Negative Affect and Drinking among Indigenous Youth: Disaggregating Within- and Between-Person Effects.

Negative affect (depression/anxiety) and alcohol use among Indigenous youth in Canada remain a concern for many communities. Disparate rates of these struggles are understood to be a potential outcome of colonization and subsequent intergenerational trauma experienced by individuals, families, and communities. Using a longitudinal design, we examined change in alcohol use and negative affect, and reciprocal associations, among a group of Indigenous adolescents. Indigenous youth (N = 117; 50% male; Mage=12.46-16.28; grades 6-10) from a remote First Nation in northern Quebec completed annual self-reported assessments on negative affect (depression/anxiety) and alcohol use. A Latent Curve Model with Structured Residuals (LCM-SR) was used to distinguish between- and within-person associations of negative affect and alcohol use. Growth models did not support change in depression/anxiety, but reports of drinking increased linearly. At the between-person level, girls reported higher initial levels of depression/anxiety and drinking; depression/anxiety were not associated with drinking. At the within-person level, drinking prospectively predicted increases in depression/anxiety but depression/anxiety did not prospectively predict drinking. When Indigenous adolescents reported drinking more alcohol than usual at one wave of assessment, they reported higher levels of negative affect than expected (given their average levels of depression/anxiety) at the following assessment. Our findings suggest that when Indigenous youth present for treatment reporting alcohol use, they should also be screened for negative affect (depression/anxiety). Conversely, if an Indigenous adolescent presents for treatment reporting negative affect, they should also be screened for alcohol use.

The impact of cultural identity, parental communication, and peer influence on substance use among Indigenous youth in Canada.

Heavy drinking and smoking have been found to be among the leading causes of morbidity and mortality within Indigenous youth in North America. The focus of this study was to examine the relative roles of cultural identity, parent-child communication about the harms of substance use (SU), and perception about peers' opinions on heavy drinking and cigarette smoking among Indigenous youth. Strong Indigenous cultural identity, parent-child communication about SU, and affiliation with peers who do not use and/or who disapprove of substance use were all expected to reduce risk for heavy drinking and smoking. Substance use beliefs were hypothesized to mediate these effects. Youth (N = 117; Mage = 14.07; grades 6-11) from two Indigenous communities in Quebec completed self-reports. Consistent with the hypotheses, strong cultural identity predicted increased negative beliefs about substance use, which predicted reduced drinking and smoking. Similarly, affiliating with peers who did not use alcohol predicted decreased positive beliefs about alcohol use, which predicted reduced drinking. Affiliating with peers who did not smoke cigarettes predicted reduced cigarette smoking. Parental influences were not supported in this model. Intervention strategies may benefit from targeting cultural identity, peer groups, and substance use beliefs among Indigenous youth.

Evaluation of the Training in Early Detection for Early Intervention (TEDEI) e-learning course using Kirkpatrick's method.

BACKGROUND: Early intervention in cerebral palsy could improve motor outcome but is only possible following early identification of those affected. There is a need for training of healthcare professionals (HCPs) in early detection of atypical motor development. We developed a video-based e-learning course - Training in Early Detection for Early Intervention (TEDEI) - to address this need. We evaluated whether participation in the course improved knowledge and changed behaviour of HCPs. METHODS: Participants were 332 HCPs (38% physiotherapists, 35.8% occupational therapists), predominantly UK-based (83.7%). Analysis of training effects used mixed methods and followed Kirkpatrick's model, first assessing "Reaction" through a feedback questionnaire involving Likert scale and free text responses (n = 141). "Learning" was assessed through multiple choice questions (MCQs): all 332 HCPs completed a pre-course quiz of 6 MCQs followed by the course, then a 16 item post-course quiz including the 6 pre-course questions. "Behaviour" was assessed through in-depth qualitative interviewing of 23 participants. RESULTS: "Reaction": TEDEI was found to be effective, engaging and well structured. "Learning": Scores improved significantly between the pre-course and post-course quiz, median improvement 1/6 (z = 5.30, p < 0.001). HCPs also reported a perceived improvement in their knowledge, confidence and ability. "Behaviour": HCPs could see how TEDEI would improve their clinical practice through having an assessment framework, ways of working better with parents, and developing observational skills useful for tele-health assessments. CONCLUSION: Our brief e-learning course on early detection for early intervention was viewed positively, improved knowledge and showed potential for positive changes in practice. Kirkpatrick's model provided a useful framework for undertaking this evaluation.

