Faculty Bibliography

PURPOSE/OBJECTIVE:Greenhouse gases are driving climate change. This article explores the adverse health effects of climate change on a particularly vulnerable population: children and adults with respiratory conditions. APPROACH/METHODS:This review provides a general overview of the effects of increasing temperatures, extreme weather, desertification, and flooding on asthma, chronic obstructive lung disease, and respiratory infections. We offer suggestions for future research to better understand climate change hazards, policies to support prevention and mitigation efforts targeting climate change, and clinical actions to reduce individual risk. FINDINGS AND CONCLUSIONS/CONCLUSIONS:Climate change produces a number of changes to the natural and built environments that may potentially increase respiratory disease prevalence, morbidity, and mortality. Nurses might consider focusing their research efforts on reducing the effects of greenhouse gases and in directing policy to mitigate the harmful effects of climate change. Nurses can also continue to direct educational and clinical actions to reduce risks for all populations, but most importantly, for our most vulnerable groups. CLINICAL RELEVANCE/CONCLUSIONS:While advancements have been made in understanding the impact of climate change on respiratory health, nurses can play an important role in reducing the deleterious effects of climate change. This will require a multipronged approach of research, policy, and clinical action.

Levetiracetam is a commonly prescribed antiepileptic drug for seizure prophylaxis in patients with traumatic brain injury (TBI). Levetiracetam metabolism has been reported to be non-dependent on hepatic cytochrome P450 (CYP450) isoenzyme system. Furthermore, levetiracetam and its metabolites are reported to be eliminated from systemic circulation via renal excretion. Therefore, due to its well-known renal clearance mechanism with no dosage adjustments recommended for hepatic impairment, levetiracetam is often chosen as the drug of choice in patients with suspected or ongoing hepatic dysfunction. Furthermore, monitoring of liver enzymes is often not considered to be critical in levetiracetam therapy. However, hepatotoxicity is still possible with levetiracetam. Here, we report on an 18-year-old male with TBI who developed transaminitis with levetiracetam therapy which resolved following the discontinuation of levetiracetam. A close monitoring of liver enzymes and early recognition of hepatotoxicity is still necessary and critical to preventing major sequelae stemming from levetiracetam-induced hepatotoxicity.

OBJECTIVES:Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS:An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS:Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS:As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

Psychiatric disorders are amongst the most prevalent and impairing conditions in childhood and adolescence. Unfortunately, it is well known that general practitioners (GPs) and other frontline health providers (i.e., child protection workers, public health nurses, and pediatricians) are not adequately trained to address these ubiquitous problems (Braddick et al. Child and Adolescent mental health in Europe: infrastructures, policy and programmes, European Communities, 2009; Levav et al. Eur Child Adolesc Psychiatry 13:395-401, 2004). Advances in technology may offer a solution to this problem with clinical decision support systems (CDSS) that are designed to help professionals make sound clinical decisions in real time. This paper offers a systematic review of currently available CDSS for child and adolescent mental health disorders prepared according to the PRISMA-Protocols (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols). Applying strict eligibility criteria, the identified studies (n = 5048) were screened. Ten studies, describing eight original clinical decision support systems for child and adolescent psychiatric disorders, fulfilled inclusion criteria. Based on this systematic review, there appears to be a need for a new, readily available CDSS for child neuropsychiatric disorder which promotes evidence-based, best practices, while enabling consideration of national variation in practices by leveraging data-reuse to generate predictions regarding treatment outcome, addressing a broader cluster of clinical disorders, and targeting frontline practice environments.

OBJECTIVES: To investigate whether response to lithium treatment in pediatric bipolar disorder can be predicted by changes in white matter microstructure in key cortico-limbic tracts involved in emotion regulation. METHODS: Eighteen clinically referred lithium-naive patients (mean age 15.5 years) were administered clinical rating scales and diffusion tensor imaging (DTI) examinations at baseline and following 4 weeks of lithium treatment. Clinical ratings were repeated following 8 weeks of treatment. Patients with Clinical Global Impressions (CGI) ratings of 1 ("very much improved") or 2 ("much improved") were classified as responders. Ten healthy volunteers received baseline and follow-up DTI examinations. Using the ENIGMA pipeline, we investigated the relationship between changes in fractional anisotropy (FA) in the cingulum hippocampus (CGH) and clinical response to lithium. RESULTS: Patients demonstrated significantly lower FA compared to healthy volunteers in the left and right CGH white matter at baseline. Following 4 weeks of lithium treatment, FA in the left CGH increased in patients, but no significant changes in FA were observed among the untreated healthy volunteers. Lithium responders had a significantly greater increase in FA compared to non-responders. Moreover, baseline (pre-treatment) FA in the left CGH white matter significantly predicted week 8 overall CGI severity score, with post hoc analyses indicating that these effects were evident for both severity of depression and mania. CONCLUSIONS: Our findings suggest that response to lithium treatment in pediatric bipolar disorder is associated with normalization of white matter microstructure in regions associated with emotion processing.

