Hemp Growing

The groups did not differ on sex or ethnicity ; however, there was a relation of follow-up status with age , with post-hoc tests indicating that CHR individuals whose symptoms remitted were significantly younger than controls at baseline. Group status was significantly associated with both antipsychotic use and any other psychotropic use at baseline; in both cases, individual chi-squared tests indicated that all four CHR groups were more likely to be treated with medication relative to controls but did not differ from each other. The same pattern was observed for cannabis use, whereby a significant overall association was observed between current use and group status with individual tests showing that current cannabis use was more common among all CHR groups relative to controls but that the prevalence did not differ across CHR subgroups. Non-parametric Kruskal Wallis tests performed on the continuous time-lapse variable indicated that the groups did not differ on the lapse-of-time between cortisol collection and daily stressor assessment , cortisol collection and life event assessment , or cortisol collection and trauma assessment .Age was positively associated with life event exposure and life event distress in controls and all four CHR groups, with daily stressor distress in CHR remitted, symptomatic, and progressed groups, and with cortisol in controls, CHR remitted, and CHR converted groups . Female sex was likewise positively associated with life event exposure in controls, daily stressor exposure in the CHR remitted group, daily stressor distress in CHR symptomatic individuals,grow cannabis and with all five psychosocial stressor measures in the CHR progression of positive symptoms group. In contrast, ethnicity was not associated with any stress measure or cortisol in any group.

With regards to psychotropic medication, antipsychotic use at baseline was negatively correlated with daily stressor exposure in the CHR remitted group and with life event exposure and trauma in the CHR progressed group, but positively associated with daily stressor distress in CHR individuals who later converted to psychosis; similarly, other psychotropic medication was negatively correlated with daily stressor exposure in the remitted group but positively correlated with daily stressor and life event distress variables in the converter group. Current cannabis use was associated positively with daily stressor exposure, life event distress, and trauma in the control group and with life event exposure in remitted and symptomatic groups. The above analyses identified the following baseline factors as potential confounders in the relationship between stress and cortisol: age, sex, current antipsychotic use, current other psychotropic medication use, and current cannabis use. However, owing to multicollinearity issues , all models included antipsychotic use only as a covariate, with sensitivity analyses performed using other psychotropic medication in place of antipsychotic use. We were additionally concerned that controlling for current cannabis use might obscure important relationships between stress and cortisol , given that recent evidence indicates that stress can precipitate cannabis use in healthy and clinical samples , and therefore included cannabis use as a covariate in sensitivity analyses only.ANCOVAsand logistic regression indicated significant main effects of group status on basal cortisol and all stress measures after adjustment for age, sex, and antipsychotic use at baseline . Post-hoc comparisons indicated that only CHR convertors were characterised by elevated basal cortisol compared to controls , no other group differences were observed. With regards to continuous stress measures , all four CHR subgroups were characterised by significantly higher scores relative to controls; for daily stressor exposure only, symptomatic, progressed, and converted groups also showed significantly higher scores relative to remitted CHR youth. To confirm that the greater exposure to life events observed in CHR subgroups was not simply due to events that could be caused by illness, we additionally compared groups on exposure to independent life events and observed a significant main effect of group status .

Post-hoc tests indicated that all CHR subgroups, except for the remitted group, reported increased exposure to independent life events compared to controls. Finally, childhood trauma was more common in all CHR groups compared to controls but did not distinguish among CHR subgroups. All results were largely unchanged when cannabis use was included as an additional covariate and other psychotropic medication use was additionally included in place of antipsychotic medication, with the exception that CHR remitted youth no longer showed significantly greater life event exposure compared to controls.In line with predictions, stressor-cortisol concordance varied according to the lapse-of-time between assessments : When acquired on the same day as saliva sampling, all stress measures showed significant, positive correlations with cortisol , except for life event distress scores which were positively correlated but not significantly. In contrast, stress measures were not significantly correlated with cortisol in any other time-lapse category except for life event exposure and cortisol which were positively associated when the lapse-of time was 31 days or longer. To account for the moderating effect of time-lapse between assessments, interaction terms were additionally included in subsequent regression models.The current study aimed to further characterise the nature of HPA axis abnormalities among individuals at-risk for psychosis by examining psychosocial stressors, basal cortisol, and the concordance between these measures in a large sample of CHR youth categorised according to clinical status at the two-year follow-up. In line with hypotheses, all CHR groups were characterised by significantly greater psychosocial stressor exposure and distress relative to healthy controls; however, only those who converted to psychosis demonstrated elevated basal cortisol levels. In contrast to expectations, whilst CHR converters showed the greatest degree of stressor-cortisol concordance when pooled across stressors, confidence intervals substantially overlapped with the control group; moreover, the degree of concordance among CHR youth who remitted, remained symptomatic, or whose positive symptoms had progressed at follow-up was lower than that observed in the control group. After adjustment for potential confounders and correction for multiple testing, only CHR converters showed elevated basal cortisol relative to healthy controls.

This finding cannot be simply attributed to greater stressor exposure or distress experienced by CHR converters relative to controls, as these features characterised all CHR subgroups. This elevation might instead reflect an amplification of the normative adolescent increase in cortisol secretion , or metabolic abnormalities [more common among CHR youth ], independent of stress exposure. Consistent with a recent meta-analysis , pairwise comparisons showed that basal cortisol levels did not distinguish CHR converters from CHR non-converters. Whilst this suggests that within the CHR population, baseline cortisol levels do not signal risk for psychosis transition, repeated measurement of cortisol is needed to determine whether longitudinal increases predict poorer outcomes in this group. Moreover, it should be assumed that at 2-year follow-up there are some false negative cases in the CHR non-converted groups , and thus differences between converters and non-converters may increase with a longer follow-up period. We predicted that the degree of stressor-cortisol concordance, when pooled across stressors,indoor cannabis grow system would increase in parallel with the level of symptom expression at follow-up . Whilst the highest degree of concordance was indeed observed among the CHR converters, the control group was intermediate, and pooled beta coefficients in the three non-converted CHR subgroups were approximately zero . Moreover, confidence intervals for pooled stressor-cortisol concordance estimates for all CHR sub-groups showed a high degree of overlap with the control group ; it has been proposed that for many effect sizes, confidence intervals overlapping by greater than 50% suggests that effect sizes are not significantly different . Thus, none of the CHR subgroups showed significant hyper- or hypo-responsivity of the HPA axis in response to psychosocial stressors encountered in the natural environment when compared to controls. Stressor-cortisol concordance was, however, substantially higher among CHR converters compared to all other CHR subgroup . This finding is consistent with the only previous study to examine the relationship between stressor-cortisol concordance and outcome status in CHR individuals: Labad and colleagues similarly reported a moderate-to-strong correlation between salivary cortisol and stressful life events among those who later transitioned to psychosis, but only a weak correlation in the non-transitioned CHR group . Overall, we found few significant associations between individual stressors and basal cortisol across all groups . Whilst this could be due to the HPA axis and/or stress measures employed, previous studies of at-risk youth which have used different measures have likewise found inconsistent associations between stress and cortisol . Similarly, in healthy subjects, correlations between self-reported stress and cortisol have not been observed . Although the exact mechanisms underlying HPA responsivity to stress are unknown , it has been demonstrated that there are individual differences in responsivity that are partially determined by genetic variants that modify the effect of acute and chronic stress/trauma on cortisol levels in healthy adolescents and adults and patients with psychosis . Thus, genetic and other vulnerability factors are likely responsible for the different patterns of association between stressors and cortisol that we observed across both individual stressor types and, when pooled across stressors, CHR subgroups.Despite the large overall sample size, individual CHR subgroups were notably smaller there by reducing our ability to detect statistically significant associations between psychosocial stressors and cortisol.

Conversely, as we did not adjust for multiple comparisons in our primary analyses examining stressor-cortisol concordance, some significant associations may have arisen by chance. However, we tested specific a priori hypotheses and were largely interested in the overall pattern of stressor-cortisol concordance rather than statistical significance. Moreover, we adjusted for a range of potential confounders which, had we not accounted for these variables, would have led to spurious associations. A further limitation is that a small proportion of participants , experienced a long delay between baseline assessment visits, which led to a large lapse-of-time between completion of psychosocial stressor assessments and cortisol collection. Including these participants in the analyses increased statistical power to test the moderating effect of time-lapse on stressor-cortisol concordance.There are a range of other stressors relevant to psychosis that might conceivably impact on HPA axis function ; it is possible that examining a wider range of stressors might yield different patterns of stressor-cortisol concordance across CHR subgroups. Similarly, our findings are specific to basal salivary cortisol, other measures may have produced different results. Whilst the aim of our study was to examine the relationship between baseline features and subsequent outcome , it is important to note that there are limitations with this approach. First, we did not account psychosocial stressors and other confounding factors/events that may have occurred in the time between baseline and follow-up. Indeed, it is possible that stressor cortisol concordance at follow-up does in fact distinguish between CHR subgroups, but that our measure at baseline was too distal to outcome. Second, CHR individuals are at elevated risk for a wide range of psychiatric disorders, particularly depression and anxiety , and so worsening of prodromal symptoms/transition to psychosis is only one of several potential outcome measures, all of which will inevitably involve more false negatives the shorter the follow-up period. Indeed, a recent study suggested that well-established risk factors are better at predicting poor functioning in CHR populations than transition to psychosis . The extent to which stressor-cortisol concordance at baseline is associated with other non-psychotic disorders and functioning at follow-up is therefore warranted.We assessed HPA axis function using basal salivary cortisol collected in the laboratory, as it is more reliable and, unlike home sampling methods, unlikely to be influenced by confounding factors such as exercise . However, meta-analytic evidence indicates that the effect of chronic stress on cortisol varies across cortisol measures; whilst diurnalcortisol, afternoon/evening cortisol, and the CARi are elevated following chronic stress, basal morning levels are lower and the diurnal rhythm appears to be flatter . Employing alternative cortisol measures might therefore reveal different patterns of stressor-cortisol concordance across CHR individuals and controls. Indeed, using a home sampling procedure, Cullen and colleagues reported a negative correlation between the CARi and negative life event distress in at-risk children with a family history of schizophrenia but a positive correlation in typically-developing children , whilst a study of adults found that diurnal cortisol was associated negatively with stressful life event exposure in first-episode psychosis patients, most of whom were receiving antipsychotic medication, but positively in controls . Thus, employing multiple measures of cortisol may be more informative than basal cortisol alone and enable the identification of dissociated relationships in at-risk individuals/psychosis patients and healthy controls.

OD had significant metabolite alterations in markers of neuronal integrity , cell membrane turnover/synthesis , glutamate concentration , cellular bio-energetics , and astrocyte integrityin frontal lobe regions implicated in the development and maintenance of addictive disorders. OD had lower NAA, Glu, Cr and mI concentrations than CON in the DLPFC and lower NAA, Cr and mI in the ACC. The metabolite concentration deficits in OD were most pronounced in the DLPFC, were associated with various substance use measures, and correlated with worse performance on measures of global cognition, executive and visuospatial functioning. However, OD and CON were equivalent in regional GABA concentrations, most cognitive domains, and self-regulation measures. Relative to 3 week abstinent ALC, OD had significantly lower NAA, Cr, Cho and mI concentrations in the DLPFC, with NAA and Cho deficits having cognitive ramifications. Consistent with most previous reports, we found metabolite deficits in the ACC of OD. In addition, OD had similar deficits in NAA, Cr, and Glu concentrations in the DLPFC. This suggests reduced neuronal and astrocyte viability and cellular bioenergetics in both the ACC and DLPFC, with additional glutamatergic injury in the DLPFC. ACC Glu and also DLPFC NAA and Cho metabolite abnormalities related to poorer cognitive function, which, however, did not differ significantly from CON. Of note, GABA concentrations in ACC and DLPFC of OD were equivalent to those in smoking CON, similar to findings in 3-week abstinent ALC versus smoking CONand 1 week abstinent ALC vs. mostly nonsmoking CON. However, ACC GABA reductions were reported in abstinent individuals with cocaine- and polysubstance-dependence. The POC and occipital region have been used as control regions in MRS studies as they are typically not altered in addiction. This appears to be true also for OD, who showed the most pronounced metabolite deficits in anterior frontal brain regions.The lateral OFC sub-serves motivation, drive, reward valuation, and aspects of social executive skills,vertical grow system is affected in opiate dependence and other drug abuse, and the OFC has altered brain activity in decision making task-based fMRI studies of individuals with substance use disorders.

