Randomized Noninferiority Trial of Telehealth Delivery of Cognitive Behavioral Treatment of Insomnia Compared to In-Person Care.

Objective: Insomnia is prevalent and is associated with a range of negative sequelae. Cognitive behavioral treatment for insomnia (CBT-I) is the recommended intervention, but availability is limited. Telehealth provides increased access, but its efficacy is not certain. The objective of this study was to compare the efficacy of CBT-I delivered by telehealth to in-person treatment and to a waitlist control.Methods: Individuals with DSM-5 insomnia disorder (n = 60) were randomized to telehealth CBT-I, in-person CBT-I, or 8-week waitlist control. CBT-I was delivered over 6-8 weekly sessions by video telehealth or in-person in an outpatient clinic. Follow-up assessments were at 2 weeks and 3 months posttreatment. The Insomnia Severity Index (ISI) was the primary outcome. Change in ISI score was compared between the CBT-I group in an intent-to-treat, noninferiority analysis using an a priori margin of -3.0 points. All analyses were conducted using mixed-effects models. Data collection occurred from November 2017-July 2020.Results: The mean (SD) change in ISI score from baseline to 3-month follow-up was -7.8 (6.1) points for in-person CBT-I, -7.5 (6.9) points for telehealth, and -1.6 (2.1) for waitlist, and the difference between the CBT-I groups was not statistically significant (t28 = -0.98, P = .33). The lower confidence limit of this between-group difference in the mean ISI changes was greater than the a priori margin of -3.0 points, indicating that telehealth treatment was not inferior to in-person treatment. There were significant improvements on most secondary outcome measures but no group differences.Conclusions: Telehealth CBT-I may produce clinically significant improvements in insomnia severity that are noninferior to in-person treatment. CBT-I is also associated with significant gains across a range of domains of functioning. Telehealth is a promising option for increasing access to treatment without loss of clinical gains.Trial Registration: ClinicalTrials.gov identifier: NCT03328585.

Treatment of social anxiety disorder and attenuated psychotic symptoms with cannabidiol.

Anxiety disorders in young people are frequently comorbid with other mental disorders and respond unsatisfactorily to first-line treatment in many cases. Here, we report the case of a 20-year-old man with severe social anxiety disorder, major depressive disorder, insomnia and attenuated psychotic symptoms despite ongoing treatment with cognitive behavioural therapy and mirtazapine who was treated with adjunctive cannabidiol (CBD) in doses between 200 and 800 mg/day for 6 months. During treatment with CBD, he experienced subjective benefits to his anxiety, depression and positive symptoms during treatment that were confirmed by clinicians and by standardised research instruments. Findings from this case study add to existing evidence in support of the safety of CBD and suggest that it may be useful for young people with treatment refractory anxiety and for attenuated psychotic symptoms.

Global research priorities for youth mental health.

AIM: Over the past two decades, the youth mental health field has expanded and advanced considerably. Yet, mental disorders continue to disproportionately affect adolescents and young adults. Their prevalence and associated morbidity and mortality in young people have not substantially reduced, with high levels of unmet need and poor access to evidence-based treatments even in high-income countries. Despite the potential return on investment, youth mental disorders receive insufficient funding. Motivated by these continual disparities, we propose a strategic agenda for youth mental health research. METHOD: Youth mental health experts and funders convened to develop youth mental health research priorities, via thematic roundtable discussions, that address critical evidence-based gaps. RESULTS: Twenty-one global youth mental health research priorities were developed, including population health, neuroscience, clinical staging, novel interventions, technology, socio-cultural factors, service delivery, translation and implementation. CONCLUSIONS: These priorities will focus attention on, and provide a basis for, a systematic and collaborative strategy to globally improve youth mental health outcomes.

The inflammation paradox in the evolution of mammalian pregnancy: turning a foe into a friend.

A widely discussed physiological puzzle of mammalian pregnancy is the immunological paradox, which asks: why is the semi-allogenic fetus not attacked by the mother's adaptive immune system? Here, we argue that an additional, and perhaps more fundamental paradox is the question: why is embryo implantation so similar to inflammation while inflammation is also the greatest threat to the continuation of pregnancy? Equally puzzling is the question of how this arose during evolution. We call this the inflammation paradox. We argue that acute endometrial inflammation was ancestrally a natural maternal reaction to the attaching blastocyst, a situation still observed in the opossum. Eutherian implantation arose through a transformation of the acute inflammation into a process essential for implantation by causing vascular permeability and matrix reorganization as well as by suppressing the effects deleterious to the fetus. We propose that this model allows us to understand the differences between 'good inflammation' and 'bad inflammation'. Further, it allows us to understand the influence of inflammation on the outcome of pregnancy and maternal health.

Expression of Selenoproteins Is Maintained in Mice Carrying Mutations in SECp43, the tRNA Selenocysteine 1 Associated Protein (Trnau1ap).

