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.

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.

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.

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.

ClinicalTrials.gov NCT01772082.

Background: The evaluation of syncope is challenging and is often associated with a high volume of repeat diagnostic testing. Early use of an implantable cardiac monitor (ICM) is recommended for patients with unexplained syncope following initial non-diagnostic workup. However, limited data is available on the patient journey prior to ICM. The aim of this study was to characterize healthcare utilization and referral pathways experienced during syncope evaluation, prior to insertion of ICM. Methods: ICM patients were identified in the 2014-2016 U.S. Medicare Fee-for-service claims database. Included patients were ≥18 years of age, had a syncope claim within 3 months prior to ICM insertion, and had continuous enrollment for ≥2 years baseline. Syncope-related encounters were defined as unique healthcare visits with a syncope diagnosis code. All specialist consultations within an encounter were captured. Results: Of 982 patients identified, 550 (56%) were female; mean age was 74 years. Mean time from first syncope encounter to ICM insertion was 236 days (min-max 1-1,081), with mean of 4.7 (min-max 1-30) total syncope-related encounters per patient. Out of 6 possible service locations, patients presented at a mean of 2.2 (min-max 1-5) different sites of service for syncope; 38% (375 of 982) of patients had been seen at ≥3 sites of service. Of 982 patients, 362 (37%) had presented to the ED, 399 (41%) had been hospitalized, 668 (68%) had been seen in outpatient hospital, and 534 (54%) in an office setting. A mean of 2.9 (min-max 0-9) specialist types had been consulted per patient, out of a total of 11 possible categories. One quarter of patients (745) had seen a cardiologist, 300 (10%) had seen an electrophysiologist (EP), and 155 (5.3%) a neurologist (Table). During initial syncope encounter, a cardiologist was consulted in 449 (27%) and EP in only 105 (6.2%) of patients. Conclusion: Wide variability was observed in both time and patient pathway between first syncope presentation and ICM. A more standardized approach to the triage and management of syncope patients has potential to reduce the volume of repeat evaluations and diminish associated delays in establishing diagnosis and appropriate treatment.

Background: People with T2DM have increased risks of CV morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce risks of CV events, but the degree to which they are used in clinical practice remains unknown. Our objectives were to describe glucose-lowering drug utilization in U.S. patients with T2DM and established CVD (eCVD) in 2014-18. Methods: Annual drug use by adults (≥ 18 years) with T2DM and eCVD (during the same 12-months) was determined from the MarketScan claims database. Results: We identified 345,340 (2014) to 227,418 (half year 2018) patients with T2DM and eCVD; hypertension and ischemic heart disease were the most prevalent eCVDs. About 55-60% of patients used any type of glucose lowering drug. Although the use of GLP-1 RA and SGLT2i increased 6.2 and 9.5 percentage points respectively across 2014-18, the use of dipeptidyl peptidase-4 inhibitors (DPP-4i) decreased by 3.7 points and use of other glucose lowering drugs decreased by 10.8 points. Patients who used GLP-1 RA and SGLT2i were 8 years younger than users of DPP-4i or other glucose lowering drugs. SGLT2i users had the lowest prevalence of chronic heart failure and chronic kidney disease. Conclusion: Despite recent increases, GLP 1-RA and SGLT2i are significantly underused among patients with T2DM and eCVD in the MarketScan claims database. Disclosure M.L. Ganz: None. A.V. Ustyugova: Employee; Self; Boehringer Ingelheim International GmbH. N. Sawalhi-Leckenby: None. S. de Souza: None. R. Gao: None. D. Homsy: None. E. Gunnarsson: None. L. Zhang: None. N. Desai: None.