The Role of Therapeutic Engagement, Oral Language Proficiency, and Core Learning Indicators on the Effects of Therapy for Youth with Depression

Youth with depression, particularly ethnic minority youth, have low rates of engagement in mental health services, indicating a large need to better understand the role of engagement in effective treatments for depression (Merikangas et al., 2011). Cognitive behavioral therapy (CBT) is one of the leading psychotherapeutic treatments available for youth with depression (Weisz, McCarty, & Valeri, 2006), but several questions still remain regarding why and in what circumstances this therapy is most appropriate. CBT posits that part of the positive treatment effects is accounted by learning certain cognitive and behavioral skills during and outside of session (i.e., through active homework assignments). This study examined: a) the association between engagement (i.e., homework completion and consumer satisfaction) in a school-based group CBT program and changes in depressive symptoms; b) the mediational role of core learning indicators (social functioning and negative cognitions) in the relationship between engagement and change in depressive symptoms; and c) the moderational role of youth English oral language proficiency. The sample of 99 predominantly low-income ethnic minority youth (66.0% female; 85.9% Latino), ages 10 to 14 (M = 12.03, SD = 1.04), participated in the Act & Adapt Program (Polo, Connor, Jensen-Doss, & Weisz, 2009), a manualized group CBT program delivered across nine public schools. Multiple regression analyses revealed that neither engagement variable was directly associated with changes in depressive symptoms. Furthermore, neither change in social functioning nor negative cognitions mediated the engagementtreatment outcome relationship. On the other hand, English oral language 2 proficiency moderated the relationship between homework completion and depressive symptoms (β = -.0002, t = - 2.45, ΔR2 = .05, p \u3c .05), as well as between consumer satisfaction and depressive symptoms (β = .01, t = 2.21; ΔR2 = .04, p \u3c.05). Specifically, those with high levels of English oral language proficiency had an association between increased homework completion and depressive symptoms, while those with low levels of English oral language proficiency did not have a significant association between homework completion and depressive symptoms. Additionally, those with low English oral language proficiency had an association between increased consumer satisfaction and decreased depressive symptoms, while those with high English oral language proficiency did not have a significant association between homework completion and depressive symptoms. There was some evidence of a moderated mediational effect, with oral language proficiency moderating the indirect effect homework completion on treatment outcomes via negative cognitions. However, probing of this moderation revealed no significant indirect effects at the 10th, 25th, 50th, 75th, or 90th percentile. Implications are discussed for researchers and clinicians to take into consideration youths’ oral language proficiency and how language proficiency may interact with engagement in impacting youth treatment outcomes for depression

Electrophysiological evidence of enhanced performance monitoring in recently abstinent alcoholic men

RATIONALE: Chronic alcoholism is associated with mild to moderate cognitive impairment. Under certain conditions, impairment can be ameliorated by invoking compensatory processes. OBJECTIVE: To identify electrophysiological mechanisms of such compensation that would be required to resolve response conflict. METHODS: 14 abstinent alcoholic men and 14 similarly aged control men performed a variation of the Eriksen flanker task during an electroencephalography (EEG) recording to examine whether alcoholics could achieve and maintain control-level performance and whether EEG markers could identify evidence for the action of compensatory processes in the alcoholics. Monitoring processes engaged following a response were indexed by the correct related negativity (CRN) and error related negativity (ERN), two medial-frontal negative event-related potentials. RESULTS: The alcoholics were able to perform at control levels on accuracy and reaction time (RT). Alcoholics generated larger ERN amplitudes following incorrect responses and larger CRNs following correct responses than controls. Both groups showed evidence of post-error slowing. Larger CRN amplitudes in the alcoholics were related to longer RTs. Also observed in the alcoholics was an association between smaller CRN amplitudes and length of sobriety, suggesting a normalization of monitoring activity with extended abstinence. CONCLUSIONS: To the extent that greater amplitude of these electrophysiological markers of performance monitoring indexes greater resource allocation and performance compensation, the larger amplitudes observed in the alcoholic than control group support the view that elevated performance monitoring enables abstinent alcoholics to overcome response conflict, as was evident in their control-level performance

