Faculty Bibliography

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.

OBJECTIVE:To test whether rates of bipolar disorder (BD) have changed over time or vary across geographic regions after adjusting for design features meta-analyzing epidemiologic studies reporting BD prevalence in adults worldwide. DATA SOURCES:Searches in PubMed and PsycINFO using the terms (epidemiology OR community OR prevalence) AND (mania OR "bipolar disorder" OR cyclothymi*) AND adult and backward searches from published reviews were conducted. STUDY SELECTION:Eighty-five epidemiologic studies published in English from 1980 onward that reported prevalence rates for BD or mania for subjects ≥ 18 years old were included. DATA EXTRACTION:We coded BD prevalence, method of data collection, diagnostic criteria, year of study, country, and quality of study design and data reporting. Meta-regression tested whether sample characteristics influenced prevalence rates using the metafor package in R. RESULTS:Eighty-five effect sizes, from 44 countries, from studies spanning the years 1980-2012, included 67,373 people with BD. Lifetime prevalence for BD spectrum was 1.02% (95% CI, 0.81%-1.29%). Prevalence was moderated by the inclusion of BD not otherwise specified (P = .009) and by geographic region; rates from Africa and Asia were less than half of those from North and South America. Rates did not change significantly over 3 decades after controlling for design features. CONCLUSIONS:The overall prevalence rate is consistent with historical estimates, but rates vary significantly across studies. Differences in methodology contribute to the perception that rates of BD have increased over time. Rates varied markedly by geographic region, even after controlling for all other predictors. Research using consistent definitions and methods may expose specific factors that confer risk for BD.

Resting-state functional connectivity is the synchronization of brain regions with each another. Alterations are suggestive of neurologic or psychological disorders. This article discusses methods and approaches used to describe resting-state brain connectivity and the results in neurotypical and diseased brains.

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.

BACKGROUND:Despite recent focus on patient safety in primary care, little attention has been paid to errors of omission, which represent significant gaps in care and threaten patient safety in primary care but are not well studied or categorized. The purpose of this study was to develop a typology of errors of omission from the perspectives of primary care providers (PCPs) and understand what factors within practices lead to or prevent these omissions. METHODS:A qualitative descriptive design was used to collect data from 26 PCPs, both physicians and nurse practitioners, from the New York State through individual interviews. One researcher conducted all interviews, which were audiotaped, transcribed verbatim, and analyzed in ATLAS.ti, Berlin by 3 researchers using content analysis. They immersed themselves into data, read transcripts independently, and conducted inductive coding. The final codes were linked to each other to develop the typology of errors of omission and the themes. Data saturation was reached at the 26th interview. RESULTS:PCPs reported that omitting patient teaching, patient followup, emotional support, and addressing mental health needs were the main categories of errors of omission. PCPs perceived that time constraints, unplanned patient visits and emergencies, and administrative burden led to these gaps in care. They emphasized that organizational support and infrastructure, effective teamwork and communication, and preparation for the patient encounter were important safeguards to prevent errors of omission within their practices. DISCUSSION/CONCLUSIONS:Errors of omission are common in primary care and could threaten patient safety. Efforts to eliminate them should focus on strengthening organizational attributes of practices, improving teamwork and communication, and assigning manageable workload to PCPs. CONCLUSIONS:Practice and policy change is necessary to address gaps in care and prevent them before they result in patient harm.

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.

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.

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