A cluster randomised controlled trial of an early childhood parenting programme delivered through early childhood education centres in rural Zimbabwe.

BACKGROUND: Early childhood is a critical period for child development. Effective approaches to support families in low-resource settings in the use of responsive and stimulating parenting are needed. AIM: The aim of this study was to examine the effects of the Reach Up early childhood parenting programme on children's development, parenting attitudes and practices, when delivered through early childhood development (ECD) centres in Zimbabwe. METHODS: A cluster randomised controlled trial was conducted in Sanyati, a rural district in Zimbabwe. Twenty-four of 51 available centres were randomised to intervention (n = 12) or control (n = 12) groups. Sixteen mothers with a child aged 12-30 months were recruited from each centre's catchment area (n = 189 intervention; n = 193 control). The intervention comprised two home visits per month delivered by centre teaching assistants over a period of 27 months. Primary outcomes were child Developmental Quotient (DQ), Language, Eye and Hand coordination, Performance and Practical Reasoning subscale scores assessed at follow-up. Secondary outcomes were mothers' attitudes about child development, parenting practices and maternal depressive symptoms all measured at baseline and follow-up. Intention to treat analyses was conducted using mixed-effects regression models with the standard error adjusted for cluster and inverse proportionality weights to adjust for attrition. Significance was set at P < 0.05. RESULTS: A total of 285 (74.6%) of 382 children enrolled were tested, with 97 children lost to follow-up. The intervention improved the children's DQ by 3.55 points (95% CI 0.82 to 6.28), Eye and Hand by 3.58 (95% CI 0.59 to 6.56) and Practical Reasoning by 4.19 (95% CI 0.96 to 7.42). No significant improvements to Performance or Language scores, parenting attitudes, parenting practices and depressive symptoms were identified. CONCLUSIONS: A home visiting intervention delivered by ECD teaching assistants promoted children's development. This suggests that outreach from preschools may be an effective platform for delivery of parenting interventions.

A Randomized, Factorial Phase II Study to Determine the Optimal Dosing Regimen for 68Ga-Satoreotide Trizoxetan as an Imaging Agent in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

68Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumor (NET) detection and localization. However, the optimal peptide mass and radioactivity ranges for 68Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomized, 2 × 3 factorial, multicenter phase II study. Methods: Patients received 68Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on days 16-22, at 1 of 3 68Ga radioactivity ranges (40-80, 100-140, or 160-200 MBq). Whole-body PET/CT imaging was performed 50-70 min after each injection. The primary endpoint was the detection rate of NET lesions imaged by 68Ga-satoreotide trizoxetan relative to contrast-enhanced CT (for each of the 6 peptide mass and radioactivity range combinations). Results: Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by 68Ga-satoreotide trizoxetan PET/CT or PET alone was at least twice as high as the number detected by contrast-enhanced CT across the 6 studied peptide mass and radioactivity range combinations. There were no differences between the 2 peptide mass ranges or between the 3 radioactivity ranges in the number of identified lesions. However, a trend toward a lower relative lesion count was noted in the liver for the 40- to 80-MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by 68Ga-satoreotide trizoxetan. The median diagnostic sensitivity of 68Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. Conclusion: A radioactivity of 100-200 MBq with a peptide mass of up to 50 µg was confirmed as the optimal dosing regimen for 68Ga-satoreotide trizoxetan to be used in future phase III studies.

A home visit-based early childhood stimulation programme in Brazil-a randomized controlled trial.

Home visiting programmes are increasingly recognized as one of the most effective interventions to improve child health and development in low-income settings. However, the best platforms to deliver such programmes remain unclear. We conducted a randomized controlled trial to test the relative effectiveness of child development agents (CDAs) and community health workers (CHWs) as two possible delivery platforms for early childhood development (ECD) focused home visiting intervention in São Paulo, Brazil. A total of 900 children aged 9-15 months were screened for potential study inclusion between January and March 2015. Children who did not attend crèches at enrolment were included in the trial. Children were randomly assigned to control or to receive biweekly home visits either through a CHW in the areas covered by the Brazilian Family Health Strategy (FHS) or by a newly hired cadre of CDAs in the areas not covered by the FHS. The primary study outcome was children's development (cognition, motor, language and social emotional skills) assessed after 12 months of intervention with the PRIDI and Caregiver-Reported Early Development Instruments tools. A total of 826 mother-child dyads were enrolled in the trial. In intention-to-treat analysis, neither intervention arm improved study outcomes. In per-protocol (PP) analysis, the CDA programme resulted in a 0.22 standard deviation increase in children's development (95% confidence interval [0.01-0.43]). The results presented in this study suggest that home visiting programmes have the potential to improve child development among poor urban families in Brazil. However, delivering home visiting interventions through already active CHWs may not be feasible in the Brazilian context and coordination across sectors is essential to effective ECD policies.

