Monthly Archives: November 2023

ERO results are consistent with those obtained in the DTSA models

The significance of family type alcoholic family or community family and number of parents who smoke was greatest in the younger age ranges. Effects are measured in changes in logit from baseline. When significant, SNP effects were about 1.0 for having two copies of the risk allele in the recessive genetic models, and the delta ERO effect was about 0.5 per standard deviation. When significant, the parental smoking effect was about 0.2 per smoker, the family type effect ranged from 1.0 to almost 2.0, and the gender effect ranged from about 0.5 to 1.0.In the logistic regression analyses used to investigate the duration of the transition from regular alcohol use to alcohol dependence as a function of the age of onset of alcohol dependence, genotype was not significant in any age range in both linear and quadratic models for duration. In the linear model for duration, modeled as log, Delta ERO values at Fz are signficant in the youngest age range, and both Fz and Cz ERO values are significant in the oldest age range.Duration was significant in the three youngest age ranges. In the quadratic model for duration, modeled as the sum of log and log2 , the Fz and Cz ERO values are significant only in the oldest age range. The effect of duration of drinking was significant in the three youngest age ranges with an overall U-shape in the two youngest age ranges. Since the beta value for the log term is negative and the beta value for the log2 term is positive, the rising part of the U-shape masks the Fz ERO effect in the youngest age range . For the tests of the rapidity of the transition from regular alcohol use to alcohol dependence as a function of the age onset of regular alcohol use, those who become regular alcohol users in the youngest age range were much more likely to become alcohol dependent either in the same age range or the subsequent age range than those who become regular alcohol users in the age ranges 16–17 years or 18–19 years . Viewing this from a slightly different perspective,vertical farm supply the fraction of those who transition from alcohol use to alcohol dependence in less than 2 years in the oldest age range is much smaller than that in the youngest age range.

A Cochran-Armitage trend test of this phenomenon shows a p-value of less than 8 × 10−5 for the hypothesis of no trend. There were age-related trends in the genotypic distributions of those who became alcohol dependent in any of the four age ranges in the illicit drug sub-sample. For the first trend test, of the change of genotypic distribution with age of those who became alcohol dependent at any age, the hypothesis of no trend could be rejected at a 0.003 level for rs978437, rs7800170, and rs1824024, SNPs which were significant for alcohol dependence in the entire population, and at a 0.035 level for rs2061174 and rs2350786. This means that in those who became alcohol dependent, having two copies of the major allele was the prevalent condition for who became alcohol dependent in the earliest age range, while not having two copies of the major allele was the prevalent condition of those who become alcohol dependent in the oldest age range. For the second trend test, of the change of genotypic distribution with time from initiation of alcohol use to time of alcohol dependence of those who began regular alcohol use in the youngest age range and who became alcohol dependent at any age, the hypothesis of no trend could be rejected at a 0.025 level for all of the SNPs. This means that in those who became immediately alcohol dependent, having two copies of the major allele was the prevalent condition, while in those who took the longest to become alcohol dependent, not having two copies of the major allele was the prevalent condition. The results are presented in table 4. This suggests a genetic influence on the rapidity of the transition from regular alcohol use to alcohol dependence among those who become regular alcohol users in the earliest age range. The pattern of significance of the ERO and SNP factors for the onset of regular alcohol use and of alcohol dependence is different between the youngest and oldest age ranges within the entire sample, as is evident in table 2. These differences are primarily the result of differences between the populations of regular alcohol users in the two age ranges. The proportion of the at-risk sample who become regular users of alcohol increased from 15% to 43% between the two age ranges. Biological factors are significant in both the onset of regular alcohol use and of alcohol dependence in the youngest age range. The prevalence of regular drinking in the oldest age range has eliminated the effect of the biological factors in its onset; only the onset of alcohol dependence is affected by biological factors.

In the older age range, since it is likely that much of the onset of alcohol dependence is driven by past drinking, particularly since relatively few of those who become alcohol dependent in the oldest age range have been drinking for a short time, those factors which are significant for regular alcohol use in the youngest age range are significant for alcohol dependence. Furthermore, it is likely that a biologically specific sub-population of the youngest group particularly sensitive to the effects of alcohol has been effectively eliminated from the at risk group in the oldest age range . In the illicit drug use sub-sample in the youngest age range, CHRM2 is a greater factor for the onset of alcohol dependence than in the entire sample. However, EROs are not a factor in the onset of alcohol dependence in this group. The range of ERO values in the illicit drug use sub-sample does not differentiate those who become alcohol dependent from those who do not, although ERO values differentiate the illicit drug sub-sample from their complement in the entire sample. The illicit drug use sample shows greater and more extensive genetic effects than the entire sample, since the result of selecting the illicit drug use sub-sample is to remove those subjects whose alcohol dependence is unlikely to be genetically affected from the analysis. In examining the results of the logistic regression analysis of the transition from regular alcohol use to alcohol dependence in the youngest age range, the U-shaped effect of the duration of drinking suggests the presence of two distinct factors, one a susceptibility to rapidly become dependent subsequent to the onset of regular alcohol use and the other a gradual effect of continued alcohol consumption. The masking of the ERO effect by the rising component of the duration factor suggests that ERO is associated with a long term behavior pattern involving substance abuse. The absence of a genotypic effect is the result of including all those who become alcohol dependent in the analysis, not just those in the genetically more vulnerable, as can be observed by comparing the under 16 results between the regular alcohol user group and the illicit drug user group. In summary, for the youngest age range the pattern of significance of the ERO and SNP phenotypes for the onset of regular alcohol use and of alcohol dependence,vertical farm tray as well as the pattern of significance in the transition from alcohol use to alcohol dependence suggests that delta ERO value indexes an element of propensity to use drugs to excess, while the CHRM2 SNPs index an age related effect of alcohol consumption on the brain with the behavioral outcome of dependence, as we explain below. We view the age-varying genotypic effect of the CHRM2 SNPs as an instance of a gene environment interaction.

In our case the immediate genotypic effects are upon the activation level of the type 2 muscarinic receptors and the environment is the neuroanatomic and neurophysiological context in which the action of the muscarinic receptors is taking place. This environment undergoes significant changes as the brain develops from the early teens into the early twenties, as we have noted above. In the transition from alcohol non-use to regular use of alcohol to alcohol dependence, we note that alcohol consumption has significant effects on the development of addiction in adolescent animals and humans . The cholinergic M2 receptor gene belongs to a family of muscarinic acetylcholine G-protein coupled receptors with five known subtypes . The M2 receptors in the mesolimbic dopaminergic system play a significant role in modulating the level of dopamine release . This has a important effect in governing the reward system , including modulating the effects of alcohol on it . M2 receptors also modulate synaptic transmission in cortical circuits affecting the pyramidal neurons . It is not possible to determine the precise nature of the interaction between the genotypic effect on the cholinergic M2 receptors and the age-varying neuroanatomic/ neurophysiologcial environment given the data at our disposal. Given the age-related patterns of genotypic action we have described above, it is possible that the effect of alcohol consumption on the brain varies with the genotype of the cholinergic M2 receptors and the age of onset of regular drinking. Specifically, when alcohol is consumed regularly in the youngest age range, perhaps better described as a particular stage in brain maturation centered in this age range, the addiction producing effects on those who have two copies of the major allele are accelerated compared to those who do not, leading to rapid transition from regular alcohol use to alcohol dependence.Those without two copies of the major allele may take longer to manifest the effects of alcohol use. As the age of the initiation of alcohol use increases, it appears that the cumulative risk for alcohol dependence when carried into the adult years is greater in those without two copies of the major allele than in those with two copies. We draw this last conclusion on the basis of the trend tests on our own data and the results of the studies of Wang et al. and Dick et al. . In those who become regular users of alcohol under the age of 16, a majority of those who became alcohol dependent within two years had the risk genotype; the majority of those who become alcohol dependent four years or more after their onset of regular drinking did not have the initial risk genotype. A contributing factor to the age specificity of the effect of the CHRM2 SNPs could be a frailty effect. The frailty effect would play a role if there were relatively easy access to alcohol in the youngest age range, at least for those most at risk. Among those who have the major alleles, those who are genetically most vulnerable become alcohol dependent rapidly, leaving only those who have some protective factor. Thus risk for those with the major alleles will decrease with age, since those without the protective factors will have become alcohol dependent, leaving primarily those with protective factors at potential risk. We also note that if the illicit drug user population had easier access to alcohol than the entire population as a whole, the greater genetic effects seen in the illicit drug usersub-sample might in part be the result of a gene-environment interaction, akin to those described in Dick and Kendler , in which looser social controls over behavior accentuate genetic effects. Since 80% of the illicit drug use sub-sample are from COGA rather than community families, this is a plausible hypothesis. The specific environment of the most vulnerable group is more likely to accentuate genetic effects, rather than to diminish them.We found that SNPs reported to be significant in adults were significant in adolescents in this sample, particularly for those in the youngest age ranges, and for those who had ever used an illicit drug. However, in our results, the major allele was the risk allele, while in the results of Wang et al. and consequently of Dick et al. , the minor allele was the risk allele.

Drug law enforcement has been especially susceptible to differential justice by geography in California

Community principles of proportionality that inform prosecution policies and practices may differ even within a county, and represent those of wealthier suburban populations with political power and the ability to prioritize crime reduction without bearing the costs of punishment . Those costs are high. Criminal records, particularly felony convictions, create a broad range of legal and social barriers that persist long after time is served. Restrictions range from the loss of voting rights, parental rights, public benefits that support health and education, employment and occupational licensing, and housing – creating conditions that can in turn impact mental and physical health . Associations between the risk of criminal justice exposure and place of residence present the possibility that collateral consequences will be unequally distributed and exacerbate inequalities by race and location . Considering the significance of criminal history for the severity of punishment for subsequent offenses, including eligibility to receive drug diversion rather than a felony conviction and incarceration, the effects of living in a punitive location are likely to compound over time. Geographic differences in conviction rates also have implications for costs. Punitive charging and sentencing decisions are made by counties but costs are passed on to the state; a felony conviction can receive a sentence to state prison, while county jails and probation supervise those with misdemeanors . In essence, the decisions of more punitive counties to impose higher rates of imprisonment are subsidized by less punitive counties .Can criminal justice reforms reduce widespread geographic variation in case outcomes? Studies of the enactment of three strikes laws have found effects are limited, as local officials ignore or bend the laws to fit existing policies and practices, maintaining geographic disparities . However,commercial vertical farming system mandatory minimum sentencing laws that seek to maximize punishment may affect circumvention differently than reforms that aim to reduce punishment. Little research has evaluated how reforms to reduce punishments affect geographic disparities, a significant evidence gap considering the national trend towards decarceration reforms currently underway. One exception is a study of California’s Proposition 36, passed in 2000, which mandated that individuals arrested for non-violent drug offenses receive treatment instead of incarceration.

The study found an overall reduction in incarceration for drug possession, but relative differences between counties persisted, and were driven by local ideological dispositions and policy preferences regarding drug use . Prior to the passage of Prop 47 in 2014, possession of a controlled substance and possession of concentrated cannabis were classified as “wobbler” offenses, which are charged as felonies by default, but provide prosecutors with the discretion to reduce them to misdemeanors. This discretion was introduced through a penal code amendment in 1969 to reduce caseloads at overburdened superior courts responsible for hearing felony cases, by allowing lesser felonies to be adjudicated as misdemeanors in municipal courts at the prosecutor’s discretion . Research conducted in 2010 found the proportion of arrests for possession of a controlled substance that were charged as felonies varied across California counties from 25 to 100 percent . Even after controlling for case characteristics and criminal history, county of residence was a strong predictor of felony filings following arrest . California law does not dictate how wobblers should be prosecuted, nor does it define the quantity of drug that differentiates possession from sale, the latter of which is always a felony. Charging policies are established by district attorneys and differ across counties; the study found that some simply charged all possession cases as felonies, and others considered the quantity of the drug, prior criminal record, and concurrent charges. The extant research has found that Prop 47 led to fewer arrests, bookings, and custody time on average for Prop 47 offenses , and identified county variation in changes in arrests and jail populations following passage . However, how Prop 47 impacted geographic disparities in the severity of case dispositions has not been investigated. While the reclassification of drug possession offenses to misdemeanors may have reduced county variation in felony convictions for drug possession, felony convictions for concurrent offenses or for drug offenses that remained felonies may have increased in more punitive counties, potentially offsetting a reduction in geographic disparities. This study will assess the effect of Prop 47 on county variation in felony convictions in two ways. First, we will test whether there was a change in county variation in the probability of a felony conviction for those arrested for drug possession.

