Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.

Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.

Responding to the Youth Fentanyl Crisis: Practical Guidance for Child Psychiatrists.

Deaths due to unintentional opioid overdose among youth living in the United States have risen at an extraordinary rate over the past 4 years.1 After remaining stable over the preceding decade, the rate of drug overdose deaths increased more than 2.3-fold from 2019 to 2021 to a record high of 5.49 deaths per 100,000 youth.1 This rise in fatal overdoses is largely due to increased prevalence of illicitly manufactured fentanyl in the drug supply. In 2021, fentanyl was identified in 77.1% of overdose deaths among US adolescents, a 23.5-fold increase from 2010, compared to 13.3% for benzodiazepines, 5.8% for prescription opioids, and 2.3% for heroin.1 Compared to other phases of the opioid crisis, fentanyl-related overdoses are characterized by extraordinarily broad geographic and sociodemographic reach.

Editorial: Marijuana Legalization and Suicide in Adolescents and Transitional-Age Youth: Important Future Directions for This Line of Research.

Marijuana legalization (ML) processes for medical and recreational use in the United States have been prompted by the potential for positive downstream legal effects of decriminalization, including fewer cannabis-related arrests and prosecutions, which have historically disproportionately impacted minoritized communities. However, ML evolved through primarily political processes, with minimal scientific guidance to inform policies. Commercialization has increased youth cannabis access, diversion of parental cannabis, and proliferation of high-potency products, which, along with early use, are associated with poor mental health outcomes.1 Taken together, these findings raise concerns about the impact of medical (MML) and recreational marijuana legalization (RML) on youth mental health.

A systematic review of evidence on integrated management of psychiatric disorders in youth who use cannabis.

Given the risks to mental health associated with cannabis use in youth and the increase in cannabis legalization worldwide and in the U.S., there is a need to understand existing evidence-based approaches to integrated management of psychiatric disorders in youth who use cannabis. This systematic review aimed to appraise the current evidence on integrated treatment for adolescents and young adults with common psychiatric disorders who engage in regular cannabis use. A total of 989 studies were screened for inclusion. Study's titles and abstracts were screened and advanced to full text review for further screening by two independent reviewers. Thirty-five full-text articles were reviewed, with five articles ultimately meeting all criteria for inclusion. Five randomized controlled trials examined the effects of therapeutic interventions in youth with common psychiatric disorders who used cannabis, including two studies on depression, one on bipolar disorder, one on anxiety and one on PTSD were reviewed. No studies were considered high in risk of bias. Overall, there is a paucity of research on the treatment of comorbid adolescent mental health disorders and cannabis use, which limits the ability to draw evidence-based treatment recommendations.

Adolescent Cannabis Use, Comorbid Attention-Deficit/Hyperactivity Disorder, and Other Internalizing and Externalizing Disorders.

Cannabis use often co-occurs with attention-deficit/hyperactivity disorder and other internalizing and externalizing disorders. Treatment planning, including pharmacologic and psychosocial interventions, for these comorbid disorders require thorough diagnostic evaluation to determine the extent of social, emotional, and behavioral impairments, severity of substance use, and motivation for change. Improved understanding of these comorbid disorders will inform treatment planning that address current symptoms and behaviors and may also prevent the development of mental health and substance use disorders in early adulthood.

Adolescent Cannabis Use, Comorbid Attention-Deficit/Hyperactivity Disorder, and Other Internalizing and Externalizing Disorders.

Cannabis use often co-occurs with attention-deficit/hyperactivity disorder and other internalizing and externalizing disorders. Treatment planning, including pharmacologic and psychosocial interventions, for these comorbid disorders require thorough diagnostic evaluation to determine the extent of social, emotional, and behavioral impairments, severity of substance use, and motivation for change. Improved understanding of these comorbid disorders will inform treatment planning that address current symptoms and behaviors and may also prevent the development of mental health and substance use disorders in early adulthood.

Treatment of Adolescent Cannabis Use Disorders.