Correction to: Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR).

The original article contained incorrect terminology for one of the cardiac measures; throughout the manuscript and supplementary information 'intraventricular septum wall thickness' should have been given as 'interventricular septum wall thickness'. Corrections should also be noted for Tables 1 and 4: in the Table 1 legend 'Low risk - Neither above at baseline' should read 'Low risk - Neither above threshold at baseline'; in Table 4, the rows 'Mild: eGFR > 60 to < 90 ml/min/1.73 m2' and 'Moderate: eGFR > 30 to < 60 ml/min/1.73 m2' should read 'Mild: eGFR ≥ 60 to < 90 ml/min/1.73 m2' and 'Moderate: eGFR ≥ 30 to < 60 ml/min/1.73 m2', respectively. The original article also contained a mistake in the text of the Pharmacokinetics sub-section of Results; 'There were no apparent differences in revusiran Cmax between patients with mild (eGFR: 30 and < 60 ml/min/1.73 m2) or moderate (eGFR: 60 to < 90 ml/min/1.73 m2) renal impairment when compared with patients with normal (eGFR: ≥ 90 ml/min/1.73 m2) renal function at Weeks 0, 26, and 52 (p > 0.20) (Supplementary Fig. 6)' should read 'There were no apparent differences in revusiran Cmax between patients with mild (eGFR: ≥ 60 to < 90 ml/min/1.73 m2) or moderate (eGFR: ≥ 30 and < 60 ml/min/1.73 m2) renal impairment when compared with patients with normal (eGFR: ≥ 90 ml/min/1.73 m2) renal function at Weeks 0, 26, and 52 (p > 0.20) (Supplementary Fig. 6)'.

Survive and Thrive in Brazil: The Boa Vista Early Childhood Program: study protocol of a stepped-wedge, randomized controlled trial.

BACKGROUND: A growing body of evidence suggests that early life health and developmental outcomes can be improved through parental support programs. The objective of this project was to test the feasibility, impact, and relative cost-effectiveness of an adapted "Reach Up and Learn" program delivered through home-visiting programs as well as through center-based parenting groups on child health and development in the municipality of Boa Vista, Brazil. METHODS: A randomized, stepped-wedge design was used to roll out and evaluate the two parenting platforms in Boa Vista municipality. A total of 39 neighborhoods with a high Neighborhood Vulnerability Index were selected for the study. For the first phase of the program, nine neighborhoods were randomly selected for home visits, and two were randomly selected for the center-based parenting groups. In the second phase of the program, 10 neighborhoods were added to the home-visiting program, and eight were added to the center-based program. In the final phase of the program, the remaining 10 control areas will also be assigned to treatment. Study eligibility will be assessed through a baseline survey completed by all pregnant women in the 39 study areas. Pregnant women will be eligible to participate in the study if they are either classified as poor, were under age 20 years when they became pregnant, or if they indicate to have been exposed to domestic or sexual violence. To assess program impact, an endline survey will be conducted when children reach age 2 years. The primary study outcome is child development at age 2 years as measured by the PRIDI instrument. Secondary outcome will be infant mortality, which will be assessed linking municipal vital registration systems to the program rollout. DISCUSSION: This trial will assess the feasibility and impact of parenting programs rolled out at medium scale. The results from the trial should create evidence urgently needed for guiding Brazil's national Criança Feliz program as well as similar efforts in other countries. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03386747. Registered on 13 December 2017. All items of the World Health Organization Trial Registration Data Set are available in this record.

DISCOVERY: prevalence of transthyretin (TTR) mutations in a US-centric patient population suspected of having cardiac amyloidosis.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a multisystem disease that presents with polyneuropathy and/or cardiomyopathy. METHODS: DISCOVERY, a multicenter screening study, enrolled patients with clinically suspected cardiac amyloidosis to determine the frequency of transthyretin (TTR) mutations and assess disease characteristics. RESULTS: Of 1007 patients, the majority were from the US (84%), Black/African American (56%), male (63%), and with a mean (standard deviation) age of 65 (13) years. Among 1001 patients with genotyping results, 74 (7%) had a pathogenic TTR mutation (71/836 [8%] from the US). Val122Ile was the most common mutation, found in 11% of Black/African American patients overall; Black/African American ethnicity was an independent predictor of having a pathogenic TTR mutation. Additional independent predictors of such mutations in the total population and Black/African American group were interventricular septum thickness, low electrocardiogram voltage, and age. CONCLUSIONS: Pathogenic TTR mutations occurred in 8% of US patients with suspected cardiac amyloidosis. Most mutations were Val122Ile, almost exclusively found in Black/African American patients. Disease often remains undetected until advanced and difficult to treat, therefore, clinicians should assess at-risk patients for hATTR amyloidosis as early as possible.

