Psychopharmacologic Treatment of Children Prenatally Exposed to Drugs of Abuse

Objective This pilot study compared the pharmacologic treatment history and clinical outcomes observed in pediatric outpatients with psychiatric disorders exposed to drugs of abuse in utero to those of an age-matched, sex-matched and psychiatric disorder-matched, non-drug-exposed group. Methods In this matched cohort study, medical records of children treated at an academic, child and adolescent psychiatry outpatient clinic were reviewed. Children with caregiver-reported history of prenatal drug exposure were compared with a non-drug-exposed control group being cared for by the same providers. Patients were rated with the Clinical Global Impressions—Severity scale (CGI-S) throughout treatment. The changes in pre-treatment and post-treatment CGI-S scores and the total number of medication trials were determined between groups. Results The drug-exposed group (n = 30) had a higher total number of lifetime medication trials compared with the non-drug-exposed group (n = 28) and were taking significantly more total medications, at their final assessment. Unlike the non-drug-exposed group, the drug-exposed group demonstrated a lack of clinical improvement. Conclusions These results suggest that in utero drug-exposed children may be more treatment-refractory to or experience greater side effects from the pharmacologic treatment of psychiatric disorders than controls, although we cannot determine if early environment or drugs exposure drives these findings

Instructional Models for Course-Based Research Experience (CRE) Teaching

The course-based research experience (CRE) with its documented educational benefits is increasingly being implemented in science, technology, engineering, and mathematics education. This article reports on a study that was done over a period of 3 years to explicate the instructional processes involved in teaching an undergraduate CRE. One hundred and two instructors from the established and large multi-institutional SEA-PHAGES program were surveyed for their understanding of the aims and practices of CRE teaching. This was followed by large-scale feedback sessions with the cohort of instructors at the annual SEA Faculty Meeting and subsequently with a small focus group of expert CRE instructors. Using a qualitative content analysis approach, the survey data were analyzed for the aims of inquiry instruction and pedagogical practices used to achieve these goals. The results characterize CRE inquiry teaching as involving three instructional models: 1) being a scientist and generating data; 2) teaching procedural knowledge; and 3) fostering project ownership. Each of these models is explicated and visualized in terms of the specific pedagogical practices and their relationships. The models present a complex picture of the ways in which CRE instruction is conducted on a daily basis and can inform instructors and institutions new to CRE teaching

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Successful passive sentence comprehension among Danish adolescents with Autism Spectrum Disorders

Background and aims Language abilities vary greatly across children with autism spectrum disorders (ASD). In the present study, we investigate passive sentence comprehension, which has been underexplored among individuals with autism spectrum disorders and found to be delayed among other clinical populations. This study is the first to assess grammatical comprehension among Danish-speaking adolescents with autism spectrum disorders. Methods Fifteen Danish-speaking adolescents with autism (mean age: 14.9 years; age range: 13–18 years) participated in a picture selection task assessing comprehension of passive sentences relative to active sentences. We compared our findings for adolescents with autism spectrum disorders to those of 15 typically developing Danish-speaking adolescents matched for age and nonverbal reasoning as measured by the Matrix subtest of the WISC-IV/WAIS-IV. We also analyzed associations between passive comprehension and nonverbal reasoning. Results The results showed ceiling effects for both groups on all sentence types indicating that Danish adolescents with autism spectrum disorders do not face problems comprehending passive sentences. However, when considering variation within the autism spectrum disorder group, correct passive comprehension was highly significantly associated with nonverbal reasoning for the autism spectrum disorder group ( r  = .75), while this was not the case for the typically developing adolescents. Analyses of the few errors produced showed a preference for Theta-role reversal errors in the autism spectrum disorder and the typically developing groups. Conclusions Danish-speaking adolescents with high-functioning autism spectrum disorders do not show impairment in passive sentence comprehension. Correlation analyses however show that for adolescents with autism spectrum disorders, passive sentence comprehension is associated with nonverbal reasoning. We discuss how these results can be viewed as consistent with the few previous studies on passive comprehension in individuals with autism spectrum disorders. Implications Our study provides additional cross-linguistic evidence that passive comprehension is not problematic for individuals with high-functioning autism spectrum disorders. The finding of the relationship between nonverbal reasoning and passive sentence comprehension may inform clinical best practices as children with autism spectrum disorders who underperform in measures of nonverbal reasoning may benefit from additional receptive language screening

