Viral load versus CD4⁺ monitoring and 5-year outcomes of antiretroviral therapy in HIV-positive children in Southern Africa: a cohort-based modelling study.

OBJECTIVES Many paediatric antiretroviral therapy (ART) programmes in Southern Africa rely on CD4⁺ to monitor ART. We assessed the benefit of replacing CD4⁺ by viral load monitoring. DESIGN A mathematical modelling study. METHODS A simulation model of HIV progression over 5 years in children on ART, parameterized by data from seven South African cohorts. We simulated treatment programmes with 6-monthly CD4⁺ or 6- or 12-monthly viral load monitoring. We compared mortality, second-line ART use, immunological failure and time spent on failing ART. In further analyses, we varied the rate of virological failure, and assumed that the rate is higher with CD4⁺ than with viral load monitoring. RESULTS About 7% of children were predicted to die within 5 years, independent of the monitoring strategy. Compared with CD4⁺ monitoring, 12-monthly viral load monitoring reduced the 5-year risk of immunological failure from 1.6 to 1.0% and the mean time spent on failing ART from 6.6 to 3.6 months; 1% of children with CD4⁺ compared with 12% with viral load monitoring switched to second-line ART. Differences became larger when assuming higher rates of virological failure. When assuming higher virological failure rates with CD4⁺ than with viral load monitoring, up to 4.2% of children with CD4⁺ compared with 1.5% with viral load monitoring experienced immunological failure; the mean time spent on failing ART was 27.3 months with CD4⁺ monitoring and 6.0 months with viral load monitoring. Conclusion: Viral load monitoring did not affect 5-year mortality, but reduced time on failing ART, improved immunological response and increased switching to second-line ART.

Sports after Busy Work: Work-Related Cognitive Failure Corresponds to Risk Bearing Behaviors and Athletic Injury

Although employees are encouraged to take exercise after work to keep physically fit, they should not suffer injury. Some sports injuries that occur after work appear to be work-related and preventable. This study investigated whether cognitive failure mediates the influence of mental work demands and conscientiousness on risk-taking and risky and unaware behaviour during after-work sports activities. Participants were 129 employees (36% female) who regularly took part in team sports after work. A structural equation model showed that work-related cognitive failure significantly mediated the influence of mental work demands on risky behaviour during sports (p < .05) and also mediated the directional link between conscientiousness and risky behaviour during sports (p < .05). A path from risky behaviour during sports to sports injuries in the last four weeks was also significant (p < .05). Performance constraints, time pressure, and task uncertainty are likely to increase cognitive load and thereby boost cognitive failures both during work and sports activities after work. Some sports injuries after work could be prevented by addressing the issue of work redesign.

Risk charts to guide targeted HIV-1 viral load monitoring of ART: development and validation in patients from resource-limited settings.

BACKGROUND HIV-1 RNA viral load (VL) testing is recommended to monitor antiretroviral therapy (ART) but not available in many resource-limited settings. We developed and validated CD4-based risk charts to guide targeted VL testing. METHODS We modeled the probability of virologic failure up to 5 years of ART based on current and baseline CD4 counts, developed decision rules for targeted VL testing of 10%, 20% or 40% of patients in seven cohorts of patients starting ART in South Africa, and plotted cut-offs for VL testing on colour-coded risk charts. We assessed the accuracy of risk chart-guided VL testing to detect virologic failure in validation cohorts from South Africa, Zambia and the Asia-Pacific. FINDINGS 31,450 adult patients were included in the derivation and 25,294 patients in the validation cohorts. Positive predictive values increased with the percentage of patients tested: from 79% (10% tested) to 98% (40% tested) in the South African, from 64% to 93% in the Zambian and from 73% to 96% in the Asia-Pacific cohorts. Corresponding increases in sensitivity were from 35% to 68% in South Africa, from 55% to 82% in Zambia and from 37% to 71% in Asia-Pacific. The area under the receiver-operating curve increased from 0.75 to 0.91 in South Africa, from 0.76 to 0.91 in Zambia and from 0.77 to 0.92 in Asia Pacific. INTERPRETATION CD4-based risk charts with optimal cut-offs for targeted VL testing may be useful to monitor ART in settings where VL capacity is limited.

Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality.