Occlusion for stimulus deprivation amblyopia.

BACKGROUND: Stimulus deprivation amblyopia (SDA) develops due to an obstruction to the passage of light secondary to a condition such as cataract. The obstruction prevents formation of a clear image on the retina. SDA can be resistant to treatment, leading to poor visual prognosis. SDA probably constitutes less than 3% of all amblyopia cases, although precise estimates of prevalence are unknown. In high-income countries, most people present under the age of one year; in low- to middle-income countries, people are likely to be older at the time of presentation. The mainstay of treatment is correction of the obstruction (e.g., removal of the cataract) and then occlusion of the better-seeing eye, but regimens vary, can be difficult to execute, and traditionally are believed to lead to disappointing results. OBJECTIVES: To evaluate the effectiveness of occlusion therapy for SDA in an attempt to establish realistic treatment outcomes and to examine evidence of any dose-response effect and assess the effect of the duration, severity, and causative factor on the size and direction of the treatment effect. SEARCH METHODS: We searched CENTRAL (2018, Issue 12), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Embase.com; and five other databases. We used no date or language restrictions in the electronic searches. We last searched the databases on 12 December 2018. SELECTION CRITERIA: We planned to include randomized controlled trials (RCTs) and controlled clinical trials of participants with unilateral SDA with visual acuity worse than 0.2 LogMAR or equivalent. We specified no restrictions for inclusion based upon age, gender, ethnicity, comorbidities, medication use, or the number of participants. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We identified no trials that met the inclusion criteria specified in the protocol for this review. AUTHORS' CONCLUSIONS: We found no evidence from RCTs or quasi-randomized trials on the effectiveness of any treatment for SDA. RCTs are needed in order to evaluate the safety and effectiveness of occlusion, duration of treatment, level of vision that can be realistically achieved, effects of age at onset and magnitude of visual defect, optimum occlusion regimen, and factors associated with satisfactory and unsatisfactory outcomes with the use of various interventions for SDA.

Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR).

PURPOSE: The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. METHODS: Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction. RESULTS: Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events. CONCLUSIONS: Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded. CLINICAL TRIAL REGISTRATION: NCT02319005.

Characterizing the Randot Preschool stereotest: Testability, norms, reliability, specificity and sensitivity in children aged 2-11 years.

PURPOSE: To comprehensively assess the Randot Preschool stereo test in young children, including testability, normative values, test/retest reliability and sensitivity and specificity for detecting binocular vision disorders. METHODS: We tested 1005 children aged 2-11 years with the Randot Preschool stereo test, plus a cover/uncover test to detect heterotropia. Monocular visual acuity was assessed in both eyes using Keeler Crowded LogMAR visual acuity test for children aged 4 and over. RESULTS: Testability was very high: 65% in two-year-olds, 92% in three-year-olds and ~100% in older children. Normative values: In 389 children aged 2-5 with apparently normal vision, 6% of children scored nil (stereoblind). In those who obtained a threshold, the mean log threshold was 2.06 log10 arcsec, corresponding to 114 arcsec, and the median threshold was 100 arcsec. Most older children score 40 arcsec, the best available score. We found a small sex difference, with girls scoring slightly but significantly better. Test/retest reliability: ~99% for obtaining any score vs nil. Agreement between stereo thresholds is poor in children aged 2-5; 95% limit of agreement = 0.7 log10 arcsec: five-fold change in stereo threshold may occur without any change in vision. In children over 5, the test essentially acts only as a binary classifier since almost all non-stereoblind children score 40 arcsec. Specificity (true negative rate): >95%. Sensitivity (true positive rate): poor, <50%, i.e. around half of children with a demonstrable binocular vision abnormality score well on the Randot Preschool. CONCLUSIONS: The Randot Preschool is extremely accessible for even very young children, and is very reliable at classifying children into those who have any stereo vision vs those who are stereoblind. However, its ability to quantify stereo vision is limited by poor repeatability in children aged 5 and under, and a very limited range of scores relevant to children aged over 5.

ASTEROID: A New Clinical Stereotest on an Autostereo 3D Tablet.

