Screening for symptoms of childhood traumatic stress in the primary care pediatric clinic.

BACKGROUND: Childhood traumatic experiences may result in post-traumatic stress disorder. Although pediatricians are encouraged to address these traumas in clinical encounters, measures of childhood traumatic stress have not been adopted by primary care clinicians. In this study, we describe the feasibility and potential utility of the UCLA Brief Screen, a validated screener for childhood traumatic stress symptoms, in pediatric primary care clinics. METHODS: Children 6-17 years of age presenting for routine well-child care in community-based pediatric clinics were eligible for traumatic stress screening. We described the feasibility and acceptability of screening based on screener adoption by eligible pediatric clinicians. We assessed the potential utility of screening based on prevalence and distribution of potentially traumatic events and traumatic stress symptoms in this general pediatric population. Finally, we compared results of the UCLA Brief Screen with those of the Patient Health Questionnaire-A to evaluate associations between symptoms of traumatic stress, depression, and suicidality among adolescents in this community setting. RESULTS: 14/18 (77.8%) pediatric clinicians in two clinics offered an adapted UCLA Brief Screen during 2359/4959 (47.6%) eligible well-child checks over 14 months. 1472/2359 (62.4%) of offered screeners were completed, returned, and scored. One-third (32.5%) of completed screeners captured a potentially traumatic event experience described by either children or caregivers. Moderate to severe traumatic stress symptoms were identified in 10.7% and 5.2% of patients, respectively. Concurrent depression screening revealed that 68.3% of adolescents with depressive symptoms reported a potentially traumatic event (PTE) and 80.5% had concurrent traumatic stress symptoms. Adolescents reporting a PTE were 3.5 times more likely to report thoughts of suicide or self-harm than those without this history. CONCLUSIONS: Results from this pilot study suggest that traumatic stress screening in the pediatric primary care setting may be feasible and may identify and classify mental health symptoms missed with current screening practices for depression. The prevalence of PTEs and traumatic stress symptoms associated with PTEs support the potential utility of a standardized screening in early identification of and response to children with clinically important symptoms of childhood traumatic stress. Future research should evaluate meaningful clinical outcomes associated with traumatic stress screening.

Delirium in the NICU.

Delirium in the NICU is an underrecognized phenomenon in infants who are often complex and critically ill. The current understanding of NICU delirium is developing and can be informed by adult and pediatric literature. The NICU population faces many potential risk factors for delirium, including young age, developmental delay, mechanical ventilation, severe illness, and surgery. There are no diagnostic tools specific to infants. The mainstay of delirium treatment is to treat the underlying cause, address modifiable risk factors, and supportive care. This review will summarize current knowledge and areas where more research is needed.

Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma.

Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety.

Feasibility of Assessing Adolescent and Young Adult Heart Transplant Recipient Mental Health and Resilience Using Patient-Reported Outcome Measures.

BACKGROUND: Although adolescents and young adults may be particularly prone to mental health symptoms after heart transplant, screening practices are variable. OBJECTIVE: To assess the feasibility of using patient-reported outcome (PRO) measures to assess mental health, functional status, and resiliency in posttransplant adolescents and young adult patients. METHODS: Patients transplanted between ages 15 and 25 years at 3 centers completed 6 PRO instruments via web-based platforms: PROMIS instruments for anxiety, depression, satisfaction with social roles, and physical functioning; the Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5; and the Connor-Davidson Resilience Scale-10. Feasibility (completion, time to completion, and measure missingness) and PRO results were described and compared between patients with congenital heart disease and cardiomyopathy. RESULTS: Nineteen patients (median age at transplant 17.7 y [interquartile range 16.3, 19.2 y], 84% male) were enrolled at an average of 3 ± 1.8 years after transplant. Enrollment was 90% among eligible patients. Measure missingness was zero. The average completion time was 12 ± 15 minutes for all instruments. Timely PRO completion was facilitated by in-clinic application. The PRO results indicated that 9 patients (47%) had at least mild posttraumatic stress disorder symptoms (≥11 points on Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5). Among them, 4 patients had scores >28 suggestive of probable posttraumatic stress disorder. Two (11%) and 6 (32%) patients had anxious and depressive symptoms, respectively. The cardiomyopathy cohort had a higher median Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5 score than that of the congenital heart disease subgroup (11.0 vs 6.0; P = 0.015). Twelve (63%) had resiliency scores that were lower than the population average. No significant differences were found in PRO results between patients with cardiomyopathy and congenital heart disease apart from the posttraumatic stress disorder assessment. CONCLUSIONS: This novel PRO-based approach to psychiatric screening of adolescents and young adult patients after transplant appears feasible for assessing mental health, functional status, and resiliency, with excellent enrollment and completion rates. These instruments characterized the burden of mental health symptoms within this adolescents and young adult heart transplant cohort, with a high prevalence of posttraumatic stress disorder symptoms. Resiliency scores were lower than in a comparison population. Electronically-administered PRO administration could facilitate more consistent mental health screening in this at-risk group.

