Pearls & Oy-sters: Whole-Genome Sequencing in Critically Ill Neurologic Patient Leads to Diagnosis With Treatment Implications.

Many adult patients with a history of seizures and global developmental delay do not have an identified etiology for their epilepsy. Rapid whole-genome sequencing (rWGS) can be used to identify a genetic etiology in critically ill patients to provide actionable interventions. In this case, a 27-year-old patient with a history of epilepsy, global developmental delay, and intellectual disability presented with altered mental status and new abnormal movements. The patient acutely declined over the course of 24-48 hours of presentation, including nonconvulsive status epilepticus leading to intubation for airway protection, 2 episodes of ventricular tachycardia requiring synchronized cardioversion, and 1 episode of supraventricular tachycardia. The patient was found to be in metabolic crisis. Metabolic workup and rapid whole-genome sequencing were sent. Patient was treated with 10% dextrose in normal saline and a mitochondrial cocktail. She received treatment with ammonia scavengers and hemodialysis with resolution of metabolic crisis. rWGS found a homozygous pathogenic variant in TANGO2 and a de novo pathogenic variant in KCNQ1, ultimately leading to the creation of a metabolic emergency protocol and implantable cardioverter defibrillator placement. This case highlights the use of rWGS in an acutely ill patient leading to actionable interventions. It also highlights the utility and importance of genetic sequencing in reevaluation of adult neurologic patients.

Mapping recovery: A qualitative node map approach to understanding factors proximal to relapse among adolescents in a recovery high school.

INTRODUCTION: Despite data suggesting that recovery high schools are largely effective in reducing substance use, relapse in these settings is common. The goal of the current study was to characterize factors proximal to relapse among adolescents in a local recovery high school. METHOD: Data for this study were 200 de-identified node maps (i.e., graphical break downs of a relapse event; randomly chosen from 600 available node maps) from the charts of students at a local recovery high school in a large Midwest city (Mean Age = 16.8 ± 1.9 years, 64.1% male, 89.1% White). A four-phase process of qualitative data sorting examined features most frequently described in relapse episodes. RESULTS: The most common elements reported were using with others (n = 153, 76.5%), away from home (n = 156, 78.0%), and in response to negative affect (n = 93, 48.4%). Six relapse pathways emerged: coping (n = 30), acting out (n = 15), unexpected temptation (n = 30), planned lapse (n = 19), resistant to recovery (n = 27), and passive agency (n = 30). The pathways identified represent three critical failures in the recovery system: failure to cope, failure to guard against temptation, and failure of belief. Identifying these system failures can contribute to increased rapport and engagement, as well as planning for detailed and specific factors proximal for relapse for any given individual, both on the individual and system levels. CONCLUSION: The use of node maps aligned with previous work, showed good face and content validity, can be used to reduce blame and increase engagement in substance use treatment among adolescents, and produced novel micro-frames with new vocabulary to accurately understand common factors associated with relapse among adolescents.

Translating preclinical models of alcohol seeking and consumption into the human laboratory using intravenous alcohol self-administration paradigms.

Preclinical models of alcohol use disorder (AUD) have advanced theoretical, mechanistic, and pharmacological study of the human condition. "Liking" and "wanting" behaviors reflect core processes underlying several models of AUD. However, the development and application of translational models of these preclinical approaches are at an incipient stage. The goal of this study was to examine how intravenous free-access and progressive-ratio, operant-response human alcohol self-administration paradigms can be used as translational human model parallels of preclinical "liking" and "wanting." Participants were 40 adults (mean age = 23.7, SD = 2.0; 45% female) of European descent who reported 12.6 drinking days (SD = 5.2) out of the previous 30 (average = 4.1 drinks per drinking day [SD = 1.7]). Individuals diverged in their alcohol self-administration behavior, such that free-access and progressive-ratio paradigm outcomes were not significantly correlated (p = 0.44). Free-access alcohol seeking was related to enjoying alcohol (p < 0.001), but not craving (p = 0.48), whereas progressive-ratio seeking at similar levels of alcohol exposure was related to craving (p = 0.02), but not enjoying (p = 0.30). Family history of alcoholism, venturesomeness traits, and disinhibition traits were unrelated (ps > 0.70) to preferred level of breath alcohol concentration (BrAC) in the free-access session, a measure of liking alcohol. Family history of alcoholism, disinhibition traits, and recent drinking history were significantly related (ps < 0.05) to alcohol seeking in the progressive-ratio paradigm, a measure of wanting alcohol. We conclude that intravenous alcohol self-administration paradigms show promise in modeling behaviors that characterize and parallel alcohol "liking" and "wanting" in preclinical models. These paradigms provide a translational link between preclinical methods and clinical trials.

