Phylogenetic approach reveals that virus genotype largely determines HIV set-point viral load

HIV virulence, i.e. the time of progression to AIDS, varies greatly among patients. As for other rapidly evolving pathogens of humans, it is difficult to know if this variance is controlled by the genotype of the host or that of the virus because the transmission chain is usually unknown. We apply the phylogenetic comparative approach (PCA) to estimate the heritability of a trait from one infection to the next, which indicates the control of the virus genotype over this trait. The idea is to use viral RNA sequences obtained from patients infected by HIV-1 subtype B to build a phylogeny, which approximately reflects the transmission chain. Heritability is measured statistically as the propensity for patients close in the phylogeny to exhibit similar infection trait values. The approach reveals that up to half of the variance in set-point viral load, a trait associated with virulence, can be heritable. Our estimate is significant and robust to noise in the phylogeny. We also check for the consistency of our approach by showing that a trait related to drug resistance is almost entirely heritable. Finally, we show the importance of taking into account the transmission chain when estimating correlations between infection traits. The fact that HIV virulence is, at least partially, heritable from one infection to the next has clinical and epidemiological implications. The difference between earlier studies and ours comes from the quality of our dataset and from the power of the PCA, which can be applied to large datasets and accounts for within-host evolution. The PCA opens new perspectives for approaches linking clinical data and evolutionary biology because it can be extended to study other traits or other infectious diseases.

Transcranial Doppler-detected cerebral embolic load during transcatheter aortic valve implantation

Transcatheter aortic valve implantation (TAVI) is an alternative to surgery for high-risk patients with severe aortic valve stenosis. Periprocedural stroke is reported at an incidence up to 10%. Magnetic resonance imaging studies have identified new onset of clinically silent ischaemic cerebral lesions more frequently (68-84%). So far, few data are available about cerebral embolism during TAVI. The aim of this study was to determine the frequency of high-intensity transient signals (HITS) and to explore differences in the HITS pattern between transfemoral and transapical access and between self-expanding (SE) and balloon-expandable (BE) deployment technique.

Increasing Utilization of US Electric Grids via Smart Technologies: Integration of Load Management, Real Time Pricing, Renewables, EVs and Smart Grid Sensors

Electric power grids throughout the world suffer from serious inefficiencies associated with under-utilization due to demand patterns, engineering design and load following approaches in use today. These grids consume much of the world’s energy and represent a large carbon footprint. From material utilization perspectives significant hardware is manufactured and installed for this infrastructure often to be used at less than 20-40% of its operational capacity for most of its lifetime. These inefficiencies lead engineers to require additional grid support and conventional generation capacity additions when renewable technologies (such as solar and wind) and electric vehicles are to be added to the utility demand/supply mix. Using actual data from the PJM [PJM 2009] the work shows that consumer load management, real time price signals, sensors and intelligent demand/supply control offer a compelling path forward to increase the efficient utilization and carbon footprint reduction of the world’s grids. Underutilization factors from many distribution companies indicate that distribution feeders are often operated at only 70-80% of their peak capacity for a few hours per year, and on average are loaded to less than 30-40% of their capability. By creating strong societal connections between consumers and energy providers technology can radically change this situation. Intelligent deployment of smart sensors, smart electric vehicles, consumer-based load management technology very high saturations of intermittent renewable energy supplies can be effectively controlled and dispatched to increase the levels of utilization of existing utility distribution, substation, transmission, and generation equipment. The strengthening of these technology, society and consumer relationships requires rapid dissemination of knowledge (real time prices, costs & benefit sharing, demand response requirements) in order to incentivize behaviors that can increase the effective use of technological equipment that represents one of the largest capital assets modern society has created.

