Benchmark Calculations for Perchlorate from Three Human Cohorts

The presence of low concentrations of perchlorate in some drinking water sources has led to concern regarding potential effects on the thyroid. In a recently published report, the National Academy of Sciences indicated that the perchlorate dose required to cause hypothyroidism in adults would probably be > 0.40 mg/kg-day for months or longer. In this study, we calculated benchmark doses for perchlorate from thyroid-stimulating hormone (TSH) and free thyroxine (T(4)) serum indicators from two occupational cohorts with long-term exposure to perchlorate, and from a clinical study of volunteers exposed to perchlorate for 2 weeks. The benchmark dose for a particular serum indicator was defined as the dose predicted to cause an additional 5 or 10% of persons to have a serum measurement outside of the normal range. Using the data from the clinical study, we estimated the half-life of perchlorate in serum at 7.5 hr and the volume of distribution at 0.34 L/kg. Using these estimates and measurements of perchlorate in serum or urine, doses in the occupational cohorts were estimated and used in benchmark calculations. Because none of the three studies found a significant effect of perchlorate on TSH or free T(4), all of the benchmark dose estimates were indistinguishable from infinity. The lower 95% statistical confidence limits on benchmark doses estimated from a combined analysis of the two occupational studies ranged from 0.21 to 0.56 mg/kg-day for free T(4) index and from 0.36 to 0.92 mg/kg-day for TSH. Corresponding estimates from the short-term clinical study were within these ranges

Heterogeneity of genetic parameters for calving difficulty in Holstein heifers in Ireland

Calving difficulty is a trait that greatly affects animal welfare, herd profitability, and the amount of labor required by cattle farmers. It is influenced by direct and maternal genetic components. Selection and breeding strategies can optimize the accuracy of genetic evaluations and correctly emphasize calving difficulty in multiple-trait indices provided there are accurate estimates of genetic parameters. In Ireland, large differences exist in the age at which heifers first give birth to calves. The objective of this study was to estimate genetic parameters for calving difficulty in first-parity Holsteins and to determine whether these differed with age of the heifer at calving. Transformed calving difficulty records for 18,798 Holstein heifers, which calved between January 2002 and May 2006, were analyzed using univariate, multitrait, and random regression linear sire-maternal grandsire models. The model that 1) fitted a second-order random regression of dam age at first parity for the direct component, 2) treated the maternal component as a single trait regardless of dam age, and 3) fitted a single residual variance component was optimal. Heritabilities for direct (0.13) and maternal (0.04) calving difficulty were significantly different from zero. These 2 components were moderately negatively correlated (¿0.47). Estimates of direct genetic variance and heritability were heterogeneous along the dam age trajectory, decreasing initially with dam age before subsequently increasing. Heritability estimates ranged between 0.11 and 0.37 and were higher for records with younger and older dams at parturition. Genetic correlations between the direct components of calving difficulty decreased from unity to 0.5 with increasing distance between dam ages at parturition. The results of this study indicated that heterogeneity of direct genetic variance existed for calving difficulty, depending on dam age at first parturition

Core Outcome Set for GROwth restriction: deVeloping Endpoints (COSGROVE).

BACKGROUND: Foetal growth restriction (FGR) refers to a foetus that does not reach its genetically predetermined growth potential. It is well recognised that growth-restricted foetuses are at increased risk of stillbirth, foetal compromise, early neonatal death and neonatal morbidity. Later in life, they are prone to health problems, including increased risk of cardiovascular diseases and neurodevelopmental disorders. Interventions for preventing and treating FGR have been studied in many trials, but evidence is often difficult to synthesise and compare because of differences in the selection and definition of outcomes. To enable future trials to measure similar, meaningful outcomes, we are developing two core outcome sets (COS) - one for prevention and the other for treatment of FGR. METHODS: We will review the literature to identify previously reported outcomes. An international panel of relevant stakeholders who have experience of FGR (parent or carer of a baby that was growth restricted, health professional involved in the care of mothers and babies affected by FGR, a person with expertise in FGR research) will rate the importance of each of those outcomes in a series of three sequential online rounds of a Delphi study. Participants will be able to add items to the proposed list in round 1. A final face-to-face consensus meeting will be held with representatives of each stakeholder group at which a final list of outcomes for inclusion in the COS will be agreed. DISCUSSION: The development of COSs in FGR will ensure the collection and reporting of a minimum dataset agreed by stakeholder consensus and will reduce inconsistencies in the reporting of outcomes across relevant trials. Such standardisation in the reporting of outcomes will improve synthesis of evidence and generalisability of knowledge in the future by reducing heterogeneity in outcomes between trials and thus improve the results of systematic reviews and meta-analyses. Ultimately, we hope that the COSs will lead to an improvement in the quality of evidence-based clinical practice, enhance patient care, and improve the quality and consistency of research. TRIAL REGISTRATION: Not applicable. This study is registered in the Core Outcome Measures for Effectiveness (COMET) database

