Transitions in mental health and addiction care for youth and their families: a scoping review of needs, barriers, and facilitators.

INTRODUCTION: Transitional-aged youth (TAY) with mental health and/or addictions (MHA) concerns and their families experience significant challenges finding, accessing, and transitioning through needed MHA care. To develop appropriate supports that assist TAY and their families in navigating MHA care, their experiences of transitions in the MHA care system must be better understood. This scoping review identifies and explores the needs, barriers, and facilitators for TAY and their families when transitioning through MHA care. METHODS: This scoping review commenced with a search of five relevant databases. Three research team members were involved in title, abstract, and full-text scanning and data extraction. Sources focusing on TAY anywhere between the ages of 12-29 years and meeting the study objectives were included. Extractions compiled background and narrative information about the nature and extent of the data. Analysis and synthesis of findings involved numerical description of the general information extracted (e.g., numbers of sources by country) and thematic analysis of narrative information extracted (e.g., family involvement in TAY help-seeking). RESULTS: A total of 5894 sources were identified. Following title and abstract scanning, 1037 sources remained for full-text review. A total of 66 sources were extracted. Findings include background information about extracted sources, in addition to five themes that emerged pertaining to barriers and facilitators to access and transitions through care and the needs and roles of TAY and families in supporting help-seeking and care transitions: holistic supports, proactive preparation, empowering TAY and families, collaborative relationships, and systemic considerations. These five themes demonstrate approaches to care that can ensure TAY and families' needs are met, barriers are mitigated, and facilitators are enhanced. CONCLUSION: This review provides essential contextual information regarding TAY with MHA concerns and their families' needs when seeking care. Such findings lend to an enhanced understanding of how MHA programs can support this population's needs, involve family members as appropriate, reduce the barriers experienced, and work to build upon existing facilitators.

The Use of Bacteriophages and Immunological Monitoring for the Treatment of a Case of Chronic Septicemic Cutaneous Ulcerative Disease in a Loggerhead Sea Turtle Caretta caretta.

In this case study, phage therapy was applied to treat a multidrug-resistant case of septicemic cutaneous ulcerative disease (SCUD) caused by Citrobacter freundii in a loggerhead sea turtle Caretta caretta. Phages were applied topically, intravenously, into the carapace, and into the exhibit water using various phage cocktails specific to the causative agent over an 8-month period. This was performed in conjunction with antimicrobial therapy. The animal was monitored through weekly cultures, photographs, and complete blood cell counts, as well as immune assays (phagocytosis, plasma lysozyme and superoxide dismutase activity, and plasma electrophoresis profiles). The animal, in comparison to an untreated, unaffected control, had elevated antibody titers to the administered phages, which persisted for at least 35 weeks. Although cultures were clear of C. freundii after phage treatment, the infection did return over time and immune assays confirmed deficiencies when compared to a healthy loggerhead sea turtle. Immune parameters with statistically significant changes over the study period included the following: decreased phagocytosis, increased alpha- and gamma-globulin protein components, and an increased albumin : globulin ratio. When C. freundii appeared again, the multidrug-resistant status had reverted back to normal susceptibility patterns. Although not completely known whether it was another subspecies of bacteria, the therapy did resolve the multidrug-resistant challenge. Phage therapy in combination with antimicrobial agents may be an effective treatment for sea turtles with normally functioning immune systems or less-severe infections. Additional research is needed to better understand and quantify sea turtle immunology.

Economic evaluation of interventions for treatment-resistant depression: A systematic review.

