The last decade has witnessed major reductions in child mortality and a focus on saving lives with key interventions targeting major causes of child deaths, such as neonatal deaths and those due to childhood diarrhea and pneumonia. With the transition to Sustainable Development Goals, the global health community is expanding child health initiatives to address not only the ongoing need for reduced mortality, but also to decrease morbidity and adverse exposures toward improving health and developmental outcomes. The relationship between adverse environmental exposures frequently associated with factors operating in the prepregnancy period and during fetal development is well established. Also well appreciated are the developmental impacts (both short- and long-term) associated with postnatal factors, such as immunostimulation and environmental enteropathy, and the additional risks posed by the confluence of factors related to malnutrition, poor living conditions, and the high burden of infections. This article provides our current thinking on the pathogenesis and risk factors for adverse developmental outcomes among young children, setting the scene for potential interventions that can ameliorate these adversities among families and children at risk.

Important and heartening downward trends in global mortality for children <5 years of age have been achieved in recent years. For a summary, see Table 1. In light of this encouraging progress, there is an emerging recognition of the importance of newborn survival in reducing child mortality. Strategies to address newborn survival1 will also be a critical part of the maternal and child health goals within the United Nations’ Sustainable Development Goal 3 for health and well-being.2 Although global burden of disease data have typically focused on children <5 years of age, more recent evidence points to a continued burden of morbidity and ill health among older children and adolescents.3 

TABLE 1

Global Trends in Under-5 Mortality

The global under-5 mortality rate has dropped nearly 53% since 1990, from around 91 deaths per 1000 live births to 43 per 1000 live births in 2015.4  
In 2000, for example, there were 9.8 million annual deaths of children <5 years of age.5 Pooled estimates for 42 countries that included >90% of all such deaths identified leading causes as: 
 ○ neonatal conditions (33%), 
 ○ diarrhea (22%), 
 ○ pneumonia (21%), 
 ○ malaria (9%), and 
 ○ HIV (3%)5  
In 2013, mortality rates reduced to 5.9 million deaths per year6 with a major shift in the causes: 
 ○ preterm birth complications cause 15% of all under-5 deaths and, along with other neonatal causes, represent 44% of all deaths7
 ○ pneumonia (15%), 
 ○ diarrhea (9%), 
 ○ malaria (7%), and 
 ○ AIDS (2%) deaths have declined in relative terms, and even more so in absolute terms.8  
The global under-5 mortality rate has dropped nearly 53% since 1990, from around 91 deaths per 1000 live births to 43 per 1000 live births in 2015.4  
In 2000, for example, there were 9.8 million annual deaths of children <5 years of age.5 Pooled estimates for 42 countries that included >90% of all such deaths identified leading causes as: 
 ○ neonatal conditions (33%), 
 ○ diarrhea (22%), 
 ○ pneumonia (21%), 
 ○ malaria (9%), and 
 ○ HIV (3%)5  
In 2013, mortality rates reduced to 5.9 million deaths per year6 with a major shift in the causes: 
 ○ preterm birth complications cause 15% of all under-5 deaths and, along with other neonatal causes, represent 44% of all deaths7
 ○ pneumonia (15%), 
 ○ diarrhea (9%), 
 ○ malaria (7%), and 
 ○ AIDS (2%) deaths have declined in relative terms, and even more so in absolute terms.8  

Increasingly, the global health community is expanding child health initiatives to address not only the ongoing need for reduced mortality, but also to decrease morbidity and adverse exposures toward improving health and developmental outcomes.9 In addition, reductions in child mortality have not been universally realized and significant disparities exist for marginalized populations.10 According to the 2016 Global Nutrition Report, 159 million children have stunted growth worldwide, reflecting a rate of reduction that is far lower than the targets set by the World Health Assembly.11 The data suggest that, notwithstanding the leading infectious disease–associated deaths, iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 million children in 2013.3 Not only are developmental deficits important consequences of conditions associated with a higher risk of mortality (such as intrauterine growth restriction, prematurity, and birth asphyxia),12 but they may also be associated with a range of factors related to living conditions (eg, sanitation), poverty, and undernutrition.13 More recently, the association of Zika virus infection during pregnancy and microcephaly highlights the importance of emerging infectious diseases and the risks of adverse neurodevelopmental outcomes.14 By using Early Child Development Index data from Demographic and Health Surveys as well as Multiple Indicator Cluster Surveys in 35 low- and middle-income countries, estimates of the prevalence of neurodevelopmental deficits have recently been published, indicating that 14.6% of children had low Early Child Development Index scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains.15 Risk factors for such deficits should be considered in the context of sensitive time periods in fetal and childhood physical and neurodevelopment. For the purposes of this journal supplement, neurodevelopment is defined as the dynamic interrelationship between environment, genes, and the brain whereby the brain develops across time to establish sensory, motor, cognitive, socioemotional, cultural, and behavioral adaptive functions. This definition has been modified for this effort from an earlier version recently published in Nature.16 

As will be explored more fully below and throughout this supplement, the implications of potential insults are compounded by their timing (ie, during critical and sensitive periods of neurodevelopment). A sensitive period is a time in development during which the brain is particularly responsive to stimuli or insults followed by an extended period of ongoing responsiveness, but to a lesser degree (eg, language development); by contrast, a critical period refers to a time in development when the presence or absence of an experience results in irreversible change (eg, binocular vision).17,18Figure 1 depicts neural network development from the prenatal period into adulthood, including key time periods, sensitive and critical, for specific domains. An example of the former might be the formation of a healthy attachment between infant and caregiver, which requires an adult who is invested in the child’s needs during the first 2 years of life. An example of the latter is the need to treat children born with cataracts in the first few months of life for children to ever develop normal vison. For most aspects of human behavioral development, the concept of sensitive periods is the most applicable, given the prolonged course of brain development and the enormous range of experiences to which children from different cultures and societies are exposed. Although not all developmental domains follow sensitive periods, of those that do, most sensitive periods occur during the first few years of life. Importantly, not all sensitive periods are the same, even within the same general domain. For example, the acquisition of syntax likely follows a much more compressed time table than the acquisition of vocabulary, which may extend throughout much of the lifespan. Similarly, the formation of attachments likely follows a different time table than the acquisition of executive functions (ie, cognitive control), which, like vocabulary, is apt to be broadly tuned.