OFC metabolite concentrations did not differ between OD and CON, the latter including mostly non-smokers. However, and in contrast to DLPFC and ACC findings, OD showed elevated Glu and Cho concentrations in the OFC when compared to a subset of CON, the small group of smoking CON. Although the small group size warrants caution when interpreting results, our finding of lower OFC Cho concentration in smoking vs. nonsmoking CON is consistent with lower Cho measured in frontal, midbrain and vermis regions of smoking vs. non-smoking controls. In OD, lower DLPFC Glu and strong trends for lower ACC GABA correlated with greater severity and duration of opiate use. These findings are congruent with other neuroimaging studies that reported lower DLPFC GM density and poorer functional connectivity between DLPFC and parietal regions associated with greater duration of opiate use. ACC Glu and NAA were not related to opiate use, consistent with previous reports. However, greater cocaine and marijuana misuse in our OD group was associated with significantly lower metabolite concentrations, commensurate with findings in other substance using/ dependent populations. Metabolite concentrations in the DLPFC and ACC of OD related to executive function, visuospatial skills, global cognition and working memory, but not to self-regulation measures. Previous 1H MRS studies in opiate dependence did not report on such relationships, but studies in marijuana-dependent and recreational ecstasy users reported relationships between altered frontal metabolite levels and impaired cognition or higher impulsivity. Although previous research in opiate addicts reported neuropsychological deficit, our OD group performed in the average range across various cognitive domains and self-regulation measures. There is some evidence that buprenorphine maintenance is associated with better cognition compared to other maintenance drugs, and buprenorphine has been shown to improve brain perfusion in cocaine dependence; correspondingly, buprenorphine may have had an effect on cognitive performance in OD in this study. Future studies on the effects of buprenorphine on brain function and cognition in OD may be useful to inform effective treatment.

Our study showed that OD on maintenance therapy had greater anterior frontal brain metabolite abnormalities than 3 week abstinent ALC, and we found previously that even 1 week abstinent ALC did not show metabolite abnormalities in the DLPFC. The greater DLPFC metabolite abnormalities in OD may relate to the greater relapse rate in opiate than alcohol dependence, which may require differently tailored approaches for treatment of OD and ALC. Metabolite deficits in the DLPFC of OD are more reminiscent of 1H MRS results in poly-substance users, recreational cannabis users, and methamphetamine dependent individuals. The DLPFC is critically involved in executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. As such, DLPFC brain metabolite abnormalities, in addition to those in ACC, may be promising targets to monitor the efficacy of cognitive behaviour therapy in OD treatment, especially as they correlate with cognition and substance use behaviour. This study has limitations. Drug use histories were based on self-report and gender effects across groups could not be assessed due to the small number of females . Menstrual cycle appears to affect brain GABA levels, but data on the time since last menstrual cycle was not collected. However, excluding the female participants from statistical analyses did not alter the finding of no significant GABA differences between groups. The number of analysed spectra for some comparisons was relatively small, especially those involving smoking CON with OFC and POC VOIs; therefore, these analyses need to be considered hypothesis generating rather than definitive. Further, differences to previous metabolite and neuropsychological research in OD may relate to differences in comorbid tobacco, alcohol, marijuana and stimulant abuse as pointed out previously. Of note in this context is the relatively low lifetime and current alcohol use in our OD sample. An additional limitation is that the duration of buprenorphine maintenance therapy was not assessed, although OD had to be on therapy for at least 3 months. Furthermore, the results may not be generalizable to OD who are not on buprenorphine therapy. Finally, we cannot rule out the possible contributions of premorbid, developmental,cannabis grow tray and dietary/nutritional factors to the neurobiological group effects reported.

That genetic factors have an age-specific influence on the onset of alcohol dependence is suggested by the findings that there are strong genetic effects contributing to risk for alcohol dependence particularly connected with early onset of drinking activity . Correspondingly, the rate of adult alcohol dependence is significantly greater among those who start drinking at a relatively early age than among those who start drinking after the age of 19. Studies of adolescent brain development point to neurophysiological factors that could enhance the likelihood of substance use/abuse in those between 14 years of age and 17 years of age . Significant changes in the dopaminergic system occur during adolescence, as well as growth and refinement of prefrontal and limbic circuitry . As a result of the early enhanced activity of the mesolimbic system in contrast to the more slowly maturing prefrontal control systems and their connections to other brain regions, changes in the adolescent brain may lead to enhanced risk taking compared to earlier and later stages of maturation. specifically, these changes may lead to a reduced cognitive control of the reward system in the brain in early to middle adolescence, leading to increased risk for alcohol and other substance abuse disorders . Alcohol dependence and risk for alcoholism in both adults and adolescents is associated with reduced power in event related oscillations in a number of different experiments which elicit a P3 or P300 response. ERO power in a task that elicits a P3 response is also associated with a number of SNPs in the CHRM2 gene . Alcohol dependence in adults was found to be associated with a number of SNPs in the cholinergic M2 receptor genein two studies . A refinement of the study of Wang et al.showed that the association was present only in those subjects who had comorbid illicit drug dependence . This group of subjects and their family members form a genetically vulnerable group, that is, a group whose alcohol dependent members have a more heritable form of the disorder. The alcohol dependent members of this group had a significantly earlier age of onset of drinking compared to the alcohol dependent subjects without comorbid drug dependence. A generalized measure of externalizing psychopathology including alcohol dependence and illicit drug dependence is associated with the same group of SNPs in the CHRM2 gene . Additionally, there is variation in the genetic factors associated with alcohol dependence; multiple genetic factors were found to contribute to a DSM-IV diagnosis of alcohol dependence in adults . Some differences were found between genetic factors involved in alcohol consumption in adolescents and in young adults in twin study models. In order to investigate the age specificity of the genetic and endophenotypic factors noted above on the early onset of alcohol use and dependence, we studied adolescents and young adults drawn from the Collaborative Studies on the Genetics of Alcoholism sample . Because we wanted to understand the processes which lead from non-drinking to regular drinking to alcohol dependence we used both the onset of regular alcohol use and of alcohol dependence as dependent variables.

As we noted above, more severe cases of alcohol dependence in adults were found associated with earlier ages of onset of drinking and are more likely to be the result of genetic factors, thus we hypothesized that specific genetic and related neurophysiological endophenotypes would have a greater predictive power in those with the earliest ages of onset. Discrete time survival analysis was used to investigate the contribution of genetic variants in CHRM2, ERO power, and environmental factors to the onset of regular alcohol use and of alcohol dependence in adolescents and young adults, to deal with the first two items of investigation. DTSA provides age-specific measures for the effects associated with predictive variables. Additional statistical tests, including both genetic and endophenotypic independent variables, were used to link the onset of regular alcohol use to the onset of alcohol dependence, to deal with the third item of investigation. To deal with the fourth item, the same DTSA methodology as was used for the entire sample was applied to a behaviorally defined sub-sample, the definition of which is discussed subsequently . The results of the DTSA calculations suggested further investigation of age related changes in the genotypic distributions of those who became alcohol dependent. A further test was made to determine whether there was an effect of alcohol use on our endophentypic covariates.Data were analyzed in a cross sectional sample of subjects who were assessed at least once when they were between the ages of 12 and 25 years. They were drawn from multiplex alcoholic families and a set of community families in the Collaborative Studies on Genetics of Alcoholism . Written informed consent was obtained from all subjects, and the Institutional Review Boards of each collaborative site approved all procedures. The procedures used by COGA for diagnostic interviews and recording and analyzing EEG data have been described previously . A detailed description of population characteristics of alcohol use and dependence are given in ‘‘Population description’’ section.A substantial literature indicates that alcohol dependence and risk for alcoholism are associated with reduced levels of brain activity when subjects respond to infrequent target stimuli within a sequence of non-target stimuli . Representation of this response in terms of brain rhythms or EROs has proved fruitful . The ERO amplitudes used in this study were obtained from responses to rare target stimuli that elicited a P3 component in a visual oddball experiment at three midline leads . Three leads were chosen because of topographical variation in the significance of results in previous studies . The amplitudes were calculated using the S-transform applied to the recorded data for the delta frequency band extending from 300 to 700 ms post-stimulus. Jones et al.provides a complete description of the experiment and the calculation of the values. The values were log transformed and non-parametric age regression was performed on the variables and the standardized residuals used for further analysis.

Drinking patterns, however, fluctuate over time. Changes in college drinking can reflect periods of transition, such as moving from home to the freshman year of college . Other transitions have less often been studied, such as when students return to their home environment over the summer , or the transition from summer back to university. Drinking is also likely to escalate during celebrations, including 21st birthdays, spring-break parties, and campus-centered events such as football games . An annual celebration at our university is the 1-day Sun God Festival, which on May 16, 2014 occurred during our study of the impact of a program aimed at decreasing campus heavy drinking . That year the festival attracted more than 16,000 participants, among which 155 attendees received student-conduct violations primarily for alcohol, 70 needed help to sober up on site, 21 required more intense medically monitored treatment for intoxication on site, 21 were transported to a healthcare facility, and 11 participants were arrested . Our 2014 campus heavy drinking prevention study gathered drinking-related data at 8 time points over 55 weeks. Ninety-two percent of students who entered the study completed at least 7 assessments, which allowed us to compare drinking patterns across a range of relatively rarely studied transitions, and to evaluate predictors of drinking patterns at each time point. In light of concerns expressed about heavy episodic, or “binge,” drinking, the analyses focus on drinking quantities. These longitudinal data were used to test the following 4 hypotheses. Despite the single-day duration of the Sun God event, Hypothesis 1 predicted that drinking quantities will increase during the month of the Sun God Festival compared with earlier alcohol-related practices. reflecting recent results with students mandated for counseling for drinking infractions and potential dampening effects parents might have on drinking practices, Hypothesis 2 stated that students will decrease drinking quantities over the summer. reflecting drinking practices related to specific environments , Hypothesis 3 anticipated students will resume higher quantities upon return to school.

Hypothesis 4 stated that predictors of drinking patterns over time will encompass a wide range of characteristics that include demography,pots for cannabis plants substance use, and environment as well as attitudes toward drinking.Following approval by our university’s Human Protections Committee, in November, 2013, questionnaires were emailed to 4,000 freshmen using questions derived from the Semi-Structured Assessment for the Genetics of Alcoholism interview . Data were gathered as part of an experimental protocol in which subjects with low and high LRs were assigned either to watch 1 of 2 sets of videos aimed at decreasing heavy drinking or to a control group and followed over time . With about a 70% response rate to the mailings, we identified recent drinkers who did not meet lifetime criteria for alcohol or illicit drug dependence, bipolar disorder, antisocial personality disorder, or schizophrenia . Asian individuals who became physically ill after 1 or 2 drinks, and who were probable homozygotes for aldehyde dehydrogenase mutations, were also excluded . The drinking related questions included recent 30-day histories of the days on which alcohol was consumed, numbers of standard drinks on usual and maximum drinking days, and alcohol problems. Subjects’ LRs to alcohol early in their drinking careers, and before tolerance was likely to develop, were evaluated using the Self-Rating of the effects of Alcohol questionnaire as the average number of standard drinks required for up to 4 effects the first 5 times of drinking . These included drinks to first feeling any effect, slurring speech, unsteady gait, and unwanted falling asleep, with higher scores indicating needing more drinks for effects, or a lower LR per drink . The Cronbach alpha for the SRE in the current sample was 0.88, with repeat reliabilities in the literature >0.66 . Based on the time frame described at the bottom of Fig. 1, 90% of subjects who were invited to participate agreed to enter the experimental protocol where they were paid $20 for each of 8 Internet-based assessments. As part of the prevention study , students were randomly assigned to either a control condition with no intervention or watched 5 alcohol-related educational videos over the first 3 months. Subjects were then followed and evaluated with Internet-based assessments similar to the baseline SSAGA based questionnaire . Among the 500 students enrolled, 462completed at least 7 of the 8 assessments and were included in these analyses, with any missing data handled using SPSS multiple imputation . Potential baseline predictors representing the 3 domains had to be limited to those included in the campus heavy drinking prevention study.

For demography, for reasons stated in the Introduction, we selected age, sex, and self-reports of an EA ethnicity, with the latter representing the largest ethnic background that related to heavy drinking in a past university-based study . Regarding substance use patterns, reflecting our long-term interest in LR, we included SRE-based LR scores along with SSAGA based alcohol problems and usual and maximum quantities in the prior month. Recent cannabis use from the SSAGA was included because of the high prevalence of experience with this drug on campus as well as the relationship between alcohol and cannabis use patterns . Finally, several environment and attitude items that have related to higher drinking quantities in our prior studies were selected as baseline predictors, including a short version of the Alcohol Expectancy Questionnaire that has a Cronbach alpha of 0.88 in this population and similar retest reliabilities. As described elsewhere , this AEQ version included 3 items with the highest factor loadings from each of 4 AEQ sub-scales . The second relevant measure was the Beck Depression Inventory with Cronbach alpha of 0.91 and retest reliability of 0.93 . Using alcohol to cope with stress was measured by the 6-item Drinking to Cope scale that used a 4-point scale to measure frequencies of using alcohol to cope with specific stressors . Injunctive norms were evaluated using a modification of the scale of Lewis and colleagues as the sum of the subject’s estimate of approval on a 7-point scale regarding 14 drinking behaviors by the typical same-sex person, with higher scores indicating greater approval, and descriptive norms related to the usual number of drinks per occasion estimated for typical students . Finally, the perceptions of drinking in 4 close peers were based on the Important People and Activities Scale that included an estimate of whether each peer drank alcohol in the prior month, and, if so,cannabis flood table the frequency and maximum number of drinks per day . Statistical analyses included product–moment correlations between baseline characteristics and drinking usual and maximum quantities during the 30 days prior to each assessment. Baseline items that related significantly to a relevant outcome were simultaneously entered into multiple linear regression analyses to determine which predictors were most robust when considered in the context of other significant predictors, as well as the proportion of the variance explained . As alcohol outcomes are sometimes evaluated as count variables, the regression analyses were also run using Poisson and negative binomial approaches. Differences in drinking quantities between assessments were evaluated with repeated measure analyses of variance. reflecting non normal distributions of drinking quantities, square-root transformations were used for these variables in correlations, multiple linear regressions, and repeated measure analyses.From among the original 500 students enrolled in the campus prevention protocol, the subjects in the current analyses were 462 individuals who completed at least 7 of the 8 assessments over the 55 weeks, of which all but 12 participated in all 8 periods. As shown in the first data column of Table 1, regarding demography, at the time of the baseline assessment used in these analyses , subjects were an average of 18 years old, 63% were female, and about a third were EA.

