Communicating a balanced perspective can be validating and empowering to the adolescent and the family

In order to protect participant confidentiality the vignette is a composite interview and any identifying information was altered. Clinical Vignette: Alicia is a sixteen- year old Latina female who was brought in by both parents upon the suggestion of their daughter’s therapist. The therapist has been seeing Alicia for six months for generalized anxiety and angry outbursts starting shortly after her parents divorced. The therapist reports that the divorce, although amicable, was stressful for Alicia and her younger brother. The therapist was concerned about an increase in Alicia’s anxiety and depression symptoms and a recent emergence of odd ideas that familiar people had changed in some way. The therapist was unsure what to make of Alicia’s new concerns and wondered if Alicia was exaggerating her level of distress in order to get both parents more involved or merely coping poorly in reaction to changes in the family. In session with her therapist, Alicia reported that at times, her surroundings would seem “unreal” but could not elaborate further. Over the past six months, Alicia became withdrawn and more “stressed” about what her friends think of her. Thoughts that people are communicating with her in special ways are increasingly preoccupying. Parents report that up until three months ago, Alicia performed well academically, receiving B’s, and socialized daily with several close friends from her soccer team. However, Alicia now has trouble completing assignments and is at risk of failing one class. She has missed several soccer practices in a row and comes straight home from school instead of hanging out with friends. At the PART appointment, Alicia was well-groomed and dressed appropriately for her age. There were no signs of psychomotor retardation; however, she exhibited moderate tension . Alicia was engaged throughout the interview and maintained good eye contact,marijuana curing except during the times when discussing her sadness over her parents’ divorce. She appeared depressed and anxious.

She denied suicidal and homicidal ideations. She answered questions spontaneously and directly, although she spoke softly throughout the conversation, particularly when mentioning current unhappiness. Alicia’s thought process was linear and coherent. Alicia was able to answer questions and recall her past without difficulties. When questioned about her depression and anxiety, Alicia reported that she was having “a hard time” and that she found therapy helpful. A fictionalized excerpt from the initial interview transcript is as follows. A discussion of confidentiality is omitted for purposes of brevity, but it always included, as is a parallel interview with parents, legal guardian or other informant. These symptoms were rated in the attenuated range, with a 4 rating on unusual thought content. The rating is based on Alicia’s endorsement of puzzlement and confusion regarding familiar people, feeling that others had changed and ideas of reference . These thoughts are unanticipated and are experienced as not within Alicia’s control. Alicia reports that she is 50% sure that the experiences she’s having are real and that these thoughts are compelling, preoccupying, distressing. These thoughts are also getting in the way of school and socializing with friends. Given that these experiences started within the past year , occur at least once per week and cause daily distress, these symptoms qualify for an APS syndrome on the SIPS/SOPS. The case illustrates that symptoms develop over time, becoming progressively worse over the course of a year. Alicia’s thoughts that her friends might be imposters or that she is receiving special messages from strangers are compelling but skepticism about the reality of these ideas remains intact. She realizes that this is not really happening, but at times, for example, when she is at the mall with friends, the thought is overwhelming and she must get home to feel calmer. In the interview, Alicia readily provided an alternative explanation for these experiences with minimal prompting from the examiner. Many clinicians might consider these symptoms to be fully psychotic, and would not ask questions to determine her level of conviction . The advent of the SIPS and CAARMS has set an arbitrary threshold to full psychotic intensity of symptoms that was never defined in DSM-IV , and may differ from the threshold set by clinicians in typical practice.

Key determinants of a symptom being at a fully psychotic level of intensity on the SIPS are full conviction regarding the externally generated nature of the symptoms well as the frequency and duration of symptoms. Although the SIPS provides a definition that can be clearly operationalized and applied reliably, future research should examine the validity of the psychosis threshold for purposes of defining risk and outcome . Psychosis risk assessment does not end with the completion of the SIPS or CAARMS. Communicating the results of the assessment is an opportunity to provide psychoeducation, manage anxiety and give adolescents and families hope. As is always the case in clinical work, it is often helpful to use the teen’s language to describe the symptoms in defining the risk syndrome . Similar to all diagnostic feedback, basic education includes a brief summary of the available evidence: definition of the diagnosis, basic etiology, and prognosis of risk rates, highlighting the importance of early intervention and recommending treatments. When families are given information they gain perspective and a greater sense of control over emerging changes that may otherwise be puzzling and disruptive. Feedback may require more than one visit as families can only take in a small amount of information at a time, especially under a high emotional load. This often requires a careful balance between giving sufficient information about risk without increasing the family’s anxiety about their adolescent’s current symptoms. Informing families of the actual risk can alleviate the doom families may feel. At the same time, it is important to communicate to families that addressing symptoms in the early stages may prevent further decline in functioning regardless of the diagnostic outcome. In order to support treatment engagement, it is important to process these reactions with the family while addressing misconceptions and stigma through an accurate and hopeful portrayal of attenuated psychotic symptoms, and of established psychosis. Family members consistently report that before a risk assessment they were not sure what to make of their child’s recent changes in behavior and mood; they often felt confused, not knowing whether to take the “wait and see approach” or seek professional advice: “At first I thought she was going through a phase. All teenagers go through some angst and get moody but it seemed like there was something more than that. I wasn’t sure.” Many families have historical experience with a relative with schizophrenia and fear that their child will experience a similarly devastating future of chronic institutionalization. For most people,pruning marijuana the words “psychosis” or “schizophrenia” can be stigmatizing labels. However, symptoms such as unusual perceptual experiences or thoughts are part of a continuum of normal experiences .

In describing the concept of a continuum to families, the example of social anxiety can be used. Social anxiety falls on a continuum where an adolescent can move from having a normative concern about what others think of him/her to less socially acceptable paranoid ideation. It is the interpretation of these experiences that causes distress or disability and these symptoms are amenable to psychological interventions used to treat depression and anxiety, such as CBT. However, normalization of the experience does not mean there is nothing to worry about.The presence of attenuated psychotic symptoms and their associated distress and impairment can be taxing for the adolescent’s family. We often recommend that families find their own support, such as individual therapy or a parent support group. CHR syndromes are often superimposed on pre-existing conditions, overlap to varying degrees with other disorders that are common in adolescence, and attenuated psychotic symptoms are often present across a variety of disorders. Therefore, accurately differentiating between CHR syndromes and other psychiatric problems might not be possible in the initial stages of disturbance, especially in younger patients. In order to minimize “false-negatives,” research studies typically follow individuals who present with attenuated psychotic symptoms and comorbid DSM-IV diagnosis longitudinally in order to ascertain eventual risk for conversion to psychosis. This ambiguity regarding diagnosis and outcome can be anxiety-provoking for clients and their families. Continual psycho education and feedback to families can help, and attenuated psychotic symptoms, as well as other symptoms the client presents with, should be targeted in treatment regardless of the formal diagnosis. We will now briefly consider common comorbid disorders and, where possible, differential diagnosis for CHR adolescents. Substance use and abuse are, of course, common among CHR youth and psychotic experiences are common in non-CHR individuals using substances . Similar to assessing any potential substance-induced disorder, the first task is to establish a time course, determining whether the attenuated psychotic symptoms are limited to periods of intoxication and withdrawal. Substance use can interact with underlying vulnerabilities to trigger attenuated and full psychosis, with accumulating evidence that early cannabis use may play such a role . However, without clear periods of attenuated psychotic symptoms outside of substance use, a CHR syndrome cannot be diagnosed. Drawing a timeline of attenuated psychotic symptoms and substance use with the patient can help clinicians make this distinction.Comorbidity between CHR syndromes and mood and anxiety disorders is high: 59% of CHR individuals are estimated to meet criteria for a mood disorder, and 28% to meet criteria for an anxiety disorder , consistent with retrospective reports of anxiety and depression before illness onset in psychotic populations . These mood and anxiety symptoms can be caused or aggravated by distress associated with attenuated psychotic symptoms, can emerge independently from attenuated psychotic symptoms, or the attenuated psychotic symptoms can mark the severity of the mood/anxiety syndromes. Additionally, there is evidence suggesting that CHR individuals with comorbid mood- and anxiety symptoms have worse outcomes longitudinally and an increased risk of transitioning to psychosis . Finally, readers should be reminded that mood disorders with psychotic features are a targeted outcome of the CHR syndrome; the definition of psychotic “conversion” is not limited to schizophrenia . Suspected attenuated psychotic symptoms which co-occur with mood- and anxiety disorders need to be assessed along the dimensions of onset, frequency, impairment, conviction and distress just as would be the case if these symptoms occur without comorbid symptomatology. Children and adolescents diagnosed with Pervasive Development Disorders can present with social impairments, disorganized thought and speech, blunted affect and constricted interests which are also common in adolescents diagnosed with CHR syndromes. There is evidence suggesting that individuals with PDD have a higher risk of developing psychosis than individuals who do not meet criteria for PDD , and some studies report significant comorbidity between PDD and CHR syndromes . In some cases, PDD can be differentiated from CHR syndromes by developmental history: pervasive developmental disorders have an early onset , and are stable over time. In contrast, CHR syndromes often emerge in adolescence or early adulthood, and are diagnosed after a period of increased symptoms and a deterioration of functioning compared to baseline. However, the expression of PDD symptoms can change in adolescence, with what can appear to be “odd ideas” compared to peers . Furthermore, determining the absence or presence of CHR syndromes in individuals with a low IQ using traditional interview methods might be unreliable , and this needs to be considered when diagnosing CHR syndromes in those with PDD. There is compelling evidence from our group and others that characteristics related to how a person reacts to alcohol earlier in life correlates with the later development of heavy drinking, alcohol-related problems, and risk for alcohol use disorders . These include our own low level of response model , Newlin and Thomson’s Differentiator Model , and King’s Modified Differentiator Model . In our own work the less intense alcohol response at rising and peak alcohol levels is supported by a host of hormonal and electrophysiological data , with fMRI responses indicating potential LR group differences in some cognitive processes . However, despite the robust correlation between the intensity of one’s reaction to alcohol and the subsequent development of alcohol-related problems, it is not known if the level of response relates to another well-established phenomenon, tolerance.

The final products are usually with multiple of five carbons

Terpenes are natural products with diverse functions in different organisms. These compounds have benefited human society since antiquity, applied as materials , traditional medicines , pharmaceuticals , and cosmetics . The versatile functions and applications of terpenes owe to their diverse chemical structures, with more than 55,000 molecules known . Nature employs a concise paradigm to build such structures, in which isopentenyl pyrophosphate and dimethylallyl pyrophosphate , fivecarbon units derived from the 2-C-methyl-D-erythritol 4-phosphate pathway or mevalonate pathway , are first polymerized head-to-tail into prenyl pyrophosphates, including geranyl , farnesyl , and geranylgeranyl pyrophosphates. Then, the prenyl pyrophosphates are processed, mostly cyclized, by terpene synthases to produce terpene scaffolds . Lastly, the optional tailoring proteins, including P450s and glycosyltransferases , modify the scaffolds to afford the final products. Through this paradigm, structural diversities of the final products are introduced from different numbers of five-carbon units polymerized, varied cyclizations , and optional post modifications.Terpenes with non-multiple of five carbons are rare in nature and challenging to sample, even though this chemical space is valuable to explore for novel applications. We reported heterologous expression of the lepidopteran mevalonate pathway, a propionyl-CoA ligase, and terpene cyclases in E. coli to produce several novel sesquiterpene analogs containing 16 carbons . The LMVA pathway produces 6-carbon analogs of IPP and DMAPP, homoIPP and homo-DMAPP , in a reaction sequence highly similar to the canonical MVA pathway . The difference is that the thiolase condenses a propionyl-CoA and an acetyl-CoA making 3-ketovaleryl-CoA in the LMVA pathway instead of the condensing two acetyl-CoA to produce acetoacetyl-CoA in the canonical MVA pathway . The “extra” carbon from the propionyl-CoA is transformed into HIPP/HDMAPP,grow trays combined with two 5-carbon isoprenoid precursors to afford the sixteen-carbon products.

