Predicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy

Control of soil-transmitted helminths relies heavily on regular large-scale deworming of high-risk groups (e.g., children) with benzimidazole derivatives. Although drug resistance has not yet been documented in human soil-transmitted helminths, regular deworming of cattle and sheep has led to widespread benzimidazole resistance in veterinary helminths. Here we predict the population dynamics of human soil-transmitted helminth infections and drug resistance during 20 years of regular preventive chemotherapy, using an individual-based model. With the current preventive chemotherapy strategy of mainly targeting children in schools, drug resistance may evolve in soil-transmitted helminths within a decade. More intense preventive chemotherapy strategies increase the prospects of soil-transmitted helminths elimination, but also increase the speed at which drug efficacy declines, especially when implementing community-based preventive chemotherapy (population-wide deworming). If during the last decade, preventive chemotherapy against soil-transmitted helminths has led to resistance, we may not have detected it as drug efficacy has not been structurally monitored, or incorrectly so. These findings highlight the need to develop and implement strategies to monitor and mitigate the evolution of benzimidazole resistance.</p

Mapping onto Eq-5 D for patients in poor health

<p>Abstract</p> <p>Background</p> <p>An increasing amount of studies report mapping algorithms which predict EQ-5 D utility values using disease specific non-preference-based measures. Yet many mapping algorithms have been found to systematically overpredict EQ-5 D utility values for patients in poor health. Currently there are no guidelines on how to deal with this problem. This paper is concerned with the question of why overestimation of EQ-5 D utility values occurs for patients in poor health, and explores possible solutions.</p> <p>Method</p> <p>Three existing datasets are used to estimate mapping algorithms and assess existing mapping algorithms from the literature mapping the cancer-specific EORTC-QLQ C-30 and the arthritis-specific Health Assessment Questionnaire (HAQ) onto the EQ-5 D. Separate mapping algorithms are estimated for poor health states. Poor health states are defined using a cut-off point for QLQ-C30 and HAQ, which is determined using association with EQ-5 D values.</p> <p>Results</p> <p>All mapping algorithms suffer from overprediction of utility values for patients in poor health. The large decrement of reporting 'extreme problems' in the EQ-5 D tariff, few observations with the most severe level in any EQ-5 D dimension and many observations at the least severe level in any EQ-5 D dimension led to a bimodal distribution of EQ-5 D index values, which is related to the overprediction of utility values for patients in poor health. Separate algorithms are here proposed to predict utility values for patients in poor health, where these are selected using cut-off points for HAQ-DI (> 2.0) and QLQ C-30 (< 45 average of QLQ C-30 functioning scales). The QLQ-C30 separate algorithm performed better than existing mapping algorithms for predicting utility values for patients in poor health, but still did not accurately predict mean utility values. A HAQ separate algorithm could not be estimated due to data restrictions.</p> <p>Conclusion</p> <p>Mapping algorithms overpredict utility values for patients in poor health but are used in cost-effectiveness analyses nonetheless. Guidelines can be developed on when the use of a mapping algorithms is inappropriate, for instance through the identification of cut-off points. Cut-off points on a disease specific questionnaire can be identified through association with the causes of overprediction. The cut-off points found in this study represent severely impaired health. Specifying a separate mapping algorithm to predict utility values for individuals in poor health greatly reduces overprediction, but does not fully solve the problem.</p

Assessing peripheral arteries in South African black women with type 2 diabetes mellitus

Objectives. To determine the value of ankle and toe blood pressure indices and pedal pulse palpation in the assessment of peripheral arterial disease in subjects with type 2 diabetes mellitus (DM).Design. Cross-sectional study.Subjects. A convenience sample of 85 female subjects with type 2 DM underwent a series of peripheral vascular assessments at the diabetes clinic of a community hospital.Outcome measures. Palpation of the pedal pulses, Doppler derived ankle brachial systolic blood pressure indices, photo plethysmographic-derived toe brachial systolic blood pressure indices and antero-posterior radiographs of both feet.Results. Mean values were 1.15 (standard deviation (SD): 0.17) and 0.76 (SD: 0.17) for ankle brachial index (ABI) and toe brachial index (T'Bl) respectively. The differences between the two indices increased from 0.36 (95% confidence interval (CI): 0.32 - 0.41) to 0.58 (95% CI: 0.46- 0.70) depending on whether ABI was less or greater than 1.3. The correlation coefficient for left versus right foot was 0.62 and 0.71 for ABI and TBI respectively. The relationship between ABI and TBI is non-linear with a cut point close to 1.3. Both ABI and TBI were significantly lower in subjects who had both pedal pulses absent on palpation.Conclusions. The relationship between ABI and TBI is linear, below an ABI of 1.3. but with a wide 95% prediction interval. If both pedal pulses are absent the ABI is significantly diminished compared with when both pulses are present, even though not necessarily below 0.9. 