Within this group, we will examine whether there was an increase in felony convictions for concurrent offenses, which would suggest mitigation of Prop 47’s effects. Second, we will assess the change in felony conviction probability for individuals arrested for non-Prop 47 felony drug offenses, such as sale and transport, which may also result in Prop 47 convictions. California law does not specify the amount of drug that differentiates sale from possession, and those arrested for sale might have their charges reduced to possession. If this group of defendants continues to have charges reduced to possession, which is now a misdemeanor, we would see a reduction in their felony convictions. Yet prosecutors in more punitive counties may use their discretion to buffer this effect. For example, the practice of reducing sale to possession during plea bargaining could decline in these counties, potentially increasing cross-county variation in felony convictions following these arrests. Felony conviction. Separately for Prop 47 arrests and non-Prop 47 felony drug arrests, we determined whether the event resulted in a felony conviction for any offense associated with the arrest. We used any felony conviction as our primary outcome, because prosecutors have the discretion to consolidate arrest charges into an individual filing, or to alter offenses to negotiate a plea, and the charges prosecutors file may have been affected by Prop 47. For example, it is possible that prosecutors were more likely to file felony charges for non-Prop 47 offenses after passage, to counteract the drop in felonies due to reduced classification of Prop 47 offenses. By defining the outcome as any felony conviction, we attempted to account for possible changes in specific charges filed, and capture the severity of the overall case disposition following the arrest. Arrests with no disposition were assumed not to have been prosecuted. If Prop 47 shifted law enforcement practices, some individuals arrested during the pre-Prop 47 period might not have been arrested had they committed their crimes during the post-Prop 47 period. To assess the plausibility of such compositional changes in the populations arrested, we first compared pre- and post-policy groups on demographic characteristics, concurrent charges,commercial vertical farms and criminal histories, separately for Prop 47 offenses and non-Prop 47 felony drug offenses. Pearson’s chi-squared tests were used for categorical variables and Wilcoxon rank-sum tests for skewed continuous variables.

In the presence of compositional changes, we cannot estimate the effects of Prop 47 on arrest outcomes for individuals who would only have been arrested under pre-Prop 47 conditions, because a comparable group is not represented in the post-Prop 47 period. Furthermore, estimating the effect of reclassification on individuals unlikely to be arrested under the new laws would be of little value. Therefore, propensity score matching was used to assess the effect of the “treatment on the treated,” comparing arrest outcomes only among individuals who were likely to be arrested regardless of the reclassification of offenses. Each individual who was arrested after Prop 47 was matched with an individual who was approximately as likely, given their covariates, to have been arrested after Prop 47 was adopted, but was in fact arrested pre-Prop 47. We generated propensity scores using a logit model predicting the log odds that an arrest occurred during the post-Prop 47 vs. pre-Prop 47 period. Predictors included all available demographic variables, and concurrent arrest and criminal history variables likely to affect the arrest disposition. These consisted of age, gender, race/ethnicity; county and calendar month of arrest; any concurrent arrest, separately for felony or misdemeanor classifications: property, violent, sex, weapons, and other; whether the arrest included a probation or parole violation; number of prior arrests; prior arrest for a Prop 47 drug offense ; a measure of the severity of conviction history ; dummies for types of prior felony convictions, including drug, property, violent, sex, weapons, and other; any prior prison sentence and any prior jail sentence. For sale/transport arrests, we also include whether there was a concurrent Prop 47 drug offense. To accommodate non-linearities in age and the number of prior arrests, we use restricted cubic splines with five knots at equally spaced percentiles of each variable’s distribution. Propensity scores were estimated separately for arrests for Prop 47 and sale/transport offenses.Using within-county one-to-one matching without replacement, post-Prop 47 arrestees were matched on the logit of their propensity score to pre-Prop 47 arrestees, within a maximum of 0.2 of the standard deviations of the logit of the propensity score . For Prop 47 drug arrests, 5.6% of the post-Prop 47 group was dropped due to insufficient matches. For sale/transport arrests, 7.8% of the post Prop 47 group was dropped. Covariate balance across propensity-score matched treatment and control groups was checked to assess the adequacy of the propensity score models. Standardized mean differences in all covariates were less than 5% in both samples. For each arrest category, we used a set of mixed logit models to examine the variance in county probabilities of felony conviction pre- and post-Prop 47 among propensity score matched samples. First, we specified the model to include county-specific random intercepts and random coefficients for the policy effect with an unstructured covariance structure.

This generated an estimate of the covariance of pre-Prop 47 mean felony conviction probability with Prop 47 effects on conviction probability, which would indicate whether counties with higher pre-Prop 47 means declined to a greater degree, thus reducing variance in the outcome. Second, models were specified such that counties had separate random intercepts for pre- and post-Prop 47 periods, which generated an estimate of the variance in county probability of felony conviction in each period. We used a likelihood ratio test to compare the fit of this model using an exchangeable covariance structure, which restricts the variance in pre and post intercepts to be equal, to one with an unstructured covariance structure, which allows the variance to differ pre- and post-Prop 47 implementation, as a test of the change in county variance. The latter model is the most flexible and was used to generate the policy effects on the marginal probabilities of felony conviction. For county-specific estimates of outcomes pre vs. post-Prop 47, we generated empirical Bayes estimates of county random pre- and post-Prop 47 implementation intercepts from the models with unstructured covariance and calculated the linear combinations of fixed and random effects corresponding to pre- and post-Prop 47 periods. We also used fixed effects models with county dummy variables, interacted with the pre-post Prop 47 variable to generate marginal probability estimates of within-county pre-post change. A large proportion of arrests had no disposition . We assumed these cases were either never presented to the district attorney or the district attorney did not file charges, and therefore assigned an outcome of no conviction. We compared case characteristics for those with and without dispositions and found support for this assumption. Those without dispositions were less severe cases, and therefore less likely to result in conviction. For example, a larger proportion had no concurrent arrests . They were also less likely to have concurrent felony arrests . It is possible, however, that some of these cases resulted in convictions and the disposition was never reported by the court. We therefore conducted a sensitivity analysis that assumed the most severe extreme: that all sale/transport cases with missing dispositions received a felony conviction, and that all Prop 47 cases with missing dispositions received felony convictions if they occurred in the pre-Prop 47 period or if they included a concurrent felony arrest in the post period. Prop 47 arrests without concurrent felony arrests in the post period are unlikely to have received a felony conviction, since the Prop 47 offense was at that point classified as a misdemeanor.Changes in the outcomes of Prop 47 arrest events must be considered in the context of potential changes in the composition of arrestees .

The WIHS began with baseline recruitment in 1994 and has undergone three recruitment waves since

Future studies of strategies for managing chronic inflammation in HIV may consider using an inflammation burden composite and examining how changes in inflammation burden affect complex motor performance given this neurocognitive domain appears to be more strongly associated with inflammation relative to other domains.People living with HIV experience high rates of mental illness, including elevated rates of depression and anxiety . In the United States , poverty and social deprivation are concentrated among PLHIV , and may contribute to poor mental health. An important challenge that low-income PLHIV in the USA frequently face is food insecurity , which includes food insufficiency and hunger, poor quality diets, persistent uncertainty around access to food and having to engage in personally or socially unacceptable food procurement . Food insecurity has been associated with a range of poor mental health outcomes including depression , anxiety , symptoms of post-traumatic stress disorder , substance use and suicidality . While people who experience mental illness likely face more barriers to accessing healthy food, evidence from longitudinal and qualitative studies indicates that food insecurity contributes to symptoms of common mental illness . Provision of food support to food-insecure individuals in a manner consistent with the preservation of dignity has been shown to reduce symptoms of depression . These findings raise questions about how symptoms of common mental illness occurring in the setting of adverse social and structural factors should be addressed. Mental illness and its treatment are often formulated according to a ‘bio-psychosocial’ model in which multidimensional influences on mental health are addressed concurrently through psychotropic medications, psychological interventions and services aimed at improving social circumstances. Yet, in practice, psychotropic medications often predominate. In the USA, data have shown significant upward trends over the past two decades for the use of psychotropic medications alone, compared to significant downward trends for the use of psychotherapy and psychotropic medications together or psychotherapy alone . One in six US adults is now prescribed a psychotropic medication,industrial vertical farming rising to one in five among non-Hispanic White adults and one in four among adults aged 60–85 years .

Pharmaceutical drugs are prominent for several reasons. Psychotropic medications have the most extensive evidence base among mental health interventions, as their effects can be measured through randomised controlled trials more easily than other forms of intervention. In meta-analyses of trials, common classes of psychotropic medications including antidepressants and antipsychotics show modest but significant therapeutic effects for their respective indications . Prescribing drugs is also less labour-intensive than psychological or social interventions, and often more accessible and time-efficient for service users. In the USA specifically, the market-based structure of the healthcare system may contribute to higher rates of psychotropic medications, which have the financial and promotional backing of for-profit pharmaceutical companies . Conversely, reimbursement rates for non-pharmacological treatments by Medicare have been falling steadily for many years, driving psychologists and other allied professionals away from low-income service users . Furthermore, psychotropic medications adhere to a medical model of intervention that accords with the clinical education of prescribers. The paucity of social science training in clinical curricula leaves clinicians lacking the intellectual tools and frameworks to fully understand how social-structural issues may drive distress . Consequently, social interventions may be placed at lower priority than pharmaceutical drugs by default, principally through unfamiliarity and misunderstanding on the part of clinicians. The vulnerability of public funding for social support to changes in fiscal policies and political ideologies may also contribute to the primacy of pharmacologic interventions. In the USA, public spending on social safety net institutions has undergone a sustained reduction since the 1980s . The welfare reforms of 1996 had a particularly detrimental effect on the provision of social support, significantly curtailing access to government income for non-disabled adults, with the most severe restrictions targeting those without dependent children . Notably, this development has left federal disability income as one of the last forms of substantial government assistance available to many indigent adults in the USA . Recent studies have suggested that this shift may be fuelling a ‘medicalisation of poverty’, as diagnoses of chronic illness – and particularly mental illness – play an increasingly important economic role for struggling adults to obtain income security through disability status .

In this respect, diagnoses of mental illness, accompanied by treatment with psychotropic medications, can act as an important gateway to a level of income stability otherwise unobtainable for many in the current US context of widespread working poverty under welfare reform . Identifying these social and economic realities does not imply that disabled individuals are malingering, or that clinicians are prescribing for non-clinical reasons, but suggests instead that we consider the impact, at a population level, of structural factors that incentivise the prescription of psychotropic drugs for socially deprived individuals. These arguments raise the question of whether social adversity might drive higher rates of psychotropic prescriptions, independent of psychiatric symptoms. Few empirical studies have attempted to investigate this possibility. We used data from the Women’s Interagency HIV Study , an ongoing prospective cohort study at nine sites across the USA, to investigate the associations between food insecurity and psychotropic medication use among a broadly representative population of women living with HIV in the USA. Our previous studies in the WIHS cohort have demonstrated dose–response relationships between food insecurity and poor mental health outcomes, including depression , anxiety, stress, symptoms of post-traumatic stress disorder , substance use and mental health-related quality of life . Here we used a cross sectional sub-sample of the WIHS cohort for which data on psychotropic medication use were available to test two successive hypotheses: food insecurity would be associated with psychotropic medication use in a dose–response relationship among women living with HIV, mirroring the dose–response relationships between food insecurity and symptoms of common mental illness found in previous studies; and if we additionally adjusted for symptoms of common mental illness, any positive associations between food insecurity and psychotropic medication use would remain significant.Our study was a cross-sectional analysis of data from the WIHS, a prospective cohort study of HIV-seropositive women and demographically similar HIV-seronegative women in the USA. Cohort recruitment, demographics and retention are described elsewhere . WIHS participants undergo structured interviews and physical examinations every 6 months at nine sites across the USA and have blood and other biological samples taken.

