Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial.

BACKGROUND: In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. METHODS: SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. FINDINGS: Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. INTERPRETATION: Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. FUNDING: National Institute of Neurological Disorders and Stroke.

Establishing Sickle Cell Disease Stroke Prevention Teams in Africa is Feasible: Program Evaluation Using the RE-AIM Framework.

We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team's readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program's 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program's feasibility and short-term sustainability.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [StrokePreventioninNigeria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers.

BACKGROUND: Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case-control studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre-diagnostic exposure assessments and biological samples. METHODS: Eligibility criteria, follow-up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses. RESULTS: Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388 120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother-child pairs within 5 years. Harmonised data currently includes over 20 "core" variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades. CONCLUSIONS: The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case-control studies offer the potential for breakthroughs in paediatric cancer aetiologic research.

Long-term exposure to urban air pollution and lung cancer mortality: A 12-year cohort study in Northern China.

Cohort evidence that links long-term exposures to air pollution and mortality comes largely from the United States and European countries. We investigated the relationship between long-term exposures to particulate matter <10µm in diameter (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) and mortality of lung cancer in Northern China. A cohort of 39,054 participants were followed during 1998-2009. Annual average concentrations for PM10, NO2, and SO2 were determined based on data collected from central monitoring stations. Lung cancer deaths (n=140) were obtained from death certificates, and hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusting for age, gender, BMI, education, marital status, smoking status, passive smoking, occupation, alcohol consumption, etc. Each 10mg/m(3) increase in PM10 concentrations was associated with a 3.4%-6.0% increase in lung cancer mortality in the time-varying exposure model and a 4.0%-13.6% increase in the baseline exposure model. In multi-pollutant models, the magnitude of associations was attenuated, most strongly for PM10. The association was different in men and women, also varying across age categories and different smoking status. Substantial differences exist in the risk estimates for participants based on assignment method for air pollution exposure.

Racial disparity in the association between body mass index and self-reported asthma in children: a population-based study.

OBJECTIVE: To examine the racial disparity in the association between obesity and asthma in US children and adolescents. METHODS: This study was based on a nationally representative, random-digit-dial sample of US households with children less than 18 years of age from the National Survey of Children's Health in 2011/2012 and 2007. The study sample included 88,668 children ages 10-17 with data on body mass index (BMI), parental reporting of asthma diagnosis, and potential confounders. Multiple logistic regression analysis was performed to estimate the crude and adjusted odds ratios stratified by child race/ethnicity. RESULTS: The prevalence of overweight was 15.2% and obesity was 14.1%. Self-reported asthma diagnosis was 16.7% in our study sample. Obese children were 51% more likely to have asthma compared to normal weight children after controlling for child's sex, child age, socioeconomic status, environmental tobacco smoke (ETS), and neighborhood conditions. Our study also shows that the strength of this association varied by race/ethnicity after stratification. Being male, being non-Hispanic Black or Multi-racial, below the Federal Poverty Level, ETS and having detracting neighborhood elements were also significantly associated with higher odds of having a self-reported asthma diagnosis. CONCLUSION: We observed a racial difference in the association between BMI and asthma in US children. Our findings have significant public health implications and may help public health practitioners to target children and adolescents at higher risk of prevention and intervention efforts.

Poor sleep quality associated with high risk of hypertension and elevated blood pressure in China: results from a large population-based study.

Little information is available concerning the association between sleep quality and blood pressure (BP) in Chinese individuals. This study evaluated the association between sleep quality, as determined by the Pittsburgh sleep quality index (PSQI), and hypertension in a rural Chinese population. Using a multistage cluster and random sampling method, a representative sample of 9404 adults aged 20-93 years in northeastern China was selected from 2012 to 2013. Sleep quality was assessed by PSQI, and trained observers measured BP. A sleep disorder (SD) was diagnosed for any participant with a score of 6 or greater. Overall, 1218 male participants (25.53%) and 1261 female participants (27.22%) were defined as having SDs. Compared with the normal subjects, participants with hypertension had higher global PSQI scores and subscores in all elements. The odds ratios (ORs) of hypertension, systolic hypertension and diastolic hypertension among participants with SDs were 2.38 (95% confidence interval (CI): 2.13-2.65), 2.52 (95% CI: 2.26-2.80) and 1.93 (95% CI: 1.74-2.14) in contrast to the reference group, respectively. The risk for hypertension in poor sleepers with subscores over 0 in all of the elements was significantly increased, with ORs ranging from 1.16 (95% CI: 1.04-2.30) to 3.88 (95% CI: 1.24-12.16). The global PSQI score and its components were associated with hypertension and high BP.

