Faculty Bibliography

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

OBJECTIVE: The U.S. Department of Justice has called for the creation of trauma-informed juvenile justice systems in order to combat the negative impact of trauma on youth offenders and frontline staff. Definitions of trauma-informed care have been proposed for various service systems, yet there is not currently a widely accepted definition for juvenile justice. The current systematic review examined published definitions of a trauma-informed juvenile justice system in an effort to identify the most commonly named core elements and specific interventions or policies. METHOD: A systematic literature search was conducted in 10 databases to identify publications that defined trauma-informed care or recommended specific practices or policies for the juvenile justice system. RESULTS: We reviewed 950 unique records, of which 10 met criteria for inclusion. The 10 publications included 71 different recommended interventions or policies that reflected 10 core domains of trauma-informed practice. We found 8 specific practice or policy recommendations with relative consensus, including staff training on trauma and trauma-specific treatment, while most recommendations were included in 2 or less definitions. CONCLUSION: The extant literature offers relative consensus around the core domains of a trauma-informed juvenile justice system, but much less agreement on the specific practices and policies. A logical next step is a review of the empirical research to determine which practices or policies produce positive impacts on outcomes for youth, staff, and the broader agency environment, which will help refine the core definitional elements that comprise a unified theory of trauma-informed practice for juvenile justice. (PsycINFO Database Record

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.

BACKGROUND AND PURPOSE: Resting-state functional MR imaging has been used for motor mapping in presurgical planning but never used intraoperatively. This study aimed to investigate the feasibility of applying intraoperative resting-state functional MR imaging for the safe resection of gliomas using real-time motor cortex mapping during an operation. MATERIALS AND METHODS: Using interventional MR imaging, we conducted preoperative and intraoperative resting-state intrinsic functional connectivity analyses of the motor cortex in 30 patients with brain tumors. Factors that may influence intraoperative imaging quality, including anesthesia type (general or awake anesthesia) and tumor cavity (filled with normal saline or not), were studied to investigate image quality. Additionally, direct cortical stimulation was used to validate the accuracy of intraoperative resting-state fMRI in mapping the motor cortex. RESULTS: Preoperative and intraoperative resting-state fMRI scans were acquired for all patients. Fourteen patients who successfully completed both sufficient intraoperative resting-state fMRI and direct cortical stimulation were used for further analysis of sensitivity and specificity. Compared with those subjected to direct cortical stimulation, the sensitivity and specificity of intraoperative resting-state fMRI in localizing the motor area were 61.7% and 93.7%, respectively. The image quality of intraoperative resting-state fMRI was better when the tumor cavity was filled with normal saline (P = .049). However, no significant difference between the anesthesia types was observed (P = .102). CONCLUSIONS: This study demonstrates the feasibility of using intraoperative resting-state fMRI for real-time localization of functional areas during a neurologic operation. The findings suggest that using intraoperative resting-state fMRI can avoid the risk of intraoperative seizures due to direct cortical stimulation and may provide neurosurgeons with valuable information to facilitate the safe resection of gliomas.

Relationships between spatially remote brain regions in human have typically been estimated by moment-to-moment correlations of blood-oxygen-level dependent signals in resting-state using functional MRI (fMRI). Recently, studies using subject-to-subject covariance of anatomical volumes, cortical thickness, and metabolic activity are becoming increasingly popular. However, question remains on whether these measures reflect the same inter-region connectivity and brain network organizations. In the current study, we systematically analyzed inter-subject volumetric covariance from anatomical MRI images, metabolic covariance from fluorodeoxyglucose positron emission tomography images from 193 healthy subjects, and resting-state moment-to-moment correlations from fMRI images of a subset of 44 subjects. The correlation matrices calculated from the three methods were found to be minimally correlated, with higher correlation in the range of 0.31, as well as limited proportion of overlapping connections. The volumetric network showed the highest global efficiency and lowest mean clustering coefficient, leaning toward random-like network, while the metabolic and resting-state networks conveyed properties more resembling small-world networks. Community structures of the volumetric and metabolic networks did not reflect known functional organizations, which could be observed in resting-state network. The current results suggested that inter-subject volumetric and metabolic covariance do not necessarily reflect the inter-regional relationships and network organizations as resting-state correlations, thus calling for cautions on interpreting results of inter-subject covariance networks.

