News - MAPS

Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.

Exploring the Intersection of Gaming Addiction and Autism Spectrum Disorder: “Virtual Autism”

Greetings, MAPS Community,

During the recent Medical Academy of Pediatric Special Needs (MAPS) conference in the
Spring of 2024, I had the privilege of presenting on Screen Addiction and
Neurodevelopmental Disorders, which has been the focus of my research and clinical
practice. Specifically, I discussed how excessive screen use can exacerbate symptoms
across various neuropsychiatric disorders and even mimic diagnoses.

Drawing from my experience in treating patients with gaming addiction and
neurodevelopmental disorders, one question has persistently been on my mind: Could
individuals diagnosed with Autism Spectrum Disorder (ASD) who also meet the criteria
for gaming addiction inadvertently influence the outcomes of ASD treatment studies?

My hypothesis posits that some cases of gaming addiction might present symptoms
that closely mimic those of ASD, leading to the term “Virtual ASD.” In these cases,
individuals may receive an ASD diagnosis despite having fewer physiological
abnormalities typically associated with the condition. This overlap between gaming
addiction and ASD has the potential to impact the effectiveness of ASD treatments in
research settings significantly.

Simply stated, patients with gaming addiction (mimicking ASD) respond better to
addiction treatment. It doesn’t respond well to the biomedical treatments for ASD, such
as Folate, B12, Sulforaphane, Detox, etc., that we have learned from MAPS and other
brilliant providers. Yet, they were included in Autism research for those biomedical
treatments, potentially reducing the effectiveness of those treatments in research.

Gaming Addiction not Autism? Is this misdiagnosis.

This is not a misdiagnosis. ASD is diagnosed clinically, meaning diagnoses are based on
clinical observation. Whoever presents with the signs and symptoms of Autism and
meets the criteria will be diagnosed as Autism, including those with “Virtual Autism.”
However, the prognosis can be different among those with “Virtual Autism.” Successfully
treating the dependency on screens can drastically improve their Autism symptoms to
the point where some individuals no longer meet the criteria for diagnosis. A lack of
awareness of Gaming disorder also contributes to this, which is newly added to
diagnosable conditions in ICD-11. Autism individuals who have diagnosable conditions
as the underlying cause are not new to this field; approximately 20% of children with
ASD have a diagnosable genetic syndrome. These syndromes can be due to missing or
extra stretches of DNA, misspellings in genes, or biochemical abnormalities. (ASD and
Associated Genetic Conditions | CHOP Research Institute)

My child has a Gaming addiction. Does that mean my child has “Virtual Autism” and not
Autism?

Some people have “Virtual Autism,” and we don’t know the accurate prevalence, which
I’m planning to conduct research. Some are Classical Autism individuals who are also
addicted to Gaming. Nonetheless, both populations benefit from the treatment of
Gaming Addiction. “Virtual Autism” patients will likely improve more than classical
Autism individuals with gaming disorder, but treating gaming addiction improves
Autism symptoms for classical autism cases, too.

Step back, please; what is gaming disorder?

Gaming disorder is defined in the 11th Revision of the International Classification of
Diseases (ICD-11) as a pattern of gaming behavior (“digital-gaming” or “video-gaming”)
characterized by impaired control over gaming, increasing priority given to gaming over
other activities to the extent that gaming takes precedence over other interests and
daily activities, and continuation or escalation of gaming despite the occurrence of
negative consequences.

How is gaming disorder identified?

For gaming disorder to be diagnosed, the behavior pattern must be severe enough that
it results in significant impairment to a person’s functioning in personal, family, social,
educational, occupational, or other important areas and would normally have been
evident for at least 12 months.

What is “Virtual Autism”?

For those unfamiliar with the concept, “Virtual Autism” refers to a scenario where
individuals exhibit symptoms or behaviors resembling those of ASD, such as social
difficulties, repetitive behaviors, and communication challenges, without the typical
underlying physiological abnormalities observed in individuals with ASD. Interestingly,
treating screen dependency in these cases can drastically improve ASD-like symptoms.
The term “virtual” implies that the presentation of autism-like symptoms is not primarily
due to inherent neurological differences associated with ASD but may be influenced by
excessive screen use. It’s crucial to note that virtual autism is not recognized and
diagnosed as ASD. My concern lies in the potential misattribution of gaming addiction
symptoms to ASD, which could inadvertently include individuals in studies whose
physiological conditions differ significantly from traditional ASD cases. This could lead to
misleading conclusions in research findings or diminish the significance of biomedical
research outcomes.

