Systematic comparison of different techniques to measure hippocampal subfield volumes in ADNI2

OBJECTIVE: Subfield-specific measurements provide superior information in the early stages of neurodegenerative diseases compared to global hippocampal measurements. The overall goal was to systematically compare the performance of five representative manual and automated T1 and T2 based subfield labeling techniques in a sub-set of the ADNI2 population. METHODS: The high resolution T2 weighted hippocampal images (T2-HighRes) and the corresponding T1 images from 106 ADNI2 subjects (41 controls, 57 MCI, 8 AD) were processed as follows. A. T1-based: 1. Freesurfer + Large-Diffeomorphic-Metric-Mapping in combination with shape analysis. 2. FreeSurfer 5.1 subfields using in-vivo atlas. B. T2-HighRes: 1. Model-based subfield segmentation using ex-vivo atlas (FreeSurfer 6.0). 2. T2-based automated multi-atlas segmentation combined with similarity-weighted voting (ASHS). 3. Manual subfield parcellation. Multiple regression analyses were used to calculate effect sizes (ES) for group, amyloid positivity in controls, and associations with cognitive/memory performance for each approach. RESULTS: Subfield volumetry was better than whole hippocampal volumetry for the detection of the mild atrophy differences between controls and MCI (ES: 0.27 vs 0.11). T2-HighRes approaches outperformed T1 approaches for the detection of early stage atrophy (ES: 0.27 vs.0.10), amyloid positivity (ES: 0.11 vs 0.04), and cognitive associations (ES: 0.22 vs 0.19). CONCLUSIONS: T2-HighRes subfield approaches outperformed whole hippocampus and T1 subfield approaches. None of the different T2-HghRes methods tested had a clear advantage over the other methods. Each has strengths and weaknesses that need to be taken into account when deciding which one to use to get the best results from subfield volumetry

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Quantifying morbidities by Adjusted Clinical Group system for a Taiwan population: A nationwide analysis

<p>Abstract</p> <p>Background</p> <p>The Adjusted Clinical Group (ACG) system has been used in measuring an individual's and a population's morbidities. Although all required inputs for running the ACG system are readily available, patients' morbidities and their associations to health care utilizations have been rarely studied in Taiwan. Therefore, the objective of this study was using the ACG system to quantify morbidities for Taiwanese population and to examine their relationship to ambulatory utilizations and costs.</p> <p>Methods</p> <p>This secondary analysis examined claims data for ambulatory services provided to 2.71 million representative Taiwanese in 2002 and 2003. People were grouped by the ACG system according to age, gender, and all ambulatory diagnosis codes in a given year. The software collapses the full set of ACGs into six morbidity categories (Non-users, Healthy, Low-morbidity, Moderate-, High- and Very-high) termed Resource Utilization Bands (RUBs). Each ACG was assigned a relative weight (RW), which was calculated as the ratio of mean ambulatory cost for each ACG to that for the overall. The distribution of morbidities was compared between years 2002 and 2003. The consistency of the distributions of visits, costs, and RWs of each ACG were examined for a two-year period. The relationship between people's morbidities and their ambulatory utilizations and costs was assessed.</p> <p>Results</p> <p>Ninety-eight percent of the subjects were correctly assigned to ACGs. Except for non-users (7.9 ~ 8.3%), most subjects were assigned to ACGs of acute and minor diseases and ACGs of moderate-to-high-morbid chronic diseases. The distributions of ACG-based morbidities were highly consistent (r = 0.949, <it>p < 0.001</it>) between 2002 and 2003. The ACG-specific visits (r = 0.955, <it>p < 0.001</it>), costs (r = 0.966, <it>p < 0.001</it>) and RWs (r = 0.991, <it>p < 0.001</it>) were correlated across two years. People grouped to the high-morbid ACGs had more visits and costs than those grouped to the low-morbid ACGs. Forty-six percent of the total ambulatory costs were spent by eighteen percent of the population, who were grouped to the High- and Very-high-morbidity RUBs.</p> <p>Conclusion</p> <p>This study demonstrated the feasibility, validity, and reliability of using the ACG system to measure morbidities in a Taiwan population and to explain their associations with ambulatory utilizations and costs for the whole country.</p

Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis

MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE

Validation of ACG Case-mix for equitable resource allocation in Swedish primary health care