With the LMVA pathway expressed in E. coli, we established a biosynthesis platform for novel homoterpenes deviating from the “multiple of five carbons” rule. While the previous study successfully produced the final homosesquiterpenes, the details of the LMVA pathway, especially the production of HIPP and HDMAPP in the E. coli host was not assayed. Moreover, the production needs optimization because low C16 terpene titers have hindered us from accumulating and purifying these products for characterization. Here, we investigate the LMVA pathway by introducing a promiscuous phosphatase, NudB , to hydrolyze the terpene precursors to their corresponding alcohols. These alcohols are readily detected by gas chromatography . Using the alcohols as the final product, we were able to engineer and optimize the LMVA pathway to increase the production of HIPP, the direct product of LMVA and the starting substrate for homoterpenes synthesis. Also, the higher 3-methyl-3-buten-1-ol analogs have excellent fuel properties, making them candidates for next-generation biofuels.The atoB knockout and atoB yqeF double knockout strains were generated using the λ red recombinase protocol previously described . A kanamycin resistance cassette flanked by FLP recognition target sites was amplified from the plasmid pKD13 with primers KO_kan_F and KO_kan_R. The 1000 base pair homology regions upstream and downstream of atoB and yqeF were amplified using the primer pairs atoB_US_F/atoB_US_R and atoB_DS_F/atoB_DS_R, and yqeF_US_F/yqeF_US_R and yqeF_DS_F/yqeF_DS_R using BW25133 genomic DNA as template, respectively. The homology regions were designed to knock out the entire gene except for the starting ATG and the last 21 base pairs to avoid disrupting potential downstream ribosomal binding sites. The upstream and downstream homology sequences were combined with the kanamycin cassette by using NEBuilder HiFi DNA Assembly , and a second PCR was done to amplify the three-part fusion DNA sequences using primer pairs atoB_US_F/atoB_DS_R or yqeF_US_F/yqeF_DS_R using the corresponding assembly product. To generate marker-free atoB knockout, E. coli 6C01, the pKD46 plasmid with the λ red recombination genes and a temperature-sensitive replicon was transformed into chemically competent E. coli BL21 cells and selected on carbenicillin LB agar plates at 30oC. Plasmid-containing cells were made electrocompetent, and expression of recombination genes was induced with 0.1% arabinose. ~600 ng of the three-part PCR product was introduced into the cells by electroporation, and positive colonies were selected for on LB kanamycin plates grown at 37oC overnight.

To remove the kanamycin resistance cassette, pCP20 was transformed into the selected kanamycin resistance cells using electroporation and selected on carbenicillin and kanamycin LB agar plates at 30oC. The resulting colonies were streaked on an LB plate without antibiotic and grew overnight at 42oC to remove the cassette. The resulting colonies were streaked on an LB plate without antibiotic, a carbenicillin LB agar plate, and a kanamycin LB agar plate, respectively, to confirm the loss of the kanamycin cassette and pCP20.Two plasmids bearing the pathway genes were co-transformed into E. coli expression hosts using a room temperature electroporation method, in which the electrocompetent bacterial cells were prepared at room temperature freshly .The gene sequences were codon-optimized for E. coli and cloned into the pJL02 and pJL01 plasmid series . With the constructs in hand, we tested C6-isoprenol production in E. coli. First, we screened the CoA ligases, catalyzing the first step in beta-oxidation, with the well-characterized MeD as the acyl-CoA dehydrogenase. After production, we used GC-FID to quantify C6-isoprenol in the broths. The C6-isoprenol production varied substantially with different CoA ligases, suggesting this is a key step in the whole pathway. Among the genes we tested, PcCL gave rise to the highest production at 58.6 mg/L , a result consistent with the reported kinetics data . Also, we noticed that the combination of CsCL with MeD had a decreased production of 6.9 mg/L, down from the 27.3 mg/L produced by CsCL/MlD, suggesting that MlD is a better homolog for the second step . This hypothesis was supported by the screening results of the second step catalyzed by acyl-CoA dehydrogenase. The PcCL and MlD pair gave the highest C6-isoprenol production at 110.3 mg/L, so we used this pair of genes for the first two steps of the beta-oxidation pathway in the following experiments. Endpoint optical density analysis was performed to evaluate the impact of the expression of different beta-oxidation genes on cell growth. The results indicated the expression of the CoA ligases and acyl-CoA dehydrogenase barely impacts the growth. The slight growth inhibition effect in the high C6- isoprenol production, e.g., the PcCL/MlD,drying marijuana may result from the toxicity of C6-isoprenol. After optimizing the pathway genes to increase the production efficiency, we turned to the host genes that may degrade the key intermediate, 3-ketovaleryl-CoA.

As mentioned before, this intermediate can be degraded by a thiolase into acetyl-CoA and propionyl-CoA. Therefore we focused on two E. coli chromosomal thiolase genes, atoB and yqeF, which have substrate preference for short-chain betaketoacyl-CoA and were proposed to degrade 3-ketovalerylCoA. We conducted in-frame single-gene knockouts to delete these two genes in E. coli BL21 in sequence, and PCR confirmed the genotypes of the knockout mutants . The intermediate strain E. coli BL21 ΔatoBand the final double knockout strain E. coli BL21 ΔatoB ΔyqeF were then used for C6-isoprenol production using the plasmid combination of pJL01-MlD/pJL02-PcCL. The production of C6-isoprenol and the consumption of valeric acid were quantified. The results showed that while the knockout of atoB did not impact the C6-isoprenol titer, the double knockout strain, 6C02, increased the C6-isoprenol production to 390 mg/L, and the C6- isoprenol yield from valeric acid doubled to 44 mol% over the wild-type strain . We noticed even after knocking out the thiolase genes, only around half of the valeric acid is transformed into C6-isoprenol. The loss of valeric acid may come from the evaporation and the flux into side directions in the metabolic network, such as the degradation of 3-ketovaleryl-CoA by other thiolases in E. coli .In the C6-isoprenol runs, we noticed that the levels of isoprenol were generally negatively correlated to the levels of C6-isoprenol. For the sources of isoprenol, we reason that in addition to the E. coli native MEP pathway, the LMVA pathway may contribute the major portion via acetoacetylCoA, instead of 3-ketovaleryl-CoA, to C6-isoprenol. Through the LMVA pathway, the productions of C6-isoprenol and isoprenol use the same precursor, acetyl-CoA, resulting in the negatively correlated levels of C6-isoprenol and isoprenol. Also, the knockout of the short-chain acyl-CoA thiolase increased the supply of acetoacetyl-CoA and the production of IPP, resulting in an increased isoprenol titer of 14.4 mg/L compared to 2.1 mg/L for the wild-type strain. Hence, we proposed that acetoacetyl-CoA is readily accepted by the LMVA pathway, and it’s betaoxidation precursor, butyric acid, might be a substate of the beta-oxidation LMVA pathway. To test this hypothesis, we fed 1 g/L butyric acid instead of valeric acid to strain 6C02 containing pJL01-MlD and pJL02-PcCL.

After production, GC-FID and GC-MS confirmed the isoprenol production, quantified at 301.8 mg/L . This result validates butyric acid is a good substrate for the beta-oxidation LMVA pathway for IPP/isoprenol production. The successful transformation of butyric acid into C5 alcohols by C4A suggests that the beta-oxidation LMVA pathway has substrate promiscuity. To explore the substrate spaces of this pathway, we tested other fatty acids as substrates. Without supplementing hexanoic acid, E. coli 6C02 with the beta-oxidation LMVA pathway also produces a small amount of C7-isoprenol, confirmed by the synthetic standard using GC-FID and GC-MS . Supplementing hexanoic acid increased the production of C7-isoprenol significantly . Therefore, the betaoxidation LMVA pathway can activate hexanoic acid and transform it to C7-isoprenol, albeit with low efficiency. C7-isoprenol production without hexanoic acid supplementation is likely from endogenous hexanoyl-CoA in E. coli. We also tried fatty acid analogs with functional group substitutes, including 5- chloro-valeric acid, 4-pentenoic acid, 4-amino-butyric acid, 5,5,5-trifluorovaleric acid, and 4- bromobutyric acid. We conducted comparative GC-FID/GC-MS analysis and fragment search in GC-MS for lack of standards of the expected alcohol products. However, none of the expected substituted alcohols were detected, suggesting these fatty acid analogs are poor substrates for the beta-oxidation LMVA pathway . The substrate promiscuity assays suggest the beta-oxidation LMVA pathway can produce IPP and C7-IPP, expanding the product chemical space of the homoterpene biosynthesis platform. The isopentenols, including isoprenol and prenol, are drop-in alcohol biofuels and have versatile potential fuel applications: prenol is one of the top 10 Department of Energy Co-Optimization of Fuels & Engines gasoline blendstocks and has synergistic blending effects for research octane number , and isoprenol is the precursor of 1,4- dimethylcyclooctane , a high-performance jet fuel blendstock . Previous studies have shown that for alcohol biofuels, molecules with longer chain lengths have a better blend stability with conventional fuels, and are less hygroscopic than their shorter chain congeners . Our pathway to C6-isoprenol and C7-isoprenol from biomass-derived fatty acids makes it possible to produce these chain-extended isoprenol analogs sustainably. With the synthesized C6-isoprenol and C7-isoprenol, we were able to test some important fuel properties of these novel isoprenol analogs. We first estimated their water solubility based on their logP values. High water solubility contributes to the high hygroscopic nature of alcohol fuels, increasing the possibility of phase separation when blended with conventional hydrocarbon fuel. Also, for microbial bio-fuel production process, molecules with high logP and low water solubility will partition into the organic phase in a two-phase extractive fermentation, resulting in low product toxicity to the producing microbes . Increasing carbon chain length leads to decreasing polarity of alcohols, resulting in lower water solubilities. The logP of isoprenol analogs were determined using an HPLC method, with C4-C8 strain chain alcohols as references. The result revealed that the one-carbon increase of the chain length of isoprenol decreases the water solubility to 22.12 g/L from 65.36 g/L. Moreover, the addition of two carbons to isoprenol further decreases the water solubility to 6.6 g/L . The decreasing trend of the water solubility was expected, and these data reflect the trend quantitatively. The energy density of the isoprenol analogs was determined by testing their gross heats of combustion using a standard method . The energy density tests revealed C6-isoprenol has a higher heating value of 35.524 MJ/kg, while C7-isoprenol had an HHV of 39.468 MJ/kg . These numbers are similar or higher to the HHVs of isopentenols tested in the same batch. We also determined the RONs of the 10% alcohol RBOB gasoline blends using the recently published AFIDA method .

Subjects were asked to identify the sex of the faces by using a response box

There has been an explosion in research elucidating the underlying molecular mechanisms of the circadian rhythm and how this influences multi-scale functions in the brain from basic cellular functions to larger scale networks. Recent studies have identified the molecular controls of the circadian clock that is regulated by the CLOCK/Brain and Muscle ARNT-like 1 system. It has been shown that core clock genes, clock circadian regulator, CLOCK and BMAL1 contribute to epileptic excitability.Interestingly, mTOR regulates BMAL1 proteostasis and TSC mouse models show abnormal circadian rhythms that can be corrected following genetic lowering of BMAL1 levels.On the contrary, BMAL1 functions as a translational factor that links circadian timing to the mTOR signaling pathway and BMAL1 knockout mice have lowered seizure thresholds.Decreased CLOCK protein levels were seen in resected brain tissue from patients with intractable epilepsy and that these changes can alter cortical circuits.Tying together BMAL1/CLOCK and mTOR pathways may provide additional insights into epileptogenesis and potential novel drug targets. Sleep is an important process in memory creation through regulation of normal synaptic homeostasis. Animal studies have demonstrated abnormal synaptic potentiation induced by epileptiform activity and seizures. In patients with focal epilepsy, a high density EEG study uncovered a widespread increase in slow wave activity, a marker of increased synaptic strength or excitability,cannabis curing that correlated with the burden of epileptic activity and cognitive impairment.Seizures during sleep can not only impair learning but increase mortality risk in patients with epilepsy. Clinical studies have demonstrated that sudden unexpected death in epilepsy is more common during sleep.