No difference in between-country variability in use of newly approved orphan and non- orphan medicinal products - a pilot study

<p>Abstract</p> <p>Background</p> <p>Regulators and payers have to strike a balance between the needs of the patient and the optimal allocation of resources. Drugs indicated for rare diseases (orphan medicines) are a special group in this context because of their often high per unit costs. Our objective in this pilot study was to determine, for drugs used in an outpatient setting, how utilisation of centrally authorised drugs varies between countries across a selection of EU member states.</p> <p>Methods</p> <p>We randomly selected five orphan medicines and nine other drugs that were centrally authorised in the European Union between January 2000 and November 2006. We compared utilisation of these drugs in six European Union member states: Austria, Denmark, Finland, Portugal, The Netherlands, and Sweden. Utilisation data were expressed as Defined Daily Doses per 1000 persons per year. Variability in use across countries was determined by calculating the relative standard deviation for the utilisation rates of individual drugs across countries.</p> <p>Results</p> <p>No association between orphan medicine status and variability in use across countries was found (P = 0.52). Drugs with an orphan medicine status were more expensive and had a higher innovation score than drugs without an orphan medicine status.</p> <p>Conclusions</p> <p>The results show that the variability in use of orphan medicines in the different health care systems of the European Union appears to be comparable to the other newly authorised drugs that were included in the analysis. This means that, although strong heterogeneity in access may exist, this heterogeneity is not specific for drugs with an orphan status.</p

Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality

BACKGROUND: Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide-degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). METHODS AND RESULTS: We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. CONCLUSIONS: Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD

Calibration of 14C Histograms:A Comparison of Methods

The interpretation of C-14 histograms is complicated by the non-linearity of the C-14 time scale in terms of Calendar years, which may result in clustering of C-14 ages in certain time intervals unrelated to the (geologic or archaeologic) phenomenon of interest. One can calibrate C-14 histograms for such distortions using two basic approaches. The KORHIS method constructs a C-14 histogram before calibration is performed by means of a correction factor. We present the CALHIS method based on the Groningen calibration program for individual C-14 ages. CALHIS first calibrates Single C-14 ages and then sums the resulting calibration distributions, thus yielding a calibrated C-14 histogram. The individual calibration distributions are normalized to a standard Gaussian distribution before superposition, thus allowing direct comparison among various C-14 histograms. Several experiments with test data sets demonstrate that CALHIS produces significantly better results than KORHIS. Although some problems remain (part of the distortions due to C-14 variations cannot be eliminated), we show that CALHIS offers good prospects for using C-14 histograms, particularly with highly precise and accurate C-14 ages.</p

Escherichia coli bacteriuria in female adults is associated with the development of hypertension

AbstractObjectiveTo investigate whether Escherichia coli bacteriuria is associated with the development of hypertension during a long-term follow-up.MethodsA prospective cohort study was performed among the participants of two population-based studies. Between 1974 and 1986 all women aged 39 to 68 years old, who lived in Utrecht, the Netherlands, were invited to participate in a breast cancer screening program. The participants completed a questionnaire, underwent a medical examination, and collected a morning urine sample that remained stored. From 1993 to 1997 another population-based study was performed. We performed a full cohort analysis for 444 women who participated in both studies. E. coli bacteriuria was diagnosed by a real-time PCR. Hypertension was defined as the use of antihypertensive medication and/or a measured systolic blood pressure of at least 160 mmHg or a diastolic blood pressure of 95 mmHg or higher. The mean follow-up was 11.5±1.7 years.ResultsForty women (9%) had E. coli bacteriuria at baseline. Women who had bacteriuria at baseline had a mean blood pressure at study endpoint of 133±20 mmHg systolic and 78±11 mmHg diastolic, and women without bacteriuria had values of 129±20 and 78±11 mmHg, respectively (p-values for difference 0.33 and 0.88). Although E. coli bacteriuria was not associated with the blood pressure as a continuous variable, it was associated with the development of hypertension during follow-up (OR 2.8, 95% CI 1.4–5.5).ConclusionE. coli bacteriuria may increase the risk of future hypertension