FIGURE 1

The neural network: development from the prenatal period into adulthood, including key time periods (ie, sensitive and critical) for specific domains. (Reprinted with permission from Bhattacharjee Y. Baby Brains – The First Year. National Geographic. Available at: http://ngm.nationalgeographic.com/2015/01/baby-brains/bhattacharjee-text.)

FIGURE 1

The neural network: development from the prenatal period into adulthood, including key time periods (ie, sensitive and critical) for specific domains. (Reprinted with permission from Bhattacharjee Y. Baby Brains – The First Year. National Geographic. Available at: http://ngm.nationalgeographic.com/2015/01/baby-brains/bhattacharjee-text.)

During sensitive periods, when there is maximal brain plasticity, experiences can “cut both ways.” That is, positive experiences are likely to direct development along a typical trajectory, whereas negative experiences can undermine this trajectory. This association is particularly true if such negative experiences continue beyond the sensitive period. Accordingly, interventions are more likely to be met with success when implemented early, when many brain regions and circuits are at their peak of plasticity. However, effective interventions are also needed throughout the life-course from early childhood through young adulthood to achieve the best possible outcomes for those who did not receive appropriate support at earlier time points. For example, recent advances in understanding the molecular signals that regulate the opening and closing of sensitive periods, such as those reported in animal models by Hensch and colleagues,19,21 may prove particularly helpful in developing new “late-onset” interventions.

Although healthy debates continue about the data quality, complexity of causality, and mechanisms involved, multiple lines of evidence link impaired early-life development with later health impairment. Examples that provoke challenging genetic, epigenetic, microbiologic, and metabolomic models for understanding include potential development and metabolic consequences of diseases of poverty, such as repeated enteric infections in early childhood in impoverished areas.22 The associations of key prenatal factors and being small for gestational age (SGA) with an increased risk of mortality23 and subsequent stunting are well recognized.13 

The fact that a range of periconceptual, fetal, and postnatal factors affect health and neurodevelopmental outcomes in an interconnected manner is well established. Increasingly, at both the population and individual level, there is a cooccurrence of malnutrition (ie, both overnutrition and undernutrition) and infectious and noncommunicable diseases, each of which has strong nutritional and inflammatory components that impact and are impacted by neurodevelopment, particularly in the context of pregnancy, birth outcomes, infant feeding, and maternal health, including adolescents. A host of environmental factors have been identified in low-resource settings (LRS) that increase the risk for altering the course of neurodevelopment.24,25Figure 2 illustrates an early adversity causal model of the interactions between early childhood adversity, biological changes, and long-term outcomes. Specific examples of early-life insults and adversities that are of particular relevance to LRS include:

FIGURE 2

Early adversity causal model: Interactions between early childhood adversity, biological changes, and long-term outcomes. Reprinted and adapted with permission from Annie E. Berens, medical student, Harvard Medical School. IUGR, intrauterine growth restriction; LBW, low birth weight; SGA, small for gestational age.

FIGURE 2

Early adversity causal model: Interactions between early childhood adversity, biological changes, and long-term outcomes. Reprinted and adapted with permission from Annie E. Berens, medical student, Harvard Medical School. IUGR, intrauterine growth restriction; LBW, low birth weight; SGA, small for gestational age.

  • Prematurity: Preterm birth, particularly in LRS where fewer interventions and services are available, can lead to both short- and long-term deficits in neurodevelopment,26 including specific impairments in attention27 and higher-order cognitive skills.28 Although multifactorial in origin, prematurity risks include maternal undernutrition, micronutrient deficiencies, as well as subclinical infections and inflammation; these risks may vary in different populations and are affected by genetic influences. Given the prevalence of prematurity in the United States and globally, it is fortunate that some progress on solutions to the health care of such children worldwide has been made,29 such as with recently developed nutritional guidelines for preterm infants.30 

  • Nutrition: Malnutrition, including both undernutrition and overnutrition, clearly has implications for all aspects of child development. An abundance of evidence exists implicating undernutrition as an independent causal factor in altering physical and neurologic development, with both short- and long-term implications for health and quality of life.31 

  • Infectious disease and inflammation: It is well known that chronic diarrheal illness, often due to poor sanitation, food safety, and water quality, is associated with chronic inflammation. In a cohort of Bangladeshi infants living in poverty, Jiang et al32 have reported decreased scores on the Bayley Scales of Infant and Toddler Development33 in association with febrile illness as a clinical marker of inflammation and a variety of proinflammatory cytokines. This is an impressive demonstration that children experiencing early inflammatory processes are at risk for diminished or delayed development. Whether there is catch-up later in life is unknown.

  • Violence: Child maltreatment increases the risk of both adverse neural34,35 and cardiovascular outcomes.36 A recent systematic review of population-based surveys, including data for 96 countries, estimates that 1 billion children ages 2 to 17 years, representing over half of all children globally, experienced violence in the past year.37 This pervasive exposure to conflict and violence in early childhood can have far-reaching consequences for the physical and mental health of future generations.38 

  • Toxic stress: For the purposes of this article, toxic stress will be defined by using key concepts introduced by the National Scientific Council on the Developing Child, which described toxic stress as being the excessive or prolonged activation of the physiologic stress response systems in the absence of the buffering protection afforded by stable, responsive relationships and the result of cumulative adverse childhood experiences.39 There is now extensive evidence from neuroscience, molecular biology, and epigenetics illustrating that increases in heart rate, blood pressure, and serum glucose, coupled with elevations in stress hormones and inflammatory cytokines fuel the fight or flight response to deal with acute threat.39,42 Furthermore, excessive or prolonged activation of stress response systems can lead to long-term disruptions in brain development, immune status, metabolic systems, cardiovascular function, and gene expression. Animal and human studies have found associations between early-life adversity and toxic stress to changes in brain architecture and gene expression, potentially resulting in long-term and even intergenerational physical and mental health consequences. Importantly, toxic stress is most deleterious to the developing brain when it occurs during a sensitive or critical period of development and may have lifelong effects. Consequently, toxic stress is an important concept with implications for the research, clinical, and policy arenas.