On Ribosome Load, Codon Bias and Protein Abundance

Different codons encoding the same amino acid are not used equally in protein-coding sequences. In bacteria, there is a bias towards codons with high translation rates. This bias is most pronounced in highly expressed proteins, but a recent study of synthetic GFP-coding sequences did not find a correlation between codon usage and GFP expression, suggesting that such correlation in natural sequences is not a simple property of translational mechanisms. Here, we investigate the effect of evolutionary forces on codon usage. The relation between codon bias and protein abundance is quantitatively analyzed based on the hypothesis that codon bias evolved to ensure the efficient usage of ribosomes, a precious commodity for fast growing cells. An explicit fitness landscape is formulated based on bacterial growth laws to relate protein abundance and ribosomal load. The model leads to a quantitative relation between codon bias and protein abundance, which accounts for a substantial part of the observed bias for E. coli. Moreover, by providing an evolutionary link, the ribosome load model resolves the apparent conflict between the observed relation of protein abundance and codon bias in natural sequences and the lack of such dependence in a synthetic gfp library. Finally, we show that the relation between codon usage and protein abundance can be used to predict protein abundance from genomic sequence data alone without adjustable parameters.

Stress and Strain Adaptation in Load-Dependent Remodeling of the Embryonic Left Ventricle

Altered pressure in the developing left ventricle (LV) results in altered morphology and tissue material properties. Mechanical stress and strain may play a role in the regulating process. This study showed that confocal microscopy, three-dimensional reconstruction, and finite element analysis can provide a detailed model of stress and strain in the trabeculated embryonic heart. The method was used to test the hypothesis that end-diastolic strains are normalized after altered loading of the LV during the stages of trabecular compaction and chamber formation. Stage-29 chick LVs subjected to pressure overload and underload at stage 21 were reconstructed with full trabecular morphology from confocal images and analyzed with finite element techniques. Measured material properties and intraventricular pressures were specified in the models. The results show volume-weighted end-diastolic von Mises stress and strain averaging 50–82% higher in the trabecular tissue than in the compact wall. The volume-weighted-average stresses for the entire LV were 115, 64, and 147Pa in control, underloaded, and overloaded models, while strains were 11, 7, and 4%; thus, neither was normalized in a volume-weighted sense. Localized epicardial strains at mid-longitudinal level were similar among the three groups and to strains measured from high-resolution ultrasound images. Sensitivity analysis showed changes in material properties are more significant than changes in geometry in the overloaded strain adaptation, although resulting stress was similar in both types of adaptation. These results emphasize the importance of appropriate metrics and the role of trabecular tissue in evaluating the evolution of stress and strain in relation to pressure-induced adaptation.

On Ribosome Load, Codon Bias and Protein Abundance

Different codons encoding the same amino acid are not used equally in protein-coding sequences. In bacteria, there is a bias towards codons with high translation rates. This bias is most pronounced in highly expressed proteins, but a recent study of synthetic GFP-coding sequences did not find a correlation between codon usage and GFP expression, suggesting that such correlation in natural sequences is not a simple property of translational mechanisms. Here, we investigate the effect of evolutionary forces on codon usage. The relation between codon bias and protein abundance is quantitatively analyzed based on the hypothesis that codon bias evolved to ensure the efficient usage of ribosomes, a precious commodity for fast growing cells. An explicit fitness landscape is formulated based on bacterial growth laws to relate protein abundance and ribosomal load. The model leads to a quantitative relation between codon bias and protein abundance, which accounts for a substantial part of the observed bias for E. coli. Moreover, by providing an evolutionary link, the ribosome load model resolves the apparent conflict between the observed relation of protein abundance and codon bias in natural sequences and the lack of such dependence in a synthetic gfp library. Finally, we show that the relation between codon usage and protein abundance can be used to predict protein abundance from genomic sequence data alone without adjustable parameters.

Assessment of total uncertainty in cocaine and benzoylecgonine wastewater load measurements

To check the effectiveness of campaigns preventing drug abuse or indicating local effects of efforts against drug trafficking, it is beneficial to know consumed amounts of substances in a high spatial and temporal resolution. The analysis of drugs of abuse in wastewater (WW) has the potential to provide this information. In this study, the reliability of WW drug consumption estimates is assessed and a novel method presented to calculate the total uncertainty in observed WW cocaine (COC) and benzoylecgonine (BE) loads. Specifically, uncertainties resulting from discharge measurements, chemical analysis and the applied sampling scheme were addressed and three approaches presented. These consist of (i) a generic model-based procedure to investigate the influence of the sampling scheme on the uncertainty of observed or expected drug loads, (ii) a comparative analysis of two analytical methods (high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry), including an extended cross-validation by influent profiling over several days, and (iii) monitoring COC and BE concentrations in WW of the largest Swiss sewage treatment plants. In addition, the COC and BE loads observed in the sewage treatment plant of the city of Berne were used to back-calculate the COC consumption. The estimated mean daily consumed amount was 107 ± 21 g of pure COC, corresponding to 321 g of street-grade COC.