Background: The extraordinarily high prevalence of treatment-resistant depression (TRD), coupled with its high economic burden to both healthcare systems and society, underscore how critical it is that resources are managed optimally to address the significant challenge it presents. Objective: To review the literature on economic evaluation in TRD systematically, with the aim of informing future studies by identifying key challenges specific to the area, and highlighting good practices. Methods: A systematic literature search across seven electronic databases was conducted to identify both within-trial and model-based economic evaluations in TRD. Quality of reporting and study design was assessed using the Consensus Health Economic Criteria (CHEC). A narrative synthesis was conducted. Results: We identified 31 evaluations, including 11 conducted alongside a clinical trial and 20 model-based evaluations. There was considerable heterogeneity in the definition of treatment-resistant depression, although with a trend for more recent studies to use a definition of inadequate response to two or more antidepressive treatments. A broad range of interventions were considered, including non-pharmacological neuromodulation, pharmacological, psychological, and service-level interventions. Study quality as assessed by CHEC was generally high. Frequently poorly reported items related to discussion of ethical and distributional issues, and model validation. Most evaluations considered comparable core clinical outcomes - encompassing remission, response, and relapse. There was good agreement on the definitions and thresholds for these outcomes, and a relatively small pool of outcome measures were used. Resource criteria used to inform the estimation of direct costs, were reasonably uniform. Predominantly, however, there was a high level of heterogeneity in terms of evaluation design and sophistication, quality of evidence used (particularly health state utility data), time horizon, population considered, and cost perspective. Conclusion: Economic evidence for interventions in TRD is underdeveloped, particularly so for service-level interventions. Where evidence does exist, it is hampered by inconsistency in study design, methodological quality, and availability of high quality long-term outcomes evidence. This review identifies a number of key considerations and challenges for the design of future economic evaluations. Recommendations for research and suggestions for good practice are made. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=259848&VersionID=1542096, identifier CRD42021259848.

Navigation for youth mental health and addictions: protocol for a realist review and synthesis of approaches and practices (The NavMAP standards project).

INTRODUCTION: Mental health and/or addiction (MHA) concerns affect approximately 1.2 million children and youth in Canada, yet less than 20% receive appropriate treatment for these concerns. Youth who do not receive appropriate support may disengage from care and may experience lasting MHA issues. Families of these youth also support them in finding and accessing care. Thus, system supports are needed to help youth and their families find and equitably access appropriate care. Navigation is an innovation in MHA care, providing patient-centred support and care planning that helps individuals and families overcome barriers to care. Despite the increasing availability of navigation services for youth with MHA concerns, practices and models vary, and no single source has synthesised evidence regarding approaches and outcomes for this population into comprehensive standards. METHODS AND ANALYSIS: The proposed research will bring together evidence in youth MHA navigation, to establish this important system support as a factor that can enhance the integration and continuity of care for these youth. Our team, which includes researchers, administrators, clinical leads, an MHA navigator and youth and caregivers with lived experience, will be involved in all project stages. Realist Review and Synthesis methodology will be used, the stages of which include: defining scope, searching for evidence, appraising studies and extracting data, synthesising evidence and developing conclusions, and disseminating findings. ETHICS AND DISSEMINATION: Ethics approval is not required, as the study involves review of existing data. Dissemination plans include scientific publications and conferences and online products for stakeholders and the general public.

Review of Florida Red Tide and Human Health Effects.

This paper reviews the literature describing research performed over the past decade on the known and possible exposures and human health effects associated with Florida red tides. These harmful algal blooms are caused by the dinoflagellate, Karenia brevis, and similar organisms, all of which produce a suite of natural toxins known as brevetoxins. Florida red tide research has benefited from a consistently funded, long term research program, that has allowed an interdisciplinary team of researchers to focus their attention on this specific environmental issue-one that is critically important to Gulf of Mexico and other coastal communities. This long-term interdisciplinary approach has allowed the team to engage the local community, identify measures to protect public health, take emerging technologies into the field, forge advances in natural products chemistry, and develop a valuable pharmaceutical product. The Review includes a brief discussion of the Florida red tide organisms and their toxins, and then focuses on the effects of these toxins on animals and humans, including how these effects predict what we might expect to see in exposed people.

Investigating the gene expression profiles of rehabilitated Florida manatees (Trichechus manatus latirostris) following red tide exposure.