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.

The major objective of preclinical translational epilepsy research is to advance laboratory findings toward clinical application by testing potential treatments in animal models of seizures and epilepsy. Recently there has been a focus on the failure of preclinical discoveries to translate reliably, or even to be reproduced in different laboratories. One potential cause is a lack of standardization in preclinical data collection. The resulting difficulties in comparing data across studies have led to high cost and missed opportunity, which in turn impede clinical trials and advances in medical care. Preclinical epilepsy research has successfully brought numerous antiseizure treatments into the clinical practice, yet the unmet clinical needs have prompted the reconsideration of research strategies to optimize epilepsy therapy development. In the field of clinical epilepsy there have been successful steps to improve such problems, such as generation of common data elements (CDEs) and case report forms (CRFs and standards of data collection and reporting) by a team of leaders in the field. Therefore, the Translational Task Force was appointed by the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES), in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) to define CDEs for animal epilepsy research studies and prepare guidelines for data collection and experimental procedures. If adopted, the preclinical CDEs could facilitate collaborative epilepsy research, comparisons of data across different laboratories, and promote rigor, transparency, and impact, particularly in therapy development.

Background/UNASSIGNED:Schizophrenia, a neurodevelopmental disorder, involves abnormalities in functional connectivity (FC) across distributed neural networks, which are thought to antedate the emergence of psychosis. In a cohort of adolescents and young adults at clinical high risk (CHR) for psychosis, we applied data-driven approaches to resting-state fMRI data so as to systematically characterize FC abnormalities during this period and determine whether these abnormalities are associated with psychosis risk and severity of psychotic symptoms. Methods/UNASSIGNED:Fifty-one CHR participants and 47 matched healthy controls (HCs) were included in our analyses. Twelve of these CHR participants developed psychosis within 3.9 years. We estimated one multivariate measure of FC and studied its relationship to CHR status, conversion to psychosis and positive symptom severity. Results/UNASSIGNED:Multivariate analyses revealed between-group differences in whole-brain connectivity patterns of bilateral temporal areas, mostly affecting their functional connections to the thalamus. Further, more severe positive symptoms were associated with greater connectivity abnormalities in the anterior cingulate and frontal cortex. Conclusions/UNASSIGNED:Our study demonstrates that the well-established FC abnormalities of the thalamus and temporal areas observed in schizophrenia are also present in the CHR period, with aberrant connectivity of the temporal cortex most associated with psychosis risk.

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.

OBJECTIVES: This study examined patient experiences after receiving elevated diabetes screening values using blood collected at a dental clinic. It explores patients' reactions to screening, whether or not they sought recommended medical follow-up, and facilitating factors and barriers to obtaining follow-up care. METHODS: At the comprehensive care clinics at a large, urban College of Dentistry in the United States, haemoglobin A1C (HbA1C) values were obtained from 379 study participants who had not been previously diagnosed with diabetes. In all, 169 (44.6%) had elevated HbA1C values. We analysed quantitative and qualitative data concerning these patients' follow-up with primary care providers (PCPs). RESULTS: We were able to contact 112 (66.3%) of the 169 study participants who had an elevated HbA1C reading. Of that group, 61 (54.5%) received recommended follow-up care from a PCP within 3 months, and an additional 28 (25.0%) said they intended to seek such care. Qualitative themes included the following: the screening letter - opportunity or burden, appreciation for the 3-month follow-up call and barriers to medical follow-up that included the following: lack of knowledge about diabetes, not understanding the importance of follow-up, busyness, financial concerns, fear and denial. CONCLUSIONS: Quantitative and qualitative data demonstrate that dentists, dental hygienists and nurses are well poised to discover and translate new models of patient-centred, comprehensive care to patients with oral and systemic illness.