Beginning in 2009, a standardised and detailed neurocognitive assessment was added to the WIHS Core exams and administered every 2 years. From April 2013 through March 2016, the Food Insecurity Sub-study collected data every 6 months on food security, nutrition and other key socio-economic variables from all WIHS participants. For the current analysis, women living with HIV who participated in the Food Insecurity Sub-study from April 2013 through March 2015 and also had neurocognitive and psychiatric variables during the same time period were included . Data collection for psychotropic medication use was staggered across four WIHS visits during this period, at five study sites: San Francisco, CA; Chicago, IL; Washington, DC; Bronx, NY and Brooklyn, NY.The primary outcomes were four categories of prescribed psychotropic medication use . WIHS participants are asked to bring a list of medications to each visit and are also asked specifically whether they are using any medications ‘for psychological conditions or depression’ and for the name of the medication. Self-reported psychotropic medications were coded as antidepressants ,vertical agriculture farming sedatives/hypnotics/tranquilisers/anxiolytics or antipsychotics as appropriate. Using these data, we constructed a pooled outcome for any psychotropic medication use and made three separate binary outcomes corresponding to each individual drug class. Other outcomes included symptoms of depression, generalised anxiety disorder and mental health-related quality of life. Symptoms of depression were measured using the Center for Epidemiologic Studies Depression score, a widely used self-report instrument that asks participants how often they experience symptoms of depression including low mood, low self esteem, poor concentration, sleeping difficulties, poor appetite and others . Scores range from 0 to 60, with higher scores indicating greater depressive symptoms. CESD score is a core WIHS study measure collected from WIHS participants at each visit. The internal consistency of the CESD in our sample was high . We measured symptoms of generalised anxiety disorder using the Generalised Anxiety Disorder-7 scale, a 7-item self-report instrument used to screen for and categorise the severity of GAD in primary care . Participants were asked how often they experience symptoms of GAD including worry, restlessness, irritability and others, with responses scored from 0 to 21. In the WIHS, collection of GAD-7 data only began in October 2013. GAD-7 data were therefore only available for approximately 75% of the women participating in our study. The internal consistency of the GAD-7 in the sample was high . Mental health-related quality of life was measured using the Mental Health Summary score of the Medical Outcomes Study HIV Health Survey scale . The MOS-HIV scale, a widely used quality of life measure developed and validated among PLHIV, comprises 35 questions across ten domains, providing a total score out of 100. The MHS is calculated from the total MOS-HIV score by means of a standardised method that transforms the scores of relevant domains into a standardised t-score with a mean of 50 and standard deviation of 10. MHS is a continuous variable composed of four sub-scales where lower scores indicate worse mental health-related quality of life and higher scores indicate better mental health-related quality of life . WIHS participants undergo the MOS-HIV annually . Since psychotropic medication data were staggered across four study visits , MHS data were only available for approximately 50% of the women contributing data to this study.

The internal consistency of the MHS was 0.80.Data were obtained from WIHS visits at which women both completed the HFSSM and had coded psychotropic medication data available, creating a cross-sectional sample staggered over four study visits . Initially, we examined associations of FS with common mental illness to confirm whether the dose–response relationships found in previous studies were reproduced in this sub-sample. To examine associations of FS with CESD score, GAD-7 score and MHS score, we ran multi-variable linear regressions. Next, we tested associations between FS and psychotropic medication use in two successive models. First, we ran multi-variable logistic regressions to examine associations of FS with any psychotropic medication use and antidepressant, sedative and antipsychotic use individually, adjusting for race/ethnicity, income, education, heavy drinking and illicit substance use. For any psychotropic medication use, antidepressant use and sedative use, we then ran multi-variable logistic regressions also adjusted for CESD score and GAD-7 score . We did not include antipsychotic use as an individual outcome in this fully adjusted model because depression and anxiety are not clinical indications for antipsychotic use, which would render the outcome difficult to interpret . The area under the receiver operating characteristic curve, which ranges from 0.5 to 1.0 , was used to quantify how well the models explained the outcomes . All analyses were completed using Stata version 14 .There were 905 women in the sample . Approximately two-thirds identified as African-American, while just under half reported an annual income less than $12 000. Over one-third were categorised as food-insecure . In total, one-third were taking psychotropic medication. The most common class was antidepressants , followed by sedatives and then antipsychotics . In adjusted analyses, compared to high FS, marginal, low and very low FS were significantly associated with increasingly higher CESD and GAD-7 scores and with increasingly lower MHS scores, exhibiting a consistent dose– response relationship across all three outcomes . Of the other variables studied, self-identifying as African American/Black, having an income ⩾$24 001, and having at least a high school education were all variously associated with better mental health . Illicit substance use was associated with higher CESD and GAD-7 scores and lower MHS scores. For the psychotropic medication use outcomes, we first performed adjusted analyses in the absence of adjustment for CESD and GAD-7 scores. We found that marginal and low FS were associated with 2.06 and 1.99 times higher odds of any psychotropic medication use, respectively, compared to high FS . While very low FS was associated with 1.50 times higher odds of any psychotropic medication use, this was not statistically significant. Associations between FS and each individual category of psychotropic medication use exhibited a similar pattern of findings, with the adjusted odds ratios consistently highest for marginal FS.

Pattern 14 represents cases with a missing value on alcohol screen result

The Trauma Quality Programs research database housed in the NTDB for the year 2107 is the time frame for this study. Though initially the researcher intended to include data from 2013-2017, data from years other than 2017 had to be excluded. In effort to standardize the type of data collected by local, regional, and state trauma registries, the NTDB designs a National Trauma Data Standard Data Dictionary that is designed to establish a national standard for the collection of trauma registry data while also providing the operational definitions for the NTDB. In summary, the NTDS provides the exact standards for trauma registry data submitted to the NTDB. Prior to the 2017 data dictionary, trauma registry programs had limited selections regarding data related to drug use. The options provided by the NTDB registry only included whether drug use was present and whether it was confirmed by a test or by prescription. It did not allow the trauma data abstractor to specifically identify the type of drug found. In 2017, the data dictionary was revised to include a drug screening category that aimed at recording the first positive drug screen result within 24 hours after the first hospital encounter. Typically, in trauma hospitals reporting to NTDB and within the context of trauma, acquisition of a urine and blood drug and alcohol screen is standard expectation of practice. It then provided a list of 15 options for the abstractor to choose from. Because it was impossible to isolate cannabinoid use in earlier data sets, the researcher was only able to use the 2017 NTDB data set, which at the beginning of the study was the latest available data set by the NTDB. As of February 13th, 2021 the 2018 NTDB data set was not available. All the trauma data used in this study are organized by an element INC_KEY, which is a designated unique identifier for each record. The designated unique identifier INC_KEY expresses a unique clinical visit/episode by an individual at a participating trauma center. It is important to consider that an individual could have been included/counted more than once in the registry because of more than one traumatic event within the year. The Participant Use File Trauma data set contained all the demographic, environmental,commercial vertical farming and clinical data information. However, it did not identify or delineate TBI cases as such. Therefore, a separate data set that contained ICD 10 Diagnosis Codes had to be utilized to identify TBI cases which then could be used to create a merged data set that is complete.

The 2017 PUF Trauma data set was uploaded to SPSS version 25 on September 10th, 2020. The PUF Trauma data set included a total of 997,970 unique identifier cases. A frequency analysis was performed to ensure no duplicate cases were found . The PUF Trauma data set included 328 unique variables. Next, the PUF ICD-10 Diagnosis data set was uploaded and examined. The PUF ICD Diagnosis data set is organized via the same INC_KEY identifiers. The PUF ICD Diagnosis data set included 3 variables: ICD CM diagnosis code, ICD CM diagnoses code Blank Inappropriate Values and ICD Clinical Modification version. This data set was used to distinguish TBI cases from cases related to other traumas such as pneumothorax, liver laceration or femur fractures.Additionally, the selection of TBI related ICD 10 codes was corroborated by examining a list of codes found in existing studies on TBI which validated the inclusion of the specifically identified TBI codes in this study. Though these other studies included ICD 10 Diagnosis codes related to concussion injuries , these codes were excluded from this study as the researcher was only interested in identifying cases with either a moderate or severe TBI and concussions are designated as mild TBI. The following codes were ultimately selected: S02.0xx ; S02.1 ; S06.1 ; S02.19XD ;S06.2 ; S06.30 ; S06.31 ; S06.32 ; S06.33 ; S09.X . Next, PUF ICD 10 Diagnosis codes were regrouped into the following categories via numerical representation. ICD 10 Diagnosis code S02.0xx was grouped into group 3683-3687; S02.1 into group 3688; S02.19XD into group 3738; S06.1 into group 4008-4025; S06.2 into groups 4026-4045; S06.3, S06.31, S06.32, and S06.33 into groups 4046-4095; S09.X into groups 4310-4311. A missing value analysis for the ICD 10 Diagnosis code variable revealed no missing values. A new variable titled ‘TBI” was created in the PUF ICD-10 Diagnosis data set where if a TBI related ICD 10 code was assigned, the value ‘1’ was given. If not, it was assigned a value of ‘0’. A frequency analysis on the ‘TBI’ variable was then done to determine the number of TBI codes which were found to be 131,518.The final data set to be used in the analysis consisted of 15 variables not including the cases themselves: sex, age in years, race , ethnicity, alcohol screen result, total GCS, cannabinoids , positive for drugs , comorbid condition currently receiving chemotherapy, comorbid condition disseminated cancer, comorbid condition mental/personality disorder, comorbid condition substance abuse disorder, comorbid condition alcohol use disorder , crash intrusion and motorcycle crash.

The new data set contained 324 total variables. The variables present were identified as subsets of the following categories: work-related injury, patients occupational industry, patient’s occupation, ICD 10 primary external cause, ICD 10 place of injury code, ICD 10 additional External cause code, protective devices, child specific restraint, airbag deployment variables, report of physical abuse, investigation of physical abuse, caregiver at discharge, transport modes, initial emergency service system vital signs , time to EMS response, time from dispatch to ED/hospital, interfacility transfer, pre-hospital cardiac arrest, trauma center criteria for admission, vehicular/pedestrian or other risk, mechanism of injury , total time between ED/hospital arrive and ED discharge, systolic blood pressure, pulse rate, temperature, respiratory rate and assistance, pulse oximetry, supplemental oxygen, height, weight, primary method of payment, signs of life, emergency room disposition, hospital discharge disposition, comorbid conditions , total intensive care unit length of stay, total ventilator days, length of stay , hospital complications, procedural interventions, medications administered, blood transfusions, withdrawal of life support, facility level, year of discharge, ISS, and AIS derived ISS. Variables that would not be included in the final analysis were removed. Example of variables removed were ventilator days, length of stay and blood transfusions. Some of the variables that incorporated more than one value, such as race, ethnicity, alcohol screen result and drugs, were concatenated to form new variables. A description of how each variable was dealt with is delineated below. This was done to facilitate the analysis of more than one categorical variable to be treated as one. In SPSS the missing values analysis module provides two different methods to analyze missing data, the first is the Expectation-Maximization method and the second is the Regression Imputation method . Expectation-Maximization provides statistical estimates such as estimated means, covariances and correlations. The Regression Imputation method is dependent on the Expectation-Maximization method to fill in the missing values using predicted values from a regression of one variable on another within the analysis . Both analyses were performed to assess any patterns of missing values. A missing value analysis was conducted. This analysis produces a univariate statistics table showing the total number of cases within each variable,commercial vertical farming systems the mean and standard deviations, the missing counts and percentages and the number of extremes. It is here that the extent of missing data can be observed and identified.A separate-variance t Test table is displayed by SPSS as part of the missing value analysis. This table can help identify variables whose pattern of missing values may be influencing the quantitative variables.

When age is missing, the mean alcohol screen result is .0031 compared to .0652 when age is present. This large difference in mean alcohol screen result scores when age is present indicates that the data missing is not missing at random. However, it is important to consider that these differences cannot be solely attributed to the patient’s provision of information, as these are all clinical tests performed by hospital personnel. If data is missing, it is most likely due to the reasons mentioned above, and not necessarily because the patient was choosing to withhold information. The cross tabulations of categorical variables versus indicator variables table shows similar information to that found in the separate-variance t test table. This table provides information that can help determine whether there are differences in missing data among different categories. Males were found to have a documented value in alcohol screen 30.4% compared to 19.3% in females. This may indicate that there are differences in missing values among males and females. Similarly, males were found to have a documented THC result 28.4% of the time compared to females at 22.1% of the time. This indicates that the data is missing at random. Differences were smaller between males and females for the variables of total GCS and ethnicity, with males having a documented result for total GCS 94% of the times compared to 93.1% for females. Ethnicity was documented for 93.2% of the times with male participants and 92.9% for females. The small difference indicates that the data is not missing at random. For the variable of race, no drastic differences were noted between ethnicity, and THC Combo. However, the variable of alcohol screen result was found to be largely different in the American Indian group when compared to the other groups . Looking at ethnicity, non-Hispanic patients had a value for alcohol screen result 27.5% of the time compared to 21.4% of the time for Hispanic or Latino patients. Non-Hispanic patients had a THC value documented 26% of the time compared to 23.3% of the time in Hispanic or Latino patients. Total GCS was present in 93.8% of the time in the non-Hispanic group compared to 94.7% of the time for Hispanic or Latino group. This shows that data missing amongst these variables can be attributed to chance. When considering the cross tabulation for THC Combo, or THC presence, it was found that patients who had a negative test for THC were more likely to have missing data for alcohol result when compared to those who tested positive. For those who tested negative, 55.8% had a value reported for alcohol screen result compared to 86.5% for those who tested positive. This aligns with the clinical scenario in that patients who had a blood sample drawn to test for substances had a higher chance of testing positive than those who did not get a blood sample drawn, as all substances are tested using the same sample and sample time. If a patient was having blood drawn to test for alcohol, they were also likely to be tested for other substances. The results were similar when looking at all the positive for drugs table. Patients who tested negative for all other substances were more likely to have missing data for alcohol screen result when compared to those who had a positive test. For those who tested negative, 53.8% of the time there was a value documented for alcohol compared to 83.7% of the time in the presence of a positive substance test. This supports the idea that data for THC Combo may be missing if alcohol screen result is missing, which indicates that the missing values for THC may not be missing completely at random.When patterns in SPSS are requested, a bar chart displaying the percentage of cases for each pattern is tabulated. The bar chart seen below in Table 13 shows that almost 40% of the cases in the dataset have Pattern 40, and the missing value patterns chart, as seen in Table 12, shows that this is the pattern for cases with a missing value on alcohol screen result and THC Combo. Pattern 49 represents cases with a missing value on age, alcohol screen result and THC combo. The bar chart shows that almost 15% of the cases in the dataset have Pattern 1, and the missing value patterns charts shows that this is the pattern for cases with no missing values. Pattern 28 represents cases with a missing value on THC combo. .

