care, home-health care, and outpatient drugs. The personas include a frail older adult with a hip fracture with subsequent hip replacement and an older person with complex multimorbidity, including heart failure and diabetes. We demonstrate their comparability by examining the characteristics and clinical diagnoses captured across countries.Data collection/extraction methodsData collected by ICCONIC partners.Principal findingsAcross 11 countries, the identification of HNHC patient personas was feasible to examine variations in healthcare utilization, spending, and patient outcomes. The ability of countries to examine linked, individual-level data varied, with the Netherlands, Canada, and Germany able to comprehensively examine care across all seven domains, whereas other countries such as England, Switzerland, and New Zealand were more limited. All countries were able to identify a hip fracture persona and a heart failure persona. Patient characteristics were reassuringly similar across countries.ConclusionAlthough there are cross-country differences in the availability and structure of data sources, countries had the ability to effectively identify comparable HNHC personas for international study. This work serves as the methodological paper for six accompanying papers examining differences in spending, utilization, and outcomes for these personas across countries

Overweight across the life course and adipokines, inflammatory and endothelial markers at age 60-64 years: evidence from the 1946 birth cohort.

BACKGROUND/OBJECTIVES: There is growing evidence that early development of obesity increases cardiovascular risk later in life, but less is known about whether there are effects of long-term excess body weight on the biological drivers associated with the atherosclerotic pathway, particularly adipokines, inflammatory and endothelial markers. This paper therefore investigates the influence of overweight across the life course on levels of these markers at retirement age. SUBJECTS/METHODS: Data from the Medical Research Council National Survey of Health and Development (n=1784) were used to examine the associations between overweight status at 2, 4, 6, 7, 11, 15, 20, 26, 36, 43, 53 and 60-64 years (body mass index (BMI)⩾25 kg m(-2) for adult ages and gender-specific cut-points for childhood ages equivalent to BMI⩾25 kg m(-2)) and measurements of adipokines (leptin and adiponectin), inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6)) and endothelial markers (E-selectin, tissue plasminogen activator (t-PA) and von Willebrand factor) at 60-64 years. In addition, the fit of different life course models (sensitive periods/accumulation) were compared using partial F-tests. RESULTS: In age- and sex-adjusted models, overweight at 11 years and onwards was associated with higher leptin, CRP and IL-6 and lower adiponectin; overweight at 15 years and onwards was associated with higher E-selectin and t-PA. Associations between overweight at all ages earlier than 60-64 with leptin, adiponectin, CRP and IL-6 were reduced but remained apparent after adjustment for overweight at 60-64 years; whereas those with E-selectin and t-PA were entirely explained. An accumulation model best described the associations between overweight across the life course with adipokines and inflammatory markers, whereas for the endothelial markers, the sensitive period model for 60-64 years provided a slightly better fit than the accumulation model. CONCLUSIONS: Overweight across the life course has a cumulative influence on adipokines, inflammatory and possibly endothelial markers. Avoidance of overweight from adolescence onwards is likely important for cardiovascular disease prevention

Discovery of High-Affinity Protein Binding Ligands – Backwards

BACKGROUND: There is a pressing need for high-affinity protein binding ligands for all proteins in the human and other proteomes. Numerous groups are working to develop protein binding ligands but most approaches develop ligands using the same strategy in which a large library of structured ligands is screened against a protein target to identify a high-affinity ligand for the target. While this methodology generates high-affinity ligands for the target, it is generally an iterative process that can be difficult to adapt for the generation of ligands for large numbers of proteins. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a class of peptide-based protein ligands, called synbodies, which allow this process to be run backwards--i.e. make a synbody and then screen it against a library of proteins to discover the target. By screening a synbody against an array of 8,000 human proteins, we can identify which protein in the library binds the synbody with high affinity. We used this method to develop a high-affinity synbody that specifically binds AKT1 with a K(d)<5 nM. It was found that the peptides that compose the synbody bind AKT1 with low micromolar affinity, implying that the affinity and specificity is a product of the bivalent interaction of the synbody with AKT1. We developed a synbody for another protein, ABL1 using the same method. CONCLUSIONS/SIGNIFICANCE: This method delivered a high-affinity ligand for a target protein in a single discovery step. This is in contrast to other techniques that require subsequent rounds of mutational improvement to yield nanomolar ligands. As this technique is easily scalable, we believe that it could be possible to develop ligands to all the proteins in any proteome using this approach