PURPOSE: To describe a new stereotest in the form of a game on an autostereoscopic tablet computer designed to be suitable for use in the eye clinic and present data on its reliability and the distribution of stereo thresholds in adults. METHODS: Test stimuli were four dynamic random-dot stereograms, one of which contained a disparate target. Feedback was given after each trial presentation. A Bayesian adaptive staircase adjusted target disparity. Threshold was estimated from the mean of the posterior distribution after 20 responses. Viewing distance was monitored via a forehead sticker viewed by the tablet's front camera, and screen parallax was adjusted dynamically so as to achieve the desired retinal disparity. RESULTS: The tablet must be viewed at a distance of greater than ∼35 cm to produce a good depth percept. Log thresholds were roughly normally distributed with a mean of 1.75 log10 arcsec = 56 arcsec and SD of 0.34 log10 arcsec = a factor of 2.2. The standard deviation agrees with previous studies, but ASTEROID thresholds are approximately 1.5 times higher than a similar stereotest on stereoscopic 3D TV or on Randot Preschool stereotests. Pearson correlation between successive tests in same observer was 0.80. Bland-Altman 95% limits of reliability were ±0.64 log10 arcsec = a factor of 4.3, corresponding to an SD of 0.32 log10 arcsec on individual threshold estimates. This is similar to other stereotests and close to the statistical limit for 20 responses. CONCLUSIONS: ASTEROID is reliable, easy, and portable and thus well-suited for clinical stereoacuity measurements. TRANSLATIONAL RELEVANCE: New 3D digital technology means that research-quality psychophysical measurement of stereoacuity is now feasible in the clinic.

Vision screening for correctable visual acuity deficits in school-age children and adolescents.

BACKGROUND: Although the benefits of vision screening seem intuitive, the value of such programmes in junior and senior schools has been questioned. In addition there exists a lack of clarity regarding the optimum age for screening and frequency at which to carry out screening. OBJECTIVES: To evaluate the effectiveness of vision screening programmes carried out in schools to reduce the prevalence of correctable visual acuity deficits due to refractive error in school-age children. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 4); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 3 May 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster-randomised trials, that compared vision screening with no vision screening, or compared interventions to improve uptake of spectacles or efficiency of vision screening. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results and extracted data. Our pre-specified primary outcome was uncorrected, or suboptimally corrected, visual acuity deficit due to refractive error six months after screening. Pre-specified secondary outcomes included visual acuity deficit due to refractive error more than six months after screening, visual acuity deficit due to causes other than refractive error, spectacle wearing, quality of life, costs, and adverse effects. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We identified seven relevant studies. Five of these studies were conducted in China with one study in India and one in Tanzania. A total of 9858 children aged between 10 and 18 years were randomised in these studies, 8240 of whom (84%) were followed up between one and eight months after screening. Overall we judged the studies to be at low risk of bias. None of these studies compared vision screening for correctable visual acuity deficits with not screening.Two studies compared vision screening with the provision of free spectacles versus vision screening with no provision of free spectacles (prescription only). These studies provide high-certainty evidence that vision screening with provision of free spectacles results in a higher proportion of children wearing spectacles than if vision screening is accompanied by provision of a prescription only (risk ratio (RR) 1.60, 95% confidence interval (CI) 1.34 to 1.90; 1092 participants). The studies suggest that if approximately 250 per 1000 children given vision screening plus prescription only are wearing spectacles at follow-up (three to six months) then 400 per 1000 (335 to 475) children would be wearing spectacles after vision screening and provision of free spectacles. Low-certainty evidence suggested better educational attainment in children in the free spectacles group (adjusted difference 0.11 in standardised mathematics score, 95% CI 0.01 to 0.21, 1 study, 2289 participants). Costs were reported in one study in Tanzania in 2008 and indicated a relatively low cost of screening and spectacle provision (low-certainty evidence). There was no evidence of any important effect of provision of free spectacles on uncorrected visual acuity (mean difference -0.02 logMAR (95% CI adjusted for clustering -0.04 to 0.01) between the groups at follow-up (moderate-certainty evidence). Other pre-specified outcomes of this review were not reported.Two studies explored the effect of an educational intervention in addition to vision screening on spectacle wear. There was moderate-certainty evidence of little apparent effect of the education interventions investigated in these studies in addition to vision screening, compared to vision screening alone for spectacle wearing (RR 1.11, 95% CI 0.95 to 1.31, 1 study, 3177 participants) or related outcome spectacle purchase (odds ratio (OR) 0.84, 95% CI 0.55 to 1.31, 1 study, 4448 participants). Other pre-specified outcomes of this review were not reported.Three studies compared vision screening with ready-made spectacles versus vision screening with custom-made spectacles. These studies provide moderate-certainty evidence of no clinically meaningful differences between the two types of spectacles. In one study, mean logMAR acuity in better and worse eye was similar between groups: mean difference (MD) better eye 0.03 logMAR, 95% CI 0.01 to 0.05; 414 participants; MD worse eye 0.06 logMAR, 95% CI 0.04 to 0.08; 414 participants). There was high-certainty evidence of no important difference in spectacle wearing (RR 0.98, 95% CI 0.91 to 1.05; 1203 participants) between the two groups and moderate-certainty evidence of no important difference in quality of life between the two groups (the mean quality-of-life score measured using the National Eye Institute Refractive Error Quality of Life scale 42 was 1.42 better (1.04 worse to 3.90 better) in children with ready-made spectacles (1 study of 188 participants). Although none of the studies reported on costs directly, ready-made spectacles are cheaper and may represent considerable cost-savings for vision screening programmes in lower income settings. There was low-certainty evidence of no important difference in adverse effects between the two groups. Adverse effects were reported in one study and were similar between groups. These included blurred vision, distorted vision, headache, disorientation, dizziness, eyestrain and nausea. AUTHORS' CONCLUSIONS: Vision screening plus provision of free spectacles improves the number of children who have and wear the spectacles they need compared with providing a prescription only. This may lead to better educational outcomes. Health education interventions, as currently devised and tested, do not appear to improve spectacle wearing in children. In lower-income settings, ready-made spectacles may provide a useful alternative to expensive custom-made spectacles.