While not shown in the table, 36% were Asian, 16% Hispanic, and 14% listed other ethnic backgrounds . Substance use patterns in the month prior to baseline included an average of 4 standard drinks on a usual occasion and a maximum of 6 drinks at any occasion in the past month, with more than 40% having used cannabis in that same time period. Early in their drinking careers, these students required an average of 4 drinks to produce up to 4 potential alcohol effects as measured by the SRE questionnaire. While at baseline no subject was alcohol dependent, 45% reported 1 or more of 19 possible alcohol problems in the prior month, including about 20% each for ARBs and/or drinking more or for longer periods than intended, with about 15% each reporting needing more drinks to get effects and/ or consuming 4 or more drinks per occasion and/or drinking heavily for at least 2 consecutive days . Table 1 also lists scores for several environment and attitude characteristics shown in our prior work to relate to heavier drinking, including alcohol expectancies , depressive symptoms, using alcohol to cope with stress , descriptive and injunctive drinking norms, and drinking among peers. The final item in Table 1 reports that in the prevention protocol, 86% viewed educational videos, while 14% were controls, and, as discussed below, the assignment to active intervention versus control groups did not relate to patterns of increases and decreases in drinking over time. Table 2 and Fig. 1 present maximum and usual drinks per occasion across Periods 5, 6, and 7 that include the spring– summer–fall periods of the study. To place these dates into perspective, the legend in Fig. 1 presents dates for the academic quarters. While the emphasis in these analyses is on the Sun God–summer–return to school time frames set off by vertical bars in Fig. 1, the previously described school year drinking patterns for Times 1 to 4, and 8 are also shown. The current results demonstrate changes from prior to subsequent periods, including 18% increases in maximum drinking quantities during the Sun God Festival Period , 29% reductions in alcohol quantities over the summer , and 31% increases when students returned to school in the fall . Note that if the time frame prior to the Sun God Festival is used as a base, the decrease from Time 4 to summer was almost 17%. During summer months, 60.0% of these students lived with their parents, 22.1% were away from campus but not with parents, and 18.1% remained in campus dorms. While not shown in the figure, the patterns of drinking across the key time periods were similar for students in the control group and those in the active educational groups during the campus prevention protocol. Returning to Table 1, the remaining 6 data columns give product–moment correlations between baseline characteristics and drinking quantities the 30 days prior to Sun God, summer, and school return assessments. Regarding demography, on a univariate level an EA ethnicity was associated with higher drinking quantities in all follow-up periods, older age related to lower drinking during Sun God and school return periods, but female sex was only related to lower maximum drinks over the summer. All baseline substance-related variables correlated with higher quantities over the year, including higher SRE scores that indicated a lower LR per drink, higher baseline alcohol quantities, and cannabis use. Among environment/attitude baseline measures, higher depression scores correlated with lower drinking during the summer and return to school periods, and higher injunctive norms only related to heavier drinking during the Sun God and school return periods. Other than for AEQ, higher scores for all remaining variables in this group of potential predictors were more consistently related to higher alcohol intake across time frames. The experimental condition in which a person was placed did not relate to whether drinking at any time period across the 55 weeks was higher or lower. Therefore, to better identify baseline characteristics that are more likely to stand alone as predictors, all significant predictors of drinking for each follow-up period were entered into a simultaneous entry multiple linear regression analysis to evaluate which items performed most robustly when evaluated in the context of others. As shown in Table 3, the most consistent predictors of higher drinking quantities across multiple periods included higher SRE scores , higher baseline maximum quantities, and descriptive norms .

The government’s plan popularly referred to as “The Normalization Plan,” will transform this prime location just minutes walk from downtown Copenhagen, from a space of alterity and opposition into a marketable place comprised of privately owned homes and businesses. This paper explores how control over urban space is integral to maintaining Danish national identity that is premised on restricted conceptions of cultural citizenship and belonging. Two questions are central to this inquiry: 1) How are social and political marginality being constructed, negotiated and resisted in Denmark?; 2) What insights are generated when groups defined as ‘marginal’ by the state challenge state authority and compete for control of urban spaces? The policing and privatization of Christiania is indicative of broader challenges to maintaining an ethnically and culturally homogeneous “white” Danish nation, the reformation of citizenship and the welfare state, and the project of creating a space of European nations. Following Gupta and Ferguson’s call for a critical, ethnographically grounded consideration of the spatialized production of difference this paper is an ethnographically grounded consideration of the spatialized production of difference that examines how control over urban spaces are generative; creating contending social imaginaries and oppositional identities that destabilize state projects seeking to eradicate opposition by controlling the urban environment. In 2002, a new government was elected in Denmark, and Christiania’s future as a legitimized “social experiment” under the previous Social Democratic government was in jeopardy. The new government, elected on a neoliberal agenda that promised significant reform of the welfare state, began plans to “normalize” the squatter community. The goals were to end the flourishing, illegal hash trade, privatize the space and then develop the area through state generated privatization. This process colloquially entitled, “The Normalization Plan,” cannabis indoor greenhouse will effectively displace Christiania’s many residents who cannot afford market rates, and will transform this prime location, just minutes walk from downtown Copenhagen, from a space of alterity and opposition into a marketable neighborhood comprised of privately owned homes and businesses.

Christiania is not numbered, arranged and orderly. Order is intuited, embodied and experienced, not marked and organized through the nomenclature and disciplinary sciences of the state. There are few signs, mostly for businesses, and the houses are named not addressed. For example, I lived in Karlsvogn or the Farmer’s Wagon which was also known as the home of my two roommates. My house did not have an address, and was not located on a map, but it was well-known as one of the oldest cooperative houses in Christiania. The history of the place gave it an identity. Those residing within it became associated with this history because the house was an activist house, and by association, those living within it were linked to the activists. State-generated Normalization and the reformation of the built environment are strategies of discipline that aims to silence the oppositional histories in order to replace the contentious past with the grand narratives of nation-building, military past and the ‘rational’ organization of the market. According to Foucault , normalization is created through a range of disciplinary apparatuses that instantiate “the subject” who is disciplined into being through the restriction of bodily movements in carefully constructed spaces of control and surveillance. The most famous example is Jeremy Bentham’s Panopticon, a potent symbol of self- discipline and spatial control . Foucault argues using the example of urban plagues, that normalization functions through the creation of surveiled and orderly spaces structured on formal scientific systems of evaluation, production and investigation. The transformation of unruly and undisciplined bodies into coherent, self-regulating subjects occurs through the control of spaces and the creation of manageable populations. Discipline and control are achieved through scientific disciplines that naturalize the use of timetables, regulate embodied practices through repetitive exercises, and the creation knowledges that rank and order, placing limits on practices through pathologization and criminalization. The various apparatuses and accompanying knowledges encourage subject’s complicity in their self regulation. Foucault’s normalization is about foreclosures, silences, and limitations on practices deemed excessive. Difference and the possibility of authentic politics are limited. In Christiania, state generated Normalization is a strategy of control, but one that is overtly using the built environment to control and eradicate, and subvert. Christiania’s Normalization is about privatization, the management of dissent through spatial strategies, and the use of overt force to silence oppositional voices. periment, which has been labeled a failure, and transform the space into a multi-use, privately owned area. A new Christiania is being imagined and forcefully created. The new urban space will be fully integrated into the surrounding urban area complete with paved roads, additional parking and a new bridge to reduce driving time from the center of Copenhagen.

I agree with Kathleen Bubinas who asserts that, “Politically-dictated urban renewal programs restrict access to cityspace by those racial and ethnic groups deemed or publicly constructed as “dangerous” . Since 1980 there has been an ongoing process of transforming the greater Copenhagen area into a regional economic power . Part of this process is the concept of “Creative Copenhagen,” and the privatization of public lands in Sydhaven, Øresund, and Christiania. “Creative Copenhagen” is a state generated plan to repackage and develop the cityspace, and Christiania’s privatization is central to making Copenhagen attractive to investment. Privatizing Christiania, a prime location just minutes from downtown, would integrate this valuable area into Copenhagen, and raise property values while neutralizing its oppositional character. A similar process of repackaging the cityscape is occurring in cities throughout the Europe and the United States. Setha Low makes the point that: “Increasing privatization through public/private partnerships between municipalities and local businesses has transformed such places as Bryant Park and Union Square in the center of New York City into safe, middle-class environments maintained by strict surveillance and police control” . Like other cities, Copenhagen is being transformed into an elite urban space that is eradicating subversive, contentious places through increased police presence and the use of surveillance technologies. Christiania’s transformation from an interstitial, danger zone of alterity into a managed and marketable space is integrally interlinked to making Copenhagen fit for elite consumption and hi-tech production. The Creative Copenhagen plan is a response to economic globalization and regional development initiative which Hansen argues, “must be seen against the background of competition between cities.” Creative Copenhagen is a strategy which attempts to ensure Copenhagen’s place among European Cities by marketing an image of entrepreneurial creativity in the North . In order to ensure Copenhagen’s place as a city attractive to capital investment,cannabis growing equipment public lands are sold to private corporations that have significantly less accountability to the electorate and when the area is developed the poor and marginal residents are displaced . The increasing privatization of public lands suggests a strategy of close cooperation with private firms and organizations as a means of ensuring global competitiveness. The Creative Copenhagen development plan is also an extension of EU economic development policy aimed at transforming Copenhagen into a node in the European market. Regional development policy focuses on the regeneration of urban areas and is supported by EU Cohesion Funds1 . Competing visions of the urban built environment 2 are part of transnational processes reforming cities throughout Europe. This neoliberal imaginary is integral to transforming Christiania into a simulacrum of itself so that the city of Copenhagen can be marketed, rehabilitated and fully integrated into a European city.

The impacts of these processes are evident in struggles over meaning, history and place, providing insights into the political implications and the social impacts of the reconfiguration of cities. By neoliberal imaginary I mean a mixture of neoliberalism, which describes a form of renewed economic liberalism and a political philosophy which reestablished itself in the 1970’s, combined with the establishment of a emergent social imaginary . Neoliberal imaginary is a political philosophy which guides social, political and economic interactions. It operates as a political philosophy, presented as a transparent good and logical approach to the management of society in a democratic modern nation. Proponents reject earlier forms of government intervention into private life and the economy epitomized by the welfare state. Instead, progress and social justice are achieved through the free-market, individual choice and accountability, with the state playing a minor, but supportive role to entrepreneurial citizens by ensuring a fair playing field. In 2002, the government announced that Christiania will be “closed.” This new government, elected on a neoliberal agenda promised significant reform to the welfare state promising to transform the bureaucracy intensive structure into a trimmed down, efficient “minimal” welfare state. I began my research during the summer of 2003 and Christiania was, once again, in the political limelight. “Normalization” had become a national buzzword and provided the government with certain rhetorical strategies to publicly defend and legitimize their plan to privatize the area. The Normalization Plan, bureaucratic nomenclature for a complex set of political and cultural processes, was taken-up by the media and transformed into a catch-all phrase. Normalization encapsulated state authority. By contrast, the state argued Normalization was a transparent, lawful process that would simply make things more equitable by integrating and legalizing the Christiania area. Most of all, Normalization came to mean the ending of “special treatment” for Christianitter. The state argued communal ownership and control over public space provided an unfair advantage, one that was not available the rest of the law abiding Danes. In Christiania, The Normalization Plan signaled “the death of Christiania’s spirit;” the replacement of autonomy by state bureaucracy and impersonal laws. The Normalization Plan entails several key changes to the legal, spatial and economic management of the Christiania Area. The first step of normalization was to transform Christiania from a quasi-legal into an illegal space. The initial phase terminated the legal rights of residence and management that had been afforded the Christianitter in 1986. On June 4, 2004 the government unanimously approved the new lawthat ended the scarce legal protections afforded residents of Christiania. The goal was to remove any legal protection offered under the“Christiania Law,” which provided the scant legal protections offered by the social democratic government in 1989. Despite the popular and political support Christiania enjoyed as a space of cultural experimentation and freedom L205 was passed unanimously by the Danish Parliament . With the new legal framework in position, the government began implementing a series of changes that would end Christiania’s self-government, privatize the communally held properties, and the government argued, integrate the community fully into the market economy thus providing all Danish citizens access to the space through the implementation of neoliberal principles of freedom of choice and the “fair” mechanisms of value and competition operating in a free market. Communally owned houses would be privatized, placed on the market, and sold at fair market value. Ideally all citizens would have the opportunity and right to purchase into the community, assuming they have the resources. According to the government, the clear and fair rules of the market would replace Christiania’s labyrinthine and socially opaque system. Under the old system, Christianitter decide by vote who lives in their community. As houses become available, a social network of would-be residents is alerted through their contacts in the community. New residents are often chosen based on their commitment to Christiania and their qualities as “good neighbors.” Commitment takes the form of providing support, which often translates into free labor; working for the good of the community in a way that is perceived as selfless. It is extremely difficult to get a place to live, even on a temporary basis as I found out during my fieldwork. As one of my contacts said, “You must have very good connections to get a place in Christiania.”In one respect, the decision-making process based on an Arendtian ideal of dialogue, deliberation and consensus is being heavily critiqued by the state, despite the stated desire to implement similar principles such as dialogue, open communication and transparency using the internet. Christianitter often remark that the “state does not know what to do with us. We agree be consensus and that takes a long time.” Decision-making through deliberation by involved citizens is a hallmark of liberal democracy.