A Kinetostatic Formulation for Load-Flow Visualization in Compliant Mechanisms

Load flow visualization, which is an important step in structural and machine assembly design may aid in the analysis and eventual synthesis of compliant mechanisms. In this paper, we present a kineto-static formulation to visualize load flow in compliant mechanisms. This formulation uses the concept of transferred forces to quantify load flow from input to the output of a compliant mechanism. The magnitude and direction of load flow in the constituent members enables functional decomposition of the compliant mechanism into (i) Constraints (C): members that are constrained to deform in a particular direction and (ii) Transmitters (T): members that transmit load to the output. Furthermore, it is shown that a constraint member and an adjacent transmitter member can be grouped together to constitute a fundamental building block known as an CT set whose load flow behavior is maximally decoupled from the rest of the mechanism. We can thereby explain the deformation behavior of a number of compliant mechanisms from literature by visualizing load flow, and identifying building blocks.

Planetary Gear Modal Vibration Experiments and Correlation against Lumped-Parameter and Finite Element Models

Experimental modal analysis techniques are applied to characterize the planar dynamic behavior of two spur planetary gears. Rotational and translational vibrations of the sun gear, carrier, and planet gears are measured. Experimentally obtained natural frequencies, mode shapes, and dynamic response are compared to the results from lumped-parameter and finite element models. Two qualitatively different classes of mode shapes in distinct frequency ranges are observed in the experiments and confirmed by the lumped-parameter model, which considers the accessory shafts and fixtures in the system to capture all of the natural frequencies and modes. The finite element model estimates the high-frequency modes that have significant tooth mesh deflection without considering the shafts and fixtures. The lumped-parameter and finite element models accurately predict the natural frequencies and modal properties established by experimentation. Rotational, translational, and planet mode types presented in published mathematical studies are confirmed experimentally. The number and types of modes in the low-frequency and high-frequency bands depend on the degrees of freedom in the central members and planet gears, respectively. The accuracy of natural frequency prediction is improved when the planet bearings have differing stiffnesses in the tangential and radial directions, consistent with the bearing load direction. (C) 2012 Elsevier Ltd. All rights reserved.

Viral load monitoring of antiretroviral therapy, cohort viral load and HIV transmission in Southern Africa: A mathematical modelling analysis

In low-income settings, treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission.

The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring

We examined the effect of switching to second-line antiretroviral therapy (ART) on mortality in patients who experienced immunological failure in ART programmes without access to routine viral load monitoring in sub-Saharan Africa.

Outcomes of antiretroviral treatment in programmes with and without routine viral load monitoring in Southern Africa

Objectives: To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with those in Malawi and Zambia, where monitoring is based on CD4 cell counts. Methods: We included 18 706 adult patients starting ART in South Africa and 80 937 patients in Zambia or Malawi. We examined CD4 responses in models for repeated measures and the probability of switching to second-line regimens, mortality and loss to follow-up in multistate models, measuring time from 6 months. Results: In South Africa, 9.8% [95% confidence interval (CI) 9.1–10.5] had switched at 3 years, 1.3% (95% CI 0.9–1.6) remained on failing first-line regimens, 9.2% (95% CI 8.5–9.8) were lost to follow-up and 4.3% (95% CI 3.9–4.8) had died. In Malawi and Zambia, more patients were on a failing first-line regimen [3.7% (95% CI 3.6–3.9], fewer patients had switched [2.1% (95% CI 2.0–2.3)] and more patients were lost to follow-up [15.3% (95% CI 15.0–15.6)] or had died [6.3% (95% CI 6.0–6.5)]. Median CD4 cell counts were lower in South Africa at the start of ART (93 vs. 132 cells/μl; P < 0.001) but higher after 3 years (425 vs. 383 cells/μl; P < 0.001). The hazard ratio comparing South Africa with Malawi and Zambia after adjusting for age, sex, first-line regimen and CD4 cell count was 0.58 (0.50–0.66) for death and 0.53 (0.48–0.58) for loss to follow-up. Conclusion: Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.