Cannabis Grow

Data on treatment, outcome and post-crash transportation were collected from medical records. If a patient was admitted to the hospital, the outcome of treatment was reassessed at day 30 after a crash to be consistent with the World Health Organization definition of road traffic death. Alcohol-use information was obtained in various ways: from patients who verbally indicated that they had consumed alcohol prior to the injury; from relatives or from those who transported patients to the hospital; or by physical examination by a health provider, or laboratory testing. These data were then entered into the NIEM electronic database. This study was reviewed and approved by the Faculty of Medicine Siriraj Hospital Institutional Review Board. We conducted a retrospective review study using data collected by the NIEM registry during the 2008–2015 New Year holiday and 2008–2014 Songkran holiday. We excluded patients who died at the scene and those who were not transported to hospitals because no transportation method for these patients had been recorded in the registry. Severe RTI patients were defined as patients who were admitted to the hospital, were referred, or had died in the emergency department.Subsequently, we categorized data into two cohorts: a control group, and an EMS utilization group, which included patients who were transported to hospitals by FR, BLS, ILS, or ALS ambulances. The registry also recorded the vehicle type. We further classified the data according to whether the victims were vulnerable road users or non-vulnerable road users.We also categorized the time of the day that patients visited hospitals,vertical outdoor farming dividing the day by 06:00–17:59 and 18:00–05:59.

Patients who used helmets and seat belts were combined. Mortality included death in EDs and during referral, death in the initial 24 hours after admission, and death 1–30 days after admission. Survival was defined as patients who either survived after 30 days of admission or were discharged from hospital.Logistic regression was used to analyze the primary outcome, which was the association between EMS utilization and mortality of RTI patients; we then adjusted the outcome for factors that affected injury severity, such as age, sex, being a vulnerable road user, road characteristics, alcohol consumption, and helmet or seat belt use.We conducted subgroup analyses to identify factors related to the mortality of patients who were transported by EMS. Univariate analysis was conducted using chi-square test and Fisher’s exact test. We included factors that have been proven to be associated with RTI severity, as mentioned above, and level of EMS in a multiple logistic regression model. P values <0.05 were considered significant. We calculated statistics using R version 3.2.1.This study describes outcomes of severe RTI patients transported by EMS compared with patients transported by private vehicles. We conducted the analysis using a nationwide registry in Thailand, which has the highest traffic accident mortality rate in the world. Moreover, the registry collected data during holidays with a high incidence of RTIs. In this cohort, severe RTI patients transported by ambulance had a higher mortality rate than patients transported to hospitals by private vehicles, and this finding is in line with those of other studies.The higher mortality rate might be attributed to the fact that patients who were transported by EMS were more severely injured than those in the control group.

Our results demonstrated that approximately 40% of severe RTI patients were transported to hospitals by ambulance, which was less than reports from other countries. Recently, Huang et al. reported that 73.4% of RTI patients in Taiwan were transported by EMS. One possible reason for not using EMS may have been that patients might not have known or might have forgotten the four-digit number for ambulance services.This contact number is different from those of other public service agencies such as the police and fire departments. A continuous advertisement of the emergency number should be done to increase EMS use in Thailand. The demographic data revealed that the patients who used EMS had more factors that increased injury severity than the control group; for example, our analysis demonstrated that severe RTI patients transported by ambulance reported current alcohol consumption more than those who were not. Recent studies have reported that alcohol intoxication is associated with greater injury severity and higher mortality rates among RTI patients.We also found that severe RTI patients transported by EMS were more often injured on highways than patients who were not. This shows that the patients in the EMS use group were more severely injured than those in the control group, since accidents on highways were more likely to have occurred at high speed, which was associated with more severe injuries.Although we analyzed multiple logistic regression to adjust for confounding factors, certain factors related to injury severity were not included in the registry, such as vehicle speed, comorbidity, prehospital care time, or injury severity scores.To find out the real effect of EMS use in clinical outcomes of RTI patients, the registry should collect information about other factors related to severity of injuries. The subgroup analysis identified factors associated with mortality among severe RTI patients transported by EMS. It demonstrated that patients who were transported by ALS teams had significantly increased mortality. This might have been due to the fact that patients transported by ALS teams were at higher risk of increased severity when compared with patients transported by other EMS levels.

Another possibility is that ALS team use might increase the on-scene time, due to prehospital interventions such as administering intravenous fluids or performing endotracheal intubation,rolling grow table as opposed to the “scoop and run” concept. This concurs with findings of previous studies that the use of ALS teams did not improve clinical outcomes.The Ontario Prehospital Advanced Life Support Major Trauma Study demonstrated that implementation of ALS teams did not improve the survival of major trauma patients when compared with patients treated by BLS teams.The study also revealed that among patients with a Glasgow Coma Score less than 9 who needed endotracheal intubation, those transported by ALS teams had a significantly lower survival rate.However, our registry did not collect prehospital care time and prehospital intervention. Further studies should be conducted to determine the real effect of ALS teams on the clinical outcomes of RTI patients by analyzing all confounding factors. Helmet or seat belt use was a factor that reduced mortality in severe RTI patients transported by ambulance. This concurred with the findings of previous studies that showed that these protective devices reduce injury severity.Abu-Zidan et al. reported that restrained RTI patients showed significantly less severe injury as well as fewer surgeries compared with unrestrained patients.Furthermore, Nash et al. reported that seat belt use was associated with a significant reduction in injury severity, mortality rate, and length of stay among RTI patients.Liu et al. reviewed 61 observational studies and found that helmet use was a significant factor in reducing mortality and head injury in motorcycle crashes.Only 13.89% of patients in this cohort wore a helmet or seat belt, although Thai law requires helmet and seat belt use. Further studies should be conducted to explore barriers to helmet and seat belt use.Although we analyzed data from the largest RTI registry in the country, revealing high mortality rates among RTI patients, our study has certain limitations. First, because it was a retrospective observational study, there were missing data regarding accident time, helmet and seat belt use, alcohol consumption status, and road characteristics. Second, the collection method in the registry had a potential for recall bias since the data collectors interviewed patients or their relatives at the hospital. Third, the registry collects data only in the long holiday periods. Given the lack of data for non-holidays the registry could not represent the effect of EMS utilization during non-holidays. We also excluded patients who died at the scene and were not transported to hospitals. This might have changed the injury severity of the whole population. Furthermore, the analysis combined patients using helmet and seat belt in one variable as a protective factor for overall RTI patients, when the injuries have different mechanisms. Further investigation should conduct subgroup analysis comparing those using motorcycles vs. four-wheel vehicles. Moreover, as mentioned earlier, the registry did not collect data on confounding variables that could affect clinical outcomes, such as ISS, prehospital care time, vehicle speed, or patient comorbidities. Lacking prehospital intervention is another limitation.