Adaptations Made to Pediatric Consultation-Liaison Psychiatry Service Delivery During the Early Months of the COVID-19 Pandemic: A North American Multisite Survey.

BACKGROUND: The COVID-19 pandemic led to rapid changes in clinical service delivery across hospital systems nationally. Local realities and resources were key driving factors impacting workflow changes, including for pediatric consultation-liaison psychiatry service (PCLPS) providers. OBJECTIVE: This study aims to describe the early changes implemented by 22 PCLPSs from the United States and Canada during the COVID-19 pandemic. Understanding similarities and differences in adaptations made to PCLPS care delivery can inform best practices and future models of care. METHODS: A 20-point survey relating to PCLPS changes during the COVID-19 pandemic was sent to professional listservs. Baseline hospital demographics, hospital and PCLPS workflow changes, and PCLPS experience were collected from March 20 to April 28, 2020, and from August 18 to September 10, 2020. Qualitative data were collected from responding sites. An exploratory thematic analysis approach was used to analyze the qualitative data that were not dependent on predetermined coding themes. Descriptive statistics were calculated using Microsoft Excel. RESULTS: Twenty-two academic hospitals in the United States and Canada responded to the survey, with an average of 303 beds/hospital. Most respondents (18/22) were children's hospitals. Despite differences in regional impact of COVID-19 and resource availability, there was significant overlap in respondent experiences. Restricted visitation to one caregiver, use of virtual rounding, ongoing trainee involvement, and an overall low number of COVID-positive pediatric patients were common. While there was variability in PCLPS care delivery occurring virtually versus in person, all respondents maintained some level of on-site presence. Technological limitations and pediatric provider preference led to increased on-site presence. CONCLUSIONS: To our knowledge, this is the first multicenter study exploring pandemic-related PCLPS changes in North America. Findings of this study demonstrate that PCLPSs rapidly adapted to COVID-19 realities. Common themes emerged that may serve as a model for future practice. However, important gaps in understanding their effectiveness and acceptability need to be addressed. This multisite survey highlights the importance of establishing consensus through national professional organizations to inform provider and hospital practices.

A Clinical Pathway to Standardize Care of Children With Delirium in Pediatric Inpatient Settings.

Pediatric delirium is an important comorbidity of medical illness in inpatient pediatric care that has lacked a consistent approach for detection and management. A clinical pathway (CP) was developed to address this need. Pediatric delirium contributes significantly to morbidity, mortality, and costs of inpatient care of medically ill children and adolescents. Screening for delirium in hospital settings with validated tools is feasible and effective in reducing delirium and improving outcomes; however, multidisciplinary coordination is required for implementation. The workgroup, composed of international experts in child and adolescent consultation psychiatry, reviewed the literature and developed a flowchart for feasible screening and management of pediatric delirium. When evidence was lacking, expert consensus was reached; stakeholder feedback was included to create the final pathway. A CP expert collaborated with the workgroup. Two sequential CPs were created: (1) "Prevention and Identification of Pediatric Delirium" emphasizes the need for systematic preventive measures and screening, and (2) "Diagnosis and Management of Pediatric Delirium" recommends an urgent and ongoing search for the underlying causes to reverse the syndrome while providing symptomatic management focused on comfort and safety. Detailed accompanying documents explain the supporting literature and the rationale for recommendations and provide resources such as screening tools and implementation guides. Additionally, the role of the child and adolescent consultation-liaison psychiatrist as a resource for collaborative care of patients with delirium is discussed.

Developing a Clinical Pathway for Somatic Symptom and Related Disorders in Pediatric Hospital Settings.