More generally speaking, Meyer argues that experiences of victimization in the forms of stigma, prejudice, and discrimination that GBM experience may be the cause for the higher prevalence of mental health conditions in GBM populations and refers to this as minority stress . Stigma may also help explain why HIV-positive GBM were more likely to report a substance use disorder in our study. HIV-related stigma has been linked to poorer mental health in a meta-analysis by Logie and Gadalla and a review by Smit and colleagues . Readers should be cautious when interpreting our results. Most notably our results rely on participants’ retrospective self-report of recent substance use and sexual behavior and compare these data with lifetime mental health diagnoses. As such, we are limited in determining causal direction, but instead position these findings as a more representative profile of GBM who had ever been diagnosed with a mental health condition given our use of respondent-driven sampling. We did not conduct diagnostic interviews to account for undiagnosed conditions, and thus underestimated the true burden of mental health issues. We attempted to address current symptomology through the inclusion of AUDIT and HADS scores. However, given the paucity of validation studies for AUDIT, but particularly HADS within GBM populations, we caution the interpretation of these findings and call for new research validation studies with GBM populations. Regardless, our analyses demonstrate some measure of construct validity in that higher scores on both measures were linked to reporting mental health conditions in our study. Our measure of sexual orientation “outness” was only asked for gay-identified participants, and a general measure should be included in future studies. A nurse-administered structured interview was used to assess mental health diagnoses and current treatments to ensure these questions were more accurately understood and answered. Given the potential impact of social desirability and reporting bias , we used CASI to collect data regarding illicit substance use. However,4×8 grow table with wheels we did not use drug testing to confirm or correct self-report data and likely underestimated the true prevalence of substances used .

Despite these shortcomings, one of the strengths of our study is the use of RDS to overcome previous sampling shortfalls with GBM and produce a more accurate representation of the population parameters of these variables of interest for the GBM population of Metro Vancouver. Our study also adds new data regarding the detailed prevalence of substance use and mental health conditions among GBM populations in Canada filling a gap in currently available published literature. Finally, our work goes further to examine explicitly the relationship between substance use and mental health conditions among GBM identifying important relationships that have implications for counseling and public health services, interventions, and policy. The greater burden of mental health conditions and higher prevalence of substance use in GBM populations highlight the need for a more explicit focus on these issues in research and service provision. Mental health specialists should be aware of the relationships with sexuality and substance use when working with GBM clients, particularly issues regarding identity disclosure, number of sexual partners, and higher background community prevalence of substance use . Future research should seek to validate current measures and to confirm the relationship between substance use and mental health conditions, which has been demonstrated to produce a syndemic including suicidal ideation among GBM and HIV acquisition . Our study was based in a major metropolitan area, which may limit generalizability to GBM in rural or remote regions, whom are a population with distinct needs and challenges that should be further examined. In order to evaluate generalizability, additional research is needed to explore these issues among GBM populations in other urban and non-urban centers across Canada, particularly if these studies employ RDS or other more representative sampling methods. Given the role of social factors in mental well-being, future research should directly examine experiences of homophobia or heterosexism as possible precursors to substance use and/or mental health issues, along with potential mediators and protective factors.

Examining demographic factors independent of one another may not reflect the diversity of experiences that exists among GBM. Using an intersectional approach, which looks at how multiple identities such as race, sexual orientation, and class, interact with one another to shape experiences , may also explain the distribution and experiences of mental health and substance use within diverse communities of GBM. In spite of experiences of marginalization and discrimination, many GBM do not go on to develop mental health conditions or engage in harmful substance use. Shilo, Antebi, and Mor found that factors such as support of family and friends, meaningful connections with the LGBT community, and having a steady partner, protect against developing poorer mental health in lesbian, gay, bisexual, queer, and questioning adults. Thus, more focus on factors such as these that promote resiliency in GBM would be beneficial to include in future research on mental health and substance use in these populations. Compared with the Canadian population, GBM living in Metro Vancouver have increased levels of substance use and mental health conditions. The strong link between substance use and mental health among GBM has important implications for public health promotion programming and care service provision. A number of social determinants increase the likelihood of mental health diagnosis among GBM, including disclosure of sexuality, low income, and race/ethnicity. GBM living with HIV were significantly more likely to have a lifetime doctor-substance use disorder compared with HIV negative GBM. Greater attention to these issues is needed across all health and social services given their disproportionate effect on GBM populations. Health promotion and interventions should address issues of substance use, mental health, and sexuality in unison and future research can help direct these efforts by examining possible precursors of these issues, which may be the result of discrimination, prejudice, and stigma.Tobacco use in the general population has declined substantially in the past three decades, but rates remain high in certain populations.Among homeless adults, tobacco-related chronic diseases including heart disease, cancer and chronic obstructive pulmonary disease are common and contribute significantly to the increased morbidity and mortality in this population.Among a clinic-based sample of homeless adults aged 50 and older, tobacco-attributable deaths accounted for 26% of the overall mortality and 54% of substance-related mortality.

The health consequences of smoking occur disproportionately among older individuals because of the cumulative effects of long term smoking.Among older adults, tobacco-related chronic diseases, particularly chronic obstructive pulmonary disease and coronary heart disease, are among the most common reasons for emergency health care services and preventable hospitalizations.Current tobacco use contributes significantly to all-cause mortality among older adults, suggesting that tobacco cessation at any age is likely to significantly reduce tobacco-related morbidity and mortality.In a nationally representative sample, older adults were less likely to quit smoking than younger adults because of reduced interest in quitting smoking,grow tray stand higher nicotine dependence, and lower support for smoke-free norms.This highlights the need for tobacco cessation interventions that address tobacco-related beliefs and practices among older adults. Over the past 2 decades, the median age of homeless adults increased from 37years in 1990 to almost 50years in 2010.Despite increased tobacco-related morbidity and mortality among older homeless adults, little is known about tobacco use and cessation behaviors in this population. Prior research on tobacco use in the homeless population has focused on younger adults, where the average age of study participants in previous studies was less than 44 years.The high prevalence of tobacco use and the increased burden of tobacco-related chronic diseases with aging underscore a need for studies that characterize tobacco use and cessation behaviors among older homeless adults in order to develop tobacco control interventions that address the unique needs of this population. We conducted a study of a cohort of homeless individuals aged 50 and older sampled from the community to examine rates of and factors associated with tobacco cessation. We hypothesized a priori that current smoking would be associated with symptoms of depression, substance use disorders, history of incarceration, and history of staying in shelters.We also hypothesized that persons who reported smoking heavily or having symptoms of depression at enrollment would be less likely to make a quit attempt at follow-up.The HOPE HOME Study is a longitudinal study of life course events, geriatric conditions, and their associations with health-related outcomes among older homeless adults. From July 2013 to June 2014, we enrolled a population-based sample of 350 homeless adults aged 50 years and older from homeless encampments, recycling centers, overnight homeless shelters, and free and low-cost meal centers serving at least three meals a week in Oakland, California. Participants were eligible if they were English-speaking, aged 50 years and older, defined as homeless as outlined in the Homeless Emergency Assistance and Rapid Transition to Housing Act, and able to provide informed consent, as determined by a teach-back method.The University of California, San Francisco Institutional Review Board reviewed and approved all study protocols.The study included an enrollment visit and a follow-up visit at 6 months. Study interviews took place at a community-based site. After determining eligibility, study staff administered an in-depth structured enrollment interview and collected extensive contact information from participants. We asked participants to check in with study staff in person or by telephone each month.

If participants missed two or more check-in visits, study staff reached out to participants using their contact information. From January 2014 to January 2015, we conducted 6-month follow-up visits with each of the participants who completed an enrollment interview. We gave participants gift cards to a major retailer for their participation: $5 for the screening interview, $20 for the enrollment interview, $5 for each month check-in, and $15 for the follow-up interview.We used previously validated questions on tobacco use at the enrollment and 6-month follow-up interviews. We asked participants whether they had ever smoked 100 cigarettes in their lifetime, and classified those who did as ever-smokers. We classified ever-smokers who reported smoking “every day or some days” as current smokers, and those who reported “not smoking at all” as former smokers. We asked current daily smokers to report the number of cigarettes smoked daily. For current non-daily smokers, we estimated average daily cigarette consumption based on self-reported numbers of cigarettes smoked on smoking days in the past 30 days. Participants reported how soon they had smoked their first cigarette after waking, which we dichotomized as greater or less than 30 minutes. We asked current smokers about their intentions to quit smoking . We asked current smokers to report whether they had stopped smoking for 1 day or longer in the past 6 months because they were trying to quit smoking. We asked participants who responded affirmatively to making a quit attempt to report the length of their last quit attempt. We defined reporting a quit attempt in the past 6-months at the follow-up visit as the primary outcome variable. We determined the proportion of participants who were abstinent for 30 days and 90 days at the 6-month study visit using self-reported information on the length of the last quit attempt. At the 6-month follow-up visit, we obtained additional information from participants on their quitting behaviors.If participants reported having made a quit attempt during the past 6 months, we asked them to report the medications, strategies, and support system they had used during their last quit attempt. Participants reported whether they had used nicotine replacement therapy and/ or any of the US Food and Drug Administration -approved medications for smoking cessation during their last quit attempt. Participants reported whether they had used other strategies to quit smoking including gradually cutting back on cigarettes, switching to smokeless tobacco, other combustible tobacco , or electronic cigarettes, or giving up cigarettes all at once. Participants self-reported their use of a telephone quit line, group or one-on-one smoking cessation counseling, hypnosis or acupuncture, and other internet or family-based support for smoking cessation. Participants also reported whether they had received advice to quit cigarette smoking from their health care provider in the past 6 months, and whether they had acted on the advice to quit smoking.Participants self-reported age, gender and race/ethnicity at the enrollment visit.

The past decade has seen a proliferation of cognitive training intervention trials aimed at remediating or reversing substance-related cognitive deficits . However, their implementation into clinical practice is almost non-existent, despite promising results and now having more flexible, precise, engaging and convenient modes of delivery . Gathering more data in this still-developing area is essential to facilitate translation. Even the most widely tested training interventions, such as cognitive bias modification, need more data to fully appraise their benefit for addiction treatment . This section summarizes recent advances in CT, identifies limitations in the evidence base, and highlights priorities and directions for future research to bridge the gap between science and practice. Current CT approaches can be broadly divided into: general cognitive remediation, working memory training , inhibitory control training , and cognitive bias modification .In SUD, general cognitive remediation approaches such as cognitive enhancement therapy and cognitive remediation therapy aim to reduce substance use and craving by targeting EF and self-regulation. Cognitive remediation has been shown to improve cognition in domains of working memory , verbal memory, verbal learning, attention, and processing speed . Positive outcomes have also been shown to be associated with increased neuroplasticity in emotion regulation-related fronto-limbic networks in individuals with schizophrenia and co-morbid SUD . A recent study delivered 12 two-hour group sessions of clinician-guided CRT and computerized CT over 4 weeks to a sample of female residents completing residential rehabilitation and found significant improvements in EF, response inhibition, self-control,grow table and quality of life relative to treatment as usual. Similar research has reported comparable improvements in cognitive functioning following CRT and CET , and improved cognitive functioning has been associated with reduced substance use at 3- and 6-month follow-ups .