Adaptation of the "ten questions" to screen for autism and other neurodevelopmental disorders in Uganda.

Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener and additional questions on autism spectrum disorder behaviors. We then conducted household screening of 1169 children, 2-9 years of age, followed by clinical assessment of children who screened positive and a sample of those who screened negative to evaluate the validity of the screener. We found that 320 children (27% of the total) screened positive and 68 children received a clinical diagnosis of one or more moderate to severe neurodevelopmental disorders (autism spectrum disorder; cerebral palsy; epilepsy; cognitive, speech and language, hearing, or vision impairment), including 8 children with autism spectrum disorders. Prevalence and validity of the screener were evaluated under different statistical assumptions. Sensitivity of the 23Q ranged from 0.55 to 0.80 and prevalence for ≥1 neurodevelopmental disorders from 7.7/100 children to 12.8/100 children depending on which assumptions were used. The combination of screening positive on both autism spectrum disorders and Ten Questions items was modestly successful in identifying a subgroup of children at especially high risk of autism spectrum disorders. We recommend that autism spectrum disorders and related behavioral disorders be included in studies of neurodevelopmental disorders in low-resource settings to obtain essential data for planning local and global public health responses.

A Multiple Indicators Multiple Cause (MIMIC) model of respiratory health and household factors in Chinese children: the seven Northeastern cities (SNEC) study.

In China, with the rapid economic development and improvement of living standards over the past few decades, the household living environment has shifted dramatically. The aim of the present study is to assess the impact of home environment factors on respiratory symptoms and asthma in Chinese children. Investigators analyzed data collected in the 25 districts from the seven Northeastern cities to examine health effects on respiratory symptoms and asthma in 31,049 children aged 2-14 years. Factor analysis was used to reduce 33 children's lifestyle and household variables to six new 'factor' variables. The multiple indicators multiple causes approach was used to examine the relationship between indoor air pollution and respiratory health status, controlling for covariates. Factor analyses generated six factor variables of potential household risk factors from an original list of 33 variables. The respiratory symptoms and asthma were significantly associated with the recent home renovation factor (estimate = 0.076, p < 0.001), pet ownership factor (estimate = 0.095, p < 0.001), environmental tobacco smoke (ETS) exposure factor (estimate = 0.181, p < 0.001) and PVC-flooring factor (estimate = 0.031, p = 0.007). Home ventilation factor was not related to any respiratory condition (estimate = 0.028, p = 0.074). Independent respiratory health effects existed for multiple household environmental factors recent home renovation, pet ownership, ETS, and PVC-flooring.

Models of comprehensive multidisciplinary care for individuals in the United States with genetic disorders.

Approaches to providing comprehensive coordinated care for individuals with complex diseases include the medical home approach, the chronic care model in primary care, and disease-specific, multidisciplinary specialty clinics. There is uneven availability and utilization of multidisciplinary specialty clinics for different genetic diseases. For 2 disorders (ie, hemophilia and cystic fibrosis), effective national networks of specialty clinics exist and reach large proportions of the target populations. For other disorders, notably, sickle cell disease, fewer such centers are available, centers are less likely to be networked, and centers are used less widely. Models of comanagement are essential for promoting ongoing communication and coordination between primary care and subspecialty services, particularly during the transition from pediatric care to adult care. Evaluation of the effectiveness of different models in improving outcomes for individuals with genetic diseases is essential.

Ellen R. Grass Lecture: Rapid EEG analysis for intensive care decisions in status epilepticus.