The evidence to support the intimate and inextricable role of food and nutrition, including in mortality and human development is compelling.13 Suboptimal nutrition, associated with fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc, along with suboptimal breastfeeding, is associated with ∼45% of all deaths of children <5 years of age.13 The Pelotas cohort of 3500 infants followed up to 30 years of age, adjusted for potential confounders, showed that participants who were breastfed for at least 12 months, as compared with <1 month, scored on average 3.76 points higher on IQ tests, achieved 0.91 extra years of education, and earned higher monthly incomes.43 These effects are especially notable given the known benefits of exclusive breastfeeding for newborn and child survival44 and the impacts on the burden of morbidity due to gastrointestinal and respiratory infections.45 Stunting is included among the 2013 World Health Assembly nutrition targets, but the world is off track for achieving the global target of reducing stunting prevalence by 40% by 2025.11 As per the latest estimates,46 the median prevalence of stunting in the 65 countdown countries with data from 2009 or later is 32%, and ranges from 9% in China to 58% in Burundi. Progress in these domains has been relatively slow, despite the calls for action at the World Health Assembly and through The Lancet Undernutrition Series in 2013.13,44 Few countries have launched comprehensive programs integrating child survival and nutrition at scale.11,46 

A significant advance in recent years is the recognition of the relationship between maternal undernutrition, indeed even preconceptional factors, such as maternal height, and fetal growth restriction, resulting in SGA births.47 Not only has SGA been shown to compound the risk of neonatal mortality, especially among preterm infants,47 but it has also been shown to account for at least a fifth of all stunting in children at 18 months of age.13 This association could be stronger in South Asia, which has significantly higher rates of maternal malnutrition and SGA births. To illustrate, both maternal height and BMI were found to be independently associated with childhood stunting in Pakistan,48 and similar relationships have been shown from an analysis of data from the National Family Health Survey of India.49,50 

Stunting has been associated with impaired cognitive development, effects that are only partially mitigated by schooling.51 In addition, although the magnitude and duration of effects in the postnatal period and infancy remain controversial, relative to the importance of maternal and fetal effects, some studies have provided intriguing insight into critical opportunities for benefit. In a large study in rural Pakistan with community health workers providing integrated nutrition and child development messaging, although there were developmental benefits at 24 months of age, there was no impact on nutritional outcomes.52 However, nutritional intervention in the first 2 years of life has been reported to be associated with as much as a 10% higher IQ score and 46% higher wages in later life.53 

Given the close nexus between poverty and undernutrition, it is not surprising that significant correlations between poverty and brain development have been demonstrated.54,55 Other research looking at factors associated with neurodevelopment and poverty has focused on the toxic effects of violence, abuse, and exposure to conflict. Data from the recent Lancet series on early child development56 also suggest that by using conjoint estimates of poverty and stunting, some 200 million children worldwide are at risk for suboptimal development with huge economic costs over their lifetimes and potentially across generations. These data do not, as yet, take into account the number of families and young children affected by violence, abuse, and exposure to conflict. It is now estimated that at least 40% of the global burden of maternal and child mortality lies in countries affected by national or subnational conflict and population displacement.57 The growing knowledge of the biology of typical and atypical child and brain development, and the potential impact of interventions during sensitive periods of brain development may ameliorate the global burden of adversity and risk. The key focus on the first 1000 days of life points to the importance of the period of fetal development, during which the adverse effects on brain development and linear growth are maximal and the potential for interventions is at a maximum.

Our appreciation of the interaction between inflammation associated with chronic infection and various aspects of child development has been greatly informed by the recognition of both the prevalence and nature of “environmental enteropathy” (EE).58 EE with disrupted intestinal barrier function, intestinal inflammation, and impaired absorptive function is postulated to impair early childhood growth and neurodevelopment. The fact that inflammation during key life periods may play a critical role in affecting nutrition, EE, and development has been well recognized for well over 2 decades59 and was convincingly demonstrated in a series of studies in Malawi and Zimbabwe.60,62 These indicate that low-grade exposure to environmental pathogens may create an environment of immunostimulation and may relate to changes in the microbiome63 or the insulinlike growth factor axis.64 In separate studies, children in Kenya or Jamaica who received treatment with the antihelminthic drug albendazole compared with placebo had significantly better growth, fitness, and cognitive function.65,66 

Despite surprisingly comparable growth curves in the first few months of life, the fall from the expected growth trajectory from 4 to 24 months of age in children living in impoverished areas of Asia, Africa, and Latin America has been remarkably consistent in decade-plus reviews as well as in current multisite studies.3,67 The extent to which stunted growth is a reflection of intestinal parasitic or other infections or is predictive of impaired cognitive development, or that the latter may occur with an EE independent of stunted growth, has been and remains the topic of many studies ranging from work in Guatemala,53 the Philippines,51 Kenya,63 Jamaica,64,67 Peru,68,69 and Brazil70,71 to the current work by the Interactions of Malnutrition and Enteric Infections: Consequences for Child Health and Development consortium.72 

Evidence continues to mount that enteric infections and enteric or systemic inflammation in early childhood or prenatally can impair growth and development and perhaps even increase later life associations with obesity, metabolic syndrome or cardiovascular disease.22,32,73 Murine models also confirm that infection can impair growth and undernutrition can greatly worsen infection burdens and their growth impairment, documenting a potential “vicious cycle” with such enteric pathogens as cryptosporidium or enteroaggregative Escherichia coli.74,75 Although stunting may be an increasingly imperfect surrogate for the long-term effects of early life enteric infections, Victora et al43 have noted that the height-for-age z score around the second birthday can be the best predictor of “human capital” in terms of educational attainment, economic productivity, and even the weight of future offspring.