Importantly, CET and CRT also demonstrate preliminary efficacy for SUD patients with cognitive impairments. However, their duration, intensity, and high cognitive demand—coupled with a current paucity of large-scale, methodologically rigorous clinical trials—may currently preclude their widespread implementation in clinical settings. Another manualized therapist-assisted group intervention is Goal Management Training , which trains EF and sustained attention and emphasizes the transfer of these skills to goal-related tasks and projects in everyday life. When combined with mindfulness meditation, GMT has been found to significantly improve WM, response inhibition and decision making in alcohol and stimulant outpatients relative to TAUand more recently also in poly substance users in a therapeutic community . A meta-analysis of GMT more broadly concluded that it provides small to moderate improvements in EF which are consistently maintained at 1–6 month followups . As such, GMT is likely to be an effective candidate cognitive remediation approach for SUD treatment; however, substantially more research is needed to validate this assertion, particularly regarding the translation of cognitive improvements into improved substance use outcomes.The most widely researched EF training intervention, WMT requires participants to repeatedly manipulate and recall sequences of shapes and numbers through computerized tasks that become increasingly difficult over time . WMT aims to extend WM capacity, so individuals can better integrate, manipulate, and prioritize important information, with the aim of supporting more adaptive decision making that leads to reduced substance use . Relative to many other approaches, WMT is intensive, typically requiring 19–25 days of training and as such, retention is often poor . While WMT has been shown to lead to improvements in near transfer effects , there is limited evidence supporting far-transfer effects of WMT on other measures of EF and importantly, on substance related outcomes . Reduced alcohol consumption 1 month after training was reported following WMT in heavy drinkers , but most studies have failed to demonstrate or even measure changes in substance use . For example, non-treatment seekers with alcohol use disorder who were trained with Cogmed showed improved verbal memory but no clinically significant reductions in alcohol consumption or problem severity .

While a study of treatment-seekers improved WM and capacity to plan for the future on a delay discounting task, there was no measurement of substance use outcomes . Similarly, studies of methadone maintenance and cannabis have found no evidence of far-transfer effects , although Rass et al.showed WMT-related reductions in street drug use among methadone users. Other forms of WMT have reported similar near-transfer but not substanceuse-related findings with methamphetamine patients and a mixed group of substance use patients. As such, the greatest limitation in the WMT literature is the failure to consistently examine substance use outcomes and therefore there is insufficient evidence at this time to support the utility of WMT as an effective adjunctive treatment for SUD.Since deficits in inhibitory control are associated with increased drug use , ICT aims to bolster inhibitory control through the repeated practice of tasks [e.g., go/no-go , stop-signal task]. Such tasks require individuals to repeatedly inhibit prepotent motor responses to salient stimuli . In a seminal study, a beer-GNG task which trained heavily drinking students to inhibit responses to “beer” stimuli resulted in significantly reduced weekly alcohol intake relative to students trained towards “beer” stimuli . A recent RCT of 120 heavily drinking students found that a single session of either ICT or approach bias modificationled to significant reductions in alcohol consumption relative to matched controls . Similarly, Kilwein et al.found that a single session of ICT reduced alcohol consumption and alcohol approach tendencies in a small sample of heavily drinking men . Despite these promising findings, each of the aforementioned ICT studies used community samples, and it has not yet been established whether these results will generalise to treatment seekers. Two meta-analyses recently concluded that ICT leads to small but robust reductions in alcohol consumption immediately after training . Di Lemma and Field reported reduced alcohol consumption in a bogus taste test after a single session of ICT or cue-avoidance training . Others have observed reduced alcohol consumption 1 and 2 weeks after ICT . These findings highlight the promise of ICT though there remains a paucity of research assessing long-term drinking outcomes outside of laboratory settings. Future studies of ICT with clinical populations should consider testing multi-session approaches akin to WMT. To date, few studies have trialled multi-session ICT: One found it to be ineffective for heavily drinking individuals, while another found that 2 weeks of ICT resulted in modest reductions of alcohol consumption among individuals with AUDs, compared to WMT or a control condition .CBM aims to directly interrupt and modify automatic processes in response to appetitive cues. Attentional bias modification aims to modify the preferential allocation of attentional resources to drug cues by repeatedly shifting attention to neutral or positive cues and away from drug-related cues. Despite several null findings , significant effects have included the reduction of alcohol consumption in non-treatment seeking heavy or social drinkers . Among treatment seekers, five sessions of AtBM have been shown to significantly delay time to relapserelative to controls who received sham training .

Similarly, six sessions significantly reduced alcohol relapse rates at a one-year follow-up relative to a sham training condition in a sample of treatment seekers with AUD . Among methadone maintenance patients, AtBM reduced attentional bias to heroin-related words, temptations to use, and number of lapses relative to TAU . However, among individuals with cocaine use disorder, it failed to reduce attentional bias, craving, and cocaine use . Likewise, 12 sessions of AtBM vs. sham training during residential treatment for methamphetamine use disorder failed to reduce craving and preferences for methamphetamine images . A systematic review of alcohol, nicotine,vertical rack and opioid AtBM studies concluded that despite numerous negative findings in the literature, eight out of 10 multiple-session studies resulted in reduced addiction symptoms , but without concomitant reductions in attentional bias . Approach bias modification , which uses the Approach Avoidance Task, requires an avoidance response to drug cuesand an approach response to non-drug cues. Several trials have examined alcohol ApBM, with evidence that short-term abstinence is increased by up to 30% with four consecutive training sessions during inpatient withdrawal and by 8%–13% at 12-month follow-up . Alcohol ApBM has demonstrated relatively consistent, moderate reductions in drinking behavior when delivered to clinical populations , and it was even added to the German guidelines for the treatment of AUD . Early neuroimaging evidence has examined the neuroadaptations that occur pre-to-post-cognitive bias modification training. This work has focused on two samples of abstinent alcoholics undergoing an fMRI cue-reactivity task. Participants showed higher baseline reactivity to alcohol cues within the amygdala/nucleus accumbens and the medial prefrontal cortex, respectively . The same samples, following a 3-week implicit avoidance task , showed reduced amygdala and medial prefrontal reactivity . Notably, these brain changes were associated with reduced craving and approach bias to alcohol stimuli but not abstinence 12 months later. While preliminary, these findings suggest that neuroadaptations associated with cognitive bias modification have clinical relevance and warrant replication in larger SUD samples using robust, active placebo-controlled designs. To date, only one study has been published that trialled ApBM in an illicit drug-using sample of non-treatment-seeking adults with cannabis use disorder . Relative to sham-training, four sessions resulted in blunted cannabis cue-induced craving but not less cannabis use. Overall, evidence suggests that ApBM is associated with reduced approach bias and reduced consumption behaviors for alcohol, smoking, and unhealthy foods . Recently, six sessions of ApBM delivered to 1,405 alcohol-dependent patients significantly reduced alcohol relapse rates at a 1-year follow-up relative to a sham-training condition . However, as these reductions were also observed following AtBM and a combined AtBM and ApBM condition, the authors concluded that all active CBM training conditions had a small but robust long-term effect on relapse rates. Finally, a meta-analysis of alcohol and smoking CBM studies showed a small but significant effect on clinical outcomes for alcohol , but a lack of evidence that reduced approach bias led to improved outcomes .

This assertion was challenged by Wiers et al.who noted that the review conflated proof-of-principle lab-studies and clinical RCTs and different samples . Importantly, these populations likely have differences in motivation/awareness for receiving an intervention to reduce alcohol use, which could explain inconsistencies in the reported effectiveness of CBM across populations .Currently CBM, particularly ApBM, appears one of the most promising approaches for individuals seeking treatment for AUDs; however, its effectiveness for other drugs is yet to be established. The most extensively trialled CT approach is WMT, which has shown promising results in alcohol and stimulants users. However, its high cognitive demand, training intensity, and apparent lack of far-transfer effects limit its application to clinical populations. ICT holds much promise for reducing alcohol consumption in heavy drinkers, but requires testing in treatment-seekers. Finally, more intensive group based approaches such as CRT/CET and GMT may improve EF and quality of life; however, their impact on substance use outcomes remains largely untested. Synergistic approaches now warrant exploration. Indeed, a study that combined WMT and AtBM has shown promising feasibility and improved EF, though substance use outcomes were not assessed. It may also prove fruitful to adopt staggered CT approaches, capitalizing on the brain,s capacity to repair itself during withdrawal, early and later abstinence by strengthening cognitive control and dampening cue-reactivity , prior to engaging in more intensive and cognitively demanding but ecologically valid group training for more extensive remediation .While there may be logistical challenges to the adoption of CT in clinical practice , the main impediment to implementing CT in clinical practice is the absence of robust evidence for treatment success of any one particular approach. This is largely due to the vast heterogeneity of studies, particularly regarding differences in treatment settings, samples , cognitive intervention approaches, number and duration of training sessions, targeted mechanisms, targeted drugs of concern and varying primary outcome measures. Similarly, the absence of brief, ecologically valid, easily-administered measures of cognition precludes the identification of candidates who are most likely to benefit from CT . As such, the evidence base for CT remains hampered by the marked lack of studies on clinical populations,the counter-intuitive neglect of assessing relevant substance use outcomes,the lack of adequately-powered RCTs,the limitations of research designs,lack of attention to individual-level trajectories of cognitive improvements in relation to substance use and quality of life outcomes , and a simple focus on direct relations between cognitive deficits and outcomes without considering person and environmental mediators and moderators of this relation .

VPA exhibits high plasma protein binding with therapeutic concentrations; however, saturation of plasma proteins may occur in the setting of acute intoxication and result in increased free VPA concentrations amenable to HD.While published data are limited, high-flux HD has been shown to be sufficient without the need for concomitant charcoal hemoperfusion.Furthermore, HD should be considered to remove ammonia or correct severe metabolic disturbances during VPA toxicity. Hyperammonemia caused by VPA toxicity is a complex process; it involves depletion of carnitine stores and ultimately results in inhibition of carbamoyl-phosphate synthetase, the primary enzyme responsible for ammonia incorporation into the urea cycle. The use of L-carnitine in the treatment of VPA-induced hyperammonemia is secondary to its ability to assist in the metabolism of long-chain fatty acids. We present a patient with two presentations of VPA toxicity, eight months apart, each successfully treated with HD and L-carnitine. The cases presented provide insight on the detrimental effects that VPA toxicity can cause and review current evidence-based treatment options. Additionally, the second presentation sheds light on the unfortunate repercussions that an incomplete discharge reconciliation can have, namely the lack of patient care transition from inpatient to outpatient when a significant medication event occurred in hospital and subsequent medication changes were made. A 32-year-old African-American male with a history of bipolar disorder, hypertension, and previous suicide attempts was brought to the emergency department with altered mental status .He was prescribed lisinopril 10mg by mouth daily, hydrochlorothiazide 25mg PO daily, and divalproex sodium delayed release 500mg PO every morning and 1000mg PO nightly. Upon presentation,flood and drain tray the patient was responsive only to painful stimuli with a Glasgow Coma Score of 12. Vitals included a blood pressure of 152/70 mmHg and heart rate of 110 beats per minute.

Computed tomography of the brain/head was unremarkable. However, magnetic resonance imaging revealed cerebral edema and possible laminar necrosis. On presentation, pertinent laboratory values included the following: VPA 481.9 µg/dL, lactate 6.9 mmol/L, ammonia 303 µmol/L, and platelets 135 x 103 microL and serum creatinine 2.61 mg/dL. Other chemistries and liver function tests were within normal limits . The urine drug screen, serum alcohol level, acetaminophen level, and salicylate level were unremarkable. The patient required intubation for AMS and acute respiratory failure, and a temporary dialysis catheter was emergently placed for HD. Prior to HD and three hours after initial presentation, VPA level rose to greater than 600 µg/mL . The patient was dialyzed six hours after presentation for a total of six hours; post HD he was started on intravenous L-carnitine 1,300 mg q4h based on literature recommendations and received lactulose 30 grams PO once.During his hospitalization, platelets reached a nadir of 63 x 103 microL, but other pertinent laboratory results remained WNL. The patient improved clinically to include a GCS of 15, allowing successful extubation on hospital day 2. VPA was not to be continued upon discharge and he was transferred to a psychiatric facility for further evaluation.During the second presentation, the patient was found unconscious and diaphoretic in his bedroom by his caregiver. He had AMS and was unable to communicate effectively. Home medications included venlafaxine 75 mg PO daily, benztropine 2 mg PO daily and divalproex sodium DR 500 mg PO twice daily. Although he was not discharged on divalproex sodium during his last visit, he had continued to refill this prescription at his outpatient pharmacy. Notably, the patient also had been using marijuana regularly the previous week. Baseline laboratory values on arrival include the following abnormalities: ammonia 48 µmol/L, VPA level 420 µg/mL, lactate 2.6 mmol/L, glucose 67 mg/dL, and platelets 127 x 103 microL. Other laboratory values were WNL. Although he did not immediately require HD, nephrology was emergently consulted in light of the complications of his previous admission. A repeat VPA level of 272 µg/mL was drawn five hours after the initial level before HD , and the patient was dialyzed for four hours. L-carnitine 2,640 mg PO q8h and lactulose 10 g PO four times a day were initiated. Laboratory findings one hour after HD included ammonia 84 µmol/L and VPA level 105 µg/ mL. His mental status and symptoms improved , and the patient was able to follow commands appropriately. He was discharged on hospital day 2 to a psychiatric facility with instructions to continue L-carnitine 2,640 mg PO every eight hours given continued elevation in ammonia levels. This presentation scored a 10 on the Naranjo scale indicating a definite adverse drug reaction.We present a unique patient with two separate presentations of VPA toxicity necessitating aggressive measures and treatment with HD and L-carnitine. On the first admission, cerebral edema was visualized on MRI and a peak VPA level of greater than 600 µg/mL was reduced to 199 µg/L at the end of a six-hour HD session.

