The Utility of Cardiopulmonary Exercise Testing in Difficult Asthma

Background: Unexplained persistent breathlessness in patients with difficult asthma despite multiple treatments is a common clinical problem. Cardiopulmonary exercise testing (CPX) may help identify the mechanism causing these symptoms, allowing appropriate management.

Methods: This was a retrospective analysis of patients attending a specialist-provided service for difficult asthma who proceeded to CPX as part of our evaluation protocol. Patient demographics, lung function, and use of health care and rescue medication were compared with those in patients with refractory asthma. Medication use 6 months following CPX was compared with treatment during CPX.

Results: Of 302 sequential referrals, 39 patients underwent CPX. A single explanatory feature was identified in 30 patients and two features in nine patients: hyperventilation (n = 14), exercise-induced bronchoconstriction (n = 8), submaximal test (n = 8), normal test (n = 8), ventilatory limitation (n = 7), deconditioning (n = 2), cardiac ischemia (n = 1). Compared with patients with refractory asthma, patients without “pulmonary limitation” on CPX were prescribed similar doses of inhaled corticosteroid (ICS) (median, 1,300 µg [interquartile range (IQR), 800-2,000 µg] vs 1,800 µg [IQR, 1,000-2,000 µg]) and rescue oral steroid courses in the previous year (median, 5 [1-6] vs 5 [1-6]). In this group 6 months post-CPX, ICS doses were reduced (median, 1,300 µg [IQR, 800-2,000 µg] to 800 µg [IQR, 400-1,000 µg]; P < .001) and additional medication treatment was withdrawn (n = 7). Patients with pulmonary limitation had unchanged ICS doses post CPX and additional therapies were introduced.

Conclusions: In difficult asthma, CPX can confirm that persistent exertional breathlessness is due to asthma but can also identify other contributing factors. Patients with nonpulmonary limitation are prescribed inappropriately high doses of steroid therapy, and CPX can identify the primary mechanism of breathlessness, facilitating steroid reduction.

A Multicenter Blinded Study to Evaluate KRAS Mutation Testing Methodologies in the Clinical Setting

Evidence that activating mutations of the KRAS oncogene abolish the response to anti-epidermal growth factor receptor therapy has revolutionized the treatment of advanced colorectal cancer. This has resulted in the urgent demand for KRAS mutation testing in the clinical setting to aid choice of therapy. The Am of this study was to evaluate six different KRAS mutation detection methodologies on two series of primary colorectal cancer samples. Two series of 80 frozen and 74 formalin-fixed paraffin-embedded tissue samples were sourced and DNA was extracted at a central site before distribution to seven different testing sites. KRAS mutations in codons 12 and 13 were assessed by using single strand conformation polymorphism analysis, pyrosequencing, high resolution melting analysis, dideoxy sequencing, or the commercially available TIB Molbiol (Berlin, Germany) or DxS Diagnostic innovations (Manchester, UK) kits. in frozen tissue samples, concordance in KRAS status (defined as consensus in at least five assays) was observed in 66/80 (83%) cases. In par-affin tissue, concordance was 46/74 (63%) if all assays were considered or 71/74 (96%) using the five best performing assays. These results demonstrate that a variety of detection methodologies are suitable and provide comparable results for KRAS mutation analysis of clinical samples. (J Mol Diagn 2009, 11:543-552; DOI: 10.2353/jmoldx.2009.090057)

Towards accurate estimation of the proportion of true null hypotheses in multiple testing

Background

Biomedical researchers are now often faced with situations where it is necessary to test a large number of hypotheses simultaneously, eg, in comparative gene expression studies using high-throughput microarray technology. To properly control false positive errors the FDR (false discovery rate) approach has become widely used in multiple testing. The accurate estimation of FDR requires the proportion of true null hypotheses being accurately estimated. To date many methods for estimating this quantity have been proposed. Typically when a new method is introduced, some simulations are carried out to show the improved accuracy of the new method. However, the simulations are often very limited to covering only a few points in the parameter space.

