Safety and Feasibility of a Diagnostic Algorithm Combining Clinical Probability, d-Dimer Testing, and Ultrasonography for Suspected Upper Extremity Deep Venous Thrombosis: A Prospective Management Study.

BACKGROUND Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). OBJECTIVE To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. DESIGN Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States. PATIENTS 406 inpatients and outpatients with suspected UEDVT. MEASUREMENTS The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. RESULTS The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). LIMITATIONS This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally. CONCLUSION The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT. PRIMARY FUNDING SOURCE None.

Limited clinical benefit of minority K103N and Y181C-variant detection in addition to routine genotypic resistance testing in antiretroviral therapy-naive patients

OBJECTIVE: The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. DESIGN: We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naïve patients in whom no NNRTI resistance mutations were detected by routine resistance testing. METHODS: Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. RESULTS: Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. CONCLUSION: As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the sole implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered.

Finite element analysis predicts experimental failure patterns in vertebral bodies loaded via intervertebral discs up to large deformation

Vertebral compression fracture is a common medical problem in osteoporotic individuals. The quantitative computed tomography (QCT)-based finite element (FE) method may be used to predict vertebral strength in vivo, but needs to be validated with experimental tests. The aim of this study was to validate a nonlinear anatomy specific QCT-based FE model by using a novel testing setup. Thirty-seven human thoracolumbar vertebral bone slices were prepared by removing cortical endplates and posterior elements. The slices were scanned with QCT and the volumetric bone mineral density (vBMD) was computed with the standard clinical approach. A novel experimental setup was designed to induce a realistic failure in the vertebral slices in vitro. Rotation of the loading plate was allowed by means of a ball joint. To minimize device compliance, the specimen deformation was measured directly on the loading plate with three sensors. A nonlinear FE model was generated from the calibrated QCT images and computed vertebral stiffness and strength were compared to those measured during the experiments. In agreement with clinical observations, most of the vertebrae underwent an anterior wedge-shape fracture. As expected, the FE method predicted both stiffness and strength better than vBMD (R2 improved from 0.27 to 0.49 and from 0.34 to 0.79, respectively). Despite the lack of fitting parameters, the linear regression of the FE prediction for strength was close to the 1:1 relation (slope and intercept close to one (0.86 kN) and to zero (0.72 kN), respectively). In conclusion, a nonlinear FE model was successfully validated through a novel experimental technique for generating wedge-shape fractures in human thoracolumbar vertebrae.

Detection of muscle wasting in patients with chronic heart failure using C-terminal agrin fragment: results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF).

AIMS Skeletal muscle wasting affects 20% of patients with chronic heart failure and has serious implications for their activities of daily living. Assessment of muscle wasting is technically challenging. C-terminal agrin-fragment (CAF), a breakdown product of the synaptically located protein agrin, has shown early promise as biomarker of muscle wasting. We sought to investigate the diagnostic properties of CAF in muscle wasting among patients with heart failure. METHODS AND RESULTS We assessed serum CAF levels in 196 patients who participated in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Muscle wasting was identified using dual-energy X-ray absorptiometry (DEXA) in 38 patients (19.4%). Patients with muscle wasting demonstrated higher CAF values than those without (125.1 ± 59.5 pmol/L vs. 103.8 ± 42.9 pmol/L, P = 0.01). Using receiver operating characteristics (ROC), we calculated the optimal CAF value to identify patients with muscle wasting as >87.5 pmol/L, which had a sensitivity of 78.9% and a specificity of 43.7%. The area under the ROC curve was 0.63 (95% confidence interval 0.56-0.70). Using simple regression, we found that serum CAF was associated with handgrip (R = - 0.17, P = 0.03) and quadriceps strength (R = - 0.31, P < 0.0001), peak oxygen consumption (R = - 0.5, P < 0.0001), 6-min walk distance (R = - 0.32, P < 0.0001), and gait speed (R = - 0.2, P = 0.001), as well as with parameters of kidney and liver function, iron metabolism and storage. CONCLUSION CAF shows good sensitivity for the detection of skeletal muscle wasting in patients with heart failure. Its assessment may be useful to identify patients who should undergo additional testing, such as detailed body composition analysis. As no other biomarker is currently available, further investigation is warranted.

