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.

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.

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)'.

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.

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.

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.

Genetic analysis of complex traits in the emerging Collaborative Cross.

The Collaborative Cross (CC) is a mouse recombinant inbred strain panel that is being developed as a resource for mammalian systems genetics. Here we describe an experiment that uses partially inbred CC lines to evaluate the genetic properties and utility of this emerging resource. Genome-wide analysis of the incipient strains reveals high genetic diversity, balanced allele frequencies, and dense, evenly distributed recombination sites-all ideal qualities for a systems genetics resource. We map discrete, complex, and biomolecular traits and contrast two quantitative trait locus (QTL) mapping approaches. Analysis based on inferred haplotypes improves power, reduces false discovery, and provides information to identify and prioritize candidate genes that is unique to multifounder crosses like the CC. The number of expression QTLs discovered here exceeds all previous efforts at eQTL mapping in mice, and we map local eQTL at 1-Mb resolution. We demonstrate that the genetic diversity of the CC, which derives from random mixing of eight founder strains, results in high phenotypic diversity and enhances our ability to map causative loci underlying complex disease-related traits.

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.

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.

Inequality in early childhood: risk and protective factors for early child development.

Inequality between and within populations has origins in adverse early experiences. Developmental neuroscience shows how early biological and psychosocial experiences affect brain development. We previously identified inadequate cognitive stimulation, stunting, iodine deficiency, and iron-deficiency anaemia as key risks that prevent millions of young children from attaining their developmental potential. Recent research emphasises the importance of these risks, strengthens the evidence for other risk factors including intrauterine growth restriction, malaria, lead exposure, HIV infection, maternal depression, institutionalisation, and exposure to societal violence, and identifies protective factors such as breastfeeding and maternal education. Evidence on risks resulting from prenatal maternal nutrition, maternal stress, and families affected with HIV is emerging. Interventions are urgently needed to reduce children's risk exposure and to promote development in affected children. Our goal is to provide information to help the setting of priorities for early child development programmes and policies to benefit the world's poorest children and reduce persistent inequalities.

Use of the PedsQL in childhood intermittent exotropia: estimates of feasibility, internal consistency reliability and parent-child agreement.

PURPOSE: To evaluate the PedsQLs performance in children with intermittent exotropia (X[T]) in terms of feasibility, internal consistency, floor-ceiling effects and levels of parent-child agreement. METHODS: Children with X(T) aged <12 years were recruited from 26 UK Hospital Eye Clinics/Orthoptic Departments. QOL was assessed using child (n = 166) and proxy (n = 392) versions of the PedsQLv4. Feasibility was assessed by percentage of missing responses; internal consistency by Cronbach's alpha and agreement by Bland-Altman plots and intraclass correlations. Analyses included age and gender comparisons. RESULTS: Missing response rates were no higher than 1.8%. Cronbach's alpha reached ≥ 0.70 on all but one parent-rated scale and on most child-rated Total, Psychosocial Summary and Social Functioning scales, but was <0.70 on most child-rated Physical, Emotional and School Functioning scales. On parent-rated scales, there were no floor effects; ceiling effects reached 27-56% in parents' Physical, Social and School Functioning. On child-rated scales, there were 0-1% floor effects and 0-28% ceiling effects. Parent-child agreement was fair to poor and varied by child's gender. CONCLUSIONS: Proxy-rated PedsQLs demonstrated good internal consistency/feasibility in parents of children with X(T); child-rated reports appeared acceptable, although caution is advised regarding Physical, Emotional and School Functioning scales in younger children. Low-fair agreement between proxy and self-ratings is common in paediatric QOL assessment, reiterating the importance of obtaining both perspectives. We encourage future studies to explore the influence of child's age and gender, and the relationship of the proxy respondent.

Interventions for unilateral and bilateral refractive amblyopia.

