Cannabis Grow

If a participant pressed to collect 20 on a trial meant to be a 240 trial, or tried to collect 20 or 40 on a dedicated 280 trial, the participant received the collected amount, thereby reducing the number of punished trials.fMRI data were analyzed using Analysis of Functional Neuroimages software . Single-subject data preprocessing procedures are outlined in Reske et al. . Multiple regressor analysis and individual linear contrasts were computed in 3dDeconvolve, including six motion regressors as well as baseline and linear drift. Deconvolution was performed to examine the decision contrast and outcome contrast . Voxels were resampled into 4 3 4 3 4-mm3 space, and whole-brain voxel wise normalized percentage signal change, the main dependent measure, was determined by dividing the beta coefficient for each of the predictors of interest by the beta coefficient for the baseline regressor and multiplying by 100. A Gaussian spatial filter blurred percentage signal change values, which were then normalized to Analysis of Functional Neuroimages Talairach coordinates . Individual subject values for risky decisions, safe decisions, risky win outcomes, and risky loss outcomes for each voxel included in a whole-brain mask were extracted for statistical analyses. Individual voxels meeting a p , .01 significance criterion as a result of statistical tests outlined below were evaluated further to determine whether they comprised a significant brain cluster after correction for multiple comparisons. In categorical analyses, for each voxel, a linear mixed effects model was performed in R to identify significant regions of percentage signal change between PSUs and DSUs for decision and outcome analyses separately. Group was the between-subjects variable, and subject was a random variable. Within-subject variables were decision type and outcome type . Cohen’s d was calculated to determine effect sizes. In dimensional analyses, multiple regressions were computed for each brain voxel,cannabis grow equipment with two separate dependent variables: 1) percentage signal change for risky minus safe decisions and 2) percentage signal change for risky wins minus losses. Predictors in each regression were the following: 1) baseline stimulant uses, 2) interim stimulant uses, 3) baseline marijuana uses, and 4) interim marijuana uses.

In extracting significant whole-brain clusters, neuroimaging analysis software has been criticized for underestimating spatial autocorrelation, leading to insufficient multiple com parison corrections. In response to these concerns, 1) the updated 3dFWHMx program was employed to more reliably estimate true autocorrelation and smoothness present following blurring and 2) an updated version of 3dClustSim was run to account for autocorrelation given our voxel/whole-brain mask size, 10,000 Monte Carlo simulations and two-sided thresholding with an overall voxel p statistical threshold of .01 and a corrected clusterwise alpha value of .01. Data smoothness was approximately 6 mm, and . 19 neigh boring voxels comprised a significant brain cluster.Three hypotheses were tested. First, consistent with the prediction that PSUs would exhibit riskier task performance than DSUs, PSUs more frequently made a risky decision following a win compared with DSUs, while DSUs more frequently made a safe decision following a risky win. This pattern supports previous findings that PSUs are more reactive to rewards . Second, although it was predicted that PSUs would show greater activation in reward processing striatal regions to risky wins than to risky losses when compared with DSUs, our re sults demonstrated the opposite effect, with PSUs exhibiting lower striatal BOLD signals across outcomes than DSUs. However, this finding is consistent with a longitudinal study of sensation-seeking adolescents in which striatal hypoactivation predicted future problematic drug use; the authors theorized that lower striatal activity may lead to a compensatory mechanism in which one seeks out increased risk to gain greater stimulation, thereby balancing reward center hypo activation . PSUs exhibited greater temporo-occipital BOLD signals to wins than to losses, findings consistent with a recent meta-analysis reporting that 86% of addiction-related neuroimaging studies demonstrate significant visual cortex activity to drug cues . Although the RGT did not test drug-related responses, our results demonstrate an analo gous relationship to general reward cues, suggesting that PSUs may allocate greater visual attention to risky rewards than to risky losses. Middle temporal lobe is involved in memory of reward-based information critical for future oriented decision making, suggesting that PSUs may be less able to consolidate information about outcomes differ ently . Together, PSUs are characterized by visual attention and memory activation during risky rewards but blunted responsivity to loss outcomes. Our third prediction was supported in that PSUs exhibited lower PFC, insula, and cingulate BOLD signals than DSUsduring risky feedback. These findings align with a recent study conducted by our research group demonstrating that during a task evaluating how individuals learn to make decisions, PSUs exhibited lower insula and ACC activation across all available outcomes than DSUs .

Such pat terns are consistent with previous reports of PFC, insula, and ACC attenuations in chronic stimulant users that are linked with decreased ability to adapt behavior using prior experiences/ reduced inhibitory control, interoceptive awareness, and conflict monitoring, respectively . Thus, young adults pre disposed to SUD may have prior deficits in recruiting neural effort toward critical decision-making processes. Nonhypothesized group differences also emerged in thalamic, precuneus, and posterior cingulate regions that warrant discussion. PSUs showed relatively greater pre cuneus and posterior cingulate BOLD signals when making risky decisions than when making safe decisions when compared with DSUs. Such differences are consistent with previous findings in SUD samples that heightened activation of these areas during exteroceptive awareness may underlie the maintenance and exacerbation of substance use . Greater thalamic response to risky reward versus loss feedback in PSUs is consistent with research demon strating that thalamic BOLD signals are linked to relapse in cocaine-dependent individuals . Thalamus acts as a relay center for the brain by sending sensory information to insula for further interoceptive processing ; hypo activation to loss may reflect differences in relay and integration of information during decision making. With respect to baseline characteristics, DSUs endorsed higher baseline levels of state depression than PSUs, which may have affected RGT performance given that individuals with depression tend to be risk averse . However, given that mean scores for DSUs are substantially below the Beck Depression Inventory threshold for clinical depression [in nonclinical populations, scores above 20 indicate depression ; it is unlikely that DSUs performed in a manner consistent with samples with depression].Across OSUs, lower frontal, temporal, parietal, insular,cannabis grow table and thalamic BOLD signals during risky decisions compared with safe decisions predicted greater future marijuana use . These regions are considered important for executive functions such as inhibitory control, working memory, and attention as well as for being relay centers for integrating information critical for decision making . Therefore, blunted responses in these regions while making choices between risky and safe optionsdose–response effect may exist between brain activation and marijuana use, the relationship between brain activation and stimulant use may be better defined through a categorical perspective that includes accompanying clinical symptomology. Although PSUs and DSUs used marijuana at significantly high rates , groups did not differ categorically in marijuana abuse/dependence frequency. In contrast, stimulant use in and of itself might not be related to brain differences unless it is accompanied by clinical problems, suggesting that a categorical perspective is a more useful way to conceptualize differences.

Cambodia has the highest HIV prevalence of any Asian country, and over the last decade has experienced the most serious HIV/AIDS epidemic in Southeast Asia. Heterosexual contact is the major route of HIV trans mission, and female sex workers remain the group at highest risk. Although crucial progress has been made in reducing risky sexual behavior, including widespread condom use and promotion of reduced number of sexual partners, HIV prevalence among FSW remains high, ranging from 11% to 26%. Poverty, low literacy, a high prevalence of sexually transmitted infections, and a highly mobile work force are contributing factors to the epidemic. Recent research has also identified drug use and, in particular, amphetamine-type stimulant use as a serious emerging problem associated with HIV risk among FSW, which threatens to reverse downward trends in HIV infection rates in the region. Amphetamine-type stimulants include a range of syn thetic psychostimulants, including methamphetamine, amphetamine, and ecstasy, which can be injected, smoked, or taken orally. Effects of these drugs include euphoria, alertness, arousal, increased libido, increased sympathetic nervous responses, , and perceived increases in confidence, energy and physical strength. In Cambodia, a pill form of methamphetamine known as “yama” is widely produced, trafficked, and used. The tablets gener ally contain about 25% methamphetamine. “Crystal” is generally about 85% metham phetamine and more addictive. Although yama pills aresw allowed, both forms are usually melted and the vapors inhaled, resulting in rapid neurologic effects. Use of ATS has been associated with elevated HIV risk behavior in many countries and in several population sub groups. The United Nations Office on Drugs and Crime reports that use of these drugs is widespread in Asia and increasing rapidly in Cambodia. In Cambodia, ATS are highly available both in pill and crystalline form and are generally ingested or smoked; injection use is uncommon. The Cambodia National Authority for Combating Drug Abuse estimated that 70% of all drug users in Cambodia use ATS. The drug accounts for the majority of all drug seizures by authorities, and, in pill form, has been ranked as the leading drug of abuse for the past nine years with consistent increases since 2006, at which time it was estimated that 30,000 tablets of yama were consumed orally or smoked there daily. Use is particularly high among vulnerable populations, including FSW,men who have sex with men , and street children.Self-reported measures of drug use have the advantage of being noninvasive and permit evaluation over longer time periods compared with bio chemical assessments. However, study participants may misrepresent drug use due to social desirability bias, stigma, poor recall, poorly worded questions, or poorly worded response categories in surveys and interviews, all of which could result in mis-classification of measured exposures. Although studies have shown that the use of Audio Computer-Assisted Self Interview increases reporting of sensitive and stigmatized behaviors, research suggests that the validity of self-reported drug use varies by population, race/ ethnicity, mental health, and drug treatment status, although not by gender. Accuracy has varied in studies of arrestee populations but have been reported as higher in groups sampled in emergency department and STI clinics. Those that report more frequent drug use, compared to infrequent use, are more likely to self-report recent drug use. Urine toxicology assessments provide sensitive and valid measures of many drug types; but some, like ATS, are restricted to a short time frame due to rapid metabolization. The detection window may also depend on the physical condition of the individual , route of drug ingestion , frequency of use, and drug-related factors such as purity. To explore the validity of self-reported ATS use among young FSW in Phnom Penh, Cambodia, we com pared self-reported ATS use with results from concur rently collected urine toxicology tests. We also examine whether sociodemographic, sex-work venue, and HIV status were associated with validity of self-reported ATS use.Young women at high risk of HIV infection were the target study population. Inclusion criteria were age 15–29 years, understanding of spoken Khmer, Cambodian ethnicity, reporting of at least two different sexual partners in the last month or engaging in transactional sex within the last three months, plans to stay in the Phnom Penh area for 12 months, being biologically female, and being able to provide voluntary informed consent. Study methods have been described previously. In brief, trained field assistants from the CWDA recruited women from community locations, provided study information, and obtained group informed consent. Women who consented were then seen by appointment at the YWHS-2 clinic site; free transportation was provided. Participants received US $5 and condoms at each study visit. Contact information was collected to facilitate participant tracking and maximize follow-up. Women were asked to enroll for a one-year study with quarterly study visits.All study visits included administration of a structured questionnaire in Khmer by trained inter viewers who queried participants about sociodemo graphic characteristics, health care, occupational and sexual risk exposures, alcohol and self-reported ATS use as well as testing for HIV and ATS using blood and urine samples, respectively.

Modeling abstinent and non-abstinent remission in all family members with life-time AUD allows for the possibility that abstinent and non-abstinent remitted individuals may have characteristics, such as social responsiveness, that contribute to their ability to remit but that are different from those linked to their development of AUDs. The goals of this study were to estimate the strength of the association of probands’ persistent AUD, non-abstinent remission and abstinent remission with relatives’ AUD/remission status, and to test whether this association differed in related and unrelated proband relative pairs.This study explicitly modeled abstinent and non-abstinent remission in probands who were recruited from AUD treatment programs and in their first-degree family members with life-time AUDs to test for familial associations of remission in high-risk families and to define a phenotype which can be used to explore associations of remission with potentially heritable characteristics. Results showed that individuals who were related to an abstinent proband were more than three times as likely to be abstinent themselves, compared to individuals related to a proband with persistent AUD; this association was not significant in unrelated pairs. The significant association of probands’ with relatives’ abstinent remission in related but not in unrelated proband-relative pairs suggests there are familial influences on abstinent remission which may be due to genetic or familial environmental factors. The familial association of abstinent remission in this sample selected for high-risk for AUDs has not been observed previously. The association of abstinence in one family member with abstinence in another stands in contrast to a host of null findings regarding familial influences on remission from other studies in population-based,hydro tray high-risk and clinical samples using a variety of definitions of remission.

The current analyses used an explicit abstinent and non-abstinent remission phenotype, distinct from AUDs and consistent with the idea that the distribution of risks for development of, and for remission from, AUDs may not lie on the same continuum. Our results suggest that there may be genetic or familial environmental influences on abstinent remission and demonstrate that departing from the more common risk factor-to-remission comparisons within families may indeed prove useful. When remission is the target phenotype, remission in all family members should be measured explicitly, rather than measuring it as an outcome only in target subjects but not in their relatives. This will facilitate the examination of potentially heritable characteristics underpinning abstinent outcomes, such as social responsiveness, that may increase the likelihood of remission, as well as the investigation of family environments associated with remission from AUDs. Much more work will need to be conducted to identify heritable traits that may be related to abstinent remission and to probe for mediators and moderators of their effect. In addition to potentially heritable effects on abstinent remission, another explanation for the current findings might rest with a social contagion model, or the spread of behavior within a family due to social proximity. Analysis of large social networks from a population-based study indicated that both heavy drinking and abstinence clustered in networks, and also that the heavy drinking or abstinence of relatives and friends at one time-point were associated with changes in the subject’s alcohol consumption, to heavier drinking or abstinence, at a subsequent time-point. The same may be true within families affected by severe AUDs, where abstinence in one person may influence another family member with an AUD to try to quit drinking. This possibility is consistent with evidence that abstinence is the most stable form of remission among individuals with severe AUDs . If older family members with life-time AUD are abstinent as younger family members are developing alcohol problems, it is possible that younger members, if they recognize severe problems in themselves, may look to older members for direction or example, or that older members may recognize problems in younger members and intervene. In fact, analysis of twin data showed that the variance associated with treatment-seeking for alcohol problems was accounted for primarily by familial influences, with 41% of the variance due to genetics, 40% due to shared environment, and just 19% to unique environment.