Sociodemographic and access-related correlates of health-care utilization among African American injection drug users: The BESURE study.

Persons who inject drugs (PWID) may have less access to, and utilization of, health-care services, and African American PWID may be less likely than other racial groups to utilize health care in the United States. The present study evaluated the prevalence of health-care utilization (HCU) among a cohort of African American PWID in Baltimore. Data were from the 2012 Baltimore National HIV Behavioral Surveillance study. Participants were adult PWID and recruited using respondent-driven sampling (RDS). They completed a comprehensive sociobehavioral survey and voluntary HIV test with trained study interviewers. Analyses included descriptive and bivariate statistics to examine the prevalence of HCU, defined as seeing a health-care provider in the past year. Poisson regression assessed correlates of HCU. Participants were 61% male; 23% self-reported HIV seropositivity. Nearly 90% reported unemployment and/or disability; HCU prevalence was 85%. Significant negative correlates of HCU included age and higher injection frequency; positive correlates included previous incarceration and moderate financial stability. Interaction analyses showed unemployed publicly insured individuals had 30% higher HCU than unemployed and uninsured individuals (χ2 = 2.52; p < .05). There is a need to improve health-care utilization among PWID. High prevalence of disability was still found, despite insurance coverage and access to care in this population. While the recent Affordable Care Act has increased health-care coverage and access, our results suggest that is only a first step to improving health outcomes among PWID; targeted intervention to integrate these individuals is still needed.

Integrating a Parenting Intervention With Routine Primary Health Care: A Cluster Randomized Trial.

OBJECTIVE: More than 200 million children globally do not attain their developmental potential. We hypothesized that a parent training program could be integrated into primary health center visits and benefit child development. METHODS: We conducted a cluster randomized trial in the Caribbean (Jamaica, Antigua, and St Lucia). Fifteen centers were randomly assigned to the control (n = 250 mother-child pairs) and 14 to the intervention (n = 251 mother-child pairs) groups. Participants were recruited at the 6- to 8-week child health visit. The intervention used group delivery at 5 routine visits from age 3 to 18 months and comprised short films of child development messages, which were shown in the waiting area; discussion and demonstration led by community health workers; and mothers' practice of activities. Nurses distributed message cards and a few play materials. Primary outcomes were child cognition, language, and hand-eye coordination and secondary outcomes were caregiver knowledge, practices, maternal depression, and child growth, measured after the 18-month visit. RESULTS: Eight-five percent of enrolled children were tested (control = 210, intervention = 216). Loss did not differ by group. Multilevel analyses showed significant benefits for cognitive development (3.09 points; 95% confidence interval: 1.31 to 4.87 points; effect size: 0.3 SDs). There were no other child benefits. There was a significant benefit to parenting knowledge (treatment effect: 1.59; 95% confidence interval: 1.01 to 2.17; effect size: 0.4). CONCLUSIONS: An innovative parenting intervention, requiring no additional clinic staff or mothers' time, was integrated into health services, with benefits to child cognitive development and parent knowledge. This is a promising strategy that merits further evaluation at scale.