Results

Here I have carried out extensive in silico experiments to compare some commonly used methods for estimating the proportion of true null hypotheses. The coverage of these simulations is unprecedented thorough over the parameter space compared to typical simulation studies in the literature. Thus this work enables us to draw conclusions globally as to the performance of these different methods. It was found that a very simple method gives the most accurate estimation in a dominantly large area of the parameter space. Given its simplicity and its overall superior accuracy I recommend its use as the first choice for estimating the proportion of true null hypotheses in multiple testing.

Beyond the United States and Japan: Testing Yamagishi's emancipation theory of trust across 31 nations

We examined the relationship between Individualism/Collectivism and generalized social trust across 31 European nations participating in the European Social Survey. Using multi-level regression analyses, the current study provides the first empirical investigation of the effects of cultural norms of Individualism/Collectivism on generalized social trust while accounting for individuals' own cultural orientations within the same analysis. The results provide clear support for Yamagishi and Yamagishi (1994) emancipation theory of trust, showing a significant and positive relationship between Individualism/Collectivism and generalized social trust, over and above the effect of a country political history of communism and ethnic heterogeneity. Having controlled for individual effects of Individualism/Collectivism it is clear that the results of the current analysis cannot be reduced to an individual-level explanation, but must be interpreted within the context Of macrosocial processes. We conclude by discussing potential mechanisms that could explain why national individualism is more likely to foster trust among people than collectivism.

Microcomputed tomography imaging in a rat model of delayed union/non-union fracture

We aimed to develop a clinically relevant delayed union/non-union fracture model to evaluate a cell therapy intervention repair strategy. Histology, three-dimensional (3D) micro-computed tomography (micro-CT) imaging and mechanical testing were utilized to develop an analytical protocol for qualitative and quantitative assessment of fracture repair. An open femoral diaphyseal osteotomy, combined with periosteal diathermy and endosteal excision, was held in compression by a four pin unilateral external fixator. Three delayed union/non-union fracture groups established at 6 weeks-(a) a control group, (b) a cell therapy group, and (c) a group receiving phosphate-buffered saline (PBS) injection alone-were examined subsequently at 8 and 14 weeks. The histological response was combined fibrous and cartilaginous non-unions in groups A and B with fibrous non-unions in group C. Mineralized callus volume/total volume percentage showed no statistically significant differences between groups. Endosteal calcified tissue volume/endosteal tissue volume, at the center of the fracture site, displayed statistically significant differences between 8 and 14 weeks for cell and PBS intervention groups but not for the control group. The percentage load to failure was significantly lower in the control and cell treatment groups than in the PBS alone group. High-resolution micro-CT imaging provides a powerful tool to augment characterization of repair in delayed union/non-union fractures together with outcomes such as histology and mechanical strength measurement. Accurate, nondestructive, 3D identification of mineralization progression in repairing fractures is enabled in the presence or absence of intervention strategies. (c) 2007 Orthopaedic Research Society.

Testing quantum contextuality of continuous-variable states

We investigate the violation of noncontextuality by a class of continuous-variable states, including variations of entangled coherent states and a two-mode continuous superposition of coherent states. We generalize the Kochen-Specker (KS) inequality discussed by Cabello [A. Cabello, Phys. Rev. Lett. 101, 210401 (2008)] by using effective bidimensional observables implemented through physical operations acting on continuous-variable states, in a way similar to an approach to the falsification of Bell-Clauser-Horne-Shimony-Holt inequalities put forward recently. We test for state-independent violation of KS inequalities under variable degrees of state entanglement and mixedness. We then demonstrate theoretically the violation of a KS inequality for any two-mode state by using pseudospin observables and a generalized quasiprobability function.

