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Background: Randomized controlled trials offer the best design for eliminating bias in estimating treatment effects but can be slow and costly in rare disease research. Additionally, an equal randomization approach may not be optimal in studies in which prior evidence of superiority of one or more treatments exist. Supplementing prospectively enrolled, concurrent controls with historical controls can reduce recruitment requirements and provide patients a higher likelihood of enrolling in a new and possibly superior treatment arm. Appropriate methods need to be employed to ensure comparability of concurrent and historical controls to minimize bias and variability in the treatment effect estimates and reduce the chances of drawing incorrect conclusions regarding treatment benefit., Methods: MILES was a phase III placebo-controlled trial employing 1:1 randomization that led to US Food and Drug Administration approval of sirolimus for treating patients with lymphangioleiomyomatosis. We re-analyzed the MILES trial data to learn whether substituting concurrent controls with controls from a historical registry could have accelerated subject enrollment while leading to similar study conclusions. We used propensity score matching to identify exchangeable historical controls from a registry balancing the baseline characteristics of the two control groups. This allowed more new patients to be assigned to the sirolimus arm. We used trial data and simulations to estimate key outcomes under an array of alternative designs., Results: Borrowing information from historical controls would have allowed the trial to enroll fewer concurrent controls while leading to the same conclusion reached in the trial. Simulations showed similar statistical performance for borrowing as for the actual trial design without producing type I error inflation and preserving power for the same study size when concurrent and historical controls are comparable., Conclusion: Substituting concurrent controls with propensity score-matched historical controls can allow more prospectively enrolled patients to be assigned to the active treatment and enable the trial to be conducted with smaller overall sample size, while maintaining covariate balance and study power and minimizing bias in response estimation. This approach does not fully eliminate the concern that introducing non-randomized historical controls in a trial may lead to bias in estimating treatment effects, and should be carefully considered on a case-by-case basis. Borrowing historical controls is best suited when conducting randomized controlled trials with conventional designs is challenging, as in rare disease research. High-quality data on covariates and outcomes must be available for candidate historical controls to ensure the validity of these designs. Additional precautions are needed to maintain blinding of the treatment assignment and to ensure comparability in the assessment of treatment safety.MILES ClinicalTrials.gov Number: NCT00414648.

As individuals may respond differently to treatment, estimating subgroup effects is important to understand the characteristics of individuals who may benefit. Factors that define subgroups may be correlated, complicating evaluation of subgroup effects, especially in observational studies requiring control of confounding variables. We address this problem when propensity score methods are used for confounding control. A common practice is to evaluate candidate subgroup identifiers one at a time without adjusting for other candidate identifiers. We show that this practice can be misleading if the treatment effect modification attributed to a candidate identifier is in truth due to the effect of other correlated true effect modifiers. Whereas jointly analyzing multiple identifiers provides estimates of the desired subgroup effects adjusted for the effects of the other identifiers, it requires the propensity scores to adequately reflect the underlying treatment selection processes and balance the covariates within each subgroup of interest. Satisfying the requirement in practice is hard since the number of strata may increase quickly, while the per stratum sample size may decrease dramatically. A practically helpful approach is utilizing the whole cohort for the propensity score estimation with modeling of interaction terms to reflect the potentially different treatment selection processes across strata. We empirically examine the performance of the whole cohort approach by itself and with subjecting the interaction terms to variable selection. Our results using both simulations and real data analysis suggest that the whole cohort approach should explore inclusion of high-order interactions in the propensity score model to ensure adequate covariate balance across strata, and that variable selection is of limited utility.

Epigenetics is the study of the transmission of cell memory through mitosis or meiosis that is not based on the DNA sequence. At the molecular level the epigenetic memory of a cell is embedded in DNA methylation, histone post-translational modifications, RNA interference and histone isoform variation. There is a tight link between histone post-translational modifications (the histone code) and DNA methylation, as modifications of histones contribute to the establishment of DNA methylation patterns and vice versa. Interestingly, proteins have recently been identified that can simultaneously read both methylated DNA and the histone code. UHRF1 ful-fills these requirements by having unique structural domains that allow concurrent recognition of histone modifications and methylated DNA. Herein, we review our current knowledge of UHRF1 and discuss how this protein ensures the link between histone marks and DNA methylation. Understanding the molecular functions of this protein may reveal the physiological relevance of the linkage between these layers of epigenetic marks.

This article describes a 1-hour behavioral intervention designed to promote female condoms and safer sex to women at a high risk for sexually transmitted diseases (STDs). The intervention includes a promotional videotape; a skills-oriented counseling session with a nurse clinician; assorted take-home items, including a videotape for men; and free supplies of female and male condoms. Designed for women ages 18 to 34 attending public STD clinics, the intervention is developed using a systematic process of formative evaluation influenced by principles of social marketing and drawing on the social cognitive theory. The effect of the intervention on female and male condom use is evaluated using a pretest-posttest design with 1,159 women. Most elements of the intervention could be replicated in settings other than STD clinics and delivered by persons other than nurse clinicians.

Since every cell of a multicellular organism contains the same genome, it is intriguing to understand why genetically homogenous cells are different from each other and what controls this. Several observations indicate that DNA methylation has an essential regulatory function in mammalian development, which is to establish the correct pattern of gene expression, and that DNA methylation pattern is tightly correlated with chromatin structure. Various physiological processes are controlled by specific DNA methylation patterns including genomic imprinting, inactivation of the X chromosome, regulation of tissue-specific gene expression and repression of transposons. Moreover, aberrant methylation could confer a selective advantage to cells, leading to cancerous growth. In this review we focus on the epigenetic molecular mechanisms during normal development and discuss how DNA methylation could affect the expression of genes leading to cancer transformation.

A study has been carried out on the immunosuppressive activity of high doses of peptichemio (PTC) in CBA mice. Humoral response to sheep erythrocytes, delayed hypersensitivity to oxazolone, and cellular proliferation in lymph nodes and spleen of animals sensitized with oxazolone have been investigated. The results demonstrated that PTC had a definite immunosuppressive action, as shown by the inhibition of primary response to inoculation of sheep erythrocytes, by depression of delayed hypersensitivity to oxazolone, and by marked inhibition of 125IUdr incorporation in lymph nodes of sensitized animals. It is suggested that the inhibitory action is mediated by an effect on actively proliferating B or T lymphoid cells, although involvement of macrophages cannot be ruled out.