Search

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.

Background and Aims: Studies on adolescent alcohol use and cognition are often unable to separate the potential causal effects of alcohol use on cognition from shared etiological influences, including genetic influences or other substance use comorbidities also known to be associated with cognition, such as nicotine use. The present study aimed to fill this gap and clarify the relationship between adolescent alcohol use and young adult cognition by accounting for both measured and unmeasured confounders. Design: A random effects model accounting for nesting in families was used to control for measured confounders. Next, co‐twin comparisons were conducted within the full sample and in monozygotic twin pairs (MZ) to control for unmeasured genetic and environmental confounders shared by co‐twins. Participants/Setting: Participants were 812 individuals (58.6% female, 361 complete pairs, 146 MZ pairs) from the longitudinal FinnTwin12 study in Finland. Measurements Adolescent alcohol use was indexed with measures of frequency of use and intoxication averaged across ages 14 and 17. Cognitive outcomes were measured at average age 22 and included Trail Making Test, California Stroop test, Wechsler Adult Intelligence subtests (Vocabulary, Block Design, Digit Symbol), Digit Span subtest of Wechsler Memory Scale, Mental Rotation Test and Object Location Memory test. Covariates included sex, parental education, general cognitive ability, current alcohol use and nicotine use. Findings Greater frequency of alcohol use and frequency of intoxication across adolescence was associated with decreased vocabulary scores in the co‐twin control [freq: stnd beta = −0.12, 95% confidence interval (CI) = −0.234, −0.013] and MZ only co‐twin control models (freq: stnd beta = −0.305, 95% CI = –0.523, −0.087; intox: stnd beta = −0.301, 95% CI = ‐0.528, −0.074). Conclusions: In Finland, there appears to be little evidence that adolescent alcohol use causes cognitive deficits in young adulthood, except modest evidence for association of higher adolescent alcohol use with lower young adult vocabulary scores. [ABSTRACT FROM AUTHOR]

Background Associations between childhood trauma, neurodevelopment, alcohol use disorder (AUD), and posttraumatic stress disorder (PTSD) are understudied during adolescence. Methods Using 1652 participants (51.75% female, baseline M age = 14.3) from the Collaborative Study of the Genetics of Alcoholism, we employed latent growth curve models to (1) examine associations of childhood physical, sexual, and non-assaultive trauma (CPAT, CSAT, and CNAT) with repeated measures of alpha band EEG coherence (EEGc), and (2) assess whether EEGc trajectories were associated with AUD and PTSD symptoms. Sex-specific models accommodated sex differences in trauma exposure, AUD prevalence, and neural development. Results In females, CSAT was associated with higher mean levels of EEGc in left frontocentral (LFC, ß = 0.13, p = 0.01) and interhemispheric prefrontal (PFI, ß = 0.16, p < 0.01) regions, but diminished growth in LFC (ß = −0.07, p = 0.02) and PFI (ß = −0.07, p = 0.02). In males, CPAT was associated with lower mean levels (ß = −0.17, p = 0.01) and increased growth (ß = 0.11, p = 0.01) of LFC EEGc. Slope of LFC EEGc was inversely associated with AUD symptoms in females (ß = −1.81, p = 0.01). Intercept of right frontocentral and PFI EEGc were associated with AUD symptoms in males, but in opposite directions. Significant associations between EEGc and PTSD symptoms were also observed in trauma-exposed individuals. Conclusions Childhood assaultive trauma is associated with changes in frontal alpha EEGc and subsequent AUD and PTSD symptoms, though patterns differ by sex and trauma type. EEGc findings may inform emerging treatments for PTSD and AUD. [ABSTRACT FROM AUTHOR]

Limitations of bone defect reconstruction include poor bone healing and osteointegration with acrylic cements, lack of strength with bone putty/paste, and poor osteointegration. Tissue engineering aims to bridge these gaps through the use of bioactive implants. However, there is often a risk of infection and biofilm formation associated with orthopedic implants, which may develop anti-microbial resistance. To promote bone repair while also locally delivering therapeutics, 3D-printed implants serve as a suitable alternative. Soft, nanoporous 3D-printed filaments made from a thermoplastic polyurethane and polyvinyl alcohol blend, LAY-FOMM and LAY-FELT, have shown promise for drug delivery and orthopedic applications. Here, we compare 3D printability and sustained antibiotic release kinetics from two types of commercial 3D-printed porous filaments suitable for bone tissue engineering applications. We found that both LAY-FOMM and LAY-FELT could be consistently printed into scaffolds for drug delivery. Further, the materials could sustainably release Tetracycline over 3 days, independent of material type and infill geometry. The drug-loaded materials did not show any cytotoxicity when cultured with primary human fibroblasts. We conclude that both LAY-FOMM and LAY-FELT 3D-printed scaffolds are suitable devices for local antibiotic delivery applications, and they may have potential applications to prophylactically reduce infections in orthopedic reconstruction surgery. [ABSTRACT FROM AUTHOR]