Substance use includes alcohol and drugs such as marijuana

Traumatic brain injuries can lead to a variety of secondary conditions that could result in cognitive, behavioral, motor, and somatic impairments that cause long-term disability and poor quality of life . Causes of TBI. The leading causes of injuries resulting in TBI prevalence are traffic related, such as motor vehicle crashes, or non-traffic related, such as falls. Falls are the leading cause of TBI with almost 81% of emergency department room visits in adults over the age of 65 attributed to falls . Motor vehicle collisions are the leading cause of TBI related deaths, with rates being highest for adults between the ages of 15-24, 25-35 and older adults greater than 75 . Substance use and TBI. Notably, up to 51% of all TBI patients have substance use exposure at the time of injury .Current existing research suggest that in general, substance-exposed patients may have worse TBI outcomes, including greater rates of mortalityand severity of injury. Research has also shown that these patients suffer worse functional outcomes, which can result in socioeconomic burden to patients and the nation at large. This healthcare burden has been calculated to be approximately $76.5 billion in 2010 alone . Substance use and mechanisms of injury. There is a substantial body of research elucidating the influence of alcohol on TBI prevalence and outcomes . Alcohol use results in impairments such as diminished motor control, blurred vision, and poor decision making, which in turn has been shown to increase the risk for TBI . This research has been used to create public health policies, public education efforts, and prevention programs that have made a significant health impact, such as reducing the number of alcohol-impaired drivers . While it is known that there is significant alcohol use related to TBI, little is known about the influence of marijuana on the prevalence, severity and outcomes related to TBI . Marijuana use and mechanisms of injury. Marijuana is an drug that despite being federally and legally regulated, remains the most widely used drug in the U.S. . Marijuana use has been shown to result in similar cognitive impairments as alcohol use, such as lack of coordination, alterations in reaction time, inability to pay attention, and decision-making abilities, suggesting marijuana users are similarly at increased risk for TBI . There is some indirect evidence of this,vertical farm company in that it has been shown that marijuana users in general are about 25% more likely to be involved in a motor vehicle collision and that the older adult marijuana users have a greater risk for falls .

Both short and long-term marijuana exposure has been shown to impair driving ability; marijuana is the drug most often reported in association with impaired motor vehicle collisions, including fatal ones . It has also been shown that the overall risk of being involved in a motor vehicle collision increases by a factor of 2 soon after an individual has used marijuana . Motor vehicle collisions make up almost two thirds of U.S. trauma center admissions and are the leading cause of TBI related deaths . Approximately 60% of MVC patients tested positive for drugs and alcohol . Despite the increase in marijuana use and exposure, concrete data linking marijuana exposure at time of injury and TBI prevalence and severity is scarce . Adding to the concern, national surveys on drug use and health have documented an increase in individual daily marijuana use over the last 5 years. Study Objectives In summary, there is no body of research documenting the relationship between marijuana exposure and TBI prevalence and severity. As the number of states legalizing marijuana for both medical and recreational use increases, it is imperative to resolve the ambiguity within the research available regarding the influence of marijuana exposure on TBI. This study will fill important gaps in knowledge about this emerging public health concern by documenting the prevalence of marijuana exposure in a national sample of TBI patients, and determine the relationship between marijuana exposure, mechanism of injury, and TBI severity. Study aims are to: 1) assess the prevalence of marijuana exposure in patients with moderate or severe TBI at time of injury; 2) examine correlates associated with marijuana exposure at the time of injury; and 3) examine the relationship between marijuana exposure, mechanism of injury and TBI severity. Results will provide the first quantifiable national-level evidence of the impact of marijuana exposure on TBI. Results will also serve as the basis for research that can inform policy and public safety standards and metrics regarding marijuana exposure and its effect on TBI.A search strategy was implemented by searching the PUBMED electronic bibliographic database between January 17-19 in 2019. No restrictions were applied on publication status and publication date. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search strategy included the terms traumatic brain injury, severity, substance, substance abuse, marijuana, THC, cannabis, and drug use.

Only publications in English were sought. Reference lists of review papers were searched to ensure all relevant literature was included. An example of the search strategy for this review is shown in Figure 1. To be included in this systematic review, studies must have been peer-reviewed, published in English, involve human subjects only, and must have investigated the use of marijuana in adult patients reported to have sustained a moderate to severe TBI. We did not consider participants below the age of 16 because pediatric trauma patients present differently than do adults, and are treated with different intervention protocols than in adults. A preliminary search identified the fact that articles subsumed marijuana exposure under the broader umbrella term of substance use/abuse. Therefore, substance and substance abuse terms were included to ensure a wide sensitivity to studies involving drugs such as marijuana. Exclusion criteria Patients with a diagnosis of mild TBI were excluded because up to 40% of mild TBI patients do not seek medical attention, and therefore, findings would not be representative . Similarly, the following studies were excluded from this review: studies that did not assess for marijuana exposure at time of injury, marijuana post-TBI, cellular based studies, clinical review papers, editorials, case reports, pediatric studies and studies using nonhuman subjects. Selection Process Study selection was conducted in a two-stage process. First, studies were screened by titles and abstracts for potential inclusion. Next, studies identified as relevant for potential inclusion underwent a full-text evaluation. Studies that included any information about marijuana exposure at the time of injury were included, including studies where marijuana was bundled with other substances as either a variable or via analysis, because it was assumed there would still be relevant information embedded within the study. The studies were reviewed a second time to ensure all inclusion criteria were met and included if they did.Data was extracted from studies that met selection criteria. Data from the studies were used to achieve the primary aims of this systematic review: to examine marijuana exposure and use in TBI prevalence, severity and outcomes.

The following data were abstracted to summarize specific study features and address the review’s aims: 1) study characteristics, including authors names, publication year, country, design, sample size, and methods utilized, 2) participant characteristics such as mean age and type of TBI, 3) information about whether other substances besides marijuana, such as alcohol, methamphetamines, cocaine, opiates, benzodiazepines, narcotics, stimulants, speed, hallucinogens and heroin were documented and/or analyzed 4) results, including the prevalence of marijuana, TBI outcomes, and if a relationship between marijuana and TBI was present. Data Management Search results, including abstracts and full-text articles, were exported to an Excel file for data management. The decision for inclusion or exclusion in the review process was recorded in the Excel file,vertical farm equipment as well as a rationale for exclusion of studies. Reference management was done through the Papers©, a reference management software used to manage bibliographies and references. A reference library of PDF documents was maintained through the software and allows a variety of features such as collecting, curating, merging of studies as well as the insertion of citations in-text. Level of evidence and risk of bias were assessed for each of the included studies. The Levels of Evidence were assessed using the National Heart, Lung and Blood Institute categories. The NHLBI Levels of Evidence framework rates evidence on four major levels,placing the highest rating on evidence that is acquired from Randomized Controlled Trials with an extensive body of data; RCTs are assigned a level “A” according to the NHLBI. Level B studies are RCTs with a limited body of data, usually involving a smaller sample size, include a subgroup analysis of RCTs, and may include study results that are inconsistent. Level C studies are those that employ a non-randomized study design, such as observational studies. Finally, Level D studies include studies that utilized mechanism-based reasoning that involve anecdotal findings based on expert opinion. Risk of bias of included articles was assessed using the National Heart, Lung and Blood Institute quality assessment tool for observational cohort and cross-sectional studies. The NHLBI offers six various study quality assessment tools, three of which apply to observational cohort studies, cross-sectional studies, and case series studies. The quality assessment of observational cohort and cross-sectional studies tool was utilized. The NHLBI quality assessment tool is comprised of 14 criteria/questions that address study objectives, study population, sample size, exposures and outcome measures, and key potential confounding variables. An example of NHLBI quality assessment tool for observational cohort and cross-sectional studies is presented in Table 2. Potential sources of bias were rated as either “yes”, “no”, “cannot determine”, “not applicable”, or “not reported”. Each study was given an overall bias rating of good, fair, or poor. Table 2 delineates responses to each of the 14 questions in the NHLBI quality assessment tool, while Table 3 addresses the types of biases encountered, the presence or lack thereof of confounding variables, and other information that aid in the assessment of biases.Results from the included studies were reviewed for the outcome of interest and were reported under seven themes: presence of marijuana exposure; time frame in which marijuana exposure was measured; method used to measure marijuana exposure; information on other substances if they were bundled with marijuana exposure; and the presence of a specific link between marijuana exposure and TBI severity. Due to the range and diversity of study results and designs, a meta-analysis was not possible. Additionally, given the differences in the conceptualization and definition of marijuana exposure across the studies included, and the heterogeneity in methods, sample data, collection and findings, a narrative interpretation and descriptive analysis of the findings was necessary. The literature search yielded 939 studies . After duplicates were removed, 710 records remained; studies were then eliminated according to the inclusion and exclusion criteria as mentioned above. A total of 31 studies were excluded based on the following sub-categories: nine studies were excluded because they were case reports, 1 because it was a book chapter, 16 because they were clinical reviews, 2 because they were commentaries, 1 because it was an editorial and 2 because they were issue briefs. This was followed by the exclusion of 305 studies because they investigated substance abuse because of TBI, hence post-TBI. Then, 124 studies were excluded because they investigated conditions other than TBI, while another 28 studies were excluded because they only investigated participants who had sustained a mild TBI. Thirty four studies were excluded based on investigating cellular morphology and changes in TBI patients; a subject that surpasses the purpose of this study. One hundred and nine studies were excluded because they did not examine marijuana; these studies investigated alcohol as the primary, and at times, the only substance utilized by participants. A further 15 studies were excluded because the studies involved non-human participants. Thirty-six studies were excluded because they did not investigate the use of any substances in their TBI participants. Finally, 2 studies were eliminated because they were non-English publications, and 17 studies were further excluded on the grounds of including participants aged 16 years or younger. A total of 8 studies met eligibility requirements for final inclusion.

All participants provided consent or assent to participate and received a $50 honorarium

This body of evidence, however, has been criticized for not considering the potential counterfactual that, for reasons related to experimentation, the same youth who initiated e-cigarettes first may have been likely to try cigarettes had ANDS been unavailable, and that most e-cigarette-only youth vape infrequently and are not necessarily using devices containing nicotine. Few studies consider other pathways, most notably from cigarettes to ANDS, which is arguably a pathway of harm reduction should smoking be eventually reduced or stopped. Findings from a growing body of qualitative research suggest that the positioning of ANDS as a “gateway” into smoking cigarettes may not align with the reasons why some youth report vaping.For example, a study of 16 young adult vapers in New Zealand found that participants, who smoked and vaped, used ANDS to either recreate or replace rituals of smoking, and non-smoking vapers tended to dislike smoking and vaped to foster social connectedness. Another study of disadvantaged young adult smokers and ex-smokers in Scotland found that although most participants preferred smoking, the few who used e-cigarettes were motivated by health concerns and desires to quit smoking.Qualitative studies have also highlighted that vapers are not a homogenous group and that meanings of vaping vary across users,vertical farm companies which suggests a need for a more nuanced understanding of the role of vaping for youth with different NT initiation pathways, particularly in light of ‘gateway’ concerns that early ANDS initiation leads to cigarette smoking initiation.