To address this gap in understanding, I proposed three key research topics and am in
the process of conducting studies.

  • Prevalence of Gaming Disorder in ASD: Quantifying the number of ASD patients
    who also meet the diagnostic criteria for gaming disorder based on the ICD-11.
  • Comparison of Treatment Responses: Investigating whether gaming disorder
    comorbidity influences treatment response in individuals with ASD by replicating
    established biomedical treatment studies across ASD, ASD/Gaming Disorder, and
    typically developing control groups.
  • Effects of Screen Fasting: Assessing the impact of screen fasting on ASD symptom
    severity in ASD-only and ASD/Gaming Disorder populations to explore potential
    associations between gaming behavior and symptom improvement.

Our hypothesis suggests that the recent surge in ASD diagnoses may, in part, be
attributed to the inclusion of individuals with gaming disorders. We believe that these
researches have the potential to inform diagnostic practices, treatment approaches, and
future research directions in the field of neurodevelopmental disorders. I’m excited
about the potential implications of this work and look forward to updating you on our
progress at the next MAPS conference.

If you may also wonder,

  • How much is too much video game/Screen time?
  • Kids can’t make friends without video games or screen
  • School and work require computers, so it’s impossible to stay away from
  • What’s safer content? Is TV ok?
  • My kid is clearly addicted; how to treat it?

I will be presenting again about Screen Addiction at the Fall 2024 MAPS Conference. If
you want to learn more about it, please join us in the Fall!

Citations:

World Health Organization (WHO)

– Kushima M, Kojima R, Shinohara R, et al. Association Between Screen Time
Exposure in Children at 1 Year of Age and Autism Spectrum Disorder at 3 Years of
Age: The Japan Environment and Children’s Study. JAMA Pediatr. 2022;176(4):384-
391. doi:10.1001/jamapediatrics.2021.5778

– Harlé B. Intensive early screen exposure as a causal factor for symptoms of
autistic spectrum disorder: The case for «Virtual autism». Trends Neurosci Educ.
2019;17:100119. doi:10.1016/j.tine.2019.100119

– Christakis DA. Early Media Exposure and Autism Spectrum Disorder: Heat and
Light. JAMA Pediatr. 2020;174(7):640-641. doi:10.1001/jamapediatrics.2020.0659

A Comprehensive Approach to Managing Seasonal Allergies and Mast Cell Activation in Pediatric Patients

Seasonal allergies and mast cell activation represent significant challenges for pediatric patients, impacting their daily lives and necessitating effective management strategies. Patients with Asthma, Autism, PANS/PANDAS, and other autoimmune conditions are especially vulnerable to having “flares” this time of year. Incorporating a holistic approach that encompasses environmental controls, targeted supplements, and appropriate medications is imperative for optimizing therapeutic outcomes and improving the quality of life for affected children.

Understanding Seasonal Allergies and Mast Cell Activation

Seasonal allergies, clinically referred to as allergic rhinitis, arise from hypersensitivity reactions to environmental allergens such as pollen, mold spores, and animal dander. Mast cell activation syndrome (MCAS) is characterized by dysregulated mast cell activity, leading to the release of excessive inflammatory mediators and subsequent allergic symptoms.

Distinguishing between mast cell activation and IgE-mediated allergies is crucial in the management of allergic conditions in pediatric patients. IgE-mediated allergies involve the immune system’s production of immunoglobulin E (IgE) antibodies in response to specific allergens, leading to the activation of mast cells and basophils upon subsequent exposure. This cascade triggers the release of histamine and other inflammatory mediators, precipitating allergic symptoms. In contrast, mast cell activation syndrome (MCAS) encompasses a broader spectrum of symptoms arising from dysregulated mast cell activity, independent of IgE-mediated mechanisms. While both conditions can manifest with allergic symptoms, MCAS may involve a wider array of triggers and can present with more variable and systemic manifestations beyond typical allergic reactions like gastrointestinal, behavioral, and neurologic symptoms. Consequently, the distinction between these entities informs diagnostic and therapeutic approaches, guiding clinicians in tailoring interventions to address the underlying pathophysiology and optimize outcomes for pediatric patients.

