Death In Early Childhood Research Articles

Hippocampal malformation associated with sudden death in early childhood: a neuropathologic study: Part 2 of the investigations of The San Diego SUDC Research Project.

Sudden unexplained death in childhood (SUDC), while rare, accounts for an important fraction of unexpected deaths in children >1 year of age. Previously we reported an association between febrile seizures, hippocampal maldevelopment, and sudden, unexpected deaths in young children (1-6 years), termed "hippocampal maldevelopment associated with sudden death (HMASD)." Here, we characterize in greater detail the hippocampal pathology in a large cohort of cases (n = 42) of this entity, and attempt to define possible new entities responsible for sudden, unexplained death in young children without HMASD/febrile seizure phenotypes. We performed comparative analysis on cases, which we classified in a cohort of 89 sudden and unexpected deaths as HMASD, explained deaths, SUDC with febrile seizure phenotype (SUDC-FS) but without hippocampal pathology, and SUDC (without hippocampal pathology or febrile seizure phenotype). The frequency of each subgroup was: HMASD 48% (40/83); SUDC 27% (22/83); SUDC-FS 18% (15/83); explained 7% (6/83). HMASD was characterized clinically by sudden, sleep-related death, term birth, and discovery in the prone position. Key morphologic features of HMASD were focal granule cell bilamination of the dentate gyrus with or without asymmetry and/or malrotation of the hippocampus, associated with significantly increased frequencies of 11 other developmental abnormalities. We identified no other distinct phenotype in the unexplained categories, except for an association of febrile seizures without hippocampal maldevelopment. HMASD is a distinct clinicopathologic entity characterized by a likely developmental failure of neuronal migration in the dentate gyrus. Future research is needed to determine the causal role of HMASD in sudden death in early childhood.

Sudden unexpected death in early childhood: general observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project.

PurposeThe purpose of this study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in a large retrospective cohort, and to confirm the association of sudden unexplained death in children (abbreviated by us for unexplained deaths as SUDC) with hippocampal pathology and/or febrile seizures.MethodsWe undertook analysis of a retrospective cohort of 151 cases, of which 80 % (121/151) were subclassified as SUDC, 11 % (16/151) as explained, 7 % (10/151) as undetermined, and 3 % (4/151) as seizure-related.ResultsThere were no significant differences between SUDC and explained cases in postnatal, gestational, or postconceptional age, frequency of preterm birth, gender, race, or organ weights. In contrast, 96.7 % (117/121) of the SUDC group were discovered during a sleep period compared to 53.3 % (8/15) of the explained group (p < 0.001), and 48.8 % (59/121) of the SUDC cases had a personal and/or family history of febrile seizures compared to 6.7 % (1/15) of the explained group (p < 0.001). Of the explained deaths, 56 % (9/16) were subclassified as infection, 31 % (5/16) cardiac, 6 % (1/16) accidental, and 6 % (1/16) metabolic. Two of the three cases specifically tested for cardiac channelopathies at autopsy based upon clinical indications had genetic variants in cardiac genes, one of uncertain significance. Bacterial cultures at autopsy typically revealed organisms interpreted as contaminants. Two of the four seizure-related deaths were witnessed, with two of the brains from these cases showing generalized malformations. Hippocampal anomalies, including a specific combination we termed hippocampal maldevelopment associated with sudden death, were found in almost 50 % (40/83) of the SUDC and undetermined cases in which hippocampal sections were available.ConclusionsThis study highlights the key role for the hippocampus, febrile seizures, and sleep in SUDC pathophysiology. It also demonstrates the role of known predisposing conditions such as cardiac channelopathies and infections in causing sudden unexpected death in childhood, and the need for improved ancillary testing and protective strategies in these cases, even when the cause of death is established at autopsy.

Musculoskeletal/Radiological Manifestations of Mucolipidosis II (I-Cell disease) in late Adolescence/Early Adulthood.

