Functional features defining the efficacy of cholesterol-conjugated, self-deliverable, chemically modified siRNAs.

Progress in oligonucleotide chemistry has produced a shift in the nature of siRNA used, from formulated, minimally modified siRNAs, to unformulated, heavily modified siRNA conjugates. The introduction of extensive chemical modifications is essential for conjugate-mediated delivery. Modifications have a significant impact on siRNA efficacy through interference with recognition and processing by RNAi enzymatic machinery, severely restricting the sequence space available for siRNA design. Many algorithms available publicly can successfully predict the activity of non-modified siRNAs, but the efficiency of the algorithms for designing heavily modified siRNAs has never been systematically evaluated experimentally. Here we screened 356 cholesterol-conjugated siRNAs with extensive modifications and developed a linear regression-based algorithm that effectively predicts siRNA activity using two independent datasets. We further demonstrate that predictive determinants for modified and non-modified siRNAs differ substantially. The algorithm developed from the non-modified siRNAs dataset has no predictive power for modified siRNAs and vice versa. In the context of heavily modified siRNAs, the introduction of chemical asymmetry fully eliminates the requirement for thermodynamic bias, the major determinant for non-modified siRNA efficacy. Finally, we demonstrate that in addition to the sequence of the target site, the accessibility of the neighboring 3' region significantly contributes to siRNA efficacy.

Physical activity in COPD: Minimal clinically important difference for medical events.

Estimates of the minimal clinically important difference (MCID) for physical activity (PA) in chronic obstructive pulmonary disease (COPD) are needed. The objective is to provide an anchor-based estimate of the MCID for daily step count. PA was promoted in persons with COPD using a pedometer (Omron HJ-720ITC) alone or a pedometer plus interactive website for 3 months. Participants wore the pedometer daily and received phone calls monthly to ascertain medical events. Medical events were counted when a participant self-reported that he/she had (1) worsening of breathing, (2) change to breathing medications, (3) medical care from an emergency room for any reason, or (4) hospitalization for any reason. Generalized linear regression models assessed daily step count as change at the end of study and averaged over the 15, 31, or 61 days centered on the event, in those with an event compared to those without one. All categories of events carried equal weight in the analyses. We studied 93 persons, 46 of whom had an event. Participants who experienced an event had a decrease of 1086 (95% confidence interval (CI): -2124 to -48) or 887 (95% CI: -2030 to 257) steps/day in the pedometer plus website or pedometer alone groups, respectively, compared to those without one. In the days centered on an event, participants who had an event experienced a decrease of 882-983 steps/day (pedometer plus website) or a decrease of 351-495 steps/day (pedometer alone), compared to those without one. The MCID for PA in COPD ranges from 350 steps/day to 1100 steps/day.

Self-reported task-oriented physical activity: A comparison with objective daily step count in COPD.

BACKGROUND: Low physical activity (PA) is associated with adverse health outcomes independent of airflow limitation in COPD. Self-reported assessments are often limited to global estimates of PA and may not be directly translatable to patients' goals and motivations. We developed a task-oriented PA checklist and examined its performance relative to pedometer-assessed daily step count in two COPD cohorts. METHODS: Task-oriented daily physical activity (DPA) was assessed in two COPD cohorts using either interviewer-administered recall questionnaire (DPA-R, Cohort 1, n = 109) or a self-administered diary-format daily checklist (DPA-C, Cohort 2, n = 175). Daily step count was measured in both cohorts using the Omron HJ-720 ITC pedometer. Univariate associations between individual DPA items and [a] cross-sectional and [b] longitudinal change (Cohort 1) in daily step count were assessed using a Pearson's correlation. Composite scores comprised of individual DPA items with univariate association p-values <0.1 were tested for association with daily step count using multivariate models. RESULTS: Tasks associated with average daily step count in both cohorts included putting on shoes, showering, washing hair, walking for exercise, the frequency of walks >10 min, and walking on an incline (Pearson's rho range = 0.14-0.43). A composite score of these 6 DPA items demonstrated significant associations with baseline average daily step count in both cohorts (ρ = 0.5 & 0.47, Cohorts 1 & 2, respectively) and longitudinal change in daily step count (ρ = 0.46, Cohort 1). CONCLUSIONS: Self-reported task-oriented assessments complement direct monitoring and have potential clinical utility in exercise counseling to increase PA among COPD patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01772082.

Determinants and outcomes of change in physical activity in COPD.

Determinants of change in physical activity and outcomes of physical activity promotion are unclear. In this secondary analysis of a randomised controlled trial of a physical activity intervention, we assess predictors of change in physical activity and the effects of increasing physical activity on chronic obstructive pulmonary disease (COPD) measures. Physical activity was promoted in 94 subjects with COPD using the Omron HJ-720ITC pedometer alone or the pedometer plus a website that provides goal setting, feedback, motivational and educational messages, and social support for 3 months. We assessed forced expiratory volume in 1 s (FEV1), 6-min walk test (6MWT) distance, depression, social support and markers of systemic inflammation (C-reactive protein (CRP) and interleukin (IL)-6). Data from both groups were combined and subjects categorised as responders (increased steps per day) or nonresponders (decreased steps per day). Linear regression models explored predictors of change in physical activity and assessed the effect of response on changes in COPD measures. The cohort of responders (n=62) and nonresponders (n=32) had mean FEV1 1.89±0.64 L (63±22% predicted). Baseline steps per day, diagnosis of depression, social support, oxygen use and season significantly predicted change in daily step count. Responders had increases in physical activity (2038 steps per day), FEV1 (308 mL) and 6MWT distance (43.6 m), and decreases in CRP (7.84 mg·L-1) and IL-6 (2.73 ng·mL-1) compared with nonresponders (p<0.0001-0.009). History of depression, social support, oxygen use and season predict change in physical activity, and should be routinely assessed in exercise counselling. Increases in physical activity are associated with improvements in lung function, exercise capacity and systemic inflammation.

Promoting physical activity in COPD: Insights from a randomized trial of a web-based intervention and pedometer use.

RATIONALE: Low physical activity is highly prevalent among COPD patients and is associated with increased healthcare utilization and mortality and reduced HRQL. The addition of a website to pedometer use is effective at increasing physical activity; however, the timeline of change and impact of environmental factors on efficacy is unknown. METHODS: U.S. Veterans with COPD were randomized (1:1) to receive either (1) a pedometer and website which provided goal-setting, feedback, disease-specific education, and an online community forum or (2) pedometer alone for 3 months. Primary outcome was change in daily step count. Secondary outcomes included 6MWT distance, HRQL, dyspnea, depression, COPD knowledge, exercise self-efficacy, social support, motivation, and confidence to exercise. Generalized linear mixed-effects models evaluated the effect of the pedometer plus website compared to pedometer alone. RESULTS: Data from 109 subjects (98.5% male, mean age 68.6 ± 8.3 years) were analyzed. At 13 weeks, subjects in the pedometer plus website group had significant increases daily step count from baseline relative to the pedometer alone group (804 ± 356.5 steps per day, p = 0.02). The pedometer plus website group had significant improvements in daily step count from baseline beginning in week 3 which were sustained until week 13. In subgroup analyses, the pedometer plus website attenuated declines in daily step count during the transition from summer to fall. No significant differences in secondary outcomes were noted between groups. CONCLUSIONS: A website added to pedometer use improves daily step counts, sustains walking over 3 months, and attenuates declines in physical activity due to season.