Testing

Accurate diagnosis of allergic conditions, including IgE-mediated allergies and mast cell activation syndrome (MCAS), is pivotal for effective management in pediatric patients. Testing for IgE-mediated allergies often involves skin prick tests or blood tests to detect allergen-specific IgE antibodies. These tests help identify specific allergens triggering allergic responses, guiding allergen avoidance strategies and treatment decisions. In contrast, diagnosing MCAS can be more challenging due to its heterogeneous presentation and lack of standardized diagnostic criteria. Laboratory assessments, including serum tryptase levels, chromogranin A and urinary histamine, leukotriene, and prostaglandin metabolites, may aid in corroborating the diagnosis, although results may vary. Clinical evaluation, including a thorough history and physical examination, remains paramount in identifying potential triggers and distinguishing MCAS from other allergic conditions. Integration of laboratory findings with clinical assessment enables clinicians to formulate tailored management plans, incorporating environmental controls, targeted therapies, and pharmacological interventions to alleviate symptoms and improve the quality of life for pediatric patients affected by allergic conditions.

Allergies and the Gut Microbiome

The gut microbiome also plays a crucial role in shaping immune development and regulation, with alterations in its composition implicated in the pathogenesis of allergic diseases in children. Research suggests that a diverse and balanced gut microbiota promotes immune tolerance and helps mitigate allergic sensitization. Therefore, interventions aimed at modulating the gut microbiome hold promise as holistic approaches to managing allergic diseases in pediatric patients. Probiotic supplementation, prebiotic fibers, and a diet rich in fruits, vegetables, and fiber can foster a favorable gut microbiota profile, enhancing immune homeostasis and reducing the risk of allergic conditions. Additionally, promoting breastfeeding in infancy, minimizing antibiotic use when possible, and encouraging outdoor play and exposure to diverse environmental microbes may further support healthy immune development and reduce the incidence of allergic diseases in children. By addressing the gut microbiome as part of a holistic treatment approach, healthcare providers can optimize therapeutic outcomes and improve the overall well-being of pediatric patients with allergic diseases.

Environmental Controls

  1. Allergen Avoidance: Implementing measures to reduce exposure to allergens is paramount. This includes maintaining indoor air quality through the use of high-efficiency particulate air (HEPA) filters in ventilation systems and minimizing outdoor activities during peak pollen seasons. Taking a shower before bedtime can also be helpful.
  2. Environmental Hygiene: Regular cleaning practices, such as dusting surfaces and laundering bedding in hot water, aid in mitigating indoor allergen accumulation. Employing allergen-proof covers for bedding and pillows further minimizes exposure, and taking shoes off at the door can lower the accumulation of indoor pollution.
  3. Humidity Regulation: Maintaining indoor humidity levels within the optimal range of 30-50% impedes mold proliferation and dampens allergic reactions. Utilization of dehumidifiers and proper ventilation systems facilitates humidity control.

Supplemental Support

  • Diet: A low amine/histamine diet called a “FAILSAFE DIET” can be helpful for many allergy sufferers.
  1. Quercetin: As a natural flavonoid with potent antioxidant and anti-inflammatory properties, quercetin stabilizes mast cells and modulates histamine release. Dietary sources include onions, apples, and berries, while supplementation may offer additional benefits.
  2. Other Natural Mast Cell Stabilizers: Luteolin, Stinging Nettles, Milk Thistle, Chinese Skullcap, Moringa, Fisetin, and Black Cumin Seed Oil have been shown to stabilize mast cell degranulation.
  3. Probiotics: Augmenting gut microbiota with probiotic strains like Lactobacillus rhamnosus GG and Bifidobacterium longum confer immunomodulatory effects, attenuating allergic responses and enhancing mucosal immunity.

Pharmacological Interventions

  1. Antihistamines: H1 receptor antagonists, available over-the-counter or via prescription, serve as a cornerstone therapy for alleviating allergic rhinitis symptoms by blocking histamine-mediated responses. H2 blockers can also be helpful if GI symptoms are involved.
  2. Nasal Corticosteroids: Intranasal corticosteroid sprays exert potent anti-inflammatory effects, ameliorating nasal congestion, sneezing, and rhinorrhea in pediatric patients with allergic rhinitis. 
  3. Mast Cell Stabilizers: Cromolyn sodium nasal spray or ocular formulations mitigate mast cell degranulation, thereby curtailing the release of inflammatory mediators and ameliorating allergic symptoms in the nose and eyes.

