Secondary Trial Outcomes Research Articles

Diagnostic performance of ultrasound vs. ultrasound-guided FNAc in thyroid nodules: data from the ElaTION trial.

ElaTION is a large multi-centre pragmatic randomised controlled trial, performed in 18 secondary/tertiary hospitals across England, comparing elastography ultrasound-guided fine needle aspiration cytology (EUS-FNAC) with ultrasound-guided FNAC (US-FNAC) alone in the diagnostic assessment of thyroid nodules. Secondary trial outcomes, reported here, assessed the accuracy of ultrasound-alone (US) compared with US-guided FNAC to inform and update current practice guidelines. Adults with single or multiple thyroid nodules who had not undergone previous FNAC were eligible. Radiologists assessed all thyroid nodules using US alone, thereby enabling assessment of its accuracy (sensitivity and specificity) versus US-FNAC. Of the 982 participants, a final definitive diagnosis was obtained in 688, who were included in the final analyses. The sensitivity of US-alone was the same as US-FNAC (0.91, [95% CI 0.85, 0.97] vs 0.87 [95%CI 0.80-0.95], p=0.37). US alone had statistically significant lower specificity than US-FNAC alone (0.48 vs 0.67 respectively, p<0.0001). The malignancy rate on histology in a nodule classified as benign on ultrasound (U2) was 9/263 (3.42%) and on cytology (Thy2) was 15/353 (4.25%), whereas the malignancy rate in a nodule that was benign on both (U2, Thy2) was 3/210 (1.43%). Malignancy risk for U3, U4, and U5 nodules was 68/304 (22.4%), 43/83 (51.8%), and 29/38 (76.3%) respectively (p<0.0001). Yet 80/982 (8%) patients were discharged despite having U3-U5 scans with Thy1 (non-diagnostic) FNAC and no definitive diagnosis.Malignancy risk was higher in smaller nodules: <10mm 23/60 (38.3%), 10-20mm 46/162 (28.4 %), and >20mm 80/466 (17.2%) (p<0.0001). Nodules with indeterminate cytology with atypical features (Thy3a) carried a similar malignancy risk to those with indeterminate cytology (Thy3/3f): 27/95 (28.4%) versus 42/113 (37.2%) respectively (p=0.18). Ultrasound alone appears to be an effective diagnostic modality in thyroid nodules, confirming the recommendations of recent guidelines and the BTA classification. However, findings also suggest caution regarding existing recommendations for conservative management of non-diagnostic (Thy1/Bethesda I) and atypical (Thy3a/Bethesda III) nodules. In those cases, ultrasound (U3-5) features may help identify high-risk subgroups for more proactive management.

Abstract 64: Biomarkers of Atrial Cardiopathy and Outcomes After Cryptogenic Stroke: The ARCADIA Trial

Background: Atrial cardiopathy is associated with incident ischemic stroke in the absence of clinical atrial fibrillation in prospective cohorts. Whether biomarkers of atrial cardiopathy predict recurrent stroke is less clear. Methods: In the ARCADIA trial, a multicenter randomized trial of apixaban versus aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy, we explored whether the biomarkers P-wave terminal force in ECG lead V 1 (PTFV1), N-terminal pro-Brain natriuretic peptide (NT-proBNP), or left atrial diameter index (LADI) predicted primary and secondary trial outcomes: (1) recurrent stroke of any type; (2) recurrent ischemic stroke or systemic embolism; and (3) recurrent stroke of any type or death. We analyzed the full cohort using Cox proportional hazard models , sequentially adjusting for treatment effect, demographic factors, and clinical risk factors. NT-proBNP concentrations were log-transformed. Results: With 1,015 of the target 1,100 participants enrolled (mean age 68 years, 54.3% female, 21.1% Black, and 8.1% Hispanic) and mean follow-up of 1.8 years, the trial was stopped for futility. Recurrent stroke occurred in 80 patients (annualized rate, 4.4%) and death in 54 patients. NT-proBNP significantly predicted recurrent stroke; recurrent ischemic stroke or systemic embolism; and recurrent stroke or death after adjusting for other risk factors, while PTFV1 and LADI did not (Table). NT-proBNP predicted recurrent stroke and death most strongly and with little change after adjusting for other risk factors. Treatment effect was not significant in any of the models. Conclusions: In this population of patients with cryptogenic stroke and evidence of atrial cardiopathy, NT-proBNP is a predictor of recurrent stroke and, with greater magnitude, of a composite of stroke or death. The role of NT-proBNP measurement in management after stroke deserves further study.

