Recruitment, retention, and adherence in a clinical trial: The Pediatric Heart Network's Marfan Trial experience.

BACKGROUND/AIMS: The Pediatric Heart Network Marfan Trial was a randomized trial comparing atenolol versus losartan on aortic root dilation in 608 children and young adults with Marfan syndrome. Barriers to enrollment included a limited pool of eligible participants, restrictive entry criteria, and a diverse age range that required pediatric and adult expertise. Retention was complicated by a 3-year commitment to a complex study and medication regimen. The Network partnered with the Marfan Foundation, bridging the community with the research. The aims of this study are to report protocol and medication adherence and associated predictive factors, and to describe recruitment and retention strategies. METHODS: Recruitment, retention, and adherence to protocol activities related to the primary outcome were measured. Retention was measured by percentage of enrolled participants with 3-year outcome data. Protocol adherence was calculated by completion rates of study visits, ambulatory electrocardiography (Holter monitoring), and quarterly calls. Medication adherence was assessed by the number of tablets or the amount of liquid in bottles returned. Centers were ranked according to adherence (high, medium, and low tertiles). Recruitment, retention, and adherence questionnaires were completed by sites. Descriptive statistics summarized recruitment, retention, and adherence, as well as questionnaire results. Regression modeling assessed predictors of adherence. RESULTS: Completion rates for visits, Holter monitors, and quarterly calls were 99%, 94%, and 96%, respectively. Primary outcome data at 3 years were obtained for 88% of participants. The mean percentage of medication taken was estimated at 89%. Site and age were associated with all measures of adherence. Young adult and African American participants had lower levels of adherence. Higher adherence sites employed more strategies; had more staffing resources, less key staff turnover, and more collaboration with referring providers; utilized the Foundation's resources; and used a greater number of strategies to recruit, retain, and promote protocol and medication adherence. CONCLUSION: Overall adherence was excellent for this trial conducted within a National Institutes of Health-funded clinical trial network. Strategies specifically targeted to young adults and African Americans may have been beneficial. Many strategies employed by higher adherence sites are ones that any site could easily use, such as greeting families at non-study hospital visits, asking for family feedback, providing calendars for tracking schedules, and recommending apps for medication reminders. Additional key learnings include adherence differences by age, race, and site, the value of collaborative learning, and the importance of partnerships with patient advocacy groups. These lessons could shape recruitment, retention, and adherence to improve the quality of future complex trials involving rare conditions.

Respiratory Responses to Ozone Exposure. MOSES (The Multicenter Ozone Study in Older Subjects).

RATIONALE: Acute respiratory effects of low-level ozone exposure are not well defined in older adults. OBJECTIVES: MOSES (The Multicenter Ozone Study in Older Subjects), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults. METHODS: We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.9 ± 4.5 yr old; 60% female) to 0, 70, and 120 ppb ozone for 3 hours with intermittent exercise. Outcome measures included spirometry, sputum markers of airway inflammation, and plasma club cell protein-16 (CC16), a marker of airway epithelial injury. The effects of ozone exposure on these outcomes were evaluated with mixed-effect linear models. A P value less than 0.01 was chosen a priori to define statistical significance. MEASUREMENTS AND MAIN RESULTS: The mean (95% confidence interval) FEV1 and FVC increased from preexposure values by 2.7% (2.0-3.4) and 2.1% (1.3-2.9), respectively, 15 minutes after exposure to filtered air (0 ppb). Exposure to ozone reduced these increases in a concentration-dependent manner. After 120-ppb exposure, FEV1 and FVC decreased by 1.7% (1.1-2.3) and 0.8% (0.3-1.3), respectively. A similar concentration-dependent pattern was still discernible 22 hours after exposure. At 4 hours after exposure, plasma CC16 increased from preexposure levels in an ozone concentration-dependent manner. Sputum neutrophils obtained 22 hours after exposure showed a marginally significant increase in a concentration-dependent manner (P = 0.012), but proinflammatory cytokines (IL-6, IL-8, and tumor necrosis factor-α) were not significantly affected. CONCLUSIONS: Exposure to ozone at near ambient levels induced lung function effects, airway injury, and airway inflammation in older healthy adults. Clinical trial registered with www.clinicaltrials.gov (NCT01487005).

