Mechanical properties derived from phase separation in co-polymer hydrogels.

Hydrogels can be synthesized with most of the properties needed for biomaterials applications. Soft, wettable, and highly permeable gels with a practically unlimited breadth of chemical functionalities are routinely made in the laboratory. However, the ability to make highly elastic and durable hydrogels remains limited. Here we describe an approach to generate stretchy, durable hydrogels, employing a high polymer-to-crosslink ratio for extensibility, combined with an aggregating copolymer phase to provide stability against swelling. We find that the addition of aggregating co-polymer can produce a highly extensible gel that fails at 1000% strain, recovers from large strains within a few minutes, maintains its elasticity over repeated cycles of large amplitude strain, and exhibits significantly reduced swelling. We find that the gel׳s enhanced mechanical performance comes from a kinetically arrested structure that arises from a competition between the disparate polymerization rates of the two components and the aggregation rate of the unstable phase. These results represent an alternative strategy to generating the type of stretchy elastomer-like hydrogels needed for biomedical technologies.

Polymer fluctuation lubrication in hydrogel gemini interfaces.

Interfacial sliding speed and contact pressure between the sub-units of particulate soft matter assemblies can vary dramatically across systems and with dynamic conditions. By extension, frictional interactions between particles may play a key role in their assembly, global configuration, collective motion, and bulk material properties. For example, in tightly packed assemblies of microgels - colloidal microspheres made of hydrogel - particle stiffness controls the fragility of the glassy state formed by the particles. The interplay between particle stiffness and shear stress is likely mediated by particle-particle normal forces, highlighting the potential role of hydrogel-hydrogel friction. Here we study friction at a twinned "Gemini" interface between hydrogels. We construct a lubrication curve that spans four orders of magnitude in sliding speed, and find qualitatively different behaviour from traditional lubrication of engineering material surfaces; fundamentally different types of lubrication occur at the hydrogel Gemini interface. We also explore the role played by polymer solubility and hydrogel-hydrogel adhesion in hydrogel friction. We find that polymer network elasticity, mesh size, and single-chain relaxation times can describe friction at the gel-gel interface, including a transition between lubrication regimes with varying sliding speed.

Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach.

OBJECTIVE: To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension. METHODS: Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs) for treatment of adult hypertension (DBP: 90-115 mmHg). Random-effects meta-regression adjusting for baseline blood pressure (BP) was used to analyse the data. Mean change in SBP and DBP was estimated for each individual drug and dose combination. RESULTS: In all, 31 RCTs (n = 13,110 patients) were included in the analysis. Six studies include trial arms with candesartan, six irbesartan, 13 losartan, two olmesartan, five telmisartan and 12 valsartan. The weighted average reduction in mean SBP and DBP for valsartan 160 mg was -15.32 mmHg (95% CI: -17.09, -13.63) and -11.3 mmHg (95% CI: -12.15, -10.52) and for 320 mg was -15.85 mmHg (95% CI: -17.60, -14.12) and -11.97 mmHg (95% CI: -12.81, -11.16); these are statistically significantly greater reductions compared with losartan 100 mg, which was -12.01 mmHg (95% CI: -13.78, -10.25) and -9.37 mmHg (95% CI: -10.18, -8.54) for SBP and DBP respectively. There is evidence that valsartan 160 mg reduces SBP and DBP more than irbesartan 150 mg and reduced DBP more than candesartan 16 mg. No other statistically significant difference in efficacy is demonstrated. CONCLUSION: Valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg and shows comparable efficacy to other ARBs in patients with essential hypertension.

Using mixed treatment comparisons and meta-regression to perform indirect comparisons to estimate the efficacy of biologic treatments in rheumatoid arthritis.

Mixed treatment comparison (MTC) is a generalization of meta-analysis. Instead of the same treatment for a disease being tested in a number of studies, a number of different interventions are considered. Meta-regression is also a generalization of meta-analysis where an attempt is made to explain the heterogeneity between the treatment effects in the studies by regressing on study-level covariables. Our focus is where there are several different treatments considered in a number of randomized controlled trials in a specific disease, the same treatment can be applied in several arms within a study, and where differences in efficacy can be explained by differences in the study settings. We develop methods for simultaneously comparing several treatments and adjusting for study-level covariables by combining ideas from MTC and meta-regression. We use a case study from rheumatoid arthritis. We identified relevant trials of biologic verses standard therapy or placebo and extracted the doses, comparators and patient baseline characteristics. Efficacy is measured using the log odds ratio of achieving six-month ACR50 responder status. A random-effects meta-regression model is fitted which adjusts the log odds ratio for study-level prognostic factors. A different random-effect distribution on the log odds ratios is allowed for each different treatment. The odds ratio is found as a function of the prognostic factors for each treatment. The apparent differences in the randomized trials between tumour necrosis factor alpha (TNF- alpha) antagonists are explained by differences in prognostic factors and the analysis suggests that these drugs as a class are not different from each other.