Mucolipidosis type II (I-Cell disease) is a rare autosomal recessive lysosomal disorder, resulting from functional deficiency of lysosomal enzymes due to an impaired targeting of the enzymes to lysosomes, which leads to an abnormal cell architecture and the overflow of lysosomal enzymes into the body fluids. The life expectancy of the patients is poor, with multisystem deterioration leading to death in early childhood. According to the available reports, patients with I-cell disease do not survive beyond the first decade of life. Here, we describe and illustrate various radiological-musculoskeletal manifestations of a rare case of mucolipidosis II who has been a survivor up to now, 20 years old. The course of her disease has been complicated by early severe visual compromise due to optic nerve swelling, hearing loss and mitral valve regurgitation/stenosis, bilateral carpal tunnel, and severe growth impairment. Our case demonstrates several skeletal features of dysostosis multiplex. At the age of 20, she is wheelchair bound and her medical course is complicated by recurrent pneumonia, treated with multiple hospitalizations, antibiotics, and BiPAP. She is on outpatient palliative care, Do Not Resuscitate/Do Not Intubate (DNR/DNI) status.

Molybdenum Cofactor and Sulfite Oxidase Deficiency

A universal molybdenum-containing cofactor is necessary for the activity of all eukaryotic molybdoenzymes. In humans four such enzymes are known: Sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase and a mitochondrial amidoxime reducing component. Of these, sulfite oxidase is the most important and clinically relevant one. Mutations in the genes MOCS1, MOCS2 or GPHN - all encoding cofactor biosynthesis proteins - lead to molybdenum cofactor deficiency type A, B or C, respectively. All three types plus mutations in the SUOX gene responsible for isolated sulfite oxidase deficiency lead to progressive neurological disease which untreated in most cases leads to death in early childhood. Currently, only for type A of the cofactor deficiency an experimental treatment is available.

Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project.

BackgroundSpinal muscular atrophy (SMA) is the most common pan-ethnic cause of early childhood death due to mutations in a single gene, SMN1. Most chromosome 5 homologs have a functional gene and dysfunctional copy, SMN2, with a single synonymous base substitution that results in faulty RNA splicing. However, the copy number of SMN1 and SMN2 is highly variable, and one in 60 adults worldwide are SMA carriers. Although population-wide screening is recommended, current SMA carrier tests have not been incorporated into targeted gene panels.MethodsHere we describe a novel computational protocol for determining SMA carrier status based solely on individual exome data. Our method utilizes a Bayesian hierarchical model to quantify an individual’s carrier probability given only his or her SMN1 and SMN2 reads at six loci of interest.ResultsWe find complete concordance with results obtained with the current qPCR-based testing standard in known SMA carriers and affecteds. We applied our protocol to the phase 3 cohort of the 1,000 Genomes Project and found carrier frequencies in multiple populations consistent with the present literature.ConclusionOur process is a convenient, robust alternative to qPCR, which can easily be integrated into the analysis of large multi-gene NGS carrier screens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0246-2) contains supplementary material, which is available to authorized users.

Mortality after Parental Death in Childhood: a Nationwide Cohort Study from Three Nordic Countries.

Background Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood. Methods and Findings This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43–1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71–2.00) than parental natural death (MRR = 1.33, 95% CI 1.24–1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment. Conclusions Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies. Please see later in the article for the Editors' Summary

Broad-based molecular autopsy: a potential tool to investigate the involvement of subtle cardiac conditions in sudden unexpected death in infancy and early childhood

ObjectivesSudden unexplained death in children is a tragic and traumatic event, often worsened when the cause of death cannot be determined. This work aimed to investigate the presence of putative...

Abstract 3301: Uncovering novel radiation sensitivity syndromes through exome sequencing