Alcohol consumption was defined using patient history data and physical examination by the physician, which is not the gold standard. Blood alcohol levels should perhaps be included in the registry. Improving the registry will help enhance our understanding of these characteristics as well as the effects of EMS utilization on clinical outcomes. Aside from our suggestions to improve the registry, there are further implications from the results of this study. Since we found that the RTI patients transported by EMS during the holidays had increased mortality rates, we recommend that this group of patients be evaluated in a trauma resuscitation room earlier, especially for patients transported by ALS teams. And to reduce time spent in the ED, prehospital notification should be given to receiving hospitals by the ambulance team before arrival.The incidence of spinal epidural abscess , a highly morbid and potentially lethal deep tissue infection of the central nervous system, has risen significantly over the past decade.1, 2 Our tertiary care institution has experienced an increase of more than 200%, from 2.5 to 8 cases per 10,000 hospital admissions since 2005.Although the reasons are not clearly defined, various factors, such as an expanded, comorbidly ill, aging population, and procedures or behaviors predisposing to bacteremia, have been posited to contribute to the increased incidence of SEA.Because SEA may rapidly and unpredictably evolve to irreversible neurologic injury and diagnostic delays remain common,our goal was to use these data to inform a discrimination model that could be employed at the time of initial clinical presentation to prioritize potential cases for expeditious, advanced imaging to optimize patient outcomes.The design and selection criteria for cases and controls have been previously described.To ensure clinical relevance, the case and control groups were drawn from patients who presented with findings that either raised concern for SEA or who underwent a “rule-out” evaluation; magnetic resonance imaging or computed tomography and micro-biologic data were used to assign patients to the appropriate group. Baystate Medical Center , a 720-bed tertiary-care, regional, academic medical center currently serving a population of approximately 850,000 people in western Massachusetts experiences more than 33,000 annual adult discharges with a corresponding case-mix index of 1.72, indicating high severity and complexity of its inpatients relative to their diagnosis related group. Encounters were coded as “confirmed” SEA if there was a radiologist-confirmed finding of an epidural lesion on advanced imaging with a positive culture from lesion or blood; “probable” if there was a radiologist confirmed epidural lesion in the absence of positive cultures from lesion or blood; and “control” if no lesion was identified by the radiologist on the imaging study. This study was approved by the institutional review board.We preliminarily evaluated baseline comparison between cases and controls using univariable analyses and direct visualization methods. Because our goal was to develop a discrimination model, we used the Integrated Discrimination Improvement Index to identify candidate discriminators.The IDI represents the degree to which a candidate variable increases the event probability in cases, while decreasing the event probability in controls, thus discriminating cases from non-cases. We selected candidate predictive factors if they were immediately discernible upon clinical presentation and if their univariable IDI was >0.02, suggesting meaningful discrimination properties. To reduce bias in the prediction model, candidate variables had to have at least 20 events to be considered.The multi-variable logistic regression model initially included all candidate variables and was then refined using a backwards selection process, with a p-value for removal of 0.05. We used Youden’s J7 to identify the cut point that maximized sensitivity and specificity. Areas under the receiver operator curve of the full- vs. restricted-models were compared using previously described methods.We assessed model fit using the Hosmer-Lemeshow goodness of fit and Stukel tests. Because measures of model validation may be overly optimistic when derived on the sample used for coefficient estimation, we generated bootstrapped validation measures.We used Stata 14.2 and R for analyses.

Duration of each injection was 0.2 s and injection volume was 0.2 ml. Each injection was followed by a 60-s timeout period, during which the chamber was dark and lever presses had no programmed consequences. One-hour sessions were conducted five days per week . All monkeys had learned to respond under the FR10 schedule for the particular training drug prior to beginning this study. After completing the previous experiments, monkeys self administered the training dose of each drug for at least five sessions until responding was stable . Self administration behavior was then extinguished by substituting vehicle for THC, anandamide, or cocaine, but maintaining the presentation of the brief-stimulus associated with each injection. Then we tested reinstatement of extinguished drug-taking behavior by priming injections of THC or URB597 in all three groups of monkeys. Reinstatement effects of each pretreatment were studied for three consecutive sessions starting after at least three days of stable vehicle extinction. Food was withheld 12 h prior to this procedure. Anaesthesia was induced and maintained with isoflurane . Monkeys were weighed, prepared with a venous line , placed on a surgery table and kept warm by heat lamps.After animals were stabilized , URB597 or its vehicle was intravenously injected 1 h prior to euthanasia and the venous line was flushed with 0.5 ml of saline. Body temperature, SPO2,vertical agriculture pulse and rate of respiration were recorded every 10 min. After 1 h, monkeys were euthanized with Euthasol . Death was confirmed by the absence of respiration and heart beat on ECG. Brains were quickly removed, the cerebella were separated and forebrains were dissected. Each hemisphere was cut into 3 parts by two coronal sections made at approximately AP +12.5 and −5.