OBJECTIVE To determine the effect of nonadherence to antiretroviral therapy (ART) on virologic failure and mortality in naive individuals starting ART. DESIGN Prospective observational cohort study. METHODS Eligible individuals enrolled in the Swiss HIV Cohort Study, started ART between 2003 and 2012, and provided adherence data on at least one biannual clinical visit. Adherence was defined as missed doses (none, one, two, or more than two) and percentage adherence (>95, 90-95, and <90) in the previous 4 weeks. Inverse probability weighting of marginal structural models was used to estimate the effect of nonadherence on viral failure (HIV-1 viral load >500 copies/ml) and mortality. RESULTS Of 3150 individuals followed for a median 4.7 years, 480 (15.2%) experienced viral failure and 104 (3.3%) died, 1155 (36.6%) reported missing one dose, 414 (13.1%) two doses and, 333 (10.6%) more than two doses of ART. The risk of viral failure increased with each missed dose (one dose: hazard ratio [HR] 1.15, 95% confidence interval 0.79-1.67; two doses: 2.15, 1.31-3.53; more than two doses: 5.21, 2.96-9.18). The risk of death increased with more than two missed doses (HR 4.87, 2.21-10.73). Missing one to two doses of ART increased the risk of viral failure in those starting once-daily (HR 1.67, 1.11-2.50) compared with those starting twice-daily regimens (HR 0.99, 0.64-1.54, interaction P = 0.09). Consistent results were found for percentage adherence. CONCLUSION Self-report of two or more missed doses of ART is associated with an increased risk of both viral failure and death. A simple adherence question helps identify patients at risk for negative clinical outcomes and offers opportunities for intervention.

Implementation and Operational Research: Risk Charts to Guide Targeted HIV-1 Viral Load Monitoring of ART: Development and Validation in Patients From Resource-Limited Settings.

BACKGROUND HIV-1 RNA viral load (VL) testing is recommended to monitor antiretroviral therapy (ART) but not available in many resource-limited settings. We developed and validated CD4-based risk charts to guide targeted VL testing. METHODS We modeled the probability of virologic failure up to 5 years of ART based on current and baseline CD4 counts, developed decision rules for targeted VL testing of 10%, 20%, or 40% of patients in 7 cohorts of patients starting ART in South Africa, and plotted cutoffs for VL testing on colour-coded risk charts. We assessed the accuracy of risk chart-guided VL testing to detect virologic failure in validation cohorts from South Africa, Zambia, and the Asia-Pacific. RESULTS In total, 31,450 adult patients were included in the derivation and 25,294 patients in the validation cohorts. Positive predictive values increased with the percentage of patients tested: from 79% (10% tested) to 98% (40% tested) in the South African cohort, from 64% to 93% in the Zambian cohort, and from 73% to 96% in the Asia-Pacific cohort. Corresponding increases in sensitivity were from 35% to 68% in South Africa, from 55% to 82% in Zambia, and from 37% to 71% in Asia-Pacific. The area under the receiver operating curve increased from 0.75 to 0.91 in South Africa, from 0.76 to 0.91 in Zambia, and from 0.77 to 0.92 in Asia-Pacific. CONCLUSIONS CD4-based risk charts with optimal cutoffs for targeted VL testing maybe useful to monitor ART in settings where VL capacity is limited.

Ambulatory blood pressure and physical activity in heart failure

Background. Ambulatory blood pressure (ABP) measurement is a means of monitoring cardiac function in a noninvasive way, but little is known about ABP in heart failure (HF) patients. Blood pressure (BP) declines during sleep as protection from consistent BP load, a phenomenon termed "dipping." The aims of this study were (1) to compare BP dipping and physical activity between two groups of HF patients with different functional statuses and (2) to determine whether the strength of the association between ambulatory BP and PA is different between these two different functional statuses of HF. ^ Methods. This observational study used repeated measures of ABP and PA over a 24-hour period to investigate the profiles of BP and PA in community-based individuals with HF. ABP was measured every 30 minutes by using a SpaceLabs 90207, and a Basic Motionlogger actigraph was used to measure PA minute by minute. Fifty-six participants completed both BP and physical activity for a 24-hour monitoring period. Functional status was based on New York Heart Association (NYHA) ratings. There were 27 patients with no limitation of PA (NYHA class I HF) and 29 with some limitation of PA but no discomfort at rest (NYHA class II or III HF). The sample consisted of 26 men and 30 women, aged 45 to 91 years (66.96 ± 12.35). ^ Results. Patients with NYHA class I HF had significantly greater dipping percent than those with NYHA class II/III HF after controlling their left ventricular ejection fraction (LVEF). In a mixed model analysis (PROC MIXED, SAS Institute, v 9.1), PA was significantly related to ambulatory systolic and diastolic BP and mean arterial pressure. The strength of the association between PA and ABP readings was not significantly different for the two groups of patients. ^ Conclusions. These preliminary findings demonstrate differences between NYHA class I and class II/III of HF in BP dipping status and ABP but not PA. Longitudinal research is recommended to improve understanding of the influence of disease progression on changes in 24-hour physical activity and BP profiles of this patient population. ^ Key Words. Ambulatory Blood Pressure; Blood Pressure Dipping; Heart Failure; Physical Activity. ^