Passive range of motion exercise to enhance growth in infants following the Norwood procedure: a safety and feasibility trial.

OBJECTIVE: The aim of this study was to evaluate the safety and feasibility of a passive range of motion exercise programme for infants with CHD. Study design This non-randomised pilot study enrolled 20 neonates following Stage I palliation for single-ventricle physiology. Trained physical therapists administered standardised 15-20-minute passive range of motion protocol, for up to 21 days or until hospital discharge. Safety assessments included vital signs measured before, during, and after the exercise as well as adverse events recorded through the pre-Stage II follow-up. Feasibility was determined by the percent of days that >75% of the passive range of motion protocol was completed. RESULTS: A total of 20 infants were enrolled (70% males) for the present study. The median age at enrolment was 8 days (with a range from 5 to 23), with a median start of intervention at postoperative day 4 (with a range from 2 to 12). The median hospital length of stay following surgery was 15 days (with a range from 9 to 131), with an average of 13.4 (with a range from 3 to 21) in-hospital days per patient. Completion of >75% of the protocol was achieved on 88% of eligible days. Of 11 adverse events reported in six patients, 10 were expected with one determined to be possibly related to the study intervention. There were no clinically significant changes in vital signs. At pre-Stage II follow-up, weight-for-age z-score (-0.84±1.20) and length-for-age z-score (-0.83±1.31) were higher compared with historical controls from two earlier trials. CONCLUSION: A passive range of motion exercise programme is safe and feasible in infants with single-ventricle physiology. Larger studies are needed to determine the optimal duration of passive range of motion and its effect on somatic growth.

Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles.

OBJECTIVE: To assess the variability in asymmetric growth and its association with neurodevelopment in infants with single ventricle (SV). STUDY DESIGN: We analyzed weight-for-age z-score minus head circumference-for-age z-score (HCAZ), relative head growth (cm/kg), along with individual growth variables in subjects prospectively enrolled in the Infant Single Ventricle Trial. Associations between growth indices and scores on the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II (BSID-II) at 14 months were assessed. RESULTS: Of the 230 subjects enrolled in the Infant Single Ventricle trial, complete growth data and BSID-II scores were available in 168 (73%). Across the cohort, indices of asymmetric growth varied widely at enrollment and before superior cavopulmonary connection (SCPC) surgery. BSID-II scores were not associated with these asymmetry indices. In bivariate analyses, greater pre-SCPC HCAZ correlated with higher MDI (r = 0.21; P = .006) and PDI (r = 0.38; P < .001) and a greater HCAZ increase from enrollment to pre-SCPC with higher PDI (r = 0.15; P = .049). In multivariable modeling, pre-SCPC HCAZ was an independent predictor of PDI (P = .03), but not MDI. CONCLUSION: In infants with SV, growth asymmetry was not associated with neurodevelopment at 14 months, but pre-SCPC HCAZ was associated with PDI. Asymmetric growth, important in other high-risk infants, is not a brain-sparing adaptation in infants with SV. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00113087.

Outcomes during and after long-term tocilizumab treatment in patients with giant cell arteritis.