Stiffness, Strength, and Failure Modes of Implant-Supported Monolithic Lithium Disilicate Crowns: Influence of Titanium and Zirconia Abutments

PURPOSE The objective of this study was to evaluate stiffness, strength, and failure modes of monolithic crowns produced using computer-aided design/computer-assisted manufacture, which are connected to diverse titanium and zirconia abutments on an implant system with tapered, internal connections. MATERIALS AND METHODS Twenty monolithic lithium disilicate (LS2) crowns were constructed and loaded on bone level-type implants in a universal testing machine under quasistatic conditions according to DIN ISO 14801. Comparative analysis included a 2 × 2 format: prefabricated titanium abutments using proprietary bonding bases (group A) vs nonproprietary bonding bases (group B), and customized zirconia abutments using proprietary Straumann CARES (group C) vs nonproprietary Astra Atlantis (group D) material. Stiffness and strength were assessed and calculated statistically with the Wilcoxon rank sum test. Cross-sections of each tested group were inspected microscopically. RESULTS Loaded LS2 crowns, implants, and abutment screws in all tested specimens (groups A, B, C, and D) did not show any visible fractures. For an analysis of titanium abutments (groups A and B), stiffness and strength showed equally high stability. In contrast, proprietary and nonproprietary customized zirconia abutments exhibited statistically significant differences with a mean strength of 366 N (Astra) and 541 N (CARES) (P < .05); as well as a mean stiffness of 884 N/mm (Astra) and 1,751 N/mm (CARES) (P < .05), respectively. Microscopic cross-sections revealed cracks in all zirconia abutments (groups C and D) below the implant shoulder. CONCLUSION Depending on the abutment design, prefabricated titanium abutment and proprietary customized zirconia implant-abutment connections in conjunction with monolithic LS2 crowns had the best results in this laboratory investigation.

Influence of Abutment Design on Stiffness, Strength, and Failure of Implant-Supported Monolithic Resin Nano Ceramic (RNC) Crowns

BACKGROUND Recent technical development allows the digital manufacturing of monolithic reconstructions with high-performance materials. For implant-supported crowns, the fixation requires an abutment design onto which the reconstruction can be bonded. PURPOSE The aim of this laboratory investigation was to analyze stiffness, strength, and failure modes of implant-supported, computer-assisted design and computer-aided manufacturing (CAD/CAM)-generated resin nano ceramic (RNC) crowns bonded to three different titanium abutments. MATERIALS AND METHODS Eighteen monolithic RNC crowns were produced and loaded in a universal testing machine under quasi-static condition according to DIN ISO 14801. With regard to the type of titanium abutment, three groups were defined: (1) prefabricated cementable standard; (2) CAD/CAM-constructed individualized; and (3) novel prefabricated bonding base. Stiffness and strength were measured and analyzed statistically with Wilcoxon rank sum test. Sections of the specimens were examined microscopically. RESULTS Stiffness demonstrated high stability for all specimens loaded in the physiological loading range with means and standard deviations of 1,579 ± 120 N/mm (group A), 1,733 ± 89 N/mm (group B), and 1,704 ± 162 N/mm (group C). Mean strength of the novel prefabricated bonding base (group C) was 17% lower than of the two other groups. Plastic deformations were detectable for all implant-abutment crown connections. CONCLUSIONS Monolithic implant crowns made of RNC seem to represent a feasible and stable prosthetic construction under laboratory testing conditions with strength higher than the average occlusal force, independent of the different abutment designs used in this investigation.

The role of transforming growth factor beta signaling in cardiac hypertrophy and fibrosis in heart failure

Objective. To determine whether transforming growth factor beta (TGF-β) receptor blockade using an oral antagonist has an effect on cardiac myocyte size in the hearts of transgenic mice with a heart failure phenotype. ^ Methods. In this pilot experimental study, cardiac tissue sections from the hearts of transgenic mice overexpressing tumor necrosis factor (MHCsTNF mice) having a phenotype of heart failure and wild-type mice, treated with an orally available TGF-β receptor antagonist were stained with wheat germ agglutinin to delineate the myocyte cell membrane and imaged using fluorescence microscopy. Using MetaVue software, the cardiac myocyte circumference was traced and the cross sectional area (CSA) of individual myocytes were measured. Measurements were repeated at the epicardial, mid-myocardial and endocardial levels to ensure adequate sampling and to minimize the effect of regional variations in myocyte size. ANOVA testing with post-hoc pairwise comparisons was done to assess any difference between the drug-treated and diluent-treated groups. ^ Results. There were no statistically significant differences in the average myocyte CSA measured at the epicardial, mid-myocardial or endocardial levels between diluent treated littermate control mice, drug treated normal mice, diluent-treated transgenic mice and drug-treated transgenic mice. There was no difference between the average pan-myocardial cross sectional area between any of the four groups mentioned above. ^ Conclusions. TGF-β receptor blockade using oral TGF-β receptor antagonist does not alter myocyte size in MHCsTNF mice that have a phenotype of heart failure. ^