To investigate a Florida manatee (Trichechus manatus latirostris) mortality event following a red tide bloom in Southwest Florida, an RNA sequencing experiment was conducted. Gene expression changes in white blood cells were assessed in manatees rescued from a red tide affected area (n = 4) and a control group (n = 7) using RNA sequencing. The genes with the largest fold changes were compared between the two groups to identify molecular pathways related to cellular and disease processes. In total, 591 genes (false discovery rate <0.05) were differentially expressed in the red tide group. Of these, 158 were upregulated and 433 were downregulated. This suggests major changes in white blood cell composition following an exposure to red tide. The most highly upregulated gene, Osteoclast associated 2C immunoglobulin-like receptor (OSCAR), was upregulated 12-fold. This gene is involved in initiating the immune response and maintaining a role in adaptive and innate immunity. The most highly downregulated gene, Piccolo presynaptic cytomatrix protein (PCLO), was downregulated by a factor of 977-fold. This gene is associated with cognitive functioning and neurotransmitter release. Downregulation of this gene in other studies was associated with neuronal loss and neuron synapse dysfunction. Among the cellular pathways that were most affected, immune response, including inflammation, wounds and injuries, cell proliferation, and apoptosis were the most predominant. The pathway with the most differentially expressed genes was the immune response pathway with 98 genes involved, many of them downregulated. Assessing the changes in gene expression associated with red tide exposure enhances our understanding of manatee immune response to the red tide toxins and will aid in the development of red tide biomarkers.

Rethinking satisfaction surveys: minute survey.

The Minute Survey uses 2 questions to assess patient's satisfaction. The first question asks the patient to rate overall satisfaction with the care. The second question asks the patient to explain what worked well and what needed improvement. The Minute Survey reduces cost of conducting satisfaction surveys by (1) reducing cost of printing, (2) reducing cost of handling and mailing, (3) increasing response rate and thus reducing the need for follow-up reminder, and (4) by relying on time to dissatisfied patient as opposed to percent of dissatisfied patients. We report response rate of 34% to 77% to minute surveys. The combination of Minute Survey and analysis of time to dissatisfied patient may reduce the cost of conducting satisfaction surveys by 89% compared with Consumer Assessment of Healthcare Providers and Systems survey suggested for use by Centers for Medicare and Medicaid.

dSno facilitates baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2.

A screen for modifiers of Dpp adult phenotypes led to the identification of the Drosophila homolog of the Sno oncogene (dSno). The dSno locus is large, transcriptionally complex and contains a recent retrotransposon insertion that may be essential for dSno function, an intriguing possibility from the perspective of developmental evolution. dSno is highly transcribed in the embryonic central nervous system and transcripts are most abundant in third instar larvae. dSno mutant larvae have proliferation defects in the optic lobe of the brain very similar to those seen in baboon (Activin type I receptor) and dSmad2 mutants. This suggests that dSno is a mediator of Baboon signaling. dSno binds to Medea and Medea/dSno complexes have enhanced affinity for dSmad2. Alternatively, Medea/dSno complexes have reduced affinity for Mad such that, in the presence of dSno, Dpp signaling is antagonized. We propose that dSno functions as a switch in optic lobe development, shunting Medea from the Dpp pathway to the Activin pathway to ensure proper proliferation. Pathway switching in target cells is a previously unreported mechanism for regulating TGFbeta signaling and a novel function for Sno/Ski family proteins.

Tutorial on monitoring time to next medication error.

Alemi and colleagues in this issue of the journal have proposed that rare events can be monitored by shifting from frequency of the event to the examination of the time to the event. This article examines their claim with data obtained from an acute care hospital in the United States. We examined the data on medication omissions to see whether changes in underlying process can be detected through control charts. Medication errors are rare; the article examines medication errors due to omission, which makes the phenomena rarer. The empirical question was whether changes in process of care could be detected using control charts from data on medication omissions. Two different types of control chart, the XmR and Tukey charts, were used to analyze the data. The control chart with the tightest control limits was chosen for further interpretation. The XmR chart showed that there was sufficient power to detect unusual days in which the time to omission error was higher than historical norm. This article suggests that even rare events can be monitored through judicious use of time to the event. It shows the viability of safety teams using time to sentinel events to monitor progress in reducing frequency of sentinel events.

Disrupted avoidance learning in functional neurological disorder: Implications for harm avoidance theories.