Somatic symptom and related disorders (SSRDs) are commonly encountered in pediatric hospital settings. There is, however, a lack of standardization of care across institutions for youth with these disorders. These patients are diagnostically and psychosocially complex, posing significant challenges for medical and behavioral health care providers. SSRDs are associated with significant health care use, cost to families and hospitals, and risk for iatrogenic interventions and missed diagnoses. With sponsorship from the American Academy of Child and Adolescent Psychiatry and input from multidisciplinary stakeholders, we describe the first attempt to develop a clinical pathway and standardize the care of patients with SSRDs in pediatric hospital settings by a working group of pediatric consultation-liaison psychiatrists from multiple institutions across North America. The authors of the SSRD clinical pathway outline 5 key steps from admission to discharge and include practical, evidence-informed approaches to the assessment and management of children and adolescents who are medically hospitalized with SSRDs.

Suicide Risk Screening in Pediatric Hospitals: Clinical Pathways to Address a Global Health Crisis.

BACKGROUND: Youth suicide is on the rise worldwide. Most suicide decedents received healthcare services in the year before killing themselves. Standardized workflows for suicide risk screening in pediatric hospitals using validated tools can help with timely and appropriate intervention, while attending to The Joint Commission Sentinel Event Alert 56. OBJECTIVE: Here we describe the first attempt to generate clinical pathways for patients presenting to pediatric emergency departments (EDs) and inpatient medical settings. METHODS: The workgroup reviewed available evidence and generated a series of steps to be taken to feasibly screen medical patients presenting to hospitals. When evidence was limited, expert consensus was used. A standardized, iterative approach was utilized to create clinical pathways. Stakeholders reviewed initial drafts. Feedback was incorporated into the final pathway. RESULTS: Clinical pathways were created for suicide risk screening in pediatric EDs and inpatient medical/surgical units. The pathway outlines a 3-tiered screening process utilizing the Ask Suicide-Screening Questions for initial screening, followed by a brief suicide safety assessment to determine if a full suicide risk assessment is warranted. This essential step helps conserve resources and decide upon appropriate interventions for each patient who screens positive. Detailed implementation guidelines along with scripts for provider training are included. CONCLUSION: Youth suicide is a significant public health problem. Clinical pathways can empower hospital systems by providing a guide for feasible and effective suicide risk-screening implementation by using validated tools to identify patients at risk and apply appropriate interventions for those who screen positive. Outcomes assessment is essential to inform future iterations.

Essential Elements of a Collaborative Mental Health Training Program for Primary Care.

Mental health integration in primary care is based on creating an environment that encourages collaboration and supports appropriate care for patients and families while offering a full range of services. Training programs for primary care practitioners should include sessions on how to build and maintain such a practice along with information on basic mental health competencies.

Development of the Vanderbilt Assessment for Delirium in Infants and Children to Standardize Pediatric Delirium Assessment By Psychiatrists.

BACKGROUND: Pediatric delirium assessment is complicated by variations in baseline language and cognitive skills, impairment during illness, and absence of pediatric-specific modifiers within the Diagnostic and Statistical Manual of Mental Disorders delirium criterion. OBJECTIVE: To develop a standardized approach to pediatric delirium assessment by psychiatrists. METHODS: A multidisciplinary group of clinicians used Diagnostic and Statistical Manual criterion as the foundation for the Vanderbilt Assessment for Delirium in Infants and Children (VADIC). Pediatric-specific modifiers were integrated into the delirium criterion, including key developmental and assessment variations for children. The VADIC was used in clinical practice to prospectively assess critically ill infants and children. The VADIC was assessed for content validity by the American Academy of Child and Adolescent Psychiatry Delirium Special Interest Group. RESULTS: The American Academy of Child and Adolescent Psychiatry-Delirium Special Interest Group determined that the VADIC demonstrated high content validity. The VADIC (1) preserved the core Diagnostic and Statistical Manual delirium criterion, (2) appropriately paired interactive assessments with key criterion based on development, and (3) addressed confounders for delirium. A cohort of 300 patients with a median age of 20 months was assessed for delirium using the VADIC. Delirium prevalence was 47%. CONCLUSION: The VADIC provides a comprehensive framework to standardize pediatric delirium assessment by psychiatrists. The need for consistency in both delirium education and diagnosis is highlighted given the high prevalence of pediatric delirium.

Pediatric Somatic Symptom Disorders.

Somatic symptom disorder (SSD) is a common disorder encountered in pediatric medicine. It involves the presentation of physical symptoms that are either disproportionate or inconsistent with history, physical examination, laboratory, and other investigative findings. SSDs result in significant impairment with considerable increase in healthcare utilization, school absenteeism, and the potential for unnecessary diagnostic evaluation and treatment intervention. Patients and families often feel dismissed and may worry that a serious condition has been missed. Primary care providers are frequently frustrated due to a lack of a successful approach to patients and families impacted by SSD. The result is often a cycle of disability, frustration and missed opportunities for collaboration towards enhanced patient functionality. This review summarizes the current evidence-based understanding, as well as insights from clinician experience, on the evaluation and management of pediatric SSD.