An external pilot study to test the feasibility of a randomised controlled trial comparing eye muscle surgery against active monitoring for childhood intermittent exotropia [X(T)].

INTRODUCTION: The evidence base for the treatment of strabismus (squint) is poor. Our main aim is to improve this evidence base for the treatment of a common type of childhood squint {intermittent exotropia, [X(T)]}. We conducted an external pilot study in order to inform the design and conduct of a future full randomised controlled trial (RCT). METHODS: Children of between 6 months and 16 years with a recent diagnosis of X(T) were eligible for recruitment. Participants were recruited from secondary care at the ophthalmology departments at four UK NHS foundation trusts. Participants were randomised to either active monitoring or surgery. This report describes the findings of the Pilot Rehearsal Trial and Qualitative Study, and assesses the success against the objectives proposed. RECRUITMENT AND RETENTION: The experience gained during the Pilot Rehearsal Trial demonstrates the ability to recruit and retain sites that are willing to randomise children to both trial arms, and for parents to agree to randomisation of their children to such a study. One child declined the group allocation. A total of 231 children were screened (expected 240), of whom 138 (60%) were eligible (expected 228: 95%) and 49 (35% of eligible) children were recruited (expected 144: 63% of eligible). Strategies that improved recruitment over the course of the trial are discussed, together with the reasons why fewer children were eligible for recruitment than initially anticipated. Attrition was low. Outcome data were obtained for 47 of 49 randomised children. TRIAL PROCESSES AND DATA COLLECTION: The Trial Management processes proved effective. There were high levels of completion on all of the data collection forms. However, the feedback from the treatment orthoptists revealed that some modifications should be made to the length and frequency of the health service assessment and travel assessment questionnaires, thus reducing the burden on participants in the main trial. Modifications to the wording of the questions also need to be made. MONITORING OF BIAS: Children who recruited to the trial were older and had more severe strabismus than those children eligible but declining participation. Strategies to account for this in a full trial are proposed. REASONS FOR PARTICIPATION OR DECLINING STUDY: These were identified using qualitative interviews. The principal reasons for declining entry into the study were strong preferences for and against surgical treatment. HARMS: There were no serious unexpected adverse events. Two children had overcorrection of their X(T) with reduction in binocular vision following surgery, which is in line with previous studies. No children in the active monitoring arm developed a constant strabismus although two showed some reduction in control. CONCLUSIONS: The SamExo study has demonstrated that it is possible to recruit and retain participants to a randomised trial of surgery compared with active monitoring for X(T). For longer-term full RCTs, in order to maximise the generalisability of future studies, consideration needs to be given to planning more time and clinic appointments to assess eligibility and to allow consideration of participation; the greater use of research nurses for recruitment; and accommodating the strong preferences of some parents both for and against surgical intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44114892. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 39. See the NIHR Journals Library website for further project information.

Surrendering control, or nothing to lose: Parents' preferences about participation in a randomised trial of childhood strabismus surgery.

BACKGROUND: Intermittent exotropia is the most common form of divergent strabismus (squint) in children. Evidence regarding its optimum management is limited. A pilot randomised controlled trial has recently been completed (Surgery versus Active Monitoring in Intermittent Exotropia trial) to determine the feasibility of a full randomised controlled trial. PURPOSE: To identify drivers for and barriers against parents' participation in Surgery versus Active Monitoring in Intermittent Exotropia and to seek their views on information received, the need for randomisation, and enhancing acceptability. METHODS: Multiple method qualitative study using semi-structured telephone interviews to explore parents' motivations and trial screening logs to provide an indication of common barriers. Exploratory thematic analysis identified key themes. RESULTS: A total of 48 interviews were conducted (14 participants; 34 non-participants). Barriers included no desire for surgery/preference to 'wait and see', wanting surgery immediately, feeling uncomfortable about 'surrendering control' over decision-making/being managed 'at random', lack of confidence in the effectiveness of surgery, believing the risks outweighed the benefits, and lack of trust. Drivers included desiring surgery, 'nothing to lose', benefits offsetting the risks, and being in a trial would result in better care. Some also mentioned 'doing their bit' for research. Suggestions for enhancing acceptability included allowing choice of treatment group, giving more time for decision-making, expanding on information given, and improving communication. Many felt the necessity of randomisation was adequately explained, but there was some indication that it was misunderstood. Information extracted from the screening logs of 80/89 eligible non-participants indicated the most prevalent barrier was not wanting surgery/preferring to observe (56%), followed by desiring surgery straightaway (15%). Opposition to randomisation/wanting to retain control was recorded in 9% of cases as was the belief that the child's squint was not severe enough to warrant surgery. LIMITATIONS: Interviews were not audio-recorded. Not all who consented to interview could be contacted, although the response/contact rate was good (48/62). A few parents did not provide reasons for refusing the trial. CONCLUSION: Opposition to surgery and concerns about surrendering control were common obstacles to participation, whereas parents keen for their child to undergo the operation but happy to defer tended to embrace a 'nothing to lose' attitude. Many non-participants would have consented if allowed to choose group, although most of these would have chosen observation. While most parents felt happy with information given and that randomisation was adequately explained, it is of concern that there may be some misunderstanding, which should be addressed in any trial. These findings will inform future trials in childhood exotropia, for example, consideration of preference arms and improving communication. Lessons learnt from the Surgery versus Active Monitoring in Intermittent Exotropia trial could prove valuable to paediatric and surgical trials generally.