Abstract INTRODUCTION: The study of genetic disorders resulting in heightened sensitivity to ionizing radiation provides important molecular insights to DNA damage checkpoint and repair mechanisms. Individuals with these disorders have an increased risk of cancer and developmental abnormalities. We identified patients with unexplained radiation sensitivity disorders through the Texas Children's Cancer Center and Genetics Consult Service at Texas Children's Hospital. Children were screened for the known disorders prior to enrolling in a research study with whole exome sequencing. SUBJECTS: We identified three families with documented ionizing radiation sensitivity: (1) a sibling pair, one of whom had sternal osteomyelitis and a lung transplant (age 2) and a brother with eosinophilia and pneumonia (age 1); (2) a sibling pair, one child with astrocytoma (age 2) with severe leukoencephalopathy after radiation and a sister with medulloblastoma (age 2) and atypical encapsulated neuroma (age 13); and (3) a proband with leukemia and astrocytoma (age 2). All parents were unaffected. METHODS: We performed Illumina whole exome sequencing of probands and parents (when available), calling single nucleotide variants and insertions/deletions with ATLAS and PINDEL. We removed events &amp;gt;1% in 1079 unaffected normal samples, &amp;gt;1% dbSNP, or &amp;gt; = 20 individuals in Exome Aggregation Consortium. We kept rare missense and truncating variants, and prioritized rare compound heterozygous, homozygous, or mutations shared by affected sibs. RESULTS: In the proband with sternal osteomyelitis and lung transplant, we identified and validated compound heterozygous missense mutations in NDNL2 (MAGEG1), a small, intronless gene. NDNL2 is involved in the SMC5-SMC6 complex, and suggested to play a role in DNA repair. The known functions of NDNL2 may explain the finding of the patient's cells displaying altered phosphorylation upon DNA damage for NBN (absent) and SMC1 (reduced). We are currently investigating the link between mutant NDNL2 and phosphorylation of NBN and SMC1. In kindred 2 (previously shown to transmit a SMARCB1 splice site mutation), the siblings share rare compound heterozygous missense mutations in ROBO1, and a nonsense mutation in MEGF6. In kindred 3, the proband with leukemia and astrocytoma was known to carry a large Xp deletion, but we identified no obvious candidate underlying radiation sensitivity. CONCLUSION: Careful study of rare kindreds with unexplained radiation sensitivity may provide new insights to the DNA damage response. Interestingly, two families also carried a known genetic condition (SMARCB1 mutation and Xp microdeletion) that may explain cancer phenotype but does not appear to underlie radiation sensitivity. The very rare biallelic missense mutations in NDNL2 implicate it as a candidate radiation sensitivity gene to be validated by further functional testing. Both siblings in this family had severe infections resulting in death in early childhood. Citation Format: Deborah I. Ritter, Andrea K. Petersen, Katherine M. Haines, Ryan C. Zabriskie, David A. Wheeler, Sharon E. Plon. Uncovering novel radiation sensitivity syndromes through exome sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3301. doi:10.1158/1538-7445.AM2015-3301

Cancer Mortality Among People Living in Areas With Various Levels of Natural Background Radiation.

There are many places on the earth, where natural background radiation exposures are elevated significantly above about 2.5 mSv/year. The studies of health effects on populations living in such places are crucially important for understanding the impact of low doses of ionizing radiation. This article critically reviews some recent representative literature that addresses the likelihood of radiation-induced cancer and early childhood death in regions with high natural background radiation. The comparative and Bayesian analysis of the published data shows that the linear no-threshold hypothesis does not likely explain the results of these recent studies, whereas they favor the model of threshold or hormesis. Neither cancers nor early childhood deaths positively correlate with dose rates in regions with elevated natural background radiation.

Characterization of a Novel Dioxomolybdenum Complex by Cyclic Voltammetry

Metalloenzymes that carry a pterin-based molybdenum cofactor in their center catalyze numerous reactions in the human body and play a crucial role in its metabolism. Specifically, these enzymes promote redox reactions and oxygen transport in the body. Their absence may cause many problems leading to disability or even death in early childhood. Therefore, model compounds need to be synthesized and analyzed to investigate the reactivity, redox potential, and geometry of these cofactors. This study focused on electrode processes and determined the redox potentials of the new bis-(4-mercapto-5-(p-tolyl)-3H-1,2-dithiole-3-thione)-dioxomolybdenum complex by cyclic voltammetry. The 4-mercapto-5-(p-tolyl)-3H-1,2-dithiole-3-thione ligand underwent irreversible oxidation and reduction at thiol and thione functional groups. The new dioxomolybdenum complex showed a quasi-reversible two-stage electrode process.