Primary Pediatric Care Psychopharmacology: Focus on Medications for ADHD, Depression, and Anxiety.

The evidence base for psychopharmacologic interventions in youth with depressive and anxiety disorders as well as attention/deficit hyperactivity disorder (ADHD) has dramatically increased over the past two decades. Psychopharmacologic interventions commonly utilized in the pediatric primary care setting-selective serotonin (norepinephrine) reuptake inhibitors (SSRIs/SSNRIs), stimulants and α2 agonists-are reviewed. General pharmacologic principles are summarized along with class-related side effects and tolerability concerns (e.g., suicidality and activation in antidepressant-treated youth as well as insomnia, irritability, anorexia in stimulant-treated pediatric patients). Selected landmark trials of antidepressant medications in youth with depressive disorders [Treatment of Adolescent Depression Study (TADS) and the Treatment of SSRI-Resistant Depression Study (TADS)] and anxiety disorders [Child/Adolescent Anxiety Multimodal Study (CAMS) and Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS)] are described in addition to the Multimodal Treatment of ADHD Study. Finally, available data are presented that are related to prediction of treatment outcomes in youth with depressive disorders, anxiety disorders, and ADHD.

Challenges and Promises of Pediatric Psychopharmacology.

Most prescriptions for psychotropic medications are written by primary care physicians, yet pediatricians, many of whom are teaching residents and medical students about pediatric psychopharmacology, often feel inadequately trained to treat mental health concerns. Over the past several decades, the number, size, and quality of psychopharmacologic studies in youth has greatly increased. Here we review the current evidence for efficacy and safety of each of the major pharmacologic drug classes in youth (psychostimulants, antidepressants, mood stabilizers, and antipsychotics). Psychostimulants have a robust body of literature supporting their evidence as first-line treatment for attention-deficit/hyperactivity disorder. Selective serotonin reuptake inhibitors (SSRIs) have documented efficacy for pediatric depression and multiple different anxiety disorders with childhood onset. Combining cognitive-behavioral therapy with SSRI treatment enhances treatment benefit and minimizes adverse events of medication. Mood stabilizers, including lithium and anticonvulsant medications, have a less robust strength of evidence and come with more problematic side effects. However, they are increasingly prescribed to youth, often to treat irritability, mood lability, and aggression, along with treatment of bipolar disorder. Antipsychotics have long been a mainstay of treatment for childhood-onset schizophrenia, and in recent years, the evidence base for providing antipsychotics to youth with bipolar mania and autistic disorder has grown. Most concerning with antipsychotics are the metabolic side effects, which appear even more problematic in youth than adults. By better understanding the evidence-based psychopharmacologic interventions, academic pediatricians will be able to treat patients and prepare future pediatrician to address the growing mental health care needs of youth.

Mindfulness-Based Intervention for Adolescents with Recurrent Headaches: A Pilot Feasibility Study.

Recurrent headaches cause significant burden for adolescents and their families. Mindfulness-based interventions (MBIs) have been shown to reduce stress and alter the experience of pain, reduce pain burden, and improve quality of life. Research indicates that MBIs can benefit adults with chronic pain conditions including headaches. A pilot nonrandomized clinical trial was conducted with 20 adolescent females with recurrent headaches. Median class attendance was 7 of 8 total sessions; average class attendance was 6.10 ± 2.6. Adherence to home practice was good, with participants reporting an average of 4.69 (SD = 1.84) of 6 practices per week. Five participants dropped out for reasons not inherent to the group (e.g., extracurricular scheduling); no adverse events were reported. Parents reported improved quality of life and physical functioning for their child. Adolescent participants reported improved depression symptoms and improved ability to accept their pain rather than trying to control it. MBIs appear safe and feasible for adolescents with recurrent headaches. Although participants did not report decreased frequency or severity of headache following treatment, the treatment had a beneficial effect for depression, quality of life, and acceptance of pain and represents a promising adjunct treatment for adolescents with recurrent headaches.

Clinical reasoning: a 12-year-old boy with ascending weakness.

