Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p<10 -4. The first best signal was rs770182 (p = 3.65 × 10 -6) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p<10 -4 (p = 7.15 × 10 -6, 2.79 × 10 -5 and 4.93 × 10 -5, respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10 -4 in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10 -4 and 9.48 × 10 -5, respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p<10 -2) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.

Twin and family studies have shown that there is substantial evidence for a genetic component in the vulnerability to nicotine dependence (ND). The purpose of this study was to perform a meta-analysis on two genome-wide association (GWA) data involving 1079 cases of ND and 1341 controls in Caucasian populations. Through meta-analysis we identified 50 SNPs associated with ND with p<10-4. The best associated SNP rs7163369 (p=3.27×10-6) was located at 15q26 within SLCO3A1 gene while the second best SNP was rs9308631 (p=9.06×10-6) at 2q12.1 near ANAPC1. The third interesting locus rs688011 (p=1.08×10-5) was at 11q23.2 intergenic between NCAM1 and TCC12. Through meta-analysis, we found two additional ND associated genes ZCCHC14 (the top SNP was rs13334632, p=1.28×10-5) and KANK1 (the top SNP was rs13286166, p=1.49×10-5). The first top SNP rs7163369 within SLCO3A1 in the meta-analysis was replicated in the Australian twin-family study of 778 families (p=6.11×10-5) while SNP rs9653414 within ANAPC1 (p=4.61×10-5) in the meta-analysis was replicated in the family sample (p=9.31×10-4). Furthermore, rs2241617 in ZCCHC14 and rs4742225 in KANK1 showed strong associations with ND (p=1.06×10-7 and 4.81×10-7, respectively) in the replication sample. In addition, several SNPs of these loci (ANAPC1, KANK1, NACM1, TCC12, SLCO3A1 and ZCCHC14) were associated with alcohol dependence. In conclusion, we identified several loci associated with ND through meta-analysis of two GWA studies. These findings offer the potential for new insights into the pathogenesis of ND.

Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia; however, little is known about the etiology of FTD. To identify new genetic loci associated with FTD, we conducted the first genome-wide association meta-analysis of two datasets of 835 cases of FTD and 2,694 controls with 729,454 single-nucleotide polymorphisms (SNPs). Logistic regression analysis of FTD as a binary trait, adjusted for age and sex, was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 61 SNPs associated with FTD with p < 10-4. The most significant association with FTD was observed with rs1783925 (p = 4.4 × 10-7) within PKNOX2 gene at 11q24.2 while the second interesting locus was rs2277644 (p = 1.18 × 10-5) within MYH13 at 17p13. Haplotype analyses of PKNOX2 and MYH13 loci further supported the associations with FTD. The third locus was PHF2 at 9q22.31 (the top SNP was rs12238738 with p = 2.08 × 10-5) while the fourth locus was GPC6 at 13q32 (the top SNP was rs17196161 with p = 3.12 × 10-5). In conclusion, we identified four new loci (PKNOX2, MYH13, PHF2, and GPC6) associated with FTD. These findings offer the potential for new insights into the pathogenesis of FTD and schizophrenia.

Family, twin and adoption studies have clearly demonstrated that genetic factors are important in modulating the vulnerability to alcohol dependence. Several genome-wide association (GWA) studies of alcohol dependence have been conducted; however, few loci have been replicated. A meta-analysis was performed on two GWA studies of 1283 cases of alcohol dependence and 1416 controls in Caucasian populations. Through meta-analysis we identified 131 SNPs associated with alcohol dependence with p<10-4. The best novel signal was rs6701037 (p=1.86 × 10-7) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p=4.71 × 10-7) at 2q22.1 within THSD7B. The third novel locus was NRD1 at 1p32.2 (the top SNP was rs2842576 with p=7.90 × 10-6). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p=1.47 × 10-6) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p=1.39 × 10-2) Furthermore, several flanking SNPs of the top hits in the meta-analysis demonstrated borderline associations with alcohol dependence in the family sample (top SNPs were rs2269655, rs856613, and rs10496768 with p=4.58 × 10-3, 2.1 × 10-4, and 2.86 × 10-3 for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p<2 × 10-5) in the meta-analysis. In conclusion, we identified three new loci (KIAA0040, THSD7B and NRD1) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence.

Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p<10-3) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.1 (rs3846329, p=0.000675) were two novel genes which have not been associated with IQ in other studies. It has been reported that NTM might play a role in late-onset Alzheimer disease while NR3C2 may be associated with cognitive function and major depression. The associations of these two genes were well-replicated by single-marker and haplotype analyses in the IMAGE sample. In conclusion, our findings provide evidence that chromosome regions of 11q25 and 4q31.1 contain genes affecting IQ. This study will serve as a resource for replication in other populations.

This paper analyzes the diffusion of internet-based distance education technology (NETDE) among the US associate colleges. The study finds that an institution with experience in using an earlier generation distance education technology is more likely to adopt NETDE than an institution without such an experience. The finding supports the view of Cohen and Levinthal (1990) that an organization's 'absorptive capability' plays a significant role in its innovative activities. Institution size also facilitates the adoption of NETDE. We relate this size effect to market power because the size effect is partly caused by customer switching costs present in the NETDE market. Finally, we find that, among public institutions, the presence of close competitors motivates an institution to adopt NETDE earlier.