In the current study, all probands had by definition been treated, which precluded examination of familial associations for treatment-seeking; however, abstinent relatives had the highest rates of treatment seeking in the sample, suggesting an association of relatives’ with probands’ treatment-seeking. More than 40% of probands and relatives were remitted in this high-risk sample, with abstinence the most common type of remission in probands and abstinent and non abstinent remission equally common in relatives. An earlier study in the COGA sample found that more than 50% of all subjects with life-time alcohol dependence reported periods of abstinence lasting 3 months or more, with 16.1% reporting abstinence of 5 or more years. Similar to the relatives in the current study, abstainers were older than individuals who never abstained, had a greater number of life-time symptoms and were more likely to have sought formal treatment and to have attended self-help groups. Other sampling frames also show similarities to the current data. Abstinent individuals with life-time AUD from population-based data had more AUD symptoms than remitted non-abstinent individuals. In a national sample of individuals self-identified as ‘in recovery’, abstainers compared to non-abstainers were older, more likely to have received professional treatment and to have attended self-help meetings, and had significantly more life-time alcohol dependence symptoms. These similarities across a range of samples suggest that individuals who become abstinent, regardless of sampling frame, represent a severe end of the AUD continuum. In the current study, abstinence may represent a common end-point for individuals with severe AUD. It is possible that non-abstinent remitters will become abstinent for a period, or periods, of time. Given that nearly half of abstinent relatives in the current study had been remitted for 10 or more years, abstinence may indeed represent an end-point for subjects who remit from severe AUDs.Despite efforts to improve mental health over the last 60 years, planting table suicide remains a critical public health concern worldwide.Suicide was the second leading cause of death globally in 2012 among individuals aged 15–29years,with an estimated 80%–90% of suicide deaths attributable to mental health or substance use disorders.Significant gaps remain in empirical research examining suicidality among marginalised populations. Marginalised women, such as sex workers who are street involved or use drugs, experience disproportionately high levels of social and health-related risks and harms, including stigma, discrimination and violence as a result of dynamic structural drivers including poverty, criminalisation and racism.

While sex workers are a diverse population working from indoor in-call and out-call venues to street-based settings, previous studies high light substantial unmet mental health needs of more marginalised and street-involved sex workers. Studies among street-based sex workers and those who use drugs underscore the associations of social exclusion, depression and post-traumatic stress disorder with suicidality.Research demonstrates greater risk for suicidality among those with a history of trauma and among street-involved sex workers who report historical experiences of violence and childhood abuse.Furthermore, indigenous women are vastly over-represented among street-based sex workers in North America and face devastating and multi-generational effects of trauma and socioeconomic dislocation as a result of colonialism, racialised policies and displacement from land and home communities.Various biological, interpersonal and sociostructural factors contribute to our understanding of suicidal behaviours. While evidence has demonstrated that some forms of cognitive behavioural therapy and pharmacological interventions may reduce suicidality, the literature is hampered by publication bias and significant heterogeneity of strategies and outcome measures.Due to ethical challenges and limitations to studying suicide and its proxies , there remains a paucity of evidence from randomised controlled trials to support the efficacy of prevention interventions.Researchers have largely focused on examining suicidality outcomes , which may not be fully generalisable to understanding suicide or accurately evaluating treatment approaches.Furthermore, stigma continues to hinder research and reporting of suicidality.There remains an urgency to better understand pathways to suicidality, with literature highlighting the need for innovative psycho logical and psychosocial treatments and tailored inter vention approaches for key marginalised populations.Given the complex aetiological pathways to suicide and limited effectiveness of well-established evidence-based interventions to reduce the burden of suicidality, the US National Institute of Mental Health has called for innovative research on suicide prevention and treatment for suicidality. A number of psychedelic drug therapies are being revisited following a 40-year hiatus in research into their potential for the treatment of depression, anxiety, PTSD, eating disorders and addiction.Psychedelic drugs include the classic serotonergic psychedelics or ‘hallucinogens’ lysergic acid diethylamide , psilocybin, dimeth yltryptamine and mescaline, as well as the ‘enactogen’ or ‘empathogen’ methylene dioxymethamphetamine ,all of which are being investigated in clinical/preclinical studies for their neuropharmacological functions and potential as adjuncts to psychotherapy.While renewed interest in psychedelic medicine is challenged by various funding and methodological and legal impediments, the emerging evidence indicating improved outcomes for some individuals suffering from mental health and addiction issues has generated new scientific inquiry and an imposing obligation to advance this research.Recent observational studies in the USA demonstrate significant associations between life time psychedelic use and reduced recidivism and intimate partner violence among populations of prison inmates and reduced psychological distress and suicidality among the general adult population.

Despite the multifaceted structural and social inequities that shape poor mental health burden among margin alised and street-involved sex workers, there remains a paucity of data on suicide rates and research that system atically examines factors that potentiate or mitigate suicidality among sex workers, particularly in the global north. Some evidence suggests that psychedelic drug use may be protective with regard to suicidality and is associated with significant improvements in psychological well-being and reductions in depression and anxiety in clinical settings,yet existent research is characterised by large gaps. Given the urgency of addressing and preventing suicide and calls for prioritising innovative interventions, this study aimed to longitudinally investigate whether life time psychedelic drug use is associated with a reduced incidence of suicidality among a community-based prospective cohort of marginalised women. We postulated that psychedelic drug use would have an independent protective effect on suicidality over the study period.Data for this study were drawn from a large, communi ty-based, prospective cohort of women sex workers initiated in 2010, known as An Evaluation of Sex Workers Health Access . Eligibility criteria for study participants included cisgender or transgender women, 14 years of age or older, who exchanged sex for money within the last 30 days. AESHA participants completed interviewer-administered questionnaires and HIV/sexually transmitted infection /hepatitis C virus serology testing at enrolment and biannually. Experiential staff are represented across interview, outreach and nursing teams, including coordinators with substantial community experience. Participants were recruited across Metro Vancouver using time–location sampling and community mapping strategies, with day and late-night outreach to outdoor sex work locations , indoor sex work venues and online. Weekly outreach by experiential staff is conducted to over 100 sex work venues by outreach/nursing teams operating a mobile van, with regular contact as well as encouraging drop-in to women only spaces at the research office, contributing to an annual retention rate of >90% for AESHA participants. The main interview questionnaire elicits responses related to sociodemographics , the work environment , client characteristics , intimate partners , trauma and violence and comprehensive injection and non-injection drug use patterns. The clinical questionnaire relates to overall physical, mental and emotional health, and HIV testing and treatment experiences to support education, referral and linkages with care. The research team works in close partnership with the affected community and a diversity of stakeholders and regularly engages in knowledge exchange efforts. AESHA is monitored by a Community Advisory Board of over 15 sex work, women’s health and HIV service agencies, as well as representatives from the health authority and policy experts, and holds ethical approval through Providence Health Care/University of British Columbia Research Ethics Board. All participants receive an honorarium of $C40 at each biannual visit for their time, expertise and travel. To capture initial episodes of suicidality, analyses for this study were restricted to AESHA participants who had never thought about or attempted suicide at base line and completed at least one follow-up visit between January 2010 and August 2014. Those with missing observations for suicidality at baseline were excluded from analysis, and one additional participant was excluded because reported suicidality was missing at follow-up.

As shown by the representative experiment depicted in Fig. 3, four peaks of enzyme activity were resolved by MonoQ chromatography , which were all effectively inhibited by BTNP . Multiple peaks of anandamide amidohydrolase activity have been already observed after pa tial purification from pig brain microsomes, but the significance of these putative isoforms is still unknown.The recent cloning of an hydrolase involved in the degradation of long-chain fatty acid amides, including anandamide, should help shed light on this question. In the rat, anandamide amidohydrolase activity is mainly localized in liver and brain. When tested on crude microsomes prepared from rat liver tissue, BTNP inhibited anandamide hydrolysis with an IC50 that was about 100-fold greater than that measured in brain microsomes . However, this marked difference likely resulted from BTNP degradation by liver enzymes, rather than from the existence of tissue-specific amidohydrolase isoenzymes. Two findings support such conclusion. First, after FPLC fractiona tion, anandamide amidohydrolase activity from liver was in hibited by BTNP as effectively as the activity from brain . Second, incubation of BTNP with a mixture of brain and liver microsomes for 10 min at 37°C prevented the inhibition of anandamide hydrolysis . The regional distribution of anandamide hydrolysis in the rat central nervous system, paralleling that of CBi cannabinoid receptors, suggests that this enzymatic reaction may be at least in part responsible for the biological disposition of anan damide. Yet, it is still unclear whether anandamide ami dohydrolase activity is localized in neurons, in glial cells or in both. We prepared cell-type specific cultures of neurons or astrocytes from the cortex of embry onic rats,grow table and measured anandamide amidohydrolase activity in homogenates of these cultures. Supporting a preferential neuronal localization, we found that the enzyme activity was 12-fold greater in neurons than in astrocytes .

BTNP was equally potent in inhibiting anandamide amidohydrolase activity, producing in either cell type an in hibition of approximately 80% at 0.5 xM . Noteworthy, Shivachar and coworkers have previously reported that cultures of rat cortical astrocytes contain negligible levels of anandamide amidohydrolase activity. This discrepancy may be due to different culture con ditions and/or assay sensitivity. To determine whether BTNP inhibits anandamide hydrol ysis in intact cells, we tested its effects on primary cultures of rat cortical neurons, incubated for 4 min in a medium con taining [ 3H]anandamide. As previously noted, [ 3H]anand amide was readily hydrolyzed by the neurons, and virtually all of the [ 3H]arachidonate produced in this reaction was found esterified into cellular phospholipids, most prominently into phosphatidylcholine and phosphatidylethanolamine. BTNP prevented [ 3H]anandamide hydrolysis by theneurons in a concentration-dependent manner, as indicated by a reduced incorporation of [3H]arachidonate into PC and PE, as well as by an increased intracellular accumulation of un metabolized [3H]anandamide. Both effects occurred with an IC5o close to 0.1 u,M . We have also investigated the effects of BTNP on the en zymes involved in anandamide biosynthesis. In mixed cortical cultures, formation of anandamide and other 7V-acylethanol amines is thought to be mediated by a D-type phospholipase activity, and is stimulated by the Ca2+ ionophore ionomycin. To determine whether BTNP inhibits JV-acyletha nolamine formation we labeled cortical cultures overnight with [3H]ethanolamine, and stimulated them with ionomycin either in the presence or in the absence of BTNP . Radioactivity in the TV-acylethanolamine fractions, de termined after TLC fractionation, was: control 83 ±41 dpm, ionomycin 123 ±9 dpm, ionomycin plus BTNP 248 ± 35 dpm . These results suggest that BTNP inhibits anandamide degradation without affecting the formation of anandamide and other JV-acylethanolamines. Next, we measured the effects of BTNP on the biosynthesis of 7V-arachidoyl PE, a putative anadamide precursor. Particulate fraction of the rat brain tissue were incubated at 37°C for 60 min in the presence of di[14C]arachidonoyl phosphatidylethanolamine and the N arachidonoyl PE produced was fractionated by TLC. Under these conditions, BTNP inhibited A^-arachidonoyl PE with an IC50 of approximately 2 u.M. Despite having a comprehensive tobacco control policy, cigarette smoking continues to be the leading cause of preventable morbidity and mortality in China and other developing countries, as it already is in developed countries today, and accounts for 5 million deaths globally each year. When cigarettes are smoked, a host of harmful chemicals contribute to the deleterious effects. Mounting scientific evidence proves the association between chronic smoking and lung cancer, chronic obstructive pulmonary disease, vascular disease, stroke, and peptic ulcer disease, as well as a wide range of other adverse health effects.

Understanding the mechanism of nicotine dependence and developing better therapies to help with smoking cessation is an urgent need. Emerging technologies, such as neuroimaging and genomics, have contributed to new insights into the neurophar macology of tobacco addiction. There is considerable literature from functional neuroimaging studies assessing the effects of chronic cigarette smoking on brain structure and function. However, while several studies have examined gray matter differences between smokers and non-smokers, much is less known about the white matter structural changes in brain in chronic cigarette smokers. Using magnetic resonance imaging to examine the brain structure and function in chronic cigarette smoker provides a better understanding about the adverse effects of chronic cigarette smoking on brain. Diffusion tensor imaging is a sensitive method to measure micro-structural changes by detecting self-diffusion of water molecules caused by Brownian motion and providing parameters of the diffusion tensor, the most commonly used parameter is fractional anisotropy.Increased FA indicates a non-spherical tensor with preferential orientation in a particular direction, while a decreased FA indicates more isotropic diffusion which has been found to becharacteristic of disrupted or damaged whiter matter. It has been widely used to identify and quantify white matter abnormalities in psychiatric and neurological diseases, such as schizophrenia showed significantly higher levels of FA in the corpus callosum than nonsmokers; the low Fagerstro¨m scores group exhibited significantly higher levels of FA in the body of the corpus callosum than the high Fagerstro¨m group and the nonsmokers. Jacobsen et al reported that prenatal and adolescent exposure to tobacco smoke showed higher FA in anterior cortical white matter; adolescent smoking also showed higher FA in internal capsule. Recently, Xiaochu Zhang et al examined a relatively large sample of smokers and found that the most highly dependent smokers exhibited lower prefrontal FA, which was negatively correlated with Fagerstro¨m Test of Nicotine Dependence. In the present study,4×8 grow table with wheels we examined white matter changes in a relatively large sample of nicotine dependent smokers and non smokers matched for a number of demographic variables using DTI.Eighty-eight subjects , 19–39 years of age, were recruited from the local community using advertisements. They were initially screened during a semi-structured telephone interview to assess smoking, medical, psychiatric, medication, and substance use history.