In California, the overall prevalence of youth cigarette smoking continues to decline, even with the emergence of ANDS. We conducted in-depth qualitative interviews with 49 Californian youth between the ages of 15-25, who reported ever vaping nicotine, to consider whether and how the meanings and role of vaping varies by youth’s pathways of initiation of vaping and smoking. By understanding how youth, with various NT use pathways, make sense of their vaping practices, we can more fully understand youth’s motivations for vaping and identify innovative and responsive prevention, treatment, and policy efforts that may be better tailored to youth’s unique needs and experiences. This study is based on narrative data from in-depth interviews with youth. Volunteers were recruited using street-level outreach methods ,through Facebook advertising, and by referral to participate in a 2-hour openended interview designed to collect descriptive data on the participant’s background and everyday life; their NT use pathways and current use practices, the socio-cultural meanings of e-cigarettes and cigarettes in youths’ lives; and perceptions of NT control policies. In person or by phone, participants were screened for eligibility which included being between 15-25 years old, reporting ever vaping nicotine, and living in the San Francisco Bay area. Preceding the interview, a questionnaire was administered that included basic demographics and questions about NT use, including age of initiation and past 30-day use. We obtained parental consent from eligible volunteers under the age of 18.Study procedures were approved by our Institutional Review Board. Interviews were digitally recorded, professionally transcribed, and integrated with ATLAS.ti, a qualitative data management software program.

The first stage of analysis included coding all transcripts to isolate narratives by topic into manageable analytical segments. The codelist was developed by the authors, informed by existing literature and preliminary analysis of interviews. Codes were extensive and included perceptions of smoking and vaping, initiation stories, social motivations of use, pathways of use, cessation motivation, and future intentions of use. Using questionnaire data on age of initiation of both vaping and smoking, the lead author categorized each participant according to 3 pathways: vaping-to-smoking, smoking-to-vaping, and vaping only, and then grouped interview transcripts by pathways to structure analysis of the coded data and to compare whether participants’ perceived role of vaping varied by pathway of use. The lead and second author then conducted a second phase of thematic analysis to identify emergent themes from the narrative data.We also examined divergent and conflicting discourses within interviews to reduce threats to validity by challenging our a priori assumptions, including the use of ANDS for cessation. 33 Quotations from participants introduced below are identified by participant-selected pseudonyms to maintain anonymity. The most common pathway reported among participants was smoking-to-vaping, with 36 of 49 participants characterized into this pathway. Eight participants began vaping prior to smoking and five participants reported only vaping but never smoking . Though youth held different attitudes about vaping—many were indifferent, others regarded them as “lame”, and a few considered vaping “cool”—nevertheless, participants’ narratives about their initiation pathways revealed important insights into the role that vaping played in their lives. Overall, analysis illustrated that regardless of pathway, youth considered vaping to be a valuable alternative to smoking, often chosen in consideration of relative risk.

The ways in which participants across pathways described vaping as an alternative varied, yet their discussions collectively highlighted widespread acknowledgement of the risks associated with smoking and how they attempted to minimize those risks by vaping. This qualitative study sought to understand the perceived role of vaping among youth who initiated vaping according to different pathways of nicotine use. Overall, youth, regardless of initiation pathway, were fully aware of the health consequences of smoking, and their decisions to vape reflected considerations of relative risk where vaping was seen as a suitable alternative to smoking. Some studies suggest that vaping as an alternative to smoking does not suggest a rational process of risk reduction but instead illustrates the ways in which nicotine consumption can be maintained in settings where smoking is prohibited.However, narratives from our participants reflected the ways in which youth considered risk reduction whereby vaping was strategically used to replace or reduce smoking to minimize short and long-term health risks, as a less harmful form of nicotine for coping with stress, or to temporarily engage in the positive social aspects of youthful experimentation while reducing the personal risks smoking presented. The fact that youth consider relative risks and integrate ANDS as a transitional behavior towards smoking cessation highlights the need to acknowledge harm reduction in constructing public health messaging and policies. To date, studies have not sufficiently considered the practice of harm reduction among young people despite some qualitative research suggesting that they may very well be seeking out relatively less harmful nicotine products, like ANDS, either in lieu of or to reduce/quit smoking cigarettes. For example, in a qualitative study of 50 young e-cigarette users in Scotland and Northern England, McKeganey and colleagues found that decisions to continue vaping were often related to youth’s perceptions that e-cigarettes were less harmful than smoking. Likewise, Robertson and colleagues, found that though vaping was originally intended for smoking cessation among some of their participants, vaping “failed to meet their expectations” and therefore goals to eliminate smoking shifted into goals to reduce smoking. Participants in our study were generally more positive about vaping as a suitable replacement for smoking. But, like Robertson’s participants, they similarly perceived the reduction in smoking that vaping facilitated to be valuable on the pathway towards eventual smoking cessation. Tobacco harm reduction approaches emphasize the substitution of less harmful forms of nicotine for more harmful combustible tobacco products for smokers,vertical farming racks who are unable or unwilling to quit.Though some approaches to tobacco control may be considered harm reduction strategies ,most often abstinence is an explicitly-stated goal and discussions of reducing harm remain controversial, particularly when it comes to nicotine use by young people. This is largely due to concerns about the developmental risks associated with any nicotine consumption and the threat of long-term addiction,combined with beliefs that young people behave irrationally and are in need of protection.This study suggests, instead, that youth are applying a logic of risk reduction to negotiate their nicotine use. Though tobacco harm reduction is arguably viewed as a “source of one of the most divisive…debates in tobacco control history,”our study highlights that tobacco harm reduction may be gaining momentum not as an explicit tobacco control strategy but rather as a “consumer-led health initiative” due to youth’s use of vaping to reduce smoking-related harms.Our findings should be interpreted in light of the following limitations. First the sample is not a representative sample of young vapers in the San Francisco bay area nor can it suggest which pathway of NT use is most common. Qualitative research is well-suited for identifying under explored or unanticipated phenomena to inform hypotheses for future studies. Second, this study did not set out to compare perceptions across initiation pathways and, thus, did not have equal numbers of participants in each pathway. However, it is intriguing that the majority of ever vapers recruited into the study were classified in the smoking-to-vaping pathway, particularly in light of the invisibility of young people characterized by this pathway in the existing literature.

Notably, since this was a study of youth who reported ever vaping, none were characterized into a smoking-only pathway. Future research should consider meanings of vaping among never vaping youth, both who smoke and those who do not. Also, this study cannot predict to what extent vaping for harm reduction ultimately leads to smoking cessation. This issue should be examined in future studies with longitudinal designs. Finally, we included a broad range of youth, 15-25 years old. Because qualitative research concerned with identifying variation of experience, we focused broadly on youth, as a socially-constructed category defined less by chronology and more by its progression of stages.Repeated, heavy exposure to methamphetamine is associated with central nervous system dysfunction across multiple neurotransmitter systems, including dopamine , serotonin, GABA, and glutamate . METH exerts particularly potent effects on the dopaminergic system by acting on the vesicular monoamine transporter and DA transporter to stimulate release of DA from presynaptic vesicles and inhibit its reuptake, resulting in excessive levels of synaptic DA . DA is highly active in frontostriatal pathways and DAergic excess disrupts frontal cortical circuitry that regulates motivation, self-control, decision-making and executive function, thereby perpetuating the cycle of addiction . METH-dependence is linked to negative neurocognitive outcomes in domains supported by frontostriatal structures, including learning, memory, executive function, attention/working memory, and cognitive control . Cross-sectional brain imaging studies of METH exposure demonstrate lower gray matter volumes and greater white matter abnormalities in frontostriatal and limbic regions such as the striatum, amygdala, hippocampus, and the prefrontal cortex . Positron emission tomography studies, which have enabled in vivo and regionally-specific evaluation of DAergic activity, provide evidence of DAergic dysfunction in METH users across a number of molecular markers in both the striatum and PFC . Notably, this DAergic dysregulation correlates with markers of neurobehavioral dysfunction, including psychomotor and memory impairment, impulsivity, and psychiatric distress . While adverse neurocognitive findings are frequently observed in METH users, METH use is not always associated with neurocognitive impairment and the reasons for this heterogeneity are unknown . Therefore, a major area of research interest lies in determining what factors may attenuate or exacerbate risk for METH-related CNS dysfunction and associated neurocognitive deficits. Thus far, investigations of a dose dependent relationship with greater METH exposure leading to more severe neurocognitive deficits have resulted in null findings . Self-reported duration of METH use, frequency of use, length of abstinence, and cumulative lifetime exposure do not predict neurocognitive performance . While parameters of drug exposure show little predictive value, individual differences in genetic and environmental factors may account for considerable variability in risk for METH-related neurocognitive deficits . Identifying genetic variations that influence an individual’s vulnerability to METH effects can inform personalized approaches to mitigate METH-related neurocognitive impairment. The catechol-O-methyltransferase enzyme is implicated in DA neurotransmission in the PFC, and specifically assists in regulating clearance of DA from the synapse via metabolic degradation . Functional variation in the COMT gene occurs at a single nucleotide polymorphism resulting in a valine to methionine amino acid substitution . Compared to the Val allele, the Met allele is associated with reduced thermostability and enzymatic activity, leading to slower degradation of DA at the synapse and higher DA concentration in the PFC . In contrast, the Val allele is associated with more efficient DA catabolism and lower levels of synaptic DA. In healthy adults, Met-carriers outperform Val-carriers on tests of PFC-dependent neurocognition, including executive function and working memory .

Another issue concerns the lack of adequate diagnostic criteria for neuropathic pain

One major issue is the placebo response which seems to have increased in recent trials of neuropathic pain and may lead to an underestimation of drug effects.Placebo response has been found to be higher in HIV-related neuropathies,and in patients with low or variable pain scores at inclusion.Conversely it seems to be lower in postherpetic neuralgia.The use of diagnostic algorithms for neuropathic pai and screening tools should contribute to reducing diagnostic heterogeneity . Lastly, a largely debated issue concerns the heterogeneity of patient phenotypes in clinical trials, which may reflect various underlying mechanisms.Interestingly, the results of a number of very recent trials or posthoc analyses of recent trials suggest that some drugs might be differentially effective in patients classified based on their sensory phenotypes.Our updated therapeutic algorithm for neuropathic pain based on GRADE differs in many ways from prior therapeutic recommendations. The latter generally proposed TCAs, pregabalin, gabapentin and lidocaine patches as first line for neuropathic pain. We now also propose gabapentin ER/enacarbil, duloxetine and venlafaxine as first line based on strong GRADE recommendation for use. We no longer recommend lidocaine patches as first line because of weak final quality of evidence. However, owing to an excellent safety profile, high values and preferences, paucity of alternative well tolerated and safe medications, short term positive studies, we propose a weak GRADE recommendation for use as generally second line for peripheral neuropathic pain. Strong opioids are now recommended as third line, contrasting with several prior recommendations in which they were generally considered as first or second line.This mainly stems from the consideration of potential risk of abuse,vertical farming technology particularly with high doses and concerns about a recent increase in prescription opioid-associated overdose mortality, diversion, misuse and other opioid-related morbidity particularly in USA, Canada and UK.

High concentration capsaicin patches and cannabinoids are considered for the first time in therapeutic recommendations for neuropathic pain. Capsaicin patches are proposed as second-line for peripheral neuropathic pain because of high quality of evidence, but modest effect size, training requirements, and potential safety concerns on sensation with long-term use.We provide a weak recommendation against the use of cannabinoids in neuropathic pain, mainly because of negative results, potential misuse, abuse, diversion and long term mental health risks particularly in susceptible individuals.One important issue when proposing recommendations is to assess to what extent they are applied by practitioners and whether this may contribute to improving their practice. Few studies have investigated the real-life impact of evidence-based recommendations on physicians’ practices. It has recently been reported that the drug treatment of postherpetic neuralgia by primary care physicians was roughly consistent with the US recommendations issued some years before.In contrast, a recent large study of general practitioners’ adherence to current French recommendations observed a paucity of appropriate recall of first-line drugs.One important educational objective of the present guidelines will be to facilitate their dissemination and subsequently assess their real life implementation in various countries.Interest in early detection and prevention of schizophrenia and other psychotic disorders stems from evidence of brain structural changes and decline in function around the time of psychosis onset, suggesting that the pre-onset or ‘prodromal’ period affords a window of opportunity for preventive intervention. Identifying predictors and mechanisms of conversion to psychosis among such individuals ascertained to be in a clinical high risk or prodromal clinical state are critical steps in the search for preventive strategies. Achieving these aims requires sample sizes much larger than those typically available at a single research centre within a reasonable time period. The North American Prodrome Longitudinal Study is a consortium of eight programs focusing on the psychosis prodrome.