Implications for the human food chain of models of cadmium accumulation in sheep.

Critical limits for cadmium in parts of the human food chain are considered to have too small margins of safety and some limits are regularly exceeded. There is concern about the exposure of some sections of the population to cadmium in the human food chain, in particular regarding offal, which is a major source of cadmium to some sectors. The kidney is the first organ of sheep to reach the limit of fitness for human consumption. A model (based on a meta-analysis) predicts that this would occur after a mean of just 130 days of feeding sheep the maximum permitted cadmium concentration in feed (in the European Union) in the organic form. Thus it is not surprising that sheep organs are found routinely to exceed cadmium limits. Since reduction of maximum cadmium levels in sheep feed or of the duration of their exposure are not economically viable measures of control, routine removal of liver and kidney from older sheep from the food chain is recommended as the best option to reduce human dietary cadmium intake from sheep origin.

Parametric modelling of cost data in medical studies.

The cost of medical resources used is often recorded for each patient in clinical studies in order to inform decision-making. Although cost data are generally skewed to the right, interest is in making inferences about the population mean cost. Common methods for non-normal data, such as data transformation, assuming asymptotic normality of the sample mean or non-parametric bootstrapping, are not ideal. This paper describes possible parametric models for analysing cost data. Four example data sets are considered, which have different sample sizes and degrees of skewness. Normal, gamma, log-normal, and log-logistic distributions are fitted, together with three-parameter versions of the latter three distributions. Maximum likelihood estimates of the population mean are found; confidence intervals are derived by a parametric BC(a) bootstrap and checked by MCMC methods. Differences between model fits and inferences are explored.Skewed parametric distributions fit cost data better than the normal distribution, and should in principle be preferred for estimating the population mean cost. However for some data sets, we find that models that fit badly can give similar inferences to those that fit well. Conversely, particularly when sample sizes are not large, different parametric models that fit the data equally well can lead to substantially different inferences. We conclude that inferences are sensitive to choice of statistical model, which itself can remain uncertain unless there is enough data to model the tail of the distribution accurately. Investigating the sensitivity of conclusions to choice of model should thus be an essential component of analysing cost data in practice.

Meta-analysis of feeding trials investigating cadmium accumulation in the livers and kidneys of sheep.

Human cadmium intake derives mainly from food sources, and cadmium can be present in high concentrations in some offal. A meta-analysis using random effects modeling was carried out to integrate the results of 21 controlled randomized trials in which sheep were fed diets with elevated cadmium levels and cadmium concentrations in their livers and kidneys were recorded after slaughter. Resulting predictions of cadmium accumulation in sheep are applicable to a broad set of exposure situations allowing the critical examination of cadmium in the human food chain. The product of the cadmium concentration in the feed and the duration of exposure to that feed were significant predictors of the cadmium concentration in livers and kidneys. The predominantly organic rather than inorganic form of cadmium in the feed further increased accumulation. Other variables (dry matter intake, the vehicle of the elevated cadmium in the diet, animal age, weight, and sex) were not significant. As a result, the prime measure to decrease the risk of cadmium from animal origin adversely affecting human health should be restricting the animals' cumulative cadmium intake. It is suggested that this might be achieved by preventing the livers and kidneys of older animals from entering the human food chain.

Baseline adjustments for binary data in repeated cross-sectional cluster randomized trials.

Analysis of covariance models, which adjust for a baseline covariate, are often used to compare treatment groups in a controlled trial in which individuals are randomized. Such analysis adjusts for any baseline imbalance and usually increases the precision of the treatment effect estimate. We assess the value of such adjustments in the context of a cluster randomized trial with repeated cross-sectional design and a binary outcome. In such a design, a new sample of individuals is taken from the clusters at each measurement occasion, so that baseline adjustment has to be at the cluster level. Logistic regression models are used to analyse the data, with cluster level random effects to allow for different outcome probabilities in each cluster. We compare the estimated treatment effect and its precision in models that incorporate a covariate measuring the cluster level probabilities at baseline and those that do not. In two data sets, taken from a cluster randomized trial in the treatment of menorrhagia, the value of baseline adjustment is only evident when the number of subjects per cluster is large. We assess the generalizability of these findings by undertaking a simulation study, and find that increased precision of the treatment effect requires both large cluster sizes and substantial heterogeneity between clusters at baseline, but baseline imbalance arising by chance in a randomized study can always be effectively adjusted for.