Smokers who had smoked 10 cigarettes per day or more during the previous year and had no period of smoking abstinence longer than 3 months in the past year, and met DSM-IV criteria for nicotine dependence were eligible for this study. All smokers self reported no smoking for the 12 hours before scanning. Nicotine patches were provided as needed. Nonsmoking history was defined as having smoked no more than five cigarettes lifetime. Participants were excluded if they were a minority other than Han Chinese or had: a diagnosis of mental retardation, current or past alcohol or drug abuse/dependence, a current or past central nervous system disease or condition, a medical condition or disease with likely significant central nervous system effects, history of head injury with skull fracture or loss of consciousness greater than 10 min, a physical problem that would render study measures difficult or impossible, any current or previous psychiatric disorder, a family history of a psychotic disorder, current or previous use of electroconvulsive therapy or psychotropic medications, or a positive pregnancy test. A licensed psychiatrist conducted all clinical interviews. The protocol was approved by the university ethics committee and the studies were carried out in accordance with the Declaration of Helsinki. Subjects were fully informed about the measurement and MRI scanning in the study. Written informed consent was given by all study participants. None of the participants reported daily consumption of alcohol, and none reported experiencing social consequences secondary to alcohol use, or any history with difficulty ceasing alcohol intake. All non-smokers in this sample reported no history of smoking behavior in the past.Diffusion tensor images were preprocessed using previously published methods . The diffusion data set was pre-aligned to correct for head motion, and the effects of gradient coil eddy currents using software tools from the FMRIB software library . After these steps, the diffusion tensor at each voxel was calculated using the FMRIB diffusion toolbox in FSL. The resulting FA images were trans formed into Montreal Neurological Institute standard space with Statistical Parametric Mapping 5 by means of the following steps: the b = 0 images were co-registered with the structural T1 image for that individual, the same co-registration parameters were applied to the FA maps , each individual’s T1 image was then normalized to the SPM T1 template , and the same normalization parameters were then applied to the co-registered FA images. Finally, FA images were smoothed with an 8-mm full width at half-maximum Gaussian kernel. Then, all images were re sampled with a final voxel size of 26262 mm3 . Each FA image was then spatially smoothed by an 8-mm full-width at half the maximum Gaussian kernel in order to decrease spatial noise and compensate for the inexact nature of normalization.Between-group tests were performed on diffusion tensor images of FA using a parametric two sample t-test on a voxel-by-voxel basis using SPM5 software. A prior white matter mask from WFU_PickAtlas was used to restrict the search volume for analysis.

Clusters of 100 voxels or more, surviving an uncorrected threshold of p,0.001, were considered significant. For visualization of the regions showing significantly different FA values between the two groups, significant clusters were superimposed onto SPM5’s spatially normalized template brain. Fiber tracts corresponding to the clusters were identified with reference to the Johns Hopkins University DTI-based White Matter Atlas analyses was performed. MarsBar 0.41 was used to extract ROIs containing all the voxels classified as white matter from spatially normalized and smoothed FA images. Then, mean FA values of the ROI were calculated using log_roi_batch v2.0 . Finally, the aver age FA values of individual clusters were calculated for each subject. A two-sample t-test was used to compare these FA values of the clusters between smokers and non-smoking controls. We used P,0.05 as a statistical threshold to search for significant differences. Correlational analysis of FA values with smoking-related factors including age of smoking onset, number of cigarettes smoked per day, years of smoking and smoking cravings were examined using bivariate correlational analysis . The T1-weighted images were segmented by using VBM5.1 procedures into white matter, gray matter, and CSF . Then, the white matter volumes were compared between groups by univariate GLM using total brain volume as covariate.The present study provides evidence of micro-structural white matter modifications in chronic smokers as measured by whole brain analysis of FA using DTI. Specifically, increased FA was found in white matter of the bilateral fron to-parietal cortices in cigarette smokers relative to healthy non-smoking comparison subjects. In contrast to the findings here with chronic cigarette smokers, previous studies with other drug dependent subjects revealed decreased FA in white matter of the brain. In patients with heroin dependence, reduced FA was observed in the bilateral frontal subgyral cortices, right precentral, and left cingulate gyrus. In cocaine-dependent subjects, lower FA was reported in inferiorfrontal white matter at the anterior-posterior commissure plane, in frontal white matter at the anterior commissure-posterior commissure plane, and in the genu and rostral body of the anterior corpus callosum. Similarly, lower FA in the right frontal white matter is also frequently reported in methamphet amine users and alcohol drinkers, and recently reported in chronic ketamine users. Convergent evidence suggests that chronic drug use is associated with decreased FA in white matter of the multiple brain regions, especially in the frontal lobe. Results of this study, along with previous findings, suggest increased FA, such that the effects of chronic cigarette smoking on brain white matter are different from effects of other addictive drugs. Increased FA may reflect increased maturation in cell packing density, fiber diameter, and directional coherence.

People with HIV are twice as likely to engage in heavy alcohol use and two to three times more likely to meet criteria for an alcohol use disorder in their lifetime than the general population . Heavy alcohol use not only promotes the transmission of HIV through sexual risk-taking behavior and nonadherence to antiretroviral therapy , but also directly exacerbates HIV disease burden by compromising the efficacy of ART and increasing systemic inflammation . In addition to increased risk for physical illness , there is substantial evidence indicating that comorbid HIV and heavy alcohol use is more detrimental to brain structure and results in higher rates of neurocognitive impairment than either condition alone . The impact of comorbid HIV and heavy alcohol use on the central nervous system is especially important to consider in the context of aging. The population of older adults with HIV is rapidly growing; approximately 48% of PWH in the U.S. are aged 50 and older and the prevalence of PWH over the age of 65 increased by 56% from 2012 to 2016 . Trajectories of neurocognitive and brain aging appear to be steeper in PWH , possibly due to chronic inflammation and immune dysfunction, long-term use of ART, frailty, and cardiometabolic comorbidities . In addition to HIV, rates of alcohol use and misuse are also rising in older adults . The neurocognitive and physical consequences of heavy alcohol use are more severe among older than younger adults, and several studies also report accelerated neurocognitive and brain aging in adults with AUD . While mechanisms underlying these effects are poorly understood, older adults may be more vulnerable to alcohol-related neurotoxicity due to a reduced capacity to metabolize alcohol, lower total-fluid volume,plant bench indoor and diminished physiologic reserve to withstand biological stressors . Altogether, these studies support a hypothesis that PWH may be particularly susceptible to the combined deleterious effects of aging and heavy alcohol use.

For example, in a recent longitudinal report, Pfefferbaum et al. reported that PWH with comorbid alcohol dependence exhibited faster declines in brain volumes in the midposterior cingulate and pallidum above and beyond either condition alone. There is considerable heterogeneity, however, in profiles of neurocognitive functioning across individuals with HIV and AUD . Patterns of alcohol consumption rarely remain static throughout the course of an AUD, but rather are often characterized by discrete periods of heavy use. This episodic pattern of heavy consumption may similarly impact the stability of HIV disease , which may in part explain why some PWH with AUD exhibit substantial neurocognitive deficits while others remain neurocognitively intact. Self-report estimates of alcohol use, however, often fail to predict neurocognitive performance . Methods for quantifying heavy drinking are also inconsistent across studies. For example, some studies classify individuals based on DSM criteria for AUD whereas others define heavy drinking based on “high-risk” patterns of weekly consumption . These methods characterize the chronicity of drinking and psychosocial aspects of alcohol misuse, but they are suboptimal for quantifying discrete periods of heavy exposure and high level intoxication that may confer higher risk for neurocognitive dysfunction. Binge drinking, defined by the National Institute on Alcohol Abuse and Alcoholism as 4 or more drinks for women and 5 or more drinks for men within approximately 2 hours, may more precisely capture discrete episodes of heavy exposure. The relationship between binge drinking and neurocognitive functioning remains poorly understood across the lifespan and particularly in the context of HIV. Thus, the current study examined two primary aims to better understand the impacts of HIV, binge drinking, and age on neurocognitive functioning. The first study aim examined the independent and interactive effects of HIV and binge drinking on global and domain-specific neurocognitive functioning.

We hypothesized that: 1) neurocognitive performance would be poorer with each additional risk factor such that the HIV-/Binge- group would exhibit the best neurocognition, followed by the single-risk groups , and finally the dual-risk group; and 2) these group differences would be explained by a detrimental synergistic effect of HIV and binge drinking on neurocognition. The second study aim examined whether the strength of the association between age and neurocognition differed by HIV/Binge group. We hypothesized that: 1) older age would relate to poorer neurocognition; and 2) that this negative relationship would be strongest in the HIV+/Binge+ group. Participants included 85 PWH and 61 HIV- adults who reported drinking alcohol in the 30 day period prior to their study visit. Participants were further stratified based on their recent binge drinking status, resulting in the following four groups: HIV+/Binge+ , HIV-/Binge+ , HIV+/Binge- , HIV-/Binge- . All participants were enrolled in NIH-funded research studies at the University of California, San Diego’s HIV Neurobehavioral Research Program, and gave written informed consent as approved by the UCSD Institutional Review Board. The current cross-sectional study is a secondary analysis of data from each participant’s baseline visit at the HIV Neurobehavioral Research Program from 2003-2019. Exclusion criteria for the current analysis were: 1) current diagnosis of non-alcohol substance use disorders ; 2) diagnosis of psychotic or mood disorder with psychotic features; 3) presence of a neurological or medical condition that may negatively affect cognitive functioning, such as traumatic brain injury, stroke, or epilepsy; 4) positive urine toxicology for illicit drugs or positive Breathalyzer test for alcohol on the day of study visit; 5) report of no “recent” alcohol consumption.Binge drinking was assessed per NIAAA criteria for binge drinking . Binge drinking behavior was dichotomized such that participants who had any binge drinking episode in the last 30 days were classified as binge drinkers . Lifetime history of alcohol exposure, including quantity and frequency, was assessed via a semi-structured timeline follow-back interview that evaluates drinking patterns across different periods in an individual’s life. Current depressive symptoms were assessed using the Beck Depression Inventory-II, a self-report measure .

The Composite International Diagnostic Interview was administered to evaluate current and lifetime mood and SUDs . Notably, the parent grants from which baseline data were drawn were funded prior to the publication of the DSM 5. Therefore, diagnoses were made in accordance with DSM-IV criteria where alcohol/substance abuse is met when participants report recurring problems as a result of continued alcohol/substance use; and alcohol/substance dependence is met when participants experience symptoms of tolerance, withdrawal, and/or compromised control over their alcohol/substance use . In order to remain consistent with the current DSM 5 criteria and nomenclature, alcohol/substance abuse and dependence criteria were combined to capture AUD and SUD. Neuromedical Assessment Participants were tested for HIV by enzyme-linked immunosorbent assay with Western Blot confirmation. All participants completed a comprehensive medical evaluation including self-report measures, structured neurological and medical evaluations,vertical outdoor farming and blood samples to assess the presence of medical comorbidities and HIV disease characteristics. HIV viral load in plasma was measured using reverse transcriptase-polymerase chain reaction , where viral load was deemed undetectable below 50 copies/mL. Neurocognitive Assessment Participants were administered a comprehensive battery of neurocognitive assessments measuring global and domain-specific neurocognitive performance: global function, verbal fluency, executive function, processing speed, learning, delayed recall, working memory, and motor skills . Raw scores from each neuropsychological test were converted into demographically-corrected T-scores . Global and domain-specific continuous T-scores were derived from averaging the demographically-corrected T-scores across all tests and within each neurocognitive domain, respectively . These global and domain-specific T-scores were used as primary outcomes for comparisons of neurocognition between HIV/Binge groups. Demographic, psychiatric, medical, alcohol and substance use, and HIV disease characteristics were compared between the four HIV/Binge groups using analysis of variance or chi-square tests, as appropriate. Pair-wise comparisons were conducted to follow up on significant omnibus results using Tukey’s Honest Significant Difference tests for continuous outcomes or Bonferroni adjustments for categorical outcomes. Nonparametric Wilcoxon tests were used to for continuous variables with skewed distributions. To examine the first study aim, one-way ANOVA and Tukey’s HSD tests were used to compare mean global and domain neurocognitive T-scores between the four HIV/binge drinking groups. For any significant one-way ANOVA result, a 2 x 2 factorial ANCOVA was used to model independent and interactive effects of HIV and binge drinking status, covarying for total drinks consumed in the last 30 days and any demographic or non-alcohol-related clinical characteristics that differed between groups at p<0.05 . These demographic covariates were included to increase confidence that any observed difference in neurocognition between HIV/Binge groups would not be attributable to confounding effects of age and sex that may that may exist above and beyond the T-scores’ demographic corrections. To further support any findings indicating additive main effects, Jonckheere-Terpstra tests for ordered alternatives examined whether there was a statistically significant negative relationship between the number of risk factors and neurocognitive performance . Finally, to examine the second study aim, multiple linear regressions modeled the interaction between age and HIV/Binge status group on global and domain-specific T-scores, also covarying for total drinks consumed in the last 30 days, sex, and lifetime history of non-alcohol. Our examination of age as a predictor of demographically-corrected T-scores will allow understanding of how the effect of age in certain vulnerable groups may go above and beyond that of normal controls on whom demographic corrections were based.