Association of Escherichia coli O157:H7 tir polymorphisms with human infection

<p>Abstract</p> <p>Background</p> <p>Emerging molecular, animal model and epidemiologic evidence suggests that Shiga-toxigenic <it>Escherichia coli </it>O157:H7 (STEC O157) isolates vary in their capacity to cause human infection and disease. The translocated intimin receptor (<it>tir</it>) and intimin (<it>eae</it>) are virulence factors and bacterial receptor-ligand proteins responsible for tight STEC O157 adherence to intestinal epithelial cells. They represent logical genomic targets to investigate the role of sequence variation in STEC O157 pathogenesis and molecular epidemiology. The purposes of this study were (1) to identify <it>tir </it>and <it>eae </it>polymorphisms in diverse STEC O157 isolates derived from clinically ill humans and healthy cattle (the dominant zoonotic reservoir) and (2) to test any observed <it>tir </it>and <it>eae </it>polymorphisms for association with human (vs bovine) isolate source.</p> <p>Results</p> <p>Five polymorphisms were identified in a 1,627-bp segment of <it>tir</it>. Alleles of two <it>tir </it>polymorphisms, <it>tir </it>255 T>A and repeat region 1-repeat unit 3 (RR1-RU3, presence or absence) had dissimilar distributions among human and bovine isolates. More than 99% of 108 human isolates possessed the <it>tir </it>255 T>A T allele and lacked RR1-RU3. In contrast, the <it>tir </it>255 T>A T allele and RR1-RU3 absence were found in 55% and 57%, respectively, of 77 bovine isolates. Both polymorphisms associated strongly with isolate source (p < 0.0001), but not by pulsed field gel electrophoresis type or by <it>stx</it>1 and <it>stx</it>2 status (as determined by PCR). Two <it>eae </it>polymorphisms were identified in a 2,755-bp segment of 44 human and bovine isolates; 42 isolates had identical <it>eae </it>sequences. The <it>eae </it>polymorphisms did not associate with isolate source.</p> <p>Conclusion</p> <p>Polymorphisms in <it>tir </it>but not <it>eae </it>predict the propensity of STEC O157 isolates to cause human clinical disease. The over-representation of the <it>tir </it>255 T>A T allele in human-derived isolates vs the <it>tir </it>255 T>A A allele suggests that these isolates have a higher propensity to cause disease. The high frequency of bovine isolates with the A allele suggests a possible bovine ecological niche for this STEC O157 subset.</p

Integrins as therapeutic targets: lessons and opportunities.

The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets

Random Error in Exposure and Shape of Exposure Response

Although statistical analyses of epidemiological data usually treat the exposure variable as being known without error, estimated exposures in epidemiological studies often involve considerable uncertainty. This paper investigates the theoretical effect of random errors in exposure measurement upon the observed shape of the exposure response. The model utilized assumes that true exposures are log-normally distributed, and multiplicative measurement errors are also log-normally distributed and independent of the true exposures. Under these conditions it is shown that whenever the true exposure response is proportional to exposure to a power r, the observed exposure response is proportional to exposure to a power K, where K < r. This implies that the observed exposure response exaggerates risk, and by arbitrarily large amounts, at sufficiently small exposures. It also follows that a truly linear exposure response will appear to be supra-linear—i.e., a linear function of exposure raised to the K-th power, where K is less than 1.0. These conclusions hold generally under the stated log-normal assumptions whenever there is any amount of measurement error, including, in particular, when the measurement error is unbiased either in the natural or log scales. Equations are provided that express the observed exposure response in terms of the parameters of the underlying log-normal distribution. A limited investigation suggests that these conclusions do not depend upon the log-normal assumptions, but hold more widely. Because of this problem, in addition to other problems in exposure measurement, shapes of exposure responses derived empirically from epidemiological data should be treated very cautiously. In particular, one should be cautious in concluding that the true exposure response is supra-linear on the basis of an observed supra-linear form