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.^

Prediction of bendig load capacity of timber beams by finite element method simulation of knots and grain deviation

A finite element model was used to simulate timberbeams with defects and predict their maximum load in bending. Taking into account the elastoplastic constitutive law of timber, the prediction of fracture load gives information about the mechanisms of timber failure, particularly with regard to the influence of knots, and their local graindeviation, on the fracture. A finite element model was constructed using the ANSYS element Plane42 in a plane stress 2D-analysis, which equates thickness to the width of the section to create a mesh which is as uniform as possible. Three sub-models reproduced the bending test according to UNE EN 408: i) timber with holes caused by knots; ii) timber with adherent knots which have structural continuity with the rest of the beam material; iii) timber with knots but with only partial contact between knot and beam which was artificially simulated by means of contact springs between the two materials. The model was validated using ten 45 × 145 × 3000 mm beams of Pinus sylvestris L. which presented knots and graindeviation. The fracture stress data obtained was compared with the results of numerical simulations, resulting in an adjustment error less of than 9.7%

Analytical bearing capacity of strip footing in weightless materials with power-law failure criteria

Sokolovskii’s method of characteristics is extended to provide analytical solutions for the ultimate load at the moment of plastic failure under plane-strain conditions of shallow strip foundations on weightless rigid-plastic media with a noncohesive power-law failure envelope. The formulation is made parametrically in terms of the instantaneous friction angle, and the key idea to obtain the bearing capacity is that information can be transmitted from the free surface (where external loads are known) to the contact plane of the foundation. The methodology can consider foundations adjacent to a slope, external surcharges at the free surface, and inclined loads (both on the slope and on the foundation). Sensitivity analyses illustrate the influence on bearing capacity of changes in the different geometrical parameters involved. An application example is presented and design plots are provided, and model predictions are compared with results of bearing capacity tests under low gravity.

Optical sensing of the fatigue damage state of CFRP under realistic aeronautical load sequences

We present an optical sensing methodology to estimate the fatigue damage state of structures made of carbon fiber reinforced polymer (CFRP), by measuring variations on the surface roughness. Variable amplitude loads (VAL), which represent realistic loads during aeronautical missions of fighter aircraft (FALSTAFF) have been applied to coupons until failure. Stiffness degradation and surface roughness variations have been measured during the life of the coupons obtaining a Pearson correlation of 0.75 between both variables. The data were compared with a previous study for Constant Amplitude Load (CAL) obtaining similar results. Conclusions suggest that the surface roughness measured in strategic zones is a useful technique for structural health monitoring of CFRP structures, and that it is independent of the type of load applied. Surface roughness can be measured in the field by optical techniques such as speckle, confocal perfilometers and interferometry, among others.

Development of a procedure for the structural evaluation of superheavy load routes.

Texas Department of Transportation, Austin

Statistical tests of load-unload response ratio signals by lattice solid model: Implication to tidal triggering and earthquake prediction

Statistical tests of Load-Unload Response Ratio (LURR) signals are carried in order to verify statistical robustness of the previous studies using the Lattice Solid Model (MORA et al., 2002b). In each case 24 groups of samples with the same macroscopic parameters (tidal perturbation amplitude A, period T and tectonic loading rate k) but different particle arrangements are employed. Results of uni-axial compression experiments show that before the normalized time of catastrophic failure, the ensemble average LURR value rises significantly, in agreement with the observations of high LURR prior to the large earthquakes. In shearing tests, two parameters are found to control the correlation between earthquake occurrence and tidal stress. One is, A/(kT) controlling the phase shift between the peak seismicity rate and the peak amplitude of the perturbation stress. With an increase of this parameter, the phase shift is found to decrease. Another parameter, AT/k, controls the height of the probability density function (Pdf) of modeled seismicity. As this parameter increases, the Pdf becomes sharper and narrower, indicating a strong triggering. Statistical studies of LURR signals in shearing tests also suggest that except in strong triggering cases, where LURR cannot be calculated due to poor data in unloading cycles, the larger events are more likely to occur in higher LURR periods than the smaller ones, supporting the LURR hypothesis.