Prognostic interictal electroencephalographic biomarkers and models to assess antiseizure medication efficacy for clinical practice: A scoping review.

Antiseizure medication (ASM) is the primary treatment for epilepsy. In clinical practice, methods to assess ASM efficacy (predict seizure freedom or seizure reduction), during any phase of the drug treatment lifecycle, are limited. This scoping review identifies and appraises prognostic electroencephalographic (EEG) biomarkers and prognostic models that use EEG features, which are associated with seizure outcomes following ASM initiation, dose adjustment, or withdrawal. We also aim to summarize the population and context in which these biomarkers and models were identified and described, to understand how they could be used in clinical practice. Between January 2021 and October 2022, four databases, references, and citations were systematically searched for ASM studies investigating changes to interictal EEG or prognostic models using EEG features and seizure outcomes. Study bias was appraised using modified Quality in Prognosis Studies criteria. Results were synthesized into a qualitative review. Of 875 studies identified, 93 were included. Biomarkers identified were classed as qualitative (visually identified by wave morphology) or quantitative. Qualitative biomarkers include identifying hypsarrhythmia, centrotemporal spikes, interictal epileptiform discharges (IED), classifying the EEG as normal/abnormal/epileptiform, and photoparoxysmal response. Quantitative biomarkers were statistics applied to IED, high-frequency activity, frequency band power, current source density estimates, pairwise statistical interdependence between EEG channels, and measures of complexity. Prognostic models using EEG features were Cox proportional hazards models and machine learning models. There is promise that some quantitative EEG biomarkers could be used to assess ASM efficacy, but further research is required. There is insufficient evidence to conclude any specific biomarker can be used for a particular population or context to prognosticate ASM efficacy. We identified a potential battery of prognostic EEG biomarkers, which could be combined with prognostic models to assess ASM efficacy. However, many confounders need to be addressed for translation into clinical practice.

Response to photic stimulation as a measure of cortical excitability in epilepsy patients.

Studying states and state transitions in the brain is challenging due to nonlinear, complex dynamics. In this research, we analyze the brain's response to non-invasive perturbations. Perturbation techniques offer a powerful method for studying complex dynamics, though their translation to human brain data is under-explored. This method involves applying small inputs, in this case via photic stimulation, to a system and measuring its response. Sensitivity to perturbations can forewarn a state transition. Therefore, biomarkers of the brain's perturbation response or "cortical excitability" could be used to indicate seizure transitions. However, perturbing the brain often involves invasive intracranial surgeries or expensive equipment such as transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups, or animal model studies. Photic stimulation is a widely used diagnostic technique in epilepsy that can be used as a non-invasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans. This involves changing the frequency of strobing light, sometimes triggering a photo-paroxysmal response (PPR), which is an electrographic event that can be studied as a state transition to a seizure state. We investigate alterations in the response to these perturbations in patients with genetic generalized epilepsy (GGE), with (n = 10) and without (n = 10) PPR, and patients with psychogenic non-epileptic seizures (PNES; n = 10), compared to resting controls (n = 10). Metrics of EEG time-series data were evaluated as biomarkers of the perturbation response including variance, autocorrelation, and phase-based synchrony measures. We observed considerable differences in all group biomarker distributions during stimulation compared to controls. In particular, variance and autocorrelation demonstrated greater changes in epochs close to PPR transitions compared to earlier stimulation epochs. Comparison of PPR and spontaneous seizure morphology found them indistinguishable, suggesting PPR is a valid proxy for seizure dynamics. Also, as expected, posterior channels demonstrated the greatest change in synchrony measures, possibly reflecting underlying PPR pathophysiologic mechanisms. We clearly demonstrate observable changes at a group level in cortical excitability in epilepsy patients as a response to perturbation in EEG data. Our work re-frames photic stimulation as a non-invasive perturbation paradigm capable of inducing measurable changes to brain dynamics.

