Pre-trial evaluation of the potential for unblinding in drug trials: a prototype example

Blinding is an important design feature of randomised trials that may reduce bias in the results, compared to the situation where blinding is not possible or is not maintained. The literature provides some guidance for the evaluation of blinding in ongoing or completed studies, but the question of pre-trial assessment of the potential for unblinding has not been addressed. This paper describes the design and analysis of a prototype experiment for the pre-trial assessment of blinding in a drug trial. This work was motivated by a trial using antibiotic therapy, in which the investigators were concerned about the possibility of subjects being able to differentiate active medication from placebo, and thus become unblinded to their treatment assignment. A small experiment was mounted in which participants had to divide a random mixture of tablets into two groups. Statistical methods were developed to calculate the probability of a given number of similar tablets being classified into the same group by chance, with a modification to allow for some participants having constrained their responses to have equal numbers of tablets in each group. Differentiation of tablets by taste (the initial concern of the investigators) was not statistically different from chance. A smaller set of data on differentiation by appearance (a possibility not originally considered) had borderline statistical significance. After reviewing all these results, the investigators decided to proceed with the study without modifying the tablets, in part because subjects in the study would be unlikely to compare the two types of medication side-by-side. Our results suggest that blinding might sometimes be compromised in unexpected ways. Whenever possible, we suggest that similar and larger such experiments be carried out before the trial to assess whether blinding might be compromised. The methods proposed here could easily be adapted to evaluate the results of such experiments.     

Care-seeking behavior and out-of-pocket expenditure for sick newborns among urban poor in Lucknow, northern India: a prospective follow-up study

Background  

The state of Uttar Pradesh, India accounts for one-quarter of India's neonatal deaths and 8 percent of those worldwide. More than half (52%) of these deaths occur due to infections. In order to achieve Millennium Development Goal-4 of reducing child mortality by two-thirds by the year 2015, it is important to study factors which affect neonatal health. In Uttar Pradesh there is meager data for spending on health care in general and neonates in particular.     

Lymphocytic thrombophilic arteritis presenting as localized livedo racemosa

A 28-year-old Costa Rican woman presented with a 6-year history of an asymptomatic progressive localized livedo racemosa on her limbs. Histological examination revealed a lymphocytic vasculitis targeting the arterioles in the deep dermis. In addition, a distinct hyalinised fibrin ring was noted at the periphery of the vessel lumen. These findings were consistent with the recently described entity known as lymphocytic thrombophilic arteritis. An extensive array of investigations did not show any underlying systemic disease, and the patient has remained in good health without treatment.     

Racial Disparities in Stage-Specific Colorectal Cancer Mortality: 1960�C2005

Objectives. We examined whether racial disparities in stage-specific colorectal cancer survival changed between 1960 and 2005.Methods. We used US Mortality Multiple-Cause-of-Death Data Files and intercensal estimates to calculate standardized mortality rates by gender and race from 1960 to 2005. We used Surveillance, Epidemiology, and End Results (SEER) data to estimate stage-specific colorectal cancer survival. To account for SEER sampling uncertainty, we used a bootstrap resampling procedure and fit a Cox proportional hazards model.Results. Between 1960–2005, patterns of decline in mortality rate as a result of colorectal cancer differed greatly by gender and race: 54% reduction for White women, 14% reduction for Black women, 39% reduction for White men, and 28% increase for Black men. Blacks consistently experienced worse rates of stage-specific survival and life expectancy than did Whites for both genders, across all age groups, and for localized, regional, and distant stages of the disease.Conclusions. The rates of stage-specific colorectal cancer survival differed among Blacks when compared with Whites during the 4-decade study period. Differences in stage-specific life expectancy were the result of differences in access to care or quality of care. More attention should be given to racial disparities in colorectal cancer management.Although colorectal cancer mortality rates have declined since 1960, these declines have been uneven,^1–3 and racial disparities in mortality rates have increased. Factors contributing to increased mortality rates among Blacks include racial differences in risk factors, prevention, detection, and treatment.⁴ Blacks receive less colorectal screening,⁵ and their cancer is detected at more advanced stages.^6,7 Important differences exist in how colorectal cancer is detected, but not necessarily in how it is treated once detected. Significant improvements have occurred in colorectal cancer treatment through time, yet these improvements may not be distributed equally across all racial groups. Previous research has also found Black–White differences in stage-specific colorectal cancer survival rates, suggesting disparities in the management of cancer.^8–10In this article, we assessed whether differences in stage-specific colorectal cancer survival rates reflected racial differences over 4 decades. In doing so, we adjusted for differences in incidence and screening, focusing instead on the management of tumors once they are found. Racial disparities are likely a product of a broad set of social, biological, and environmental factors. By observing changes in stage-specific mortality over time, rather than statically at a cross-sectional moment, we may develop a better understanding of how these factors have contributed to increased racial disparities.     

Association of <Emphasis Type="Italic">IL-10</Emphasis> Gene Polymorphism (−819C &gt; T, −592C &gt; A and −1082G &gt; A) with Preterm Birth

Objective

To analyze the association of IL-10 gene and its polymorphisms with preterm birth (PTB).

Methods

Five hundred and fifty nine women with term birth and 559 with preterm birth were recruited from Lucknow, India. Genetic association analysis was conducted between cases and controls. Subjects recruited as cases were women (aged between 18–40 y) with singleton delivery before 37 wk of gestation and controls were with delivery after or on 37 wk. The genotyping was performed for rs1800871, rs1800872 and rs1800896 for assessing the allelic distribution, haplotypic association and linkage disequilibrium analysis. IL-10mRNA levels were evaluated by real time quantitative polymerase chain reaction (PCR) method.

Results

The risk of PTB was found significant in women carrying IL-10 (?1082) GA genotype [OR=1.72(1.7–2.5), p=0.006]. The haplotypic analysis of studied polymorphisms for rs1800871, rs1800872 and rs1800896 depicted the association of ATA (p=0.02) and ATC (p=0.01) haplotypes with PTB. The IL-10 mRNA levels were significantly lower in cases (p=0.05).

Conclusions

IL-10 marks a protective impact in the inflammatory pathway of PTB.