OBJECTIVE: Autism Behavior Inventory (ABI) is a new measure for assessing changes in core and associated symptoms of autism spectrum disorder (ASD) in participants (ages: 3 years-adulthood) diagnosed with ASD. It is a web-based tool with five domains (two ASD core domains: social communication, restrictive and repetitive behaviors; three associated domains: mental health, self-regulation, and challenging behavior). This study describes design, development, and initial psychometric properties of the ABI. METHODS: ABI items were generated following review of existing measures and inputs from expert clinicians. Initial ABI scale contained 161 items that were reduced to fit a factor analytic model, retaining items of adequate reliability. Two versions of the scale, ABI-full (ABI-F; 93 items) and ABI-short version (ABI-S; 36 items), were developed and evaluated for psychometric properties, including validity comparisons with commonly used measures. Both scales were administered to parents and healthcare professionals (HCPs) involved with study participants. RESULTS: Test-retest reliability (intraclass correlation coefficient [ICC] = 0.79) for parent ratings on ABI was robust and compared favorably to existing scales. Test-retest correlations for HCP ratings were generally lower versus parent ratings. ABI core domains and comparison measures strongly correlated (r >/= 0.70), demonstrating good concurrent validity. CONCLUSIONS: Overall, ABI demonstrates promise as a tool for measuring change in core symptoms of autism in ASD clinical studies, with further validation required.

Resilience, which is associated with relatively positive outcomes following negative life experiences, is an important research target in the field of child maltreatment (Luthar et al., 2000). The extant literature contains multiple conceptualizations of resilience, which hinders development in research and clinical utility. Three models emerge from the literature: resilience as an immediate outcome (i.e., behavioral or symptom response), resilience as a trait, and resilience as a dynamic process. The current study compared these models in youth undergoing trauma-specific cognitive behavioral therapy. Results provide the most support for resilience as a process, in which increase in resilience preceded associated decrease in posttraumatic stress and depressive symptoms. There was partial support for resilience conceptualized as an outcome, and minimal support for resilience as a trait. Results of the models are compared and discussed in the context of existing literature and in light of potential clinical implications for maltreated youth seeking treatment.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that DeltaFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of DeltaFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of DeltaFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by DeltaFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.

Disproportionately lower educational achievement, coupled with higher grade retention, suspensions, expulsions, and lower school bonding make educational success among Black adolescents a major public health concern. Mental health is a key developmental factor related to educational outcomes among adolescents; however, traditional models of mental health focus on absence of dysfunction as a way to conceptualize mental health. The dual-factor model of mental health incorporates indicators of both subjective wellbeing and psychopathology, supporting more recent research that both are needed to comprehensively assess mental health. This study applied the dual-factor model to measure mental health using the National Survey of American Life-Adolescent Supplement (NSAL-A), a representative cross-sectional survey. The sample included 1170 Black adolescents (52% female; mean age 15). Latent class analysis was conducted with positive indicators of subjective wellbeing (emotional, psychological, and social) as well as measures of psychopathology. Four mental health groups were identified, based on having high or low subjective wellbeing and high or low psychopathology. Accordingly, associations between mental health groups and educational outcomes were investigated. Significant associations were observed in school bonding, suspensions, and grade retention, with the positive mental health group (high subjective wellbeing, low psychopathology) experiencing more beneficial outcomes. The results support a strong association between school bonding and better mental health and have implications for a more comprehensive view of mental health in interventions targeting improved educational experiences and mental health among Black adolescents.

Background Immunotherapy has demonstrated promising antitumor activity in various advanced cancers. Combined tumor targeting from multiple drugs with unique mechanisms may provide further improved outcomes. Tremelimumab (TRE) is a CTLA-4 antibody and durvalumab (DUR) blocks PD-L1. Poly-ICLC is a toll-like receptor 3 agonist. Intratumoral (intra-T) injection of poly-ICLC directly alters the tumor microenvironment (TME), and by creating an in situ vaccination, may trigger a clinically effective systemic anti-tumor response when also combined with DUR and TRE. Methods This is an ongoing Phase 1/2, open-label, multicenter study (NCT02643303). The study evaluates the use of intra-T administration of TRE and IV DUR + poly-ICLC (intra-T and intramuscular [IM]) to determine the safety, preliminary efficacy and immune activity of this regimen in patients with advanced, measurable, biopsyaccessible tumors: head and neck squamous cell carcinoma, breast cancer, sarcoma, merkel cell carcinoma, cutaneous T cell lymphoma, melanoma, genitourinary cancer, and other solid tumors. Phase 1 determines the recommended combination dosing (RCD) for the regimen with dose de-escalation based on dose limiting toxicities (DLTs) and standard 3 + 3 rules. Starting doses are: DUR, 1500 mg IV; TRE, 75 mg IV; TRE, 10 mg intra-T; poly-ICLC, 1 mg intra-T/IM. Phase 1 starts with Cohort 1A (DUR + poly-ICLC). Upon demonstration of tolerability, enrollment proceeds with Cohort 1B (DUR + IV TRE + poly-ICLC) and Cohort 1C (DUR + intra-T TRE + poly-ICLC). The RCD is the highest dose at which < 2/6 patients have DLTs. In Phase 2, up to 66 evaluable patients are treated using the RCD regimen, with enrollment of 6 patients per tumor type initially, and enrollment of 6 additional patients per 3 tumor types contingent upon at least 1 response among the initial 6 patients. Study endpoints are RCD and safety, objective response rate, progression-free survival, and overall survival. Exploratory endpoints are biological activity, including effects on the TME and immunological responses