The mechanisms for this increased risk is unclear, but rodent studies suggest that serotonin is important in arousal, in postictal recovery of respiratory function, and as a modulator of seizure severity.Improved understanding of the role of the serotonergic system in sleep, seizure susceptibility, and in the overall circadian regulation will be important in our search for preventative treatments for SUDEP.Serotonin plays a crucial role in emotional processes. A considerable number of imaging studies involving pictures of emotional faces show that changes in serotonergic function are associated with changes in amygdala reactivity when viewing negative facial expressions: Acute tryptophan depletion, which reduces central serotonin synthesis, leads to higher amygdala activity when processing negative face expressions . Several studies have found that acute/sub-acute SSRI intervention leads to a decrease in amygdala activation . Further, when the cerebral serotonin level is pharmacologically enhanced by a three-week intervention with a selective serotonin reuptake inhibitor , the ensuing decreased cerebral [11C]SB207145- PET binding in response to pharmacologically increased brain serotonin levels is associated with lower threat-related amygdala reactivity . Whereas it is relatively clear that induction of acute and sub-acute changes in serotonin neurotransmission leads to changes in emotional processing, less is known about how the neural processing of emotional information is affected by chronic cerebral serotonin depletion. Ecstasy, or 3,4-methylene-dioxymethamphetamine is a widely used recreational drug that has immediate effects interms of improved mood and feelings of empathy . In this paper, we will use the term “ecstasy” when referring to the recreational human, and “MDMA” when referring to experimental human/animal studies. MDMA exerts its primary effects on the serotonin neurotransmitter system, in particular by reversing normal serotonin transporter function and hence releasing serotonin from the storage vesicles into the synaptic cleft .

Animal studies show that repeated exposure to moderate and high doses of MDMA is associated with a reduction in cerebral serotonin levels and a decreased number of SERT binding sites. In humans, prolonged recreational use of ecstasy is also associated with reductions in SERT in both cortical and sub-cortical brain areas . Most , although not all , molecular imaging studies show that the accumulated lifetime intake of ecstasy correlates negatively with SERT binding, supporting a dose-dependent relationship between recreational ecstasy use and reductions in SERT binding. Thus, it also seems plausible that in humans, an ecstasy-associated reduction in SERT is associated with reduced cerebral serotonin levels, and that the SERT changes may even result from chronically reduced serotonin levels. Additional support for serotonin depletion in recreational ecstasy use comes from the finding of increased levels of the post-synaptic serotonin 2A receptor in most , although not all , studies where ecstasy users have had their serotonin 2A receptors measured. Importantly, lowering brain serotonin levels in preclinical models leads to low SERT combined with high serotonin 2A receptor levels, and low SERT has also been found to be associated with high serotonin 2A receptor levels in humans . The reduction in sub-cortical SERT binding in ecstasy users seems to be reversible, since a positive correlation with time of abstinence from ecstasy intake has been observed . Taken together, data from these preclinical and clinical studies indicate that there is a causal relationship between ecstasy intake and effects on the serotonergic system. Reduced SERT and serotonin after MDMA/ecstasy exposure in combination with the observed correlation between serotonin depletion and reduced SERT binding in animal studies makes it plausible that SERT binding can be regarded as a representation of the extent of chronic—but most likely reversible—serotonin depletion in long-term ecstasy users. With MDMA being an interesting and promising candidate as adjunct to psychotherapy for treatment of post-traumatic stress disorder and possibly other conditions as well , it is important to explore the possible long-term impact of this drug on serotonergic neurotransmission, as well as the functional consequences of this. Although the multiple and not always pure MDMA doses used recreationally differ from the only few—and pure—doses employed in therapy, recreational use of MDMA/ ecstasy can serve as a model for the long-term effect of repeated doses. In the present study, we used functional magnetic resonance imaging to investigate the functional effects of long-term recreational ecstasy use,curing cannabis representing a model of long-term serotonin depletion, on the neural basis of emotional responses in the amygdala.

We hypothesized that amygdala engagement to aversive stimuli would show a positive correlation with accumulated lifetime ecstasy use; a negative correlation with SERT binding, as assessed with positron emission tomography imaging, in the amygdala; and a negative correlation with time since last use of ecstasy, suggesting recovery of amygdala response.Fourteen users of ecstasy and 12 non-using control subjects were recruited by flyers, advertisements posted on relevant websites, and word of mouth. Potential candidates were invited to a face to-face screening that involved assessment of history of alcohol, tobacco, and illicit drug use and Lifetime Drinking History, as well as screening of current and previous psychiatric symptoms using the Schedules for Clinical Assessment in Neuropsychiatry interview . All participants included in the present study, which focuses on fMRI investigations not presented previously, constitute of individuals who took part in a simultaneously conducted study with PET measurements of serotonergic markers—the PET results obtained in the larger sample have been published previously . To avoid acute drug effects in the ecstasy users, use of drugs was not allowed seven days before the PET and MRI scans, which were conducted on separate days at the Neurobiology Research Unit at Rigshospitalet and at the Danish Research Centre for Magnetic Resonance at Hvidovre Hospital, respectively. Abstinence was confirmed by urine screen on the PET and MRI days. Control individuals were excluded if they reported more than 15 lifetime exposures to cannabis or had any history of use of other illegal drugs, and urine screen on the day of the scan was carried out. Demographic and drug data are presented in Table 1. No present or prior neurological or psychiatric disorders were allowed for any of the subjects, and all subjects had a normal neurological examination and were lifetime naïve to antidepressants and antipsychotics. The study was approved by the local Ethics Committee, Copenhagen and Frederiksberg, Denmark 01-124/04 with amendment 11-283038, and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.Participants were presented with pictures of faces from the Pictures of Facial Affect Series . The following types of affect were presented: neutral , anger , disgust , fear and sadness . Using a blocked design, eight pictures of each emotion were presented for three seconds, with an interval of 0.75 seconds between stimuli presentations and emotion blocks. Sixteen blocks were presented in an ABACADAE design, each letter designating a block. Each block included eight trials and lasted 30 seconds.The responses were registered during an interval starting 50 ms and ending 3750 ms from each stimuli presentation.

Regression analysis was used to investigate possible correlations between reaction times and log2 to the lifetime intake of ecstasy tablets or log2 to the number of days since the last use of ecstasy. Due to our previous findings that the effects of cumulative ecstasy lifetime intake and time since last use of ecstasy on SERT binding follow a log2distribution, we expected a log2-linear relationship between RT and lifetime intake and time since last use . Analysis and results that include lifetime intake and/or number of days since last use of ecstasy will in this manuscript refer to “log2 to” the number of accumulated lifetime doses/time since last use, but in order to improve readability, in the Results and Discussion sections, we have left out “log2 to” from the text. Differences in RT were assessed using a repeated measures analysis of variance model, with group as between-subject factor and emotion as within-subject factor . The significance level was set to α=0.05. Post hoc t-tests were carried out in order to test paired comparisons between facial expressions. The Greenhouse–Geisser method was used to correct for non-sphericity.The degree of serotonin depletion as reflected by cerebral SERT binding was assessed with PET and the selective SERT radioligand, 11C-DASB, as described in more detail by Erritzoe et al. . In short, PET data were acquired on a GE-Advance scanner as a dynamic 90-minute emission recording after intravenous injection of the radiotracer, 11C-DASB. There was maximum of 1.6 months between the 11C-DASB PET and the fMRI experiment ; approximately half of the group had PET before MRI, and vice versa. The vast majority was scanned within one to two weeks; only two were scanned with an interval of more than a month. For each participant, a mean SERT binding value from the amygdala was calculated. To confirm previous results obtained in the overlapping study sample , we used linear regression analysis to test whether the log2 to the accumulated lifetime intake of ecstasy tablets correlated with SERT binding from the amygdala. Since effects of lifetime ecstasy intake on SERT become smaller with increasing abstinence from ecstasy , we controlled for this by also including the log2 to the number of days since the last use of ecstasy in the analysis. Also using a linear regression analysis, we tested whether the log2 to the number of days since the last use of ecstasy correlated with SERT binding from the amygdala . The possible difference between ecstasy users and controls in amygdala SERT binding was tested with an independent samples t-test.Functional data were preprocessed and analyzed using the statistical parametric mapping software package . Preprocessing included spatial realignment, co-registration to the anatomical image, segmentation, and normalization to the standard Montreal Neurological Institute template, and smoothing using a symmetric 6-mm Gaussian kernel. Subject-level models were constructed using five emotional face regressors , together with regressors modulating the events by their RT values. In addition, the subject-level models included a regressor for incorrect sex discrimination answers, and 24 nuisance regressors to correct for movement artifacts, including first- and second order movement parameters and spin history effects . T-contrasts comparing BOLD responses to emotional and neutral images were created for each participant. These maps were used in group-level models assessing: the main effects of emotional face processing across all participants, differences in BOLD responses between ecstasy users and control subjects, correlations between BOLD responses and the log2 to the accumulated lifetime ecstasy intake in ecstasy users, correlations between brain activity and regional SERT binding in the amygdala in ecstasy users and control subjects, and correlations between BOLD responses and the log2 to the number of days since the last use of ecstasy in ecstasy users.

One contributor to higher ARB rates in women may be their higher BACs per drink

The link of ethnicity to ARBs may relate to heavier drinking in EAs and, potentially, Hispanics, compared to other populations such as Asian individuals . Ethnic differences may also reflect divergent patterns of alcohol metabolizing enzymes, as Asians have higher rates of mutations in both aldehyde dehydrogenase and alcohol dehydrogenase that produce greater alcohol sensitivities and contribute to lower levels of heavier drinking with subsequent lower rates of ARBs . EAs, Asians, and Hispanics also differ on cultural-based proscriptions against heavy drinking, especially in women , have different rates of low LRs unrelated to alcohol metabolism , and vary regarding typical body mass indices, with the latter likely to affect BACs per drink .This reflects women’s likely lower body weight, less first pass metabolism of alcohol, and higher body fat with corresponding less body water per pound. However, there is overlap between ethnic background and drinking patterns among women, and it is not clear if those two characteristics interact regarding ARBs. Both ethnicity and sex also relate to low LRs to alcohol . However, LR differences across EA, Hispanic, and Asian individuals , and across sexes raise questions about how LR interacts with ethnicity and sex to contribute to ARBs. A recent review highlighted the paucity of prospective studies evaluating how multiple risk factors interact in contributing to ARBs, while controlling for alcohol quantities . In response, the present analyses extracted information from a 55-week prospective study that evaluated educational approaches to preventing heavy drinking on campus . The data tested four hypotheses: Hypothesis 1 states that relationships of ethnicity to ARBs will remain even after controlling for the maximum number of drinks consumed,rolling grow room table with the highest ARB prevalence in EA and Hispanic and the lowest rates in Asian students. Hypothesis 2 is that ARB rates will be higher in females, and that the ethnic differences will remain robust after considering sex and controlling for maximum drinks. Hypothesis 3 proposes that low LRs will relate to ARBs, and that ethnic differences will remain even after considering maximum drinks and LR.

Hypothesis 4 states that ethnic group status will interact with sex and LR to predict rates of ARBs over 55 weeks. Following University of California, San Diego Human Protections Committee approval, in January, 2014, 18-year-old freshmen were selected from respondents to questionnaires emailed to UCSD students to solicit participants for a 55-week study of ways to diminish heavy drinking in college students . No student was selected because of current or past alcohol problems, and based on questions extracted from the Semi-Structured Assessment for the Genetics of Alcoholism interview , the protocol excluded nondrinkers, individuals with severe psychiatric diagnoses , students who ever met DSM-IV criteria for dependence on alcohol or illicit drugs , and Asian individuals who became physically ill after one standard drink . Five-hundred subjects were enrolled, half above and half below the median for the number of drinks required for effects the first five times of drinking using the Self Report of the Effects of Alcohol questionnaire. The SRE determines the mean number of standard drinks needed across up to four possible alcohol effects actually experienced early in the drinking career. These included the drinks required to produce any effect, slurred speech, unsteady gait, and unwanted falling asleep. The SRE has Cronbach alphas and repeat reliabilities >.88 . This retrospective self-report measure was used rather than alcohol challenges because the latter are too expensive and time consuming for use in a large population . The overlap between SRE and alcohol challenge-based LRs in predicting heavy drinking and alcohol problems is 60%, and the measures produce similar results when used in different generations of the same families . High and low LR subjects were randomly assigned to three conditions: those who watched 5 videos regarding two different prevention approaches and no-intervention controls. The latter helped control for general-campus-related changes in drinking over time, and, reflecting the emphasis in the larger study on the impact of education groups, most students were assigned to active education.The dependent variable was the number of ARBs the prior month at each assessment. Analyses began with data transformations based on distributional properties for numbers of ARBs and maximum drinks per occasion using inverse reflected and square root transformations, respectively. For the first set of analyses, to address Hypotheses 1–3, numbers of ARBs per assessment were compared across ethnic groups overall, ethnic groups among females and males separately, and ethnic groups among subjects with high and low LRs separately.