Determinants of functional capacity in patients with chronic heart failure: Role of filling pressure and systolic and diastolic function

Background Previous work suggesting a better correlation of diastolic than systolic function with exercise capacity in heart failure may reflect the -relative insensitivity and load-dependence of ejection fraction (EF). We sought the correlation of new and more sensitive methods of quantifying systolic and diastolic function and filling pressure with functional capacity. Methods We studied 155 consecutive exercise tests on 95 patients with congestive heart failure (81 male, aged 62 +/- 10 years), who underwent resting 2-climensional echocardiography and tissue Doppler imaging before and after measurement of maximum oxygen uptake (peak VO2)Results The resting EF was 3 1 % 10% and a peak VO(2)was 13 +/- 5 mL/kg/min; the majority of these patients (80%) had an ischemic cardiornyopathy. Resting EF (r 0.14, P =.09) correlated poorly with peak VO2 and mean systolic (r = 0.23, P =.004) and diastolic tissue velocities (r 0.18, P =.02). Peak EF was weakly correlated with the mean systolic (r = 0.18, P =.02) and diastolic velocities (r = 0.16, P <.04). The mean sum of systolic and diastolic velocities in both annuli (r = 0.30, P <.001) and E/Ea ratio (r 0.31, P <.001) were better correlated with peak VO2 Prediction of peak VO2 was similar with models based on models of filling pressure (R = 0.61), systolic factors (R = 0.63), and diastolic factors (R 0.59), although a composite model of filling pressure, systolic and diastolic function was a superior predictor of peak VO2 (R 0.69; all P<.001). Conclusions The reported association of diastolic rather than systolic function with functional capacity may have reflected the limitations of EF. Functional capacity appears related not only to diastolic function, but also to systolic function and filling pressure, and is most closely associated with a combination of these factors.

Prediction of functional capacity in chronic heart failure patients using myocardial tissue Doppler

Background. Exercise therapy improves functional capacity in CHF, but selection and individualization of training would be helped by a simple non-invasive marker of peak VO2. Peak VO2 in these pts is difficult to predict without direct measurement, and LV ejection fraction is a poor predictor. Myocardial tissue velocities are less load-dependent, and may be predictive of the exercise response in CHF pts. We sought to use tissue velocity as a predictor of peak VO2 in CHF pts. Methods. Resting 2D-echocardiography and tissue Doppler imaging were performed in 182 CHF pts (159 male, age 62±10 years) before and after metabolic exercise testing. The majority of these patients (129, 71%) had an ischemic cardiomyopathy, with resting EF of 35±13% and a peak VO2 of 13.5±4.7 ml/kg/min. Results. Neither resting EF (r=0.15) nor peak EF (r=0.18, both p=NS) were correlated with peak VO2. However, peak VO2 correlated with peak systolic velocity in septal (Vss, r=0.31) and lateral walls (Vsl, r=0.26, both p=0.01). In a general linear model (r2 = 0.25), peak VO2 was calculated from the following equation: 9.6 + 0.68*Vss - 0.09*age + 0.06*maximum HR. This model proved to be a superior predictor of peak VO2 (r=0.51, p=0.01) than the standard prediction equations of Wasserman (r= -0.12, p=0.01). Conclusions. Resting tissue Doppler, age and maximum heart rate may be used to predict functional capacity in CHF patients. This may be of use in selecting and following the response to therapy, including for exercise training.

Failure analysis of cold-formed steel sections

The purlin-sheeting system has been the subject of numerous theoretical and experimental investigations over the past 30 years, but the complexity of the problem has led to great difficulty in developing a sound and general model. The primary aim of the thesis is to investigate the failure behaviours of cold-formed zed and channel sections for use in purlin-sheeting systems. Both the energy method and finite strip method are used to develop an approach to investigate cold-formed zed and channel section beams with partial-lateral restraint from the metal sheeting when subjected to a uniformly distributed transverse load. The stress analysis of cold-formed zed and channel section beams with partially-lateral restraint from the metal sheeting when subjected to a uniformly distributed transverse load is investigated firstly by using the analytical model based on the energy method in which the restraint actions of the sheeting are modelled by using two springs representing the translational and rotational restraints. The numerical results have showed that the two springs have significantly different influences on the stresses of the beams. The influence of the two springs has also been found to depend on the anti-sag bar and the position of the loading line. A novel method is presented for analysing the elastic local buckling behaviour of cold-formed zed and channel section beams with partial-lateral restraint from metal sheeting when subjected to a uniformly distributed transverse load, which is carried out by inputting the cross sectional stresses with the largest compressive stress into the finite strip analysis. By using the presented novel method, individual influences of warning stress, partially lateral restraints from the sheeting and the dimensions of the cross section and position of the loading line on the buckling behaviour are investigated.