The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes

Background and objectives: The primary aim was to determine risk factors for flumazenil administration during postanesthesia recovery. A secondary aim was to describe outcomes among patients who received flumazenil. Methods: Patients admitted to the postanesthesia recovery room at a large, academic, tertiary care facility after surgery under general anesthesia from January 1, 2010, to April 30, 2015, were identified and matched to 2 controls each, by age, sex, and surgical procedure. Flumazenil was administered in the recovery phase immediately after general anesthesia, according to the clinical judgment of the anesthesiologist. Demographic, procedural, and outcome data were extracted from the electronic health record. Conditional logistic regression, accounting for the 1:2 matched-set case-control study designs, was used to assess characteristics associated with flumazenil use. Results: The incidence of flumazenil administration in the postanesthesia care unit was 9.9 per 10,000 (95% CI, 8.4–11.6) general anesthetics. History of obstructive sleep apnea (Odds Ratio [OR] = 2.27; 95% CI 1.02–5.09), longer anesthesia (OR = 1.13; 95% CI 1.03–1.24 per 30 minutes), use of total intravenous anesthesia (OR = 6.09; 95% CI 2.60–14.25), and use of benzodiazepines (OR = 8.17; 95% CI 3.71–17.99) were associated with risk for flumazenil administration. Among patients who received midazolam, cases treated with flumazenil received a higher median (interquartile range) dose than controls: 3.5 mg (2.0–4.0 mg) vs. 2.0 mg (2.0–2.0 mg), respectively (p < 0.001). Flumazenil use was correlated with a higher rate of unanticipated noninvasive positive pressure ventilation, longer postanesthesia care unit stay, and increased rate of intensive care unit admissions. Conclusions: Patients who required flumazenil postoperatively had received a higher dosage of benzodiazepines and utilized more postoperative health care resources. More conservative perioperative use of benzodiazepines may improve postoperative recovery and use of health care resources. Resumo: Justificativa e objetivos: Determinar os fatores de risco da administração de flumazenil durante a recuperação pós-anestésica e descrever os desfechos entre os pacientes que receberam flumazenil. Métodos: Os pacientes admitidos em sala de recuperação pós-anestésica de um grande centro universitário em setor terciário de cuidados pós-cirurgia sob anestesia geral entre 1° de janeiro de 2010 e 30 de abril de 2015 foram identificados e pareados com dois controles cada por idade, sexo e procedimento cirúrgico. Flumazenil foi administrado na fase de recuperação imediatamente após a anestesia geral, de acordo com a avaliação clínica do anestesiologista. Os dados demográficos, dos procedimentos e dos desfechos foram extraídos do registro eletrônico de saúde. A regressão logística condicional para os desenhos do estudo de caso-controle pareado em 1:2 foi utilizada para avaliar as características associadas ao uso de flumazenil. Resultados: A incidência da administração de flumazenil em sala de recuperação pós-anestésica foi de 9,9 por 10.000 (95% IC: 8,4-1,6) anestesias gerais. História da apneia obstrutiva do sono (razão de chances [OR] = 2,27; IC 95%: 1,02-5,09), anestesia de longa duração (OR = 1,13; IC 95%: 1,03-1,24 por 30 minutos), uso de anestesia intravenosa total (OR = 6,09; IC de 95%: 2,60-14,25) e uso de benzodiazepínicos (OR = 8,17; IC 95%: 3,71-17,99) foram associados a risco para a administração de flumazenil. Entre os pacientes que receberam midazolam, os casos tratados com flumazenil receberam uma dose mediana mais alta (intervalo interquartil) do que os controles: 3,5 mg (2,0-4,0 mg) vs. 2,0 mg (2,0-2,0 mg), respectivamente (p < 0,001). O uso de flumazenil foi correlacionado com uma taxa maior não prevista de ventilação não invasiva com pressão positiva, permanência mais longa em sala de recuperação pós-anestésica e aumento da taxa de admissões em unidade de terapia intensiva. Conclusões: Os pacientes que precisaram de flumazenil no pós-operatório receberam uma dose maior de benzodiazepínicos e usaram mais recursos de cuidados da saúde no pós-operatório. O uso mais conservador de benzodiazepínicos no período perioperatório pode melhorar a recuperação e o uso de recursos de cuidados da saúde no pós-operatório. Keywords: Flumazenil, Benzodiazepine, Postanesthesia care unit, Postoperative complications, Palavras-chave: Flumazenil, Benzodiazepínico, Sala de recuperação pós-anestésica, Complicações pós-operatória

Additional file 1 of The Association of Agent Orange Exposure with the progression of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based study of Vietnam War Era Veterans

Additional file 1. Supplemental file for detailed methods and results

Effectively training dementia care specialists and other dementia professionals on using the DICE ApproachTM with caregivers to improve the management of behavioral and psychological symptoms of dementia

Introduction: Most persons living with dementia will exhibit at least one behavioral or psychological symptom of dementia (BPSD) (Kales, et al., 2015). As brain pathology progresses, challenging behaviors can increase in frequency and severity, causing an increase in caregiver stress and burden. Furthermore, BPSD can result in unplanned hospitalizations and unnecessary use of psychotropic medications. Non‐pharmacological management of BPSD should be the first line of treatment. The DICE (Describe, Investigate, Create, Evaluate) ApproachTM was developed by experts from the University of Michigan and John Hopkins University, to help caregivers learn how to identify and manage BPSD. This project describes a statewide implementation of the DICE approach with community‐based dementia care providers.MethodsFrom September 2017 to April 2020, we held four DICE trainings (three in‐person trainings, one web‐based training) for Dementia Care Specialists (DCSs) and other dementia care professionals who work directly with family caregivers of people with dementia in Wisconsin. We assessed trainees’ knowledge and attitudes from the Dementia Attitudes Scale (DAS) and the Knowledge about Memory Loss and Care test (KAML‐C) at baseline of training, immediately after training, and six months after training. Consultations were provided to address challenging cases.ResultsParticipants (N=136) in both in‐person and online DICE trainings experienced significant changes in knowledge, self‐efficacy and attitudes from baseline to post‐training (immediately after training) assessments (p<.01) (see Table 2 for details). Narrative feedback from trainees was generally very positive. Trainees used DICE with 165 caregivers who were primarily non‐Hispanic white (92%) females (74.4%) from an urban location (68.1%), caring for their spouse (52.7%) (Table 1).Discussion: By using the DICE approach with caregivers of persons with dementia, Wisconsin’s DCSs and other dementia professionals are uniquely positioned to help reduce risks associated with BPSD, including the use of psychotropic medications. Training satisfaction was high, knowledge about BPSD increased, and attitudes improved. The DICE trainings prepared trainees to implement this intervention with 165 family caregivers. A follow‐up survey will explore the real‐world application of DICE, including barriers to its use and modifications made in communities across the state.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171246/1/alz049782.pd

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure suppressive. MiR-324-5p inhibition also blocks kainic-acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic-acid-induced seizure onset in wild-type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset