Application of Telemedicine Technology to Facilitate Diagnosis of Pediatric Postintensive Care Syndrome.

Background: Postintensive care syndrome (PICS) is well-defined in the adult literature but has not received much attention in pediatrics. Introduction: We sought to use a telemedicine platform for the characterization of PICS by creating a convenient and effective virtual follow-up clinic. Materials and Methods: Prospective single-center study in a pediatric intensive care unit (ICU) of patients aged 4-17 years who underwent any invasive procedures while admitted to the ICU. Parents completed the Weiss Functional Impairment Rating Scale (WFIRS) based on baseline behaviors before ICU admission, with the scale readministered at 1 week, 1 month, and 3 months postdischarge via secure telehealth platform. Patients with a WFIRS baseline raw score of 10 or an interval increase of 2 were referred to psychiatry for evaluation and treatment. Results: Fifty patients were enrolled. Risk factors for PICS included number of procedural interventions, length of pediatric ICU stay, number of specialty consults, sex, race, and duration of sedation/airway instrumentation. In univariate analysis, age appeared to be the only statistically significant factor associated with the development of PICS. Variables associated with a higher change in WFIRS score showed a statistically significant correlation with the number of procedures completed, the number of specialists involved, and the need for a psychiatric referral. Only 34% of total telemedicine follow-ups were completed. Discussion: There is an association between age and the development of PICS and between change in WFIRS score and number of procedures, specialist involved, and psychiatric referral. Conclusions: The use of telemedicine did not result in an improved follow-up rate when compared to outpatient clinic studies.

A link between perianal strep and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).

Perianal streptococcal dermatitis is an infection caused by group A streptococcus (GAS). Children with a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) phenotype may have tics or obsessive compulsive symptoms secondary to a systemic immune activation by GAS infecting perianal areas. In this retrospective case series, the authors describe three children with symptoms consistent with PANDAS and a confirmed perianal streptococcal dermatitis as the likely infectious trigger. Concomitant perianal dermatitis and new-onset obsessive-compulsive symptoms and/or tics are strong indications for perianal culture and rapid antigen detection test in young children.

Electronic health records identify timely trends in childhood mental health conditions.

BACKGROUND: Electronic health records (EHRs) data provide an opportunity to collect patient information rapidly, efficiently and at scale. National collaborative research networks, such as PEDSnet, aggregate EHRs data across institutions, enabling rapid identification of pediatric disease cohorts and generating new knowledge for medical conditions. To date, aggregation of EHR data has had limited applications in advancing our understanding of mental health (MH) conditions, in part due to the limited research in clinical informatics, necessary for the translation of EHR data to child mental health research. METHODS: In this cohort study, a comprehensive EHR-based typology was developed by an interdisciplinary team, with expertise in informatics and child and adolescent psychiatry, to query aggregated, standardized EHR data for the full spectrum of MH conditions (disorders/symptoms and exposure to adverse childhood experiences (ACEs), across 13 years (2010-2023), from 9 PEDSnet centers. Patients with and without MH disorders/symptoms (without ACEs), were compared by age, gender, race/ethnicity, insurance, and chronic physical conditions. Patients with ACEs alone were compared with those that also had MH disorders/symptoms. Prevalence estimates for patients with 1+ disorder/symptoms and for specific disorders/symptoms and exposure to ACEs were calculated, as well as risk for developing MH disorder/symptoms. RESULTS: The EHR study data set included 7,852,081 patients < 21 years of age, of which 52.1% were male. Of this group, 1,552,726 (19.8%), without exposure to ACEs, had a lifetime MH disorders/symptoms, 56.5% being male. Annual prevalence estimates of MH disorders/symptoms (without exposure to ACEs) rose from 10.6% to 2010 to 15.1% in 2023, a 44% relative increase, peaking to 15.4% in 2019, prior to the Covid-19 pandemic. MH categories with the largest increases between 2010 and 2023 were exposure to ACEs (1.7, 95% CI 1.6-1.8), anxiety disorders (2.8, 95% CI 2.8-2.9), eating/feeding disorders (2.1, 95% CI 2.1-2.2), gender dysphoria/sexual dysfunction (43.6, 95% CI 35.8-53.0), and intentional self-harm/suicidality (3.3, 95% CI 3.2-3.5). White youths had the highest rates in most categories, except for disruptive behavior disorders, elimination disorders, psychotic disorders, and standalone symptoms which Black youths had higher rates. Median age of detection was 8.1 years (IQR 3.5-13.5) with all standalone symptoms recorded earlier than the corresponding MH disorder categories. CONCLUSIONS: These results support EHRs' capability in capturing the full spectrum of MH disorders/symptoms and exposure to ACEs, identifying the proportion of patients and groups at risk, and detecting trends throughout a 13-year period that included the Covid-19 pandemic. Standardized EHR data, which capture MH conditions is critical for health systems to examine past and current trends for future surveillance. Our publicly available EHR-mental health typology codes can be used in other studies to further advance research in this area.