Brain fragments were snap-frozen in isopentane , wrapped in aluminium foil, and placed in dry ice. Samples were stored in the freezer for 2 days and then shipped on dry ice to the University of California Irvine for analyses. In one set of experiments, rats were sacrificed by rapid decapitation under light anaesthesia 2 h after injection of URB597 or vehicle. In other experiments, rats were food deprived for 12 h and sacrificed by decapitation 1 h after injection of URB597 or vehicle, while maintained under isoflurane anaesthesia for the duration of the experiment. In either case, brains were rapidly removed, and the hippocampus and prefrontal cortex was dissected from the fresh tissue over ice. Brain regions were frozen in dry ice, and stored at −80°C until lipid and enzymatic analyses. Cumulative-response records were obtained during all sessions to assess within-session patterns of responding. Rates of responding during self-administration sessions are expressed as responses per second averaged over the one-hour session, with responding during time-outs not included in calculations. Injections per session represent total number of injections delivered per session. Data for dose-effect curves are expressed as mean response rates and numbers of injections per session ± SEM over the last three sessions. In addition, total intake of anandamide, THC or cocaine for each session was calculated. Reinstatement data and effects of pretreatment with URB597 on drug self-administration are expressed as mean ± SEM of total numbers of injections per session over three sessions. Statistical analysis was done using single-factor repeated measures ANOVA to assess differences between vehicle and test-drug pretreatment conditions or between different doses of anandamide, THC, cocaine or URB597 and vehicle. Significant main effects were analyzed further by subsequent paired comparisons to control values using Dunnett’s test . Bonferroni t-test was used when the number of observations did not allow for the use of the Dunnett’s test. Differences between effects of vehicle and URB597 pretreatment on lipid levels and FAAH activity were analyzed using single-factor ANOVA.

Differences were considered statistically significant when p < 0.05.We found that the selective FAAH inhibitor URB597 suppresses FAAH activity and increases anandamide levels in regions of the squirrel monkey brain that participate in motivational, cognitive and emotional functions. This effect is accompanied by a marked decrease in the levels of 2-AG, a major endocannabinoid substance in the brain, even though URB597 does not affect activities of 2-AG-metabolizing enzymes such as DGL and MGL. We further observed that URB597 does not display overt reinforcing property in monkeys over a broad range of experimental conditions. Indeed, the drug did not reinforce self-administration behavior even when its cumulative intake exceeded by several folds a fully effective dose for FAAH inhibition. Furthermore, neither previous cocaine nor THC exposure predisposed monkeys to self-administer URB597: even monkeys that had previously self-administered anandamide at very high rates failed to respond to the FAAH inhibitor. Lastly, URB597 did not affect the reinforcing effects of THC or cocaine, and did not reinstate extinguished drug seeking behavior in monkeys that had previously self-administered THC or cocaine. We interpret these results to indicate that URB597, by enhancing anandamide signaling, causes a compensatory down-regulation in 2-AG mobilization; and the potentiation of anandamide-mediated transmission produced by URB597 is insufficient per se to produce reinforcing effects. Our findings further imply that FAAH inhibitors such as URB597 – which have demonstrated analgesic, anxiolytic, antidepressant and antihypertensive properties in rodents – may be used in humans without anticipated risk of inducing abuse or provoking relapse to drug use in abstinent individuals. The pharmacological profile of URB597 is strikingly different from that of THC and other direct-acting CB1 receptor agonists. Studies in rodents have shown that URB597 does not produce THC-like effects such as catalepsy, hypothermia or hyperphagia . Further, URB597 does not mimic the discriminative-stimulus actions of THC . Even further, URB597 does not increase dopamine levels in the nucleus accumbens shell of rats,hydroponics flood table a defining neurochemical feature of reinforcing drugs . Finally, URB597 does not elicit conditioned place preferences indicative of rewarding properties in rats .

However, experiments in rodents, such as those outlined above, are insufficient to model human reward based behaviors and to predict the addictive potential of drugs. Thus the present results provide the first unequivocal demonstration that URB597 lacks THC-like reinforcing properties, and suggest that this FAAH inhibitor might be used in therapy without anticipated risk of abuse or triggering relapse to drug use. Exogenous anandamide exerts potent reinforcing effects in monkeys . Thus, it may be surprising that the ability of URB597 to potentiate brain anandamide signaling does not translate into overt rewarding properties. However, there are two plausible reasons why URB597 does not support self-administration responding. First, exogenous and endogenous anandamide might each access distinct sub-populations of CB1 receptors in the brain. In particular, systemic administration could allow anandamide to reach a receptor pool that is normally engaged by 2-AG. In this context, the observation that treatment with URB597 decreases 2-AG levels in the monkey brain suggests the existence of a compensatory mechanism aimed at reducing 2-AG signaling in the face of enhanced anandamide signaling. Such a mechanism might account, at least in part, for the inability of URB597 to serve as a reinforcer. Consistent with this idea, a recent report suggests that pharmacological or genetic disruption of FAAH activity causes a down-regulation of 2-AG production in acutely dissected rodent striatal slices, which is reportedly due to vanilloid TRPV1 receptor activation . However, we were unable to replicate this observation in live animals even when using doses of URB597 that completely suppressed FAAH activity and significantly increased anandamide levels . Another possibility is that the kinetics of CB1 receptor activation may differ between anandamide and URB597 administration, as the former is likely to produce a more rapid recruitment of CB1 receptors than the latter. It is well established that effectiveness of drug reinforcement in monkeys depends on a rapid drug distribution throughout the brain . Irrespective of the mechanism involved, the impact of 2-AG down-regulation on the broad pharmacological properties of URB597 in primates remains to be determined. In conclusion, our findings with URB597 unmask a previously unsuspected functional heterogeneity within the endocannabinoid signaling system in the brain, and suggest that FAAH inhibitors such as URB597 might be used therapeutically without risk of abuse or triggering relapse to drug abuse. Feeding America is a network of food banks, food pantries, and meal programs providing food and services in the U.S.Second Harvest Heartland, a mid-western member of Feeding America, is one of the nation’s largest food banks, and supports over 1,000 food shelves and other partner programs that distribute food to over 532,000 individuals in Minnesota and western Wisconsin annually. Our institution and Second Harvest Heartland have partnered to provide food assistance to our patients since 2010. As a result of this relationship, healthy food is available in our clinics in the form of bagged groceries, and on site through an institutional food shelf. Patients are able to receive food through clinics, at discharge from an inpatient stay, or delivered to their homes through a community paramedic program or visiting nurses. To determine eligibility for food services referrals in our institution, staff or providers screen patients for food insecurity with two questions.