Parametric statistics were used because the outcome variables were continuous and had normal distributions in each HIV/Binge group. All analyses were performed using R, version 3.5.0.Demographic and clinical factors by HIV/Binge group are displayed in Table 1. The HIV-/Binge- group was younger than both HIV+ groups , and the HIV+/Binge+ group had a higher proportion of men compared to the two HIV- groups . Regarding alcohol and substance use characteristics, the two Binge+ groups had significantly higher quantity and frequency of alcohol use in the last 30 days, higher proportions of current and lifetime AUD, higher lifetime quantity and frequency of alcohol use, and a higher proportion of lifetime non alcohol SUDs compared to those of both Binge- groups . Alcohol use characteristics, including frequency of alcohol binges in the last 30 days, did not differ between the HIV-/Binge+ and HIV+/Binge+ groups . All psychiatric, medical, and HIV disease characteristics were comparable across groups.For each of those neurocognitive outcomes with a significant omnibus result, follow-up pairwise comparisons showed significant differences between only the HIV-/Binge- and the HIV+/Binge+ groups, with HIV+/Binge+ participants exhibiting poorer performance . Results of the 2 x 2 factorial ANCOVAs are shown in Table 2. Additive main effects of HIV status and binge drinking status were detected on global function and processing speed, however none of the interactions between HIV and binge drinking status on neurocognitive outcomes reached statistical significance. Additive main effects of HIV and binge drinking were further supported by results from Jonckheere-Terpstra tests indicating significantly lower global and processing speed performance by each increase in risk factor count . Binge drinking was also a significant predictor of delayed recall and working memory. Of note, the effects of binge drinking on neurocognition were not attenuated by accounting for total drinks in the last 30 days, which did not significantly relate to any neurocognitive outcome . Multiple linear regression revealed significant interactions between age and HIV/Binge group on neurocognitive outcomes of learning , delayed recall , and motor skills . Specifically, the association between age and each of those three neurocognitive outcomes was significantly more negative in the HIV+/Binge+ group compared to that of the HIV-/Binge- group . This interaction was not significant for any other neurocognitive outcome . Additional analyses comparing age-slopes between all groups revealed that the difference in age-slopes between the HIV+/Binge- and HIV-/Binge groups approached significance for delayed recall and motor skills , such that the HIV+/Binge- group had a stronger relationship between age and those neurocognitive domains. Total drinks in the last 30 days, sex, and lifetime non-alcohol SUD were not significant predictors of any neurocognitive outcomes. In addition, all results held when also covarying for current and lifetime AUD.Given the rapidly growing population of older adults with and without HIV along with the increased rates of binge drinking among them, studying the combined effects of HIV and binge drinking across the lifespan is timely and important. Partially consistent with our first hypothesis, the HIV+/Binge+ group demonstrated the worst global neurocognitive functioning ; however, the combined effects of HIV and binge drinking on global neurocognitive functioning exhibited an additive, rather than synergistic, pattern .

The patient stated she had attempted to stand up from a seated position when she “felt like [she] was going to pass out.” The patient called 911 for assistance. On further discussion, the patient revealed she had experienced one similar episode of weakness earlier in the year, but this had resolved spontaneously and was not as severe. She does not have a primary care physician and she had never sought care for this complaint. The patient said she noticed generalized abdominal pain, nausea, and constipation, associated with each of these episodes of weakness and light headedness. She denied any recent illnesses. She stated she treats her bipolar disorder with daily cannabis and consumes alcohol daily as well.She had no pertinent family history. Her social history included daily alcohol use, drinking a total of 1.75 liters of vodka over a two-week period. She started smoking when she was 16 years old, smoking a pack per day, but quit a year prior to presentation. The patient smoked cannabis daily. Her only medication was ferrous sulfate 325 milligrams daily. She had no known drug or environmental allergies. On physical exam, the patient was alert and in no acute distress but appeared tired. She was able to stand unassisted. At the time of triage, she was afebrile , her heart rate was 40 beats per minute, she was breathing 20 times per minute, her blood pressure was 115/90 millimeters of mercury, and she had an oxygen saturation of 98% on room air. She weighed 77.3 kilograms and was 1.65 meters tall . She was well developed, well nourished and speaking in complete sentences without accessory muscle use. She was oriented as to person, place and time. She was without sensory deficits and had normal muscle tone. Her strength was 4/5 with elbow flexion and extension, hand grip, knee flexion and extension,vertical agriculture and ankle dorsi- and plantar-flexion bilaterally. Deep tendon reflexes were 2+ for the bilateral brachioradialis and patellar reflexes.

No clonus could be provoked. She did not have any cranial nerve defects, and she had a normal gait and station. She had normal range of motion of all four extremities, and she did not have any edema. Her lower extremity compartments were soft in both the thighs and the lower legs bilaterally. She exhibited tenderness around her bilateral shoulders and shins. Her head was normocephalic and without signs of injury. Her oropharynx was clear and moist, and her pupils were equal, round, and reactive to light. Her conjunctiva and extraocular motions were normal. Her neck was supple and had a full range of motion, without jugular venous distention or adenopathy. On cardiovascular exam the patient was bradycardic with a regular rhythm, and she had a normal S1/S2 without gallops, friction rubs, or murmurs. On auscultation her breath sounds were clear without wheezes, rales or rhonchi. Her abdomen was non-distended, soft and non-tender throughout with normal bowel sounds. Her skin was warm and dry, and her capillary refill was less than two seconds. She did not have any rashes. Her mood, affect, and behavior were normal. The patient’s electrocardiogram is shown . The results of the patient’s initial laboratory evaluation are shown in Table 1. A test was ordered, and a diagnosis was made.This case involved a young woman with episodic weakness. She reported near syncope, transient extremity paralysis, and generalized weakness. She reported associated nausea, abdominal pain, and constipation. She also reported regular substance use in the form of marijuana and alcohol. Her review of systems was otherwise unremarkable, and notably it was negative for recent illness or gastrointestinal distress outside of this episode. With this in mind, I began to formulate a differential diagnosis. Episodic weakness, particularly extremity paralysis, suggests metabolic and electrolyte derangements such as hypokalemic periodic paralysis. Weakness may also suggest a primary neurologic condition, including Guillain-Barré syndrome, multiple sclerosis, and other demyelinating disorders. Her GI symptoms could be due to a broad array of abdominal conditions, but her substance use suggests these symptoms may be related to an ingestion. The patient’s bradycardia could be due to disseminated Lyme disease, myocarditis, or other etiologies of heart block. More information is required. I used the information provided by her physical exam to further refine my differential diagnosis. Her physical exam was notable for a tired-appearing female with bradycardia.

Pertinent negative findings included that the compartments of the legs were noted to be soft, clinically excluding a compartment syndrome. Additionally, the patient had no focal neurologic deficits based on the documented neurologic exam. Several findings, including cerebellar signs were not documented, but the patient was noted to have normal gait and station. The mention of normal compartments and the normal neurologic exam suggests that a neurologic cause is unlikely. Further, the case did not provide any imaging studies – notably, there was no neuroimaging included. The patient’s ECG showed a sinus bradycardia with sinus arrhythmia, short QTc with T-wave inversions in aVR and V1, and U waves, but it did not show a heart block. I then reviewed the patient’s laboratory findings. She was noted to have a mild anemia, elevated creatine kinase with myoglobinuria, hematuria, proteinuria, and urinary findings consistent with a urinary tract infection. Additionally, she has multiple electrolyte derangements, including hypokalemia, hyperchloremia with acidosis, hypermagnesemia and hypophosphatemia. She had an elevated creatinine and a mild transaminitis. These laboratory findings suggest her symptoms are due to a metabolic derangement. This patient had a non-anion gap metabolic acidosis. The differential diagnosis for non-anion gap metabolic acidosis includes diarrhea, intestinal fistulae, renal tubular acidosis , ureteroileostomy, ureterosigmoidostomy, toluene use, ketoacidosis, D-lactic acidosis, and administration of chloriderich solutions.After cross-referencing this with the case details, some of these diagnoses can be eliminated based on the history, exam, and review of systems. Specifically, the patient reported constipation, thereby eliminating diarrhea as a cause. She also had no surgical history, hence eliminating ureteroileostomy and ureterosigmoidostomy as causes. Although her diet is not mentioned, there is no reported history of abnormal ingestion of food or fluids; so I reasonably eliminated chloride-rich solution ingestion as a cause. This left proximal and distal RTA, toluene use, ketoacidosis, and under consideration. When cross-referencing these with the case details and laboratory findings once again, some options were not consistent with the presentation. Specifically, there was no ketonuria making ketoacidosis unlikely.

Lactic acidosis is a result of a hypoperfusion state, and the clinical case did not provide any evidence of hypoperfusion making this unlikely as well. There were some additional laboratory findings outside of the metabolic panel that needed to be considered. Namely, the patient’s hemoglobin and hematocrit were slightly abnormal . Also, she had an elevated creatine kinase and myoglobin as well as slight elevation in her aspartate transaminase. Her urine also showed some hematuria, pyuria,hydroponics flood table and proteinuria as well as findings of nitrites and leukocyte esterase. When these labs are considered in conjunction with the metabolic abnormalities, my differential diagnosis now included hypokalemic periodic paralysis, rhabdomyolysis, adrenal insufficiency, proximal and distal RTA, inflammatory myopathy, and poisoning . Adrenal insufficiency can cause metabolic derangements and presents with symptoms including fatigue, weight loss, GI complaints, and myalgias, and may also include psychiatric symptoms. In primary adrenal insufficiency, the potassium is high and sodium is low, which is not consistent with this case. In secondary or tertiary adrenal insufficiency, potassium is normal or low, sodium can be high or low, and chloride is normal with a low glucose.These are not consistent with the findings in this case either; so I eliminated adrenal insufficiency from my differential diagnosis. Inflammatory myopathies present with muscle weakness, cardiac involvement, and laboratory findings including elevated serum creatinine kinase and elevated myoglobin levels in both urine and serum. These patients usually present with acute onset of “antisynthetase syndrome,” constitutional symptoms, Raynaud’s phenomenon, and a nonerosive arthritis.While the laboratory findings here were consistent with a possible myopathy, the clinical presentation was not classic, making this a less likely possibility. Another consideration was rhabdomyolysis potentially resulting from compartment syndrome. Compartment syndrome occurs from increased fascial compartment pressure with subsequent tissue hypoperfusion, which can lead to muscle necrosis and rhabdomyolysis. The classic triad of findings in rhabdomyolysis is muscle pain, weakness, and dark urine. Patients with rhabdomyolysis usually have some combination of highly elevated creatine kinase, myoglobinuria, hyperkalemia, hyperphosphatemia, acute kidney injury, hypocalcemia, and metabolic acidosis with or without an anion gap.4 In this patient’s case, there was no clear inciting event, and her symptoms were episodic with spontaneous resolution. Additionally, she did not complain of focal pain or weakness as would be expected in compartment syndrome. Although she did have an elevated creatine kinase, the elevation was not significant and the expected laboratory findings of hyperkalemia and hyperphosphatemia were not present. I felt that compartment syndrome and rhabdomyolysis were unlikely. In this young adult patient with episodic weakness and hypokalemia, hypokalemic periodic paralysis was immediately considered as part of the differential diagnosis. This condition is characterized by attacks of weakness with a normal neurologic exam in between, as seen in this patient. Primary hypokalemic periodic paralysis follows an autosomal dominant inheritance pattern, and notably this patient had no known family history of the same. Bulbar and respiratory functions are preserved and between attacks, patients will also present with normal plasma potassium. Triggers include stress, exercise, and carbohydrates. The condition also presents with arrhythmias.There are, however, other conditions that can cause non-familial hypokalemic paralysis, including RTA.6 All three sub-types of RTA are characterized by an inability to acidify the urine. As a result of this, RTAs present with an increased urine anion gap, but this information was not provided in the case history. In distal or type 1 RTA, there is impaired hydrogen ion secretion in the distal tubule of the nephron. In proximal or type 2 RTA, there is impaired bicarbonate reabsorption in the proximal tubule of the nephron. In type 4 RTA, there is decreased aldosterone secretion or aldosterone resistance.As a result of this, type 4 RTA is associated with serum hyperkalemia while the other two types of RTA result in hypokalemia.Due to the serum potassium levels, which were not suggestive of aldosterone resistance, I eliminated type 4 RTA from my list of possibilities.In type 2 RTA, urine pH is initially high, then decreases to < 5.5. The urine pH remains above 5.5 in type 1 RTA.This patient had a urine pH of 7.0, suggesting either a type 1 RTA or an early type 2 RTA. Type 1 RTA can be hereditary or be caused by autoimmune diseases such as Sjögren’s syndrome, or as a complication of chemotherapy or toluene use. The causes of type 2 RTA include genetic abnormalities, Fanconi syndrome, monoclonal gammopathy, and carbonic anhydrase inhibitor use.There was no mention of chemotherapy or carbonic anhydrase inhibitors with the patient’s presentation. The patient had no family history of similar issues, and it would stand to reason that a genetic abnormality would have come to light before age 19 years. As such, I feel type 1 RTA is more likely than type 2 RTA. The Agency for Toxic Substances and Disease Registry notes that toluene is a solvent found in paints, nail polish, paint thinners, and adhesives, among other substances. It can have toxic effects if ingested or inhaled.The findings of acute toluene use include a hypokalemic paralysis and a metabolic acidosis. Patients are also often found to have liver injury andrhabdomyolysis, and may present with altered mentation, renal failure, and acidemia.This patient’s presentation is most consistent with type 1 RTA due to toluene use. She denied any illicit drug use but did admit to a history of alcohol ingestion and marijuana use, raising the question of whether there could be toxic alcohols or other coingestions. Unfortunately, there is no diagnostic test for toluene use. However, proximal and distal RTA can be differentiated by calculating the urinary ammonium ion concentration from the measured urine anion gap and osmolar gap. Therefore, my test of choice would be a urine electrolyte panel to calculate the anion gap and osmolar gap. Additionally, I would consult nephrology to assist in management of this patient.