This review summarizes treatments for cannabis use disorder (CUD) in adolescents. The best supported CUD treatments are cognitive behavioral psychotherapies, including family-based models that facilitate environmental changes and youth-focused models that incorporate skills training, motivational interviewing, and contingency management to promote reductions in cannabis use. Some medications show promise in reducing cannabis craving and withdrawal symptoms. Further research is needed on the efficacy and implementation of existing treatments given the changes in cannabis use trends over time and on emerging technologies that may expand access to evidence-based CUD treatments.

Cannabis Use Is Associated With Depression Severity and Suicidality in the National Comorbidity Survey-Adolescent Supplement.

Objective: To investigate the association of cannabis use with major depression and suicidal behavior in adolescence. Method: Data are from the National Comorbidity Survey-Adolescent Supplement N=10,123, a nationally representative survey of adolescents aged 13 to 18 years. Weighted logistic regression and ordinal regression analyses of major depression and suicidal behavior outcomes were conducted on cannabis variables, incorporating sociodemographic characteristics. Results: Adolescents with lifetime cannabis use have 2.07 times higher odds of mild/moderate (adjusted odds ratio [aOR]; 95% CI=1.69, 2.53) and 3.32 times higher odds of severe major depressive disorder (MDD; aOR; 95% CI=2.31, 4.75). Cannabis use (aOR 6.90, 95% CI=4.67,10.19), mild/moderate MDD (aOR 4.10, 95% CI=2.82, 5.98), and severe MDD (aOR 13.97, 95% CI = 7.59, 25.70) were associated with higher odds of suicide attempt. Past 12-month cannabis use (aOR 3.70, 95% CI = 2.16, 6.32), mild/moderate major depressive episodes (MDE) (aOR 7.85, 95% CI=3.59, 17.17), and severe MDE (aOR 36.36, 95% CI=13.68,96.64) were associated with higher odds of suicide attempt. The frequency of past 12-month cannabis use was associated with higher odds of suicide attempt and with MDE severity, with higher odds among individuals who use cannabis 3 or more days than among individuals who use cannabis less frequently, suggesting a dose effect. Among cannabis users, older age of onset of cannabis use was associated with lower odds of suicidal behaviors. Conclusion: Cannabis use is associated with higher odds of depression and depression severity in adolescence. Furthermore, depression and cannabis use are independently associated with higher odds of suicide attempt. Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

Elucidating the Neurobiologic Etiology of Comorbid PTSD and Substance Use Disorders.

Early childhood maltreatment and other traumatic event experiences ("trauma") are common among youth, including those with substance use problems including substance use disorders (SUD). Particularly, interpersonal violence is associated with high rates of comorbidity between posttraumatic stress disorder (PTSD) and SUD, and these comorbid disorders exhibit high levels of overlapping symptomatology. Theoretical models proposed to explain the bidirectional relationship between PTSD and SUD include the self-medication hypothesis and susceptibility hypothesis. In this article, we explore neurobiologic changes associated with trauma, PTSD, and SUD that underly dysregulated stress response. Examining lessons learned from recent translational and clinical research, we propose that further elucidating the neurobiologic etiology of comorbid PTSD and SUD will require a collaborative, interdisciplinary approach, including the integration of preclinical and clinical studies, exploration of biologic markers in clinical studies, and accumulation of larger studies and longitudinal studies with the power to study PTSD and SUD. Such research can transform the field and ultimately reduce high rates and costly impairment of co-occurring PTSD and SUD across the lifespan.

An Approach to Biomarker Discovery of Cannabis Use Utilizing Proteomic, Metabolomic, and Lipidomic Analyses.