This two-question screening tool is a validated, abbreviated version of the 18-item U.S. Household Food Security Scale , which is used to monitor national food security.For purposes of our referral program, we modified the screening questions to be dichotomous yes/no responses from the validated responses: often, sometimes, or never. The questions included “Within the past 12 months we worried whether our food would run out before we got money to buy more;” and “Within the past 12 months the food we bought just didn’t last and we didn’t have money to get more.” In its validation cohort, an affirmative response to either question yielded a sensitivity of 97% and specificity of 83%, compared to the gold-standard, full 18-item HFSS. If deemed food insecure by this screening process, providers will then order a “referral for food” in the EMR to connect the patient to Second Harvest Heartland for support. The patient must consent to the referral and state what specific contact information they are comfortable sharing with the partner organization. This referral provides the patient’s contact information to Second Harvest Heartland through an automated fax. The food bank staff will then assist the patient in enrolling in federal nutrition programs , in addition to locating their neighborhood food shelves and meal programs, and arranging free produce distribution that they can access on a monthly basis. Though initially intended for clinic and inpatient use, starting in 2015 this order became available for use in the ED. To advertise the referral program, focused information sessions were added to the emergency medicine resident educational conferences in late 2015, and to the new resident orientation, starting in 2016. In addition to this, semi-annual updates are integrated into the resident conferences, and the details of the referral patterns are distributed to faculty. All ED personnel were encouraged to use the referral order, including ED faculty physicians, residents, physician assistants, nursing staff, social workers, ED registration, and financial support staff. Institutional financial counselors were unforeseen allies with the program, as their workflow typically incorporated several questions that touched on financial and food security issues. From January through December 2015 , a total of 1,003 referrals were made to Second Harvest Heartland; only five were made from the ED. From January 2016 through December 2016 , there were 1,519 referrals hospital-wide, and 55 referrals were made from the ED. Table 2 outlines details of the frequency of EMR order use from all clinical sites. Of the 1,519 referrals, 1,129 were successfully contacted by Second Harvest Heartland, and 954 accepted and received assistance. Of the referred and successfully contacted households, 92% were connected with at least one new form of food assistance. This assistance included new information about geographically individualized food shelves, meal sites, and produce distribution. Of households eligible for the Supplemental Nutrition Assistance Program, 76% completed applications to the federal entitlement program. This study sought to determine whether ED referrals for food resources for patients with food insecurity would increase after the implementation of an EMR referral order, as well as to introduce provider education about this referral program. To our knowledge, we report the first experience with such an institutional EMR order for food resources in the ED.

Alcohol abuse is a global problem, constituting the seventh leading risk factor for death and disability. Worldwide, over 100 million people had an alcohol use disorder in 2016. Statistics from the National Survey on Drug Use and Health show that >85% of adults in the United States report ever having consumed alcohol, with >25% reporting binge drinking in the past month. The proportion of adults in the United States with an AUD is estimated to be 6.2%. Alcohol use behaviors are complex, and how and why people drink is partially influenced by genetic factors. However, identifying the genetic factors that increase the risk for harmful drinking has been challenging, partially because patterns of alcohol use are dynamic across the lifespan. The terms used to describe alcohol use and abuse are as diverse as the behaviors themselves. Hazardous drinking describes heavy drinking that places an individual at risk for future harm. Harmful drinking and alcohol abuse are defined as drinking that causes mental or physical damage to the individual. These descriptive terms were devised to identify individuals who would benefit from brief interventions and are assessed using screening questionnaires such as the Alcohol Use Disorders Identification Test. Alcohol dependence was, until recently, defined according to the DSM-IV and required the presence of 3 or more of 7 criteria in a 12-month period. The DSM-IV made a distinction between alcohol abuse and dependence that was removed under DSM-V and replaced with “mild”to “severe” definitions of AUD. Genetic studies encompass the wide range of alcohol use phenotypes; in this review we mirror the language used in the original studies. AUD can be viewed as the end point of a series of transitions , which begin with the initiation of use,grow rack continue with the escalation to hazardous drinking and culminate in compulsive harmful use that persists despite negative consequences.

Genome-wide association studies have been instrumental in discovering novel genetic loci associated with multiple psychiatric conditions. In the field of AUD genetics, studies have mostly focused on either levels of consumption or AUD diagnosis. Recent GWAS have now begun to identify hundreds of genome-wide significant variants, and provide evidence that the components of alcohol use behavior have a distinct genetic architecture. In this review, we provide an overview of recent molecular genetic findings of alcohol use behaviors from the largest GWAS performed to date. Other reviews have elegantly summarized findings from twin and family studies of heritability, linkage, candidate gene and GWAS [e.g. ], and we extend on recent reviews of the molecular genetics of AUD by including additional GWAS of alcohol use behaviors that identify genome-wide significant hits. In addition, we discuss the application of polygenic methods, which provide mounting evidence that alcohol use and misuse are partially distinct. Finally, we delineate future directions to investigate the different etiologic sources that underlie the life course of alcohol use behaviors. For decades, candidate gene studies were used to determine the contribution of specific genes that increase risk for AUD. Candidate gene studies tended to focus on genes that influenced pharmacokinetic and pharmacodynamic factors.One exception to this are the genes encoding ethanol metabolizing enzymes, particularly alcohol dehydrogenase and aldehyde dehydrogenase , which have repeatedly been shown to have the largest impact on alcohol consumption and risk for AUD. As study designs have evolved to incorporate GWAS, researchers have been able to scan the whole genome without any hypotheses about the underlying biology of alcohol use behaviors. Initial efforts focused on collecting clinically defined cases of AUD, but these ascertainment strategies could not amass the large sample sizes required for GWAS. 

Accordingly, multi-ethnic and clinically defined samples have been combined through the Psychiatric Genomic Consortium of Substance Use Disorders working group. The efforts of the PGC-SUD have led to a trans-ancestral meta-analysis consisting of almost 15,000 AD cases and almost 38,000 controls from 28 independent cohorts , identifying a single locus , which was robustly associated with AD. More recently, using information from electronic health records to infer AUD status, a GWAS of 274,424 multi-ethnic individuals from the Million Veterans Program cohort identified 10 loci associated with AUD. Kranzler et al showed that alcohol consumption and AUD were genetically correlated but distinct, thus allowing them to adjust for consumption in the AUD GWAS and for AUD in the GWAS of consumption. In parallel with these efforts, which have focused on clinical diagnoses, other GWAS have incorporated continuous measures of alcohol use. These include self reported weekly alcohol intake or the scores from screening questionnaires such as the AUDIT. The AUDIT can be decomposed to provide a measure of alcohol use from the first 3 questions and misuse from questions 4-10. These quantitative measures are available in large population-based cohorts such as the UK Biobank , MVP and 23andMe. The GWAS meta-analysis of AUDIT identified 10 associated risk loci. Large consortia were also formed to collate quantitative measures of alcohol use, including AlcGen and the GWAS & Sequencing Consortium of Alcohol and Nicotine Use. GSCAN have recently identified nearly 100 loci associated with alcohol consumption. The MVP study also examined alcohol consumption,greenhouse grow tables allowing for an explicit comparison between AUD and consumption in a single population; of the 18 loci detected in that study, 5 were common to both AUD diagnosis and alcohol consumption.

As the prior two paragraphs make clear, population based cohorts have provided larger sample sizes, which are critical for obtaining adequate power for GWAS. Their use can come at the cost of missing more severe alcohol use phenotypes. For example, the frequency of AUD in the UKB is lower than the population average [7% ], indicating that certain population studies may be under powered to detect genetic effects specific to dependence. The frequency of AUD in the MVP, on the contrary, was much higher [20%, ]. Despite these limitations, population based cohorts provide a cost-effective strategy for obtaining very large samples, compared to traditional study designs that require obtaining a diagnosis from clinically trained staff. The 4q23 region, which contains the genes for several alcohol metabolizing enzymes, has been associated with multiple alcohol use behaviors. This association is one of the most consistently replicated findings in the field of psychiatric genetics, although the effects are clearly ancestry-specific. There appear to be multiple signals in this region, including ADH1C , ADH4 , ADH5 and the METAP1/EIF4E region. The GSCAN consortium recently showed that there are at least 13 independent signals with minor allele frequencies over 0.001 at 4q23. Intriguingly, several of those loci are also strongly implicated in non-psychiatric, somatic traits. Beyond the alcohol metabolizing genes, the region containing the genes beta-klotho and the Fibroblast growth factor 21 has been robustly associated with alcohol consumption. The AlcGen consortium was the first to show that the A allele of rs11940694 , located in the intron of KLB, was associated with reduced alcohol consumption. This finding has since been replicated – the same SNP was associated with alcohol consumption and alcohol misuse. Beta-klotho is a transmembrane protein that acts as a cofactor for the circulating hormone fibroblast growth factor 21 by facilitating its binding to FGF receptors. Interestingly the FGF21 gene, which is located on chromosome 19, was also associated with AUDIT scores at the gene-level in humans. Beta-klotho is primarily expressed in the liver, adipose tissue and pancreas , and recent studies have shown that it regulates brain specific functions related to alcohol consumption in mice. For example, mice lacking brain expressed Klb showed increased ethanol preference. Furthermore, FGF21 was found to suppress ethanol consumption in wild-type mice but had no effect on mice lacking Klb in the brain. Previous studies have shown that FGF21 and KLB are involved in sweet and alcohol preference in mice , and a recent study in humans found increased FGF21 expression in blood after binge drinking. These findings suggest that KLB and FGF21 act as part of a brain-liver endocrine axis that regulates alcohol consumption. Future studies could explore the effects of analogues of FGF21 on alcohol consumption, which are currently being tested in clinical trials for the treatment of type 2 diabetes and obesity. Although KLB and FGF21 seem to be promising avenues for translational research, it is worth noting that while SNPs in KLB are associated with alcohol consumption, they have not yet shown any association with AUD. This implies that this system might only be relevant for the regulation of normative consumption, although studies of larger AUD populations may yet reveal a role for these loci in AUD.