BACKGROUND: Functional neurological disorder (FND) is an elusive disorder characterized by unexplained neurological symptoms alongside aberrant cognitive processing and negative affect, often associated with amygdala reactivity. METHODS: We examined the effect of negative conditioning on cognitive function and amygdala reactivity in 25 FND patients and 20 healthy volunteers (HV). Participants were first conditioned to stimuli paired with negative affective or neutral (CS +/CS -) information. During functional MRI, subjects then performed an instrumental associative learning task to avoid monetary losses in the context of the previously conditioned stimuli. We expected that FND patients would be better at learning to avoid losses when faced with negatively conditioned stimuli (increased harm avoidance). Multi-echo resting state fMRI was also collected from the same subjects and a robust denoising method was employed, important for removing motion and physiological artifacts. RESULTS: FND subjects were more sensitive to the negative CS + compared to HV, demonstrated by a reinforcement learning model. Contrary to expectation, FND patients were generally more impaired at learning to avoid losses under both contexts (CS +/CS -), persisting to choose the option that resulted in a negative outcome demonstrated by both behavioural and computational analyses. FND patients showed enhanced amygdala but reduced dorsolateral prefrontal cortex responses when they received negative feedback. Patients also had increased resting state functional connectivity between these two regions. CONCLUSIONS: FND patients had impaired instrumental avoidance learning, findings that parallel previous observations of impaired action-outcome binding. FND patients further show enhanced behavioural and neural sensitivity to negative information. However, this did not translate to improved avoidance learning. Put together, our findings do not support the theory of harm avoidance in FND. We highlight a potential mechanism by which negative contexts interfere with adaptive behaviours in this under-explored disorder.

In vivo exposure of clearnose skates, Raja eglanteria, to ionizing X-radiation: acute effects on the thymus.

To investigate for the first time the effects of ionizing radiation on thymus of a representative cartilaginous fish, juvenile clearnose skates, Raja eglanteria, were exposed to 0-75 Gy of X-radiation and sacrificed after 12 days. Morphometrics (weight, disc width and total length) and thymus and thymic cyst area were compared to controls using ANOVA. Thymus area declined logarithmically and medullary cysts increased as a function of dose (P < or = 0.05). To assess thymic recovery, skates were exposed to 0, 9, 13.5 or 18 Gy of X-radiation and sacrificed when moribund or on days 10, 20, 30 and 40 post-irradiation. Complete restoration of the thymus was not achieved during the 40-day observation period, although repopulation with pro-thymocytes and partial recovery of thymic architecture were evident histologically. The observed high radiosensitivity of R. eglanteria thymocytes was similar to responses of other vertebrates, but recovery time was prolonged.

Effects of environmental stressors on lymphocyte proliferation in Florida manatees, Trichechus manatus latirostris.

The health of many Florida manatees (Trichechus manatus latirostris) is adversely affected each year by exposure to cold weather or harmful algal blooms (red tide; Karenia brevis). Exposures can be sublethal, resulting in stressed animals that are rescued and taken to authorized facilities for rehabilitation, or lethal if exposures are prolonged or unusually severe. To investigate whether sublethal environmental exposures can impair immune function in manatees, rendering animals vulnerable to disease or death, mitogen-induced proliferation was assessed in lymphocytes from manatees exposed to cold temperatures (N=20) or red tide (N=19) in the wild, and compared to lymphocyte responses from healthy free-ranging manatees (N=32). All animals sampled for this study were adults. Lymphocytes were stimulated in vitro with either concanavalin A (ConA) or phytohemagglutinin (PHA) and proliferation was assessed after 96 h using incorporation of the thymidine analog, bromodeoxyuridine (BrdU), into newly synthesized DNA. Proliferation of lymphocytes from manatees rescued from exposure to red tide or cold-stress was approximately one-third that of lymphocytes from healthy free-ranging manatees. To examine the direct effects of red tide toxins on lymphocyte function, mitogen-induced proliferation was assessed following co-culture of lymphocytes with K. brevis toxin extracts. Stimulation indices decreased with increasing toxin concentration, with a significant decrease in proliferation occurring in the presence of 400 ng red tide toxins/ml. When lymphocytes from cold-stressed manatees were co-cultured with red tide toxin extracts, proliferative responses were reduced even further, suggesting multiple stressors may have synergistic effects on immune function in manatees.

The drop-jump screening test: difference in lower limb control by gender and effect of neuromuscular training in female athletes.