During the second admission, a peak level of 420 µg/mL decreased to 105 µg/mL after a four-hour HD session. While VPA is highly protein bound, plasma proteins become saturated during VPA toxicity, causing an increase in unbound VPA that contributes to the signs and symptoms of toxicity. These small molecules become amenable to elimination via HD allowing for more rapid decline in the serum concentration and subsequent improvement in symptoms of toxicity, as evidenced by the patient’s first presentation.Historically, charcoal hemoperfusion was used for the treatment of VPA toxicity.However, previous case reports describe the effectiveness of using HD alone. What remains unclear is the threshold in VPA concentrations where HD may be useful. Based on the literature available, the EXtracorporeal TReatments in Poisoning workgroup recommends dialysis in patients with a VPA concentration greater than 1,300 mg/L, the presence of cerebral edema, or shock.Dialysis may be used when VPA concentrations are greater than 900 µg/mL, in the presence of coma, respiratory depression requiring mechanical ventilation, acute hyperammonemia, or pH less than 7.1.Similarly, a review article evaluating extracorporeal elimination of VPA advises HD in severe VPA toxicity and a plasma VPA level >850 µg/ mL.9 During our patient’s first presentation, the suggested criteria for HD were met due to the presence of cerebral edema on MRI and the need for mechanical ventilation. In the second presentation, AMS and his ingestion history drove the decision for HD. In a patient with therapeutic VPA concentrations, HD should not significantly impact VPA levels; it may be a viable option in acute toxicity by reducing free drug and improving clinical condition. Hemodialysis is a viable option for treatment of VPA induced hyperammonemia. VPA is metabolized primarily in the liver by means of glucuronic acid conjugation and oxidative pathways via the cytochrome P450 system. The major metabolites are 2-en-VPA, 4-en-VPA, and propionic acid derivatives which are active. 2-en-VPA has a long half-life and causes cerebral edema and coma, while 4-en-VPA causes reversible hepatotoxicity. Propionic acid is responsible for causing hyperammonemia by three proposed mechanisms. Its interaction with and depletion of carnitine impairs the transportation and metabolism of long-chain fatty acids. Also, it prevents glutamine production in the kidneys, which reduces ammonia levels in the brain. Lastly, it inhibits carbamoyl phosphate synthetase, a hepatic mitochondrial enzyme responsible for eliminating ammonia within the urea cycle. The cumulative result is accumulation of ammonia, causing encephalopathy. L-carnitine has the ability to transport and metabolize long-chain fatty acids; thus, it has shown to be beneficial in VPA-induced hyperammonemia, especially in patients with hepatotoxicity, hyperammonemia,hydroponic tables canada or significant CNS depression.An interesting aspect of our case was the reported increase in cannabis use during the week prior to the second VPA ingestion. To our knowledge, there are no reports of VPA toxicity caused by cannabis ingestion. However, cannabidiol, a component of marijuana, weakly inhibits the CYP2C9 pathway.

In addition, delta-9-tetrahydrocannabinoid has high plasma lipoprotein binding. The potential for weak inhibition of VPA metabolism via CYP2C9 and displacement of protein binding due to cannabis could have contributed to the toxicity, but this interaction has not been studied.Of most interest, is the demonstration of the importance of involving a patient’s outpatient pharmacy when a medication is discontinued for toxicity. This patient’s VPA was discontinued upon discharge after the first overdose; unfortunately, measures were not put in place to prevent patient access to medication. Thus, he continued to fill this medication from his outpatient pharmacy. Including a pharmacist in hospital discharge medication reconciliation has been previously shown to decrease 30-day hospital readmission.This service is commonly provided to patients with multiple comorbidities and complicated medication regimens; however, a second occurrence of toxicity in this patient demonstrates that coordinating discharge care for patients with high-risk overdoses should be performed. Methods for reliably informing outpatient pharmacies of discharge medication reconciliation after acute care episodes are expected to improve patient safety.Electronic cigarettes and vaping products are new devices for inhaling various substances such as nicotine and cannabinoids, with or without flavoring chemicals. “Vaping,” or “Juuling,” is a term used to describe the use of e-cigarettes and vaping products.These devices, also known as e-cigs, vape pens, vapes, mods, pod-mods, tanks and electronic nicotine delivery systems, are available in different shapes and sizes.All e-cigarettes and vaping products are made of three components. The first component is the cartridge that contains e-liquid and the atomizer, a coil that heats and converts e-liquid into aerosols. E-liquids can be broadly categorized into two types: regular e-liquids made of propylene glycol Loma Linda University, Department of Emergency Medicine, Loma Linda, California containing chemical flavors and vegetable glycerine used to dissolve nicotine or cannabis e-liquids containing tetrahydrocannabinol and cannabidiol. The second component is the sensor that activates the coil, and the third component is the battery.The hookah, also known as a water pipe, is an ancient method of smoking nicotine. In this method, the coal heats the tobacco and then the smoke passes through the water reservoir before it is inhaled.Contrary to public perception, hookah use is also associated with oral, lung, and esophageal cancers, similar to smoking cigarettes.In our study, we focused on e-cigarettes, and vaping, product-use associated lung injuries . According to the United States Centers for Disease Control and Prevention , in 2018 e-cigarettes were used by 3.05 million high school and 570,000 middle school students.EVALI is a diagnosis of exclusion, with a definition outlined by the CDC for confirmed and probable cases.EVALI was first identified in August 2019 after the Wisconsin Department of Health Services and the Illinois Department of Public Health received multiple reports of a pulmonary disease of unclear etiology, possibly associated with the use of e-cigarettes and related products.Since then, more than 2000 cases of EVALI have been reported, and in 80% tetrahydrocannabinol -containing products were used.Our study aimed to identify the clinical characteristics and hospital course of adolescents diagnosed with EVALI.We performed a retrospective chart review of adolescents presenting to our hospital between January– December 2019, with diagnosis of EVALI. Subjects were identified by the International Classification of Diseases, Tenth Revision diagnostic codes outlined by official ICD-10 guidelines.The following codes were used: J68.0 ; J69.19 ; J80 ; J82 ; J84.114 ; J84.89 ; J68.9 ; T65.291 ; and T40.7X1 . We used a standardized data collection sheet. Data were collected by trained personnel who were not blinded to the objectives of study. The data extracted from the medical records were age, gender, weight, and vital signs obtained in the ED. We also compiled data on duration of symptoms, history of cough, shortness of breath, chest pain, vomiting, wheezing, rales, use of accessory muscles, and presence of altered mental status. We also included data on respiratory support, duration of hospital stay, use of steroids during treatment, and laboratory tests and imaging obtained in the hospital and a negative infectious workup or the decision by the clinical care team to treat as a case of EVALI.Exclusion criteria were gastrointestinal and central nervous system manifestations without interstitial pulmonary involvement, ingestions of cannabinoids, duplicate visits, and if it was unclear whether vaping device was used or not. We used descriptive statistics to analyze the data. Median and interquartile range were calculated for continuous variables, and proportions were calculated with 95% confidence intervals for categorical variables.

Serious mental illnesses , which typically include bipolar dis orders and schizophrenia, are characterized as chronic and debilitating conditions that place significant burdens on patients, as well as their families and society. Despite the marked improvement in managing destabilizing symptoms that followed the introduction of psychotropic medications, most patients who suffer from a SMI continue to have a limited recovery and experience poor physical health. Fifty to 80% of individuals with SMI have one or more comorbid medical conditions that may worsen prognosis and contribute to high morbidity and premature mortality. More concerning is that over 60% of the medical comorbidities observed among persons with SMIs are non fatal and preventable, yet these persons have 15 to 25 years shorter expectancy relative to the general population. Unfortunately, the medical needs of those with SMI are often neglected, which may partly explain the reason for why their morbidity and mortality are elevated. Studies of modifiable risk factors suggest that risky sexual behaviors and poor hygiene, are linked with higher risk of genitourinary, infectious, and blood borne diseases among individuals with SMIs. In creased rates of alcohol and illicit drug use, smoking, poor nutrition and lack of exercise, may be associated with higher rates of cardiovascular and respiratory conditions; and genitourinary and metabolic diseases. Patients with SMI also present for treatment with a number of serious and chronic medical conditions, and these conditions can onset up to 10 years earlier in this population compared to age matched controls. In addition,greenhouse benches having medical comorbidities place SMI patients at risk of repeat hospital visits that raise health care costs and increase the burden of disease. Not surprisingly, the problem of medical comorbidities in SMI is now considered a major public health issue due to its destabilizing effects and high cost to families and society.

Patients with SMI continue to experience elevated morbidity despite the identification of several preventable and modifiable risk factors for poor health. Thus, a study that seeks to examine associations among patients with SMI and odds of having medical comorbidities in a large integrated health system is important to inform patient care. In this study, we examined associations among 25,090 patients with a SMI diagnosis of bipolar disorder or schizophrenia and odds of having medical comorbidities relative to 25,090 patients without an SMI in a large health system. Importantly, to inform patient care planning we examined acute conditions, which are more likely to require immediate medical attention as well as severe or chronic conditions necessitating ongoing monitoring and management.Kaiser Permanente of Northern California is a nonprofit, integrated health care delivery system providing health care services to > 4 million members, serving 45% of the commercially insured population in the region. KPNC consists of a health care plan, a sole medical group, and a hospital system. Specialty health services, such as psychiatry, substance use treatment, and other specialty care, are available to all members internally. To facilitate integrated health care services, providers have access to a mature electronic health record system with each member’s medical history, including primary care, emergency department, ambulatory, hospital and specialty health care encounters. In KPNC, about 88% of members are commercially insured, 28% have Medicare and 10% have Medicaid coverage. All patients were selected from the KPNC membership for this study. Institutional review board approval was obtained from the Kaiser Foundation Research Institute.We used EHR data for this secondary, database study. These data were used to identify all health system members who 1) were at least 18 years of age, 2) had a visit to a KPNC facility in 2010, and 3) had a recorded ICD-9 diagnosis of schizophrenia or bipolar disorder in 2010. The first mention of each ICD-9 diagnosis of schizophrenia or bipolar recorded from January 1, 2010 to December 2010 were included; patients in the sample could have multiple diagnoses . We also included all current or existing behavioral health diagnoses that were additionally documented for patients with schizophrenia or bipolar during health system visits in 2010 . EHR data were also used to identify control patients without current or existing behavioral health diagnoses.

Control patients were selected for all unique patients with bipolar disorder or schizophrenia, and matched one-to-one on gender, age, and medical home facility . This method ac counted for any differences in services, types of conditions, or unobservable differences by geographic location. The final analytical sample consisted of 50,180 patients: 20,308 with bipolar disorder, 4782 with schizophrenia, and 25, 090 controls. Institutional review board approval was obtained from the Kaiser Foundation Research Institute.Age, gender, race/ethnicity, patient medical home facility, census based median neighborhood household income, and ICD-9 psychiatric and medical diagnoses were extracted from the EHR. Race/ethnicity consisted of five categories: white, Black, Hispanic, Asian, and other. Psychiatric and medical diagnoses were determined based on ICD-9 diagnoses noted during visits made over the study period and included current and existing diagnoses.Frequencies and means were used to characterize the sample. We used McNemar’s test and paired sample t-tests to determine potential differences between the matched samples of patients with SMI and controls. These analyses proceeded by examining potential differences between patients with SMI compared to controls by age, gender, race/ ethnicity and income. A series of conditional logistic regressions were then computed, predicting each of nine medical condition categories from bipolar or schizophrenia , to compare the odds associated with having medical comorbidities in patients with SMI compared to controls. We then computed a series of conditional logistic regressions predicting each of fifteen chronic or severe medical conditions from having bipolar or schizophrenia , to com pare the odds of having chronic or severe medical comorbidities in SMI patients versus controls. All conditional logistic regressions adjusted for race/ethnicity and income. SMI and control samples were matched 1- to-1 on age and gender; and thus, no significant differences were anticipated or found between matched groups regarding these relation ships .The Hochberg method was used to adjust for multiple inference testing within each medical condition category. We report Hochberg adjusted p-values for the conditional logistic regressions comparing the odds of having medical comorbidities for patients with SMI and controls. Statistical significance was defined at p < 0.05; analyses were performed using R version 2.15.0.Overall, the sample was 70.0% women, 60.0% White, 15.6% Hispanic, 12.2% Asian, 7.4% Black, 4.8% other race/ethnicity. Patients were 49 years old on average.