High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications.

We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and African-Americans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.

Attention-deficit/hyperactivity disorder genomics: update for clinicians.

Attention deficit, hyperactivity disorder (ADHD) is familial and highly heritable. Several candidate genes involved in neurotransmission have been identified, however these confer minimal risk, suggesting that for the most part, ADHD is not caused by single common genetic variants. Advances in genotyping enabling investigation at the level of the genome have led to the discovery of rare structural variants suggesting that ADHD is a genomic disorder, with potentially thousands of variants, and common neuronal pathways disrupted by numerous rare variants resulting in similar ADHD phenotypes. Heritability studies in humans also indicate the importance of epigenetic factors, and animal studies are deciphering some of the processes that confer risk during gestation and throughout the post-natal period. These and future discoveries will lead to improved diagnosis, individualized treatment, cures, and prevention. These advances also highlight ethical and legal issues requiring management and interpretation of genetic data and ensuring privacy and protection from misuse.

Parental ADHD status and its association with proband ADHD subtype and severity.

OBJECTIVE: To better understand the familial transmission of attention deficit hyperactivity disorder (ADHD), a highly heritable disorder, the effects of paternal and maternal ADHD status on probands' ADHD symptoms and subtypes were investigated. STUDY DESIGN: In 323 trios with ADHD, data from a structured interview and a self-report scale (score of >21) were used to determine ADHD probands' diagnostic status and parental ADHD status, respectively. Parental ADHD status on proband ADHD severity and subtypes was investigated. RESULTS: ADHD criteria were endorsed by 23% of fathers and 27% of mothers, and by at least one parent in 41% of the cases. ADHD severity was higher for children whose parents had ADHD versus those whose parents were without it. Paternal ADHD was associated with an increased likelihood of ADHD combined subtype (odds ratio = 3.56) and a decreased likelihood of the inattentive subtype (odds ratio = 0.34) in male children. CONCLUSIONS: Parental ADHD status appears to confer different risks for the severity of hyperactive-impulsive and inattentive symptoms depending on parental sex; however, parental ADHD self-report scale score has low to negligible correlation with proband's ADHD severity. Biparental ADHD does not appear to have an additive or synergistic effect on the proband's ADHD severity.

Analysis of GWAS top hits in ADHD suggests association to two polymorphisms located in genes expressed in the cerebellum.

Attention deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder influenced by genetic factors. Several chromosomal regions with potential linkage and candidate genes associations have been reported, but findings are often inconsistent and non-replicated. The few genome-wide association studies (GWAS) carried out so far differ for study design and phenotypes analyzed, and did not detect any association significant at the genome-wide level. In the present study we examined the top SNPs reported in the GWAS by Neale et al. 2008 in an independent cohort. Although our sample size is smaller (415 trios vs. 909), the power was sufficient to confirm the role of candidate markers in ADHD if a true association exists. Two out of 36 top SNPs were significant at alpha = 0.05 in our sample, although none was still significant after correction for multiple tests. These two SNPs are both located in genes coding for as yet uncharacterized proteins expressed in the cerebellum, XKR4 in 8q12.1, and FAM190A in 4q22.1. Three other FAM190A SNPs have TDT P-values of <10(-5) in our sample, a level of significance only reached by a total of five SNPs in our genome-wide data. While these findings could be due to chance, we cannot exclude that these markers are indeed associated to disease risk. Remarkably, brain imaging studies have shown reduction of the posterior inferior cerebellar lobules volume of ADHD boys and girls compared to controls, persistent with age and not present in unaffected siblings, suggesting that the cerebellum may be directly related to pathophysiology of ADHD.

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

Nocturnal enuresis: a suggestive endophenotype marker for a subgroup of inattentive attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear. STUDY DESIGN: Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored. RESULTS: The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis. CONCLUSIONS: Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies.

ADHD latent class clusters: DSM-IV subtypes and comorbidity.

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6-18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding.

Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling.

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817 .

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I-Psychiatric and Behavioral Interventions.