These indications are relevant, but they are open nevertheless to several possible objections. For example, although endogenous cannabimimetic compounds exist, it is conceivable that they may never engage cannabinoid receptors under physiological conditions. Indeed, if these receptors were constitutively active in the absence of agonist, as suggested by studies with heterologous expression models , there may be no need for an intrinsic cannabinoid ‘‘system,’’ intended as a group of interconnected cells that produce and respond to endogenous cannabinoids. These and similar concerns highlight the many gaps left unfilled in our understanding of intrinsic cannabinoid modulation. It is now generally agreed that substances with cannabimimetic properties are released during neuronal activity, and that these substances are inactivated by a set of mechanisms parallel to, but distinct from, those utilized for the elimination of established neurotransmitters. But where in brain and peripheral tissues do these reactions take place? And under what circumstances? Are there discrete cannabinergic pathways comparable to, say, dopaminergic ones? Or do endogenous cannabinoids act as local mediators? What behavioral needs regulate endogenous cannabinoid release?And what physiological adaptations are served by such release? To address these questions critically,microgreen rack for sale we need first to recognize certain biochemical and physiological peculiarities of the cannabinoid signaling system which distinguish it from classical neurotransmitters. The nature of these peculiarities is the key theme that will be developed in the present review.

Early reports of anandamide biosynthesis through energy-independent condensation of nonesterified arachidonate with ethanolamine have been subsequently attributed to a reversal of the anandamide amidohydrolase reaction, which participates in anandamide degradation , or to the artifactual formation of compounds with some chromatographic properties of anandamide . Since anandamide amidohydrolase requires high concentrations of arachidonate and ethanolamine when acting in reverse, much higher than those normally found in cells , this enzyme is unlikely to play a physiological role in anandamide formation . Another model of anandamide is illustrated schematically in Fig. 2. According to this model, anandamide formation proceeds from the cleavage of the phospholipid precursor, N-arachidonyl phosphatidylethanolamine , catalyzed by a phosphodiesterase activity such as phospholipase D. The precursor consumed in this reaction may be rapidly resynthesized by a second enzyme activity, N-acyltransferase, which cleaves arachidonate from the sn-1 glycerol ester position of phospholipids and transfers it to the primary amino group of PE.Under physiological conditions, formation of anandamide and resynthesis of its precursor may be initiated at the same time, when neurons are depolarized and intracellular Ca21 levels are elevated . The anandamide precursor, N-arachidonyl PE, belongs to a family of N-acylated PEs, the ethanolamine moiety of which is linked to different saturated or unsaturated fatty acids. Like N-arachidonyl PE, other N-acyl PEs are also synthesized by N-acyltransferase and, when cleaved by phosphodiesterase, give rise to acylethanolamides. In addition to their lack of activity on CB1 receptors , we know very little about the pharmacological effects of these acylethanolamides and even less about their possible biological functions .

One notable exception may be palmitylethanolamide, which is produced by cleavage of N-palmityl PE. This compound exerts significant analgesic and anti-inflammatory effects in vivo which have been attributed to its ability to interact with a CB2-like receptor sensitive to the compound SR144528 . The molecular identity of this putative receptor sub-type is unknown, although it is likely to be distinct from the cloned CB2 receptor for which palmitylethanolamide shows little or no binding affinity . The fact that both N-acyl PEs and acylethanolamides are also present in plants, where their synthesis is regulated by extracellular stimuli , suggests that this signaling mechanism has been established early in the evolution of multicellular organisms.Textbook lipid biochemistry predicts two most plausible pathways of 2-AG biosynthesis, which are depicted in Fig. 3. Phospholipase C hydrolysis of membrane phospholipids produces 1,2-diacylglycerol, which is converted to 2-AG by diacylglycerol lipase activity. Alternatively, phospholipase A1 generates a lysophospholipid, which is hydrolyzed to 2-AG by lyso-PLC activity . In addition to these phospholipase-mediated pathways, 2-AG accumulation may result from the breakdown of triacylglycerols, catalyzed by neutral lipase activity , or from the dephosphorylation of lysophosphatidic acid . The fact that 2-AG formation in cortical neurons in culture is prevented by various PLC and diacylglycerol lipase inhibitors suggests a predominant involvement of the PLC pathway . However, the phospholipid substrate and PLC isoform implicated in this reaction remain to be discovered. Also, it cannot be excluded that multiple enzyme pathways may participate in generating 2-AG, an event that is not uncommon in lipid metabolism . Regardless of its precise mechanism, 2-AG biosynthesis appears to be triggered by rises in intracellular Ca21 elicited during neuronal activity.

This was shown in hippocampal slices by applying electrical stimulations to the Schaffer collaterals, a glutamatergic fiber tract in the Ammon’s horn region that projects from CA3 to CA1 neurons. High-frequency stimulation of these fibers produced a fourfold increase in 2-AG accumulation compared to controls, which was prevented by the Na1 channel blocker tetrodotoxin or by removing Ca21 from the superfusing solution. Noteworthy, the local concentrations reached by 2-AG after stimulation were calculated to be approximately 1–2 µM . Since 2-AG binds to CB1 receptors with a Kd of 0.7–2 µM , the levels of 2-AG found after stimulation are expected to cause a substantial activation of the dense CB1 receptor population expressed in hippocampus .An essential feature of these models is that both anandamide and 2-AG may be produced and released upon demand, through a mechanism that may not require vesicle neurosecretion. In the case of anandamide, this hypothesis is supported by a variety of experimental evidence. First, the concentration of anandamide in neurons is exceedingly low under basal conditions , about 100 to 10,000 times lower than those of amino acid and amine neurotransmitters which are stored in synaptic vesicles . Second, stimulus-dependent release of anandamide from neurons is associated with anandamide formation and with de novo N-arachidonyl PE biosyn-thesis . Third, the release of anandamide may be dissociated experimentally from that of classical neurotransmitters; for example, although striatal neurons in culture rapidly take up radioactively labeled anandamide, they do not release it in a Ca21 -dependent manner, as it can be readily demonstrated with labeled amino acids or bio-genic amines . A parsimonious interpretation of these findings is that anandamide may be produced when need arises and immediately dispatched outside cells, without an intermediate step of vesicle storage.How is newly formed anandamide released, and how does it reach its cellular targets? Water-soluble neurotransmitters that are released by secretion can diffuse unhindered through the aqueous compartment of the synaptic cleft to their postsynaptic receptors. But this is probably not the case with anandamide, the hydrophobic nature of which may favor its association with lipid membranes and introduce considerable constraints to its extracellular movements. Nevertheless,cannabis grow facility layout we know that anandamide does exit neurons because it can be found in incubation media of brain slices or perfusates of brain microdialysis experiments . We also know that certain cells, such as striatal astrocytes, respond to anandamide but do not have the enzymatic machinery to produce it . This implies that anandamide may travel from one cell to another, overcoming its tendency to partition in the lipid bilayer. We do not know yet how this may occur, but enough clues are available to offer the working hypothesis illustrated in Fig. 4.This indicates that anandamide may be produced within the cell membrane and may be able to move into the extracellular space immediately after cleavage of Narachidonyl PE has taken place. As with other lipid compounds, the actual release step may be mediated either by membrane transporters or by lipid-binding proteins . The latter may also facilitate the movement of anandamide in the aqueous environment surrounding cells and help it attain its cellular targets.A close link between activity-dependent formation and extracellular release is a feature that distinguishes anandamide from classical neurotransmitters and underscores certain functional properties that may be characteristic of this endogenous cannabinoid. From a kinetic standpoint, anandamide release is unlikely to be as rapid and discrete as that of established neurotransmitters, implying that anandamide may act as a slow messenger molecule. Moreover, since anandamide release does not appear to be mediated by vesicle secretion, it is unlikely to be exclusively localized to synaptic nerve endings. As a result, anandamide may serve both synaptic and extrasynaptic signaling functions, a possibility that finds support in the presence of CB1 cannabinoid receptors in neuronal cell bodies and dendrites .

Slow and diffuse local effects are not unique to anandamide. To a certain extent they are also seen with neuroactive peptides, but they are especially characteristic of the growing family of phospholipid-derived bioactive mediators. It is perhaps not surprising that compounds like the eicosanoids and LPA would share with anandamide a number of functional properties such as release upon demand and spatially circumscribed actions. More intriguing is the fact that LPA and CB1 receptors exhibit a significant degree of sequence homology , which suggests the existence of a connection between these two apparently unrelated messenger systems. The functional significance of this link, if any, remains at present unknown. The dissimilarities with classical neurotransmitters on the one hand, and the analogies with lipid mediators on the other, emphasize the idea that anandamide may act primarily as a local modulatory substance. In agreement with this, as we have seen, may be the time course of anandamide release and the extrasynaptic range of its biological effects. But also the possibility that many cell types that express cannabinoid receptors may also be capable to synthesize anandamide , which is consistent with a localized feedback action of this lipid messenger. A critical test of this hypothesis is still lacking, however. This will have to come from the anatomical localization of the enzymes involved in anandamide formation, as well as from detailed studies on the kinetics and distribution of anandamide release and inactivation in vivo.Neurons and astrocytes in primary culture avidly internalize exogenous anandamide through a process that meets all key criteria of a carrier-mediated transport. These criteria have been defined in detail by experiments with other membrane transporters , and include time and temperature dependence as well as high substrate affinity and selectivity . Strong support to the existence of an anandamide transporter has also come from the development of a compound, N–arachidonylethanolamide , which blocks anandamide transport competitively . Using this inhibitor, it has been possible to demonstrate that high-affinity transport participates in the inactivation of exogenously administered anandamide both in vitro and in vivo . It is unclear whether AM404 also blocks the biological disposition of endogenously released anandamide; if this were the case, AM404 may be helpful to understand the physiological functions of anandamide, and may serve as a scaffold to develop therapeutic agents acting as indirect agonists at central and peripheral cannabinoid receptors. A mechanistic feature of anandamide transport is its lack of Na1 dependence, which suggests that anandamide is accumulated in cells via a carrier-mediated diffusion process driven by the concentration gradient of anandamide across the lipid bilayer. This feature differentiates anandamide from all known neurotransmitters but associates it with prostaglandin E2, the membrane transporter of which is also Na1 independent . Thus, even from the standpoint of its inactivation route, anandamide appears to behave more as a local mediator than as a bona fifide neurotransmitter. In addition, the fact that anandamide may be transported by facilitated diffusion suggests that the kinetics of its biodisposition may be slower than that of amino acid or amine transmitters. To be able to address this question, however, we must await the cloning and functional expression of the anandamide transporter protein.If cellular energy does not propel the transfer of anandamide across cell membranes, what does? Intracellular degradation may be one possibility. Indeed, a membrane-bound enzyme that catalyzes the breakdown of anandamide to arachidonic acid and ethanolamine has been identified and cloned . The intracellular localization of this enzyme, termed anandamide amidohydrolase or fatty acid amide hydrolase, is supported by studies with subcellular membrane fractions , by its deduced amino acid sequence , and by the fact that anandamide hydrolysis takes place after this lipid has been accumulated in cells .