Bone is a frequent site of tumor metastasis. The bone–tumor microenvironment is heterogeneous and complex in nature. Such complexity is compounded by relations between metastatic and bone cells influencing their sensitivity/resistance to chemotherapeutics. Standard chemotherapeutics may not show efficacy for every patient, and new therapeutics are slow to emerge, owing to the limitations of existing 2D/3D models. We previously developed a 3D interface model for personalized therapeutic screening, consisting of an electrospun poly lactic acid mesh activated with plasma species and seeded with stromal cells. Tumor cells embedded in an alginate-gelatin hydrogel are overlaid to create a physiologic 3D interface. Here, we applied our 3D model as a migration assay tool to verify the migratory behavior of different patient-derived bone metastasized cells. We assessed the impact of two different chemotherapeutics, Doxorubicin and Cisplatin, on migration of patient cells and their immortalized cell line counterparts. We observed different migratory behaviors and cellular metabolic activities blocked with both Doxorubicin and Cisplatin treatment; however, higher efficiency or lower IC50 was observed with Doxorubicin. Gene expression analysis of MDA-MB231 that migrated through our 3D hybrid model verified epithelial–mesenchymal transition through increased expression of mesenchymal markers involved in the metastasis process. Our findings indicate that we can model tumor migration in vivo, in line with different cell characteristics and it may be a suitable drug screening tool for personalized medicine approaches in metastatic cancer treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: Electronic cigarette use has escalated rapidly in recent years, particularly among youth. Little is known about the genetic influences on e‐cigarette use. This study aimed to determine whether genetic risk for regular use of combustible cigarettes or for number of cigarettes smoked per day confers risk for ever e‐cigarette use or frequency of e‐cigarette use. Design, Setting, Participants, and Measurements: We used data from 9541 young adults from the Spit for Science longitudinal cohort study (2011–2019). Polygenic scores (PGS) of regular combustible cigarette use (PGS‐RCU) and cigarettes per day (PGS‐CPD) were constructed using summary statistics from the two largest available genome‐wide association study (GWAS) meta‐analysis of European ancestry and East Asian ancestry of combustible cigarette use and used to test whether the PGS of RCU or CPD predicted lifetime e‐cigarette use and frequency of past 30‐day e‐cigarette use in a diverse sample of young adults of African (AFR), Admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS) ancestry. Findings: The PGS‐RCU was associated with lifetime e‐cigarette use in the EUR sample (OR = 1.27, 95% CI = 1.19–1.36, P = 7.53 × 10−12), but not in the other subsamples (ps > 0.12). This association remained significant after excluding regular combustible cigarette smokers (OR = 1.21, 95% CI = 1.12–1.31, P = 3.36 × 10−6). There was no statistically significant association between PGS‐CPD and lifetime e‐cigarette use and neither the PGS‐RCU nor the PGS‐CPD were associated with frequency of e‐cigarette use in the past 30 days in any of the subsamples. Conclusions: Genetic factors associated with regular combustible cigarette use appear to be associated with ever e‐cigarette use in young adults. We did not find evidence for shared genetic factors influencing heaviness of use of combustible cigarettes and current e‐cigarette use frequency. [ABSTRACT FROM AUTHOR]

Introduction: As the use of electronic cigarette (EC) continues to rise in the United States, especially among adolescents and young adults, it is necessary to better understand the factors associated with EC initiation. Specifically, it is unclear how genetic and environmental contributions influence the initiation of EC. Furthermore, the degree to which genetic and environmental influences are shared between EC initiation and conventional cigarette (CC) initiation is unknown.Methods: A sample of young adult twins ages 15-20 (N = 858 individuals; 421 complete twin pairs) was used to estimate the genetic and environmental influences on the liability of initiation unique to EC and CC as well as the degree to which these factors are shared between the two. Approximately 24% of participants initiated the use of EC, 19% initiated the use of CC, and 11% initiated the dual use.Results: Combined contributions of additive genetic and shared environmental influences were significant for CC (ACC = 0.19 [95% confidence interval {CI} = 0-0.79], p = 0.57; CCC = 0.42 [95% CI = 0-0.70], p = 0.13) and EC (AEC = 0.25 [95% CI = 0-0.83, p = 0.44; CEC = 0.42 [95% CI = 0-0.73], p = 0.12), whereas unique environmental influences were significant (ECC = 0.39 [95% CI = 0.18-0.57], p < 0.001; EEC = 0.32 [95% CI = 0.14-0.56], p < 0.001). Results also demonstrated a significant overlap of the unique environmental (rE = 0.87, p < 0.001) and familial influences contributing to correlation between the two phenotypes in the bivariate analysis.Conclusions: These preliminary results suggest that both genes and environmental influences are potential drivers of EC initiation among adolescents and young adults.Implications: This article is the first to use a sample of twin to estimate the contributions of genetic and environmental influences toward EC initiation and estimate the potential for overlapping influences with CC initiation. This study has implications for future debate about the etiology of EC and CC use with respect to potential overlapping genetic and environmental influences. [ABSTRACT FROM AUTHOR]