The sites are located at Emory University, Harvard University, University of Calgary in Canada, University of California at Los Angeles, University of California at San Diego, University of North Carolina at Chapel Hill, Yale University, and Zucker Hillside Hospital. In a prior phase of the project, these sites collaborated to combine previously collected datasets and produced a series of analyses on predictors of psychosis in the largest sample of longitudinally followed prodromal subjects worldwide . Results of these analyses indicated that risk for the onset of psychosis in this population was 35% after 2 ½ years of follow-up, with a decelerating rate of conversion over this period. The NAPLS data set was used to derive a psychosis prediction algorithm with high positive predictive power , but only modest sensitivity . The published prediction algorithm included genetic risk , more severe unusual thought content, and greater social impairment. These preliminary efforts led to a five year prospective study “Predictors and Mechanisms of Conversion to Psychosis”, funded by NIMH in 2008, also referred to as NAPLS 2 that included all eight NAPLS sites. The number of subjects in NAPLS 2 is anticipated to be sufficient to address fundamental questions about the neurobiological correlates of the development of psychosis. The goal of recruiting a sample of 720 clinical high risk participants and 240 healthy controls will be achieved by the end of 2012, and based on the previously collected NAPLS 1 data, a conversion rate of approximately 30% is expected with up to two year follow-up. This paper describes the overall methodology of the NAPLS 2 project and reports on the ascertainment and demographics of the first half of the CHR sample and 180 of the healthy controls.The central pathophysiologic assumption underlying the project is that schizophrenia reflect a process of brain volume reduction involving pruning of synapses and dendrites, that result in reduced cortical connectivity , particularly in prefrontal and superior and medial temporal lobe regions governing attention, executive, auditory-language, and memory-related functions. The first project aim is to determine whether the NAPLS 1 psychosis risk prediction algorithm can be replicated in a new and larger sample of CHR individuals.

The hypothesis is that each of four factors: genetic vulnerability to schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion-paranoia, greater social impairment at baseline, will independently predict a higher risk for conversion to psychosis, and that combining all of these indicators will substantially reduce false positive psychosis predictions over two years of follow-up. The second is to determine whether biological and neurocognitive abnormalities preceding psychosis onset contribute to predicting psychosis independently of the clinical algorithms and whether they can be combined with the clinical measures to enhance predictive utility. The third aim is to determine whether neuroanatomical, neurophysiological, neurocognitive, and neurohormonal abnormalities that precede psychosis represent stable vulnerability markers or markers of progression during the prodromal phase. This will enable us to determine whether CHR individuals who convert to psychosis show a steeper rate of change in neurobiological risk indicators compared to non-converters and healthy controls. The final aim is to develop a repository of DNA and RNA from participants meeting diagnostic criteria for a CHR state and from demographically similar healthy participants. The clinical component of the project attempts to replicate and refine the major NAPLS 1 prediction findings. The biomarkers component tests potential mechanisms of illness onset and/or progression in the neuroanatomical, electrophysiological, neurohormonal, neuropsychological,future vertical farming and genomic domains. Selection of measures attempted to reflect both vulnerability-related and progressive neuromaturational processes. Selection was limited to measures for which evidence existed with relevance to the psychosis prodrome, and which were likely to reflect pathophysiologic changes associated with clinical and/or functional deterioration. We required proven methods for the reliable collection and aggregation of data across measurement points and across sites. The selected measures span multiple critical levels of analysis . Such a multilevel perspective was assumed to be necessary given that the aberrant molecular and cellular processes underlying psychotic disorders were likely to reflect cascading influences across these five critical domains. Baseline only measures include demographics, premorbid functioning, life events and childhood trauma. Six monthly clinical assessments include SIPS, anxiety, depression, substance use and social functioning. Logs of medications, psychosocial treatments and resource utilization are updated every 6 months. Biomarker assessments of neurocognition, electrophysiology, cortisol, blood draws, and imaging occur at baseline, 1 and 2 years. Should a participant convert to psychosis, then the complete assessment is done at the time of conversion with a one year post conversion assessment to determine the diagnosis. NAPLS participants are help-seeking. They are referred from health care providers, educators, or social service agencies or they self-refer in response to intensive community education efforts. These initiatives included academic detailing, grand rounds, educational talks, mailings, postings, websites and internet hits, and public service announcements. Each site has developed extensive referral sources in their area, and routinely contact them personally, with mail outs, and through educational efforts. Potential participants undergo a telephone screen. Those who screen positive are invited to an in-person eligibility and consent evaluation. The first half of the sample N=360 was recruited over a 2 year period from January 2009 until January 2011. Overall, 1749 referrals were received as depicted in Figure 1. Based on a phone screen 618 clearly did not meet CHR criteria, but 52% were found to be suitable for a screening interview.

Of those deemed not suitable at screening some were psychotic. Examples of other reasons included not having prodromal symptoms, calling about other problems such as anxiety, depression, severe autism, non-English speaking, or outside the age range. Of those offered screening, 28% did not keep their scheduled interview and 28% were found not to meet CHR criteria. Examples of reasons for not meeting criteria at the assessment included prodromal symptoms being longstanding, not frequent enough or no longer present. Outcome of all referrals are presented in Figure 1. There were some site differences. Yale and ZHH received significantly more referrals and ruled out more at phone screening. UNC had a higher proportion of referrals that they were unable to contact further. San Diego, Emory and Yale had a higher proportion of no shows. Figure 2 depicts the referral sources and the number meeting prodromal criteria from each source. Overall, significantly more referrals came from self and family, although the majority of such referrals did not meet criteria. UCLA, Harvard, UCSD and Calgary recruited from a wide range of clinical and community services. Although Yale did receive some referrals from clinical services the majority of Yale’s were self-referrals. Referrals for ZHH were made primarily by the outpatient department intake staff and other clinical services that informed parents to contact the program directly. The majority of the referrals at Emory and UNC were self-referrals, followed by family and friends. Figure 3 elaborates on the marketing strategies and their effectiveness. Presentations and web and internet searches seemed to be the most successful, as was “word of mouth”. This was the case at most of the sites; the one exception being Emory where the majority of the referrals resulted from advertising in public places. The clinical high risk sample met the Criteria of Prodromal Syndromes which is based on the Structured Interview for Prodromal Syndromes . After a comprehensive assessment that includes administering the Structure Clinical Interview for DSM-IV and the SIPS, vignettes are developed for each CHR participant for the purpose of obtaining a consensus diagnosis. The attenuated psychotic symptoms rated on the Scale of Prodromal Symptoms are described at length and include both recent and longstanding symptoms. The vignette is written so that another rater can review the information under each symptom category and provide a reliable rating. Once approved at the site level, the vignette is presented on a conference call for a consensus decision on the symptom ratings as well as the diagnosis. The NAPLS-2 consensus call, chaired by JA, is held once a week and is attended by members of each of the eight study sites including the authors of the SIPS, Drs McGlashan and Walsh, who act as co-chairs. Submitted vignettes are individually reviewed and a consensus must be reached on each symptom rating, diagnosis and ultimate admission into the study. It is often challenging making differentiations with respect to some of the exclusion criteria listed below. But we use our calls to discuss issues such as the impact of substance abuse and use of antipsychotics. Such decisions can later be reviewed when we have followed the sample and determined the outcome of the participants in terms of conversion and remission.

A fertigation stream is applied to deliver the necessary nutrients for optimal plant growth

Consequently, there is currently an increase in the production of natural sugar alternatives based on the shift in consumer preferences toward more natural products to meet their dietary need and restrictions. Stevia, the common name for glycoside extracts from the leaves of Stevia rebaudiana, is a natural, sweet-tasting calorie-free botanical that is currently gaining popularity as a sugar substitute or as an alternative to artificial sweeteners. Recent reports project the annual growth rate of stevia compounds to be 6.1% and 8.2%, during 2015–2024 and 2017–2024, respectively. Stevia has gained industry acceptance in recent years due to its ease of cultivation in several countries across the globe and its high sweetness index . This shows that the growth of stevia’s use as a sugar substitute, despite taste limitations of the marketed glycosides, was contingent on the feasibility of its large-scale manufacturing. Thaumatin, monellin, manbinlin, pentadin, brazzein, curculin, and miraculin are sweet tasting proteins that are naturally expressed in tropical plants. Studies have found that human T1R2-T1R3 receptors expressed in taste buds in the mouth and recognize natural and synthetic sweetness while T1R1-T1R3 recognize the umami taste. These receptors, which have several binding sites, are activated when the compounds that elicit sweet taste bind to them. However, these proteins have unique binding properties and do not all bind at the same sites, which leads to varying perception of sweetness. This work focuses on thaumatins, a class of intensely sweet proteins isolated from the arils of the fruits of the West-African plant Thaumatococcus daniellii. The distinctiveness of thaumatin lies in its sweetness index being up to 3500 times sweeter than sugar. According to the 2008 Guinness World Records, it is the sweetest natural substance known to mankind.

Thaumatin I and II, the two main variants of the protein,benefits of vertical farming are comparable in their biological properties, structure, and amino acid composition. The structure consists of a single polypeptide chain of 207 amino acids that are linked together by 8 disulfide bonds. The two variants differ by only five amino acid residues. Through chemical modifications and site-directed mutagenesis, it has been determined that the residues on the cleft-containing side of the protein have the strongest effect in eliciting sweetness to taste receptors on the tongue. The specificity of these residues demonstrates the importance of the protein structure in inducing thaumatin’s sweetness. In the USA, extracted thaumatin and thaumatin B-recombinant were initially affirmed Generally Recognized as Safe flavor enhancers/modifiers, but not as sweeteners. In the USA, plant-made thaumatin I and/or thaumatin II were granted GRAS status by the FDA in 2018 for use as a sweetener . In 2020, the FDA granted GRAS status to recombinant thaumatin II produced in Nicotiana plants for use as a sweetener and as a flavor enhancer/modifier . In the EU, thaumatins are allowed as both sweeteners and flavor enhancers. Thaumatin’s safety has been extensively documented. The Joint FAO/WHO Expert Committee on Food Additives report claims that the protein is free from any toxic, genotoxic, or teratogenic effects. Thaumatin is currently used as a flavor modifier in food applications such as ice creams, chewing gum, dairy, pet foods, soft drinks, and to mask undesirable flavor notes in food and pharmaceuticals. The current top global thaumatin manufacturers are Naturex , France; Beneo Palatinit, Germany; Natex, UK and KF Specialty Ingredients, Australia. The global production of thaumatin increased to 169.07 metric tons in 2016 from 138.47 MT in 2012. However, the current production method through aqueous extraction from the fruits of the tropical plant T. daniellii limits its availability while the demand is increasing. T. daniellii is not cultivated and harvesting of the arils takes place in plants growing wild in rainforests of West Africa ranging from Sierra Leone to the Democratic Republic of Congo.

The current production process is substantially dependent on the availability and quality of the native plant from year to year, which limits thaumatin’s use as a commodity product. The emergence of recombinant DNA technology and the use of cultured cells have allowed the production of proteins in large quantities. Enzymes and structural proteins are used in many industrial applications including the production of food and beverages, bio-diesel, cosmetics, bio-polymers, cleaning materials, and waste management. Most importantly, recombinant production allows for the expression of a protein outside its native source. Therefore, there exists a viable alternative to secure the desired quantities of thaumatin reliably and sustainably, without impacting rainforest ecosystems. Notably, there have been many attempts to produce thaumatin by means of genetically engineered microorganisms and plants. Despite successfully expressing thaumatin in yeast , bacteria , fungi , and transgenic and transfected plants , biotechnological large-scale production facilities have yet to be established. Molecular farming, the production of recombinant proteins in plants, offers several advantages over bioreactor-based systems. In this application, plants are thought of as nature’s single use bioreactors, offering many benefits such as reduced upstream production complexity and costs , linear scalability, and their inability to replicate human viruses. Specifically, open-field growth of plants has the potential to meet the market’s need for a large-scale, continuous demand of a commodity product at a competitive upstream cost. It has been marked suitable for this operation as plants can be easily adapted on an agricultural scale to yield several metric tons of the purified protein per year. Here, we present a feasibility study for a protein production level of tens of metric tons per year.