Estimates of the likely prophylactic effect of tamoxifen in women with high risk BRCA1 and BRCA2 mutations.

The development of breast cancer control strategies in women at high genetic risk of breast cancer is an important issue. The likely benefit of chemopreventive approaches is of particular interest. Tamoxifen tends to be more effective in both prevention and treatment of oestrogen receptor positive tumours than oestrogen receptor negative. In this study, we combine the oestrogen-receptor specific effects of tamoxifen from randomized preventive or therapeutic trials with the oestrogen receptor status of tumours in BRCA1 and BRCA2 mutation positive women from published tumour surveys to obtain estimates of the likely effect of tamoxifen administration in mutation carriers. We used a simple two-stage procedure to estimate the benefit as a weighted average of the effect on oestrogen receptor positive tumours and oestrogen receptor negative, and using a more complex hierarchical modelling approach. Using the simple procedure and deriving the estimates of benefit from both primary prevention and therapeutic trials, we obtain an estimated reduction in risk of breast cancer from administration of tamoxifen in BRCA1 mutation positive women of 13% (RR=0.87, 95% CI 0.68--1.11). The corresponding estimated reduction in BRCA2 mutation positive women was 27% (RR=0.73, 95% CI 0.59--0.90). Using the more complex models gave essentially the same results. Using only the primary prevention trials gave smaller estimates of benefit in BRCA1 carriers but larger estimates in BRCA2, in both cases with wider confidence intervals. The benefit of prophylactic use of tamoxifen in BRCA1 mutation carriers is likely to be modest, and the effect in BRCA2 mutation carriers somewhat greater.

Cross-issue synthesis: potential application to breast cancer, tamoxifen and genetic susceptibility.

BACKGROUND: Cross-design synthesis usually refers to the inclusion in a meta-analysis of studies addressing the same question but using different designs, for example, combining results from randomised trials with those from case-control studies. Here we describe a procedure for combining information from studies addressing different but clinically related questions, referred to, for brevity, as cross-issue synthesis. METHODS: Surveys have measured the oestrogen receptor (ER) status of invasive breast cancer in women with mutations in the BRCA1 or BRCA2 gene. These mutations confer a substantially increased risk of breast cancer. These are also published randomised trials of tamoxifen administered for at least 3 years, either as an adjuvant therapy or for primary prevention, which record whether breast cancer recurred or occured respectively. These studies also give results by ER status. There are biological reasons to suppose that tamoxifen is more effective at preventing ER-positive cancers, and may have little or no effect at preventing ER-negative cancers. Women with BRCA mutations are more likely to develop ER-negative cancers. Combining meta analyses for these two types of studies supplies an estimate of the effectiveness of tamoxifen in preventing breast cancer in women with BRCA mutation. Hierarchical models were developed for this purpose. Estimation was by Markov chain Monte Carlo (MCMC). RESULTS: A range of models were fitted by MCMC. Using these, the effect of tamoxifen on the relative risk of developing breast cancer in women with a mutation in the BRCA1 gene is estimated to be 0.90 95% confidence interval (CI) (0.52, 1.61), and for the BRCA2 gene 0.71 95% CI (0.45, 1.21). DISCUSSION: This procedure can be generalised to combine information from two sets of studies addressing different, but clinically related questions.

Evidence that longer androgen receptor polyglutamine repeats are a causal factor for genital abnormalities.

Moderate to severe undermasculinized genitalia was recently shown to be associated with longer polyglutamine repeats within the androgen receptor [AR(Gln)n]. However, it was unknown whether this was because longer AR(Gln)n contributed to the: 1) etiology; 2) severity; and/or 3) testicular maldescent. Therefore, AR(Gln)n length in 175 males with abnormal genitalia were analyzed according to etiology (known or unknown), severity (complete, severe, and moderate), or testis position (abdominal, inguinal, or scrotal). Etiology (P = 0.01) and severity (P = 0.02) but not testis position (P = 0.52) were associated with AR(Gln)n length. The association between the severity of the genital abnormalities and AR(Gln)n length was due to the close association of severity with the etiology (P < 0.0001). A highly selected group with moderate to severe genital abnormalities and multiple criteria to exclude known etiological factors had a greater AR(Gln)n length (mean, 25.33) than all other samples (mean, 23.11; P = 0.0004). The results suggest that AR(Gln)n length does not influence the severity of undermasculinization or testis descent but instead contributes to the causation of genital abnormalities in a subset of patients. These findings, together with a demonstrated relationship between severity and multifactorial etiology, are incorporated into a proposed model for the involvement of AR(Gln)n length in genital abnormalities.