Case-control study of factors associated with virologic failure in HIV-infected children on HAART in Botswana, a developing African country

According to the United Nations Program on HIV/AIDS (UNAIDS, 2008), in 2007 about 67 per cent of all HIV-infected patients in the world were in Sub-Saharan Africa, with 35% of new infections and 38% of the AIDS deaths occurring in Southern Africa. Globally, the number of children younger than 15 years of age infected with HIV increased from 1.6 million in 2001 to 2.0 million in 2007 and almost 90% of these were in Sub-Saharan Africa. (UNAIDS, 2008).^ Both clinical and laboratory monitoring of children on Highly Active Anti-Retroviral Therapy (HAART) are important and necessary to optimize outcomes. Laboratory monitoring of HIV viral load and genotype resistance testing, which are important in patient follow-up to optimize treatment success, are both generally expensive and beyond the healthcare budgets of most developing countries. This is especially true for the impoverished Sub-Saharan African nations. It is therefore important to identify those factors that are associated with virologic failure in HIV-infected Sub-Saharan African children. This will inform practitioners in these countries so that they can predict which patients are more likely to develop virologic failure and therefore target the limited laboratory monitoring budgets towards these at-risk patients. The objective of this study was to examine those factors that are associated with virologic failure in HIV-infected children taking Highly Active Anti-retroviral Therapy in Botswana, a developing Sub-Saharan African country. We examined these factors in a Case-Control study using medical records of HIV-infected children and adolescents on HAART at the Botswana-Baylor Children's Clinical Center of Excellence (BBCCCOE) in Gaborone, Botswana. Univariate and Multivariate Regression Analyses were performed to identify predictors of virologic failure in these children.^ The study population comprised of 197 cases (those with virologic failure) and 544 controls (those with virologic success) with ages ranging from 3 months to 16 years at baseline. Poor adherence (pill count <95% on at least 3 consecutive occasions) was the strongest independent predictor of virologic failure (adjusted OR = 269.97, 95% CI = 104.13 to 699.92; P < 0.001). Other independent predictors of virologic failure identified were: First Line NNRTI with Nevirapine (OR = 2.99, 95% CI = 1.19 to7.54; P = 0.020), Baseline HIV-1 Viral Load >750,000/ml (OR = 257, 95% CI = 1.47 to 8.63; P = 0.005), Positive History of PMTCT (OR = 11.65, 95% CI = 3.04-44.57; P < 0.001), Multiple Care-givers (>=3) (OR = 2.56, 95% CI = 1.06 to 6.19; P = 0.036) and Residence in a Village (OR = 2.85, 95% CI = 1.36 to 5.97; P = 0.005).^ The results of this study may help to improve virologic outcomes and reduce the costs of caring for HIV-infected children in resource-limited settings. ^ Keywords: Virologic Failure, Highly Active Anti-Retroviral Therapy, Sub-Saharan Africa, Children, Adherence.^

Means and method for soil testing

An inexpensive device which is easily operated to accurately measure the Coulomb parameters of the soil. The Coulomb parameters are used in Coulomb's equation to calculate the shearing stresses along a failure surface of the soil. The device includes an instrument to test soil shear strength to which several weights have been added. To obtain the Coulomb parameters, the instrument is placed on the soil to be tested and weights are incrementally added to it. The instrument is rotated at each weight increment and the shearing stresses are read from its calibrated dial. The stresses are plotted on a graph from which the Coulomb parameters are determined. The shearing stress of the soil with any known force applied to it can then be determined.