Developing and evaluating a team development intervention to support interdisciplinary teams.

INTRODUCTION: Incentivizing the development of interdisciplinary scientific teams to address significant societal challenges usually takes the form of pilot funding. However, while pilot funding is likely necessary, it is not sufficient for successful collaborations. Interdisciplinary collaborations are enhanced when team members acquire competencies that support team success. METHODS: We evaluated the impact of a multifaceted team development intervention that included an eight-session workshop spanning two half-days. The workshop employed multiple methods for team development, including lectures on empirically supported best practices, skills-based modules, role plays, hands-on planning sessions, and social interaction within and across teams. We evaluated the impact of the intervention by (1) asking participants to assess each of the workshop sessions and (2) by completing a pre/postquestionnaire that included variables such as readiness to collaborate, goal clarity, process clarity, role ambiguity, and behavioral trust. RESULTS: The content of the team development intervention was very well received, particularly the workshop session focused on psychological safety. Comparison of survey scores before and after the team development intervention indicated that scores on readiness to collaborate and behavioral trust were significantly higher among participants who attended the workshop. Goal clarity, process clarity, and role ambiguity did not differ among those who attended versus those who did not. CONCLUSIONS: Multicomponent team development interventions that focus on key competencies required for interdisciplinary teams can support attitudes and cognitions that the literature on the science of team science indicate are predictive of success. We offer recommendations for the design of future interventions.

Smilodon fatalis siblings reveal life history in a saber-toothed cat.

The saber-toothed cat Smilodon fatalis is known predominantly from "predator trap" deposits, which has made many aspects of its life history difficult to infer. Here, we describe an association of at least two subadult and one adult S. fatalis from Pleistocene coastal deposits in Ecuador. The assemblage likely derived from a catastrophic mass mortality event, and thereby provides insights into the behavior of the species. The presence of a P3 in the subadult dentaries suggests inheritance, a rare instance of familial relatedness in the fossil record. The siblings were at least two years old and were associated with an adult that was likely their mother, indicating prolonged parental care in S. fatalis. Comparison with the growth of pantherine cats suggests that S. fatalis had a unique growth strategy among big cats that combines a growth rate that is similar to a tiger and the extended growth period of a lion.

Identification with ancestral culture is associated with fewer internalizing problems among older Naskapi adolescents.

The manifestations of externalizing and internalizing behaviors among minority adolescents might best be understood by examining their relation to culturally specific factors, such as cultural identity, as well as to factors that seem to be relevant across cultures, such as age and gender. In this study, we examined the roles of age and gender in moderating the relation between self-reported cultural identity and externalizing and internalizing problems and the interaction between Indigenous and Mainstream cultural identity in relation to problematic behaviors. The participants included 61 students (32 female) with a mean age of 14.5 years (SD = 1.69) from a Naskapi reserve in Quebec, Canada. Age moderated the relation between identification with Indigenous culture and internalizing symptomatology. Indigenous and Mainstream cultural identity did not interact in predicting internalizing or externalizing problems. Consistent with the available evidence regarding the centrality of identity in adolescent development, the magnitude of the inverse relation between identification with Indigenous culture and number of clinical internalizing symptoms appears to increase in significance later in adolescence. The lack of an interaction between Indigenous and Mainstream cultural identity in relation to internalizing and externalizing problems suggests that it is the need to consider both cultures individually without the assumption that one negates the other.

Evaluation of renal markers of T1D in Sprague-Dawley exposed to 2-aminoanthracene.