BACKGROUND: A valgus lower limb alignment has been noted during noncontact anterior cruciate ligament injuries. A video drop-jump test can indicate an athlete's ability to control lower limb axial alignment in the coronal plane. HYPOTHESES: Female athletes have decreased knee separation distances on landing and acceleration; male athletes have a neutrally aligned lower limb position. A neuromuscular training program will significantly increase knee separation distance in female athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The authors tested 325 female and 130 male athletes aged 11 to 19 years. The distance between the hips, knees, and ankles was measured during a drop-jump test. The separation distance between the knees and ankles was normalized by the hip separation distance. A neuromuscular training program (Sportsmetrics) was completed by 62 female athletes, and their jump-landing characteristics were reexamined. RESULTS: A marked decrease in knee separation distance was found on takeoff in 80% of female athletes and in 72% of male athletes. There was no difference between male and female athletes in the normalized knee and ankle separation distance during the landing and takeoff phases. The knee separation distance on landing was 23 +/- 9 cm in the female athletes and 22 +/- 8 cm in the male athletes. The normalized knee separation distance was 51% +/- 19% in the female athletes and 51% +/- 15% in the male athletes. After training, statistically significant increases were found in the female athletes in the knee separation distance on landing (29 +/- 8 cm, P < .0001) and in the normalized knee separation distance (68% +/- 18%, P < .0001). The trained female athletes had significantly greater knee separation distance and normalized knee separation distance than did the males (P < .0001). CONCLUSIONS: The majority of untrained female and male athletes demonstrated a valgus alignment appearance on the video test. After neuromuscular training, female athletes had improved knee separation distances and a more neutral lower limb alignment on landing and takeoff.

Familiality of clinical characteristics in schizophrenia.

Few studies have assessed the familiality of clinical characteristics in schizophrenia. Therefore, we set out to investigate the familiality of the following characteristics; age of onset, course of disorder, employment status at onset, impairment during disorder, marital status at onset, mode of onset and premorbid functioning. Clinical characteristics were recorded using the Operational Criteria Checklist for Psychotic Illness for 155 subjects with an RDC diagnosis of schizophrenia, schizoaffective disorder, or psychosis of unknown origin, from 61 families multiply affected by schizophrenia. Age of onset, course of disorder, impairment during disorder, mode of onset, and premorbid functioning were shown to be familial. The familiality of these clinical characteristics supports their use in the delineation of homogeneous subsets for future genetic studies.

Cooperative transcriptional activation by Klf4, Meis2, and Pbx1.

The Kruppel-like factor Klf4 is implicated in tumorigenesis and maintaining stem cell pluripotency, and Klf4 can both activate and repress gene expression. We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or GC box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. In HepG2 cells, reducing expression of endogenous Meis2 or Pbx1 decreases p15 gene expression and increases the number of cells entering S phase. Although DNA binding by all three proteins contributes to full cooperative activation, the sequence requirements for binding by Meis2 and Pbx1 are variable. In the E-cadherin promoter, a Pbx-like site is required for full activation, whereas in the p15 promoter, the Klf4 site appears to play the major role. Through a bioinformatics search we identified additional genes with conserved binding sites for Klf4, Meis2, and Pbx1 and show that at least some of these genes can be activated cooperatively by Klf4 and Meis2/Pbx1. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. This provides a mechanism to modulate transcriptional regulation by the multifunctional Klf4 transcription factor.

An autoinhibitory effect of the homothorax domain of Meis2.

Myeloid ecotropic insertion site (Meis)2 is a homeodomain protein containing a conserved homothorax (Hth) domain that is present in all Meis and Prep family proteins and in the Drosophila Hth protein. The Hth domain mediates interaction with Pbx homeodomain proteins, allowing for efficient DNA binding. Here we show that, like Meis1, Meis2 has a strong C-terminal transcriptional activation domain, which is required for full activation of transcription by homeodomain protein complexes composed of Meis2 and Pbx1. We also show that the activity of the activation domain is inhibited by the Hth domain, and that this autoinhibition can be partially relieved by the interaction of Pbx1 with the Hth domain of Meis2. Targeting of the Hth domain to DNA suggests that it is not a portable trans-acting repression domain. However, the Hth domain can inhibit a linked activation domain, and this inhibition is not limited to the Meis2 activation domain. Database searching reveals that the Meis3.2 splice variant, which is found in several vertebrate species, disrupts the Hth domain by removing 17 codons from the 5'-end of exon 6. We show that the equivalent deletion in Meis2 derepresses the C-terminal activation domain and weakens interaction with Pbx1. This work suggests that the transcriptional activity of all members of the Meis/Prep Hth protein family is subject to autoinhibition by their Hth domains, and that the Meis3.2 splice variant encodes a protein that bypasses this autoinhibitory effect.