Nonconvulsive status epilepticus in intensive care units (ICUs) is common and increases the risk of death. Nonconvulsive status epilepticus treatment delays are associated with poor patient outcomes. Continuous EEG or EEG-video monitoring is used in ICU settings to diagnose subtle seizures and nonconvulsive status epilepticus among at-risk populations including patients with closed head injuries and altered consciousness, stroke, subarachnoid hemorrhage, neonates at-risk for sepsis or hypoxic-ischemic encephalopathy, and children who have undergone surgery for congenital heart disease. However expert EEG interpretation, currently required for accurate diagnosis, often lags behind the real-time recordings by hours or even longer. At most hospitals the numbers of at-risk patients in intensive care units far exceeds the capacity of the available EEG equipment and personnel to perform and interpret EEGs. Seizure-detection software, compressed EEG spectral arrays, and near real-time remote EEG interpretation have brought us closer to the goal of real-time analysis of EEG for intensive care decisions, but even at major tertiary referral centers the vast majority of at-risk ICU patients do not undergo EEG monitoring. Additional technological advances, innovative use of EEG technologists and ICU personnel, and clinical trials of new EEG monitoring technology and associated clinical outcomes are needed to achieve the goal of optimal use of EEG data for intensive care decisions.

Complications of invasive subdural electrode monitoring at St. Louis Children's Hospital, 1994-2005.

OBJECT: The purpose of this study was to better define the incidence of complications associated with placement of subdural electrodes for localization of seizure foci and functional mapping in children. METHODS: The authors retrospectively reviewed the records of 112 consecutive patients (53 boys, 59 girls; mean age 10.9 years, range 10 months-21.7 years) with medically intractable epilepsy who underwent invasive monitoring at the Pediatric Epilepsy Center at St. Louis Children's Hospital between January 1994 and July 2005. There were 122 implantation procedures (85 grids and strips, 32 strips only, five grids only, four with additional depth electrodes), with a mean monitoring period of 7.1 days (range 2-21 days). Operative complications included the need for repeated surgery for additional electrode placement (5.7%); wound infection (2.4%); cerebrospinal fluid leak (1.6%); and subdural hematoma, symptomatic pneumocephalus, bone flap osteomyelitis, and strip electrode fracture requiring operative retrieval (one patient [0.8%] each). There were four cases of transient neurological deficit (3.3%) and no permanent deficit or death associated with invasive monitoring. CONCLUSIONS: Placement of subdural grid and strip electrodes for invasive video electroencephalographic monitoring is generally well tolerated in the pediatric population. The authors found that aggressive initial electrode coverage was not associated with higher rates of blood transfusion or perioperative complications, and reduced the frequency of repeated operations for placement of supplemental electrodes.

Antiepileptic drug development for "therapeutic orphans".

Epilepsy is the most common serious neurological disorder among children. Excluding the elderly, the incidence of epilepsy is highest among children. About half of children with epilepsy have epilepsy syndromes that have unique onset in childhood. Clinical drug trials of antiepileptic drugs (AEDs) among children have been primarily performed using drugs developed for the larger adult partial epilepsy market. The current AED drug development system essentially renders children with epilepsy "therapeutic orphans" who can only benefit from AED development if a drug developed for adult partial epilepsy happens to also be effective for a pediatric epilepsy syndrome. The rapid evolution of different seizure types and childhood epilepsy syndromes, and rapid changes in baseline neurological status, make distinguishing clinical changes due to study drugs in clinical trials and the natural history of the epilepsy syndrome difficult. Unique ethical issues (e.g., informed consent), practical and logistical issues (e.g., serum AED level monitoring with microassay methods), as well as major financial and regulatory disincentives for the pharmaceutical industry are additional barriers to need-based AED development for children. A government-funded pediatric epilepsy group or consortium to conduct clinical trials similar to the successful Children's Oncology Group (COG) and regulations plus financial incentives that encourage the pharmaceutical industry to develop AEDs specifically for children are needed.

Infantile spasms and Lennox-Gastaut syndrome.

Infantile spasms and Lennox-Gastaut syndrome are rare but are important to child neurologists because of the intractable nature of the seizures and the serious neurologic comorbidities. New antiepileptic drugs offer more alternatives for treating both infantile spasms and Lennox-Gastaut syndrome. Selected children with infantile spasms are candidates for epilepsy surgery. Vagus nerve stimulation, corpus callosotomy, and the ketogenic diet are all options for selected children with Lennox-Gastaut syndrome. The epidemiology, clinical manifestations of the seizures, electroencephalographic characteristics, prognosis, and treatment options are reviewed for infantile spasms and Lennox-Gastaut syndrome. Additional therapies are needed for both infantile spasms and Lennox-Gastaut syndrome as many children fail to achieve adequate seizure control in spite of newer treatments.