Diarrheal illnesses, a surrogate for enteric infections, EE, and stunting or impaired “catch-up growth”68 have also been associated with impaired cognitive development. Specifically, the cognitive impairment most affected appears to be semantic (versus phonemic) fluency and higher executive function, somewhat analogous to the cognitive deficits seen in Alzheimer’s disease.76 Because of this, a specific allele of the Apo-lipoprotein E (ApoE4), which has been associated with an increased risk of late-onset Alzheimer’s disease, has been examined and, surprisingly, has been found to be protective against the cognitive deficits seen in children with heavy diarrhea burdens.77Table 2 provides some highlights of this seminal research. Taken together, these findings of a potential benefit of the ApoE4 allele in protecting the cognitive development of children (or enteropathy in mice)78 with repeated diarrhea or enteropathy in early childhood (or specific infections in mice) could help explain a potential selective advantage for this ApoE4 allele despite its clear association with an increased risk for Alzheimer’s disease in later life (an effect that has been termed “antagonistic pleiotropy,” or when a single gene controls more than a single trait, ≥1 of which has beneficial and ≥1 of which has detrimental effects on the fitness of the host). Thus, the evolutionary benefit of ApoE4 (perhaps like other genes, such as the sickle cell trait gene) may only persist in the presence of such health threats as diarrhea or enteropathy (or malaria). As conditions improve, one could imagine the changing “evolutionary value” of different traits over time.

TABLE 2

Potential Role of ApoE4 in Cognition

A specific allele of ApoE4, which has been associated with an increased risk of late-onset Alzheimer’s disease, has been found to be protective against the cognitive deficits seen in children with heavy diarrhea burdens.77  
The potential link between ApoE4 and cognition has been extended to targeted transgenic mice expressing the human ApoE4 allele. Findings include: 
 protected intestinal villus morphometry, 
 improved growth trajectories, and 
 reduced shedding of Cryptosporidium parasites in experimental infections with malnutrition.78  
The bridge with basic studies may lie in Colton and Czapiga’s work79,80 showing that: 
 these mice exhibit increased expression of cationic amino acid transporter-1 that is responsible for arginine uptake. 
A specific allele of ApoE4, which has been associated with an increased risk of late-onset Alzheimer’s disease, has been found to be protective against the cognitive deficits seen in children with heavy diarrhea burdens.77  
The potential link between ApoE4 and cognition has been extended to targeted transgenic mice expressing the human ApoE4 allele. Findings include: 
 protected intestinal villus morphometry, 
 improved growth trajectories, and 
 reduced shedding of Cryptosporidium parasites in experimental infections with malnutrition.78  
The bridge with basic studies may lie in Colton and Czapiga’s work79,80 showing that: 
 these mice exhibit increased expression of cationic amino acid transporter-1 that is responsible for arginine uptake. 

The long-term and even transgenerational effects of early childhood infectious, inflammatory, or nutritional challenges increase the human and health system costs. These costs may be compounded by potential epigenetic mechanisms that may be involved, leading to long-term intergenerational effects. Military recruits whose mothers were pregnant with them in the Dutch hunger winter of 1944 to 1945 were more likely to be obese and, in later life, had problems with certain cognitive functions.81,82 Potential mechanisms could involve leptin promoter methylation, which has been shown to occur during postzygotic development in mice and in humans.83 Indeed, leptin promoter methylation has been shown in recruits who were exposed periconceptionally to the Dutch hunger winter.83,84 

Thus, translating basic laboratory research and models into relevance to child nutrition, inflammation, and neurodevelopment holds promise for elucidating not only host and microbiome determinants of the metabolic pathways involved, but also potential practical biomarkers of risk. These biomarkers could be used to assess the effectiveness of innovative interventions to optimize these critical determinants in early childhood. The critical roles of the microbiota in influencing susceptibility to (and being influenced by) malnutrition and enteric and other infections are rapidly growing areas of research and are beyond the scope of this overview.85,86 Similarly, relevant metabolic and other biomarkers of intestinal barrier function, microbial translocation, inflammatory and immunologic signaling, and local and systemic inflammation are important areas of research and clinical application.87,88 

Based on what we know about the effects of early-life adversity and sensitive or critical periods in development, what should our research priorities be? First, we need to improve our understanding of the dose, timing, and duration of early adversity. For example, which forms of adversity, at which levels, and at which time periods exert the greatest impact on development? Why and how does susceptibility to stress vary with age, especially during sensitive periods of heightened or diminished sensitivity to environmental influences? Are these sensitive periods limited to early childhood or could there be windows of opportunity even later, especially in adolescence or adult life? If this can be established, this information will be critical for developing and targeting interventions. More recently, a systematic review of key interventions that can impact maternal, newborn, and child health and nutrition outcomes has shown the potential of integrating strategies for health, nutrition, and nurturing care across the life course89 with much potential for intergenerational benefits.56 

Second, much more needs to be known about how experience is biologically embedded. Acquiring this knowledge will require in-depth research into potential mechanisms that link various stress and protective pathways to tailor interventions to different neural and behavioral systems. To address the burden of impaired neurodevelopment and develop strategies that include an appreciation of individual biological differences, it is critically important to link basic molecular research with complementary translational and clinical research and evidence-based service delivery. Such efforts must include an appreciation of host genetic, microbiologic, metabolic, and environmental (including cultural, family, and community) factors. A systems biology approach and characterization of gene networks in the assessment of neurodevelopmental disorders is emerging as a potential future approach to assessing individual variations in neural network configuration and differential vulnerabilities to neurocognitive deficits.

Third, it is imperative that we improve our armamentarium of tools that can be used to assess the impact of early adversity. Currently, the most widely used tools are relatively coarse behavioral measures (eg, developmental exams) that lack sensitivity to underlying neural mechanisms, cannot be used early in life given the infant’s limited behavioral repertoire, and are largely developed in Western, high-resource countries. There are now many more promising models as well as genetic and metabolomic tools available to us that may help us understand mechanisms and develop biomarkers and interventions.

Finally, as mentioned previously, advances in the neurobiology of sensitive or critical periods will likely lead to new discoveries in ways to rescue or reopen these important time periods in brain development. If we were able to rescue a sensitive period later in life, without neural circuitry becoming unstable (ie, sensitive periods may exist in the first place because newly formed neural systems crave stability), then we may be able to develop targeted interventions much later in life that have comparable efficacy to those implemented early in life. Work on all these fronts should vastly improve our knowledge of how to intervene in the lives of children exposed to early-life adversity and must receive adequate support and funding for research. And while we wait for the science to improve the understanding and pathogenesis of neurodevelopmental risks and deficits, we know enough about evidence-based practices that can ameliorate the effect of such adversities during sensitive time periods to prioritize this for action. What is needed is an integrated and accelerated strategy for research in this field that prioritizes action across the discovery, development, and delivery pathways with concomitant investments in monitoring and evaluation.