<p>Abstract</p> <p>Background</p> <p>Adequate resource allocation is an important factor to ensure equity in health care. Previous reimbursement models have been based on age, gender and socioeconomic factors. An explanatory model based on individual need of primary health care (PHC) has not yet been used in Sweden to allocate resources. The aim of this study was to examine to what extent the ACG case-mix system could explain concurrent costs in Swedish PHC.</p> <p>Methods</p> <p>Diagnoses were obtained from electronic PHC records of inhabitants in Blekinge County (approx. 150,000) listed with public PHC (approx. 120,000) for three consecutive years, 2004-2006. The inhabitants were then classified into six different resource utilization bands (RUB) using the ACG case-mix system. The mean costs for primary health care were calculated for each RUB and year. Using linear regression models and log-cost as dependent variable the adjusted R²was calculated in the unadjusted model (gender) and in consecutive models where age, listing with specific PHC and RUB were added. In an additional model the ACG groups were added.</p> <p>Results</p> <p>Gender, age and listing with specific PHC explained 14.48-14.88% of the variance in individual costs for PHC. By also adding information on level of co-morbidity, as measured by the ACG case-mix system, to specific PHC the adjusted R²increased to 60.89-63.41%.</p> <p>Conclusion</p> <p>The ACG case-mix system explains patient costs in primary care to a high degree. Age and gender are important explanatory factors, but most of the variance in concurrent patient costs was explained by the ACG case-mix system.</p

In Vivo Binding and Retention of CD4-Specific DARPin 57.2 in Macaques

The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost.To investigate the in vivo use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4(+) cells and exhibited potent inhibitory activity against SIV infection in vitro. DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4(+) cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4(+) cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4(+) cell types (T cells, monocytes, dendritic cells) in vivo and in vitro with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation.We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells in vivo, warranting further studies on possible clinical use of the DARPin technology

Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models

Mineralized collagen fibrils have been usually analyzed like a two phase composite material where crystals are considered as platelets that constitute the reinforcement phase. Different models have been used to describe the elastic behavior of the material. In this work, it is shown that, when Halpin-Tsai equations are applied to estimate elastic constants from typical constituent properties, not all crystal dimensions yield a model that satisfy thermodynamic restrictions. We provide the ranges of platelet dimensions that lead to positive definite stiffness matrices. On the other hand, a finite element model of a mineralized collagen fibril unit cell under periodic boundary conditions is analyzed. By applying six canonical load cases, homogenized stiffness matrices are numerically calculated. Results show a monoclinic behavior of the mineralized collagen fibril. In addition, a 5-layer lamellar structure is also considered where crystals rotate in adjacent layers of a lamella. The stiffness matrix of each layer is calculated applying Lekhnitskii transformations and a new finite lement model under periodic boundary conditions is analyzed to calculate the homogenized 3D anisotropic stiffness matrix of a unit cell of lamellar bone. Results are compared with the rule-of-mixtures showing in general good agreement.The authors acknowledge the Ministerio de Economia y Competitividad the financial support given through the project DPI2010-20990 and the Generalitat Valenciana through the Programme Prometeo 2012/023. The authors thank Ms. Carla Gonzalez Carrillo by her help in the development of some of the numerical models.Vercher Martínez, A.; Giner Maravilla, E.; Arango Villegas, C.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ. (2014). Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models. 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Polym Eng Sci 13:139–145Martínez-Reina J, Domínguez J, García-Aznar JM (2011) Effect of porosity and mineral content on the elastic constants of cortical bone: a multiscale approach. Biomech Model Mechanobiol 10:309–322Orgel JPRO, Miller A, Irving TC, Fischetti RF, Hammersley AP, Wess TJ (2001) The in situ supermolecular structure of type I collagen. Structure 9:1061–1069Padawer GE, Beecher N (1970) On the strength and stiffness of planar reinforced plastic resins. Polym Eng Sci 10:185–192Pahr DH, Rammerstofer FG (2006) Buckling of honeycomb sandwiches: periodic finite element considerations. Comput Model Eng Sci 12:229–242Reisinger AG, Pahr DH, Zysset PK (2010) Sensitivity analysis and parametric study of elastic properties of an unidirectional mineralized bone fibril-array using mean field methods. Biomech Model Mechanobiol 9:499–510Reisinger AG, Pahr DH, Zysset PK (2011) Elastic anisotropy of bone lamellae as a function of fibril orientation pattern. 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Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Assessing socioeconomic health care utilization inequity in Israel: impact of alternative approaches to morbidity adjustment