For participants who consented to having data abstracted from their electronic health record , we abstracted HIV viral load and CD4 counts. Data were abstracted only if the person had had a test within the past year, and the most recent test result was used. Viral load was dichotomized as detectable or undetectable . For the analysis, we focused on undetectable viral load as the outcome of interest. Patient-Provider relationship was measured using the Engagement with Health Care Provider scale , a 13-item instrument in which clients rate their interactions with their providers on a scale of 1 “always” to 4 “never”. Responses are summed to get a total score of 1-52, with lower scores indicated greater engagement. Appointment Adherence. Appointment adherence is the percentage of scheduled clinical appointments that were actually attended in the six months prior to the study visit. First, we generated descriptive statistics to summarize the baseline data. Second, we used bivariate linear and logistic regression analysis to examine relationships between trauma and various indicators of health. Third, we used bivariate linear and logistic regression analysis to examine factors that are associated with the two outcomes of interest: quality of life and undetectable viral load. In past focus group discussions with clinic patients, quality of life emerged as one of the most important outcomes of interest for patients themselves, and it is one that clinicians and other care team members want for patients as well. At the same time, viral suppression is a major focus of the HIV Care Continuum and remains a national priority in HIV/AIDS care and treatment. Thus, we elected to focus on trauma’s impact on one patient- centered outcome and one HIV Care Continuum outcome in this analysis. All analyses were conducted using Stata 14 . Participants in the study were 104 women living with HIV . Four participants identified as transgender or intersex; they were included in all analyses as the intervention being evaluated is clinic-wide and the four women represent an important portion of the clinic’s patient population.

The participants’ mean age was 52 years and almost 80% were women of color. Approximately half had a high school education or less,indoor growers only 20% were working for pay, and 61% reported food insecurity in the past year. Almost all participants were living in stable housing. The mean ACE score was 4.2, and more than half of participants reported four or more ACEs. In this study, lifetime trauma and recent trauma were also common , and many participants reported having experienced threats, abuse, and violence as a result of disclosing their HIV status to others . Participants who reported four or more ACEs were significantly more likely to report both lifetime and recent trauma. ACE scores and THS scores were highly correlated . Most study participants had been living with HIV for a substantial number of years, and the majority reported that they were currently on ART medications . Of the 96 participants who had available viral load data, 68 had an undetectable viral load . Of the 83 participants who reported being on HIV medications and who had available viral load data, 66 had an undetectable viral load. Two participants who reported not being on ART also had undetectable viral loads.One-third met the diagnostic criteria for PTSD ; almost one-half reported at least moderate levels of depression symptoms ; and more than one-quarter reported at least moderate levels of anxiety symptoms . Although the mean alcohol use disorder screening scores were low overall and 52.4% of participants reported no current alcohol use at all, 17% of participants reported binge drinking and 22.1% met the threshold for further alcohol use disorder screening, indicating high levels of use among those who do drink. Almost one-half of participants reported tobacco use in the past three months; 27.9% reported use of cocaine, amphetamines, sedatives, and/or illicit opioids in the past 3 months; and 17.3% reported at least moderate levels of drug abuse, reaching the threshold for further investigation or intensive assessment. Ratings of patient-provider relationship were very high with a mean of 1.2. We also investigated various forms of social health. Among study participants, the mean total Empowerment Scale score was 3.0 out of a total possible score of 4.0. Mean social support for all participants was 3.2. When asked how open or ‘out’ they were about their HIV status, 24 reported being completely out, while 24 reported being not at all out, and 7 participants had never told anyone of their HIV-positive status. However, participants overall reported only moderate levels of total HIV related stigma .

The mean quality of life score was 13.8, with 54.8% of participants scoring below 13, indicating poor quality of life.Next, we examined relationships between trauma and various indicators of health . Experiences of lifetime trauma, as measured by the THS, were significantly associated with ART medication use among participants; for each additional trauma experienced, participants had significantly reduced odds of being on ART medications . Similarly, participants with higher numbers of trauma experiences had significantly lower odds of reporting good 30-day HIV medication adherence . In contrast, there were no significant relationships between trauma and CD4 count, or whether the participant had an undetectable viral load . We then considered the relationship between trauma and behavioral health outcomes. Experiencing more traumatic events was significantly associated with higher PTSD symptom scores , higher depressive symptom scores , and higher anxiety symptom scores , as well as greater odds of reaching the diagnostic thresholds for all three . In addition, although higher counts of traumatic events were significantly associated with higher alcohol use scores , they were not significantly associated with the AUDIT screening threshold that would indicate an alcohol use disorder . Higher THS counts were also not associated with self-reported use of tobacco, cannabis, or sedatives in the past three months, but were significantly associated with recent use of cocaine , amphetamines , and illicit opioids . Higher counts on the THS were also associated with higher odds of self-reported overall “hard” drug use . Finally, more traumatic experiences was associated with higher drug abuse screening raw scores and with greater odds of having a positive drug abuse diagnosis .In examining well-being and social health outcomes, we found that trauma was associated with significantly greater HIV stigma . Trauma was also significantly negatively associated with quality of life and mental well being; those with more traumatic experiences had lower quality of life scores , as well as lower psychological well being scores .

Trauma was not, however, significantly associated with empowerment, social support, or disclosure.In this sample of women living with HIV, we found near-universal reports of lifetime trauma, including childhood and adult trauma, as well as a significant minority who reported incidents of abuse and threats in the past 30 days. These findings support the growing body of literature documenting high rates of trauma and PTSD among WLHIV , and uniquely add to it by documenting high mean ACE scores in a population of WLHIV for the first time. In examining quality of life as one of our two main outcomes of interest,trimming tray we found that over half of the women experienced poor quality of life despite the broad availability and use of antiretroviral therapy and despite most participants having an undetectable viral load. Those who had experienced more trauma had significantly poorer overall quality of life compared to those who had experienced less trauma. We also found that traumatic experiences were significantly associated with greater symptoms of depression, anxiety, and PTSD, worse HIV-related stigma, and poorer mental well being. In addition, trauma was associated with greater alcohol and drug use and higher drug abuse screening test scores. The link between adverse childhood experiences and later substance use and substance use disorders has been well described . The high level of substance use in this population is very concerning due to the known disproportionally high rates of death among WLHIV from substance use . In examining the impact of trauma on our second main outcome of interest, we did not find a significant relationship between trauma and having an undetectable viral load. However, trauma was significantly negatively associated with being on antiretroviral medications for HIV and with ART adherence, both of which are key outcomes on the HIV Care Continuum and are key contributors to the likelihood of achieving an undetectable viral load. These findings support prior research that has documented the impact of trauma sequelae such as PTSD and depression symptoms on HIV medication adherence . For individuals who have experienced significant trauma, the increased risk of PTSD symptoms such as avoidance behaviors, depression, and HIV-related stigma may make it more difficult to engage in self-care and to adhere to treatment regimens. Although we did not identify a significant relationship between trauma and an undetectable viral load, other studies have documented this relationship . In addition, the high rates of virologic suppression in our sample may have affected this study’s ability to detect the link between trauma and virologic suppression despite the identified association of trauma with the key predictors of it. This study had several limitations. First, because the data reported here are cross-sectional, causality cannot be determined. However, the associations between lifetime trauma and poor quality of life, PTSD, depression, anxiety, and substance use suggest a role for trauma in later health outcomes for WLHIV. Second, the sample size was relatively small. Within this clinic, however, the 104 patients who participated in the study accounted for approximately two thirds of all clinic patients who were eligible for the study at baseline. At the same time, the clinic population is fairly representative of the national population of women living with HIV, particularly in urban areas. Therefore, the study has some degree of generalizability to the larger population of WLHIV in the United States. Another limitation of the study was the measurement of trauma. Although we used three different measures that covered childhood, lifetime, and recent trauma, there are many other types of trauma that we did not measure. For example, although we recorded race, we did not include a specific measure of experiences and impact of racism in the study. Similarly, many patients in the clinic have been involved with the foster care and/or the prison systems, where trauma and violence are common, and we did not record this information or the impact that it may have had on their health outcomes. It is possible that individuals may have experienced other traumatic events that we did not measure. The overall study, however, has many strengths. These baseline data, as well as data from the parallel study with clinic staff , are being used to inform implementation of TIHC in the clinic. This includes educating staff about the impact of trauma on health, creating a safe and welcoming environment for patients, screening patients for the consequences of trauma, and using data to identify the most effective ways to respond to past and ongoing trauma . In addition, the results presented here are from the baseline stage of a larger longitudinal mixed-methods study that will allow us to evaluate the impact of trauma-informed health care on health outcomes for WLHIV. This larger study includes survey and EHR data collection at multiple times over a number of years, as well as qualitative data collection with both patients and staff to contextualize the findings of survey data. Although this baseline study was neither designed nor powered to elucidate the pathways to explain the relationship between trauma, poor quality of life, and other poor health outcomes, the results add to a growing recognition that the current national focus on virologic suppression is insufficient as a measure for health and well-being of WLHIV .The psychoactive effects of D 9 -tetrahydrocannabinol, the major pharmacological ingredient of Cannabis sativa, are produced through the activation of selective G protein-coupled membrane receptors . The abundant expression of cannabinoid receptors in brain and the behavioral consequences of their activation, ranging in humans from euphoria to memory deficits, underscore the potential importance of the endogenous signaling system by which these receptors are thought to be engaged . Yet, the biochemical nature, anatomical distribution, and physiological functions of such signaling systems remain elusive.

Participants returned for follow-up measures and cotinine testing 6 and 12 months after baseline. Study incentives were $30 for the baseline, $35 for the 6-month, and $40 for the 12-month follow-up visits.Cessation information and local treatment options were provided. The research design and study procedures were approved by the University of California, San Francisco Institutional Review Board.In this longitudinal study of adolescent e-cigarette use with self-reported and biomarker data, 80.3% of the sample continued to use e-cigarettes at 12 months, with significantly greater ecigarette use frequency, dependence, and nicotine exposure. The percentage of daily e-cigarette users doubled from 14.5% at baseline to 29.8% at 12-month follow-up. The patterns of ecigarette use observed over time indicate substantial persistence and the use of greater amounts of nicotine over time . These findings lend support to concerns regarding the addictiveness of e-cigarettes for adolescents. In the United States, prevalence of past-month e-cigarette use increased dramatically among adolescents in 2018, whereas cigarette use declined and cannabis use remained constant. Results of this study suggest that increased prevalence of recent e-cigarette use may lead to frequent use, dependence, and greater nicotine exposure. Dependence scores at baseline were low on average, with most participants meeting a classification of “not dependent,” and 13.3% meeting a classification of moderate to heavy dependence. By 12 months, the percentage classified with moderate to heavy dependence increased to 23.3%. These findings would suggest that factors other than dependence are driving early use of e-cigarettes, and that over the course of just 1 year, more teens become daily users and more heavily dependent. Along with the self-reported increase in frequency of e-cigarette use and dependence, cotinine levels increased over time, reflecting increased exposure to nicotine. The increase in cotinine levels may be both the result of increased dependence and a catalyst for the development of dependence. Adolescents who become increasingly dependent on e-cigarettes may increase their nicotine use, thereby worsening dependence. Notably,pot drying devices with higher nicotine yield became increasingly popular over the course of the 12-month trial, consistent with the reports of greater nicotine dependence and higher cotinine levels.

Transitions from single to dual and dual to single nicotine product use were observed in approximately one in three users over the study period. None of the baseline dual users abstained from both products at either follow-up, which may be partially due to their higher dependence on e-cigarettes at baseline, as well as the normalization of smoking behavior and associations between smoking cues that can perpetuate use of both products. Consistent with prior research, adolescent participants offered a wide range of reasons for e-cigarette use. The top three reasons for initiating and continuing use were socializing, enjoyment, and flavors. The top three reasons for quitting were a desire for self-improvement, difficulty maintaining an e-cigarette device, and getting in trouble for vaping at home or school. The top flavors were fruit, menthol/mint, and candy. Taken together with experimental research demonstrating the influence of flavors on adolescents’ product choices, these findings suggest that efforts to reduce adolescent e-cigarette use ought to include regulatory action that addresses kid-friendly flavors. Little research has examined adolescents’ reasons for quitting e-cigarette use, and our findings preliminarily suggest that adolescents perceive parental controls and appropriate disciplinary consequences to be impactful.All participants were recruited from the San Francisco Bay Area, and a majority were male and White, which may limit generalizability. The sample size was relatively small, although adequate to detect significant differences over time in this repeated-measures study design. The combination of self-report and biomarker data was a study strength. Over the course of a year, the vast majority of adolescents continued to use e-cigarettes, daily use increased from 14.5% to 29.8%, and product type evolved to higher nicotine delivery devices, with Juul being the most preferred brand at 12 months. Flavor preferences stayed fairly constant , and dependence and cotinine levels increased. Transitions from single to dual and dual to single nicotine product use were observed in approximately one in three users over the study period in about equal proportions. None of the baseline dual users abstained from both products at either follow-up. The findings indicate persistence in adolescents’ e-cigarette use, with significant increases in frequency of use and nicotine exposure over time and with associated increases in dependence.