507. AAV-Mini-Agrin for Laminin-alpha2 Deficient CMD

Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) (MDC1A) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. The laminin alpha2 gene (around 10kb) is too large to fit into adeno-associated viral (AAV) vectors. Alternatively, a mini-agrin, which has similar function as the laminin alpha2, is utilized as the therapeutic gene. Our previous study with AAV1-mini-agrin gene therapy in dyw/dyw mice showed dramatic therapeutic effects in muscle pathology, but weak on peripheral neuropathy. The objective of the current study was to see whether the nerve pathology in MDC1A mice could be improved by mini-agrin using the AAV9 vector, which has superior ability to transduce nervous system.AAV9-mini-agrin (2 × 10^11vg/pup) was injected into 2 to 3 days old homozygous dyw/dyw pups via the temporal vein. The gene therapy treatment significantly improved mouse body weight (15 ± 45g in treated mice vs. 10.±.09g of untreated homozygous mice at 11 weeks of age, n=6, p< 0.001) and quadrupled life span (41.±0.04 wks of average life span in treated group vs. 10.18±.12 wks in untreated group, n= 9 to 24, p<0.0001, Fig a). In tests for motor function, untreated dyw/dyw mice were hypoactive in an open field and had overt deficits in a marble-burying assay. AAV9-mini-agrin gene therapy led to significant increases in locomotion (p=0.0373) and a marked rescue of marble-burying (Fig b. p=0.0068), an indication of both nerve and muscle functions. Gene therapy also resulted in a significant improvement in nerve pathology vs. the untreated controls shown by toluidine blue staining with more myelinated nerve fibers, and partial restoration of the basal lamina shown by electron microscopy in the treated mice. More importantly, the treated dyw/dyw male and female mice become fertile, which has never been seen before. Genotyping of the unborn pups confirmed that they were all homozygous dyw/dyw mice. This indicates that mini-agrin can partially replace the function of laminin alpha-2 in MDC1A and achieve therapeutic effects in muscle pathology, peripheral neuropathy, and fertility. This study represents a significant advancement in AAV-mediated gene therapy for MDC1A. View Large Image | Download PowerPoint SlideFig. Life span extension and functional improvement by the treatment. a. Both AAV9-CMV-mini-agrin and AAV9-CB-mini-agrin treatment resulted in significant improvement in mouse survival. n = 9 to 24, p < 0.0001. b. Treatment led to an overt increase in marble-burying. n=5, * p< 0.01.

Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study

AbstractMucopolysaccharidosis type I–Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.

Early diagnosis of biliary atresia

Biliary atresia is the most common indication for liver transplantation in the pediatric population and the most frequent liver-related cause of death in early childhood. However, in some cases, long-term survival with the native liver can be achieved by surgical reestablishment of bile flow. The procedure of choice involves removal of the fibrotic, atretic bile duct segment and construction of a drainage route via hepatoportoenterostomy (the Kasai procedure). The outcome following hepatoportoenterostomy is closely related to the patient's age at the time of the procedure. It is universally acknowledged that the Kasai procedure performed before 60 days of age can improve the likelihood of survival with the native liver and avoid liver transplant. The problem that we continually witness in our clinical practice is late referral of patients with biliary atresia, emphasizing the importance of screening for this potentially devastating disease. The lack of bile flow into the intestine leads to acholic stools—a reliable clue that obstruction is likely. Pale, nonpigmented stools appear within the first month after birth in patients with biliary atresia. Thus, the concept of using a stool color card for screening and parent education regarding the disease was initially introduced to the local population in Japan (Tochigi Prefecture) by Matsui et al in 1993 (Screening 1993;2:201-9). Their preliminary results documented the success in ensuring a prompt diagnosis and early Kasai procedure. The concept of stool color card based mass screening has subsequently been utilized in several other countries, also resulting in earlier referral of patients with biliary atresia. In this issue of The Journal, Gu et al now report the cumulative impact of the stool color card program over the 19 years that it has been used for mass screening of biliary atresia in Tochigi Prefecture. Beginning in 1994, the stool color card was distributed to all pregnant women prior to or during the postnatal one-month health check-up and the mothers returned the completed card to the attending physician. All suspected cases of biliary atresia were referred for further examination, where the diagnosis was confirmed and patients were followed from the date of Kasai procedure until liver transplant or death up to 2013. A total of 313 230 live born infants were screened; 34 patients were confirmed to have biliary atresia. The sensitivity and specificity of stool color card screening at the one-month check-up was 76.5% and 99.9%, respectively. Mean age at the time of performance of the Kasai procedure was 59.7 days. This was associated with high rates of long-term native liver survival (88%, 77%, and 49% at 5, 10, and 15 years, respectively). These data are convincing evidence that this simple, patient-empowered screening for biliary atresia should be universally adopted to improve the outcome of affected children. Article page 897▶ Stool Color Card Screening for Early Detection of Biliary Atresia and Long-Term Native Liver Survival: A 19-Year Cohort Study in JapanThe Journal of PediatricsVol. 166Issue 4PreviewTo evaluate the sensitivity and specificity of a stool color card used for a mass screening of biliary atresia conducted over 19 years. In addition, the age at Kasai procedure and the long-term probabilities of native liver survival were investigated. Full-Text PDF