     
  • ApoE4

    apolipoprotein E4

  •  
  • EE

    environmental enteropathy

  •  
  • LRS

    low-resource setting

  •  
  • SGA

    small for gestational age

Dr Bhutta was a presenter at the original Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) scientific meeting, served as the lead author for the paper, organized the writing team, drafted the initial manuscript, incorporated edits from the additional authors and editors, and finalized the manuscript; Dr Guerrant was a presenter at the original NICHD scientific meeting, contributed to the writing of the initial manuscript, and reviewed and revised subsequent versions of the manuscript; Dr Nelson was a panelist at the original NICHD scientific meeting, contributed to the writing of the initial manuscript, and reviewed and revised subsequent versions of the manuscript; and all authors approved the final manuscript as submitted and are accountable for all aspects of the work.

FUNDING: This supplement was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the United States National Institutes of Health (NIH).

1
Bhutta
ZA
,
Das
JK
,
Bahl
R
, et al;
Lancet Newborn Interventions Review Group
;
Lancet Every Newborn Study Group
.
Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost
[published correction appears in Lancet. 2014;384(9940):308]?
Lancet
.
2014
;
384
(
9940
):
347
370
[PubMed]
2
Requejo
JH
,
Bhutta
ZA
.
The post-2015 agenda: staying the course in maternal and child survival.
Arch Dis Child
.
2015
;
100
(
suppl 1
):
S76
S81
[PubMed]
3
Kyu
HH
,
Pinho
C
,
Wagner
JA
, et al;
Global Burden of Disease Pediatrics Collaboration
.
Global and national burden of diseases and injuries among children and adolescents between 1990 and 2013: Findings from the Global Burden of Disease 2013 Study.
JAMA Pediatr
.
2016
;
170
(
3
):
267
287
[PubMed]
4
The United Nations Inter-agency Group for Child Mortality Estimation
. Levels & trends in child mortality: report 2015. Available at: www.childmortality.org/files_v20/download/IGME%20report%202015%20child%20mortality%20final.pdf. Accessed June 1, 2016
5
Black
RE
,
Morris
SS
,
Bryce
J
.
Where and why are 10 million children dying every year?
Lancet
.
2003
;
361
(
9376
):
2226
2234
[PubMed]
6
You
D
,
Hug
L
,
Ejdemyr
S
, et al;
United Nations Inter-agency Group for Child Mortality Estimation (UN IGME)
.
Global, regional, and national levels and trends in under-5 mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Inter-agency Group for Child Mortality Estimation.
Lancet
.
2015
;
386
(
10010
):
2275
2286
[PubMed]
7
Lawn
JE
,
Blencowe
H
,
Oza
S
, et al;
Lancet Every Newborn Study Group
.
Every Newborn: progress, priorities, and potential beyond survival.
Lancet
.
2014
;
384
(
9938
):
189
205
[PubMed]
8
Liu
L
,
Oza
S
,
Hogan
D
, et al
.
Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis.
Lancet
.
2015
;
385
(
9966
):
430
440
[PubMed]
9
Were
WM
,
Daelmans
B
,
Bhutta
Z
, et al
.
Children’s health priorities and interventions.
BMJ
.
2015
;
351
:
h4300
[PubMed]
10
Wise
PH
,
Darmstadt
GL
.
The grand divergence in global child health: confronting data requirements in areas of conflict and chronic political instability.
JAMA Pediatr
.
2016
;
170
(
3
):
195
197
[PubMed]
11
International Food Policy Research Institute
. Global nutrition report 2016: from promise to impact: ending malnutrition by 2030. Available at: http://ebrary.ifpri.org/utils/getfile/collection/p15738coll2/id/130354/filename/130565.pdf. Accessed June 7, 2016
12
Mwaniki
MK
,
Atieno
M
,
Lawn
JE
,
Newton
CR
.
Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review.
Lancet
.
2012
;
379
(
9814
):
445
452
[PubMed]
13
Black
RE
,
Victora
CG
,
Walker
SP
, et al;
Maternal and Child Nutrition Study Group
.
Maternal and child undernutrition and overweight in low-income and middle-income countries.
Lancet
.
2013
;
382
(
9890
):
427
451
[PubMed]
14
Panchaud
A
,
Stojanov
M
,
Ammerdorffer
A
,
Vouga
M
,
Baud
D
.
Emerging role of Zika virus in adverse fetal and neonatal outcomes.
Clin Microbiol Rev
.
2016
;
29
(
3
):
659
694
[PubMed]
15
McCoy
DC
,
Peet
ED
,
Ezzati
M
, et al
.
Early childhood developmental status in low- and middle-income countries: National, regional, and global prevalence estimates using predictive modeling.
PLoS Med
.
2016
;
13
(
6
):
e1002034
[PubMed]
16
Boivin
MJ
,
Kakooza
AM
,
Warf
BC
,
Davidson
LL
,
Grigorenko
EL
.
Reducing neurodevelopmental disorders and disability through research and interventions.
Nature
.
2015
;
527
(
7578
):
S155
S160
[PubMed]
17
Bruer
JT
.
A critical and sensitive period primer
. In:
Bailey
DB
,
Bruer
JT
,
Symons
FJ
,
Lichtman
JW
, eds.
Critical Thinking about Critical Periods
.
Baltimore, MD
:
Paul H. Brookes Publishing
;
2001
:
3
26
18
Fox
SE
,
Levitt
P
,
Nelson
CA
 III
.
How the timing and quality of early experiences influence the development of brain architecture.
Child Dev
.
2010
;
81
(
1
):
28
40
[PubMed]
19
Hensch
TK
,
Billimoria
PM
.