As shown in Table 3 regarding each figure, at each assessment ethnic group differences were evaluated using two one-way ANOVAs, first presenting the F-value for differences in prior month ARBs across ethnic groups without controlling covariates, and again as F values controlling for maximum drinks consumed the prior month and for education group assignment . The final analysis in Table 4 addressed Hypothesis 4 by evaluating main and interaction effects for numbers of ARBs across eight time points using a 3 ethnic groups by 2 sexes by 2 LR categories by 8 time points mixed-design ANOVA that controlled for maximum drinks while using education group as a covariate. At baseline, the 398 eligible participants were 18-year-old UCSD freshmen, of whom 62% were female with 40% EA, 20% Hispanic, and 41% of Asian descent . Table 2 presents the numbers of subjects across combinations of ethnicities, sex, and LR groups. The SRE values averaged 4 drinks across four possible effects actually experienced the first five times they drank. In the prior month, these students consumed on average 6 maximum and 4 usual drinks per occasion, with 4 drinking occasions per month. At baseline, 21% noted having experienced an ARB in the prior month, with an average of 0.33 such episodes . About 40% had used cannabis the prior month, and 87% were in the active intervention group in the prevention study. Table 3 presents statistical analyses associated with the 3 figures, while Table 4 shows results of a mixed-design ANOVA for the overall statistical analysis regarding Hypothesis 4. These statistical results are mentioned here because they relate to interpretations of Hypotheses. Figure 1 presents the average number of ARBs the month before each assessment for members of the three ethnic groups, with highest rates for EA students, lowest for Asian individuals, and an intermediate rate for Hispanic students. While not shown in the figures, over the 55 weeks 43.0% had at least 1 ARB, including 13.3% with 1, 8.8% with 2, 2.5% each with 4, 5, or 6 ARBs, and 0 to 1.0% each with between 7 and a maximum of 36 ARBs. As demonstrated by the absence of a significant ethnicity by time interaction in Table 4, general patterns of ups and downs in numbers of ARBs over 55-weeks were similar for the three groups where ARB values tended to diminish between January and March , increase in June in concert with a campus festival known for heavy drinking, decrease again over the summer when most students returned home ,rolling top grow tables and rose after returning to school . However, regarding Figure 1, as shown in Table 3 the ANOVAs carried out at each time point revealed significant differences in the average number of ARBs across groups at every evaluation.

After controlling for maximum drinks reported at each assessment and education group assignment, residual statistics for ethnic group differences in ARBs at each time point across EA, Hispanic, and Asian subjects remained significant at Times 2 and 4. The absence of a main effect for ethnicity in the mixed-design ANOVA in Table 4 indicates the possibility that other characteristics may have impacted results. Therefore, Figure 2 presents ARB trajectories for the three ethnic groups for female and male students separately. While not shown, during the 55 weeks, 48.0% of females and 34.7% of males reported at least one ARB, with an average of 0.30 and 0.19  ARBs per assessment, respectively. Ethnic group differences in ARBs were prominent among females, with the highest ARB rates for EA women, the lowest for Asian individuals, and intermediate, but relatively low, rates for Hispanics. Looking at each assessment for females, statistical analyses in Table 3 demonstrate significant ethnic differences in the rates of ARBs for raw ARB numbers at every assessment, which remained significant at times 4, 5 and 8 after controlling for education group and maximum drinks. Differences across ethnic groups were less apparent for males, and the ethnicity by sex by time interaction was significant in Table 4. Also, for between subjects’ analyses where time was collapsed and average scores across the eight time points were used, there was a significant sex main effect, and the ethnicity by sex interaction was a trend . Next, the potential relationship of LR to the ethnic patterns of ARBs over time was evaluated in Figure 3. Here, high and low LR subjects showed the same general pattern of ARBs across time demonstrated in Figure 1, including highest rates of ARBs per assessment for EA, lowest for Asian, and intermediate rates for Hispanic students. However, ethnic group differences in ARBs were more robust for high LR subjects, with Table 3 revealing significant differences in raw ARB numbers across the three ethnic groups at every assessment, which remained significant at Time 7 after controlling for maximum drinks and education group assignment, with a trend at Time 4 . The only significant differences in raw ARB numbers for low LR subjects were noted at Time 2 and 4, each of which lost significance once residuals were used. In Table 4 the sex by LR by time interaction was significant and the LR group by time interaction for patterns of ARBs was a trend . Thus, the relationship of LR to differences in ARB patterns across ethnic groups was modest, and was most robust when considered in the context of sex effects. Regarding Hypothesis 4, as briefly alluded to above, the overall analysis in Table 4 indicates interactions regarding ARBs among ethnicity, sex, and LR in two 3-way interactions . However, the 4-way interaction was not significant. It is important to note that cross-sectional data in Figures 1 to 3 were analyzed after controlling for the education group in which students participated. Table 4 offers additional information about effects of educational group assignment, which was used as a covariate. Here, the education group by time interaction was a trend , and the education group main effect was significant, with controls having higher ARB frequencies than the active education participants. Alcohol-related blackouts are highly prevalent phenomena associated with potentially severe problems . Recently, the prevalence of ARBs has reached alarming rates, especially in females and individuals with early onset drinking . The UCSD freshmen studied here are no exception to these trends as 43% of these students reported at least 1 ARB during the 55 weeks, including 48% in females and 35% in males. While the risk for these alcohol-related anterograde memory lapses increases with BACs , ARB vulnerabilities were also related to ethnic background, female sex, and levels of response to alcohol. The patterns and interactions among these characteristics are the focus of this paper.The current analyses added potentially useful data to the study of ARBs. The sample is relatively large, and subjects were assessed prospectively eight times over 55 weeks during a life-period likely to involve heavy drinking . Several assessments were scheduled at periods when the rates of ARBs were likely to change, including following a heavy drinking campus festival, summer break, and after returning to school as sophomores . Data were evaluated while controlling for maximum drinks, thus diminishing the possibility that ARB patterns simply reflected impacts of heavy drinking itself, and after controlling for possible effects of the prevention trial from which the data were extracted. The major questions focused on improving understanding of how ethnicity, sex, and LR related to rates of ARBs. To address Hypothesis 1, evaluations began with documentation of expected ethnic group differences in rates of ARBs across time.

Psychoactive substance users reported more heroin use in the previous 30 days than non-users

During the recent years, there is a profound change in the profile of drug abuse in China: psychoactive substances, including crystal methamphetamine , 3,4-Methylenedioxy-N-methylamphetamine , as well as ketamine and others, have surpassed heroin and become the most popular drug choice in China . As of 2014, the number of drug users officially documented by the Chinese public security department was 2.955 million, among whom approximately half were psychoactive substance users . Among the 480 thousand drug users newly reported in 2014, psychoactive substance users accounted for near 80% . Psychoactive substances are neurotoxic, and long term use may induce cognitive and behavioral implications . In addition, its attendant behaviors, including high risk sexual behaviors and injection drug use, place the users at elevated risk for HIV infection . Therefore, the increasing trends in psychoactive substance use are of particular public health concern in China. Methadone maintenance therapy could block the effects of opiate withdrawal symptoms and the euphoria produced by opioids, such as heroin, so it could reduce or even eliminate opiate use . However, its impact on psychoactive substance abuse is not as clear . As a matter of fact, psychoactive substance use has been a serious concern among MMT patients in other countries . Reasons for using psychoactive substances during MMT included negative attitudes toward methadone, increased euphoria, enhanced energetic level and sexual performance, and self-medication for depression . To combat the substance abuse issue in the country, Chinese government started piloting MMT in 2004 . During the past decade, China has established the largest MMT program worldwide . By August of 2014, 756 methadone maintenance clinics and more than 300 outreach clinics have been established in 28 provinces,flood grow tables autonomous regions and municipalities, cumulatively treating 410 thousand opiate users .

While the program has generally been successful, the issue of psychoactive substance use exists in MMT clinics in China. A pilot study indicated that a proportion of clients who attend MMT shifted their substance use habit from opiate to psychoactive substances . A cross-sectional study conducted in eastern China revealed that 6.8% and 6.2% of the current MMT clients were tested positive for methamphetamine and MDMA, respectively . Because of the newness of the drug use trend, psychoactive substance use, particularly within MMT settings, has previously received little systematic investigation. Literature has documented factors correlated psychoactive substance use, which included demographic characteristics , mental health status, alcohol and other illicit drug use , yet these associations have not been confirmed among MMT clients in China. This aim of this study was to examine the prevalence, patterns, and correlates of psychoactive substance use among MMT clients in China. We hypothesized that psychoactive substance use would be associated with a client’s demographic characteristics, drug use related factors, and his or her mental health status. The study used baseline data from a randomized controlled intervention trial before any intervention activities were delivered. In order to increase the representativeness of the study sample, MMT clients were recruited from five provinces with varying economic and drug use conditions. Only the MMT clinics with more than 80 current clients were included to ensure enough eligible participants at each clinic. A total of 68 MMT clinics were randomly selected out of 110 clinics that meet our selection criteria in the five provinces. Using a random number table, about 36 clients were randomly selected from each of the 68 participating clinics, rendering a total sample size of 2,448 clients. According to the country’s national guidelines, all MMT clients must be at least 20 years of age with opiate dependence, excluding those who are currently convicted of criminal or civil charges, and those who have severe mental disabilities .

This study included only the clients who met these criteria and were receiving MMT from the participating clinics at the time of the study. The data were collected between September 2012 and August 2013. The selected clients were approached by our project outreach staff when they came into the clinic for daily treatment. Using a standard script, our project staff explained the study purpose, procedure, risks, and benefits to the study participants. Each participant was assured of confidentiality and their right to refuse participation without affecting their treatment services. The refusal rate was less than 5%. Written informed consent was obtained from each of the participants. The study was reviewed and approved by the Institutional Review Boards of the participating institutes in the U.S. and China. The survey questionnaire was administered face-to-face using the Computer Assisted Personal Interview method, with trained interviewers reading questions to the participants and recording their responses on laptop computers. The CAPI database was developed to automatically incorporate skip patterns and logistic check to reduce human errors. The survey took place in a private office within a MMT clinic and lasted about 45 to 60 minutes. The participants received 30 yuan for their time spent on the assessment. The statistical analyses were performed using the SAS 9.4 statistical software package . Firstly, descriptive statistics and frequency distribution for demographic and drug use related factors were summarized. These characteristics were compared between psychoactive substance users and non-users. Due to the study design, the participants were clustered within MMT clinics. Participants within a particular clinic may tend to be more similar to each other than to participants from different clinics, so we used mixed-effect models with clinic-level random effects to account for the clustering effect within a clinic . Second, we descriptively analyzed the proportion of each type of psychoactive substance use during the last 30 days and in lifetime. Lastly, in order to examine the factors associated with psychoactive substance use, mixed-effect models were built for the participants’ psychoactive substance use during the past 30 days and in lifetime .

The factors included in the models were: age , gender , marital status , education , personal income during the last 30 days , duration of heroin use , duration of MMT use , heroin use in the last 30 days , lifetime alcohol use , if have friend uses drug other than heroin and alcohol , and depressive symptoms . The selection the covariates was based on our prior understanding of the population and the correlates of psychoactive substance use suggested by literature . The models included clinic-level random effects to account for correlation within the clinics.Table 1 summarizes the characteristics of the study population. Among the 2448 participants, the majority were men. The average age was 40.6 years, with about half of the participants being between the ages of 36 to 45. More than half of the participants were married or living with a regular partner at the time of the study. Approximately one third had a high school or above education. The average monthly income was 2070.0 yuan , and 763 of the participants had no income during the previous 30 days. At the time of the study,greenhouse grow table the average duration of heroin use was 14.9 years and the average duration of MMT was 3.6 years. The average daily methadone dose was 54.0 ml. Half of the participants have used alcohol in their lifetime, and 14.2% self-reported heroin use in the previous 30 days. About one tenth of the participants had friend who used drugs other than heroin and alcohol. Among the 2448 participants, 158 have used psychoactive substance use during the past 30 days, and 933 did so in lifetime. Among the 158 lifetime users, 148 reported using psychoactive substance during the past 30 days. Table 2 presents the types of psychoactive substance used in the last 30 days and in lifetime. Sedative/hypnotic/ antidiarrheal agent was the most commonly used psychoactive substance , followed by amphetamine and hallucinogens . The frequency distribution of psychoactive substance use and its cross tabulation with background characteristics are also presented in Table 1. Participants who were 35 years or younger reported more psychoactive substance use in lifetime than older participants . Those who were married or living with a regular partner were less likely to report psychoactive substance use than those who were single, divorced, separated or widowed .