Failure and impact behavior of facade panels made of glass fiber reinforced cement(GRC)

GRC is a cementitious composite material made up of a cement mortar matrix and chopped glass fibers. Due to its outstanding mechanical properties, GRC has been widely used to produce cladding panels and some civil engineering elements. Impact failure of cladding panels made of GRC may occur during production if some tool falls onto the panel, due to stone or other objects impacting at low velocities or caused by debris projected after a blast. Impact failure of a front panel of a building may have not only an important economic value but also human lives may be at risk if broken pieces of the panel fall from the building to the pavement. Therefore, knowing GRC impact strength is necessary to prevent economic costs and putting human lives at risk. One-stage light gas gun is an impact test machine capable of testing different materials subjected to impact loads. An experimental program was carried out, testing GRC samples of five different formulations, commonly used in building industry. Steel spheres were shot at different velocities on square GRC samples. The residual velocity of the projectiles was obtained both using a high speed camera with multiframe exposure and measuring the projectile’s penetration depth in molding clay blocks. Tests were performed on young and artificially aged GRC samples to compare GRC’s behavior when subjected to high strain rates. Numerical simulations using a hydrocode were made to analyze which parameters are most important during an impact event. GRC impact strength was obtained from test results. Also, GRC’s embrittlement, caused by GRC aging, has no influence on GRC impact behavior due to the small size of the projectile. Also, glass fibers used in GRC production only maintain GRC panels’ integrity but have no influence on GRC’s impact strength. Numerical models have reproduced accurately impact tests.

High fidelity simulations of failure in fiber-reinforced composites

Los ensayos virtuales de materiales compuestos han aparecido como un nuevo concepto dentro de la industria aeroespacial, y disponen de un vasto potencial para reducir los enormes costes de certificación y desarrollo asociados con las tediosas campañas experimentales, que incluyen un gran número de paneles, subcomponentes y componentes. El objetivo de los ensayos virtuales es sustituir algunos ensayos por simulaciones computacionales con alta fidelidad. Esta tesis es una contribución a la aproximación multiescala desarrollada en el Instituto IMDEA Materiales para predecir el comportamiento mecánico de un laminado de material compuesto dadas las propiedades de la lámina y la intercara. La mecánica de daño continuo (CDM) formula el daño intralaminar a nivel constitutivo de material. El modelo de daño intralaminar se combina con elementos cohesivos para representar daño interlaminar. Se desarrolló e implementó un modelo de daño continuo, y se aplicó a configuraciones simples de ensayos en laminados: impactos de baja y alta velocidad, ensayos de tracción, tests a cortadura. El análisis del método y la correlación con experimentos sugiere que los métodos son razonablemente adecuados para los test de impacto, pero insuficientes para el resto de ensayos. Para superar estas limitaciones de CDM, se ha mejorado la aproximación discreta de elementos finitos enriqueciendo la cinemática para incluir discontinuidades embebidas: el método extendido de los elementos finitos (X-FEM). Se adaptó X-FEM para un esquema explícito de integración temporal. El método es capaz de representar cualitativamente los mecanismos de fallo detallados en laminados. Sin embargo, los resultados muestran inconsistencias en la formulación que producen resultados cuantitativos erróneos. Por último, se ha revisado el método tradicional de X-FEM, y se ha desarrollado un nuevo método para superar sus limitaciones: el método cohesivo X-FEM estable. Las propiedades del nuevo método se estudiaron en detalle, y se concluyó que el método es robusto para implementación en códigos explícitos dinámicos escalables, resultando una nueva herramienta útil para la simulación de daño en composites. Virtual testing of composite materials has emerged as a new concept within the aerospace industry. It presents a very large potential to reduce the large certification costs and the long development times associated with the experimental campaigns, involving the testing of a large number of panels, sub-components and components. The aim of virtual testing is to replace some experimental tests by high-fidelity numerical simulations. This work is a contribution to the multiscale approach developed in Institute IMDEA Materials to predict the mechanical behavior of a composite laminate from the properties of the ply and the interply. Continuum Damage Mechanics (CDM) formulates intraply damage at the the material constitutive level. Intraply CDM is combined with cohesive elements to model interply damage. A CDM model was developed, implemented, and applied to simple mechanical tests of laminates: low and high velocity impact, tension of coupons, and shear deformation. The analysis of the results and the comparison with experiments indicated that the performance was reasonably good for the impact tests, but insuficient in the other cases. To overcome the limitations of CDM, the kinematics of the discrete finite element approximation was enhanced to include mesh embedded discontinuities, the eXtended Finite Element Method (X-FEM). The X-FEM was adapted to an explicit time integration scheme and was able to reproduce qualitatively the physical failure mechanisms in a composite laminate. However, the results revealed an inconsistency in the formulation that leads to erroneous quantitative results. Finally, the traditional X-FEM was reviewed, and a new method was developed to overcome its limitations, the stable cohesive X-FEM. The properties of the new method were studied in detail, and it was demonstrated that the new method was robust and can be implemented in a explicit finite element formulation, providing a new tool for damage simulation in composite materials.