"Complex" attention-deficit hyperactivity disorder, more norm than exception? Diagnoses and comorbidities in a developmental clinic.

OBJECTIVE: Current recommendations for evaluation and diagnosis of attention-deficit hyperactivity disorder (ADHD) are meant for primary care settings and may not adequately address the needs of children seen in subspecialty developmental-behavioral pediatric settings who may have higher rates of comorbid developmental, learning, and psychiatric disorders. The authors sought to characterize the diagnostic complexity of school-aged children diagnosed with ADHD after comprehensive multidisciplinary evaluation in a subspecialty developmental-behavioral pediatric clinic. METHODS: The authors conducted a retrospective medical record review of 144 patients aged 7 to 11 years who were consecutively evaluated by an interdisciplinary team (developmental-behavioral pediatrician, psychologist, educator) in a school-age clinic within a developmental-behavioral pediatrics tertiary care center from January 1, 2009 to December 31, 2009. RESULTS: After comprehensive evaluation, rates of ADHD diagnosis increased from 32.6% (n = 47) preevaluation to 54.2% (n = 78) postevaluation (p < .0001). Rates of learning disorders among children receiving a final diagnosis of ADHD increased from 2.6% (n = 2) preevaluation to 50% (n = 39) postevaluation. (p < .0001). Among children receiving a final diagnosis of ADHD, 73.1% (n = 57) were diagnosed with at least 1 comorbid psychiatric, developmental, or learning disorder. CONCLUSIONS: Among school-aged children diagnosed with ADHD in a developmental-behavioral pediatric subspecialty setting, a comprehensive evaluation including developmental, neuropsychological, and educational assessments yielded high rates of comorbid psychiatric, developmental, and learning disorders. This supports the need to provide comprehensive interdisciplinary assessment for such children to ensure the identification and treatment of not only the core symptoms of ADHD but also the comorbidities that may otherwise go unrecognized and therefore not optimally treated.

Predicting diurnal and sleep/wake seizure patterns in paediatric patients of different ages.

AIM: To identify factors that influence diurnal and sleep/wake seizure timing in children undergoing tapered drug withdrawal in an epilepsy monitoring unit. METHODS: Medical charts of patients that underwent video-EEG were reviewed. Seizures were evaluated based on their occurrence in three-hour time intervals (bins) and between wakefulness and sleep. Patients were classified according to EEG localisation and age: infants (≤3 years), children (3-12 years), and adolescents (>12-21 years). Analysis utilising generalised estimating equations with a negative binomial distribution was performed. RESULTS: A total of 390 patients (188 girls; mean age: 9.2 years; SD: 6.0) had 1,754 seizures. Generalised seizures (109 patients; 490 seizures) occurred more during wakefulness (p<0.001) and during the day (p<0.001). Modelling revealed a greater occurrence of seizures at night with increasing age (p=0.046). Temporal lobe seizures (62 patients; 271 seizures) occurred overall more frequently during wakefulness (p=0.03). Frontal lobe seizures (41 patients; 184 seizures) occurred more frequently during wakefulness in infants (p<0.05) and more frequently during sleep in adolescents (p<0.0001). Adolescents with frontal lobe seizures were 3.6 times more likely to have seizures during sleep compared to other children (95% CI: 1.8-7.2). CONCLUSION: These findings are suggestive of changes in circadian rhythmicity that may alter seizure susceptibility in different age groups. The results may assist in prediction of periods of greatest seizure propensity.

Comparison of plasmapheresis and intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis.