The success of a new product in the biotechnology process industry depends on well-integrated planning that involves market analysis, product development, process development, and addressing regulatory issues simultaneously, which requires some decisions to be made with limited information. This generates demand for a platform to help fill in those gaps and facilitate making more informed process and technology decisions. Process simulation models can be used in several stages of the product life cycle including idea generation, process development, facility design, and manufacturing. For instance, based on preliminary economic evaluations of new projects, they are used to eliminate unfeasible ideas early on. During the development phase of the product, as the process undergoes frequent changes, such models can easily evaluate the impact of these changes and identify cost-sensitive areas. PSMs are also useful for directing lab and pilot-scale studies into areas that require further optimization. Additionally, PSMs are widely used in designing new manufacturing facilities mainly as a tool for sizing process equipment and supporting utilities, as well as for estimating the required capital investment and cost of goods. This ultimately helps companies decide on building a new facility versus outsourcing to contact manufacturers. There are currently few published data-driven simulations of techno-economic models for plant-based manufacturing of proteins for pharmaceutical, bio-fuel, commercial enzyme, and food safety applications. However, to the best of our knowledge, no studies have proposed or assessed the feasibility of plant-based protein bio-production platforms on the commodity scale in tens of metric tons per year. The feasibility of production at this scale is critical for the emergence of thaumatin as a sugar substitute. Here, we present a preliminary process design, process simulation, and economic analysis for the large-scale manufacturing of thaumatin II variant by several different molecular farming production platforms. The base case scenario assumes an annual production capacity of 50 MT thaumatin. To achieve this level of production in a consistent manner, manufacturing is divided into 157 annual batches. Upstream production is attainable through open-field,urban vertical farming staggered plantation of Nicotiana tabacum plants. Each batch has a duration of 45 days and a recipe cycle time of 2 days. A full list of process assumptions can be found in Table S1. The proposed design achieves the expression of thaumatin in N. tabacum leaves using magnICON® v.3. This technology developed by Icon Genetics GmbH allows for the separation of the “growth” and the “expression” phases in a manufacturing process. Moreover, this process obviates the need to use agroinfiltration, which requires more capital and operational costs for inoculum preparation and implementation of expensive units for the infiltration process, containment of the genetically engineered agrobacteria, and elimination of bacteria-derived endotoxins.

In this design, transgenic N. tabacum or N. benthamiana plants carry a double-inducible viral vector that has been deconstructed into its two components, the replicon and the cell-to-cell movement protein. Background expression of recombinant proteins prior to induction remains minimal; however, inducible release of viral RNA replicons—from stably integrated DNA proreplicons—is triggered upon spraying the leaves and/or drenching the roots with a 4% ethanol solution resulting in expression levels as high as 4.3 g/kg fresh weight in Nicotiana benthamiana. Nonetheless, Nicotiana tabacumhas several advantages that make it more suitable for large-scale open field production such as field hardiness, high biomass yields, well-established infrastructure for large-scale processing, plentiful seed production, while attaining expression levels up to 2 g/kg FW. Furthermore, it is unlikely that transgenic tobacco material would mix with material destined for the human food or animal feed chain, unless it is grown in rotation with a food crop, but further development of strict Good Agricultural Practice for transgenic plants should overcome these issues.An alternative upstream facility design scenario was developed to evaluate the process economics of a more controlled supply of thaumatin by growing the plant host in a 10-layer vertical farming indoor environment. Nicotiana benthamiana is chosen as a host because it is known to be a model for protein expression for both Agrobacterium and virus-based systems, but its low biomass yield and difficulties regarding adaptation in the field hinder its application for open outdoor growth. However, this species grows very well in indoor, controlled environments and has high recombinant protein production. This upstream production facility uses the same method of expression and follows the same schedule as the base case upstream facility. Transient expression in plants is a method of recombinantly producing proteins without stable integration of genes in the nuclear or chloroplast genome. The main advantages of using this method are reducing the extensive amount of time needed to develop a stable transgenic line and overcoming bio-safety concerns with growing transgenic food crops in the field expressing heterologous proteins. Transient expression is attainable through several systems including biolistic delivery of naked DNA, agrobacteria, and infection with viral vectors. Notably, the use of viral vectors has been marked suitable for application on a field-scale due to the flexibility of production, and the quick accumulation of target proteins while achieving high yields. A new report has shown efficacy in delivering RNA viral particles using a 1–3 bar pressure, 1–4 mm atomizer nozzles spray devices in the presence of an abrasive to cause mechanical wounding of plant cell wall. GRAS notices GRN 738 and GRN 910 describe production of thaumatin in edible plant species and N. benthamiana, respectively. The expression of thaumatin in leaf tissue of the food crops Beta vulgaris , Spinacia oleracea , or Lactuca sativais generally lower than in N. benthamiana. However, despite having lower expression levels, the absence of pyridine alkaloids that are present in Nicotiana species is a major advantage for production in food crops because of the significant downstream resources needed to remove alkaloids in Nicotiana-based products. The ultimate solution may be a high-expressing engineered Nicotiana host devoid of alkaloid biosynthesis, but that option was not modeled in this study. The transient production facility is designed to produce 50 MT of purified thaumatin in spinach, annually, over 153 batches due to longer turnaround time required for S. oleracea compared to N. tabacum crops. Each batch has a duration of 67.8 days and a recipe cycle time of 1.94 days. The proposed base case upstream field production facility, displayed in Figure 1, consists of a 540 acre block of land divided into 22 plots, each of which is suitable for growing 318,000 kg FW of N. tabacum, carrying 477 kg of thaumatin, accounting for downstream recovery of 66.8%. It is assumed that the facility is located in a suitable climate where the growth of N. tabacum is attainable throughout the year, ignoring variations in production between batches . Each batch starts with direct seeding of transgenic N. tabacum plants in the field . The seeds are left to germinate for two weeks followed by vegetative growth for 3 more weeks post germination .

The tobacco industry’s response was to disseminate their typical smuggling arguments

The tobacco industry and its allies usually base their claims on studies paid for by the tobacco industry, while independent studies show that smuggled cigarettes only account for 2% to 6% of total consumption.These claims would all be employed in Nebraska by the tobacco industry and its allies in 1999 to defeat a $0.66 excise tax increase that Citizens for a Healthy Nebraska got introduced by Senator David Landis of Lincoln. Citizens for a Healthy Nebraska was successful in getting their proposed excise tax considered by the Legislature. In the 1999 session, Senator David Landis introduced LB 505, which sought to raise the excise tax on a pack of cigarettes from $0.34 to $1.00.In addition to raising the tax, LB 505 sought to establish the Tobacco Prevention, Control, and Enforcement Fund with approximately $0.14 of the $0.66 increase going to this fund. This would generate an estimated $14 million annually to fund tobacco control efforts in Nebraska, which was the CDC’s minimum recommended level of funding for tobacco control in Nebraska.The Tobacco Prevention, Control, and Enforcement Fund was to be administered by the Health and Human Services’ Health Promotion and Education Division, which was part of the Office of Preventive Health and Public Wellness.This effort was prior to the passage of LB 1436, the bill that designated $21 million over three years to a statewide tobacco control program, so if LB 505 would have been successful, it would have been responsible for funding a statewide tobacco control program. The purpose of this fund as defined in LB 505 was for “enforcement, counter-marketing, education, and outreach programs that specifically address the cause and prevention of smoking-related diseases and smoking prevention and cessation.”The intent of the large increase in the excise tax,hydroponic trays as explained by Senator Landis in his Statement of Intent was “to create an economic impediment to the purchase of cigarettes by adolescents in Nebraska. National Cancer Institute studies show that a 20% increase in the price of a pack of cigarettes should result in a 30% decrease in teenage smoking.”

For example, Brown and Williamson produced a report entitled “LB 505’s Effect on Nebraska Retailers” which detailed the tobacco industry’s key points for opposing LB 505 which seemed targeted to retailers. It even used language that makes it seem that the reasons are coming from another retailer and not Brown and Williamson. For example, the first sentence of the document was “This tax will only punish our stores and our legal consumers” and the last line was “Most of these sales and profits will simply be shifted to our neighbors who are not burdened by this tax.”In between these two lines were a litany of figures for lost sales, lost profits and lost workers that Brown and Williamson indicated would result from smokers purchasing their cigarettes from places other than Nebraska retail outlets. Nowhere in the document was the source of these figures cited.The testimony of Dennis Rasmussen, lobbyist for Philip Morris, at the Revenue Committee’s hearing on LB 505 focused on the same themes. Citing studies conducted by the industry-funded American Economics Group and Incontext, Inc.,Rasmussen’s handout to legislators contained sections entitled “Sales and Jobs Lost to Surrounding States,” “Lost Retail Sales,” “Unfair Burden,” and “An Unregulated Black Market in Cigarettes.”William Peters, the lobbyist for both Brown & Williamson and Lorillard, David Schulte for the Nebraska Association of Tobacco and Candy Distributors and Bob Skochdopole for the Smokeless Tobacco Council also testified against the tax increase. Testifying in favor of LB 505 were numerous representatives from the members of Citizens for a Healthy Nebraska, the American Association of Retired Persons , nine individuals from Loup County Public School and representatives from Creighton University and the University of Nebraska Medical Center.LB 505 was advanced out of by a vote of 5-3 but the committee added an amendment so that the tax increase would sunset after three years on December 31, 2002.After LB 505 advanced out of committee, the Americans For Tax Reform, sided with the tobacco industry.In a letter to State Senator Jim Jensen, Grover Norquist, President of the American For Tax Reform, reminded Jensen that he had signed the Americans for Tax Reform’s Taxpayer Protection Pledge. Norquist stated, “As you know, there is a proposal in the Nebraska legislature which would raise taxes on tobacco products.

Unless this tax increase is matched dollar for dollar by a tax cut, it would violate the terms of the Pledge.”The letter then urged Senator Jensen to vote against LB 505. Handwritten on the copy of this letter was a note indicating that it was to be faxed to Betsy Giles, a senior executive with Philip Morris.It is not known if similar letters were sent to other members of the Legislature. While LB 505 was on the floor of the Legislature, high level tobacco executives were monitoring its status. In the Weekly Status Report for the State Government Relations Department for R.J. Reynolds, Roger Mozingo, the Vice President for that department, informed T. J. Payne, R.J. Reynolds Senior Vice President of External Relations, that, as of March 18, LB 505 had not yet been scheduled for debate. Mozingo added, “A vote count of ‘hard votes’ was taken earlier this week and 20 no’s and 9 yes’s were counted. There are 49 members of the Nebraska legislature, which leaves 20 ‘swayable’ votes. An extensive grassroots effort is underway by the industry.”Later that month, the American Legislative Exchange Council sponsored a luncheon for state senators. ALEC is an association for state legislative members. Two of its major funding sources are Philip Morris and R.J. Reynolds.At that luncheon, Michael Flynn, Director of Legislation and Policy for ALEC repeated the tobacco industry position that passing LB 505 could produce a black market for smuggled cigarettes that was run by the mob. After telling senators that a semitrailer full of smuggled cigarettes could produce over a half of a million dollars in profit for the smuggler, he added, “That’s quite a temptation for organized crime – a cash bonanza.”Flynn cited Michigan as an example of a state which had seen an increase in cigarette smuggling as a result of increasing its excise tax. He also reiterated the tobacco industry’s stance that Nebraska would lose cigarette sales to neighboring states with lower excise taxes which would result in lower tax revenue.Citizens for a Healthy Nebraska responded to the luncheon by making sure that senators were informed that ALEC received funding from the tobacco industry.As part of this effort,vertical farming companies they disseminated ALEC literature that thanked Philip Morris and R.J. Reynolds for their “generous contributions”in sponsoring a States & Nation Policy Summit in 1998.They received some help in this effort from Senator Donald Preister who was a member of ALEC at the time but was also a strong tobacco control proponent . He noted to reporters that ALEC received money from the tobacco industry and he said he recalled an 1993 ALEC “orientation” for newly elected legislators that he attended in which cigarettes and lighters were given out to the state legislators that attended.Their efforts, however, did not prevent the bootlegging message from being ascribed some credibility. Major Gale Griess of the Nebraska State Patrol was quoted in an Associated Press article saying that if LB 505 passed, “Bootlegging will be a problem.”By March 31, LB 505 still had not come up for debate on the floor of the Legislature. In another weekly status report from Roger Mozingo to T. J. Payne, Mozingo wrote, “Grassroots efforts continue at a heavy pace. WKA has prepared economic impact books that will be delivered to many of the legislators the first of next week.”It is not known what WKA stands for but it likely refers to one the companies that produces economic studies that are paid for by the tobacco industry. At the same time, another study was released by In Context, Inc., which produces studies paid for by the tobacco industry, that predicted that if LB 505 passed then it would “drive more shoppers and jobs” to Nebraska’s neighbors.This new report that focused on Nebraska received mention in the Omaha World-Herald. It was also reported that the study was funded by Philip Morris.When asked how much Philip Morris paid for this study, William Lilley III, chairman of In Context Inc. and former economics professor at Yale University, declined to answer the question.