Lifetime psychoactive substance use was found to be the highest among those who had used heroin for 11–20 years .Having psychoactive substances using friends was positively correlated with psychoactive substance use in lifetime and in the past 30 days . Those who had used psychoactive substances in the last 30 days reported significantly higher level of depressive symptoms than those who had not ; this was also true for lifetime users . Table 3 summarizes the results of mixed model for psychoactive substance use in the last 30 days and in lifetime. When all were held constant, heroin use in the past 30 days was the most important factor in association with psychoactive substance use in the past 30 days . Other covariate significantly associated with psychoactive substance use in the last 30 days include younger age , having psychoactive substances using friend , and having higher level of depressive symptoms . Factors associated with lifetime psychoactive substance use included having psychoactive substance using friend , heroin use in the last 30 days , lifetime alcohol use , duration of heroin use , depressive symptoms , and age . The paper reported that a substantial proportion of the MMT clients in China either have initiated or are currently involved in psychoactive substance use. The number indicates a need for increased attention to this issue. As previous studies suggested, after cessation of opioid abuse, MMT clients might seek psychoactive substances as an attempt to achieve alternative rewarding effect . The concomitant use of psychoactive substances may lead to poor MMT adherence and compromise the treatment outcome , so the issue is in an urgent need to be prevented and controlled. The current Chinese national MMT guideline requires MMT clients to receive urine morphine test on both regular and random basis during the maintenance treatment to monitor the use of heroin . However, the guideline did not specify the testing of non-opiate substances, so urine psychoactive substance screening is not consistently performed in MMT clinics . Given the considerable prevalence of psychoactive substance use among MMT clients, urinalysis of psychoactive substances should be incorporated and routinely administered in the MMT clinics, so that psychoactive substance users could be detected and linked to treatment and care. More importantly, behavioral, psychological, and medical interventions are warranted to be integrated into the current MMT to protect the clients from the negative impacts of psychoactive substance use and to maintain the benefits of MMT . The study revealed several factors associated with psychoactive substance use among MMT clients. More psychoactive substance use was found to be associated with younger age, which was consistent with the literature which indicated that psychoactive substances were primarily popular among young people . The study also found a strong correlation between recent heroin use and recent psychoactive substance use, which suggested that client who was detected to use heroin should simultaneously receive psychoactive substance screening and interventions. In this study, high dose of methadone did not show to have a protective effect against psychoactive substance use, which was supported by previous studies . Findings also confirmed that having a psychoactive substances using friend increased the MMT clients’ likelihood of psychoactive substance use . As reported by numerous literatures, social network had an impact on psychoactive substance using behaviors by making drugs more available and emitting environmental cues to trigger craving and withdrawal . In order to reduce psychoactive substance use, intervention effort should aim to supplant the harmful friendship with non-drug-using supportive networks .The interplay between psychoactive substance use and mental illnesses has been documented by numerous studies . In particular, psychoactive substances have direct effect on monoamine regulation within the brain, producing various depressive symptoms including low mood, fatigue, sleeping disorder, appetite changes, irritability, and/or poor concentration . Conversely, depressive symptoms can reduce adherence to addiction treatment and elevate the risk of psychoactive substance use . The finding implies that the MMT services providers should closely monitor the clients’ mental health status to identify early signs of psychoactive substance use, so that interventions can be delivered in a timely manner.

Polling showed that Arizonans were supportive of smoking restrictions

With approximately 40% of Arizonans covered under some sort of clean indoor air ordinance by 2004, many of these tobacco industry-allied organizations saw their opposition efforts as merely delaying the inevitable.Lopez was not able to get HB 2629 a hearing in the House. House Speaker Jake Flake was approached jointly by Rep. Lopez, a former Republican legislator, and her ally Eric Emmert, Republican lobbyist for the East Valley Chamber of Commerce, to negotiate the introduction of the bill. Flake said he did not like the legislation because he said in “libertarian” Arizona “we don’t tell people what to do,”244 but did agree to give the bill a hearing. However when committee assignments came out, he had assigned the bill to four committees – Commerce, Health, Federal Mandates and Property Rights, and Rules – which effectively killed the bill.In Arizona, bills must be heard in committees in the order the committees were assigned. Because Rep. Phil Hansen, the chair of the Commerce Committee refused to hear the bill, Lopez could not move on to subsequent committees. Lopez went back to Speaker Flake requesting that he make good on his promise for a hearing,who claimed that he could not force committee chairs to hold hearings. Lopez then arranged for an informational hearing in the friendlier Health Committee on March 4, 2004, but because there was no vote, no action was taken on HB 2629. Meanwhile, the public was supporting HB 2629 with letters to the editor and emails to legislators, and media articles proliferated during each step of the process. According to a poll conducted by Fairbank, Maulin, Mauslin, and Associates in November 2003, 75% of Arizonans favored a statewide smoke free law totally covering workplaces, restaurants, and bars.This strong polling helped focus Arizona’s tobacco control advocates’ attention toward the goal of a statewide law, cannabis growing tables despite their prior misgivings. Rep. Lopez considered attaching the substance of HB 2629 onto some preexisting Senate bill that was being heard in the Assembly to get a hearing, but had trouble finding an appropriate Senate bill.

Part of the reason for her reticence in working the bill from the Senate side was that Rep. Lopez had made a commitment to her stakeholders that she would maintain the integrity of the bill and kill it immediately if someone amended it with preemption. Attaching it to an existing Senate bill would have entailed relinquishing control over the possible amendments the bill would face, and there existed the real possibility that bars would be exempted in this process. Lopez instead decided that the best course of action was to let the bill die. After the failure of HB 2629 in the Legislature in Spring 2004, AHA, ALA, and ACS joined with Lopez and other stakeholders like ACAS and other local advocates in supporting the idea that the best route to a statewide smoke free law would be a ballot initiative based on HB 2629.In the November 2006 election, Arizona had more ballot measures on its statewide ballot than any other state in the country. Out of those 19 measures, 3 dealt with tobacco. Proposition 201, the Smoke-Free Arizona initiative which emerged from HB 2629 and Arizona’s local smoke free ordinances, sought to make Arizona smoke free indoors with very few exceptions. It was created and backed by the ALA, AHA, ACS, AzHHA, and Campaign for Tobacco-Free Kids with support from Arizona’s tobacco control advocacy groups and a grassroots network of over two-thousand volunteers.Proposition 206, the Arizona Non-Smoker Protection Act, was a competing weak “indoor air” initiative placed on the ballot by RJ Reynolds Tobacco Company to counter Proposition 201 and to preempt local tobacco control ordinances. A third and completely unrelated initiative, Proposition 203, proposed to increase the state tobacco excise tax by 80 cents to create and fund a state-wide program of early childhood care including preschool, medical care, and daycare. The tobacco industry, specifically RJ Reynolds, concentrated on stopping the statewide smoke free policy rather than fighting the tax proposal , even though the proposed 80 cent tax increase would be the largest in Arizona’s history. Proposition 203’s 80 cent tobacco tax increase promised significant effects in terms of decreased tobacco consumption.The committee running Proposition 203 did not consult with Arizona’s tobacco control advocates who were sponsoring Proposition 201 on the allocation of the tobacco tax revenue. Because Proposition 203’s committee used the tobacco tax instrumentally with all funds going to early childhood care, they neglected to even provide backfill payments to the programs using existing cigarette tax revenues to compensate for the lowered revenues resulting from the lower consumption caused by the price increase.

The statewide smoke free initiative Proposition 201 that the health voluntaries mounted in 2006 was grounded in the successes in achieving local tobacco control policy. From Mesa in 1996 to Tucson in 1999 to Tempe in 2002, Prescott in 2003, and Flagstaff in 2005, the local ordinances paved the way for changing smoking norms. The Robert Wood Johnson Foundation Arizona Clearing the Air grant administered by ACS from 2001-2004 fueled the local clean indoor air ordinances by providing technical support to communities interested in clean indoor air. Proposition 303 passed by two-thirds of Arizonans, secured TEPP for the future and doubled Arizona’s tobacco excise tax, strengthening tobacco control in Arizona and bringing the public health issue of smoking again into the public eye. In late 2003, when Rep. Lopez broke the ice for Arizonans to seriously discuss a genuine statewide clean indoor air act, the health voluntaries began shifting their focus away from passing local initiatives to lay the groundwork for the statewide initiative. The advocate-driven local smoke free efforts in Arizona, as in most states, formed the bulwark of the tobacco control policy movement up until the statewide clean air initiative began gaining media attention in mid-2006, when local efforts were put on hold until the state initiative was decided. The news of the 201 and 206 statewide anti-smoking propositions both encouraged some communities, like the towns of Sedona and Marana, to pass their own smoke free ordinances, and discouraged others, such as Gilbert, from taking additional measures to reduce secondhand smoke. Gilbert delayed instituting smoke free public parks in 2006 because the local government wanted to wait and observe the result of the statewide smoke free propositions rather than waste time creating an ordinance if state law would later preempt it.A December 2002 poll by the Arizona Republic showed 36% of those polled wanted a statewide clean indoor air law, 7% preferred a county-level ordinance, and 22% opted for a city-level smoke free ordinance covering all indoor air locations.In total, 65% wanted a clean indoor air act at some level of government.The poll commissioned by the AzHHA and conducted by the national opinion research firm Fairbank, Maslin, Maullin & Associates in November 2003 showed 75% of Arizona voters supported a proposed state law that would prohibit smoking in all enclosed indoor workplaces in Arizona.

While the committee’s original clean indoor air act plan in 2005 was to craft a law that restricted smoking in all public places and workplaces , they ended up granting a few exemptions that other states allowed, such as a limited number of hotel rooms, retail tobacco shops,commercial grow table private residences unless used for child care, adult care or health care facility, and theatrical performances . The question of whether or not to include clean indoor air for private fraternal clubs was largely politically determined. Veterans and fraternal clubs were exempted from smoke free requirements because the Smoke-Free Arizona campaign was not willing to risk opposition from this politically powerful constituency.One innovation Smoke-Free Arizona included in the initiative language was including a 2 cent tobacco excise tax increase to fund implementation and enforcement of the law. Under Smoke-Free Arizona’s scheme, the 2 cent tax provided ADHS funding for their enforcement responsibilities. This money could then be used to provide funding for local enforcement, as ADHS delegated inspection and enforcement to County Health Departments. The origin of the tax came from a stakeholders’ meeting early on in the campaign with the ADHS regarding the statewide clean indoor air act. “Everybody from the Department of Health down to the counties all said that ‘if we’re going to be the ones doing the enforcement for the initiative, we’re going to need money,’” according to Sharlene Bozack, Steering Committee member and ACS’s Government RelationsVP.No one wanted the police to handle smoke free enforcement, as happened in Tempe, because the ordinance had not specified who would be responsible for enforcement. Tempe’s ordinance received criticism in local newspapers that forcing the police to enforce smoking violations prevented police from addressing more serious crimes. Tempe also had weak enforcement for the first five months of its clean indoor air ordinance because police were only responding to called-in complaints rather than performing inspections.Learning from Tempe’s experience, while avoiding potential barriers to enforcement like having to ask the Legislature for funding for enforcement, Smoke-Free Arizona’s language used ADHS to enforce the law and created available revenue to fund inspections with the tax provision.

