Demystifying treatment disposition patterns for psychiatrically high-risk youth referred for intensive outpatient psychiatric services: The role of demographics and telehealth.

Intensive outpatient (IOP) psychiatric treatment is increasingly deployed to meet the needs of psychiatrically high-risk youth; however, documentation of treatment disposition for in-person and/or telehealth modalities following treatment referral is largely unknown. The current study examined psychiatrically high-risk youth baseline treatment disposition patterns and explored variations according to treatment modality (telehealth vs. in-person). Using archival records of 744 adolescents (Mage = 14.91, SD = 1.60) admitted to a psychiatric IOP, multinomial logistic regressions revealed that commercially insured youth fared better than non-commercially insured youth with respect to treatment completion. When treatment modality was accounted for, youth treated on telehealth were no more likely to be psychiatrically hospitalized compared to youth treated with in-person services. However, youth treated on telehealth dropped out due to excessive absences or withdrawal/refusal to a greater extent than those treated in person. Future studies should examine clinical outcomes in addition to treatment disposition patterns to further understand youth's course of treatment at intermediate level of care settings (e.g., IOP).

Brain profiling in murine colitis and human epilepsy reveals neutrophils and TNFα as mediators of neuronal hyperexcitability.

BACKGROUND: Patients with chronic inflammatory disorders such as inflammatory bowel disease frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed. METHODS: Because intestinal disorders such as inflammatory bowel disease are robustly associated with neurological symptoms, we used three different mouse models of colitis to investigate the impact of peripheral inflammatory disease on the brain. We assessed neuronal hyperexcitability, which is associated with many neurological symptoms, by measuring seizure threshold in healthy and colitic mice. We profiled the neuroinflammatory phenotype of colitic mice and used depletion and neutralization assays to identify the specific mediators responsible for colitis-induced neuronal hyperexcitability. To determine whether our findings in murine models overlapped with a human phenotype, we performed gene expression profiling, pathway analysis, and deconvolution on microarray data from hyperexcitable human brain tissue from patients with epilepsy. RESULTS: We observed that murine colitis induces neuroinflammation characterized by increased pro-inflammatory cytokine production, decreased tight junction protein expression, and infiltration of monocytes and neutrophils into the brain. We also observed sustained neuronal hyperexcitability in colitic mice. Colitis-induced neuronal hyperexcitability was ameliorated by neutrophil depletion or TNFα blockade. Gene expression profiling of hyperexcitable brain tissue resected from patients with epilepsy also revealed a remarkably similar pathology to that seen in the brains of colitic mice, including neutrophil infiltration and high TNFα expression. CONCLUSIONS: Our results reveal neutrophils and TNFα as central regulators of neuronal hyperexcitability of diverse etiology. Thus, there is a strong rationale for evaluating anti-inflammatory agents, including clinically approved TNFα inhibitors, for the treatment of neurological and psychiatric symptoms present in, and potentially independent of, a diagnosed inflammatory disorder.

Cutting Edge: Engineering Active IKKß in T Cells Drives Tumor Rejection.

Acquired dysfunction of tumor-reactive T cells is one mechanism by which tumors can evade the immune system. Identifying and correcting pathways that contribute to such dysfunction should enable novel anticancer therapy design. During cancer growth, T cells show reduced NF-κB activity, which is required for tumor rejection. Impaired T cell-intrinsic NF-κB may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell-intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase ß (IKKß). T cell-restricted constitutively active IKKß augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control. Transfer of constitutively active IKKß-transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell-intrinsic NF-κB can result in tumor control, thus identifying a pathway with potential clinical applicability.

Developmental variations in the impact of intimate partner violence exposure during childhood.

BACKGROUND: Intimate partner violence (IPV) is a pervasive problem impacting individuals around the globe. The consequences of IPV extend beyond the adults in the relationship, as children witness a significant proportion of such violence. Exposure to IPV during childhood has devastating effects across multiple domains of functioning. METHODS: This article reviews empirical studies of the effects of exposure to IPV by developmental stage. RESULTS: The psychological, social, physical, and cognitive consequences of witnessing IPV are examined across development; from the impact of prenatal exposure to effects in infancy and toddlerhood, the preschool years, school-aged children, and adolescence. CONCLUSIONS: The review concludes by providing suggestions for future research based on the identified developmental variations, recommendations for developmentally-sensitive interventions for children who have witnessed IPV, and directions for policy to address the issue of violence exposure early in the lives of children.

Adaptive Immunity and Antigen-Specific Activation in Obesity-Associated Insulin Resistance.

Type 2 diabetes mellitus (T2D) is a metabolic disease that is strongly tied to obesity and often preceded by insulin resistance (IR). It has been established that chronic inflammation of hypertrophic adipose tissue depots in obese individuals leads to obesity-associated IR and is mediated by cells of the innate immune system, particularly macrophages. More recently, cells of the adaptive immune system, B and T lymphocytes, have also emerged as important regulators of glucose homeostasis, raising the intriguing possibility that antigen-driven immune responses play a role in disease. In this review, we critically evaluate the roles that various B and T cell subsets play in IR, and then we examine the data suggesting that antigen-driven mechanisms, such as antigen presentation and costimulation, may drive the activity of these lymphocytes.

T cell-NF-κB activation is required for tumor control in vivo.

BACKGROUND: T cells have the capacity to eliminate tumors but the signaling pathways by which they do so are incompletely understood. T cell priming requires activation of the transcription factors AP-1, NFAT and NF-κB downstream of the TCR, but whether activation of T cell-NF-κB in vivo is required for tumor control has not been addressed. In humans and mice with progressively growing tumors, the activity of T cell-intrinsic NF-κB is often reduced. However, it is not clear if this is causal for an inability to reject transformed cells, or if it is a consequence of tumor growth. T cell-NF-κB is important for T cell survival and effector differentiation and plays an important role in enabling T cells to reject cardiac and islet allografts, suggesting the possibility that it may also be required for tumor elimination. In this study, we tested whether normal T cell-NF-κB activation is necessary for the rejection of tumors whose growth is normally controlled by the immune system. METHODS: Mice with genetically impaired T cell-NF-κB activity were subcutaneously injected with MC57-SIY tumor cells. Tumor growth was measured over time, and the anti-tumor immune response was evaluated using flow cytometry and cytokine detection assays. RESULTS: Mice with impaired T cell-NF-κB activity were unable to reject tumors that were otherwise eliminated by wildtype mice, despite equal accumulation of tumor-reactive T cells. In addition, specific impairment of NF-κB signaling downstream of the TCR was sufficient to prevent tumor rejection. Tumor antigen-specific T cell-IFN-γ and TNF-α production, as well as cytotoxic ability, were all reduced in mice with impaired T cell-NF-κB, suggesting an important role for this transcription factor in the effector differentiation of tumor-specific effector T cells. CONCLUSIONS: Our results have identified the NF-κB pathway as an important signaling axis in T cells, required for the elimination of growing tumors in vivo. Maintaining or enhancing T cell-NF-κB activity may be a promising avenue for anti-tumor immunotherapy.