Conclusion

Incorporating a comprehensive approach to managing seasonal allergies and mast cell activation in pediatric patients is essential for achieving optimal therapeutic outcomes and enhancing their quality of life. By combining environmental controls, dietary choices, targeted supplements, and judicious employment of pharmacological agents, healthcare practitioners can effectively mitigate allergic symptoms and minimize disease burden in this vulnerable population. 

Citations:

  • Greiwe JC, Bernstein JA. Probiotics and allergy. In: Calder PC, Yaqoob P, eds. Diet, Immunity and Inflammation. Woodhead Publishing; 2013: 333–354.
  • Thangam EB, Jemima EA, Singh H, Baig MS, Khan M. Flavonoids exert diverse inhibitory effects on the activation of mast cells. J Biochem Mol Toxicol. 2019;33(7):e22343. doi:10.1002/jbt.22343.
  • Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 2008;122(2 Suppl):S1-84. doi:10.1016/j.jaci.2008.06.003.
  • Bisgaard, H., et al. “The Gut Microbiome in Allergic Disease: Current Understanding and Future Opportunities—2017 PRACTALL Document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology.” Journal of Allergy and Clinical Immunology, vol. 139, no. 4, 2018, pp. 1099-1110.
  • Theoharides, T. C. “Mast Cells and Mast Cell Activation Syndrome.” Journal of Investigative Medicine, vol. 64, no. 4, 2016, pp. 788-791.

Understanding PANDAS in Pediatric Health

What if your child or patient suddenly developed strange symptoms of OCD (Obsessive-compulsive disorder), severe anxiety, tics, or hyperactivity out of the blue? These symptoms can be associated with an autoimmune disorder called PANDAS.

These symptoms can appear seemingly overnight with a dramatic onset. Symptoms may include anxiety, motor and vocal tics, obsessions, compulsions, and a variety of other issues including somatic symptoms like abrupt onset of bedwetting or severe and disruptive restless sleep.

When something like this happens to a child, it’s frightening. It’s normal to have many questions as a concerned parent or practitioner, which is why I wrote my book to help guide you through everything you need to know, and why I also mentor Physicians about PANDAS syndrome.

What Causes PANDAS?

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection or PANDAS is an abnormal immune response associated with strep infections. A child with a strep infection in their throat, sinuses, or elsewhere produces antibodies that should fight the invading bacteria.

In children who develop PANDAS, the immune system goes awry, and the antibodies instead attack and inflame an area of the brain called the Basal Ganglia. This attack on a different area of the body, here a part of the brain responsible for mood, movement, and behavior, is called molecular mimicry. This immune system attack is also facilitated by the breakdown of the blood-brain barrier (BBB) by toxic mediators, immune cells, and more.

When this autoimmune attack on the brain occurs in susceptible children, the result is an abrupt onset of neuropsychiatric symptoms like anxiety, OCD, tics, and more.

How Do I Know If My Child/Patient Has PANDAS?

Some diagnostic criteria include:

  • Abrupt onset of OCD or a restrictive eating disorder
  • The OCD symptoms can include intrusive thoughts
  • The restrictive eating disorder can be linked to a fear of choking or contamination
  • In some children who have had a previous abrupt onset of symptoms, the onset may appear more subacute
  • And though the typical age group is 3-13 years, young adults, who have been undiagnosed or missed in earlier years, can present with OCD or other symptoms

Other PANDAS symptoms may include:

  • Anxiety, Separation Anxiety
  • Emotional Lability and/or Depression
  • Irritability, Aggression, Rage, and/or Severe Oppositional Behaviors
  • Behavioral (Developmental) Regression like baby talk
  • Sudden Deterioration in School Performance including ADD & ADHD of abrupt onset
  • Motor or Sensory Abnormalities including tics and handwriting deterioration
  • Somatic Signs and Symptoms, including Sleep Disturbances, Enuresis, or Urinary Frequency

How Is PANDAS Treated?

PANDAS can be a devastating diagnosis for both the parents and the child. Parents need guidance and support to manage their child’s symptoms and find the proper treatment.

Treatment of PANDAS should be individualized to the child’s behavioral and medical needs. Medications should include antibiotics and/or antimicrobials for an underlying strep infection, anti-inflammatories to calm the inflamed nervous system and nutraceuticals, botanicals, cognitive behavioral therapy and perhaps low doses of psychoactive medications for OCD and other symptoms.

Behavioral therapy is helpful in managing anxiety, depression, OCD fears, and other behavioral issues. Therapy for parents and the entire family can be beneficial for dealing with the stress of the diagnosis and managing disturbing symptoms.

Though some children may need more invasive interventions such as IVIG or plasmapheresis, the majority of children can recover with an appropriate 3-pronged approach of antimicrobials, anti-inflammatories and therapeutic and nutraceutical approaches to their care.

Find a Doctor Who Specializes in PANDAS Syndrome

It’s important for parents to know where to turn to make sure your child receives the proper diagnosis and treatment for this autoimmune disorder.

I have devoted my career to focusing on treating PANDAS and other neuropsychiatric disorders. I train and mentor clinicians in the U.S. and abroad on how to recognize, diagnose, and treat PANDAS.

If you think your child or patient is showing symptoms of PANDAS, prompt diagnosis and treatment is critical.

Pandemic Health In United States

We have a health crisis of pandemic proportions in the United States, and it has nothing to do with a virus. The crisis I am referring to is the catastrophic decline in pediatric health that we have witnessed in the last fifty years. In the 1960’s the rate of pediatric chronic disease in the U.S. was a bit over 10%. By 2007 (the last time these numbers were published), the rate was over 50%.[1, 2] The most serious illness rate in pediatrics (that which interferes with daily living) went from a rate of less than 2% in 1960 to over 8% in 2010.[3] According to the National Institute for Health Care Management (NIHCM), our current numbers include a 20% rate of obesity, 10% rate of asthma (16.8% for black children), over 20% of high school children with suicidal ideation, 9.2% rate of anxiety, and a 8.1% rate of depression.[4] If you compare pediatric health in the United States to the rest of world, you will find our outcomes behind Canada, all of western Europe, Japan, Australia, South Korea, and even countries like Croatia, Estonia, and Belarus. When you look at our place in international rankings, we typically are in the mid-30’s (there are 29 industrialized, rich nations).

We have made huge gains in the treatment of acute medical issues—particularly with infections and acute leukemias. The rise in chronic pediatric illness has been in four fundamental areas: asthma, neurodevelopmental issues (including autism, learning disabilities, and ADHD), mental health issues, autoimmune disorders, and obesity. What ties all these conditions together? The concepts of immune dysfunction and environmental toxicity. The immune dysfunction connection is obvious with conditions like autoimmunity and asthma. We now know that chronic (neuro) inflammation is involved with many mental health and neurodevelopmental issues including autism, ADHD, major depressive disorders, bipolar disorder, and schizophrenia. Environmental toxicity has also been linked with these disorders (including obesity) by directly impacting immune function, altering the endocrine response, and disrupting the gut microbiome.

What do we do about this problem? Based on the infographics from the NIHCM, our situation is not for the lack of doctor visits or vaccines: about 90% of children had seen their doctor in the past year and over 93% were up to date on all required vaccines. Clearly the answers to these problems lie outside of the traditional medical system that we currently have. I have always said that you don’t find health at the bottom of pill bottle or at the end of a needle—these are crisis interventions. Health is found through the basics of good nutrition, exercise, engagement with peers, and maintaining a clean environment for the child. All these things need to start with mom before she ever gets pregnant and continue through the process of breast feeding. Food should be organic, when possible, with minimal processing. Any animals or animal products should be from free range, organically raised animals. For children that have already developed conditions, I would recommend seeking out a MAPS trained practitioner. At MAPS, we delve into the true causes of illness and treat our patients at that level. By understanding the biochemistry and physiology of health, our practitioners can choose the best path forward for the patient in front of them and use all the tools that are available.

We do have a crisis of pediatric health here in the United States. Fortunately, we also have a solution called MAPS.

  • Van Cleave, J.G., SL; Perrin, JM, Dynamics of obesity and chronic helath conditions among children and youth. JAMA, 2011. 303(7): p. 623-30.
  • Bethell, C.D., et al., A national and state profile of leading health problems and health care quality for US children: key insurance disparities and across-state variations. Acad Pediatr, 2011. 11(3 Suppl): p. S22-33.
  • Perrin, J.M., L.E. Anderson, and J. Van Cleave, The rise in chronic conditions among infants, children, and youth can be met with continued health system innovations. Health Aff (Millwood), 2014. 33(12): p. 2099-105.
  • Management, N.I.f.H.C. The State of Children’s Health in the United States. Mini Infographics 2023 04/17/2023 [cited 2023 12/05/2023]; Available from: https://nihcm.org/publications/the-state-of-childrens-health-in-the-united-states.



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