The Proposition 201 campaign encountered opposition from the Chandler, Mesa, and Prescott Chambers of Commerce, but won the support of Tempe’s Chamber of Commerce, the Southwest Valley Chamber of Commerce in Maricopa County, and the Chinese Chamber of Commerce . In the initial 2002 City of Tempe initiative, the Tempe Chamber of Commerce opposed the smoke free ordinance initiative. For Arizona’s tobacco control advocates, this shift signaled that the Tempe smoke free model indeed had been a success. With the exception of Prescott, the chambers of commerce supporting Proposition 206 already had weak smoking ordinances in place similar to the restrictions on workplaces and restaurants Proposition 206 offered . The Tucson Chamber of Commerce which supported Proposition 206, had received yearly Tobacco Institute contributions in the 1990’s. The Arizona State Chamber of Commerce took no position on either of the smoking-related measures. Governor Janet Napolitano also endorsed Proposition 201, but waited until late October, right before the election, to do so. The Governor was a member of the Board of the American Legacy Foundation, a national foundation for tobacco control efforts. Despite the political caution Napolitano displayed as she was running for reelection in November 2006, the Proposition 201 campaign staff expected Gov. Napolitano to announce her support earlier than she did, as her polling numbers were high. In the press release announcing her support for Proposition 201, Gov. Napolitano also urged a “no” vote on Proposition 206, a key message in the Proposition 201 campaign, saying “As Attorney General, I witnessed firsthand the tactics of the tobacco industry…. Arizonans need to understand that Proposition 206 is funded by RJ Reynolds and is an attempt to protect its tobacco profits.”The Proposition 201 campaign gained the last-minute public support of the Arizona Restaurant and Hospitality Association . While the media coverage accompanying this shift in the ARHA’s tobacco control policy stance did not do justice to its full significance, the endorsement of Proposition 201 was printed in the ARHA’s trade newsletter on October 3, 2006, and the Arizona Republic did write a short article mentioning the endorsement.The Arizona Restaurant and Hospitality Association , previous recipient of Tobacco Institute contributions,opposed Rep. Lopez’s HB 2629 in 2004. ARHA President and CEO Steve Chucri testified against the bill at the Health Committee hearing.Nevertheless, Pfeifer reported that a “cultivated” “personal relationship” between Smoke-Free Arizona and the ARHA was subsequently developed resulting from Chucri’s former employment by Kevin DeMenna , enabling Michelle Pabis and Chucri to develop rapport around smoke free issues.Smoke-Free Arizona engaged in dialogue with ARHA and listened to their concerns while drafting the language for the Smoke-Free Arizona Act. According to a 2006 interview with Pfeifer, “Early on when we were directing the language they [the ARHA] said, ‘is there anyway you can pass the law in November but maybe delay implementation in restaurants or bars, give them two years to get ready?’ And we didn’t. But what we did agree was to give them three more months as we were initially to write the law to go into effect on February 1. So we changed it to May 1.”While Pfeifer did not mention Chucri’s involvement in Smoke-Free Arizona’s decision to exempt outdoor patios in their smoke free law, Chucri has said he supports permitting smoking on patios.

Mesa citizens voted 69% to 31% to preserve their smoke free ordinance

While who gets the funds to implement media campaigns and outreach is unimportant, the fact of increased Native American tobacco use prevalence indicates that TEPP must use a different strategy. Another issue reservations encountered was the fact that cigarettes cost $1.00 less in tax per pack in 2007 than they cost off-reservation because three out of Arizona’s five tobacco tax increases do not apply on the reservations. The other two tobacco taxes apply because their ballot language included reservations in the tax scheme, while the other three tobacco taxes neglected to include the necessary additional language which would include reservations. While only tribal members were supposed to be able to purchase the reduced tax cigarettes, some Arizona non-native smokers go to reservations to buy reduced-tax cigarettes. There is no concrete data substantiating claims that more than a negligible number of Arizonan smokers buy the reduced-tax cigarettes from reservations, although various billboards around the state advertised cheap cigarettes on reservations. The revenue-generating sale of tobacco for the tribes makes it more difficult for Native American tribes to pass smoke free laws and tobacco tax increases.When the 1994 initiative Proposition 200 coalition was created and the Arizona Hospital and Healthcare Association backed it with significant financial support, the tobacco industry threatened to retaliate against the hospitals. The tobacco industry threatened that if the hospitals backed Proposition 200, the industry would bring to ballot a proposition to regulate the hospitals as utilities.In response, AzHHA president John Rivers initiated Project Rolling Thunder, a plan to pass comprehensive clean indoor air acts locally,outdoor grow table as a way to force the tobacco companies to fight local clean indoor air ordinances in every Arizona city of 10,000 inhabitants or more rather than pursuing regulation of hospitals.

Rivers was never forced to use this tactic because the tobacco industry threat against the hospitals turned out to be a bluff. However, tobacco control groups started working towards the very aim Rivers had devised, although their clean indoor air laws passed one-at-a-time rather than simultaneously. Despite the fact that Rivers initially kept close to the vest the threat leveled by the tobacco industry and Project Rolling Thunder’s smoke free cities strategy, the tobacco industry’s general challenge to Proposition 200 served to galvanize Arizona tobacco control advocates to achieve city-by-city clean indoor air ordinances in a manner Arizona never previously encountered. The local ordinance battles were some of the toughest the tobacco control community in Arizona encountered; even after a local smoke free ordinance passed, tobacco industry front groups would often attempt to amend or repeal voter-approved measures, occasionally for years. Lawsuits and campaigns for exemptions were also frequent, alleging negative economic impact would or did ensue following the passage of clean indoor air ordinances. Arizonans Concerned About Smoking , the grassroots organization founded in 1966 by Betty Carnes, and one of the first nonsmokers’ rights groups in the United States,led the charge in passing most of Arizona’s local smoke free ordinances. The sustained funding of $45,000 a year ACAS receives from an endowment set up by Carnes enabled ACAS to play a major role as an independent organization in achieving Arizona’s tobacco control victories. Led by Dr. Leland Fairbanks and Dr. Donald Morris, ACAS’s single-issue focus on tobacco control made ACAS more dedicated, and often more effective than the national voluntary health associations. By far the most progressive tobacco control organization in Arizona, ACAS often times forged ahead in successfully furthering tobacco control efforts despite the health voluntaries rather than because of them.

The cities discussed below had noticeable effects on tobacco control in Arizona, either because they achieved strong smoke free ordinances, or because the political brouhaha surrounding the passage furthered the course of tobacco control in Arizona by providing public debate leading to denormalizing tobacco. These local ordinances also laid the foundation for the successful effort, through Proposition 201 in 2006, to pass a strong statewide clean indoor air act.The City of Mesa in 1996 enacted by voter initiative the first significant clean indoor air act in Arizona, approved with 55% support.The ballot initiative mounted by Mesa for Clean Air on March 26, 1996, covered indoor areas including all bars, restaurants, pool halls, and hotels.The Mesa Smoking Control Ordinance took effect July 1, 1996, with a hardship exemption for bars making more than 50% of their sales from alcohol that allowed for a separately ventilated smoking area. Before the law even became effective, it was challenged. While the Tobacco Institute funded “no” campaign was unsuccessful in preventing the Mesa Clean Air ordinance from passing, another tobacco industry challenge to the ordinance appeared in October 1996 when the National Smokers Alliance created an organization called Citizens to Repeal Proposition 200 . Led by former Mesa mayoral candidate Kat Gallant, Citizens to Repeal Proposition 200 gathered signatures for the purpose of forcing a special election to recall the ordinance. Citizens to Repeal Proposition 200 claimed large losses to business and sought the tobacco industry’s policy of “accommodation”30 of smokers and nonsmoker rather than laws requiring smoke free environments. Even though the City of Mesa had already granted exemptions to all 13 restaurants that applied for exemptions under the hardship clause in the law, which allowed that restaurants proving more than 15% reduction in sales over four months could apply for a partial and temporary exemption, the opponents wanted to stop the impending inclusion of restaurant bars.

In response to this threat mobilized by the National Smokers Alliance to force a special election which would have cost the City of Mesa an estimated $100,000, the Mesa City Council weakened the ordinance between July and December 1996 to exempt bars that made more than 50% of their sales from alcohol, rented hotel meeting rooms, banquet rooms, and the outdoor areas of restaurants . Despite the facts that the public had passed the original ordinance and the Council weakened the ordinance, the National Smokers’ Alliance still forced a public vote on the weakened version of the ordinance in March 1998.The Mesa ordinance as it stood in 1998 ended smoking in workplaces, restaurants, and restaurant-bars, and allowed smoking in bars that derive over 50% of their revenue from the sale of alcohol. Mesa’s law, in effect since 1996, inspired many subsequent local clean indoor laws,plant grow table and until Tempe passed its law in 2002, was the strongest smoke free policy in Arizona.In 1985, Tucson had been the first city in Arizona to make workplaces smoke free, although it exempted restaurants and bars. Nonsmokers, Inc., the Tucson group headed by Arizona tobacco control advocate Karen Zielaski that helped win Tucson’s ordinance, and a long-term tobacco control advocacy force in Tucson, dissolved in December 1997.A new group, Tucson Clearing the Air, formed a year later, including many former members of Nonsmokers Inc., to work in the new tobacco control environment in Arizona. Clearing the Air came together primarily through physicians from Tucson including Keith Kaback and Joel Meister, who served leadership roles. Tucson Clearing the Air guided a smoke free workplaces and restaurants ordinance through the Tucson City Council in 1999 and the Pima County Board of Supervisors in 2001. In 1999 Tucson Clearing the Air lead the movement to get the Tucson City Council to pass 4-3 a smoke free ordinance that made all restaurants smoke free. The ordinance, passed in April, went into effect October 1, 1999. By working with the City Council, the group avoided the expense of a ballot campaign. Tucson Clearing the Air did not encounter opposition, though after the council passed the ordinance the Arizona Restaurant and Hospitality Association sought exemptions to extend the hardship clause by a year, instead of the three months given to businesses. Tucson’s ordinance gave restaurants until January 2000 to file for hardship exemptions if they could show with tax receipts that they had sustained a two consecutive months of 15% or greater loss of business compared to the previous year. Few exemptions were granted. The six-month delay sought to give Pima County the opportunity to pass a similar smoke free law bringing the clean indoor air ordinance region-wide. Pima County, however, would not pass an ordinance until 2001. Due in large part to Arizonans Clearing the Air , Pima County adopted a clean air ordinance including restaurants but not bars on October 9, 2001. The ordinance had come before the Pima County Board of Supervisors twice before in the previous two years, as Tucson tobacco control advocates urged Pima County to follow Tucson’s lead. Arizonans Clearing the Air lobbied the Pima County commissioners, and banking on the success of this same measure two years prior in Tucson, Pima County’s largest city, the Supervisors voted 4-1 for smoke free restaurants and workplaces. This ordinance covered unincorporated areas in Pima County, including workplaces and more than 400 restaurants.

Philip Morris consultants exchanged many emails as Pima County’s clean air ordinance was being considered, in which they discussed mounting a signature gathering campaign costing $80,000 to $100,000 to place the Pima County smoke free ordinance on the next year’s ballot.An email sent weeks before the ordinance passed from Philip Morris lobbyist John Mangum to tobacco industry lobbyists and consultants Jack Dillard, Rip Wilson, and Trisha Hart describes how “we have been successful in delaying the proposal for the last 6 months,” even though Mangum did not “think [they] are succeeding in defeating it, despite yeoman efforts on the ground and substantial support and $$$ from PM and the other companies.”Mangum explained the significance of the Pima County effort in a September 19, 2001 email: “Pima County has about 15% of the states [sic] population, with only 4 or 5 cities. If the ban effort is successful here I anticipate the battleground will immediately move to Maricopa County [which includes Phoenix] where 70 to 75 percent of the population resides. We already are under attack in 7 or 8 of the 19 incorporated cities in Maricopa County.”The tobacco industry opposition to the Pima County clean indoor air ordinance largely resulted from this fear: “If we lose Pima County the pressure on local government in the Phoenix area will be enormous.” Although the Pima County smoke free ordinance was viewed as only a moderate gain by tobacco control advocates as it exempted bars, Philip Morris Arizona representative Jack Dillard viewed Pima County as the tipping point for smoke free ordinances in Arizona prior to its passing, and suggested a statewide preemptive ballot initiative rather than attempting to gather 19,000 valid signatures in Pima County to force a vote on the ordinance.Dillard acknowledged the tobacco industry’s defeat: “All we have to offer the public as an alternative to the new [Pima County] ordinance is a continuation of smoke filled hospitality venues.” The success of the Pima County ordinance led the incorporated town of Oro Valley to adopt a similar ordinance later the same year, in November, 2001. A Robert Wood Johnson Foundation Smokeless States Initiative grant from 2001 to 2004 helped Arizona to raise the standard for clean indoor air laws and continue denormalizing tobacco use. The more than $900,000 grant over three years funded the creation of the Arizona Clearing the Air coalition managed by ACS with Andrew Ortiz as the director of the program. This grant required the ACS, AHA, and ALA to provide matching funds, which went to fund the campaign-related expenditures, as the RWJF grant could not be used for direct political lobbying. The voluntary health organizations, along with Andrew Ortiz, coordinated Arizona Clearing the Air, which played a similar role that the RWJF-funded Coalition for Tobacco-Free Arizona had provided in the early 1990s. ACTA participated in passing 11 of the 17 local clean indoor air ordinances in place in Arizona by the end of 2004, providing strategic support and expertise to every local campaign during this period. Part of ACTA’s role involved developing a media campaign through the Riester advertising firm to educate communities on the value of clean indoor air ordinances. Despite ACTA’s organization and technical support on the local level, these local smoke free ordinances were, of course, dependant upon the political will of local city councils and the support of local tobacco control advocates. This meant that in a city like Phoenix, where the City Council was not receptive to considering a clean indoor air ordinance, ACTA’s hands were tied.