Electrical injury is responsible for approximately 1000 deaths and 3–5% of all burn admissions per year in the US. EI victims are not only hospitalized for burns, but also for skeletal muscle tetany, respiratory muscle paralysis, or ventricular fibrillation. However, these statistics do not include the victims that mainly suffer from the neuropsychological, neurological, and psychiatric sequelae associated with EI. While the past literature shows that EI sequelae is typically associated with burns due to the current’s thermal load and the body’s tissue resistance, the literature also shows that remote psychiatric effects are indicative of and distinct to EI.White matter abnormalities after EI have also been found on magnetic resonance imaging scans, particularly hyperintensities in the cerebral corticospinal tract.One morning in the spring of 2009, the 37-year-old patient was walking his dog in a densely populated city, when his dog stepped in a puddle of melted snow and suddenly jumped upwards, yelped, and started convulsing and defecating himself. The patient bent down on his right knee and grabbed the dog with his left arm as he held himself up with his right hand, which was in the puddle. He reported a ‘‘buzzing feeling” traveling up his right arm. After bringing his dog to safety, the patient returned to the site, got down on both knees, put both hands in the puddle, felt a ‘‘humming” sensation travel up both arms and felt ‘‘stuck” in that position for 2–3 s . Immediately after the shock, the patient sustained burn marks and experienced short-term memory loss and fatigue. Three days later, the patient saw an internist and reported upper right quadrant pain, headaches, numbness, weakness, fatigue, insomnia, and minimal, first degree burn marks on his right underarm and on the dorsal aspect of both forearms. The surface area was 1.1% for each forearm, and an additional 1.1% for the right underarm,cannabis drying for a total affected area of 3.3%. One week later, the patient received MRIs of the lumbosacral spine, cervical spine and brain which all reported no abnormalities. One month later, the patient visited a psychologist regarding anxiety, insomnia, and depression, and was diagnosed with post-traumatic stress disorder and retrograde amnesia. Three months after the electrical injury, the patient saw an ophthalmologist regarding pain behind his right orbital and ‘‘drooping” of the right side of his face; he was diagnosed with Bell’s palsy. Two years after the incident, the patient had an orthopedic evaluation for right side body pain, loss of right hand motor control, right hand tremors, pain behind the right orbital and headaches with no orthopedic abnormalities found. The following day, the patient visited a neurologist and a different ophthalmologist regarding the same symptoms, with no abnormalities found. Three years after the electrical injury, the patient visited a neurologist regarding hypesthesia in the right side of the face and to pinpricks to the right hand, severe pain in the right arm and hand, moderate pain in the left arm and hand, and was diagnosed with electrocution neuropathy.

Five months later, the same neurologist noted improvement of the pain in the right arm and hand area. During the same year, the patient visited a therapist and was diagnosed with PTSD, severe anxiety, and situational depression and was prescribed psychotherapy as treatment. Six years after the injury, additional documentation of the damage sustained from the electrical injury was needed to provide objective evidence as part of a lawsuit against the electric company responsible for the exposed wires. The patient visited our laboratory for an MRI DTI and quantitative volumetric analysis, and a clinical neuropsychologist for an exam. At the time of the neuropsychological exam, the patient was taking Bupropion XL, Clobex, Hydrocodone/Acetaminophen, melatonin, Klonopin , Namenda , Neurontin , and medical marijuana. On the Diller-Weinberg Test, the patient missed 39/47 stimuli, and his visual encoding/processing speed on specific Wechsler Adult Intelligence Scale subtests was between the 1st and 5th percentile. On the dominant finger tapping test, the patient scored in the 5th percentile. His performance on a timed task of fine motor dexterity was impaired between 2 – 3 standard deviations below the mean, and his motor and processing speed index was in the 2nd percentile, which is typical residual of electrical injury. The patient scored 20 less points on his Performance intelligent quotient than his Verbal IQ , which is statistically significant and notably unusual. He scored as severely depressed on his Beck, and has had severe chronic pain and PTSD symptoms in the clinical range. The patient’s past medical history was significant for meningitis at age 10, and arthritis and hypertension as an early adolescent. The patient underwent several unrelated orthopedic surgeries from sports related injuries, with the last surgery being sixteen years before the electrical injury. According to his ex-fiancé, the patient was very social and outgoing before the electrical shock, while he became withdrawn and isolated afterwards. The patient enjoyed activities such as surfing, swimming, hiking, basketball, and skateboarding, all of which he was unable to do, or did differently, after the injury. At the time of the incident, he was in good health and working as a physical trainer.Most electrical injuries happen in the workplace, while some occur in household settings. In dense cities that experience heavy snow during the winter, like Boston or New York City, residents are at a higher risk of electrocution through stray voltage when the snow starts to melt. Stray voltage is the unintended occurrence of an electrical potential between two objects due to a fault in an electrical system and is defined to be less than 10 volts by the U.S. Department of Agriculture. These circumstances, coupled with the increased conductance caused by high-salinity snow melt, can charge normally non-threatening metal objects, or puddles with ample amounts of stray voltage. Electrical injury occurs when a person has at least two points of contact with two sources of different voltage, one of which may be the earth ground The extent of electrical injury is dependent on the voltage, amperage, path of and type of the current /direct current, duration of contact, and premorbid state of the patient.Skin is the body’s primary defense against external electric currents. A dry hand may have a resistance of approximately 100,000 X, while the internal body may have a resistance of approximately 300 X due to wet and salty tissues under the skin. Skin resistance can be greatly reduced to approximately 1000 X if there is significant physical damage such as a cut, burn or abrasion, or if the skin has been wet. At roughly 16 mA for a 60 Hz AC, the average man would experience a muscle spasm known better as the ‘‘no-let-go” phenomenon, in which he would not be able to let go of the current source .In the presence of an external electric field, cell membrane permeabilization occurs as the lipids in the lipid bilayer undergo reorganization in a process known as electroporation . In turn, cell contents such as ions are able to move freely in and out of cells. Through the phenomenon of electroporation, current is able to travel through and leave the body through the second contact point to a grounding source. Clearly these aspects of EI are quite mechanistic, however, one of its enigmas include the remote neuropsychological deterioration of the patient regardless of the trajectory of the current .Duff compiled a review of twenty eight studies of EI and lightning injury patients, logging 2738 victims reporting a total of 4441 signs or symptoms. These signs/ symptoms were ‘‘categorized into nine different domains of sequelae, which included disturbance of consciousness, attention/concentration deficits, speech/language deficits, sensory deficits, memory deficits, other cognitive deficits, psychiatric complaints, somatic complaints, and neurological complaints”. Another study of the long-term sequelae of low-voltage electrical injury done by Singerman reported numbness, weakness, and memory problems as the most frequent neurological problems and anxiety, nightmares, insomnia, and flash backs of the event as the most frequent psychological problems.

Ethnicity or ethnic identity is not some immutable sense of one’s identity but rather something produced through the performance of socially and culturally determined boundaries . Hence, individuals are not passive recipients of acquired cultures but instead active agents who constantly construct and negotiate their ethnic identities within given social structural conditions . In spite of these sociological contributions, which have enriched our understanding of identity generally and ethnicity specifically, the alcohol and drugs fields have not adequately integrated these perspectives, thwarting our ability to understand the relationships between ethnicity and substance use. As such, the field is ripe with correlations between ethnic group categories and substance use problems, resulting in solutions to problems that focus on reifying questionable social group categorizations and revealing little about how drugs are connected to identities and shaped by broader social and cultural structures. It is important to note that we do not intend to argue that existing categories of ethnicity be disregarded in the alcohol and drugs fields. As Krieger and colleagues have noted in another context , surveillance data documenting health disparities, in our case in substance use, are exceedingly important in terms of identifying potential inequities in health. However, without understanding the complexity of ethnic identity and its relationship to substance use, these surveillance data may perpetuate stereotypes and the victimization of specific socially-delineated ethnic groupings, obfuscate the root causes of substance use and elated problems, and reify politicized categories of ethnicity which may have little meaning for the people populating those categories. While acknowledging that socially-deliented ethnic categories are important for documenting social injustices,marijuana grow system we must also be vigilant about questioning the appropriateness of those categories . Conceptually this type of critical approach is important for considering how substance use is related to negotiations of ethnicity over time and place and bounded by structure.

Maintaining a static and homogenous approach towards ethnic categorizations in the alcohol and drugs fields presents at least two problems. First, it risks overlooking how drugs and alcohol play into a person’s negotiation of identity, particularly ethnic identity, thus revealing little about the pathways that lead to substance use. Cultural researchers have long emphasized the importance of commodity consumption in the construction of identities and lifestyles , particularly within youth cultures , and how it can be an important factor in demarcating and constituting social group boundaries . A limited body of research in the alcohol and drugs field has emphasized the role of substance use in constructing and performing identities , particularly ethnic identities , uncovering how subgroups within traditionally-defined ethnic minority categories use drugs and alcohol to distinguish themselves from ethnically similar others. For example, in a qualitative study of Asian American youth in the San Francisco Bay area in the US, narratives illustrated how youths’ drug use and drug using practices were a way of constructing an identity which differentiated them from “other Asian” youth groups, specifically allowing them to construct an alternative ethnic identity that set them apart from the “model minority” stereotype . Thus taste cultures and consumption-oriented distinctions highlight the continuing salience of and interconnections not just between substance use and changing notions of ethnicity but also between substance use, class and ethnicity. Ethnic identity gets translated into social captial which in turn has ramifications for one’s economic and social standing . Second, failing to critically appraise our use of fixed and homogenous ethnicity categories in the alcohol and drugs fields jeopardizes our ability to identify the broader social and structural determinants of alcohol and drug use and related problems—like poverty, social exclusion, and discrimination—which are crucial issues for addressing social injustices. So often studies revealing correlations between ethnic categories and substance use related problems result in discussions about the importance of developing culturally-appropriate prevention and treatment interventions, overlooking the structural conditions that adversely affect socially-defined ethnic groupings and may result in some form of engagement with alcohol and/or drugs. For example, research on street cultures, where ethnic identifications and drugs play a central part, illustrates how some ethnic minority youth use and/or sell drugs to actively construct counter-images or ethnically-infused street cultures of resistance within their neighborhoods, which some researchers have called “neighborhood nationalism” , as a way of resisting or transcending “inferior images” ascribed to them by the wider society . These street cultures provide alternative definitions of self-identity, especially for young men, who live in communities marked by poverty and marginalization and who have little access to masculine status in the formal economy .

Such cases clearly show how drug use and sales is not the fault of the individual or a deficiency resulting from one’s ethnicity, but instead from a deficiency in society. The COVID-19 pandemic has produced major disruptions in daily life. A recent review concluded that the world population is experiencing increased stress, anxiety, and depression due to the pandemic and associated mitigation measures . In late June 2020, 40% of U.S. adults reported experiencing mental health symptoms, a stress disorder, or increasing substance use to cope with pandemic-related stress . Individuals with problematic substance use are particularly vulnerable to COVID-19 illness and psychosocial effects of the pandemic, such as stress and substance use treatment disruptions . Disruptions in treatment increase risk of overdose, a serious complication of substance use disorders . Moreover, depression and anxiety commonly co-occur with substance use disorders . Evidence suggests that in the general population, increases in alcohol consumption during COVID-19 may be driven by stress, depression, and anxiety . Effects may be even more pronounced among individuals with problematic substance use. Periods of intense stress can give light to pre-existing fissures and vulnerabilities in people’s daily lives. A better understanding of substance use problems, depressive symptoms, and anxiety during the COVID-19 pandemic among people with problematic substance use can inform intervention efforts needed now and post-pandemic. Various pandemic-related situational factors may differentially affect substance use problems . According to behavioral economics, the COVID- 19 pandemic and associated mitigation measures may decrease the negative consequences of substance use . Many individuals are now working from home and have a more flexible schedule, making some of the negative consequences of substance use less relevant than before the pandemic. Simultaneously, the pandemic has limited the availability of alternative rewarding activities that are incompatible with substance use . Substance use and associated problems may increase if individuals are home more often and unable to engage in their usual activities, especially in the evenings . Moreover, other responsibilities at home may have increased during the pandemic.

New consequences associated with substance use may emerge as lifestyles, schedules, and responsibilities shift. In sum, relationships between pandemic-related lifestyle factors, substance use,cannabis vertical farming and substance use problems are likely complex and multifaceted. To better understand how individuals with problematic substance use are experiencing the pandemic, this exploratory, cross-sectional study examined associations between substance use problems, mental health symptoms, and pandemic related increased family responsibilities and stressors. Participants were recruited June 25 to August 18, 2020 for a randomized controlled trial of Woebot for Substance Use Disorders, a novel digital therapeutic for reducing problematic substance use. Participants were recruited through Qualtrics Research Services, Stanford University listservs, a Facebook advertising campaign, and word-of-mouth. Eligibility criteria were U.S. residence, age 18-65, English literate, owning a smart phone, with past-year use of a substance, and problematic substance use . Exclusion criteria were history of severe alcohol or drug withdrawal, liver conditions, opioid overdose, or psychotic symptoms; past-year suicide attempt; past-year medical problems from drug or alcohol use; opioid use without concurrent medication-assisted treatment; past Woebot use; and pregnancy. The study protocol, approved by Stanford IRB, randomized consented participants to the Woebot for Substance Use Disorders intervention for 8 weeks or to a waitlist control condition. Only baseline measures, completed prior to randomization, were analyzed in the present study. Participants received a $25 Amazon gift card for completing the baseline survey. Correlations between substance use problems, pandemic impacts and behaviors, and mental health symptoms are presented in Table 1. Significant correlations indicated that participants who, during COVID-19, struggled with responsibilities at home, had greater mental health impacts, greater personal growth, frequented bars or large gatherings, and reported more depression and anxiety symptoms had higher SIP-AD scores. Participants who, during COVID- 19, struggled with responsibilities at home, had difficulty getting necessities, had greater mental health impacts, and worried more about their children had higher GAD-7 and PHQ-8 scores. Anxiety and depression scores were highly correlated. Participants who lost a job or income during the pandemic had higher PHQ-8 scores. Struggling with home responsibilities was associated with job or income loss, greater difficulty getting necessities, greater pandemic mental health impacts, less personal growth during the pandemic, avoiding large gatherings, and avoiding school or work. Difficulty getting necessities was associated with greater mental health impacts. Personal growth was associated with lower likelihood of avoiding large gatherings, and worrying about one’s children was associated with greater likelihood of avoiding non-essential travel. The COVID-19 precautions were significantly associated with each other. Multi-variable analyses are presented in Table 2.