Mechanical behavior and failure micromechanisms of hybrid 3D woven composites in tension

The deformation and failure micromechanisms of a hybrid 3D woven composite were studied in tension. Plain and open-hole composite coupons were tested in tension until failure in the fill and warp directions, as well as fiber tows extracted from the dry fabric and impregnated with the matrix. The macroscopic evolution of damage in the composite coupons was assessed by means of periodic unloading–reloading (to obtain the elastic modulus and the residual strain), whereas the microscopic mechanism were established by means of X-ray computed microtomography. To this end, specimens were periodically removed from the mechanical testing machine and infiltrated with ZnI-containing liquid to assess the main damage modes as a function of the applied strain. The experimental observations and the predictions of an isostrain model were used to understand the key factors controlling the elastic modulus, strength and notch sensitivity of hybrid 3D woven composites in tension. It was found that the full contribution of the glass fibers to the composite strength was not employed, due to the premature fracture of the carbon fibers, but their presence increased the fracture strain and the energy dissipated during fracture. Thus, hybridization of the 3D woven composite led to a notch-insensitive behavior as demonstrated by open-hole tests

Fail-Safe Testing of Web Applications

This dissertation introduces an approach to generate tests to test fail-safe behavior for web applications. We apply the approach to a commercial web application. We build models for both behavioral and mitigation requirements. We create mitigation tests from an existing functional black box test suite by determining failure type and points of failure in the test suite and weaving required mitigation based on weaving rules to generate a test suite that tests proper mitigation of failures. A genetic algorithm (GA) is used to determine points of failure and type of failure that needs to be tested. Mitigation test paths are woven into the behavioral test at the point of failure based on failure specific weaving rules. A simulator was developed to evaluate choice of parameters for the genetic algorithm. We showed how to tune the fitness function and performed tuning experiments for GA to determine what values to use for exploration weight and prospecting weight. We found that higher defect densities make prospecting and mining more successful, while lower mitigation defect densities need more exploration. We compare efficiency and effectiveness of the approach. First, the GA approach is compared to random selection. The results show that the GA performance was better than random selection and that the approach was robust when the search space increased. Second, we compare the GA against four coverage criteria. The results of comparison show that test requirements generated by a genetic algorithm (GA) are more efficient than three of the four coverage criteria for large search spaces. They are equally effective. For small search spaces, the genetic algorithm is less effective than three of the four coverage criteria. The fourth coverage criteria is too weak and unable to find all defects in almost all cases. We also present a large case study of a mortgage system at one of our industrial partners and show how we formalize the approach. We evaluate the use of a GA to create test requirements. The evaluation includes choice of initial population, multiplicity of runs and a discussion of the cost of evaluating fitness. Finally, we build a selective regression testing approach based on types of changes (add, delete, or modify) that could occur in the behavioral model, the fault model, the mitigation models, the weaving rules, and the state-event matrix. We provide a systematic method by showing the formalization steps for each type of change to the various models.

Performance testing of an improved driver restraint system for subcompact cars. Volume II - final report.

National Highway Traffic Safety Administration, Washington, D.C.

Heart failure management programmes in Europe

Background The ESC guidelines recommend that an organised system of specialist heart failure (HF) care should be established to improve outcomes of HF patients. The aim of this study was therefore to identify the number and the content of HF management programmes in Europe. Method A two-phase descriptive study was conducted: an initial screening to identify the existence of HF management programmes; and a survey to describe the content in countries where at least 30% of the hospitals had a programme. Results Of the 43 European countries approached, 26 (60%) estimated the percentage of HF management programmes. Seven countries reported that they had such programmes in more than 30% of their hospitals. Of the 673 hospitals responding to the questionnaire, 426 (63%) had a HF management programme. Half of the programmes (n = 205) were located in an outpatient clinic. In the UK a combination of hospital and home-based programmes was common (75%). The most programmes included physical examination, telephone consultation, patient education, drug titration and diagnostic testing. Most (89%) programmes involved nurses and physicians. Multi-disciplinary teams were active in 56% of the HF programmes. The most prominent differences between the 7 countries were the degree of collaboration with home care and GP's, the role in palliative care and the funding. Conclusion Only a few European countries have a large number of organised programmes for HF care and follow up. To improve outcomes of HF patients throughout Europe more effort should be taken to increase the number of these programmes in all countries.