Randomization at the level of primary care practice: use of pre-intervention data and random effects models.

The Anglia menorrhagia education study tests the effectiveness of an education package for the treatment of menorrhagia given to doctors at a primary care level. General practices were randomized to receive or not receive the package. It is hoped that this intervention will reduce the proportion of women suffering from menorrhagia that are referred to hospital. Data are available on the treatment and referral of women in the practices in the education and control groups, both pre- and post-intervention. We define and demonstrate a random effects logistic regression model that includes pre-intervention data for calculating the effectiveness of the intervention.

Mammographic screening in women with a family history of breast cancer: some results from the Swedish two-county trial.

BACKGROUND: The objective of this study is to compare the effectiveness of mammographic screening in women with a family history of breast cancer to those without. In the invited arm of a randomised trial of breast cancer screening, data on family history of breast cancer were available on 29.179 women aged 40-74 attending for screening. Among those women, 358 were diagnosed with breast cancer during the trial. METHODS: Those with and without a family history were compared with respect to mammographic parenchymal pattern, interval cancer rates, mean sojourn time and sensitivity of screening. In the 358 cancers, the effect of family history was estimated on survival, incidence of advanced cancers and their relationship to screen detection. RESULTS: A significantly higher proportion of high risk mammographic patterns was observed in association with family history among women aged 40-49. Interval cancer rates were higher in women with a family history, and in older women at least, mean sojourn time was shortened in women with a family history (1.89 years compared to 2.70). Survival was better (although not significantly so) in cancers in women with a family history (relative hazard=0.52) independently of detection mode and was significantly poorer in interval cancers then screen detected cancers (relative hazard=2.72) independently of family history. Similarly, interval cancers tended to be larger, and worse malignancy grade in those with and without a family history of breast cancer. CONCLUSIONS: These results suggest that the policy often adopted of annual screening for woman aged 40-49, with a family history of breast cancer, is a reasonable one, and that it may also be necessary to shorten the inter-screening interval to one year in women aged over 50 but with a positive family history.

Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males.

The androgen receptor (AR) is essential to the normal development of the male internal and external genitalia. Consequently, impairment of AR function can result in undermasculinized genitalia that vary from a completely female appearance to isolated hypospadias. Since in vitro studies demonstrate that AR function is reduced by expansion of the polyglutamine tract within the receptor [AR(Gln)(n)]; this study examined whether longer AR(Gln)(n) repeats are associated with moderate to severe undermasculinization. The average AR(Gln)(n) length of the undermasculinized group (n = 78, median 25, interquartile range 23-26) was significantly greater than that of the control population (n = 850, median 23, inter-quartile range 22-26, P = 0.002). The odds ratio of having >/=23 repeats (as opposed to

Randomised controlled trial of educational package on management of menorrhagia in primary care: the Anglia menorrhagia education study.

OBJECTIVE: To determine whether an educational package could influence the management of menorrhagia, increase the appropriateness of choice of non-hormonal treatment, and reduce referral rates from primary to secondary care. DESIGN: Randomised controlled trial. SETTING: General practices in East Anglia. SUBJECTS: 100 practices (348 doctors) in primary care were recruited and randomised to intervention (54) and control (46). INTERVENTIONS: An educational package based on principles of "academic detailing" with independent academics was given in small practice based interactive groups with a visual presentation, a printed evidence based summary, a graphic management flow chart, and a follow up meeting at 6 months. OUTCOME MEASURES: All practices recorded consultation details, treatments offered, and outcomes for women with regular heavy menstrual loss (menorrhagia) over 1 year. RESULTS: 1001 consultation data sheets for menorrhagia were returned. There were significantly fewer referrals (20% v 29%; odds ratio 0. 64; 95% confidence interval 0.41 to 0.99) and a significantly higher use of tranexamic acid (odds ratio 2.38; 1.61 to 3.49) in the intervention group but no overall difference in norethisterone treatment compared with controls. There were more referrals when tranexamic acid was given with norethisterone than when it was given alone. Those practices reporting fewer than 10 cases showed the highest increase in prescribing of tranexamic acid. CONCLUSIONS: The educational package positively influenced referral for menorrhagia and treatment with appropriate non-hormonal drugs.