A 12-year-old boy presented with 3 weeks of calf pain, tripping, and progressive inability to walk. The onset was preceded by a sore throat 4 weeks prior, but no recent immunizations and no sick contacts. He began having problems "catching his toes" for 2 weeks. He had no visual complaints and no bowel or bladder incontinence. He had no recent travel and there were no heavy metal or solvent exposures. He had no prior medical history and he was on no prescription medications. Developmentally, he was on track and had just successfully completed fifth grade. However, he was reported to be behaviorally oppositional, especially regarding his diet which was restricted to beef jerky, yogurt from a squeeze tube, and fruit drinks. Family history included diabetic peripheral neuropathy in his mother, idiopathic peripheral neuropathy in his maternal grandfather, and left lower extremity neuropathy from trauma in his father. There was no known family history of recurrent pressure palsies or cardiac problems.

Printor, a novel torsinA-interacting protein implicated in dystonia pathogenesis.

Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA DeltaE) in the C-terminal region of the AAA(+) (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA DeltaE mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and co-localizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystonia-associated torsinA DeltaE mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.

TorsinA protein degradation and autophagy in DYT1 dystonia.

Early-onset generalized dystonia (DYT1) is a debilitating neurological disorder characterized by involuntary movements and sustained muscle spasms. DYT1 dystonia has been associated with two mutations in torsinA that result in the deletion of a single glutamate residue (torsinA DeltaE) and six amino-acid residues (torsinA Delta323-8). We recently revealed that torsinA, a peripheral membrane protein, which resides predominantly in the lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), is a long-lived protein whose turnover is mediated by basal autophagy. Dystonia-associated torsinA DeltaE and torsinA Delta323-8 mutant proteins show enhanced retention in the NE and accelerated degradation by both the proteasome and autophagy. Our results raise the possibility that the monomeric form of torsinA mutant proteins is cleared by proteasome-mediated ER-associated degradation (ERAD), whereas the oligomeric and aggregated forms of torsinA mutant proteins are cleared by ER stress-induced autophagy. Our findings provide new insights into the pathogenic mechanism of torsinA DeltaE and torsinA Delta323-8 mutations in dystonia and emphasize the need for a mechanistic understanding of the role of autophagy in protein quality control in the ER and NE compartments.

Cerebellar ataxia in youths at risk for bipolar disorder.

OBJECTIVE: Structural, biochemical, and functional cerebellar abnormalities occur in individuals with or at-risk for developing bipolar disorder (BD), but the clinical implications of these abnormalities are unknown. The present study examined cerebellar function in youths who were at familial risk for BD by comparing ataxia battery scores of youths with a bipolar parent to those of healthy youths. METHODS: Trained raters administered an ataxia battery, consisting of three tasks, to children (aged 8-12 years) with at least one parent with BD type I (BDI) who themselves did not have BDI (at-risk or AR group, n = 21) and healthy comparison children (aged 8-12 years) with parents free of DSM-IV Axis I psychopathology (HC group, n = 23). RESULTS: AR youths performed worse than HC youths on the Sharpened Romberg test (subjects standing heel-to-toe) and standing on one foot with eyes open (p < 0.02). CONCLUSIONS: The results indicate that youths at familial risk for BD have more difficulty performing a Sharpened Romberg test than a HC group, suggesting that midline cerebellar dysfunction may be a biomarker for the future development of BD. Further studies examining the relationships among youths at risk for BD, coordination abnormalities, and cerebellar dysfunction are needed.

Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope.

An in-frame 3 bp deletion in the torsinA gene resulting in the loss of a glutamate residue at position 302 or 303 (torsinA DeltaE) is the major cause for early-onset torsion dystonia (DYT1). In addition, an 18 bp deletion in the torsinA gene resulting in the loss of residues 323-328 (torsinA Delta323-8) has also been associated with dystonia. Here we report that torsinA DeltaE and torsinA Delta323-8 mutations cause neuronal cell-type-specific mislocalization of torsinA protein to the nuclear envelope without affecting torsinA oligomerization. Furthermore, both dystonia-associated mutations destabilize torsinA protein in dopaminergic cells. We find that wild-type torsinA protein is degraded primarily through the macroautophagy-lysosome pathway. In contrast, torsinA DeltaE and torsinA Delta323-8 mutant proteins are degraded by both the proteasome and macroautophagy-lysosome pathways. Our findings suggest that torsinA mutation-induced premature degradation may contribute to the pathogenesis of dystonia via a loss-of-function mechanism and underscore the importance of both the proteasome and macroautophagy in the clearance of dystonia-associated torsinA mutant proteins.