Re-opening windows: Manipulating critical periods for brain development [published online ahead of print August 29, 2012].
Cerebrum
.
2012
:
11
20
Takesian
AE
,
Hensch
TK
.
Balancing plasticity/stability across brain development.
Prog Brain Res
.
2013
;
207
:
3
34
[PubMed]
21
Hensch
TK
.
The power of the infant brain.
Sci Am
.
2016
;
314
(
2
):
64
69
[PubMed]
22
Guerrant
RL
,
DeBoer
MD
,
Moore
SR
,
Scharf
RJ
,
Lima
AA
.
The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease.
Nat Rev Gastroenterol Hepatol
.
2013
;
10
(
4
):
220
229
[PubMed]
23
Kozuki
N
,
Katz
J
,
Lee
AC
, et al;
Child Health Epidemiology Reference Group Small-for-Gestational-Age/Preterm Birth Working Group
.
Short maternal stature increases risk of small-for-gestational-age and preterm births in low- and middle-income countries: Individual participant data meta-analysis and population attributable fraction.
J Nutr
.
2015
;
145
(
11
):
2542
2550
[PubMed]
24
Evans
GW
.
The environment of childhood poverty.
Am Psychol
.
2004
;
59
(
2
):
77
92
[PubMed]
25
Walker
SP
,
Wachs
TD
,
Grantham-McGregor
S
, et al
.
Inequality in early childhood: risk and protective factors for early child development.
Lancet
.
2011
;
378
(
9799
):
1325
1338
[PubMed]
26
Abbott
A
.
Neuroscience: The brain, interrupted.
Nature
.
2015
;
518
(
7537
):
24
26
[PubMed]
27
Eryigit-Madzwamuse
S
,
Wolke
D
.
Attention problems in relation to gestational age at birth and smallness for gestational age.
Early Hum Dev
.
2015
;
91
(
2
):
131
138
[PubMed]
28
Fischi-Gómez
E
,
Vasung
L
,
Meskaldji
DE
, et al
.
Structural brain connectivity in school-age preterm infants provides evidence for impaired networks relevant for higher order cognitive skills and social cognition.
Cereb Cortex
.
2015
;
25
(
9
):
2793
2805
[PubMed]
29
Lawn
JE
,
Davidge
R
,
Paul
VK
, et al
.
Born too soon: care for the preterm baby.
Reprod Health
.
2013
;
10
(
suppl 1
):
S5
[PubMed]
30
Raiten
DJ
,
Steiber
AL
,
Hand
RK
.
Executive summary: evaluation of the evidence to support practice guidelines for nutritional care of preterm infants-the Pre-B Project.
Am J Clin Nutr
.
2016
;
103
(
2
):
599S
605S
[PubMed]
31
Grantham-McGregor
SM
,
Fernald
LC
,
Kagawa
RM
,
Walker
S
.
Effects of integrated child development and nutrition interventions on child development and nutritional status.
Ann N Y Acad Sci
.
2014
;
1308
:
11
32
[PubMed]
32
Jiang
NM
,
Tofail
F
,
Moonah
SN
, et al
.
Febrile illness and pro-inflammatory cytokines are associated with lower neurodevelopmental scores in Bangladeshi infants living in poverty.
BMC Pediatr
.
2014
;
14
:
50
[PubMed]
33
Bayley
N
.
Bayley Manual for the Bayley Scales of Infant and Toddler Development
, 3rd ed.
San Antonio, TX
:
The Psychological Corporation
;
2006
34
Hanson
JL
,
Adluru
N
,
Chung
MK
,
Alexander
AL
,
Davidson
RJ
,
Pollak
SD
.
Early neglect is associated with alterations in white matter integrity and cognitive functioning.
Child Dev
.
2013
;
84
(
5
):
1566
1578
[PubMed]
35
McCrory
E
,
DeBrito
SA
,
Viding
E
.
Research Review: The neurobiology and genetics of maltreatment and adversity
.
J Child Psychol Psychiatry
.
2010
;
51
(
10
):
1079
1095
36
Carroll
JE
,
Gruenewald
TL
,
Taylor
SE
,
Janicki-Deverts
D
,
Matthews
KA
,
Seeman
TE
.
Childhood abuse, parental warmth, and adult multisystem biological risk in the Coronary Artery Risk Development in Young Adults study.
Proc Natl Acad Sci USA
.
2013
;
110
(
42
):
17149
17153
[PubMed]
37
Hillis
S
,
Mercy
J
,
Amobi
A
,
Kress
H.
Global prevalence of past-year violence against children: a systematic review and minimum estimates.
Pediatrics
.
2016
;
137
(
3
):
e20154079
38
Bhutta
ZA
.
Children of war: the real casualties of the Afghan conflict.
BMJ
.
2002
;
324
(
7333
):
349
352
[PubMed]
39
Shonkoff
JP
,
Garner
AS
;
Committee on Psychosocial Aspects of Child and Family Health
;
Committee on Early Childhood, Adoption, and Dependent Care
;
Section on Developmental and Behavioral Pediatrics
.
The lifelong effects of early childhood adversity and toxic stress.
Pediatrics
.
2012
;
129
(
1
). Available at: www.pediatrics.org/cgi/content/full/129/1/e232
[PubMed]
40
Shonkoff
JP
,
Boyce
WT
,
McEwen
BS
.
Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention.
JAMA
.
2009
;
301
(
21
):
2252
2259
[PubMed]
41
Center on the Developing Child at Harvard University
. From best practices to breakthrough impacts: a science-based approach to building a more promising future for young children and families. Available at: http://46y5eh11fhgw3ve3ytpwxt9r.wpengine.netdna-cdn.com/wp-content/uploads/2016/05/HCDC_From_Best_Practices_to_Breakthrough_Impacts.pdf. Accessed February 24, 2017
42
Cowan
CSM
,
Callaghan
BL
,
Kan
JM
,
Richardson
R
.
The lasting impact of early-life adversity on individuals and their descendants: potential mechanisms and hope for intervention.
Genes Brain Behav
.
2016
;
15
(
1
):
155
168
[PubMed]
43
Victora
CG
,
Horta
BL
,
Loret de Mola
C
, et al
.
Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil.