Tobacco related disease research in Arizona has not been publically funded since 2000

This appropriation added to an already levied $500,000 a year transfer from the Health Research Account through FY2013. Proposition 303 payed for this $5.5 million per year appropriation from the Health Research Account by allocating five percent of the 60 cent tobacco tax increase to the Health Research Account, effectively more than offsetting the fund transfer. Yet, while the Legislature got their appropriation money either way, standing to gain even more if Prop. 303 passed , had Proposition 303 lost, the $5 million-a-year appropriation would have come from the Health Education Account that funds TEPP instead of from the Health Research Account. The text of Chapter 320 of HB 2711 read: “if a Tobacco Tax referendum submitted to the voters on November 5, 2002passes, the appropriations to the DCRC [Disease Control Research Commission, now ABRC] for allocation to a biotechnology non-profit foundation [TGen] will come from the Health Research Fund instead of the Health Education Account”as per the original allocation . Filing with the Arizona Secretary of State on June 13, 2002, John Rivers, CEO of the AzHHA, chaired the campaign organization to pass Proposition 303, termed “Arizona for Healthy Futures.” The campaign used the same name as the campaign to pass Proposition 200 that created TEPP, as it again joined the AzHHA with the AHA, ALA, and ACS. Bill Pfeifer, CEO of the ALA Southwest Division served as treasurer for the campaign. Formal ballot arguments supporting Proposition 303 appeared from Governor Hull, former U.S. Surgeon General C. Everett Koop, former Arizona Attorney General Grant Woods,cannabis grow tables and a long list of health professionals. Governor Hull’s statement in the ballot information packet said, “Without these additional tobacco tax dollars, the State will be forced to use additional General Fund revenues, necessitating reductions in or elimination of other services or programs.”

Proposition 303 had almost universal support and attracted support from pro-business interests, including the Tucson Metropolitan Chamber of Commerce, which had opposed the tobacco tax increase in 1994.21, 107 While the tobacco companies did not actively oppose Proposition 303 once it was placed on the ballot, groups allied with the tobacco industry, including the Cato Institute and the Arizona Tax Research Association wrote opinion editorials warning that a tobacco tax increase would bring cigarette smuggling and that forcing smokers to pay for others’ healthcare constituted an unfair burden.According to RJ Reynolds spokesperson David Howard , RJ Reynolds planned “nothing proactive,” explaining that opposing Proposition 303 was “just not the best use of [RJ Reynolds’] resources” at the time.Not a single argument “against” Proposition 303 was filed with the Secretary of State for the ballot information pamphlet.The health voluntaries’ fundraising strategy to campaign for Proposition 303 focused on donors that had an interest in protecting the TEPP monies because they had been contractors for TEPP in the past. In a 2006 interview, Madonna noted that the Coalition “looked at where was the TEPP advertising dollar being spent… [we] got $100,000 from the Suns and Diamondbacks,” teams that for years had received TEPP advertising contracts and understood that in contributing to the Coalition’s campaign, they were investing in their own future contracts with TEPP .Additionally, because of the popular and political support for the measure, Viacom and other media companies donated billboards and air play . The Health Research Account to fund tobacco disease-related research was created in 1994 by Proposition 200 which allocated 5% of the 40 cent cigarette pack tax increase revenues for “research on preventing and treating tobacco-related diseases and addiction” through grants to Arizona researchers.In 1995, the Legislature designated the Arizona Biomedical Research Commission * to administer the Health Research Account. The Legislature created the ABRC in 1984 to fund and solicit biomedical research proposals to “protect the public health and safety by funding research into the causes, treatments, and cures of disease,” with no reference to tobacco.ABRC grants have typically lasted three years and serve as a bridge for junior researchers to apply and be awarded federal research grants.The ABRC is an independent commission of nine governor-appointed and Senate confirmed members representing the general public, medical, and scientific research communities .

Until 1997 the ABRC was funded from the General Fund through the interest and penalties paid on delinquent income taxes and occasionally also received money from the state lottery funds.By FY1997, however, tobacco tax revenue represented 100% of the funds the Commission administered for new contracts.During the implementation of Proposition 200 by the Legislature, Representative Carol Springer took advantage of the Health Research Account funding to phase-out General Fund spending on the ABRC.HB 2108, created for this purpose, established a separate account for the ABRC for its regular contracts, explicitly barring the ABRC from using the Health Research Account funds for the ABRC’s previous category of research.By FY1996 only continuing non-tobacco related contracts from previous years received general fund money, and by FY1997 the only funds the ABRC had at its disposal were earmarked for tobacco-related research from the Health Research Account.Thus, Proposition 200 revived the ABRC by giving it a new mission and transformed its task from supporting biomedical research in general to managing the Health Research Account grants for tobacco-related disease research.The ABRC did not welcome the Health Research Account’s statutory requirement that all grants given from its funds be tobacco disease-related. The ABRC’s Executive Director Dawn Schroeder and Deputy Director James Matthews saw assigning the ABRC responsibility for administering the Health Research Account as a malicious act by Senate Appropriations Chair Carol Springer.In a 2007 interview Matthews said, “It was a personal thing, she didn’t like the Commission. Her mission in life was to get rid of the Commission. So along comes the first of those tobacco tax initiatives, and she says ‘so you can take money from the initiative, but you can only spend it on tobacco.’ She didn’t want to spend state generated general funds for the Commission. She said, ‘if you can collect it from tobacco, fine.’”The Commission viewed the Health Research Account as a burden rather than an opportunity. The tobacco-related “constraint” for funding research was cited as one of the major impediments facing the ABRC in an 1998 Auditor General Report Sunset Review of the ABRC.The Report, commissioned by the Joint Legislative Budget Committee in a standard decennial automatic agency review, concurred with ABRC executive staff’s perceptions that because the “Commission’s statutory mission is not limited to supporting tobacco-related research,”commercial grow tables the “Commission and its researchers have been heavily impacted by its switch from general medical research to a more narrow focus on tobacco-related issues.” [emphasis added]As a consequence, the ABRC begrudgingly restricted its requests for proposals between FY1997 and FY2001 to tobacco-related research.

The Commission did not engage in any outreach to identify promising young investigators who could be interested in tobacco and – probably as a result – felt that the proposals decreased in quality because fewer of their grantees had moved on to federal grants than when the Commission offered unrestricted RFPs.In February 1999, when Arizona first began debating where MSA money would be allocated, the ABRC attempted to secure funding for unrestricted research through the Legislature. SB 1095 and HB 2490 , Lou-Ann Preble , and Herschella Horton would have continuously appropriated $2 million a year from the MSA payments for supporting unrestricted projects.The ABRC pushed both bills in hopes of obtaining funds to fulfill its original charter without modifying or attenuating the Health Research Account’s tobacco specific RFPs. SB 1095 addressed the ABRC’s concerns that the “transition to tobacco tax revenues has restricted the type of research the Commission may support” and cited the “Auditor General performance audit [which] contained a finding that researchers and the Commission have been heavily impacted by the funding shift.”Because these attempts to create a new unrestricted funding source failed, as did an effort in 2000 to provide the ABRC unrestricted funding from the sale of special license plates,ABRC gave up looking for new sources of funding and began exploring how they could relax the restriction that Proposition 200 funds be limited to tobacco-related research.The 2001 aim of ABRC commission members and executive staff was to shift the organization’s focus to translational research, defined as taking research from the lab and “translating” it into consumer products, particularly drugs. TGen, created in 2002, was seen as a good mechanism to accomplish this goal. The ABRC took a positive view of HB 2711 to shift $5 million per year for 5 years to TGen by transferring money from the Health Research Account, seeing it as a strategic partnership with TGen.While this $5 million a year transferred from the Health Research Fund to TGen was poised to sunset FY2007, clamors for an extension of this appropriation from the business community as well as ABRC’s own interest in keeping TGen afloat resulted in ABRC committing continued funding from the Heath Research Account to TGen, $5 million a year for an additional five years.A December 14, 2006 Arizona Republic editorial entitled “A quick ROI [Return on Investment] for Arizona” espoused preserving the tobacco tax Health Research Fund $5 million-a-year appropriation to TGen because despite it being “a relatively small share of TGen’s budget, it is crucial base support. …In order to keep the momentum going, Arizona needs to continue supporting TGen.”When ABRC’s funding of TGen expired June 30, 2007, ABRC unilaterally extended its funding through FY2012.ABRC continued to spend on TGen the money originally intended for tobacco related research. While the restriction that the Health Research Account funds had to go to tobacco-related research had already been lifted, the little remaining funds that did go to tobacco-disease related proposals diminished as the Health Research Account received additional diversions. Further erosion of funds available for tobacco research from the Health Research Account occurred in 2002 when the Legislature passed SB 1270, which took $500,000 a year for 10 years from the Health Research Account for TGen, provided that TGen contribute matching funds from private donors.The health voluntary organizations and tobacco control advocates at the time and subsequently largely ignored the Legislative diversions – and the ABRC’s – that completely stripped the Health Research Account of its original purpose. As of 2006, the ABRC typically received around 140 proposals requesting funding a year, with on average only 10 of these proposals per year specifically addressing tobacco.51 proposals were actually funded in 2006, with only four directly relating to tobacco receiving funding.Unless legislation or vigorous advocacy alters its course, the Health Research Account has lost its raison d’être of funding quality tobacco-related research. While tobacco control advocates could not reenact the Health Research Account under Proposition, the additional funding the ABRC received from Proposition 303 could have been specified for tobacco control research. Tobacco disease related research is an important element of tobacco control that Arizona’s advocates and government need to address by taking advantage of opportunities to either voter-protect the Health Research Account or create a new and secure funding source for tobacco related research.The Arizona Department of Health Services Tobacco Education and Prevention Program , created after Proposition 200 passed in 1994, is the organization that coordinates Arizona’s tobacco education, prevention, and cessation campaigns. TEPP’s history is best viewed in four periods, each influencing programming differently. From FY1995-FY1997 TEPP had restricted programming but rapid development; from FY1998-FY2001 TEPP developed a robust tobacco control program; from FY2002- FY2003 TEPP experienced program breakdown, with a weak media component, and; from FY2004-FY2007 TEPP, propelled by an emerging smoke free state climate, modernized its program to keep up with Arizona’s increasingly smoke free norms. As noted in our previous report, TEPP suffered initial setbacks that constrained the areas of tobacco control it could address.In 1995, ADHS Director Jack Dillenberg limited TEPP’s target programming population to pre-adolescents, adolescents, and pregnant women and their partners.This program maticlimitation went against the consensus that comprehensive tobacco prevention media programming is most effective when it targets a broad audience, exposes the tobacco industry, highlights the dangers of addiction, and relates the harms of secondhand smoke.This restriction slowed down TEPP’s programmatic development in secondhand smoke, prevention for older adolescents and young adults, disparate populations, cessation, youth access, and smokeless tobacco.