Advances in technology have lowered the limits of viability in premature births to 24 weeks of gestation. This brought forth a new population of children, who are born 3-4 months early and spent considerable amounts of time in neonatal intensive care unit (NICU), instead of sterile environment of mother’s womb. Besides, other problems associated with prematurity, these children often undergo invasive procedures resulting in mucosal inflammation and/ or injury by feeding tubes, endotracheal tubes, and prolonged IV catheter. To test whether “ex-preemie-infants” were different than “term-infants” with regard to their immunity, preterm infants (< 32 weeks) and term infants (control) at the corrected age of 9-12 months were analyzed for their resting and stimulated immune responses. Preterm infants had a significant Th1 skewed response, higher number of activated and functionally competent T cells compared to term infants. The critical role of neonatal environmental exposure on immune system development is imminent; nevertheless detailed mechanistic studies on pathways are warranted.

No study has focussed on the longitudinal effect of APOE-ε4 genotype on the logical memory delayed recall total (LDELTOTAL) score in late-onset Alzheimer’s disease (AD). The LDELTOTAL scores were collected at baseline, 12, 24, 36 and 48 months from 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). A linear mixed model (LMM) was used to investigate the effect of APOE-ε4 on the longitudinal changes in the LDELTOTAL scores adjusted for age, gender, education and baseline Mini Mental State Examination score. There were significant differences in LDELTOTAL scores among AD, CN, and MCI (P < 0.0001) and among APOE-ε4 alleles at baseline (P < 0.0001). In the multivariable LMM, elders with 75+ years (P = 0.0051), females (P < 0.0001), lower education (P < 0.0001), AD and MCI (both P values < 0.0001) were associated with decreased LDELTOTAL values, while the individuals with 1 or 2 APOE-ε4 allele revealed significantly lower LDELTOTAL scores (both P values <0.0001) compared with individuals without APOE-ε4 allele. Further, APOE-ε4 alleles had significant interactions with four follow-up visits, where all follow-up visits showed significantly higher LDELTOTAL score. In addition, gender showed interaction with age, education and APOE-ε4 with follow-up visits. Our findings provide the first evidence of the effect of APOE-ε4 genotype on the logical memory declines related to AD. Further, APOE-ε4 alleles showed interactions with gender and follow-up visits.

The first reported case of COVID-19 in Tennessee (TN) occurred on March 5, 2020, growing to 580,809 cases state-wide by the end of 2020. A GIS dashboard was developed using data from the TN Department of Health to communicate state-wide COVID-19 spread, and a relationship between pandemic development and rurality was observed during the first wave (through September 2020), noted in other US and global research. Because > 90% of TN counties are designated rural or mixed-rural, we examined metrics to describe development as it relates to rurality. Metrics included days to the first case/hospitalization/fatality, days between state and county peak, and days to an incidence rate of ten per 100,000. Metrics were compared within different classes of rurality, using seven rurality classification schemes. Significant differences were noted in four of the five metrics between classes of rurality. Rural counties in TN experienced significant lags to the first case, hospitalization, and fatality, and the peak cases in rural counties were delayed relative to urban counties when outlier counties with early state prison outbreaks were excluded. In rural TN counties, regardless of rurality definition, cases, hospitalizations, and fatalities were slower to appear. However, once community spread was established, rurality no longer had a protective effect.

Background: There is robust preclinical literature and preliminary clinical findings supporting the use of N-Acetylcysteine (NAC) to treat substance use disorders, including tobacco use disorder (TUD). However, randomized controlled trials have yielded mixed results and NAC's efficacy for TUD has not been established. The goals of this study were to assess the efficacy of NAC in promoting early and end-of-treatment abstinence and preventing relapse among adult smokers. Methods: This randomized, double-blinded clinical trial enrolled adult, daily smokers (N = 114; ages 23–64; 51 % female; 65 % White; 29 % Black/African American; 7% Hispanic/Latinx), who were randomized 1:1 to receive NAC (n = 59) or placebo (n = 55) (1200 mg b.i.d.) for eight weeks. Participants received brief cessation counseling and incentives for abstinence during the first three days of the quit attempt. Primary outcomes: (i) carbon monoxide (CO)-confirmed abstinence during the first three days of the quit attempt. Secondary outcomes: (ii) time to relapse; (iii) biologically confirmed abstinence at Week 8. Results: No differences were found between NAC and placebo groups on measures of early abstinence (3-day quit attempt; 11 % for NAC vs. 15 % for placebo; all p > 0.11), time to relapse (p = 0.19), and end-of-treatment abstinence (7% for NAC vs. 11 % for placebo; all p > 0.40]. Conclusions: Results indicate that NAC is a well-tolerated pharmacotherapy but is unlikely to be efficacious as a monotherapy for TUD in adults. Considered in the collective context of other research, NAC may potentially be more useful in a younger population, as a combination pharmacotherapy, or in the presence of more intensive psychosocial treatment.