Child survival and BCG vaccination: a community based prospective cohort study in Uganda.

BackgroundData on non-specific effects of BCG vaccination in well described, general population African cohorts is scanty. We report the effects of BCG vaccination on post-neonatal infant and post-infancy mortality in a cohort of children in Mbale, Eastern Uganda.MethodsA community-based prospective cohort study was conducted between January 2006 and February 2014. A total of 819 eligible pregnant women were followed up for pregnancy outcomes and survival of their children up to 5 years of age. Data on the children’s BCG vaccination status was collected from child health cards at multiple visits between 3 weeks and 7 years of age. Data was also collected on mothers’ residence, age, parity, household income, self-reported HIV status as well as place of birth. Multivariable Cox proportional hazards regression models taking into account potential confounders were used to estimate the association between BCG vaccination and child survival.ResultsThe neonatal mortality risk was 22 (95% CI: 13, 35), post-neonatal infant mortality 21 (12, 34) per 1,000 live births and the mortality risk among children between 1 and 5 years of age (post-infancy) was 63 (47, 82) per 1,000 live births. The median age at BCG vaccination was 4 days. Out of 819 children, 647 (79%) had received the BCG vaccine by 24 weeks of age. In the adjusted analysis, the rate of post-neonatal death among infants vaccinated with BCG tended to be nearly half of that among those who had not received the vaccine (adjusted HR: 0.47; 95% CI: 0.14, 1.53). BCG vaccination was associated with a lower rate of death among children between 1 and 5 years of age (adjusted HR: 0.26; 95% CI: 0.14, 0.48).ConclusionThe risk of early childhood death in Mbale, Uganda is unacceptably high. BCG vaccination was associated with an increased likelihood of child survival.

CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.

Primary Endocardial Fibroelastosis and Nonimmune Hydrops Fetalis: Case Report with Autopsy

Endocardial fibroelastosis is an important cause of congestive heart failure and death in infancy and early childhood. When present, it is commonly associated with non immune hydrops fetalis. The aim of this study is to draw attention for possible cardiac abnormalities in cases of fetal hydrops, and report a case of premature death by primary endocardial fibroelastosis with autopsy.

Quantitative measurement of retinal hemorrhages in suspected victims of child abuse

Child abuse is one of the leading causes of death in early childhood. The presence of retinal hemorrhages often supports the diagnosis. The purpose of this study was to determine whether the specific measurement of retinal hemorrhages when present on fundus photography correlates with other clinical findings typically seen in children suspected of having been abused. The medical records of children with retinal hemorrhages who were suspected of being victims of abusive head trauma from June 2003 to June 2013 and who had widefield retinal photography performed were retrospectively reviewed. Data collected included hemorrhage-covered percentage (HCP) of the central retina (posterior pole or 40° circle centered on fovea) measured by ImageJ in relation to death, length of hospital stay, presence of abnormal findings on neuroimaging or skeletal survey, and definite versus possible abuse. Significant difference in retinal hemorrhage measured on fundus photography was found in patients with axial skeletal fracture (P = 0.016), signs of severe brain trauma on neuroimaging (P = 0.014) and definite versus possible abuse (P = 0.023). No correlation of quantitative measurement of the retinal hemorrhage to length of hospital stay, death, or the presence of skull fracture was found in this cohort. The quantitative measurement of total retinal hemorrhage when present on fundus photography centered on posterior pole in children suspected of having been abused correlated with some but not all findings typically seen in abused children.