The Sno oncogene antagonizes Wingless signaling during wing development in Drosophila.

The Sno oncogene (Snoo or dSno in Drosophila) is a highly conserved protein and a well-established antagonist of Transforming Growth Factor-beta signaling in overexpression assays. However, analyses of Sno mutants in flies and mice have proven enigmatic in revealing developmental roles for Sno proteins. Thus, to identify developmental roles for dSno we first reconciled conflicting data on the lethality of dSno mutations. Then we conducted analyses of wing development in dSno loss of function genotypes. These studies revealed ectopic margin bristles and ectopic campaniform sensilla in the anterior compartment of the wing blade suggesting that dSno functions to antagonize Wingless (Wg) signaling. A subsequent series of gain of function analyses yielded the opposite phenotype (loss of bristles and sensilla) and further suggested that dSno antagonizes Wg signal transduction in target cells. To date Sno family proteins have not been reported to influence the Wg pathway during development in any species. Overall our data suggest that dSno functions as a tissue-specific component of the Wg signaling pathway with modest antagonistic activity under normal conditions but capable of blocking significant levels of extraneous Wg, a role that may be conserved in vertebrates.

In vivo exposure of clearnose skates, Raja eglanteria, to ionising X-radiation: acute effects on the peripheral blood, spleen, and epigonal and Leydig organs.

The effects of ionising radiation on the peripheral blood, spleen, and epigonal and Leydig organs of cartilaginous fishes were investigated using juvenile clearnose skates, Raja eglanteria. Skates (N = 80) were sacrificed 12 days after exposure to 0-75 Gy of X-radiation, and morphometrics (body mass, disc width, total length), mass of spleens and epigonal organs, and peripheral blood leucocyte (PBL) counts were compared to controls using ANOVA. Spleen and epigonal organ mass and PBL counts declined logarithmically as a function of radiation dose. To assess recovery from X-radiation, skates (N = 40) were exposed to 0, 9 or 18 Gy and sacrificed when moribund or on days 10, 20, 30 and 40 post-irradiation. Partial recovery of Leydig organ and splenic red pulp was evident after 40 days in skates exposed to 9 Gy, but no indication of recovery was apparent at higher doses. Median lethal dose by 30 days (LD50/30) was calculated to be 9-18 Gy, similar to that determined for other fishes.

Nitric oxide production by nurse shark (Ginglymostoma cirratum) and clearnose skate (Raja eglanteria) peripheral blood leucocytes.

Reactive nitrogen intermediates, such as nitric oxide (NO), are important immunomodulators in vertebrate immune systems, but have yet to be identified as mediators of host defence in any member of class Chondrichthyes, the cartilaginous fishes. In the present study, production of NO by nurse shark (Ginglymostoma cirratum) peripheral blood leucocytes (PBL) stimulated with bacterial cell wall lipopolysaccharide (LPS) was investigated. PBL were cultured for 24 to 96 h following stimulation with LPS at concentrations ranging from 0 to 25 microg ml(-1), in both serum-supplemented and serum-free culture conditions. Production of NO was measured indirectly using the Griess reaction, with maximal NO production occurring after 72 h using 10% FBS and 10 microg LPS ml(-1). Application of these culture conditions to PBL from another cartilaginous fish (clearnose skate, Raja eglanteria) resulted in a similar NO response. Addition of a specific inhibitor of inducible nitric oxide synthase (iNOS), L-N(6)-(1-iminoethyl)lysine (L-NIL), resulted in a significant decrease in the production of NO by PBL from both species.