Factors Associated With, and Mitigation Strategies for, Health Care Disparities Faced by Patients With Headache Disorders

To review contemporary issues of health care disparities in headache medicine with regard to race/ethnicity, socioeconomic status (SES), and geography and propose solutions for addressing these disparities. An Internet and PubMed search was performed and literature was reviewed for key concepts underpinning disparities in headache medicine. Content was refined to areas most salient to our goal of informing the provision of equitable care in headache treatment through discussions with a group of 16 experts from a range of headache subspecialties. Taken together, a multitude of factors, including racism, SES, insurance status, and geographical disparities, contribute to the inequities that exist within the health care system when treating headache disorders. Interventions such as improving public education, advocacy, optimizing telemedicine, engaging in community outreach to educate primary care providers, training providers in cultural sensitivity and competence and implicit bias, addressing health literacy, and developing recruitment strategies to increase representation of underserved groups within headache research are proposed as solutions to ameliorate disparities. Neurologists have a responsibility to provide and deliver equitable care to all. It is important that disparities in the management of headache disorders are identified and addressed

Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8⁺ T Cells in Immunotherapy-Resistant and Metastatic Cancers

SIMPLE SUMMARY: Some important signaling proteins that control how cells grow and behave not only act in the cytoplasm but also in the nucleus, where they tether to chromatin. This is especially true for protein kinase C (PKC)-θ, which acts in the nucleus to mediate cancer hallmarks that drive metastasis and in normal T cells. However, current PKC-θ inhibitors are either non-specific or target only its cytoplasmic function. In a bid to develop a novel class of PKC-θ inhibitor that maintains cytoplasmic signaling but inhibits its nuclear function, here we present a novel PKC-θ inhibitor (nPKC-θi2) that specifically inhibits nuclear translocation of PKC-θ without interrupting normal signaling in healthy T cells. We show for the first time that nPKC-θ mediates immunotherapy resistance via its activity in circulating tumor cells and dysfunctional CD8(+) T cells. Our novel inhibitor provides a means to target this process by simultaneously overcoming T-cell exhaustion and cancer stem cell burden. As part of a sequential approach with other therapies, this work paves the way for improving outcomes in cancer patients with immunotherapy-resistant relapse and metastasis. ABSTRACT: Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8(+) T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1(+)/CD8(+) T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8(+) T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8(+) T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy

Use of high-flow nasal cannula oxygenation in ICU adults: a narrative review

Oxygen therapy can be delivered using low-flow, intermediate-flow (air entrainment mask), or high-flow devices. Low/intermediate-flow oxygen devices have several drawbacks that cause critically ill patients discomfort and translate into suboptimal clinical results. These include limitation of the FiO (due to the high inspiratory flow often observed in patients with respiratory failure), and insufficient humidification and warming of the inspired gas. High-flow nasal cannula oxygenation (HFNCO) delivers oxygen flow rates of up to 60\ua0L/min and over the last decade its effect on clinical outcomes has widely been evaluated, such as in the improvement of respiratory distress, the need for intubation, and mortality. Mechanisms of action of HFNCO are complex and not limited to the increased oxygen flow rate. The main aim of this review is to guide clinicians towards evidence-based clinical practice guidelines. It summarizes current knowledge about HFNCO use in ICU patients and the potential areas of uncertainties. For instance, it has been recently suggested that HFNCO could improve the outcome of patients with hypoxemic acute respiratory failure. In other settings, research is ongoing and additional evidence is needed. For instance, if intubation is required, studies suggest that HFNCO may help to improve preoxygenation and can be used after extubation. Likewise, HFNCO might be used in obese patients, or to prevent respiratory deterioration in hypoxemic patients requiring bronchoscopy, or for the delivery of aerosol therapy. However, areas for which conclusive data exist are limited and interventions using standardized HFNCO protocols, comparators, and relevant clinical outcomes are warranted