Protocol for the air purification for eosinophilic COPD study (APECS): a randomised controlled trial of home air filtration by HEPA

IntroductionExposure to particulate matter (PM) pollution has been associated with lower lung function in adults with chronic obstructive pulmonary disease (COPD). Patients with eosinophilic COPD have been found to have...

Multi-center, pragmatic, cluster-randomized, controlled trial of standardized peritoneal dialysis (PD) training versus usual care on PD-related infections (the TEACH-PD trial): trial protocol

BackgroundPeritoneal dialysis (PD)-related infections, such as peritonitis, exit site, and tunnel infections, substantially impair the sustainability of PD. Accordingly, PD-related infection is the top-priority research outcome for patients and caregivers. While PD nurse trainers teach patients to perform their own PD, PD training curricula are not standardized or informed by an evidentiary base and may offer a potential approach to prevent PD infections. The Targeted Education ApproaCH to improve Peritoneal Dialysis outcomes (TEACH-PD) trial evaluates whether a standardized training curriculum for PD nurse trainers and incident PD patients based on the International Society for Peritoneal Dialysis (ISPD) guidelines reduces PD-related infections compared to usual training practices.MethodsThe TEACH-PD trial is a registry-based, pragmatic, open-label, multi-center, binational, cluster-randomized controlled trial. TEACH-PD will recruit adults aged 18 years or older who have not previously undergone PD training at 42 PD treatment units (clusters) in Australia and New Zealand (ANZ) between July 2019 and June 2023. Clusters will be randomized 1:1 to standardized TEACH-PD training curriculum or usual training practice. The primary trial outcome is the time to the first occurrence of any PD-related infection (exit site infection, tunnel infection, or peritonitis). The secondary trial outcomes are the individual components of the primary outcome, infection-associated catheter removal, transfer to hemodialysis (greater than 30 days and 180 days), quality of life, hospitalization, all-cause death, a composite of transfer to hemodialysis or all-cause death, and cost-effectiveness. Participants are followed for a minimum of 12 months with a targeted average follow-up period of 2 years. Participant and outcome data are collected from the ANZ Dialysis and Transplant Registry (ANZDATA) and the New Zealand Peritoneal Dialysis (NZPD) Registry. This protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.DiscussionTEACH-PD is a registry-based, cluster-randomized pragmatic trial that aims to provide high-certainty evidence about whether an ISPD guideline-informed standardized PD training curriculum for PD nurse trainers and adult patients prevents PD-related infections.Trial registrationClinicalTrials.gov NCT03816111. Registered on 24 January 2019.

Which trial do we need? Combination antimicrobial therapy for hospital-acquired bacterial pneumonia caused by Pseudomonas aeruginosa

Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05.

Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia

IntroductionLower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.MethodsPreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.Results365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).ConclusionsFindings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

Effects of an integrated poultry value chain, nutrition, gender and WASH intervention (SELEVER) on hygiene and child morbidity and anthropometry in Burkina Faso: A secondary outcome analysis of a cluster randomised trial.

Nutrition-sensitive agriculture programmes have the potential to improve child nutrition outcomes, but livestock intensification may pose risks related to water, sanitation and hygiene (WASH) conditions. We assessed the impact of SELEVER, a nutrition- and gender-sensitive poultry intervention, with and without added WASH focus, on hygiene practices, morbidity and anthropometric indices of nutrition in children aged 2-4 years in Burkina Faso. A 3-year cluster randomised controlled trial was implemented in 120 villages in 60 communes (districts) supported by the SELEVER project. Communes were randomly assigned using restricted randomisation to one of three groups: (1) SELEVER intervention (n = 446 households); (2) SELEVER plus WASH intervention (n = 432 households); and (3) control without intervention (n = 899 households). The study population included women aged 15-49 years with an index child aged 2-4 years. We assessed the effects 1.5-years (WASH substudy) and 3-years (endline) post-intervention on child morbidity and child anthropometry secondary trial outcomes using mixed effects regression models. Participation in intervention activities was low in the SELEVER groups, ranging from 25% at 1.5 years and 10% at endline. At endline, households in the SELEVER groups had higher caregiverknowledge ofWASH-livestock risks (∆ = 0.10, 95% confidence interval [CI] [0.04-0.16]) and were more likely to keep children separated from poultry (∆ = 0.09, 95% CI [0.03-0.15]) than in the control group. No differences were found for other hygiene practices, child morbidity symptoms or anthropometry indicators. Integrating livestock WASH interventions alongside poultry and nutrition interventions can increase knowledge of livestock-related risks and improve livestock-hygiene-related practices, yet may not be sufficient to improve the morbidity and nutritional status of young children.