Quantification system for the viral dynamics of a highly pathogenic simian/human immunodeficiency virus based on an in vitro experiment and a mathematical model

<p>Abstract</p> <p>Background</p> <p>Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection <it>in vitro</it>.</p> <p>Results</p> <p>We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef<it>-</it>negative (target) and Nef<it>-</it>positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID₅₀, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced.</p> <p>Conclusions</p> <p>Our method, combining <it>in vitro </it>experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the <it>in vitro </it>determination of the effect and efficacy of antiviral compounds.</p

Análise do movimento inicial de molares superiores submetidos a forças extrabucais: estudo 3D Analysis of initial movement of maxillary molars submitted to extraoral forces: a 3D study

OBJETIVO: analisar pelo método dos elementos finitos o deslocamento dos molares superiores frente a três diferentes inclinações do arco externo do aparelho extrabucal na tração do tipo cervical. MÉTODOS: maxila, dentes montados em má oclusão de Classe II e aparelho foram modelados através de formulação variacional e seus valores reproduzidos em coordenadas X, Y e Z. Foram realizadas simulações em microcomputador tipo PC, utilizando o programa ANSYS versão 8.1. Cada modelo de arco externo reproduziu linhas de força que passaram (1) acima (AcCR), (2) abaixo (AbCR) e (3) no centro de resistência (CR) do molar permanente superior de um mesmo modelo portador de má oclusão de Classe II. A avaliação restringiu-se ao movimento inicial dos molares frente à força extrabucal de 4 Newtons. RESULTADOS: o movimento distal inicial dos molares, tendo como ponto de referência a mesial do tubo, foi maior na coroa do modelo AbCR (0,47x10-6), e maior na raiz do modelo AcCR (0,32x10-6), provocando inclinações da coroa para distal e mesial, respectivamente. No modelo CR, os pontos na coroa (0,15x10-6) e raiz (0,12x10-6) deslocaram-se para distal equilibradamente, resultando em movimento de translação. Em todos os modelos, numa vista oclusal, houve tendência de rotação distal inicial da coroa, porém no modelo CR esse movimento foi muito pequeno. No sentido vertical (Z), todos os modelos revelaram movimento extrusivo (AbCR= 0,18x10-6; CR= 0,62x10-6; AcCR= 0,72x10-6). CONCLUSÃO: a simulação computacional do uso de aparelho extrabucal com tração cervical revelou a ocorrência de movimento extrusivo e distal, podendo ser por inclinação distal de coroa, de raiz ou movimento de translação.<br>OBJECTIVE: To analyze maxillary molar displacement by applying three different angulations to the outer bow of cervical-pull headgear, using the finite element method (FEM). METHODS: Maxilla, teeth set up in Class II malocclusion and equipment were modeled through variational formulation and their values represented in X, Y, Z coordinates. Simulations were performed using a PC computer and ANSYS software version 8.1. Each outer bow model reproduced force lines that ran above (ACR) (1), below (BCR) (2) and through the center of resistance (CR) (3) of the maxillary permanent molars of each Class II model. Evaluation was limited to the initial movement of molars submitted to an extraoral force of 4 Newtons. RESULTS: The initial distal movement of the molars, using as reference the mesial surface of the tube, was higher in the crown of the BCR model (0.47x10-6) as well as in the root of the ACR (0.32x10-6) model, causing the crown to tip distally and mesially, respectively. On the CR model, the points on the crown (0.15 x10-6) and root (0.12 x10-6) moved distally in a balanced manner, which resulted in bodily movement. In occlusal view, the crowns on all models showed a tendency towards initial distal rotation, but on the CR model this movement was very small. In the vertical direction (Z), all models displayed extrusive movement (BCR 0.18 x10-6; CR 0.62 x10-6; ACR 0.72x10-6). CONCLUSIONS: Computer simulations of cervical-pull headgear use disclosed the presence of extrusive and distal movement, distal crown and root tipping, or bodily movement