Early-life risk factors for chronic nonrespiratory diseases.

We have witnessed a change in disease patterns contributing to the global burden of disease, with a shift from early childhood deaths due to the classic infectious communicable diseases to years lived with disability from chronic noncommunicable diseases. In both developing and developed countries, the years lived with disability attributable to chronic disease have increased: cardiovascular diseases by 17.7%; chronic respiratory disease by 8.5%; neurological conditions by 12.2%; diabetes by 30.0%; and mental and behavioural disorders by 5.0% over the past 20 years. Recognition of the contribution made by adverse environmental exposures in early life to noncommunicable diseases in later life is increasing. These early-life exposures appear to contribute to both chronic respiratory and chronic nonrespiratory diseases. In this State of the Art article, we aim to examine early-life environmental exposures that have an epidemiological association with chronic nonrespiratory diseases, such as obesity and type II diabetes, cardiovascular disease, and neurocognitive and behavioural problems. We will highlight the potential overlap in environmental risks with respiratory diseases, and point out knowledge gaps and research opportunities.

Outcomes in the Era of Therapeutic Hypothermia

Encephalopathy in the late preterm and term infant is an important clinical condition because it can be associated with death or poor neurodevelopment in early childhood. Stages of encephalopathy (mild, moderate, and severe) soon after birth have value in predicting outcome during early infancy and even at early school-age. Prompt recognition after birth of the subset of infants in whom encephalopathy is associated with hypoxia-ischemia (hypoxic-ischemic encephalopathy [HIE]) is critical because the outcome is potentially modifiable with therapeutic hypothermia. A series of large randomized clinical trials have provided better estimates of the outcomes of moderate and severe HIE compared with the era before the hypothermia trials. Therapeutic hypothermia reduces the composite outcome of death or a major disability at 18 months to 2 years of age among term infants who have moderate or severe encephalopathy. School-age follow-up of a limited number of infants from these trials indicates that death is reduced without any evidence that the percentage of brain-injured infants is increased. Practitioners need to be aware, however, that poor outcomes among infants who have HIE who have received hypothermia treatment is common, and many gaps persist regarding the outcome of these infants at school-age and beyond.

Interventions for the Prevention and Control of Sickle Cell Disease at Primary Health Care Centres in Gwagwalada Area Council of the Federal Capital Territory, Nigeria.

With its population of 167 million, Nigeria has the highest burden of sickle cell disease (SCD) in the world with birth prevalence of 2% and 0.05% in adults due to deaths in early childhood. Sickle cell disease is thus a major contributor to Nigeria’s "under five" mortality figures. Failure to pay attention to such a widespread condition in the population is slowing progress towards Nigeria’s achievement of the Millennial Development Goals (MDG) 3-5. Although the Federal Government set up six MDG Sickle Cell Centres in 2012 in six geopolitical zones and equipped them with variant newborn high performance liquid chromatography equipment, these centres are not carrying out newborn screening in a systematic and standardized way and the equipment is not being fully utilized. There is no universal screening of babies for SCD and identification at the primary care level. The care of SCD has been confined to tertiary health care centres with few dedicated sickle cell clinics. The average age of presentation at these centres is eight years, and there is no formal referral system of patients through the lower levels of care. In developed countries, major benefits in the health and survival of patients with SCD have been achieved through the implementation of a few highly effective evidence-based interventions. A community-based intervention program is described which will provide parents, caregivers, and health care workers at primary health centres and ward levels with basic health education to look after patients with SCD, recognize early warning signs of complications, and institute appropriate referral mechanism to the comprehensive centres where advanced medical care can be given as necessary.