12-month secondary outcomes of a prostate cancer survivor symptom self-management intervention.

373 Background: Long term adverse symptoms following treatment for prostate cancer are prevalent and can negatively impact quality of life and increase healthcare seeking, even though many symptoms can be effectively self-managed. There remains a need for tools to support long term survivors to feel confident in their ability to self-manage their symptoms, potentially translating to more efficient health care utilization. Methods: We conducted a RCT of an automated tailored self-management support intervention (vs. newsletter) for long term (&gt; 1 year) Veteran survivors of prostate cancer recruited from 4/2015-2/2017 across four VA sites. Participants were randomized (278 per arm) and assessed via survey at 5 months and 12 months post enrollment. The intervention delivered tailored information regarding symptoms for urinary, sexual, bowel and general health over 3 months, allowing participants to choose focus areas. At 12 months, we assessed secondary trial outcomes; participants’ reports of use of services relative to their symptoms (urinary, bowel, sexual, general health) and their confidence in symptom self-management (scale from 5-15). We also assessed use of procedures and medications related to each symptom area via medical charts. We tested differences in reported and documented service use between arms using T-tests and Chi-square tests. We further assessed participants engagement in components of the intervention. Results: Of those randomized, 81.7% completed the 12-month survey assessment (N = 226 Intervention and N = 228 Control). The average age was 66.7, 28% were Black, and 49% were high school graduates or less. Participants in the intervention arm reported greater confidence in symptom self-management than controls (Mean: 13.5 vs. 12.9; P = 0.01). Intervention participants reported less often using services related to urinary (43.9% vs. 56.0%, P = 0.03) and sexual (42.3% vs. 57.6%, P = 0.04) health over the prior 7 months. Review of intervention paradata found that urinary and sexual health were the topics most frequently engaged with among intervention subjects. No significant differences in medical chart documented procedures related to symptom areas were found. Conclusions: This secondary trial analysis found that 12 months post enrollment, Veterans who engaged with a tailored self-management intervention were more confident in their ability to self-manage their symptoms. The associated finding of fewer visits for the most commonly chosen areas for symptom self-management suggests that such an intervention may hold promise for helping long term survivors to effectively self-manage adverse symptoms. Clinical trial information: NCT01900561.

Cholecalciferol Supplementation Does Not Affect the Risk of HIV Progression, Viral Suppression, Comorbidities, Weight Loss, and Depression among Tanzanian Adults Initiating Antiretroviral Therapy: Secondary Outcomes of a Randomized Trial

BackgroundObservational studies suggest that blood concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with morbidity, viral suppression, and mortality among adults living with HIV. ObjectivesWe evaluated the effect of cholecalciferol (vitamin D3) supplementation on the risk of HIV disease progression, HIV-1 viral suppression, comorbidities, weight change, and depression among HIV-infected individuals that were initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. MethodsWe conducted a randomized, double-blind, placebo-controlled trial of vitamin D3 supplementation among 4000 HIV-infected adult men and nonpregnant women initiating ART with insufficient serum 25(OH)D concentrations (<30 ng/mL). Participants were randomly assigned to receive either weekly 50,000-IU doses for 4 wk followed by daily 2000 IU vitamin D3 until 1 y or a matching placebo regimen given in weekly followed by daily doses until 1 y. Participants were followed up at weekly visits for the first month followed by monthly visits thereafter. We conducted intent-to-treat analyses to assess the effect of vitamin D3 supplementation on the secondary trial outcomes of HIV progression or death, viral suppression, comorbidities, change in BMI, >10% weight loss, incident wasting, and depression. ResultsDuring follow-up, 345 participants (17.2%) in the vitamin D3 group and 371 participants (18.6%) in the placebo group experienced HIV disease progression or death and there was no difference in risk between groups (RR: 0.91; 95% CI: 0.79, 1.06). Vitamin D3 supplementation did not affect the risk of an unsuppressed HIV-1 viral load (>1000 copies/mL) after 6 mo (RR: 1.10; 95% CI: 0.87, 1.41) and there was also no effect on change in BMI, risk of >10% weight loss, wasting, comorbidities, and depression (P values >0.05). ConclusionsVitamin D supplementation did not affect the risk of HIV progression, viral suppression, common morbidities, weight-related indicators, or depression among adults initiating ART in Tanzania.This trial was registered at clinicaltrials.gov as NCT01798680.