The tobacco industry efforts seemed to have the desired effect. When LB 505 came up for debate on the floor of the Legislature, Land is and other senators in support of an excise tax increase offered an amendment that would cut the increase more than in half, from $0.66 to $0.30.Even so, supporters of the amendment were only able to garner 24 votes, one short of the 25 needed to pass an amendment.The Legislature adjourned with no further action being taken on LB 505.The following year, in 2001, Citizens for a Healthy Nebraska again pushed for a large excise tax increase which was sponsored this time by Senator Jim Jensen . On January 17, 2001, Senator Jensen introduced LB 792, which sought to raise the state’s excise tax by $0.30.Newspaper reports dubbed LB 792 a “something-for-everyone” bill because the over $30 million that would be raised by the excise tax increase was to be given to foster care, water-quality monitoring, juvenile justice, emergency services, rural health and urban redevelopment projects in Omaha and Lincoln.It also included a $0.05 earmark for Tobacco Free Nebraska, which was already being funding at $7 million per year as part of LB 1436.This tax increase was to continue until July 1, 2008 so it would have provided funds for Tobacco Free Nebraska until FY2008 as compared to LB 1436 which only funded Tobacco Free Nebraska through FY2002.307, Befitting a bill that would have funded numerous different areas, there was a sizable turnout of individuals in favor LB 792 at its hearing before the Revenue Committee. In total, 25 people testified in favor of the bill.From the tobacco control community, five individuals comprising most of the member groups of the Citizens for a Healthy Nebraska coalition testified in favor of LB 792.Also testifying in support was Mark Welsch, President of GASP of Nebraska, and Richard Hunt, the founder of GASP of Nebraska. Numerous individuals from the tobacco industry and their allies appeared again to oppose an excise tax increase in Nebraska. Included were Walter Radcliffe, lobbyist for United States Smokeless Tobacco, Jim Moylan of the Nebraska Licensed Beverage Association , David Menke of No Frills Supermarkets and the Nebraska Grocery Industry Association, Derek Crawford, lobbyist for Philip Morris, Cara Potter of the Nebraska Retail Federation and David Schulte of the Nebraska Association of Tobacco and Candy Distributors.During the testimony before the Revenue Committee, the tobacco industry and its allies focused on themes similar to those expressed during the debate of LB 505 the previous two years. Radcliffe also criticized Senator Jensen’s strategy of providing earmarks to numerous interests in LB 792. Radcliffe stated, “It gives the money to different people in hopes that those people will be able to persuade enough senators to vote for the increase this year. I don’t think they can.”It was Holmquist and Dr. Paul Paulman of the Nebraska Medical Association that made Citizens for a Healthy Nebraska’s case for an excise tax increase before the Revenue Committee. Also testifying in favor of the bill from the tobacco control community in Nebraska was Mark Welsch of GASP of Nebraska.Many of the same names from previous years opposed LB 1149. Testifying against an excise tax increase again were Radcliffe of United States Smokeless Tobacco, Schulte of the Nebraska Association of Tobacco and Candy Distributors, Crawford from Philip Morris, Moylan of the Nebraska Licensed Beverage Association .The newcomers were Lon Alexander, a Tobacco Hut owner, Timothy Keigher of the Nebraska Petroleum Marketers Association and Bill Peters, formerly with the Tobacco Institute, and now testifying for Lorillard and Brown & Williamson. On February 28, 2002, Governor Johanns unveiled his budget which included a $0.50 excise tax increase in LB 1149, but, unlike LB 1149, the revenue <is the way I edited it correct?> from the tax increase was to go to the General Fund and not to health expenses.

Health advocates responded by publicly criticizing the actions of the City Council

After the Health Department finalized its draft in early October, a hearing before the Lincoln City Council was set for November 3, 2003. On October 14, the Lincoln-Lancaster County Board of Health held a meeting to recommend that the City Council approve the proposed law. The board’s president, Ed Schneider, said “It’s time we try to protect these innocent people who are not smokers . . . 80 percent of the public who have been adversely affected by secondhand smoke.”Despite the elimination of workplaces located in private residences from the requirements of being smoke free, Walt Radcliffe, the lobbyist for United States Tobacco, released a memo on October 23 that said that the enforcement provisions of the Health Department’s proposed ordinance would violate the Fourth Amendment of the United States Constitution.Specifically, Radcliffe felt that the language in the Lincoln Smoke free Air Act, which said, “The Health Director and law enforcement agencies are hereby authorized to inspect a place of employment or public place at any reasonable time to determine compliance with this Chapter,” would allow warrentless inspections that violated the Fourth Amendment.Within a few days, council members had introduced numerous amendments to weaken the proposed ordinance.Three members, Glenn Friendt, Annette McRoy and Jon Camp introduced amendments to allow smoking in bars with their amendments differing in how a bar was defined. Council member Patte Newman introduced an amendment to exempt truck stops and coffeehouses. At the time, Council member Terry Werner told reporters that he was considering introducing an amendment to allow separately ventilated areas where smoking was permitted,trimming cannabis a position promoted by the tobacco industry.Ignoring the fact that such ventilation systems do not address the health problems associated with secondhand smoke for employees, he stated, “There has to be a little room for compromise.

Maybe there’s a way to do it without compromising people’s health.”The reason why Werner felt ventilation was a possible compromise was because health advocates had not presented a united front in opposing ventilation. The American Cancer Society and a environmental health representative from the Health Department stated that the ordinance would better protect the health of the public in the form proposed by the Health Department but that ventilation would be an acceptable compromise.Other health advocates continued to reiterate their position that the ordinance should not be weakened in any way including ventilation. Werner would go on to introduce an amendment to allow separately ventilated “smoking rooms” in businesses,but he and Ken Svoboda were the two council members that were most supportive of passing a strong smoke free ordinance.Concerning the amendments, Ed Schneider, President of the Board of Health, said, “I think that [the adoption of the proposed amendments] will not give the protection to the public or employees we need. We have some empathetic, intelligent, caring council people. What we have to do is remain focused on the health issue.”With the Lincoln City Council already contemplating weakening the proposed ordinance, Jerry Irwin, the owner of a Lincoln strip bar called the Foxy Lady, began circulating petitions in 30 to 40 bars for patrons and employees to sign opposing the ordinance.166 Irwin stated that he was hoping to gather thousands of signatures to present to at the next City Council meeting. He said, “There will be a ton of people. The first hearing, that was just the first wave. There will be a lot of bar employees saying in not a problem.”By the second hearing on November 17, no changes had been made to the Health Department’s proposed ordinance but more than 15 amendments had been introduced by council members, almost all seeking to weaken the smoke free provisions within the ordinance. During the hearing, health advocates continued to focus on the health benefits to workers and the general public and testified against the tobacco industry positions raised by bar owners that their business would be harmed and that smoke free ordinances represented improper government inference.

The health advocates also argued that separately ventilated rooms were ineffective in protecting employees and the public from secondhand smoke. Following the second hearing, Lincoln Journal Star printed an editorial calling on the City Council to not weaken the proposed ordinance. It concluded, “Creating exceptions to the ban will only create problems and weaken its effect. Banning smoking in all workplaces is healthier, fairer and simpler. The City Council should approve the ban in its current form.”With the City Council still undecided, the original date for a final vote, set for November 24, came and went with no changes being made to the ordinance but no vote being taken either. Individuals from both sides of the debate continued to mobilize in support of their position by contacting the members of the City Council and the media. It was at the next meeting on December 1, that the City Council finally decided take action on the Lincoln Smokefree Air Act. Due to pressure exerted through the hospitality industry, Council Members Patte Newman and Annette McRoy, had introduced an amendment which sought to exempt bars. This amendment required that to receive an exemption the bar had to file an affidavit annually with City Clerk’s office stating that less than 60% of its gross revenue came from the sale of food. At this meeting, health advocates were able to convince the City Council to reject this bar exemption by a vote of 3 – 4 with Newman, McRoy and Friendt voting in favor.168 The turning point in the Lincoln Smoke free Air Act came after the City Council’s decision to not exempt bars. Instead of voting on the Health Department’s proposed ordinance, the City Council continued to seek a compromise position and then sets its sights on the amendment introduced by Terry Werner that sought to allow any workplace to have separately ventilated break rooms and “smoking rooms.”The language of the amendment did not make it clear whether these “smoking rooms” would be simply a room where people could go to smoke or whether it would serve as a smoking section for a restaurant or bar where employees would have to work. The amendment did limit the size of the “smoking room” by saying that it could comprise no more than 35% of the square footage of the place.

Despite the fact that the language of the amendment did not make its intent clear, the City Council decided to adopted it by a vote of 4 – 3 with Werner, Svoboda, Cook and Camp voting in favor and the three council members who wanted to exempt bars entirely voting against it.Because the City Council had adopted this amendment,drying and curing cannabis the vote on passing the ordinance was delayed for another week for to allow for further examination of the modified ordinance.The City Council’s decision to weaken the law by allowing ventilation and the subsequent delay that it caused would have further ramifications for the outcome of the ordinance. Neither side was happy with this compromise and since the vote was delayed, both health advocates and members of the hospitality industry continued to press the City Council. At the next meeting, on December 8, Patte Newman reintroduced her amendment to allow smoking in bars that took in less than 60% of their revenue from food sales. Having already rejected that amendment the previous week, some council members were surprised at Newman’s action. Council member Werner stated, “This certainly wasn’t typed up in the last five minutes. Why didn’t we have it? . . . It certainly gives the appearance of trying to hide something.”During the meeting, Newman placed a stack of petitions gathered by bar owners about 1 ½ feet high in front of her and, ignoring the polling data released by health advocates, said, “I believe the community has spoken. The exemption for bars is an exemption the community wants to see.”Despite its failure the week before, the Lincoln City Council decided to adopt the amendment to exempt bars by a 4 – 2 vote with Jon Camp switching his vote in favor.Jonathan Cook was absent from the meeting due to illness. Camp said that he decided to change his vote after he sequestered himself from the public for several days to read a book about personal freedom and responsibility written by his late father.During this meeting, the City Council also decided to remove the language limiting smoking in motel and hotels rooms to no more than 20% of the total number of rooms and 35% of total square footage for the separately ventilated “smoking room.” They replaced these hard limits with language similar to the Nebraska Clean Indoor Air Act so that the area were smoking was allowed was to be “reasonably proportionate to the preference of the users.”Because of Council member Cook’s illness, the City Council decide to delay its vote until the next week’s meeting on December 15. With the ordinance now exempting bars and allowing separately ventilated “smoking rooms” in other places, health advocates were angered by the actions of the City Council. Following the City Council meeting, Cindy Wostrel, chairperson of Tobacco Free Lincoln, told the press, “This defeats the intent of the legislation and the will of city voters.” With these changes, the health advocates stated that it would be better for the ordinance to be defeated than to pass in its current form.

Ed Schneider, the President of the Lincoln-Lancaster County Board of Health, said, “We’d rather not have any ordinance at all. This does not protect the health in this form.”The City Law Department was also critical of Newman’s amendment. They stated, “This amendment lacks consistency between exempted places of employment and public places. This amendment is also inconsistent with the intent of the proposed ordinance and the Nebraska Clean Indoor Air Act. In addition, this amendment raises many legal concerns.”The legal concerns that the Law Department were referring to were that the City could be open to lawsuits from businesses claiming that the ordinance created unequal treatment.168 Another problem with the amended ordinance was that the City Council still had not clarified whether or not employees would have to work in the separately ventilated “smoking rooms.” Regarding smoking break rooms, the ordinance stated, “The smoking break room shall not serve as a work area and no employee shall be required to enter the smoking break room in order to reach the employee’s work area. The prohibition shall not apply to employees providing janitorial and maintenance within the smoking break room,”but the only protection provided to in employees regarding the “smoking rooms” was a section which stated, “No member of the public nor any employee shall be required to enter the smoking room in order to access common areas of the place of employment or public place, including but not limited to, hallways, restrooms, lobbies, and waiting rooms.”At the next meeting on December 15, health advocates attempted to get the City Council to vote up or down on the original draft that was submitted by the Health Department. Council member Werner made a motion to adopt the original form of the ordinance but it was rejected 3 – 4 with Werner, Svoboda and Cook voting in favor.Following this setback, the health advocates tried at the meeting to get the weakened version of the ordinance defeated, but once again, they were unsuccessful. The Lincoln City Council voted 5 – 2 in favor of adopted the ordinance that allowed separately ventilated rooms and exempted bars.The two opposing votes were from Werner and Svoboda. The members of the hospitality industry were thrilled by their victory. “I’m excited. I think it was a good compromise. I think the democratic process was followed,” said Brian Kitten.On August 18, 1995, the Omaha Police Department again conducted tobacco compliance checks on 84 businesses; 24 of these merchants sold to minors.During this set of checks, several Baker’s Supermarket stores sold to minors, a second offense at four locations; therefore, they were required by the city ordinance to suspend selling tobacco for at least one day.Angered by this requirement to suspend sales, Fleming Supermarkets, the parent company of Baker’s, filed a lawsuit in the District Court of Douglas County against the City of Omaha and the Administrative Board of Appeals of the City of Omaha on the grounds that Omaha’s ordinance conflicted with state law.

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