Introduction: Relatively little is known about the molecular pathways influenced by cannabis use in humans. We used a multi-omics approach to examine protein, metabolomic, and lipid markers in plasma differentiating between cannabis users and nonusers to understand markers associated with cannabis use. Methods: Eight discordant twin pairs and four concordant twin pairs for cannabis use completed a blood draw, urine and plasma toxicology testing, and provided information about their past 30-day cannabis use and other substance use patterns. The 24 twins were all non-Hispanic whites. Sixty-six percent were female. Median age was 30 years. Fifteen participants reported that they had used cannabis in the last 30 days, including eight participants that used every day or almost every day (29-30 of 30 days). Of these 15 participants, plasma 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) and total tetrahydrocannabinol (THC) concentrations were detectable in 12 participants. Among the eight "heavy users" the amount of total THC (sum of THC and its metabolites) and plasma THC-COOH concentrations varied widely, with ranges of 13.1-1713 ng/mL and 2.7-284 ng/mL, respectively. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay measured plasma THC-COOH, THC, and other cannabinoids and metabolites. Plasma THC-COOH was used as the primary measure. Expression levels of 1305 proteins were measured using SOMAScan assay, and 34 lipid mediators and 314 metabolites were measured with LC-MS/MS. Analyses examined associations between markers and THC-COOH levels with and without taking genetic relatedness into account. Results: Thirteen proteins, three metabolites, and two lipids were identified as associated with THC-COOH levels. Myc proto-oncogene was identified as associated with THC-COOH levels in both molecular insight and potential marker analyses. Five pathways (interleukin-6 production, T lymphocyte regulation, apoptosis, kinase signaling pathways, and nuclear factor kappa-light-chain-enhancer of activated B cells) were linked with molecules identified in these analyses. Conclusions: THC-COOH levels are associated with immune system-related pathways. This study presents a feasible approach to identify additional molecular markers associated with THC-COOH levels.

Marijuana Legalization in Colorado: Increasing Potency, Changing Risk Perceptions, and Emerging Public Health Concerns for Youth.

Background: Marijuana legalization occurred gradually in Colorado through political processes. Objectives: This review aimed at describing the history of marijuana legalization and correlated shifts in product availability, use patterns, and risk perceptions and describes associated emerging concerns with this process for adolescents and young adults. Methods: This review focuses on the history of marijuana legalization and correlated shifts in product availability, use patterns, and risk perceptions. Results: Along with the legalization of marijuana, there has been strong commercialization characterized by the widespread development of dispensaries, new products including edibles and concentrates, and an overall lowering of the "price per serving" of marijuana. While the frequency of marijuana use among adolescents does not appear to have shifted substantially, young adult patterns of use have demonstrated an increase in usage. A substantial shift has occurred in the increasing use of concentrates and high potency products. Emerging concerns related to high potency products include increased acute care visits, prevalence and outcomes of comorbid mental health disorders, cannabis-induced psychosis, driving while high, marijuana-related lung injuries, and increased use during pregnancy. Yet, there are also potential medical uses of marijuana. Conclusion: To date, scientific evidence of the mental or physical effects of high potency products is currently very limited. Clinical issues related to the treatment of marijuana use and comorbid psychiatric disorders in youth are discussed with a focus on how low risk perceptions influence treatment considerations.

Systematic review and meta-analysis of socio-cognitive and socio-affective processes association with adolescent substance use.

BACKGROUND: Social impairments are important features of a substance use disorder diagnosis; and recent models suggest early impairments in socio-cognitive and -affective processes may predict future use. However, no systematic reviews are available on this topic. METHODS: We conducted a systematic review and meta-analyses exploring the association between social-cognitive and -affective processes (empathy, callous-unemotional (CU) traits, theory of mind, and social cognition) and substance use frequency (alcohol, cannabis, general drug use). We examined moderating effects of study design, gender, age, and weather conduct problems were controlled for. We also review brain studies related to social cognition and substance use disorder (SUD) risk. RESULTS: Systematic review suggested a negative association for positively valenced constructs with substance use but mixed results on the negatively valenced construct CU traits. Meta-analyses revealed moderate positive association between CU traits with alcohol and general drug use but no significance with cannabis use. Moderate effect sizes were found for CU traits in youth predicting severity of substance use by late adolescence and significantly accounted for variance independently of conduct problems. Significant moderators included gender proportions, sample type, and age. Neuroimaging meta-analysis indicated 10 coordinates that were different in youth at a high risk/with SUD compared to controls. Three of these coordinates associate with theory of mind and social cognition. CONCLUSION: Socio-cognitive and -affective constructs demonstrate an association with current and future substance use, and neural differences are present when performing social cognitive tasks in regions with strongest associations with theory of mind and social cognition.