Weight loss-induced improvement of body weight and insulin sensitivity is not amplified by a subsequent 12-month weight maintenance intervention but is predicted by adaption of adipose atrial natriuretic peptide system: 48-month results of a randomized controlled trial

BackgroundBehavioral weight loss interventions are frequently hampered by long-term inefficacy. As metabolic improvements and health-related quality of life (HRQoL) are diminished by weight regain, effective long-term strategies are highly desirable. We aimed to analyze whether an additional weight maintenance intervention could delay body weight regain and can induce a long-term improvement of metabolism and HRQoL for up to 48 months in humans. Given the short-term metabolic effects of natriuretic peptides (NP), we also investigated the role of the adipose atrial NP (ANP) system in this long-term context.MethodsAfter a successful 12-week weight reduction program 143 subjects (age>18; BMI≥27 kg/m2) were randomized (1:1) to a control group or a 12-month multimodal weight maintenance intervention focusing on nutritional counseling and physical exercises. Secondary trial outcomes including course of BMI, HOMA-IR, glucose response after oGTT (glucoseAUC), and HRQoL (SF-36) were analyzed yearly for 48 months. Adipose ANP receptor mRNA expression was analyzed during weight loss.ResultsInitial weight loss (− 4.7±1.5 kg/m2) improved glucoseAUC, HOMA-IR, and HRQoL. Although BMI was still reduced after 48 months (−1.98 [95% CI −2.61, −1.35] kg/m2), benefits on HOMA-IR, glucoseAUC, and mental health disappeared after 36 (−0.49 [−1.00, 0.02]), 18 (0.61 [−9.57, 10.79] mg dl−1 min−1), and 18 months (2.06 [−0.08, 4.20]), respectively, while improved physical health persisted up to months 48 (2.95 [0.49, 5.40]). Weight maintenance intervention inhibited weight regain and delayed impairment of HOMA-IR and glucoseAUC (but not HRQoL) for up to 12 months. However, no metabolic long-term effect was seen beyond the intervention period. Lower adipose NPR-C and higher NPR-A mRNA expression after weight loss predicted smaller regain of weight (r=0.398; p<0.05)/fat mass (FM) (r=0.391; p<0.05) and longer improvement of HOMA-IR (r=−0.422; p<0.05), respectively.ConclusionsAdditional benefits of a behavioral 12-month weight maintenance intervention after weight loss regarding body weight regain and metabolic improvement does not persist beyond the intervention period. However, weight loss-induced modulation of the adipose ANP system is probably involved in the long-term control of body weight regain and insulin sensitivity.Trial registrationClinicalTrials.govNCT00850629. Registered on February 25, 2009.

Comparing two identically protocolized, multicentre, randomized controlled trials on caregiver-mediated exercises poststroke: Any differences across countries?

BackgroundThe evidence for rehabilitation interventions poststroke lack sufficient robustness. However, variation in treatment effects across countries have been given little attention.ObjectiveTo compare two identically protocolized trials conducted in different western countries in order to identify factors that may have caused variation in secondary trial outcomes.MethodsComparative study based on individual patient data (N = 129) from two randomized controlled trials, conducted in hospitals and rehabilitation facilities in the Netherlands (N = 66) and Australia (N = 63). Patients with stroke and their caregivers were randomly allocated to an 8-week caregiver-mediated exercises intervention (N = 63; 31 Australian and 32 Dutch) or to a control group (N = 66; 32 Australian and 34 Dutch). Patient characteristics, compliance, usual care and process measures were compared across countries. We examined if study setting significantly moderated the trial outcomes: Hospital Anxiety and Depression Scale, Fatigue Severity Scale and General Self-Efficacy Scale, measured at 8- and 12 weeks follow-up. In addition, we explored if factors that were significantly different across countries caused variation in these trial outcomes.ResultsMost patients suffered an ischemic stroke, were in the subacute phase and participated with their partner. Dutch patients were younger (P = 0.005) and had a lower functional status (P = 0.001). Australian patients were recruited earlier poststroke (P<0.001), spent less time in exercise therapy (P<0.001) and had a shorter length of stay (P<0.001). The level of contamination was higher (P = 0.040) among Dutch controls. No effect modification was observed and trial outcomes did not change after controlling for cross-country differences.ConclusionsThe present study highlighted important clinical differences across countries whilst using an identical study protocol. The observed differences could result in a different potential for recovery and variation in treatment effects across trials. We argue that we can proceed faster to evaluating interventions within international pragmatic trials.

Revascularisation for Symptomatic Peripheral Artery Disease: External Applicability of the VOYAGER PAD Trial

In the VOYAGER PAD trial, rivaroxaban 2.5 mg plus aspirin significantly reduced the primary composite efficacy outcome of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death compared with aspirin alone. However, patients enrolled in the trial may not reflect patients encountered in daily clinical practice. This study described the proportion of patients eligible for VOYAGER PAD within the nationwide Danish Vascular Registry (DVR), reasons for ineligibility, and outcomes according to eligibility. In total, 32 911 patients who underwent lower extremity revascularisation for symptomatic peripheral arterial disease (PAD) in the DVR (2000-2016) were identified. Trial inclusion and exclusion criteria were applied, and the three year cumulative incidence of primary and secondary trial outcomes was estimated. Altogether, 27.1% of patients with PAD in the DVR were "VOYAGER eligible". Of those not included, 30.7% had at least one exclusion criterion ("VOYAGER excluded"), and an additional 42.3% did not fulfil the inclusion criteria ("VOYAGER not included"). The main reasons for exclusion were atrial fibrillation (32.3%), poorly regulated hypertension (20.6%), requirement for long term dual antiplatelet therapy (10.9%), cytochrome P450 inhibitors or inducers (9.7%), and renal failure (9.3%). The three year rate of the primary efficacy outcome was 10.08 per 100 person years among the "VOYAGER eligible", 16.32 among "VOYAGER excluded", and 6.98 among the "VOYAGER not included". For the primary safety outcome of thrombolysis in myocardial infarction (TIMI) major bleeding, rates were 2.24, 3.76, and 1.17, respectively. Rates of secondary endpoints were also consistently lower for patients who did not meet the inclusion criteria (predominantly due to central aorto-iliac procedures) and highest for "VOYAGER excluded" patients. "VOYAGER eligible" patients experienced a higher cumulative incidence of most endpoints than patients enrolled in the control arm of the VOYAGER PAD trial. Among patients in routine clinical practice, 27.1% were eligible for the VOYAGER PAD trial. These patients were older, had more severe vascular symptoms, higher bleeding risk, and worse prognosis than trial participants.

Effect of intensive versus limited monitoring on clinical trial conduct and outcomes: A randomized trial

Regulatory agencies have endorsed more limited approaches to clinical trial site monitoring. However, the impact of different monitoring strategies on trial conduct and outcomes is unclear. We conducted a patient-level block-randomized controlled trial evaluating the effect of intensive versus limited monitoring on cardiovascular clinical trial conduct and outcomes nested within the CoreValve Continued Access and Expanded Use Studies. Intensive monitoring included complete source data verification of all critical datapoints whereas limited monitoring included automated data checks only. This study's endpoints included clinical trial outcome ascertainment as well as monitoring action items, protocol deviations, and adverse event ascertainment. A total of 2,708 patients underwent transcatheter aortic valve replacement (TAVR) and were randomized to either intensive monitoring (n = 1,354) or limited monitoring (n = 1,354). Monitoring action items were more common with intensive monitoring (52% vs 15%; P < .001), but there was no difference in the percentage of patients with any protocol deviation (91.6% vs 90.4%; P=.314). The reported incidence of trial outcomes between intensive and limited monitoring was similar for mortality (30 days: 4.8% vs 5.5%, P=.442; 1 year: 20.3% vs 21.3%, P=.473) and stroke (30 days: 2.8% vs 2.4%, P=.458), as well as most secondary trial outcomes with the exception of bleeding (intensive: 36.3% vs limited: 32.0% at 30 days, P=.019). There was a higher reported incidence of cardiac adverse events reported in the intensive monitoring group at 1 year (76.7% vs 72.4%; P=.019). Tailored limited monitoring strategies can be implemented without influencing the integrity of TAVR trial outcomes.

Prenatal Repair and Physical Functioning Among Children With Myelomeningocele

The Management of Myelomeningocele Study (MOMS), a randomized clinical trial of prenatal vs standard postnatal repair for myelomeningocele, found that prenatal repair reduced hydrocephalus and hindbrain herniation and improved motor function in children aged 12 to 30 months. The Management of Myelomeningocele Study Follow-up (MOMS2) was conducted in children at ages 5 to 10 years. The primary (neurocognitive) outcome has already been reported. To determine whether MOMS2 participants who had prenatal repair have better physical functioning than those with postnatal repair. Participants from MOMS were recruited for participation in the follow-up study, MOMS2, conducted from April 9, 2012, to April 15, 2017. For this secondary analysis of the randomized clinical trial, trained examiners without knowledge of the treatment group evaluated the physical characteristics, self-care skills, neurologic function, and mobility of the children. Physical functioning outcomes were compared between the prenatal and postnatal repair groups. MOMS2 was conducted at the same 3 clinical sites as MOMS. Home visits were conducted for families who were unable to travel to one of the clinical sites. Of the 161 children with myelomeningocele aged 5 to 10 years old enrolled in MOMS2, 154 had a physical examination and were included in the analyses. Prenatal repair of myelomeningocele. Prespecified secondary trial outcomes of self-care skills, functional mobility, walking skills, and motor level. This analysis included 78 children with postnatal repair (mean [SD] age, 7.4 [2.1] years; 50 girls [64.1%]; 69 White children [88.5%]) and 76 with prenatal repair (mean [SD] age, 7.5 [1.2] years; 43 boys [56.6%]; 70 White children [92.1%]). Children in the prenatal repair group were more competent with self-care skills (mean [SD] percentage of maximum FRESNO Scale score, 90.8% [9.6%] vs 85.5% [17.6%]) and were commonly community ambulators per the Modified Hoffer Classification (51.3% prenatal vs 23.1% postnatal; adjusted relative risk [aRR] for sex, 1.70; 95% CI, 1.23-2.34). Children with prenatal repair also performed the 10-m walk test 1 second faster (difference in medians, 1.0; 95% CI, 0.3-1.7), had better gait quality (adjusted mean difference for home distances of 5 m, 1.71; 95% CI, 1.14-2.54), and could perform higher-level mobility skills (adjusted mean difference for motor total, 5.70; 95% CI, 1.97-11.18). Children in the prenatal repair group were less likely to have a motor function level worse than their anatomic lesion level (aRR, 0.44; 95% CI, 0.25-0.77). This secondary analysis of a randomized clinical trial found that the physical functioning benefits of prenatal repair for myelomeningocele reported at age 30 months persisted into school age. These findings indicate the benefit of prenatal repair of myelomeningocele for school-aged children. ClinicalTrials.gov Identifier: NCT00060606.

Impact of food supplements on early child development in children with moderate acute malnutrition: A randomised 2 x 2 x 3 factorial trial in Burkina Faso.

Lipid-based nutrient supplements (LNS) and corn-soy blends (CSBs) with varying soy and milk content are used in treatment of moderate acute malnutrition (MAM). We assessed the impact of these supplements on child development. We conducted a randomised 2 × 2 × 3 factorial trial to assess the effectiveness of 12 weeks' supplementation with LNS or CSB, with either soy isolate or dehulled soy, and either 0%, 20%, or 50% of protein from milk, on child development among 6-23-month-old children with MAM. Recruitment took place at 5 health centres in Province du Passoré, Burkina Faso between September 2013 and August 2014. The study was fully blinded with respect to soy quality and milk content, while study participants were not blinded with respect to matrix. This analysis presents secondary trial outcomes: Gross motor, fine motor, and language development were assessed using the Malawi Development Assessment Tool (MDAT). Of 1,609 children enrolled, 54.7% were girls, and median age was 11.3 months (interquartile range [IQR] 8.2-16.0). Twelve weeks follow-up was completed by 1,548 (96.2%), and 24 weeks follow-up was completed by 1,503 (93.4%); follow-up was similar between randomised groups. During the study, 4 children died, and 102 children developed severe acute malnutrition (SAM). There was no difference in adverse events between randomised groups. At 12 weeks, the mean MDAT z-scores in the whole cohort had increased by 0.33 (95% CI: 0.28, 0.37), p < 0.001 for gross motor; 0.26 (0.20, 0.31), p < 0.001 for fine motor; and 0.14 (0.09, 0.20), p < 0.001 for language development. Children had larger improvement in language z-scores if receiving supplements with milk (20%: 0.09 [-0.01, 0.19], p = 0.08 and 50%: 0.11 [0.01, 0.21], p = 0.02), although the difference only reached statistical significance for 50% milk. Post hoc analyses suggested that this effect was specific to boys (interaction p = 0.02). The fine motor z-scores were also improved in children receiving milk, but only when 20% milk was added to CSB (0.18 [0.03, 0.33], p = 0.02). Soy isolate over dehulled soy increased language z-scores by 0.07 (-0.01, 0.15), p = 0.10, although not statistically significant. Post hoc analyses suggested that LNS benefited gross motor development among boys more than did CSB (interaction p = 0.04). Differences between supplement groups did not persist at 24 weeks, but MDAT z-scores continued to increase post-supplementation. The lack of an unsupplemented control group limits us from determining the overall effects of nutritional supplementation for children with MAM. In this study, we found that child development improved during and after supplementation for treatment of MAM. Milk protein was beneficial for language and fine motor development, while suggested benefits related to soy quality and supplement matrix merit further investigation. Supplement-specific effects were not found post-intervention, but z-scores continued to improve, suggesting a sustained overall effect of supplementation. ISRCTN42569496.