An Experimental Test of the Relationship between Electronic Nicotine Delivery System Use and Alcohol Consumption.

BACKGROUND: Increasing research shows that the use of electronic nicotine delivery systems (ENDS) is associated with a higher rate and quantity of alcohol consumption. METHODS: The present study used a 2-session, within-subjects design to experimentally examine the relationship between ENDS use and laboratory ad libitum alcohol consumption. A total of N = 31 (mean age = 28.71, SD = 11.17; 45.2% women; 54.8% White/Caucasian) healthy adults from the community who use ENDS and endorsed liking beer completed the study, which included a beer consumption taste-test task that assessed the volume of beer consumed by the participants across 2 counterbalanced sessions: 1 in which concurrent ENDS use was allowed and 1 in which it was not. All analyses controlled for age, race, and gender. RESULTS: The effect of ENDS condition on the volume of beer consumed was not statistically significant, F(1, 30) = 0.03, p = 0.86). Results of linear mixed modeling showed that ENDS puffs were significantly related to alcohol sips (estimate = 0.23, SE = 0.07, p = 0.002) across the ad libitum session. CONCLUSIONS: Overall, ENDS use did not increase alcohol consumption; however, the data suggest that ENDS puffs might act as a prime for beer sips or that these 2 behaviors are linked through habit. Future studies should more fully measure and compare global and event-level data on ENDS and alcohol use as they might show disparate patterns of relationships.

Positive urgency worsens the impact of normative feedback on 21st birthday drinking.

BACKGROUND: The 21st birthday is associated with more alcohol consumption and negative consequences than any other occasion. The current study investigated how positive urgency, the tendency to act rashly in response to positive emotions, influences 21st birthday drinking and the effectiveness of a single event text message intervention designed to reduce 21st birthday drinking and related negative consequences. METHODS: Participants were 183 undergraduate students (69% female, 86% white) about to turn 21. Participants were randomly assigned to either a text message intervention or control condition. Those in the intervention condition received one text message the day before their 21st birthday that provided personalized normative feedback and one text message on the day of their 21st birthday. Participants reported actual alcohol consumption the day after their 21st birthday celebration. RESULTS: Hierarchical linear regression found that, after controlling for sex, intervention condition, and planned drinking, positive urgency was associated with greater number of drinks (ß = .15, p = .031) and drinking problems (ß = .25, p = .001). A moderated-mediation model was significant (B = 0.42, CI95 [.10, .76]): At high levels of positive urgency, the intervention condition was associated with drinking more than planned, which significantly mediated the relationship between intervention and alcohol-related consequences; the mediation was not significant at mean or low levels of positive urgency. CONCLUSIONS: These findings are the first to link positive urgency with 21st birthday drinking and to empirically demonstrate that positive urgency negatively impacts the effectiveness of an intervention aimed at reducing alcohol consumption.

Arnold-Chiari type 1 malformation in Potocki-Lupski syndrome.

Potocki-Lupski syndrome (PTLS) is a genetic disorder that results from an interstitial duplication within chromosome 17p11.2. Children with PTLS typically present with infantile hypotonia, failure to thrive, and global developmental delay with or without major organ system involvement. Systematic clinical studies regarding growth, cardiovascular disease, and neurocognitive profiles have been published; however, systematic evaluation of central nervous system structure by magnetic resonance imaging (MRI) of the brain has not been reported. Herein, we describe three patients with PTLS who were found-in the course of routine clinical care-to have a type 1 Arnold-Chiari malformation (CM-1). This finding raises the question of whether the incidence of CM-1 is increased in PTLS, and hence, if an MRI of the brain should be considered in the evaluation of all patients with this chromosomal duplication syndrome.

Shared Neural Correlates Underlying Addictive Disorders and Negative Urgency.