Participants with greater pandemic related mental health effects had higher SIP-AD, PHQ-8, and GAD-7 scores. Younger participants had higher SIP-AD scores, and participants without a college degree had higher GAD-7 scores . Age was not associated with GAD-7 or PHQ-8 scores, and education was not associated with SIP-AD or PHQ-8 scores. Sex, race/ethnicity, marital status, and other pandemic-related variables were not associated with SIPAD, GAD-7, or PHQ-8 scores. Because only participants with children completed the “worries about children” measure, we repeated the GAD-7 and PHQ-8 models excluding this variable. In the full sample, females had higher GAD-7 scores than males . Otherwise, only pandemic-related mental health effects remained associated with GAD-7 and PHQ-8 scores. During the COVID-19 pandemic, 40.6% of surveyed adults with substance use problems reported struggling with responsibilities at home. Struggling with responsibilities at home during the pandemic was associated with more substance use problems and greater depression and anxiety symptoms. Obtaining, using, and recovering from substances can impair one’s ability to fulfill obligations. New responsibilities resulting from the pandemic, such as full-time childcare due to school closures, may be difficult to fulfill while struggling with substance use. Results are consistent with extant literature showing that unpaid caregiving during COVID-19 was associated with increased substance use . Individuals struggling with substance use, anxiety, and depression may need support in meeting their own needs as well as their family’s needs during the pandemic. Additionally, frequenting bars or large gatherings, experiencing negative mental health effects, and perceiving more positive personal growth from the pandemic were associated with more substance use problems. Difficulty getting necessities, experiencing more negative mental health effects, and greater worry about one’s children’s well-being was associated with greater depression and anxiety symptoms. In multivariable models, controlling for demographic characteristics, negative mental health effects of the pandemic were the strongest correlate of substance use problems, depressive symptoms, and anxiety symptoms. Participants with high scores on this measure reported frequently thinking about COVID-19, worrying about their health and/or the health of their family and friends, experiencing stress due to changes in social contacts and their lifestyles, worsening of their mental/emotional health, and sleep disruptions. Findings suggest that the COVID-19 pandemic is producing major concerns that may contribute to mental health symptoms, including problematic substance use. Many individuals are using substances to cope with stress and uncertainty around the pandemic . A nationally representative sample of U.S. adults conducted early in the pandemic identified increased risk of depressive symptoms among people with lower income, fewer savings, and more stressors.While some evidence suggests that pandemic-induced psychological distress is lessening in the United States , people with problematic substance use are vulnerable to the negative effects of the pandemic . In this study, participants with more substance use problems were less likely to avoid bars and large gatherings, corroborating concerns that substance use may increase risk of contracting COVID-19 . Participants struggling to control their substance use may have found it difficult to avoid settings in which they use. Paradoxically, individuals with greater substance use problems also perceived greater personal growth from the pandemic in the forms of strengthened relationships, new possibilities, awareness of personal strength, spiritual change, and increased appreciation of life. People with problematic substance use often experience intense emotions .

Therefore, buprenorphine use could not be included as part of the inclusion criteria for the “picking up medications” outcome. Eighth, the outcome assessed in this study was self-reported service avoidance; self-report may not be reliable, or subject to differences in interpretation of the question. Finally, no hypothesis was specified a priori about which risk factors would be associated with avoiding harm reduction services, and this analysis should be considered exploratory. Despite these limitations, this study provides important new data about avoidance of medication for opioid use disorder and syringe service programs across jurisdictions. It suggests that, other than individual differences in fear of COVID-19 local service and policy contexts were much more important for determining whether people accessed these health and harm reduction services than individual differences in other characteristics between people who use drugs. Findings should inform policy efforts to increase the accessibility and flexibility of these programs: to help navigate the remainder of this pandemic and be better prepared for future disasters that may impede access to essential important public health services. In addition to male and female, TNT Online Survey participants were presented with the following gender identity response options: Transgender; Something else, please describe; and I’m not sure yet. Participant could also choose not to answer the question by leaving the item unmarked. Of the participants who viewed this item, 0.3% left it unmarked; another 5.7% of all participants did not view this item because they closed the survey before completion. For this report,outdoor cannabis grow marked response options other than male or female were combined into a single category.

Among all participants with a marked response, 3.0% indicated that they identified their gender in a way other than male or female. For race/ethnicity, participants were asked whether they were of Hispanic or Latino/Latina/Latinx/Latine origin . Those who indicated yes were classified as Hispanic or Latino regardless of race reported. Participants who selected no to the ethnicity question were classified as Non-Hispanic and were asked to select all races with which they identified from a list of six, including “Other.” If participants selected more than one race, they were classified as “More than one” race. Free-text responses were collected but not recoded. Due to the small number of participants who selected “American Indian / Alaska Native” or “Native Hawaiian / Other Pacific Islander,” these two categories were combined with “Other” into a single category for reporting results in Tables. Throughout the survey, missing data could arise if participants chose to leave a survey item unmarked or if participants closed the survey before completion . In this report, missing values are excluded from prevalence estimates. Thus, for some table rows and columns, the total sample size is less than the total 2021-2022 TNT Online Survey sample due to missing data.All current vapers were asked a series of questions about what substances, such as nicotine, were in the vapes they used. The questions were presented in different parts of the survey. First, current vapers were asked, “In the PAST 30 DAYS, how often did the vapes you used contain nicotine?” Later in the survey, current vapers were also asked, “In the PAST 30 DAYS, did any of the vapes that you used contain nicotine?” These two different ways of asking about nicotine were included in the survey to help understand how question wording might affect the way people answer. Current vapers were also asked, “In the PAST 30 DAYS, did any of the vapes that you used contain the following substances?” and were given a list of substances they could select. Finally, current vapers were asked, “Was there ever a time in the PAST 30 DAYS that you used a vape and were not sure what it contained?” The weighted responses to each of these questions are presented in Table 12. For a comments and recommendations related to designing survey items related to vape contents, see Appendix.JUUL, Puff Bar, Blu, and Vuse were the vape brands participants reported as most popular among their peers.

When asked to select the one brand of their favorite vape advertisement, most participants reported they do not have a favorite advertisement. Indicating the brand of a favorite tobacco advertisement is considered to be a measure of tobacco advertising receptivity and can be used to predict future tobacco use. These results from the TNT Online Survey suggest that most participants were not receptive to vape advertisements. Among all current vapers, it was common to use more than one vape device type during the past 30 days. Puff Bar- like disposable devices and JUUL-like pod devices were the two most commonly used device types. However, nearly half of current vapers reported that at least one time in the past 30 days they used a vape and were not sure what it contained. Besides nicotine, participants reported that the vapes they used sometimes contained marijuana, “vitamins,” and melatonin.All current users of vapes, cigarettes, cigars, hookah, and smokeless tobacco were asked about their use of flavored products in the past 30 days. Please note that flavored cigarette use in this chapter reflects use of menthol-flavored cigarettes . Questions were presented to tobacco product users in different ways. In Version A questions, separately by tobacco product, participants were asked whether any of the products they used in the past 30 days were flavored. In Version B questions, also separately by tobacco product, participants were asked whether the product they usually used were flavored. Participants who indicated that they only used “unflavored” or “tobacco flavored” products or do not know what flavor they used in the past 30 days were considered not to have used flavored products. All other indicated flavors, such as mint, fruit, candy, and “other,” were categorized as flavored product use. The TNT Online Survey did not include flavor questions related to heated tobacco, nicotine pouches, or nicotine tablets, lozenges, or toothpicks. Participants who currently used only these products are not included in this chapter. Table 13 shows the prevalence of current flavored tobacco use among current users of various products. All TNT Online Survey participants were asked to indicate how much they agreed or disagreed with nine different policy statements. Three of the statements related to the sale of tobacco products, and three statements related to the use of tobacco or marijuana products in public places.

In the Wave 2021-2022 summer cycle, participants were asked how much they agreed that certain practices “should NOT be allowed.” In the Wave 2021-2022 winter cycle, these survey questions were modified slightly and asked participants whether these same practices “should end.” Three additional policy statements were worded exactly the same way for all Wave 2021-2022 participants. Table 18 shows how participants responded to the Tobacco Endgame policy statements related to potential restrictions on tobacco sales. Table 19 shows how participants responded to the Tobacco Endgame policy statements related to tobacco or marijuana use in public places, apartment buildings, and flavored tobacco use by youth.The global rise of methamphetamine use could jeopardize current intervention efforts to address the twin epidemics of opioid use disorder and HIV infection. Use of methamphetamine is increasingly common among people with primary OUD. Prevalence of methamphetamine use disorders is increasing in Vietnam,PIPP horticulture raising concerns about increased risk of HIV infection and disruption of the substance use treatment systems, especially methadone programs. Methamphetamine use among people living with HIV could decrease retention in care, hinder medication adherence, accelerate viral replication, and further HIV disease progression. Other countries beyond South-East Asia encounter similar challenges. In low-and-middle-income countries, it is vital to identify cost-effective models of adapted evidence-based practices for addressing substance use disorders. Although there are no approved pharmacological treatments for methamphetamine use, evidence-based behavioral interventions such as motivational interviewing, contingency management, and cognitive behavioral therapy, including Matrix model, have shown efficacy in reducing methamphetamine use. However, we need to identify optimal combinations of EBI for effectiveness and cost effectiveness as many people in treatment face challenges to retention and sustained reductions in use.Motivational interviewing helps individuals to evaluate the pros and cons to change drug use and to develop personalized change behaviors. Motivational interviewing can be used in a single session or in multiple sessions. Polcin et al. compared two motivational interviewing conditions and found that both groups showed significant reductions in methamphetamine use without differences between the two groups. A greater reduction in psychiatric symptoms including anxiety and depression was found among those receiving more motivational interviewing sessions.Contingency management has shown the strongest evidence in treating methamphetamine use disorders. It is also effective in reducing other drug use including alcohol, cannabis, nicotine, and opioids. Contingency management is based on the theory of operant conditioning where incentives are used to strengthen the target behavior such as abstinence, reduction of sexual risk behaviors, or other health-promoting behaviors like retention or adherence to treatment. Contingency management effects are enhanced in combination with other psychosocial interventions or education. A recent meta-analysis shows contingency management is more efficacious than other EBI up to 1 year following the discontinuation of reinforcers.The Matrix model has shown greater reduction in methamphetamine use, risky behaviors, and more days of abstinence compared to non-standardized outpatient treatment approaches.

This intervention combines different elements of effective approaches including cognitive and behavioral treatment using accurate information on the effects of stimulants, relapse prevention skills training, 12-step program participation, and family education. Its manualized treatment protocol ensures fidelity when the model is implemented in different settings.Motivational interviewing helps individuals to evaluate the pros and cons to change drug use and to develop personalized change behaviors. Motivational interviewing can be used in a single session or in multiple sessions. Polcin et al. compared two motivational interviewing conditions and found that both groups showed significant reductions in methamphetamine use without differences between the two groups. A greater reduction in psychiatric symptoms including anxiety and depression was found among those receiving more motivational interviewing sessions.Using SMS text messages with people who use methamphetamine has been shown to reduce methamphetamine use and HIV-related sexual transmission behaviors and increase retention in HIV care among some key populations. Scripted unidirectional texts outperform bidirectional interactive text-messaging conversations in reducing methamphetamine use and HIV sexual risk behaviors and are more cost-effective than inperson therapies. Theory-driven messaging might better benefit people in the early stages of behavior change than people who are already seeking help.Despite some demonstrated efficacy, few studies have shown ways to optimize and combine treatment approaches for methamphetamine use disorders. Qualitative reports show patients found contingency management beneficial when combined with motivational interviewing and cognitive behavioral techniques for methamphetamine use disorders. Combined motivational interviewing and cognitive behavioral treatment show efficacy in reducing methamphetamine use in HIV-positive MSM. Evidence supports combining psychosocial treatment with medication-assisted treatment in people with OUD, but it is unclear whether patients with comorbid methamphetamine use disorder will experience similar benefits. Integrating screening and brief interventions, contingency management or conditional cash transfer, and cognitive behavioral therapy for the management of substance use disorders requires trained health professionals. This is challenging in settings where human resource for mental health/substance use is scarce. Therefore, besides identifying optimal combination of EBI, it is essential to recognize potential barriers to the implementation of these strategies. The study deploys a type-1 effectiveness-implementation hybrid design to evaluate the effectiveness of the proposed adaptive interventions and gather data on the implementation. To evaluate the effectiveness of the interventions, the study employs a Sequential Multiple Assignment Randomized Trial design. In the first phase, participants will be randomized into two front line interventions for 12 weeks. Based on their outcome at the end of this phase, they will be placed or randomized into three adaptive strategies for another 12 weeks . The economic evaluation that addresses Aim 2 aims to weigh public health and societal costs against public health and societal benefits attributed to the interventions of different intensities with a time horizon of 12 months. To address Aim 3, we will conduct an ethnographic evaluation to identify the multi-level factors that influence the adoption and scale-up of the interventions in methadone clinics.