OBJECTIVE: This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS). METHODS: Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms. RESULTS: Current guidelines result from consensus among the Consortium members. CONCLUSION: While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series.

PANDAS with catatonia: a case report. Therapeutic response to lorazepam and plasmapheresis.

This is a report of an 11-year-old, prepubertal boy with acute-onset urinary urgency and frequency, obsessions and compulsions related to urination, severe mood lability, inattention, impulsivity, hyperactivity, and intermittent periods of immobilization. Fever, cough, otitis, and sinusitis preceded neuropsychiatric symptoms. Antistreptolysin O and DNAse B antibody titers were elevated, and magnetic resonance imaging revealed bilateral diffuse caudate nuclei swelling. Plasmapheresis resulted in significant and rapid clinical improvement of obsessive-compulsive disorder symptoms and a simultaneous decrease in basal ganglia swelling, consistent with an immune-mediated pathophysiological process involving group A beta-hemolytic streptococci. Hyperactivity, impulsivity, and inattention improved with lorazepam, suggesting that the attention-deficit/hyperactivity disorder symptoms could be manifestations of catatonia.

Treatment of acute neuropsychiatric lupus with intravenous immunoglobulin (IVIG): a case report and review of the literature.

Neuropsychiatric lupus can be difficult to diagnose, and little prospective data exists to help direct management. In this case report we describe the acute onset of symptoms of depression, mania, and psychosis and their complete resolution 48 h following a 5-day treatment course of intravenous immunoglobulin (IVIG) in a 20-year-old woman with systemic lupus erythematosus (SLE). We review the literature on IVIG for the management of neuropsychiatric lupus. We propose that when more toxic therapies are refused or symptoms do not remit with other treatments, IVIG should be considered in patients with neuropsychiatric lupus.

A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of dexmethylphenidate hydrochloride (d-MPH, Focalin) for the treatment of attention-deficit/hyperactivity disorder (ADHD) and to test an a priori hypothesis that d-MPH would have a longer duration of action than d,l-threo-methylphenidate (d,l-MPH). METHOD: This was a randomized, double-blind study conducted at 12 U.S. centers. One hundred thirty-two subjects received d-MPH (n=44), d,l-MPH (n=46), or placebo (n=42) twice daily for 4 weeks, with titration of the dose based on weekly clinic visits. The primary efficacy variable was change from baseline to last study visit on teacher-completed Swanson, Nolan, and Pelham Rating Scale (Teacher SNAP). Secondary efficacy measures included the change on parent-completed SNAP (Parent SNAP), Clinical Global Impressions Scale-Improvement (CGI-I) score, and Math Test performance. Assessments at home in late afternoon were included to test the hypothesis that d-MPH would have a longer duration of efficacy than d,l-MPH. Safety was assessed through monitoring occurrence and severity of adverse events and discontinuations related to them. RESULTS: Treatment with either d-MPH (p=.0004) or d,l-MPH (p=.0042) significantly improved Teacher SNAP ratings compared with placebo. The d-MPH group showed significant improvements compared with placebo on the afternoon Parent SNAP ratings (p=.0003) and scores on the Math Test (p=.0236) obtained late in the afternoon at 6:00 p.m. Sixty-seven percent of patients showed improvement on d-MPH and 49% on d,l-MPH based on CGI-I scores. Both d-MPH and d,l-MPH were well tolerated, no patient in the d-MPH group and only two patients each in the d,l-MPH and placebo groups discontinued the study. CONCLUSIONS: For the treatment of ADHD, an average titrated dose of 18.25 mg/day of d-MPH is as efficacious and safe as an average titrated dose of 32.14 mg/day of d,l-MPH. Both active treatments have large effect sizes. Thus, d-MPH and d,l-MPH appear to provide similar efficacy, and d-MPH may have longer duration of action after twice-daily dosing, but additional studies are needed to determine the statistical and clinical significance of this possibility.

Energy supply chain optimization of hybrid feedstock processes: a review.

The economic, environmental, and social performances of energy systems depend on their geographical locations and the surrounding market infrastructure for feedstocks and energy products. Strategic decisions to locate energy conversion facilities must take all upstream and downstream operations into account, prompting the development of supply chain modeling and optimization methods. This article reviews the contributions of energy supply chain studies that include heat, power, and liquid fuels production. Studies are categorized based on specific features of the mathematical model, highlighting those that address energy supply chain models with and without considerations of multiperiod decisions. Studies that incorporate uncertainties are discussed, and opportunities for future research developments are outlined.