As shown in Table 1, more patients with schizophrenia or bipolar were white compared to controls; fewer controls were Hispanic, Asian, or Black relative to patients with schizophrenia or bipolar. However, more patients with schizophrenia were Black relative controls. On average, patients with bipolar or schizophrenia lived in lower income neighborhoods compared to controls. Since patients were matched on age and gender,growers equipment no evidence of differences across these measures were found among the controls and the patients with schizophrenia or bipolar .The high prevalence of medical comorbidities among patients with SMI constitutes major clinical and public health problems that have not been adequately addressed in specialty mental health programs or by mainstream health care. This issue is further compounded in individuals who have a SMI by problems associated with substandard living conditions and lack of access to routine health care services, which increase the risk of having unidentified and untreated medical conditions. Lack of preventative health care in combination with high risk health behaviors among individuals with SMI place them at increased risk of several serious and chronic medical conditions. Patients with SMI remain at risk for elevated morbidity and mortality, despite that health care reform in the U.S. has increased health care service access for this population in recent years. Given the increased likelihood for individuals with SMI to have poor health and poor health outcomes despite policy and clinical intervention, obtaining current information on the degree to which having a SMI is associated with a range of medical comorbidities from large health systems which manage these persons is critical to tailor future disease prevention efforts, early diagnosis, and treatment to their needs. To inform patient care and service planning, we examined acute and chronic medical conditions in SMI patients in a large integrated health system, where SMI patients potentially may have better access to health services than in health care systems where services are not integrated. Prior to our primary analyses, we investigated potential socioeconomic differences between controls and SMI patients. Since patients with SMI and the controls were matched by age and gender no differences were anticipated or found regarding these characteristics. Patients with SMI tended to be white relative to controls, except that more patients with schizophrenia were Black. Higher rates of Black patients with schizophrenia are largely consistent with prior research, and may be in part due to the over-diagnosis of Black persons with this disorder. Also consistent with prior work, we found more SMI patients were located in lower-income neighborhood KPNC service areas than controls. Prior work has found poor socioeconomic status can dramatically limit access to health care and increase exposure to unhealthy behaviors and lifestyles. This phenomenon may partly explain the reason for why having a SMI was disproportionately associated with higher likelihood of having almost all medical co morbidities and serious or chronic conditions examined relative to controls. Notably, while all controls and patients with a SMI had broad access to a range of health services , lower income for patients with SMI may disproportionately affect their ability to support transportation costs for health system visits and follow-up preventive care, and impact health outcomes.

It will be important for future work to more fully examine the role of income in predicting health care access and associated health outcomes in the SMI population. Perhaps in part related to access and low SES, our findings also revealed the odds associated with having acute and chronic medical conditions may not be the same for everyone with a SMI. Even given differences in study design, types of health care systems and samples studied, our results were largely consistent with prior work that has found patients with schizophrenia are at high risk of having endocrine or immune diseases. Patients with schizophrenia were more likely to have endocrine or immunity dis eases, as well as diabetes and obesity. While we could not address causal relationships with our design, the odds associated with having schizophrenia to obesity and diabetes has been linked to the use of some second-generation antipsychotic medications. This is problematic and concerning, as the long-term use of second-generation antipsychotic medications combined with obesity and adverse lifestyle behavior have been linked with higher odds of serious cardiovascular events in patients with schizophrenia and other SMI patient groups. These phenomena may potentially explain the reason for why we found that having schizophrenia was associated with higher odds of having a serious cardiovascular event, such as stroke. Future longitudinal work in this area is warranted, and will need to focus on isolating predisposing conditions and other risk factors associated with future cardiovascular events and mortality in schizophrenia. Although far in excess of control patients, the prevalence of cardiovascular disease and predisposing conditions such as diabetes, hypertension, and obesity in our bipolar sample was slightly below prior reports. Nevertheless, having bipolar was still associated with higher odds of conditions predisposing cardiovascular disease. Notably, these findings may in part explain the reason for why we also found having bipolar was associated with higher likelihood of serious cardiovascular events, including stroke. These findings are of interest be cause cardiovascular mortality is a leading cause of elevated mortality in patients with bipolar, and is well above the risk associated with unnatural causes of death such as injury and suicide. Consequently, future work in this area is warranted, and will need to determine the risk of cardiovascular disease to future cardiovascular events and car diovascular mortality in bipolar, as well as whether the rates of cardiovascular mortality may be lower in patients with bipolar in integrated health systems than the general population and other health care systems.Overall, having bipolar and schizophrenia was associated with high odds of blood borne and infectious disease and of hepatitis C. Although we did not examine routes of transmission, injection drug use, high risk sexual behaviors, or comorbid substance use, SMI patients have been found to exhibit this behavior, raising the odds of blood borne and infectious disease and hepatitis C. While substantially higher than the control estimates, the prevalence of hepatitis C in our sample fell below previously published rates of hepatitis C in individuals with SMI.

There was mild benefit associated with initiation of psychological therapies, although her mother described difficulties with new settings, social anxiety, frequent negative perseverative thoughts, and ongoing panic attacks that would vary in frequency depending on her routine and social supports.Starting in the fourth grade, she had mild academic challenges that were supported with a 504 educational plan through the end of high school.She did not receive any other medication treatment. She graduated from college with academic supports, with continued periods of significant anxiety symptoms, social withdrawal, and panic attacks. After college, she began work as an educational aide in a public school, with an exacerbation of anxiety due to this transition into adulthood and pressures of increased independence. At 22 years of age, her parents provided her with a liquid formulation of hemp oil containing *43 mg of CBD daily , which she began taking. She described feeling calmer, with fewer perseverative worries, and a cessation of panic attacks. This led to more interactions and activities with peers and improved performance at work. Her mother also noted that she became more engaged socially, calmed more easily when frustrated, and was less likely to fixate on negative aspects of various situations. She missed about 1 week of dosing when on a family vacation out of town, and after a few days without treatment, she experienced recurrence of anxiety symptoms and reemergence of panic attacks. These resolved after she was home and able to restart her CBD+ treatment. She is currently working full time and living independently. She has continued CBD+ treatment for two and a half years with sustained therapeutic benefit.Based on its morbidity and prevalence, its association with a number of co-occurring problems, such as seizures, anxiety, and sleep disturbances,13 and the paucity of efficacious therapeutic options, FXS represents an important public health problem.The present article provides a brief review of recent research that documents the promise of CBD as a therapeutic agent for patients with FXS. Also described are the cases of one pediatric and two adult patients with FXS for whom CBD+ treatment appears to have contributed to positive changes in anxiety and/or language skills, with no observed adverse events. Before starting CBD+ treatment, Patient 1 experienced heightened symptoms of anxiety, frequent tantrums, and sleep difficulties. Over the first month of CBD+ monotherapy, and subsequent 3 months of CBD+ treatment combined with speech, language, and occupational therapy, the patient made considerable progress with feeding and weight gain,ebb and flow exhibited better oral–motor coordination, had decreased social avoidance and sensory sensitivities, and showed improvements in attention span/engagement, the frequency and severity of atypical motor movements, and general level of hyperactivity.

Upon discontinuation of CBD+ treatment, the patient’s prior symptoms reemerged. While a strong therapy program and later addition of other medications likely contributed to this patient’s overall developmental progress, the temporally related improvements in anxiety, feeding, tantrums, and sleep—evident when CBD+ treatment was initially started as monotherapy and then reinstated following cessation—are compelling support for the benefits of CBD+ treatment for this patient. By maintaining his adaptive functioning scores from 1 to 3 years of age, the patient demonstrated a significant improvement over the characteristic developmental trajectory of young male children with FXS, where a decrease in adaptive functioning scores is typically observed between 2 and 6 years of age.Patient 2 showed a similarly encouraging response to CBD+ treatment, experiencing reduced anxiety, improved use of language, and better sleep within 1 week of beginning treatment with a CBD+ solution. It is also remarkable that the patient continued to demonstrate symptom improvement over the initial 6-week treatment period, with longer-term follow-up highlighting continued use of CBD+ solution with sustained benefit. In Patient 3, the use of CBD+ solution was also associated with a positive effect in a higher functioning female with FXS and long-standing anxiety symptoms. Similar to Patient 1, treatment discontinuation was associated with a recurrence of anxiety symptoms, with reinitiation of CBD+ treatment leading to symptom improvement and resulting long-term use. The present findings, coupled with the available preclinical data, highlight the potential for CBD as an intervention for individuals with FXS. The existing literature combines to demonstrate that CBD may positively impact individuals with FXS through many mechanisms, including the endocannabinoid system, GABA, and serotonin. While a number of drugs have been developed to target specific systems , CBD has the potential to yield a multifaceted benefit to individuals with FXS due to its multiple mechanisms of action. CBD has not only been shown to be generally well tolerated relative to other treatments used in this population,but also numerous studies have documented its benefits in terms of sleep quality,anxiety ,and cognitive impairment—symptoms experienced by the individuals profiled in the present case series. These data serve as stepping stones upon which proof-of-concept open-label trials should be based. As with many patients, however, those discussed herein used orally administered botanical CBD+ solution that is not regulated by the Food and Drug Administration and, thus, inconsistencies in availability, quality, purity, and labeling make research, interpretations, and clinical recommendations challenging.

The present case series is limited by its reliance on manufacturer reported cannabinoid content as well as the lack of multi-method assessment of patient symptomatology, including clinimetric data. The observed clinical benefit of CBD+ treatment in case studies, particularly with respect to caregiver-reported behavioral outcomes, must also be interpreted with caution given the significant placebo effects that have been documented in clinical trials of CBD.Only placebo-controlled trials will be able to elucidate the true therapeutic effects of CBD/ CBD+ treatment on FXS symptomatology. Until rigorous clinical trials have demonstrated the efficacy of CBD/CBD+ treatment for FXS, current treatments for the many behavioral problems associated with FXS should be utilized before off-label use of CBD+ products. In an effort to overcome existing limitations, future studies should independently test patient samples to confirm actual constituents of each CBD+ preparation and utilize well-validated caregiver-reported assessments of anxiety and other FXS symptomatology, in addition to unstructured caregiver- and clinician based reports, in an attempt to more completely track each patient’s course while in clinical care. Due to inconsistencies observed in many oral botanical preparations, rigorous examinations of pharmaceutical-grade preparations of CBD should be explored as potential treatments for children and adolescents with FXS.Adolescence is a time of subtle, yet dynamic brain changes that occur in the context of major physiological, psychological, and social transitions. This juncture marks a gradual shift from guided to independent functioning that is analogized in the protracted development of brain structure. Growth of the prefrontal cortex, limbic system structures, and white matter association fibers during this period are linked with more sophisticated cognitive functions and emotional processing, useful for navigating an increasingly complex psychosocial environment. Despite these developmental advances, increased tendencies toward risk-taking and heightened vulnerability to psychopathology are well known within the adolescent milieu. Owing in large part to progress and innovation in neuroimaging techniques, appreciable levels of new information on adolescent neuro development are breaking ground. The potential of these methods to identify biomarkers for substance problems and targets for addiction treatment in youth are of significant value when considering the rise in adolescent alcohol and drug use and decline in perceived risk of substance exposure . What are the unique characteristics of the adolescent brain? What neural and behavioral profiles render youth at heightened risk for substance use problems, and are neurocognitive consequences to early substance use observable? Recent efforts have explored these questions and brought us to a fuller understanding of adolescent health and interventional needs. This paper will review neuro developmental processes during adolescence,dry racks discuss the influence of substance use on neuromaturation as well as probable mechanisms by which these substances influence neural development, and briefly summarize factors that may enhance risk-taking tendencies.