Selenocysteine tRNA 1 associated protein (Trnau1ap) has been characterized as a tRNA[Ser]Sec-binding protein of 43 kDa, hence initially named SECp43. Previous studies reported its presence in complexes containing tRNA[Ser]Sec implying a role of SECp43 as a co-factor in selenoprotein expression. We generated two conditionally mutant mouse models targeting exons 3+4 and exons 7+8 eliminating parts of the first RNA recognition motif or of the tyrosine-rich domain, respectively. Constitutive inactivation of exons 3+4 of SECp43 apparently did not affect the mice or selenoprotein expression in several organs. Constitutive deletion of exons 7+8 was embryonic lethal. We therefore generated hepatocyte-specific Secp43 knockout mice and characterized selenoprotein expression in livers of mutant mice. We found no significant changes in the levels of 75Se-labelled hepatic proteins, selenoprotein levels as determined by Western blot analysis, enzymatic activity or selenoprotein mRNA abundance. The methylation pattern of tRNA[Ser]Sec remained unchanged. Truncated Secp43 Δ7,8mRNA increased in Secp43-mutant livers suggesting auto-regulation of Secp43 mRNA abundance. We found no signs of liver damage in Secp433-mutant mice, but neuron-specific deletion of exons 7+8 impaired motor performance, while not affecting cerebral selenoprotein expression or cerebellar development. These findings suggest that the targeted domains in the SECp43 protein are not essential for selenoprotein biosynthesis in hepatocytes and neurons. Whether the remaining second RNA recognition motif plays a role in selenoprotein biosynthesis and which other cellular process depends on SECp43 remains to be determined.

Erythrocyte polyunsaturated fatty acid levels in young people at ultra-high risk for psychotic disorder and healthy adolescent controls.

Erythrocyte polyunsaturated fatty acid (PUFA) levels from individuals at ultra-high risk (UHR) for psychosis (n = 80) were compared to existing data from healthy controls (n = 142). Results demonstrated PUFA deficits (α-linolenic acid, eicosapentanoic acid, all ω-6 PUFAs) for the UHR group. Findings provide a rationale for PUFA based interventions in emerging psychosis.

Delayed sleep onset in depressed young people.

BACKGROUND: The circadian abnormality of delayed sleep phase has been suggested to characterise a subgroup of depressed young adults with different risk factors and course of illness. We aim to assess the prevalence and factors, particularly substance use, associated with such delay in a large help-seeking cohort of young people with mental health problems. METHODS: From a consecutively recruited sample of 802 help-seeking young people, 305 (38%) had at least moderate depressive symptoms (QIDS-C16 >10), sleep data and did not have a chronic severe mental illness. Demographic and clinical characteristics were evaluated through self report and clinical interview. Delayed sleep phase was defined as a sleep onset between the hours of 02:00 a.m. - 06:00 a.m. and the characteristics of this group were compared to normal phase sleepers. RESULTS: Delayed sleep onset was reported amongst 18% (n = 56/305) of the depressed group compared to 11% of the non-depressed young people. Amongst the depressed group, delayed sleep onset was associated with tobacco, alcohol and cannabis misuse and short sleep duration (x̅: 5.8 hrs vs. x̅: 7.8 hrs). There were no differences in demographic factors, personality traits or symptoms. Tobacco smoking was very common: In logistic regression analyses only tobacco use (OR 2.28, 95% CI: 1.04 - 5.01) was associated with delayed sleep onset. There was no interaction with age. CONCLUSIONS: Delayed sleep onset was twice as common in depressed young people as the general population and young people with other mental health problems, and is a potential marker for a subgroup of mood disorders. Those with delayed sleep onset were not more severely depressed but had short sleep duration, a risk for chronic psychological ill health, and higher levels of tobacco use. Nicotine use was common in this group, has biological evidence as a sleep disrupter, and requires specifically addressing in this population.

Sexual trauma increases the risk of developing psychosis in an ultra high-risk "prodromal" population.

Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large "Ultra High Risk" (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4-14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2-4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals.

Repressor domain and nuclear localization signal of the murine Hoxa-11 protein are located in the homeodomain: no evidence for role of poly alanine stretches in transcriptional repression.

Hoxa-11 is a member of the homeodomain class of transcription factors, which play important roles in metazoan development. Hoxa-11 is particularly interesting because it is involved in a major mammalian innovation, uterus development and gestation. We are interested in the molecular changes underlying this evolutionary innovation. Although phenotypes resulting from loss of functions are well investigated (e.g., female sterility), little is known about the domains contributing to Hoxa-11 protein function. We therefore mapped the domains mediating two essential transcription factor functions, nuclear localization and transcriptional activity in the mouse Hoxa-11 protein. Our results show that the mammal-specific alanine repeat does not contribute to repressor activity, as has been hypothesized based on amino acid composition and analogy with other repressor domains. Interestingly, both the repressor domain as well as the nuclear localization signal (NLS) are located within the homeodomain, adding to the growing evidence that the homeodomain is a multifunctional domain which fulfills essential transcription factor functions beyond DNA binding. It is proposed that the high degree of conservation of the homeodomain is due to the multiple functional constraints that result from the various conserved functions accommodated in the homeodomain.