Lancet Glob Health
.
2015
;
3
(
4
):
e199
e205
[PubMed]
44
Bhutta
ZA
,
Das
JK
,
Rizvi
A
, et al;
Lancet Nutrition Interventions Review Group
;
Maternal and Child Nutrition Study Group
.
Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost?
Lancet
.
2013
;
382
(
9890
):
452
477
[PubMed]
45
Victora
CG
,
Bahl
R
,
Barros
AJ
, et al;
Lancet Breastfeeding Series Group
.
Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect.
Lancet
.
2016
;
387
(
10017
):
475
490
[PubMed]
46
United Nations Children’s Fund
;
World Health Organization
. A decade of tracking progress for maternal, newborn, and child survival: the 2015 report. Available at: www.countdown2015mnch.org/documents/2015Report/Countdown_to_2015_final_report.pdf. Accessed June 7, 2016
47
Katz
J
,
Lee
AC
,
Kozuki
N
, et al;
CHERG Small-for-Gestational-Age-Preterm Birth Working Group
.
Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis.
Lancet
.
2013
;
382
(
9890
):
417
425
[PubMed]
48
Di Cesare
M
,
Bhatti
Z
,
Soofi
SB
,
Fortunato
L
,
Ezzati
M
,
Bhutta
ZA
.
Geographical and socioeconomic inequalities in women and children’s nutritional status in Pakistan in 2011: an analysis of data from a nationally representative survey.
Lancet Glob Health
.
2015
;
3
(
4
):
e229
e239
[PubMed]
49
Corsi
DJ
,
Mejía-Guevara
I
,
Subramanian
SV
.
Risk factors for chronic undernutrition among children in India: Estimating relative importance, population attributable risk and fractions.
Soc Sci Med
.
2016
;
157
:
165
185
[PubMed]
50
Bhutta
ZA
.
What does India need to do to address childhood malnutrition at scale?
Soc Sci Med
.
2016
;
157
:
186
188
[PubMed]
51
Mendez
MA
,
Adair
LS
.
Severity and timing of stunting in the first two years of life affect performance on cognitive tests in late childhood.
J Nutr
.
1999
;
129
(
8
):
1555
1562
[PubMed]
52
Yousafzai
AK
,
Rasheed
MA
,
Rizvi
A
,
Armstrong
R
,
Bhutta
ZA
.
Effect of integrated responsive stimulation and nutrition interventions in the Lady Health Worker programme in Pakistan on child development, growth, and health outcomes: a cluster-randomised factorial effectiveness trial.
Lancet
.
2014
;
384
(
9950
):
1282
1293
[PubMed]
53
Stein
AD
,
Wang
M
,
DiGirolamo
A
, et al
.
Nutritional supplementation in early childhood, schooling, and intellectual functioning in adulthood: a prospective study in Guatemala.
Arch Pediatr Adolesc Med
.
2008
;
162
(
7
):
612
618
[PubMed]
54
Hair
NL
,
Hanson
JL
,
Wolfe
BL
,
Pollak
SD
.
Association of Child Poverty, Brain Development, and Academic Achievement.
JAMA Pediatr
.
2015
;
169
(
9
):
822
829
[PubMed]
55
Noble
KG
,
Houston
SM
,
Brito
NH
, et al
.
Family income, parental education and brain structure in children and adolescents.
Nat Neurosci
.
2015
;
18
(
5
):
773
778
[PubMed]
56
Richter
LM
,
Daelmans
B
,
Lombardi
J
;
Paper 3 Working Group
;
Early Child Development Series Steering Committee
, et al
.
Investing in the foundation of sustainable development: pathways to scale up for early childhood development.
Lancet
.
2017
;
389
(
10064
):
103
118
57
Bhutta
ZA
,
Black
RE
.
Global maternal, newborn, and child health--so near and yet so far.
N Engl J Med
.
2013
;
369
(
23
):
2226
2235
[PubMed]
58
Keusch
GT
,
Rosenberg
IH
,
Denno
DM
, et al
.
Implications of acquired environmental enteric dysfunction for growth and stunting in infants and children living in low- and middle-income countries.
Food Nutr Bull
.
2013
;
34
(
3
):
357
364
[PubMed]
59
Solomons
NW
,
Mazariegos
M
,
Brown
KH
,
Klasing
K
.
The underprivileged, developing country child: environmental contamination and growth failure revisited.
Nutr Rev
.
1993
;
51
(
11
):
327
332
[PubMed]
60
Gough
EK
,
Stephens
DA
,
Moodie
EE
, et al
.
Linear growth faltering in infants is associated with Acidaminococcus sp. and community-level changes in the gut microbiota.
Microbiome
.
2015
;
3
:
24
[PubMed]
61
Jones
AD
,
Rukobo
S
,
Chasekwa
B
, et al
.
Acute illness is associated with suppression of the growth hormone axis in Zimbabwean infants.
Am J Trop Med Hyg
.
2015
;
92
(
2
):
463
470
[PubMed]
62
Prendergast
AJ
,
Rukobo
S
,
Chasekwa
B
, et al
.
Stunting is characterized by chronic inflammation in Zimbabwean infants.
PLoS One
.
2014
;
9
(
2
):
e86928
[PubMed]
63
Stephenson
LS
,
Latham
MC
,
Kurz
KM
,
Kinoti
SN
,
Brigham
H
.
Treatment with a single dose of albendazole improves growth of Kenyan schoolchildren with hookworm, Trichuris trichiura, and Ascaris lumbricoides infections.
Am J Trop Med Hyg
.
1989
;
41
(
1
):
78
87
[PubMed]
64
Nokes
C
,
Grantham-McGregor
SM
,
Sawyer
AW
,
Cooper
ES
,
Bundy
DA
.
Parasitic helminth infection and cognitive function in school children.
Proc Biol Sci
.
1992
;
247
(
1319
):
77
81
[PubMed]
65
Shrimpton
R
,
Victora
CG
,
de Onis
M
,
Lima
RC
,
Blössner
M
,
Clugston
G
.
Worldwide timing of growth faltering: implications for nutritional interventions.
Pediatrics
.
2001
;
107
(
5
). Available at: www.pediatrics.org/cgi/content/full/107/5/e75
[PubMed]
66
Victora
CG
,
de Onis