Consistent sleep onset and maintenance of body weight after weight loss: An analysis of data from the NoHoW trial.

BackgroundSeveral studies have suggested that reduced sleep duration and quality are associated with an increased risk of obesity and related metabolic disorders, but the role of sleep in long-term weight loss maintenance (WLM) has not been thoroughly explored using prospective data.Methods and findingsThe present study is an ancillary study based on data collected on participants from the Navigating to a Healthy Weight (NoHoW) trial, for which the aim was to test the efficacy of an evidence-based digital toolkit, targeting self-regulation, motivation, and emotion regulation, on WLM among 1,627 British, Danish, and Portuguese adults. Before enrolment, participants had achieved a weight loss of ≥5% and had a BMI of ≥25 kg/m2 prior to losing weight. Participants were enrolled between March 2017 and March 2018 and followed during the subsequent 12-month period for change in weight (primary trial outcome), body composition, metabolic markers, diet, physical activity, sleep, and psychological mediators/moderators of WLM (secondary trial outcomes). For the present study, a total of 967 NoHoW participants were included, of which 69.6% were women, the mean age was 45.8 years (SD 11.5), the mean baseline BMI was 29.5 kg/m2 (SD 5.1), and the mean weight loss prior to baseline assessments was 11.4 kg (SD 6.4). Objectively measured sleep was collected using the Fitbit Charge 2 (FC2), from which sleep duration, sleep duration variability, sleep onset, and sleep onset variability were assessed across 14 days close to baseline examinations. The primary outcomes were 12-month changes in body weight (BW) and body fat percentage (BF%). The secondary outcomes were 12-month changes in obesity-related metabolic markers (blood pressure, low- and high-density lipoproteins [LDL and HDL], triglycerides [TGs], and glycated haemoglobin [HbA1c]). Analysis of covariance and multivariate linear regressions were conducted with sleep-related variables as explanatory and subsequent changes in BW, BF%, and metabolic markers as response variables. We found no evidence that sleep duration, sleep duration variability, or sleep onset were associated with 12-month weight regain or change in BF%. A higher between-day variability in sleep onset, assessed using the standard deviation across all nights recorded, was associated with weight regain (0.55 kg per hour [95% CI 0.10 to 0.99]; P = 0.016) and an increase in BF% (0.41% per hour [95% CI 0.04 to 0.78]; P = 0.031). Analyses of the secondary outcomes showed that a higher between-day variability in sleep duration was associated with an increase in HbA1c (0.02% per hour [95% CI 0.00 to 0.05]; P = 0.045). Participants with a sleep onset between 19:00 and 22:00 had the greatest reduction in diastolic blood pressure (DBP) (P = 0.02) but also the most pronounced increase in TGs (P = 0.03). The main limitation of this study is the observational design. Hence, the observed associations do not necessarily reflect causal effects.ConclusionOur results suggest that maintaining a consistent sleep onset is associated with improved WLM and body composition. Sleep onset and variability in sleep duration may be associated with subsequent change in different obesity-related metabolic markers, but due to multiple-testing, the secondary exploratory outcomes should be interpreted cautiously.Trial registrationThe trial was registered with the ISRCTN registry (ISRCTN88405328).

Effects of Group-Based Exercise on Flourishing and Stigma Consciousness among Older Adults: Findings from a Randomised Controlled Trial.

To examine the extent to which group-based exercise programs, informed by self-categorisation theory, result in improvements in psychological flourishing and reductions in age- and gender-related stigma consciousness among older adults. In the study, older adults (N=485, ≥ 65years) were randomised to similar age same gender (SASG), similar age mixed gender (SAMG), or "standard" mixed age mixed gender (MAMG) group-based exercise programs. Flourishing and stigma consciousness were assessed on six occasions during the 24-week intervention and represented secondary trial outcomes. Multilevel growth models examined the effects of the interventions on flourishing and stigma consciousness over time. Participants in the SASG and SAMG conditions demonstrated, on average, higher levels of flourishing, relative to the MAMG condition, over the course of the 24weeks (p<.05). Additionally, participants demonstrated lower levels of age- and gender-related stigma consciousness in both the SASG and SAMG conditions relative to the MAMG condition (p<.05). No time by group interaction effects were observed for either flourishing or stigma consciousness. The results provide some support for the utility of group exercise programs, informed by self-categorisation theory, to enhance psychological flourishing and reduce stigma consciousness among older adults.

