On estimands arising from misspecified semiparametric rate-based analysis of recurrent episodic conditions

Marginal rate-based analyses are widely used for the analysis of recurrent events in clinical trials. In many areas of application, the events are not instantaneous but rather signal the onset of a symptomatic episode representing a recurrent infection, respiratory exacerbation, or bout of acute depression. In rate-based analyses, it is unclear how to best handle the time during which individuals are experiencing symptoms and hence are not at risk. We derive the limiting value of the Nelson-Aalen estimator and estimators of the regression coefficients under a semiparametric rate-based model in terms of an underlying two-state process. We investigate the impact of the distribution of the episode durations, heterogeneity, and dependence on the asymptotic and finite sample properties of standard estimators. We also consider the impact of these features on power in trials designed to test intervention effects on rate functions. An application to a trial of individuals with herpes simplex virus is given for illustration.     

Baseline Mammography: What Is It and Why Is It Important? A Cross-Sectional Survey of Women Undergoing Screening Mammography

Objectives

Studies have shown that having a baseline mammogram, the first screening mammogram, available for comparison at the time of interpreting a subsequent mammogram significantly decreases the potential of a false-positive examination. Our aim was to evaluate knowledge of and perception about the significance of baseline mammograms in those women undergoing screening mammography.

Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD

Introduction: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in gut-associated lymphoid tissue is upregulated in patients with inflammatory bowel disease (IBD). Blocking adhesion molecules and thereby inhibiting migration of lymphocytes into sites of inflammation in the gut is an attractive new treatment target in drug development for IBD.

Areas covered: This review discusses the preclinical and clinical experience on SHP647 (previously called PF-00547659 and PF-00547,659), a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract.

Expert opinion: Blocking endothelial adhesion molecule MAdCAM?1 could represent an attractive target for the treatment of IBD. In the next years, the results from the phase III studies as well as data to support therapeutic drug monitoring based on drug levels to guide and optimize individual therapy will become available. Furthermore, much effort is put in the development of clinical prediction models to predict which drug is optimal for an individual patient.

Trial registration: ClinicalTrials.gov identifier: NCT03259334.

Trial registration: ClinicalTrials.gov identifier: NCT03259308.

Trial registration: ClinicalTrials.gov identifier: NCT03559517.

Trial registration: ClinicalTrials.gov identifier: NCT03566823.

Trial registration: ClinicalTrials.gov identifier: NCT01298492.     

Efficacy of the cognitive orientation to daily occupational performance with Brazilian children with developmental coordination disorder

Background: Children with Developmental Coordination Disorder (DCD) have difficulties performing daily activities which reflects negatively on participation, impacting their lives.

Objectives: To examine the effects of the cognitive orientation to daily occupational performance Approach (CO-OP Approach) protocol on occupational performance and satisfaction of Brazilian children who have DCD; to examine whether children could transfer strategies and skills learned during CO-OP to untrained goals.

Methods: A pre-post group comparison design with eight boys aged 6–10 years old. Children participated in 12 CO-OP sessions with their parents twice a week, with an extra session added to the protocol for parents´ orientation. The Canadian Occupational Performance Measure and the Performance Quality Rating Scale were used as outcome measures. The study was registered by the United States Institutes of Health at ClinicalTrials.gov (NCT03112746).

Results: Intervention resulted in higher, clinically and statistically significant, occupational performance measures according to parents, children’s, and external evaluators’ perspectives. All children improved occupational performance on their selected goals and five children could transfer the ability to use cognitive strategies to tasks not addressed in therapy.

Conclusions: This study provides initial directions for future research to investigate the applicability and to implement CO-OP approach on pediatric settings in Brazil.     

Suppression of puerarin on polymethylmethacrylate-induced lesion of peri-implant by inhibiting NF-κB activation in vitro and in vivo

Puerarin (PR), a natural isoflavone isolated from Chinese traditional plant pueraria lobata, has attracted considerable attention due to its important biological and pharmacological activities. However, its effects on lesion of peri-implant and related mechanism of action are still not clear, which require further investigation. In this study, we evaluated the effects of PR on polymethylmethacrylate (PMMA)-induced lesion of peri-implant in vitro and in vivo, and explored its possible mechanism of action. Our results indicated that PR could inhibit PMMA-induced osteoclastogenesis in RAW264.7 cells with a dose-dependent manner in vitro and effectively down-regulate mRNA and protein expressions of matrix metalloprotein 9 (MMP-9), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and receptor activator of nuclear factor (NF)-κB (RANK), primarily via the suppression of NF-κB signaling. Furthermore, we found that PMMA induction could directly cause the phosphorylation of IκB and significantly promote the nuclear translocation of p65 in RAW264.7 cells. In other words, PR was able to dose-dependently attenuate the PMMA-induced nuclear translocation of p65 in RAW264.7 cells. In vivo, PR was observed to attenuate PMMA-induced osteoclastogenesis, osteolysis, mRNA expressions of receptor activator of nuclear factor (NF)-κB ligand (RANKL) and RANK, as well as protein levels of MMP-9, TNF-α, IL-6, and p65 in a murine calvarial osteolysis model. These findings suggested that PR might be a potential therapeutic drug to lesion of peri-implant, and provided new insights for understanding its possible mechanism.