M
,
Hallal
PC
,
Blössner
M
,
Shrimpton
R
.
Worldwide timing of growth faltering: revisiting implications for interventions.
Pediatrics
.
2010
;
125
(
3
). Available at: www.pediatrics.org/cgi/content/full/125/3/e473
[PubMed]
67
Chang
SM
,
Walker
SP
,
Grantham-McGregor
S
,
Powell
CA
.
Early childhood stunting and later behaviour and school achievement.
J Child Psychol Psychiatry
.
2002
;
43
(
6
):
775
783
[PubMed]
68
Checkley
W
,
Buckley
G
,
Gilman
RH
, et al;
Childhood Malnutrition and Infection Network
.
Multi-country analysis of the effects of diarrhoea on childhood stunting.
Int J Epidemiol
.
2008
;
37
(
4
):
816
830
[PubMed]
69
Berkman
DS
,
Lescano
AG
,
Gilman
RH
,
Lopez
SL
,
Black
MM
.
Effects of stunting, diarrhoeal disease, and parasitic infection during infancy on cognition in late childhood: a follow-up study.
Lancet
.
2002
;
359
(
9306
):
564
571
[PubMed]
70
Guerrant
DI
,
Moore
SR
,
Lima
AA
,
Patrick
PD
,
Schorling
JB
,
Guerrant
RL
.
Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four-seven years later in a poor urban community in northeast Brazil.
Am J Trop Med Hyg
.
1999
;
61
(
5
):
707
713
[PubMed]
71
Niehaus
MD
,
Moore
SR
,
Patrick
PD
, et al
.
Early childhood diarrhea is associated with diminished cognitive function 4 to 7 years later in children in a northeast Brazilian shantytown.
Am J Trop Med Hyg
.
2002
;
66
(
5
):
590
593
[PubMed]
72
Mbuya
MN
,
Humphrey
JH
.
Preventing environmental enteric dysfunction through improved water, sanitation and hygiene: an opportunity for stunting reduction in developing countries.
Matern Child Nutr
.
2016
;
12
(
suppl 1
):
106
120
[PubMed]
73
DeBoer
MD
,
Chen
D
,
Burt
DR
, et al
.
Early childhood diarrhea and cardiometabolic risk factors in adulthood: the Institute of Nutrition of Central America and Panama Nutritional Supplementation Longitudinal Study.
Ann Epidemiol
.
2013
;
23
(
6
):
314
320
[PubMed]
74
Costa
LB
,
Noronha
FJ
,
Roche
JK
, et al
.
Novel in vitro and in vivo models and potential new therapeutics to break the vicious cycle of Cryptosporidium infection and malnutrition.
J Infect Dis
.
2012
;
205
(
9
):
1464
1471
[PubMed]
75
Roche
JK
,
Cabel
A
,
Sevilleja
J
,
Nataro
J
,
Guerrant
RL
.
Enteroaggregative Escherichia coli (EAEC) impairs growth while malnutrition worsens EAEC infection: a novel murine model of the infection malnutrition cycle.
J Infect Dis
.
2010
;
202
(
4
):
506
514
[PubMed]
76
Patrick
PD
,
Oriá
RB
,
Madhavan
V
, et al
.
Limitations in verbal fluency following heavy burdens of early childhood diarrhea in Brazilian shantytown children.
Child Neuropsychol
.
2005
;
11
(
3
):
233
244
[PubMed]
77
Oriá
RB
,
Patrick
PD
,
Zhang
H
, et al
.
APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil.
Pediatr Res
.
2005
;
57
(
2
):
310
316
[PubMed]
78
Azevedo
OG
,
Bolick
DT
,
Roche
JK
, et al
.
Apolipoprotein E plays a key role against cryptosporidial infection in transgenic undernourished mice.
PLoS One
.
2014
;
9
(
2
):
e89562
[PubMed]
79
Colton
CA
,
Brown
CM
,
Cook
D
, et al
.
APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress.
Neurobiol Aging
.
2002
;
23
(
5
):
777
785
[PubMed]
80
Czapiga
M
,
Colton
CA
.
Microglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport.
J Neuroimmunol
.
2003
;
134
(
1-2
):
44
51
[PubMed]
81
Ravelli
GP
,
Stein
ZA
,
Susser
MW
.
Obesity in young men after famine exposure in utero and early infancy.
N Engl J Med
.
1976
;
295
(
7
):
349
353
82
de Rooij
SR
,
Wouters
H
,
Yonker
JE
,
Painter
RC
,
Roseboom
TJ
.
Prenatal undernutrition and cognitive function in late adulthood.
Proc Natl Acad Sci USA
.
2010
;
107
(
39
):
16881
16886
[PubMed]
83
Stöger
R
.
In vivo methylation patterns of the leptin promoter in human and mouse.
Epigenetics
.
2006
;
1
(
4
):
155
162
[PubMed]
84
Tobi
EW
,
Lumey
LH
,
Talens
RP
, et al
.
DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific.
Hum Mol Genet
.
2009
;
18
(
21
):
4046
4053
[PubMed]
85
Smith
MI
,
Yatsunenko
T
,
Manary
MJ
, et al
.
Gut microbiomes of Malawian twin pairs discordant for kwashiorkor.
Science
.
2013
;
339
(
6119
):
548
554
[PubMed]
86
Blanton
LV
,
Charbonneau
MR
,
Salih
T
, et al
.
Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children.
Science
.
2016
;
351
(
6275
):
aad3311
[PubMed]
87
Mayneris-Perxachs
J
,
Lima
AA
,
Guerrant
RL
, et al
.
Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children.
Sci Rep
.
2016
;
6
:
19780
[PubMed]
88
Kosek
M
,
Haque
R
,
Lima
A
, et al;
MAL-ED network
.
Fecal markers of intestinal inflammation and permeability associated with the subsequent acquisition of linear growth deficits in infants.
Am J Trop Med Hyg
.
2013
;
88
(
2
):
390
396
[PubMed]
89
Britto
PR
,
Lye
SJ
,
Proulx
K
;
Early Childhood Development Interventions Review Group, for the Lancet Early Childhood Development Series Steering Committee
, et al
.
Nurturing care: promoting early childhood development.
Lancet
.
2017
;
389
(
10064
):
91
102

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.