How To Do Vertical Farming

Vertical farming is an innovative agricultural practice that involves growing crops in vertically stacked layers or structures, typically indoors or in controlled environments. It offers advantages like higher crop yields, reduced water usage,4×4 grow table and the ability to grow food in urban areas with limited space. Here’s a step-by-step guide on how to do vertical farming:

  1. Research and Planning: Understand the basics of vertical farming, including the different types of systems (hydroponics, aeroponics, aquaponics, etc.), required resources, and the types of crops you want to grow. Conduct thorough research to ensure you have a solid understanding of the technology and techniques involved.
  2. Choose a Location: Select an appropriate space for your vertical farm. It could be an empty warehouse, shipping container, or a purpose-built structure. Ensure the location has access to essential utilities like electricity, water, and climate control.
  3. Design and Infrastructure: Develop a layout and design for your vertical farm. Consider factors like the arrangement of growing shelves, lighting systems, irrigation, ventilation, and control systems. The goal is to optimize space utilization and create a conducive environment for plant growth.
  4. Lighting: Since vertical farms often lack natural sunlight, you’ll need to invest in high-quality artificial lighting systems. LED grow lights are commonly used because they can be customized to provide the specific light spectrum needed for plant growth.
  5. Climate Control: Maintain precise temperature, humidity, and CO2 levels in the growing environment. Use heating, ventilation, and air conditioning (HVAC) systems, as well as dehumidifiers, to create the ideal conditions for your crops.
  6. Growing Medium and Nutrient Delivery: Depending on your chosen system (hydroponics, aeroponics, etc.), select an appropriate growing medium (such as coco coir, rockwool, or perlite). Nutrients should be delivered through a nutrient solution in hydroponic systems or misted in aeroponic systems.
  7. Irrigation and Water Management: Implement an efficient irrigation system that ensures each plant receives the right amount of water and nutrients. Recycling and reusing water can help conserve resources.
  8. Crop Selection: Choose crops that are well-suited for vertical farming and have a high yield potential. Leafy greens, herbs, microgreens, and certain fruits are commonly grown in vertical farms due to their short growth cycles and space-efficient nature.
  9. Planting and Maintenance: Plant your chosen crops in the growing medium and monitor them closely. Regularly check for pests, diseases, and nutrient imbalances. Prune and harvest as needed to promote healthy growth.
  10. Data Monitoring and Automation: Implement sensors and monitoring systems to track environmental parameters like temperature, humidity, and pH levels. Automation can help maintain optimal conditions and reduce the need for manual intervention.
  11. Harvesting and Post-Harvest Handling: Harvest your crops when they reach the desired maturity. Handle harvested produce carefully to minimize damage. Proper packaging, storage, 4×8 grow table and transportation are crucial to maintain freshness.
  12. Continuous Learning and Improvement: Vertical farming is a dynamic field, so stay updated with the latest developments, techniques, and technologies. Continuously assess your system’s performance and make improvements based on your observations and data analysis.

Remember that vertical farming requires an investment of time, effort, and resources upfront. It’s important to have a clear plan and a willingness to adapt and learn as you go along.

Tobacco companies are often a significant client of the lobbyist

As a further indication that regulations are effective in reducing pesticide levels in household environments, we found no significant change in carpet dust concentrations of carbaryl, cypermethrin or permethrin, which were still approved for residential use at the time of our study. Results from repeated samples collected from a subset of 15 residences further support our findings that concentrations of chlordane, diazinon and propoxur in carpet dust decreased over time. Our findings are consistent with previous studies that also reported decreasing levels of chlorpyrifos and diazinon after the residential phase-out of these insecticides. A study of 15 farm worker homes in Salinas, California found that chlorpyrifos and diazinon concentrations in dust collected in 2006 were 40–80% lower than dust concentrations from 197 farm worker homes in Salinas collected 2000 – 2002.28 A study of 50 homes in North Carolina that collected air, dust, soil, hand wipes, urine and diet samples once per year from 2003 – 2005 found that estimated doses of chlorpyrifos and diazinon from these media decreased for children over time.Concentrations of chlorpyrifos and diazinon in maternal air samples and chlorpyrifos levels in cord blood decreased between 1999 and 2002 in New York City.In the same cohort, biomarkers of prenatal chlorpyrifos exposure showed significant decreases in detection frequencies for subjects enrolled in 2003 – 2004 compared to those enrolled in 2001 – 2002.Average urinary metabolite levels of chlorpyrifos and diazinon decreased approximately 50% in the United States National Health and Nutrition Examination Survey between 1988 – 1994 and 2003 – 2004.Taken together, modular cannabis grow racks these studies provide strong evidence that regulatory changes in residential use of chlorpyrifos and diazinon as a result of the Food Quality Protection Act resulted in decreased indoor environmental levels and decreased human exposure.

Concentrations of propoxur also decreased in maternal personal air samples and cord blood samples collected from 1999 – 2002 in New York City.Decreases in environmental and biological levels of propoxur may have been related to changes in the formulation of propoxur products during this time from ready-to-use sprays to pet collars that release less insecticide into the environment.We also found that levels of chlordane, DDT, chlorpyrifos and propoxur were higher in older residences, and that DDT and chlordane were higher in the San Francisco Bay Area, where development occurred earlier than other areas of Northern and Central California and historical indoor residential use of these compounds was more likely. A previous U.S. study observed higher DDT dust concentrations in homes built before 1940 and higher chlordane dust concentrations in residences built from 1940 – 1959 compared to homes built more recently.Levels of lead, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons are also higher in dust from older NCCLS homes compared to newer homes, suggesting that people living in older homes are exposed to higher levels of multiple persistent chemicals.In an earlier analysis of a subset of 89 of the study homes that were located near agricultural fields, we found that agricultural pesticide use near residences was a significant determinant of pesticide concentrations in carpet dust, including chlorpyrifos and four other pesticides not analyzed in this study, but not diazinon or carbaryl.However, in the current study of 434 homes, we found a significant correlation between carpet dust concentrations and agricultural use near the residence during the 12 months prior to sample collection for three of five of the study insecticides currently used in agriculture: chlorpyrifos, diazinon and carbaryl. Chlorpyrifos and diazinon are still used widely in agriculture,especially in the Central Valley of California.We observed levels of these two pesticides in carpet dust of residences in this region to be two to three times higher than in residences located in the urban San Francisco Bay Area . In APS homes located near agricultural land in the Central Valley county of Fresno, we did not observe a within-home decrease in chlorpyrifos concentrations in repeat dust samples collected over time . This may indicate that agricultural use of chlorpyrifos near APS homes, which remained fairly constant during our study period, may have obscured the effect of regulatory changes in residential chlorpyrifos use. Previous studies have observed higher chlorpyrifos concentrations in carpet dust of residences with nearby agricultural use and agricultural workers living in the home.

The significant temporal decline in carbaryl concentrations observed in repeated samples from APS homes , but not in the first sample collected from all 434 homes , may have been the result of declining agricultural use near APS homes in Fresno County from 64,589 pounds in 2002 to 15,813 pounds in 2005.In our study, permethrin concentrations in carpet dust were almost two orders of magnitude higher than the other insecticides and were relatively stable over time. Synthetic pyrethroids such as permethrin were designed to be photo stable, have a low vapor pressure and persist on surfaces for crop protection purposes.High dust concentrations of permethrin in residences are likely related to the low vapor pressure of permethrin  and increasing use of permethrin for treating insects in and around homes. In previous studies, permethrin concentrations in house dust were also at least an order of magnitude higher than other insecticides in agricultural Salinas, California,in North Carolina,and in low-income homes in Boston, Massachusetts.Detection frequencies of permethrin in personal air samples among pregnant women in New York City increased significantly from 2000 to 2006.A study of 90 families in Northern California found higher pyrethroid metabolite levels and lower chlorpyrifos metabolite levels in urine samples collected in 2007–2009 than the general U.S. population in 2001–2002.In NHANES, the geometric mean urinary concentration of 3-phenoxybenzoic acid, a metabolite of cypermethrin and permethrin, increased from 0.32 µg/g-Creatinine in 2001 – 2002 to 0.43 µg/g-Creatinine in 2007 – 2008.Further studies of exposure to pyrethroid insecticides from residential use and potential health effects are warranted given the high concentrations observed in carpet dust samples in this study and increasing urinary metabolite concentrations observed in other studies.Our study has several limitations. We only collected one carpet dust sample from most homes. Although pesticide measurements were conducted in the same laboratory and similar questionnaires were used to assess occupational and home insecticide use, we combined data on insecticide concentrations in carpet dust from two studies with different objectives and designs, including the eligibility criteria for APS residences having at least 25% of land within 500 m of the home in agricultural production. We only had information on home insecticide use during the 12 months prior to sample collection and did not ask about product formulation. The California Pesticide Use Report data does not include location information on neighborhood insecticide use for pest control. Our sampling period from 2001 – 2006 likely underestimated the impact of FQPA on residential levels of chlorpyrifos and diazinon after removal of these insecticides from the residential market in 2001 and 2004, due to the long indoor half-life and potential to store these products for long periods of time prior to use.

This study also has several strengths including a large number of carpet dust samples collected over a long period of time from a diverse study population and wide geographic area. We collected repeat house dust samples from a subset of homes and the temporal trends were similar to those observed across all homes in our study for most insecticides. We were able to adjust for potentially important confounders including home, modular green house grow rack occupational and nearby agricultural insecticide use as well as residential and carpet age. Our findings suggest that regulations limiting residential use of OP insecticides resulted in lower concentrations of these compounds in the residential environment, but these declines may be attenuated by contamination of homes due to fugitive emissions from nearby agricultural use and insecticides tracked-in by residents. Our results indicate that the persistence of OC insecticides indoors results in the potential for continued exposure, particularly in older residences. Permethrin concentrations were an order of magnitude higher than other insecticides, warranting further study. Our findings combined with bio-monitoring studies provide strong evidence that the Food Quality Protection Act resulted in decreased indoor environmental levels and human exposure to chlorpyrifos and diazinon. For the 2005-2006 Forty-Seventh Arizona Legislature, tobacco policy scores were obtained for all members. Each member’s score reflects the average of scores assigned by 6 individuals polled who demonstrated knowledge and experience with the Arizona Legislature and tobacco control policy. Each legislator was evaluated on a 0 to 10 scale, with 0 indicating a legislator was extremely pro-tobacco industry and 10 indicating the legislator was extremely pro-tobacco control. Legislators with scores ranging from 0.0 to 3.9 are considered pro-tobacco industry, those with scores from 4.0 to 6.0 are considered neutral or inconsistent, and those with scores from 6.1 to 10.0 are considered pro-tobacco control . The average for policy scores in the House and Senate were the same, but there were large differences between the two parties . Republicans in the Senate had an average tobacco policy score of 4.2 while Democrats had an average tobacco policy score of 9.0. In the Senate Edward Ableser and Ken Cheuvront shared the highest tobacco policy scores of 9.8, while Jack Harper and Robert Burns had the lowest. In the House, Meg Burton Cahill , Martha Garcia , and Linda Lopez , all shared pro-public health tobacco policy scores of 10, while Ted Carpenter , Russell Jones , and Steven Yarbrough had the lowest scores. In regression analysis, the relationship between campaign contributions from 1997 through 2006 and tobacco policy scores for 2004-2006 legislators was not statistically significant. Neither direct contributions from the tobacco industry, tobacco industry lobbying, nor tobacco lobbyist personal campaign contributions to candidates showed statistical significance in relation to tobacco policy scores. These other measures of the tobacco companies’ expenditures to candidates were included in the tobacco policy score analyses because of the low number and small amounts of direct tobacco industry contributions in Arizona.

The tobacco industry hires powerful, well-connected lobbyists in Arizona . Often, the more influential tobacco company lobbyists have other significant non-tobacco clients, sometimes obscuring which client’s interests are represented when these lobbyists make campaign contributions to candidates. The question of potential conflicts of interest also arise when Arizona’s lobbyists for the two largest tobacco companies, John Mangum for Philip Morris and Don Isaacson for R J Reynolds, also represent medical groups, including the Mayo Clinic, and health insurance companies . Arizona tobacco industry lobbyists contributed $52,391 in personal campaign contributions to Arizona candidates from 1997 through 2006, more than three times as much as the tobacco industry did.These contributions to candidates were made personally by lobbyists who represent the tobacco industry among other clients; so no clear link can be made between a particular contribution and the tobacco industry. Confidential retainer agreements from 1997 and 1998 between lobbyist Phillip MacDonnell and R J Reynolds for $50,000 a year plus expenses and Don Isaacson, show that in addition to their salaries, these lobbyists were also permitted the monthly reimbursement of “expenses” in performing “all services and assistance necessary and appropriate to perform effectively” representing tobacco company interests.It cannot completely be ruled out that none of tobacco industry lobbyists’ personal campaign contributions to candidates were given on behalf of a tobacco company client. Money represented in the Appendix does not necessarily reflect all money candidates received from lobbyists because many entries in the Arizona Secretary of State’s database of lobbying expenditures on the behalf of tobacco companies do not show who the expenditure went to or how much was given.These gaps in information decrease the usefulness of the disclosures because the recipient is not always named. Even so, the Arizona Secretary of State records show that lobbyists spent $25,367 on politicians between 1997 and 2006 on the behalf of the tobacco industry .By comparison, the tobacco industry spent $16,201 in direct campaign contributions to candidates during this same period. The tobacco industry has allied with powerful Arizona hospitality and trade associations for many years by becoming dues paying members.The Tobacco Institute paid dues to the Arizona Licensed Beverage Association, the Arizona Restaurant and Hospitality Association, The Arizona Retail Grocers Association, the Arizona Retailers Association, the Tucson Chamber of Commerce, and the Arizona Tax Research Association throughout the 1990s.These organizations generally allied with the tobacco industry for specific issues,usually around elections.