OBJECTIVE: To assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment. METHODS: Retrospective analysis of GCA patients treated with TCZ at a single centre (2010-2022). Time to relapse and annualised relapse rate during and after TCZ treatment, prednisone use, and safety were assessed. Relapse was defined as reappearance of any GCA clinical manifestation that required treatment intensification, regardless of C reactive protein levels and erythrocyte sedimentation rate. RESULTS: Sixty-five GCA patients were followed for a mean (SD) of 3.1 (1.6) years. The mean duration of the initial TCZ course was 1.9 (1.1) years. The Kaplan-Meier (KM)-estimated relapse rate at 18 months on TCZ was 15.5%. The first TCZ course was discontinued due to satisfactory remission achievement in 45 (69.2%) patients and adverse events in 6 (9.2%) patients. KM-estimated relapse rate at 18 months after TCZ discontinuation was 47.3%. Compared with patients stopping TCZ at or before 12 months of treatment, the multivariable adjusted HR (95% CI) for relapse in patients on TCZ beyond 12 months was 0.01 (0.00 to 0.28; p=0.005). Thirteen patients received >1 TCZ course. Multivariable adjusted annualised relapse rates (95% CI) in all periods on and off TCZ aggregated were 0.1 (0.1 to 0.2) and 0.4 (0.3 to 0.7), respectively (p=0.0004). Prednisone was discontinued in 76.9% of patients. During the study, 13 serious adverse events occurred in 11 (16.9%) patients. CONCLUSION: Long-term TCZ treatment was associated with remission maintenance in most patients with GCA. The estimated relapse rate by 18 months after TCZ discontinuation was 47.3%.

Ozone effects on blood biomarkers of systemic inflammation, oxidative stress, endothelial function, and thrombosis: The Multicenter Ozone Study in oldEr Subjects (MOSES).

The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion (ppb) (filtered air), 70 ppb, and 120 ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. The definition of statistical significance was p<0.01. There were no effects of ozone on the three primary markers of systemic inflammation and a prothrombotic state: C-reactive protein, monocyte-platelet conjugates, and microparticle-associated tissue factor activity. However, among the secondary endpoints, endothelin-1, a potent vasoconstrictor, increased from pre- to post-exposure with ozone concentration (120 vs 0 ppb: 0.07 pg/mL, 95% confidence interval [CI] 0.01, 0.14; 70 vs 0 ppb: -0.03 pg/mL, CI -0.09, 0.04; p = 0.008). Nitrotyrosine, a marker of oxidative and nitrosative stress, decreased with increasing ozone concentrations, with marginal significance (120 vs 0 ppb: -41.5, CI -70.1, -12.8; 70 vs 0 ppb: -14.2, CI -42.7, 14.2; p = 0.017). GSTM1 status did not modify the effect of ozone exposure on any of the outcomes. These findings from healthy older adults fail to identify any mechanistic basis for the epidemiologically described cardiovascular effects of exposure to ozone. The findings, however, may not be applicable to adults with cardiovascular disease.

Cardiovascular function and ozone exposure: The Multicenter Ozone Study in oldEr Subjects (MOSES).

BACKGROUND: To date, there have been relatively few studies of acute cardiovascular responses to controlled ozone inhalation, although a number of observational studies have reported significant positive associations between both ambient ozone levels and acute cardiovascular events and long-term ozone exposure and cardiovascular mortality. OBJECTIVES: We hypothesized that short-term controlled exposure to low levels of ozone in filtered air would induce autonomic imbalance, repolarization abnormalities, arrhythmia, and vascular dysfunction. METHODS: This randomized crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol, from June 2012 to April 2015. Subjects were exposed for 3 h in random order to 0 ppb (filtered air), 70 ppb ozone, and 120 ppb ozone, alternating 15 min of moderate exercise with 15 min of rest. A suite of cardiovascular endpoints was measured the day before, the day of, and up to 22 h after each exposure. Mixed effect linear and logit models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. Site and time were included in the models. RESULTS: We found no significant effects of ozone exposure on any of the primary or secondary measures of autonomic function, repolarization, ST segment change, arrhythmia, or vascular function (systolic blood pressure and flow-mediated dilation). CONCLUSIONS: In this multicenter study of older healthy women and men, there was no convincing evidence for acute effects of 3-h, relatively low-level ozone exposures on cardiovascular function. However, we cannot exclude the possibility of effects with higher ozone concentrations, more prolonged exposure, or in subjects with underlying cardiovascular disease. Further, we cannot exclude the possibility that exposure to ambient ozone and other pollutants in the days before the experimental exposures obscured or blunted cardiovascular biomarker response to the controlled ozone exposures.