Furthermore, although the locus probably impacts KLB, rs11940694 was found to be an expression quantitative trait locus for RFC1 gene expression in the cerebellum and hemisphere. Another well-replicated locus associated with both alcohol consumption and AUD is the region containing the glucokinase receptor gene, whose product is a regulatory protein that is produced by hepatocytes and is involved in the cellular trafficking of glucokinase. A non-synonymous SNP in GCKR, rs1260326, was robustly associated with alcohol consumption in the MVP, UKB and 23andMe samples. Intriguingly, rs1260326 has also been previously associated with multiple metabolic traits, including diabetes, obesity and liver disease. Given that alcohol consumption is strongly associated with both metabolic and lipid profiles , it is not clear whether the association with rs1260326 pinpoints a pleiotropic process central to metabolic traits, or whether alcohol causally impacts glucose metabolism and lipid levels, in part via GCKR. A recent study characterized the effects of alcohol in neural cell cultures derived from induced pluripotent stem cells and found that genes down-regulated upon alcohol exposure were involved in cholesterol homeostasis in the brain. These findings could suggest that AUD has both psychiatric and metabolic components, a theme that has also been suggested for other psychiatric disorders, such as anorexia nervosa. Additional evidence supporting this provocative hypothesis is the fact that several genes associated with alcohol use and dependence involve brain-endocrine-metabolic mechanisms. KLB is part of a brain-liver feedback loop, acetaldehyde modulates a number of ethanol effects in the brain, and enrichment analyses of alcohol-associated genes found glutamatergic enrichment not only in the brain but also in glucose and carbohydrate processing pathways. The ability to process caloric alcoholic beverages may be linked to individual differences in alcohol consumption. In general, the ‘candidate genes’ for AUD that were examined in smaller cohorts have not been replicated by larger and better powered GWAS. One exception is the corticotropin releasing hormone receptor 1 , a candidate gene extensively studied in humans and rodents before the advent of large-scale GWAS studies. CRHR1 is central to the cortisol stress response as part of the hypothalamic-pituitary-axis. Extensive preclinical literature has shown that CRHR1 is associated with relapse to drug taking in mice [e.g. ] and there is some evidence that variation in CRHR1 modulates the role of psychological stress on alcohol intake. Encouragingly, the genomic region surrounding CRHR1 has been associated with alcohol consumption and misuse in several recent GWAS studies. However, CRHR1 is located in an inversion polymorphism of roughly 900kb that is common in Europeans and induces extensive LD spanning many genes , including CRHR1 and MAPT. MAPT encodes the protein tau, is involved in Parkinson’s and Alzheimer’s disease. Further work is therefore required to determine which variant are causal, as the inversion in this region complicates the ability of GWAS to fully address this question. Recent GWAS have identified several regions containing a set of genes that have pleiotropic effects on many psychiatric disorders and related traits; these genes may be tagging a latent factor. For example, the largest GWAS of alcohol and smoking, which used over 1 million individuals, performed a multivariate GWAS approach to show that 150 loci were associated with multiple substance use phenotypes; variation at PDE4B and CUL3 were associated with both smoking and drinks per week. Similarly, CADM2 has been recently associated with alcohol and cannabis use. CADM2 is a cell adhesion molecule that influences brain wiring and appears to have a role in multiple neuropsychiatric disorders. There is now mounting evidence from independent GWAS showing an association between common genetic variants at CADM2 and risky or impulsive behaviors including risk tolerance, automobile speeding propensity, number of sexual partners , sensation seeking and drug experimentation , cannabis initiation , and obesity and body mass index. CADM2 has also been associated with cognitive phenotypes, including educational attainment. 

Although there has been much work developing and testing CBT interventions for promoting ART adherence, there is still room for improvement because traditional multi-component CBT interventions for ART adherence result in small to medium effect sizes . Overall, the current study extends the literature on distress intolerance as a psychological vulnerability factor among people living with HIV. However, there are some limitations that provide opportunities for future research. First, the present study was cross-sectional, limiting inferences that can be made about directionality. Indeed, it is just as likely that low levels of distress tolerance lead to poor adherence as it is that poor adherence is prospectively associated with low levels of distress tolerance. This may be particularly relevant among immuno compromised individuals living with HIV. For instance, if poor adherence leads to an increasing viral load, then one’s immune system is mobilized to contend with the growing viral load. This is a physiological stressor and stress increases one’s drive to escape from unpleasant situations . Thus, it is feasible that stress due to immunological reactivity from an increasing viral load further limits one’s capacity to exercise tolerance of distress. It is plausible that poor adherence resulting in an increasing viral load may subsequently increase one’s vulnerability to distress intolerance.Following, as adherence was measured using pill count at only one time point, we were unable to establish a baseline level of adherence and MEMS caps would have provided a more precise indicator of adherence. Third, as mentioned earlier, though a strength of the study was the multi-method measurement of distress tolerance, future work would benefit from employing additional objectives and newly refined subjective measures to better understand differential relations between multiple facets of distress tolerance and HIV adherence.

Future work would also benefit from assessing tolerance of HIV symptom-related distress, specifically,rolling bench and the impact of distress tolerance on other clinically relevant HIV outcomes . Finally, though the present study was quite ethnically diverse, a majority of the sample was male. Future work would benefit from recruiting a more gender-diverse sample from different geographic areas. Promoting tolerance of affective distress and distressing tasks associated with the high-adherence demands of ART for HIV management are worthwhile to consider in future research. Future investigations are needed to examine relations prospectively to identify the role of distress intolerance in the development and maintenance of poor HIV management, and then verification of clinical implications through intervention process and outcome studies.A consortium of 67 scientific institutions from 24 European countries and beyond, covering over thirty scientific disciplines ranging from anthropology to toxicology, responded to an invitation by the European Commission to study the place of addictions in contemporary European society. The resulting five-year endeavour, the Addictions and Lifestyles in Contemporary Europe – Reframing Addictions Project , went beyond this. It reframed our understanding of addictions and formulated a blueprint for re-designing the governance of addictions. This paper summarizes the project’s conclusions, pointing to new understandings of the science and policy of nicotine, illegal drugs and alcohol, hereafter collectively referred to as ‘drugs’ . Although this paper does not cover process addictions , much of what is said applies to addictions beyond drugs.It contrasts two powerful pieces of evidence: the harm done by drugs, versus the poorly structured existing governance approaches designed to manage such harm.