<p/> <p>Background</p> <p>The ability to accurately detect differential resource use between persons of different socioeconomic status relies on the accuracy of health-needs adjustment measures. This study tests different approaches to morbidity adjustment in explanation of health care utilization inequity.</p> <p>Methods</p> <p>A representative sample was selected of 10 percent (~270,000) adult enrolees of Clalit Health Services, Israel's largest health care organization. The Johns-Hopkins University Adjusted Clinical Groups^®were used to assess each person's overall morbidity burden based on one year's (2009) diagnostic information. The odds of above average health care resource use (primary care visits, specialty visits, diagnostic tests, or hospitalizations) were tested using multivariate logistic regression models, separately adjusting for levels of health-need using data on age and gender, comorbidity (using the Charlson Comorbidity Index), or morbidity burden (using the Adjusted Clinical Groups). Model fit was assessed using tests of the Area Under the Receiver Operating Characteristics Curve and the Akaike Information Criteria.</p> <p>Results</p> <p>Low socioeconomic status was associated with higher morbidity burden (1.5-fold difference). Adjusting for health needs using age and gender or the Charlson index, persons of low socioeconomic status had greater odds of above average resource use for all types of services examined (primary care and specialist visits, diagnostic tests, or hospitalizations). In contrast, after adjustment for overall morbidity burden (using Adjusted Clinical Groups), low socioeconomic status was no longer associated with greater odds of specialty care or diagnostic tests (OR: 0.95, CI: 0.94-0.99; and OR: 0.91, CI: 0.86-0.96, for specialty visits and diagnostic respectively). Tests of model fit showed that adjustment using the comprehensive morbidity burden measure provided a better fit than age and gender or the Charlson Index.</p> <p>Conclusions</p> <p>Identification of socioeconomic differences in health care utilization is an important step in disparity reduction efforts. Adjustment for health-needs using a comprehensive morbidity burden diagnoses-based measure, this study showed relative underutilization in use of specialist and diagnostic services, and thus allowed for identification of inequity in health resources use, which could not be detected with less comprehensive forms of health-needs adjustments.</p

Explicit expressions for the estimation of the elastic constants of lamellar bone as a function of the volumetric mineral content using a multi-scale approach

[EN] In this work, explicit expressions to estimate all the transversely isotropic elastic constants of lamellar bone as a function of the volumetric bone mineral density (BMD) are provided. The methodology presented is based on the direct homogenization procedure using the finite element method, the continuum approach based on the Hill bounds, the least-square method and the mean field technique. Firstly, a detailed description of the volumetric content of the different components of bone is provided. The parameters defined in this step are related to the volumetric BMD considering that bone mineralization process occurs at the smallest scale length of the bone tissue. Then, a thorough description provides the details of the numerical models and the assumptions adopted to estimate the elastic behaviour of the forward scale lengths. The results highlight the noticeable influence of the BMD on the elastic modulus of lamellar bone. Power law regressions fit the Young's moduli, shear stiffness moduli and Poisson ratios. In addition, the explicit expressions obtained are applied to the estimation of the elastic constants of cortical bone. At this scale length, a representative unit cell of cortical bone is analysed including the fibril orientation pattern given by Wagermaier et al. (Biointerphases 1:1-5, 2006) and the BMD distributions observed by Granke et al. (PLoS One 8:e58043, 2012) for the osteon. Results confirm that fibril orientation arrangement governs the anisotropic behaviour of cortical bone instead of the BMD distribution. The novel explicit expressions obtained in this work can be used for improving the accuracy of bone fracture risk assessment.The authors acknowledge the Ministerio de Economia y Competitividad for the financial support received through the project DPI2013-46641-R and to the Generalitat Valenciana for Programme PROMETEO 2016/007. The authors declare that they have no conflict of interestVercher Martínez, A.; Giner Maravilla, E.; Belda, R.; Aigoun, A.; Fuenmayor Fernández, F. (2018). Explicit expressions for the estimation of the elastic constants of lamellar bone as a function of the volumetric mineral content using a multi-scale approach. Biomechanics and Modeling in Mechanobiology. 17(2):449-464. https://doi.org/10.1007/s10237-017-0971-xS449464172Akiva U, Wagner HD, Weiner S (1998) Modelling the three-dimensional elastic constants of parallel-fibred and lamellar bone. J Mater Sci 33:1497–1509Ascenzi A, Bonucci E (1967) The tensile properties of single osteons. Ana Rec 158:375–386Barbour KE, Zmuda JM, Strotmeyer ES, Horwitz MJ, Boudreau R, Evans RW, Ensrud K, Petit MA, Gordon CL, Cauley JA (2013) Correlates of trabecular and cortical volumetric bone mineral density of the radius and tibia older men: the osteoporotic fractures in men study. 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