IMPORTANCE: Juvenile myasthenia gravis (MG) is a relatively rare autoimmune disorder. The comparative efficacy of plasmapheresis (PLEX) vs immunoglobulin as maintenance therapy is unclear for this childhood disease. OBJECTIVE: To determine whether PLEX or intravenous immunoglobulin (IVIG) therapy is more effective as maintenance therapy in this disease. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis over a 33-year period involved 54 children and adolescents with juvenile MG at a specialized neuromuscular clinic and electromyography laboratory at a tertiary care academic pediatric hospital. INTERVENTIONS: Plasmapheresis and IVIG. MAIN OUTCOMES AND MEASURES: Response to treatment was measured by both improvement in objective physical examination findings and the patients' reported improvement in symptoms and functional abilities. RESULTS: Subjective and objective outcomes correlated well. Both PLEX and IVIG had high response rates. Of the 27 patients with generalized juvenile MG receiving PLEX, IVIG, or both treatments, 7 of 7 patients treated with PLEX alone responded, 5 of 10 patients treated with IVIG alone responded, and 9 of 10 patients who received both responded. There was a significant difference in response rates between patients who received PLEX vs IVIG (P = .04). The youngest age at which PLEX was initiated via peripheral venous access was 9 years, while the youngest child who received IVIG was 9 months old. Thymectomy was performed in 17 children, of whom 11 experienced significant postoperative improvement. CONCLUSIONS AND RELEVANCE: This study provides class III evidence that PLEX and IVIG both have high response rates as maintenance therapies and are reasonable therapeutic options for juvenile MG. Plasmapheresis may have a more consistent response rate than IVIG in this setting. These findings will provide some guidance regarding the approach to therapy for juvenile MG, especially as the results differ somewhat from those of studies focusing on adult MG.

Occlusion for stimulus deprivation amblyopia.

BACKGROUND: Stimulus deprivation amblyopia (SDA) develops due to an obstruction to the passage of light secondary to a condition such as cataract. The obstruction prevents formation of a clear image on the retina. SDA can be resistant to treatment, leading to poor visual prognosis. SDA probably constitutes less than 3% of all amblyopia cases, although precise estimates of prevalence are unknown. In developed countries, most patients present under the age of one year; in less developed parts of the world patients are likely to be older at the time of presentation. The mainstay of treatment is removal of the cataract and then occlusion of the better-seeing eye, but regimens vary, can be difficult to execute, and traditionally are believed to lead to disappointing results. OBJECTIVES: Our objective was to evaluate the effectiveness of occlusion therapy for SDA in an attempt to establish realistic treatment outcomes. Where data were available, we also planned to examine evidence of any dose response effect and to assess the effect of the duration, severity, and causative factor on the size and direction of the treatment effect. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2013), EMBASE (January 1980 to October 2013), the Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2013), PubMed (January 1946 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com ), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 October 2013. SELECTION CRITERIA: We planned to include randomized and quasi-randomized controlled trials of participants with unilateral SDA with visual acuity worse than 0.2 LogMAR or equivalent. We did not specify any restrictions for inclusion based upon age, gender, ethnicity, co-morbidities, medication use, or the number of participants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study abstracts identified by the electronic searches. MAIN RESULTS: We did not identify any trials that met the inclusion criteria specified in the protocol for this review. AUTHORS' CONCLUSIONS: We found no evidence on the effectiveness of any treatment for SDA. Future randomized controlled trials are needed in order to evaluate the safety and effectiveness of occlusion, duration of treatment, level of vision that can be realistically achieved, effects of age at onset and magnitude of visual defect, optimum occlusion regimen, and factors associated with satisfactory and unsatisfactory outcomes with the use of various interventions for SDA.

Neural measures of social attention across the first years of life: characterizing typical development and markers of autism risk.

Few studies employing event-related potentials (ERPs) to examine infant perception/cognition have systematically characterized age-related changes over the first few years of life. Establishing a 'normative' template of development is important in its own right, and doing so may also better highlight points of divergence for high-risk populations of infants, such as those at elevated genetic risk for autism spectrum disorder (ASD). The present investigation explores the developmental progression of the P1, N290, P400 and Nc components for a large sample of young children between 6 and 36 months of age, addressing age-related changes in amplitude, sensitivity to familiar and unfamiliar stimuli and hemispheric lateralization. Two samples of infants are included: those at low- and high-risk for ASD. The four components of interest show differential patterns of change over time and hemispheric lateralization; however, infants at low- and high-risk for ASD do not show significant differences in patterns of neural response to faces. These results will provide a useful point of reference for future developmental cognitive neuroscience research targeting both typical development and vulnerable populations.