The paper continues by considering three bases for re-thinking the addiction concept in ways that could lead to improved strategies across different jurisdictions: recognition that there is a biological predisposition for people to seek out and ingest drugs; that heavy use over time becomes a replacement concept and descriptor for the term substance use disorder; and that quantitative risk assessment can be used to standardize harm across different drugs, based on drug potency and exposure. The paper finishes by proposing two approaches that could strengthen addictions governance: embedding governance within a well-being frame, and adopting an accountability system—a health footprint that apportions responsibility for who and what causes drug-related harm.Governance is defined as the processes and structures of public policy decision making and management that engage people across the boundaries of public agencies, levels of government, and public, private and civic spheres to carry out a public purpose that cannot be accomplished by any one sector alone. The exclusive use of top-down bureaucratic approaches cannot maximize societal benefits when dealing with ‘wicked problems’ that are highly resistant to resolution . An analysis of 28 European countries found that no single country had a comprehensive policy for all drugs within a broad societal well being approach. For more detail, see ‘Governance of Addictions: European Public Policies’, by Albareda A et al. There are at least three reasons for ineffective and poorly integrated governance. Firstly, the same harm done by drugs is defined and understood in different ways in different countries and state systems. Seen from a trans-national comparative perspective, there is a lack of a common understanding of appropriate policies, and responses are often constrained by approaches that are tied to assumptions that are not evidence-based.

Ways of thinking about the harm done by drugs vary enormously, with considerable heterogeneity between different drugs, and between international, national and local levels of governance. For detail, see ‘Concepts of Addictive Substances and Behaviours across Time and Place, by Hellman et al. Secondly, a multitude of commercial, political and public stakeholders are active in addictions governance on national and international levels. In any given society, stakeholders that have power, means and influence are likely to achieve an advantageous influential position. The concepts of addiction are also shaped by popular constructs promulgated by the mass media and customs in the general population. Stakeholder positions and perceptions of drug problems also vary over time and by area4 , implying that sustainable approaches must be interwoven into societal and governance structures. Thirdly, corporate power,dry rack cannabis through multiple channels of influence, can hinder evidence-based policy decisions. Corporate strategies often include attempts to influence civil society, science and the media, as part of a wider aim to manage and, if possible, capture institutions that set policy. Transparency is insufficient given that the multiplicity of channels with corporate power is poorly acknowledged and understood by policy makers. Therefore, the rules in place to ensure level playing fields for discussions and equitable decision-making across all factors are inadequate.The idea that human exposure to drugs did not occur until late in human evolution—thus leaving our species inexperienced—is often posited as one of the reasons that these substances cause so much harm. However, multidisciplinary scientific evidence suggests otherwise. Many substances consumed today are not evolutionary novelties. In the story of terrestrial life over the last 400 million years or so, one ongoing theme has been the “battle” between plants and the animals that eat them. Of the many defence mechanisms in existence, plants produce numerous chemicals, including tetrahydrocannabinol, cocaine, nicotine, and opiates, all of which are potent neurotoxins that deter consumption of plant tissue by animals. From an evolutionary perspective, we thus find natural selection for compounds that discourage consumption of the plant via punishment of potential consumers. By contrast, there has been no natural selection for expression of psychoactive compounds which encourage consumption , which has also been predicted by neurobiological and behavioural psychology theories of reward and reinforcement for contemporary drugs. Counterbalancing the development of plant neurotoxins, planteating animals have evolved to counter-exploit plants’ production of drugs, for instance by exploiting the anti-parasitic properties of some of them.

Many species of invertebrates and vertebrates engage in pharmacophagy, the deliberate consumption and sequestration of plant toxins, to dissuade parasites and predators. In a human context, present day examples of pharmacophagy may be seen with Congo basin hunter gatherers, amongst whom the quantity of cannabis and nicotine consumed is titrated against intestinal worm burden – the higher the intake, the lower the worm burden. In individuals treated with the anti-worm drug abendazole, the number of nicotine-containing cigarettes smoked is reduced. Although parasite-host co-evolution is recognized as a potent selective force in nature, other, subtler evolutionary dynamics may affect human and animal interactions with plant-based drugs, including that they may buffer against nutritional and energetic constraints on signalling in the central nervous system. Ethnographic research reveals that many indigenous groups classify “drugs” as food, rather than psychoactive entities, and that they are perceived as having food-like effects, most notably for increasing tolerance for fatigue, hunger and thermal stress in nutritionally-constrained environments. The causes of these perceived effects have not been a research question, but there are clues that the “food” classification may be literal rather than allegorical. Common plant toxins not only mimic mammalian neurotransmitters, they are also synthesized from the same nutritionally-constrained amino acid precursors, such as tyrosine and tryptophan. In harsh environments, toxic plants could function as a “famine food” providing essential dietary building blocks, or, may function as a direct substitute for nutritionally-constrained endogenous neurotransmitters. There is some evidence to support this hypothesis in animal research; for example, wood rats in cold environments reduce thermoregulatory costs by modulating body temperature with plant toxins consumed from the juniper plant. In the case of ethanol, its presence within ripe fruit suggests low-level but chronic dietary exposure for all fruit-eating animals, with volatilized alcohols potentially serving in olfactory localization of nutritional resources. Molecular evolutionary studies indicate that an oral digestive enzyme capable of rapidly metabolizing ethanol was modified in human ancestors near the time that they began extensively using the forest floor, about 10 million years ago; humans have retained the fast-acting enzyme to this day. By contrast, the same alcohol dehydrogenase in our more ancient and mostly tree-dwelling ancestors did not oxidize ethanol as efficiently. This evolutionary switch suggests that exposure to dietary sources of ethanol became more common as hominids adapted to bipedal life on the ground. Ripe fruits accumulating on the forest floor could provide substantially more ethanol cues and result in greater caloric gain relative to fruits ripening within the forest canopy, and our contemporary patterns of alcohol consumption and excessive use may accordingly reflect millions of years of natural dietary exposure. This evolutionary evidence does not imply that humans also evolved to specifically consume nicotine, for example, or that nicotine use is beneficial in the modern world. What is novel in the modern world is the high degree of availability, and high concentration of psychoactive agents and routes of consumption that promote intoxication. What is different with alcohol in the modern world is novel availability through fermentative technology, enabling humans to consume it as a beverage, devoid of food bulk, with higher ethanol content, and artificially higher salience than that which characterizes fruit fermenting in the wild. The evolutionary evidence has two implications: firstly, policies that prohibit the use of drugs are likely to fail because people have a biological predisposition to seek out chemicals with varying nutritional and pharmacological properties; and secondly, in present-day society, drug delivery systems have been developed that are beyond what is reflected in the natural environment, particularly with respect to levels of potency, availability and taste, which could be argued as being the more central drivers of harm. Potency is largely determined by producer organisations operating in markets, which, from the perspective of overall societal well-being, are inadequately managed. Better regulation of potency can become a major opportunity for additional policy interventions – for example with alcohol, see ‘Evidence of reducing ethanol content in beverages to reduce harmful use of alcohol’ by Rehm et al..To better understand the interference of drugs in human biology and functioning, the consensus reached in ALICE RAP was that the concept and term ‘heavy use over time’ should be proposed as the replacement for ‘substance use disorder’. In medical settings and indeed often in academic and lay settings, heavy users of drugs are commonly dichotomized into those with a ‘substance use disorder’ or not. ‘Substance use disorder’ is a clinical construct that is often used as a shorthand to identify individuals who might benefit from advice or treatment. But as a condition in itself, it is a medical artefact which occurs in all grades of severity, with no natural distinction between ‘health’ and ‘disease’. This is illustrated with alcohol.