BACKGROUND: Refractive amblyopia is a common cause of reduced visual acuity in childhood, but optimal treatment is not well defined. This review examined the treatment effect from spectacles and conventional occlusion. OBJECTIVES: Evaluation of the evidence of the effectiveness of spectacles, occlusion or both in the treatment of unilateral and bilateral refractive amblyopia. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 1), MEDLINE (January 1950 to January 2012), EMBASE (January 1980 to January 2012), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2012), 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). There were no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 24 January 2012. We manually searched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials of treatment for unilateral and bilateral refractive amblyopia by spectacles, with or without occlusion, were eligible. We included studies with participants of any age. DATA COLLECTION AND ANALYSIS: Two authors independently assessed abstracts identified by the searches. We obtained full-text copies and contacted study authors where necessary. Eleven trials were eligible for inclusion. We extracted data from eight. Insufficient data were present for the remaining three trials so data extraction was not possible. We identified no trials as containing participants with bilateral amblyopia. We performed no meta-analysis as there were insufficient trials for each outcome. MAIN RESULTS: For all studies mean acuity (standard deviation (SD)) in the amblyopic eye post-treatment was reported. All included trials reported treatment for unilateral refractive amblyopia.One study randomised participants to spectacles only compared to no treatment, spectacles plus occlusion compared to no treatment and spectacles plus occlusion versus spectacles only. For spectacles only versus no treatment, mean (SD) visual acuity was: spectacles group 0.31 (0.17); no treatment group 0.42 (0.19) and mean difference (MD) between groups was -0.11 (borderline statistical significance: 95% confidence interval (CI) -0.22 to 0.00). For spectacles plus occlusion versus no treatment, mean (SD) visual acuity was: full treatment 0.22 (0.13); no treatment 0.42 (0.19). Mean difference (MD) between the groups -0.20 (statistically significant: 95% CI -0.30 to -0.10). For spectacles plus occlusion versus spectacles only, MD was -0.09 (borderline statistical significance 95% CI -0.18 to 0.00). For two other trials that also looked at this comparison MD was -0.15 (not statistically significant 95% CI -0.32 to 0.02) for one trial and MD 0.01 (not statistically significant 95% CI -0.08 to 0.10) for the second trial.Three trials reviewed occlusion regimes.One trial looked at two hours versus six hours for moderate amblyopia: MD 0.01 (not statistically significant: 95% CI -0.06 to 0.08); a second trial 2003b reviewed six hours versus full-time for severe amblyopia: MD 0.03 (not statistically significant: 95% CI -0.08 to 0.14) and a third trial looked at six hours versus full-time occlusion: MD -0.12 (not statistically significant: 95% CI -0.27 to 0.03). One trial looked at occlusion supplemented with near or distance activities: MD-0.03 (not statistically significant 95% CI -0.09 to 0.03). One trial looked at partial occlusion and glasses versus glasses only: MD -0.01 (not statistically significant: 95% CI -0.05 to 0.03). AUTHORS' CONCLUSIONS: In some cases of unilateral refractive amblyopia it appears that there is a treatment benefit from refractive correction alone. Where amblyopia persists there is evidence that adding occlusion further improves vision. Despite advances in the understanding of the treatment of amblyopia it is currently still not possible to tailor individual treatment plans for amblyopia. The nature of any dose/response effect from occlusion still needs to be clarified. Partial occlusion appears to have the same treatment effect as glasses alone when started simultaneously for the treatment of unilateral refractive amblyopia. Treatment regimes for bilateral and unilateral refractive amblyopia need to be investigated further.

The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort.

BACKGROUND: The purpose of this study was to investigate current patterns of management and outcomes of intermittent distance exotropia [X(T)] in the UK. METHODS: This was an observational cohort study which recruited 460 children aged < 12 years with previously untreated X(T). Eligible subjects were enrolled from 26 UK hospital ophthalmology clinics between May 2005 and December 2006. Over a 2-year period of follow-up, clinical data were prospectively recorded at standard intervals from enrolment. Data collected included angle, near stereoacuity, visual acuity, control of X(T) measured with the Newcastle Control Score (NCS), and treatment. The main outcome measures were change in clinical outcomes (angle, stereoacuity, visual acuity and NCS) in treated and untreated X(T), 2 years from enrolment (or, where applicable, 6 months after surgery). Change over time was tested using the chi-square test for categorical, Wilcoxon test for non-parametric and paired-samples t-test for parametric data. RESULTS: At follow-up, data were available for 371 children (81% of the original cohort). Of these: 53% (195) had no treatment; 17% (63) had treatment for reduced visual acuity only (pure refractive error and amblyopia); 13% (50) had non surgical treatment for control (spectacle lenses, occlusion, prisms, exercises) and 17% (63) had surgery. Only 0.5% (2/371) children developed constant exotropia. The surgically treated group was the only group with clinically significant improvements in angle or NCS. However, 8% (5) of those treated surgically required second procedures for overcorrection within 6 months of the initial procedure and at 6-month follow-up 21% (13) were overcorrected. CONCLUSIONS: Many children in the UK with X(T) receive active monitoring only. Deterioration to constant exotropia, with or without treatment, is rare. Surgery appears effective in improving angle of X(T) and NCS, but rates of overcorrection are high.

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.

A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.

PURPOSE: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. RESULTS: Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients. CONCLUSION: The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.

Early childhood stunting and later fine motor abilities.

AIM: The aim of this study was to determine the effects of early childhood stunting (height for age 2SD or more below reference values) and interventions on fine motor abilities at 11 to 12 years, and the relationship between fine motor abilities and school achievement and intelligence. METHOD: A cohort of stunted children who had participated in a randomized trial of psychosocial stimulation and/or nutritional supplementation in early childhood was compared with a group of non-stunted children. Fine motor abilities were assessed in 116 stunted (67 males, 49 females) and 80 non-stunted children (43 males, 37 females) at a mean age of 11 years 8 months (SD 4.3 mo) and 11 years 9 months (SD 3.8 mo) respectively. Testers were blind to the children's group assignment. RESULTS: Two fine motor factors were derived: rapid sequential continuous movements (RSCM) and dexterity. No effect of the early intervention was found. RSCM scores were lower in the stunted group than in the non-stunted group (p=0.01), but differences in dexterity were not significant (p=0.18) after adjusting for social background. Among stunted children, the RSCM score was significantly associated with IQ (p=0.04) and school achievement (all p<0.05). INTERPRETATION: Stunting in early childhood is associated with poor scores on tests of rapid sequential continuous hand movements in later childhood. Children with poorer scores are at greater risk for low IQs and low levels of school achievement.

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.