Transdiagnostic prevention and intervention efforts are needed to address executive dysfunction

Abstract: Executive functioning (EF) is a multi-faceted construct important to activities of daily living, emotion regulation, and higher-order thinking and is often impaired in individuals with gambling disorder and/or alcohol use disorders. Deficits in EF are associated with poor treatment engagement, psychiatric comorbidities, and relapse. The present study examined EF in college students (N = 832) aged 18-24 (M= 19.23, SD=1.37, 76.5% Women) in relation to gambling and hazardous drinking. The Barkley’s Deficits in Executive Functioning was used to assess for global EF and 5 facets of EF: Time Management, Organization/Problem Solving, Self-Restraint, Self-Motivation, and Emotion-Regulation. Bivariate correlation and ANOVA analyses were conducted. Approximately 3% of college students reported problem gambling and 20% reported engagement in hazardous drinking. Compared to individuals with non-problem drinking and non-problem gambling: (1) individuals with problem gambling had worse global EF, self-restraint, emotion regulation, and self-motivation, (2) individuals with hazardous drinking had worse Global EF, self-restraint, and emotion regulation and (3) individuals with both problem gambling and hazardous drinking had worse EF on self-restraint. Implications: Impairments in several domains of EF (e.g., inhibition/self-restraint, emotion regulation, and self-motivation) were endorsed at a significantly higher rate among problematic gamblers and hazardous drinkers. Results partially support the pathways model of gambling (Blaszcynski & Nower, 2002) and support transdiagnostic prevention and intervention efforts around emotion regulation, motivation, and impulsivity

Measurement Models Matter: How Retrospective Calendar Versus Global Reports Yield Different Estimates of Treatment Outcome

Abstract: Retrospective reports are less accurate than objective measures of behavior and must be interpreted with consideration of the amount of distortion and error introduced by this methodology. The Gambling-Timeline Followback (G-TLFB) method is the gold standard retrospective assessment tool that is designed to minimize such error by asking for a specific recall of precise gambling behavior day-by-day using recall aids as compared to a global summation over time (e.g., how many gambling days in last month, how much money gambled in the last month). It remains an empirical question whether this difference in measurement format, G-TLFB versus global reports, alters the estimates of gambling treatment efficacy. Eighteen studies were identified for inclusion in a meta-analysis to explore this question. A mixed-effects subgroup analysis indicated that the effect of treatment relative to nonactive control on gambling frequency at posttreatment was significantly lower for studies using the G-TLFB (g = -0.20) than studies using other assessments (g = -0.71). There was no significant difference in the effect of treatment relative to nonactive control on gambling intensity at posttreatment between studies using the G-TLFB (g = -0.22) and studies using other assessments (g = -0.38). Implications: The G-TLFB yields more conservative and likely more precise estimates of the effect of gambling treatment on gambling frequency but not intensity than other retrospective assessments. The use of global retrospective assessments to assess gambling frequency and intensity may overestimate effects of gambling treatment on gambling frequency

Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor

Purpose: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. Results: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmaxand AUC of panobinostat, respectively. No substantial change in Tmaxor half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Conclusions: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary

Endovascular Intervention in Internal Carotid Artery Blunt Cerebrovascular Injury: An EAST Multicenter Study.

BACKGROUND: Use of endovascular intervention (EI) for blunt cerebrovascular injury (BCVI) is without consensus guidelines. Rates of EI use and radiographic characteristics of BCVI undergoing EI nationally are unknown. METHODS: A post-hoc analysis of a prospective, observational study at 16 U.S. trauma centers from 2018 to 2020 was conducted. Internal carotid artery (ICA) BCVI was included. The primary outcome was EI use. Multivariable logistic regression was performed for predictors of EI use. RESULTS: From 332 ICA BCVI included, 21 (6.3%) underwent EI. 0/145 (0%) grade 1, 8/101 (7.9%) grade 2, 12/51 (23.5%) grade 3, and 1/20 (5.0%) grade 4 ICA BCVI underwent EI. Stroke occurred in 6/21 (28.6%) ICA BCVI undergoing EI and in 33/311 (10.6%) not undergoing EI ( DISCUSSION: Pseudoaneurysm size is associated with use of EI for ICA BCVI. Stroke is more common in ICA BCVI with EI but did not occur after EI use

Grade 1 Internal Carotid Artery Blunt Cerebrovascular Injury Persistence Risks Stroke With Current Management: An EAST Multicenter Study.

BACKGROUND: Higher blunt cerebrovascular injury (BCVI) grade and lack of medical therapy are associated with stroke. Knowledge of stroke risk factors specific to individual grades may help tailor BCVI therapy to specific injury characteristics. METHODS: A post-hoc analysis of a 16 center, prospective, observational trial (2018-2020) was performed including grade 1 internal carotid artery (ICA) BCVI. Repeat imaging was considered the second imaging occurrence only. RESULTS: From 145 grade 1 ICA BCVI included, 8 (5.5%) suffered a stroke. Grade 1 ICA BCVI with stroke were more commonly treated with mixed anticoagulation and antiplatelet therapy (75.0% vs 9.6%, P DISCUSSION: While the stroke rate for grade 1 ICA BCVI is low overall, injury persistence appears to heighten stroke risk. Some strokes occurred despite initiation of medical therapy. Repeat imaging is needed in grade 1 ICA BCVI to evaluate for injury progression or resolution

Factors associated with stroke formation in blunt cerebrovascular injury: An EAST multicenter study.

BACKGROUND: Stroke risk factors after blunt cerebrovascular injury (BCVI) are ill-defined. We hypothesized that factors associated with stroke for BCVI would include medical therapy (i.e., Aspirin), radiographic features, and protocolization of care. METHODS: An Eastern Association for the Surgery of Trauma-sponsored, 16-center, prospective, observational trial was undertaken. Stroke risk factors were analyzed individually for vertebral artery (VA) and internal carotid artery (ICA) BCVI. Blunt cerebrovascular injuries were graded on the standard 1 to 5 scale. Data were from the initial hospitalization only. RESULTS: Seven hundred seventy-seven BCVIs were included. Stroke rate was 8.9% for all BCVIs, with an 11.7% rate of stroke for ICA BCVI and a 6.7% rate for VA BCVI. Use of a management protocol (p = 0.01), management by the trauma service (p = 0.04), antiplatelet therapy over the hospital stay (p \u3c 0.001), and Aspirin therapy specifically over the hospital stay (p \u3c 0.001) were more common in ICA BCVI without stroke compared with those with stroke. Antiplatelet therapy over the hospital stay (p \u3c 0.001) and Aspirin therapy over the hospital stay (p \u3c 0.001) were more common in VA BCVI without stroke than with stroke. Percentage luminal stenosis was higher in both ICA BCVI (p = 0.002) and VA BCVI (p \u3c 0.001) with stroke. Decrease in percentage luminal stenosis (p \u3c 0.001), resolution of intraluminal thrombus (p = 0.003), and new intraluminal thrombus (p = 0.001) were more common in ICA BCVI with stroke than without, while resolution of intraluminal thrombus (p = 0.03) and new intraluminal thrombus (p = 0.01) were more common in VA BCVI with stroke than without. CONCLUSION: Protocol-driven management by the trauma service, antiplatelet therapy (specifically Aspirin), and lower percentage luminal stenosis were associated with lower stroke rates, while resolution and development of intraluminal thrombus were associated with higher stroke rates. Further research will be needed to incorporate these risk factors into lesion specific BCVI management. LEVEL OF EVIDENCE: Prognostic and Epidemiologic, Level IV