The incidence of type 1 diabetes (T1D) and its associated risks of chronic kidney disease or end-stage renal disease development are on the rise. T1D is an autoimmune disease in which insulin-producing beta cells are destroyed. Increased incidence of T1D has been suggested to be a result of environmental factors such as exposure to polycyclic aromatic hydrocarbons (PAHs). 2-aminoanthracene (2AA) is a PAH that has been associated with the onset of early diabetic symptoms. This study was conducted to assess if 2AA dietary ingestion would induce T1D renal injuries. To accomplish study goals, Sprague-Dawley rats were assigned into three 2AA dietary (0, 50, and 100 mg/kg-2AA) ingestion groups for 12 weeks. Animals were evaluated for various morphometric indices, clinical markers, and gene expression. The rats in the 100 mg/kg group lost 5% less weight than the other treatment groups and converted roughly 3% more of their food intake into body mass. Renal histopathology indicated no significant difference between groups. The kidney weight per bodyweight of the 100 mg/kg treatment group was 30.1% greater than the control group. Creatinine concentration of the 100 mg/kg group was 46.2% greater than the control group. Serum glucose levels were significantly elevated in rats exposed to 2AA. On the contrary, serum albumin concentration was significantly reduced in 2AA-treated rats. T1D and genetic markers of renal injury such as FABP1, SPP1, IL-1B, and IL-7 were elevated in treated groups. These results suggest that 2AA may induce the early diabetic renal injuries.

Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism.

Evaluating the cytotoxicity of tin dioxide nanofibers.

Tin dioxide nanofibers (SnDNFs) are small fibers that have many applications. Tin dioxide nanofibers can be used in cosmetics, solar cells, toxic gas release sensors, and air pollution control. To date there have been few studies on the cytotoxicity of SnDNFs. The goal of this research is to determine if electrospun SnDNFs are toxic in a lung cancer cell line (A549). Considering the nano-scale size of the fibers, they can easily be inhaled and enter the pulmonary system and cause toxic effects in the lung. Occupational exposure to SnDNFs has been linked to pulmonary disease, making the A549 cell line important in this study. Nanofiber toxicity can vary based upon the characteristics of the fibers. Smaller nanofibers have been shown to have more toxic effects than their larger counterparts. The synthesized SnDNFs were characterized using SEM, Raman spectroscopy, and powder X-ray diffractometer (PXRD). SEM images showed the fibers to be 200-300 nm in diameter. Raman spectroscopy and PXRD indicated that the fibers were in the rutile phase. After quantifying the SnDNFs, the fibers were introduced to A549 cells at concentrations ranging from 0.02-500 µg mL-1 and incubated at 37°C. These cells were quantified with the MTT assay to measure cell proliferation (IC50 = 0.02 mg mL-1), while lactate dehydrogenase (LDH) leakage was used to determine cytotoxicity, and apoptosis assays to assess the mechanism of cell death. Increasing concentration of SnDNF generated a consequential decrease in cell proliferation and viability. The percent cytotoxicity of SnDNF was not significantly changed at the various concentrations and time frames. In order to gain additional insight about the mechanism of cytotoxicity of SnDNFs, genes with links to inflammation and apoptosis were evaluated and found to be over-expressed in treated cells. At the concentrations of SnDNF examined, SnDNF was mildly toxic to the A549 cells.

Regulation of kindling epileptogenesis by hippocampal Toll-like receptors 2.

This study examined whether Toll-like receptors 2 (TLR2) contribute to rapid kindling epileptogenesis. A TLR2 agonist, lipoteichoic acid (LTA), LTA antibody (LTA-A), or normal saline (control) was administered daily over 3 consecutive days, unilaterally into ventral hippocampus of adult male Wistar rats. Thirty minutes after the last injection, the animals were subjected to a rapid kindling procedure. The ictogenesis was gauged by comparing afterdischarge threshold (ADT) and afterdischarge duration (ADD) before the treatments, after the treatments prior to kindling, and 24 h after kindling. Kindling progression and retention were analyzed using video recording. The results showed that before kindling, LTA produced an ADT reduction. Neither LTA nor LTA-A affected baseline ADD. On kindling progression, LTA accelerated occurrence of generalized seizures, whereas LTA-A delayed this effect. Treatment with LTA-A reduced the number of secondary generalized complex partial seizures. Twenty-four hours after kindling, the rats of both the saline and LTA groups showed increased hippocampal excitability as compared with prekindling parameters. Administration of LTA-A prevented kindling-induced increase of hippocampal excitability. Immunostaining revealed that LTA-A attenuated the inflammatory response produced by seizures. These findings suggest that the activation of TLR2 in the hippocampus may facilitate limbic epileptogenesis.

Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area.

UNLABELLED: Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injection in vivo in wild-type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice. In addition, activation of Epac with the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning. SIGNIFICANCE STATEMENT: Addictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the effects of cocaine were mimicked by activation of Epac but were blocked by genetic deletion of Epac. Furthermore, cocaine-cue associative learning was impaired in mice lacking Epac. These findings uncovered a critical role of Epac in regulating the cellular and behavioral actions of cocaine.

Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery.

Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes to low regenerative capacity in the adult mammalian CNS. Here we show in adult mice that dorsal root ganglion neurons (DRGs) and CST neurons fail to upregulate Sox11 after spinal axon injury. Furthermore, forced viral expression of Sox11 reduces axonal dieback of DRG axons, and promotes CST sprouting and regenerative axon growth in both acute and chronic injury paradigms. In tests of forelimb dexterity, however, Sox11 overexpression in the cortex caused a modest but consistent behavioral impairment. These data identify Sox11 as a key transcription factor that can confer an elevated innate regenerative capacity to CNS neurons. The results also demonstrate an unexpected dissociation between axon growth and behavioral outcome, highlighting the need for additional strategies to optimize the functional output of stimulated neurons.

Is being mindful associated with reduced risk for internally-motivated drinking and alcohol use among undergraduates?

Mindfulness encompasses four core skills: observing, describing, acting with awareness, and accepting without judgment; which aim to increase one's awareness, tolerance, and acceptance of internal experiences (Baer et al., 2004). Despite promising clinical results that mindfulness reduces alcohol craving and relapse, complementary etiological research is underdeveloped. Theory suggests that those who are motivated to drink to change internal states (reduce negative/increase positive affect) are at risk for elevated alcohol use. The ability to accept one's affective state should preclude internally-motivated drinking, and thus, elevated alcohol use. The purpose of this study was to parse out which mindfulness skills are central to alcohol use. We hypothesized that accepting without judgment would be a unique negative predictor of internally-motivated drinking (drinking for coping and enhancement motives) and alcohol use. Students (N=76) completed self-report measures of past month alcohol use and four motives for drinking: to cope, for enhancement, to conform, and for social reasons. Partially supporting our hypotheses, accepting without judgment was negatively associated with drinking for coping motives, but was unassociated with drinking for enhancement motives. Interestingly, acceptance without judgment was negatively associated with drinking for conformity motives (to reduce social rejection). Unexpectedly, acting with awareness, but not accepting without judgment, was a negative predictor of alcohol use. Our findings suggest that interventions aimed at reducing coping- and conformity-motivated drinking and alcohol use by young adults may benefit from incorporating mindfulness skills training (i.e., accepting without judgment; acting with awareness).

Clinical update: communication issues and advance care planning.

OBJECTIVES: To provide a clinical update on practical strategies to enhance the quality of communication in the palliative and end-of-life medical care settings. DATA SOURCES: Published articles, textbooks, reports, and clinical experience. CONCLUSION: The components of effective and compassionate care throughout the advanced illness trajectory require thoughtful and strategic communication with patients, families, and members of the health care team. Unfortunately, few health care professionals are formally trained in communication skills. IMPLICATIONS FOR NURSING PRACTICE: Nurses who possess self-awareness and are skilled in effective communication practices are integral to the provision of high-quality palliative care for patients and families coping with advanced malignancies.

The association of technology in a workplace wellness program with health risk factor reduction.

OBJECTIVE: Determine whether there is a relationship between level of engagement in workplace wellness programs and population/individual health risk reductions. METHODS: A total of 7804 employees from 15 employers completed health risk appraisal and laboratory testing at baseline and again after 2 years of participating in their personalized prevention plan. Population and individual health risk transitions were analyzed across the population, as well as by stage of engagement. RESULTS: Of those individuals who started in a high risk category at baseline, 46% moved down to medium risk and 19% moved down to low risk category after 2 years on their prevention plan. In the group that only engaged through the Web-based technology, 24% reduced their health risks (P < 0.0001). CONCLUSIONS: Engaging technology and interactive Web-based tools can empower individuals to be more proactive about their health and reduce their health risks.