Functional Electrical Stimulation Cycling Exercise in People with Multiple Sclerosis: Secondary Effects on Cognition, Symptoms, and Quality of Life.

Functional electrical stimulation (FES) cycling is an advanced rehabilitation modality that involves systematic mild electrical stimulation of focal muscle groups to produce leg cycling movement against an adjustable work rate. The present study reports on the efficacy of an assessor-blinded, pilot randomized controlled trial of supervised FES cycling exercise in people with multiple sclerosis (MS) on secondary trial outcomes, including cognition, fatigue, pain, and health-related quality of life. Eleven adult participants with MS were randomized to receive FES cycling exercise (n = 6) or passive leg cycling (n = 5) for 24 weeks. Cognitive processing speed was assessed using the Symbol Digit Modalities Test. Symptoms of fatigue and pain were assessed using the Fatigue Severity Scale, the Modified Fatigue Impact Scale, and the short-form McGill Pain Questionnaire. Physical and psychological health-related quality of life were assessed using the 29-item Multiple Sclerosis Impact Scale. Eight participants (four, FES; four, passive leg cycling) completed the intervention and outcome assessments. The FES cycling exercise resulted in moderate-to-large improvements in cognitive processing speed (d = 0.53), fatigue severity (d = -0.92), fatigue impact (d = -0.45 to -0.68), and pain symptoms (d = -0.67). The effect of the intervention on cognitive performance resulted in a clinically meaningful change, based on established criteria. We provide preliminary evidence for the benefits of FES cycling exercise on cognition and symptoms of fatigue and pain. Appropriately powered randomized controlled trials of FES cycling exercise are necessary to determine its efficacy for people with MS.

Noncommunicable Respiratory Disease and Air Pollution Exposure in Malawi (CAPS). A Cross-Sectional Study.

Rationale: Noncommunicable respiratory diseases and exposure to air pollution are thought to be important contributors to morbidity and mortality in sub-Saharan African adults.Objectives: We set out to explore the prevalence and determinants of noncommunicable respiratory disease among adults living in Chikhwawa District, Malawi.Methods: We performed a cross-sectional study among adults in communities participating in a randomized controlled trial of a cleaner-burning biomass-fueled cookstove intervention (CAPS [Cooking and Pneumonia Study]) in rural Malawi. We assessed chronic respiratory symptoms, spirometric abnormalities, and personal exposure to air pollution (particulate matter <2.5 μm in aerodynamic diameter [PM2.5] and carbon monoxide [CO]). Weighted prevalence estimates were calculated; multivariable and intention-to-treat analyses were done.Measurements and Main Results: One thousand four hundred eighty-one participants (mean [SD] age, 43.8 [17.8] yr; 57% female) were recruited. The prevalence of chronic respiratory symptoms, spirometric obstruction, and restriction were 13.6% (95% confidence interval [CI], 11.9–15.4), 8.7% (95% CI, 7.0–10.7), and 34.8% (95% CI, 31.7–38.0), respectively. Median 48-hour personal PM2.5 and CO exposures were 71.0 μg/m3 (interquartile range [IQR], 44.6–119.2) and 1.23 ppm (IQR, 0.79–1.93), respectively. Chronic respiratory symptoms were associated with current/ex-smoking (odds ratio [OR], 1.59; 95% CI, 1.05–2.39), previous tuberculosis (OR, 2.50; 95% CI, 1.04–15.58), and CO exposure (OR, 1.46; 95% CI, 1.04–2.05). Exposure to PM2.5 was not associated with any demographic, clinical, or spirometric characteristics. There was no effect of the CAPS intervention on any of the secondary trial outcomes.Conclusions: The burden of chronic respiratory symptoms, abnormal spirometry, and air pollution exposures in adults in rural Malawi is of considerable potential public health importance. We found little evidence that air pollution exposures were associated with chronic respiratory symptoms or spirometric abnormalities and no evidence that the CAPS intervention had effects on the secondary trial outcomes. More effective prevention and control strategies for noncommunicable respiratory disease in sub-Saharan Africa are needed.Clinical trial registered with www.isrctn.com (ISRCTN 59448623).

Clinical effectiveness of pharmacy-led versus conventionally delivered antiviral treatment for hepatitis C in patients receiving opioid substitution therapy: a study protocol for a pragmatic cluster randomised trial

IntroductionHepatitis C virus (HCV) infection affects 0.7% of the general population, and up to 40% of people prescribed opioid substitution therapy (OST) in Scotland. In conventional care, less than 10%...