Negative urgency is a personality trait reflecting the tendency to act rashly in response to extreme negative emotions and is considered a transdiagnostic endophenotype for problematic levels of addictive behaviors. Recent research has begun to identify the neural correlates of negative urgency, many of which appear to overlap with neural circuitry underlying addictive disorders associated with negative urgency. The goal of this qualitative review is to summarize the extant literature concerning the neural correlates of negative urgency, to compare these correlates with those implicated with addictive disorders, and to propose new ways to begin to leverage such findings in treatment and intervention approaches. We also address current limitations in the field and make recommendations for areas for future growth in this research domain. Patterns of structure and function in the ventral striatum, frontal regions, such as the prefrontal cortex (PFC) and orbitofrontal cortex (OFC), and amygdala are common across addictive disorders and are related to both real-world risky behaviors and self-report measures of negative urgency. We propose that the time has come to move past considering this trait and these disorders as completely separate entities, and instead for the field to consider how general patterns of convergence across these disorders can lead to a more transdiagnostic approach to treatment and intervention. We suggest future work utilize these convergent patterns in the development of animal models of negative urgency, in the identification and testing of prime pharmacological and physiological interventions, and as objective biomarkers to be used when testing behavioral, pharmacological, and physiological intervention effectiveness. Little empirical work has been done to date in these areas and advances in these nascent fields would advance understanding and applications of the neuroscience of negative urgency.

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

OBJECTIVE: Limb-girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal-muscle weakness with >30 genes associated with different subtypes. The clinical-genetic overlap among subtypes and with other NMDs complicate disease-subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical-trial recruitment. Currently seven LGMD clinical trials are active but still no gene-therapy-related treatment is available. Till-date no nation-wide large-scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes' relative prevalence across US and investigate underlying disease mechanisms. METHODS: A total of 4656 patients with clinically suspected-LGMD across US were recruited to conduct next-generation sequencing (NGS)-based gene-panel testing during June-2015 to June-2017 in CLIA-CAP-certified Emory-Genetics-Laboratory. Thirty-five LGMD-subtypes-associated or LGMD-like other NMD-associated genes were investigated. Main outcomes were diagnostic yield, gene-variant spectrum, and LGMD subtypes' prevalence in a large US LGMD-suspected population. RESULTS: Molecular diagnosis was established in 27% (1259 cases; 95% CI, 26-29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late-onset Pompe disease, DNAJB6-associated LGMD subtype1E and CAPN3-associated autosomal-dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality. INTERPRETATION: Overall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

Recommendations for applying a multi-dimensional model of impulsive personality to diagnosis and treatment.

The UPPS-P Model of Impulsive Personality, a prominent model of impulsive personality derived from the Five Factor Model of Personality, is a multi-dimensional model of impulsive personality that consists of negative urgency, lack of premeditation, lack of perseveration, sensation seeking, and positive urgency. The UPPS-P model has highlighted the importance of separating multidimensional traits due to the specificity of these traits corresponding to different risk behaviors. The goal of the current review paper is to make recommendations on how to apply the UPPS-P Model of Impulsive Personality, to diagnosis of and treatment for psychopathology. However, despite impulsivity being one of the most frequently used criteria for a number of clinical disorders, our review of the Diagnostic and Statistical Manual for Mental Disorders-5 found that the UPPS-P traits are not well represented in the diagnostic criteria, which we propose limits inferences about etiology and treatment targets. Additionally, research has largely focused on the importance of these traits for risk models; our review of the literature applying the UPPS-P traits to treatment processes and outcomes concluded that this area is not yet well studied. Here, we propose the specific application of the UPPS-P model to improve diagnosis and increase treatment effectiveness.

Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder.

To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene. To properly classify the MYH8 loss-of-function variants, we either retrieved them from public databases or retrospectively collected them from individuals genetically tested by custom NGS panels or by whole-exome sequencing and confirmed using Sanger sequencing. We further evaluated the respective clinical presentations of these individuals with the MYH8 loss-of-function variants. Heterozygous loss-of-function variants in the MYH8 gene were detected in 16 individuals without trismus-pseudocamptodactyly syndrome. Four of these 16 individuals had a pathogenic or likely pathogenic variant detected in another gene that could explain their clinical presentation. Moreover, there are ∼100 MYH8 heterozygous protein-truncating and splice site variants in the ExAC database in different populations. Our results, combined with the population data, indicate that loss-of-function variants in the MYH8 gene do not cause autosomal dominant trismus-pseudocamptodactyly syndrome, and the clinical significance of these variants remains unknown at present. This result highlights the importance of considering the molecular mechanism of disease, variants published in the medical literature, and population genomic data for the correct interpretation of loss-of-function variants in genes associated with autosomal dominant diseases.