Finally, we will conclude with suggestions for future research directions.The developmental trajectory of grey matter follows an inverted parabolic curve, with cortical volume peaking, on average, around ages 12–14, followed by a decline in volume and thickness over adolescence . Widespread supratentorial diminutions are evident, but show temporal variance across regions . Declines begin in the striatum and sensorimotor cortices , progress rostrally to the frontal poles, then end with the dorsolateral prefrontal cortex , which is also late to myelinate . Longitudinal charting of brain volumetry from 13–22 years of age reveals specific declines in medial parietal cortex, posterior temporal and middle frontal gyri, and the cerebellum in the right hemisphere, coinciding with previous studies showing these regions to develop late into adolescence . Examination of developmental changes in cortical thickness from 8–30 years of age indicates a similar pattern of nonlinear declines, with marked thinning during adolescence. Attenuations are most notable in the parietal lobe, and followed in effect size by medial and superior frontal regions, the cingulum, and occipital lobe . The mechanisms underlying cortical volume and thickness decline are suggested to involve selective synaptic pruning of superfluous neuronal connections, reduction in glial cells, decrease in neuropil and intra-cortical myelination . Regional variations in grey matter maturation may coincide with different patterns of cortical development, with allocortex, including the piriform area, showing primarily linear growth patterns, compared to transition cortex demonstrating a combination of linear and quadratic trajectories, and isocortex demonstrating cubic growth curves . Though the functional implications of these developmental trajectories are unclear, isocortical regions undergo more protracted development and support complex behavioral functions. Their growth curves may reflect critical periods for development of cognitive skills as well as windows of vulnerability for neurotoxic exposure or other developmental perturbations.In contrast to grey matter reductions, white matter across the adolescent years shows growth and enhancement of pathways . This is reflected in white matter volume increase, particularly in fronto-parietal regions . Diffusion tensor imaging , a neuroimaging technique that has gained widespread use over the past decade, relies on the intrinsic diffusion properties of water molecules and has afforded a view into the more subtle microstructural changes that occur in white matter architecture. Two common scalar variables derived from DTI are fractional anisotropy , which describes the directional variance of diffusional motion, and mean diffusivity , an indicator of the overall magnitude of diffusional motion. These measures index relationships between signal intensity changes and underlying tissue structure, and provide descriptions of white matter quality and architecture . High FA reflects greater fiber organization and coherence, myelination and/or other structural components of the axon, and low MD values suggest greater white matter density . Studies of typically developing adolescents show increases in FA and decreases in MD. These trends continue through early adulthood in a nearly linear manner , though recent data suggest an exponential pattern of anisotropic increase that may plateau during the late-teens to early twenties . Areas with the most prominent FA change during adolescence are the superior longitudinal fasciculus, superior corona radiata, thalamic radiations, and posterior limb of the internal capsule . Other projection and association pathways including the corticospinal tract, arcuate fasciculus, cingulum, corpus callosum, superior and mid-temporal white matter, and inferior parietal white matter show anisotropic increases as well . Changes in subcortical and deep grey matter fibers are more pronounced, with less change in compact white matter tracts comprising highly parallel fibers such as the internal capsule and corpus callosum . Fiber tracts constituting the fronto-temporal pathways appear to mature relatively later , though comparison of growth rates among tracts comes largely from cross-sectional data that present developmental trends. The neurobiological mechanisms contributing to FA increases and MD decreases during adolescence are not entirely understood, but examination of underlying diffusion dynamics point to some probable processes. For example, decreases in radial diffusivity , diffusion that occurs perpendicular to white matter pathways, suggests increased myelination, axonal density, and fiber compactness , but have not been uniformly observed to occur during adolescence. Similarly, changes in axial diffusivity , diffusion parallel to the fibers’ principle axis, show discrepant trends, with some studies documenting decreases , and others increases in this index . Decreases in AD may be attributable to developing axon collaterals, whereas increases may reflect growth in axon diameter, processes which are both likely to occur during adolescence. Technical and demographic differences such as imaging parameters, inter-scan intervals, age range, and gender ratios may account for divergent findings. Both grey matter volume decreases and FA increases in frontoparietal regions occur well into adolescence, suggesting a close spatiotemporal relationship .

While estimates of heritability have often been derived from familial studies, work over the past 5–10 years has increasingly demonstrated that a substantial proportion of heritability is instantiated in common genetic variation captured by whole-genome genotyping arrays across a broad swath of anthropomorphic and neuropsychiatric traits . Thus, a comprehensive understanding of both normative brain and cognitive development and their relation to early SU and abuse requires genetically-informed approaches, including both familial studies of heritability and molecular genetic studies. The ABCD study will take both approaches. Another paper in this issue describes the twin component to ABCD.Human and animal studies document that early life exposures to environmental neurotoxicants including heavy metals , and prenatal exposure to drugs of abuse can negatively impact brain development, leading to maladaptive and persistent alterations in brain structure and function and cognitive and behavioral development. Despite numerous studies describing the neuro developmental toxicity of early life environmental exposures, documenting associations between in utero and early life exposures with adverse health effects is hindered by the absence of direct fetal biomarkers that can be used safely to measure exposure in large study populations. Most associations between prenatal chemical exposure and neuro developmental outcomes are based on the analyses of maternal samples obtained at the time of birth, and perhaps at one to two time points during pregnancy. This timing may be months after the exposure occurred and the pharmacokinetic and tissue distribution of various chemicals may be quite different at different stages of fetal and child development . Documenting prenatal exposure to drugs of abuse is further compounded by social stigma associated with reporting licit and illicit drug use during pregnancy . To address this gap in our understanding of fetal and early life exposures, Dr. Manish Arora and colleagues have recently developed a novel methodology to retrospectively and objectively quantify the dose and timing of environmental exposures throughout pregnancy and early childhood using naturally shed deciduous “baby” teeth .

In the following sections we briefly summarize the literature demonstrating associations between early life exposure to environmental toxicants and drugs of abuse on developmental outcomes,marijuana grow system describe the novel approach to detecting exposures to some of these toxicants in shed deciduous “baby” teeth, and present the protocol for baby tooth processing and archival. By collecting teeth and leveraging the novel tooth biomarker described below, the ABCD Study is building a valuable repository that provides a unique, exciting and valuable opportunity to study the individual, interactive and/or additive effects of early life environmental exposures on childhood neuro developmental outcomes.A growing population of children around the world is exposed to various neurotoxicants present in urban and rural environments, which may damage their developing brains. Within the last several decades, strong evidence suggests that infants and children are uniquely vulnerable to environmental toxicants due to disproportionally higher exposures, immature metabolic pathways, and rapid growth and development . It is now well accepted that low-level chronic exposure to environmental chemicals may contribute to the growing epidemic of childhood neuro developmental disorders worldwide . In adults, exposure to metals has been shown to induce psychotic behaviors or depressive symptoms and emotional instability in adults reviewed in . In children, epidemiologic studies demonstrate associations between early life exposure to metals with poor cognitive, emotional and behavioral functioning in children reviewed in . Notably, current knowledge of the neuro developmental health risks associated with environmental chemical exposure has been derived mainly from the study of single agents; however, no human is exposed to just one chemical at a time. Evidence suggest combined effects of multiple chemicals might occur at levels far below those observable for any one component reviewed in . Notably, an individual’s risk of exposure to neurotoxicants, as well as the risk of adverse outcomes associated with exposure, may vary based on socio-economic status reviewed in . Childhood socioeconomic status is characterized by a combination of factors, including family income, parental educational attainment and occupational status , and is known to be an influential factor for brain development and cognitive function .

Such associations could stem from ongoing disparities in postnatal experience or exposures, such as family stress, cognitive stimulation, environmental toxicants, or nutrition, or from corresponding differences in the prenatal environment. Given SES-related differences in brain development , and, observed relationships between brain structure and function and environmental toxicants , low SES youth may be at increased risk for negative outcomes from a multitude of environmental factors. Interactive and/or additive effects of various neurotoxicants and other environmental factors can be examined in the baby tooth biomarker as part of the ABCD study.Human studies of prenatal exposure to drugs of abuse such as alcohol , tobacco smoke , cocaine , and marijuana have shown brain and cognitive abnormalities among offspring of mothers who reported use during pregnancy. Most human studies on the impact of prenatal drug exposure on brain and cognitive development utilize retrospective samples and rely on mothers’ recollection of drug consumption patterns years after pregnancy , and/or select prospective samples of children with “heavy” exposure vs. low or no exposure. Validity of retrospective reports on maternal life style during pregnancy 10–12 years post-partum, including SU, has been shown to be sub-optimal . The ABCD protocol includes a developmental history where parents/guardians are asked to recall SU patterns both before pregnancy, and after pregnancy recognition. While data collection is on-going in the ABCD study, maternal self-report in a sample of over 2000 participants studied as of the end of May 2017, when questioned about SU prior to pregnancy most report no SU, but, approximately 25% report use of alcohol, 0.6% cocaine, 5% marijuana, and 13.6% tobacco . These percentages substantially decreased when parents/ guardians were asked about their post-pregnancy recognition SU, but some continued after pregnancy recognition. Of course, we do not know how many, if any, parent/guardians of ABCD participants denied SU when there actually was use, but, given social stigma in many communities, it is unlikely that individuals would report drug use during pregnancy if there was none. However, as described below, some of these substances can be measured using novel assays of baby teeth.As discussed above, determining exposure to environmental toxicants during the prenatal period has been hampered by the lack of appropriate biomarkers to measure direct fetal exposure. Further, until recently, no single biomarker could provide continuous, time-resolved documentation of exposure throughout the fetal and early childhood period.

Common biomarkers used for environmental assessment including maternal blood and urine are often not optimal matrixes for determining prenatal and early life exposure due to the timing and invasiveness of collection. Further, maternal biomarkers are not always a reliable measure for fetal exposure . For prenatal exposure to drugs of abuse, there are additional complications with parent self-report of licit and illicit drug use during pregnancy due to social stigma and length of time since pregnancy in remembering use patterns ∼9 to 10 years prior as will be the case in the ABCD cohort. Establishing timing of exposures, especially over the prenatal period, is a major challenge in environmental epidemiologic studies. Teeth have long been used to estimate long-term cumulative exposure, including prenatal exposure, to environmental and other substances . Notably, much of our knowledge of the impact of early life lead exposure on cognition was gained by examining associations between higher lead levels in children’s teeth and reduced IQ . However, previous tooth biomarker methods examined lead in the whole tooth providing a cumulative exposure of lifetime measure. Dr. Arora’s method incorporates laser ablation and micro-dissection techniques that leverages the physiology of tooth development to provide finely time-resolved assessments of exposure from the beginning of the 2nd trimester through the time the tooth is lost. Deciduous “baby” teeth growth proceeds in an incremental pattern,cannabis vertical farming forming rings and layers similar to the rings of a tree. Toxicants circulating in the fetal blood stream are captured in the layers and measuring the amount of toxicant in the layers provides information about exposures dose and timing. These newly developed high-dimensional analytical methods combine sophisticated histological and chemical analyses to precisely sample tooth layers and have the potential to reconstruct a timeline of exposures during early development . These methods have been tested extensively in prior research , and hold promise for establishing timelines of exposures to environmental toxicants and drugs of abuse in the ABCD sample. In addition to fine-grained timelines of exposure spanning the pre- to postnatal periods, advantages to using baby teeth as biomarkers of toxic exposures is that shed teeth can be stored relatively easily at room temperature, and does not require any invasive procedures such as blood draw.During development, enamel and dentine deposition occurs in a rhythmic manner, forming incremental lines akin to growth rings in both enamel and dentine . At birth, an accentuated incremental line, the neonatal line, is formed due to disturbances in the secretory cells during protein matrix deposition . This line forms a clear histological landmark that demarcates pre- and postnatally formed parts of teeth. Beyond the neonatal line teeth manifest daily growth lines, which allow chronological ages to be determined at various positions within tooth crowns and roots. The analytical approach involves sampling the growth rings of teeth using laser and other microdissection methods. Analyzing the sampled layers using mass spectrometers can yield time resolved information on organic and inorganic environmental compounds and their metabolites . Dr. Arora and colleagues have previously validated this biomarker for certain metals and validation for a range of organic targets is also underway in that laboratory. By collecting multiple baby teeth from individuals enrolled in the ABCD cohort, we are building a repository that may be leveraged in the future to measure not only the validated metals but also early life exposure to organics, maternal stress, and licit and illicit substances. Many other substances should be possible to measure on a detailed timeline during pre and post-natal development using baby teeth.

Previous research has shown that metabolites of licit substances, such as alcohol and tobacco, and illicit substances, such as cocaine and marijuana have been measured in the teeth of adults, though, most of these studies have been done with ground adult teeth using material from dental extractions, and do not allow for timeline of exposure in earlier development . To our knowledge, these biomarkers have not yet been validated using shed deciduous teeth, which would require contemporary measurements of more conventional biomarkers, such as maternal, newborn, and childhood urine/blood samples at various points during pregnancy and childhood. Nonetheless, there is potential for measurements of these substances in deciduous teeth by adapting existing assays, but using methods which allow timelines of exposure during development reviewed in .Participants’ parents are asked for 5 baby teeth shed between the ages of 6–13 years old. Parents either bring the teeth in during a lab visit, or mail shed teeth into the lab with provided kits . Teeth may become brittle in very cold orhot temperatures, thus shipping and storage of shed teeth occurs at room temperature. Data collection sheets completed by the parents include information about how each tooth was shed , and how it was stored .Tobacco use is the leading preventable cause of death in the US, killing over 480,000 people each year. Most of these deaths occur among cigarette smokers, 80% of whom begin smoking by age 18 and 99% of whom begin by age 25. The transition from experimentation to established smoking generally occurs in the late teens and early 20s. Tobacco use patterns vary within the population, with some people never smoking, some remaining occasional users, and others progressing to daily use or quitting. Existing research has identified 4–6 trajectories of smoking, typically classified as never-smokers, experimenters/occasional users, reducers or quitters, those who start smoking young and quickly become daily smokers, and those who start smoking as young adults and become daily smokers. Studies of smoking trajectories have primarily focused on identifying risk factors at the individual or family level, determining associations between trajectory type and health outcomes, and assessing links between trajectories and use of other products.Understanding the factors that influence smoking initiation and the transition to regular smoking is critical to developing tobacco control interventions that improve public health.