The Neurocognitive Effects of Cannabis Across the Lifespan.

Purpose of review: This review examines the neurocognitive effects of cannabis and relevant developmental factors across adolescence (age 13-21), adulthood (21-65), and older adulthood (65+). Recent findings: Cannabis use is robustly associated with poorer neurocognitive functioning; however, studies that carefully control for confounds have often not found any evidence for impairment. Notably, the endocannabinoid system may underly how cannabis use affects neurocognitive functions, including heightened vulnerability during adolescence. In contrast, the endocannabinoid system may underlie protective neurocognitive effects of cannabis in older adults. Notably, older adults have reported sharp increases in recent cannabis use. Summary: As legalization increases the accessibility, variety, and potency of cannabis, strong empirical evidence is needed to understand its neurocognitive effects across the lifespan. In particular, rigorous study designs are needed to investigate the neurocognitive effects of cannabis, including among vulnerable populations (adolescents, older adults) and mediating (e.g., endocannabinoid system) and moderating factors (e.g., alcohol use).

Integrated Treatment of Adolescents with Co-occurring Depression and Substance Use Disorder.

Substance use disorders (SUDs) are commonly co-occurring among adolescents with depression. Integrated treatment is important given treatment implications and increased rates of suicidality. All adolescents should be screened for SUD using Screening, Brief Intervention, and Referral to Treatment. Review of randomized controlled trials in adolescents reveals motivational enhancement therapy/cognitive behavioral therapy is an evidence-based intervention and should be considered first-line treatment. If depression does not improve, fluoxetine should be considered, as it is well-tolerated in substance-involved adolescents with depression. Adolescents who do not show improvement in SUD or who have severe SUD should be referred to evidence-based SUD treatment.

A novel mutation in PLP1 causes severe hereditary spastic paraplegia type 2.

Hereditary spastic paraplegia (HSP) type 2 is a proteolipid protein (PLP1)-related genetic disorder that is characterized by dysmyelination of the central nervous system resulting primarily in limb spasticity, cognitive impairment, nystagmus, and spastic urinary bladder of varying severity. Previously reported PLP1 mutations include duplications, point mutations, or whole gene deletions with a continuum of phenotypes ranging from severe Pelizaeus-Merzbacher disease (PMD) to uncomplicated HSP type 2. In this manuscript we report a novel PLP1 missense mutation (c.88G>C) in a family from Argentina. This mutation is in a highly conserved transmembrane domain of PLP1 and the mutant protein was found to be retained in the endoplasmic reticulum when expressed in vitro. Due to the variable expressivity that characterizes these disorders our report contributes to the knowledge of genotype-phenotype correlations of PLP1-related disorders.

Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits.

We characterized a large Amish pedigree and, in 384 pedigree members, analyzed the genetic variance components with covariate screen as well as genome-wide quantitative trait locus (QTL) linkage analysis of red blood cell count (RBC), hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet count (PLT), and white blood cell count (WBC) using SOLAR. Age and gender were found to be significant covariates in many CBC traits. We obtained significant heritability estimates for RBC, MCV, MCH, MCHC, RDW, PLT, and WBC. We report four candidate loci with LOD scores above 2.0: 6q25 (MCH), 9q33 (WBC), 10p12 (RDW), and 20q13 (MCV). We also report eleven candidate loci with LOD scores between 1.5 and < 2.0. Bivariate linkage analysis of MCV and MCH on chromosome 20 resulted in a higher maximum LOD score of 3.14. Linkage signals on chromosomes 4q28, 6p22, 6q25, and 20q13 are concomitant with previously reported QTL. All other linkage signals reported herein represent novel evidence of candidate QTL. Interestingly rs1800562, the most common causal variant of hereditary hemochromatosis in HFE (6p22) was associated with MCH and MCHC in this family. Linkage studies like the one presented here will allow investigators to focus the search for rare variants amidst the noise encountered in the large amounts of data generated by whole genome sequencing.