The Impact of the Left Ventricle on Right Ventricular Function and Clinical Outcomes in Infants with Single-Right Ventricle Anomalies up to 14 Months of Age.

BACKGROUND: Children with single-right ventricle anomalies such as hypoplastic left heart syndrome (HLHS) have left ventricles of variable size and function. The impact of the left ventricle on the performance of the right ventricle and on survival remains unclear. The aim of this study was to identify whether left ventricular (LV) size and function influence right ventricular (RV) function and clinical outcome after staged palliation for single-right ventricle anomalies. METHODS: In the Single Ventricle Reconstruction trial, echocardiography-derived measures of LV size and function were compared with measures of RV systolic and diastolic function, tricuspid regurgitation, and outcomes (death and/or heart transplantation) at baseline (preoperatively), early after Norwood palliation, before stage 2 palliation, and at 14 months of age. RESULTS: Of the 522 subjects who met the study inclusion criteria, 381 (73%) had measurable left ventricles. The HLHS subtype of aortic atresia/mitral atresia was significantly less likely to have a measurable left ventricle (41%) compared with the other HLHS subtypes: aortic stenosis/mitral stenosis (100%), aortic atresia/mitral stenosis (96%), and those without HLHS (83%). RV end-diastolic and end-systolic volumes were significantly larger, while diastolic indices suggested better diastolic properties in those subjects with no left ventricles compared with those with measurable left ventricles. However, RV ejection fraction was not different on the basis of LV size and function after staged palliation. Moreover, there was no difference in transplantation-free survival to Norwood discharge, through the interstage period, or at 14 months of age between those subjects who had measurable left ventricles compared with those who did not. CONCLUSIONS: LV size varies by anatomic subtype in infants with single-right ventricle anomalies. Although indices of RV size and diastolic function were influenced by the presence of a left ventricle, there was no difference in RV systolic function or transplantation-free survival on the basis of LV measures.

Association of air particulate pollution with bone loss over time and bone fracture risk: analysis of data from two independent studies.

BACKGROUND: Air particulate matter (PM) is a ubiquitous environmental exposure associated with oxidation, inflammation, and age-related chronic disease. Whether PM is associated with loss of bone mineral density (BMD) and risk of bone fractures is undetermined. METHODS: We conducted two complementary studies of: (i) long-term PM <2.5 µm (PM2.5) levels and osteoporosis-related fracture hospital admissions among 9.2 million Medicare enrollees of the Northeast/Mid-Atlantic United States between 2003-2010; (ii) long-term black carbon [BC] and PM2.5 levels, serum calcium homeostasis biomarkers (parathyroid hormone, calcium, and 25-hydroxyvitamin D), and annualized BMD reduction over a 8-year follow-up of 692 middle-aged (46.7±12.3 yrs), low-income BACH/Bone cohort participants. FINDINGS: In the Medicare analysis, risk of bone fracture admissions at osteoporosis-related sites was greater in areas with higher PM2.5 levels (Risk ratio [RR] 1.041, 95% Confidence Interval [CI], 1.030, 1.051). This risk was particularly high among low-income communities (RR 1.076; 95% CI, 1.052, 1.100). In the longitudinal BACH/Bone study, baseline BC and PM2.5 levels were associated with lower serum PTH (Estimate for baseline one interquartile increase in 1-year average BC= -1.16, 95% CI -1.93, -0.38; Estimate for baseline one interquartile increase in 1-year average PM2.5= -7.39; 95%CI -14.17, -0.61). BC level was associated with higher BMD loss over time at multiple anatomical sites, including femoral neck (-0.08%/year per one interquartile increase; 95% CI -0.14, -0.02%/year) and ultradistal radius (-0.06%/year per one interquartile increase; 95% CI -0.12, -0.01%/year). INTERPRETATION: Our results suggest that poor air quality is a modifiable risk factor for bone fractures and osteoporosis, especially in low-income communities.