Cement mantle fatigue failure in total hip replacement: Experimental and computational testing

One possible loosening mechanism of the femoral component in total hip replacement is fatigue cracking of the cement mantle. A computational method capable of simulating this process may therefore be a useful tool in the preclinical evaluation of prospective implants. In this study, we investigated the ability of a computational method to predict fatigue cracking in experimental models of the implanted femur construct. Experimental specimens were fabricated such that cement mantle visualisation was possible throughout the test. Two different implant surface finishes were considered: grit blasted and polished. Loading was applied to represent level gait for two million cycles. Computational (finite element) models were generated to the same geometry as the experimental specimens, with residual stress and porosity simulated in the cement mantle. Cement fatigue and creep were modelled over a simulated two million cycles. For the polished stem surface finish, the predicted fracture locations in the finite element models closely matched those on the experimental specimens, and the recorded stem displacements were also comparable. For the grit blasted stem surface finish, no cement mantle fractures were predicted by the computational method, which was again in agreement with the experimental results. It was concluded that the computational method was capable of predicting cement mantle fracture and subsequent stem displacement for the structure considered. (C) 2006 Elsevier Ltd. All rights reserved.

The pace of Holocene vegetation change - testing for synchronous developments

Mid to high latitude forest ecosystems have undergone several major compositional changes during the Holocene. The temporal and spatial patterns of these vegetation changes hold potential information to their causes and triggers. Here we test the hypothesis that the timing of vegetation change was synchronous on a sub-continental scale, which implies a common trigger or a step-like change in climate parameters. Pollen diagrams from selected European regions were statistically divided into assemblage zones and the temporal pattern of the zone boundaries analysed. The results show that the temporal pattern of vegetation change was significantly different from random. Times of change cluster around8.2, 4.8, 3.7, and 1.2 ka, while times of higher than average stability were found around 2.1 and 5.1 ka.Compositional changes linked to the expansion of Corylus avellana and Alnus glutinosa centre around 10.6 and 9.5 ka, respectively. A climatic trigger initiating these changes may have occurred 0.5 to 1 ka earlier, respectively. The synchronous expansion of C. avellana and A. glutinosa exemplify that dispersal is not necessarily followed by population expansion. The partly synchronous, partly random expansion of A. glutinosa in adjacent European regions exemplifies that sudden synchronous population expansions are not species specific traits but vary regionally.

Molecular testing of respiratory swabs aids early recognition of meningococcal disease in children

Early meningococcal disease (MD) diagnosis is difficult. We assessed rapid molecular testing of respiratory specimens. We performed genotyping of respiratory swabs, blood, and cerebrospinal fluid from children with suspected disease and nasal swabs (NSs) from matched controls. Thirty-nine of 104 suspected cases had confirmed disease. Four controls were carriers. Throat swab ctrA and porA testing for detection of disease gave a sensitivity of 81% (17/21), specificity of 100% (44/44), positive predictive value (PPV) of 100% (17/17), negative predictive value (NPV) of 92% (44/48), and relative risk of 12. NS ctrA and porA testing gave a sensitivity of 51% (20/39), specificity of 95% (62/65), PPV of 87% (20/23), NPV of 77% (62/81), and relative risk of 4. Including only the 86 NSs taken within 48 h of presentation, the results were sensitivity of 60% (18/30), specificity of 96% (54/56), PPV of 90% (18/20), NPV of 82% (54/66), and relative risk of 5. Swab type agreement was excellent (kappa 0.80, P

Political Violence and Child Adjustment in Northern Ireland: Testing Pathways in a Social-Ecological Model Including Single- and Two-Parent Families

Moving beyond simply documenting that political violence negatively impacts children, we tested a social ecological hypothesis for relations between political violence and child outcomes. Participants were 700 mother child (M = 12.1 years, SD = 1.8) dyads from 18 working-class, socially deprived areas in Belfast, Northern Ireland, including single- and two-parent families. Sectarian community violence was associated with elevated family conflict and children's reduced security about multiple aspects of their social environment (i.e., family, parent child relations, and community), with links to child adjustment problems and reductions in prosocial behavior. By comparison, and consistent with expectations, links with negative family processes, child regulatory problems, and child outcomes were less consistent for nonsectarian community violence. Support was found for a social ecological model for relations between political violence and child outcomes among both single- and two-parent families, with evidence that emotional security and adjustment problems were more negatively affected in single-parent families. The implications for understanding social ecologies of political violence and children's functioning are discussed.