Development and impact of arrhythmias after the Norwood procedure: A report from the Pediatric Heart Network.

OBJECTIVES: The study objective was to determine the predictors of new-onset arrhythmia among infants with single-ventricle anomalies during the post-Norwood hospitalization and the association of those arrhythmias with postoperative outcomes (ventilator time and length of stay) and interstage mortality. METHODS: After excluding patients with preoperative arrhythmias, we used data from the Pediatric Heart Network Single Ventricle Reconstruction Trial to identify risk factors for tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, junctional ectopic tachycardia, and ventricular tachycardia) and atrioventricular block (second or third degree) among 544 eligible patients. We then determined the association of arrhythmia with outcomes during the post-Norwood hospitalization and interstage period, adjusting for identified risk factors and previously published factors. RESULTS: Tachyarrhythmias were noted in 20% of subjects, and atrioventricular block was noted in 4% of subjects. Potentially significant risk factors for tachyarrhythmia included the presence of modified Blalock-Taussig shunt (P = .08) and age at Norwood (P = .07, with risk decreasing each day at age 8-20 days); the only significant risk factor for atrioventricular block was undergoing a concomitant procedure at the time of the Norwood (P = .001), with the greatest risk being in those undergoing a tricuspid valve procedure. Both tachyarrhythmias and atrioventricular block were associated with longer ventilation time and length of stay (P < .001 for all analyses). Tachyarrhythmias were not associated with interstage mortality; atrioventricular block was associated with mortality among those without a pacemaker in the unadjusted analysis (hazard ratio, 2.3; P = .02), but not after adding covariates. CONCLUSIONS: Tachyarrhythmias are common after the Norwood procedure, but atrioventricular block may portend a greater risk for interstage mortality.

Racial/ethnic and socioeconomic differences in bone loss among men.

As men age, they lose bone and are susceptible to fracture. Despite having lower fracture rates than women, men have worse fractures than women do. Racial/ethnic and socioeconomic status (SES) disparities in fracture rates exist, yet data on rates of bone loss by race/ethnicity and SES among men are limited. We examined annualized percentage change in bone mineral density (%ΔBMD) at the hip (N = 681), spine (N = 663), and forearm (N = 636) during 7 years of follow-up among men aged 30-79 years at baseline. Multivariable models tested whether race/ethnicity, income, or genetic ancestry predicted annualized %ΔBMD after controlling for an extensive set of covariates. Annualized %ΔBMD ranged from -0.65(0.04)% (femoral neck) to +0.26(0.03)% (1/3 distal radius), and changes were consistent across age groups with the exception of the ultradistal radius, where annualized declines increased with age. Neither self-identified race/ethnicity nor genetic ancestry were associated with annualized %ΔBMD. In contrast, income was strongly associated (dose-response) with annualized %ΔBMD at total hip (independent of confounders, self-identified race/ethnicity, and genetic ancestry). Fully adjusted least-square mean change in annualized %ΔBMD at the total hip were -0.24(0.12)% and -0.16(0.06)% steeper among men with low and moderate incomes, respectively, than among men with higher incomes (overall p = 0.0293). Results show a linear decline in bone that begins relatively early in life among men, that rates of bone loss do not vary with race/ethnicity (self-identified or "objectively" measured), and that income plays an important role in relation to bone loss at the hip. These data suggest that fracture risk in men may be driven in part by income-related differences in bone loss, but also, that the known higher fracture risk among white men is not the result of racial/ethnic differences in bone loss, but rather, early life exposures that lead to attainment of higher peak bone mass among minorities.