At the Accra Psychiatric Hospital there are 3 infirmaries and 23 wards total; 16 are male, six are female, and there is one children’s ward. One of the female and one of the male wards are reserved for geriatric cases. The largest special ward is reserved for forensic court cases and more aggressive males, 234 of them in total, though the official occupancy is only 60 for that particular ward. The largest female equivalent ward has 110 patients but the average number of patients in a ward is close to 50. Because there are only 500 beds and currently1,000 inpatients at the Accra Psychiatric Hospital, the congestion leaves 500 patients to sleep on the concrete or on thin mats either inside or outside. There are no fans or air conditioning either. The ones forced outside without insecticides or mosquito nets are subject to the rigors of the weather during the day and the disease carrying mosquitoes at night. These unlucky ones also share their space with ants, cockroaches, and rats. Though there is tap water available, drinking it is not encouraged, so patients have to pay a small fee for filtered drinking water. Patients eat three low quality meals a day that usually consist of rice, adding up to 3.60 cedis a day , a recent increase from the 1.20 cedis spent before 2011. Uniforms are not provided so the patients are free to wear their own or donated clothes, however it is a common and disturbing sight to see people running around stark naked or half naked with tattered clothes hanging loosely off their body. The congestion of patients and the conditions of their living situation are human rights violations in and of themselves.

To add to the situation, Dr. Osei admitted that behind the scenes, patients are sometimes physically or medically punished by nurses who are trying to control more patients than is feasibly possible. An undercover journalist also witnessed this injustice as well as pervasive drug trafficking between patients and employees. Although these acts are strictly discouraged,marijuana grow system it is hard to prevent these human violations from occurring due to a lack of staff and security. Records are kept analog, in a room full of bulging, tattered folders; though they are trying to digitalize the system, it is difficult with only 15 of the necessary 100 computers. There is also an intercom that works 80% of the time. The building, initially built as a prison and not as a hospital, is 100 years old, which makes it gruelling to clean and maintain. There is asbestos in the roofing, sewage system pipes have broken, and the buildings look like a rundown dog pound instead of a pristine, sanitary hospital. In fact, people in the West would be appalled by the conditions even if it actually were a place reserved for rogue dogs. If the Mental Health Bill passes, then remodelling of the building might start in seven years’ time. Dr. Osei proposes that if the buildings and wards ameliorate into sane conditions, then the morale of both the workers and patients will improve, and people will not want to leave the second they arrived. Pantang Hospital’s accretion of debt from insufficient funding over the past six years has led to unfinished structures, outdated equipment, shortage of prescribers, inadequate treatment programs , poor food quality, deficient road networks, old vehicles, under-supplied water and electricity, and encroachment of land and security. During my interview with Dr. Dzadey, the electricity went out in true Ghanaian fashion, and was followed by many scolding and worried phone calls about the number of the samples the laboratory was losing every minute the generator refused to work.

Water enters the pipes only twice a month so there is not enough water or disinfectants to properly clean the estate. In addition to that, the hospital is constantly buying water to fill tanks and filtered water to give to patients. The regular wards feed each patient on a mere 60 pesewas a day, but in 2008 it was rightfully increased to 2.5 cedis. Though the walls are covered in perma-dirt, and dust and a smell of sanitation chemicals lingers in the air, the facilities are much nicer and newer than at the Accra Psychiatric Hospital. The outpatient psych department is located in a three-story building, with a television in the lobby, and there is air conditioning in the consultant rooms. Possibly due to the workload and training, Dr. Dzadey also commented on how the nurses do not have the proper understanding on how to take care of patients. They complete their tasks, such as administering medicine, but there seems to be a lack of compassion in regards to keeping the patients’ best interests at heart. Ghana has only 11 psychiatrists, four of them at the higher, board certified consultant level, and 6 retired psychiatrists, four of whom continue to work at private psychiatric hospitals. In order to have an effective mental health care system in Ghana, Dr. Osei believes that there should be at least 80 working psychiatrists with half of them at the consultant level. To become a consultant psychiatrist in Ghana, one will have to complete six or seven of medical school, then five years of post-doctoral work in psychiatry. “Brain drain is a phrase all too common to the mental health care system in Ghana.Shockingly,cannabis vertical farming there are currently twenty Ghanaian psychiatrists practicing in the U.K. when there are only seventeen psychiatrists in all of Ghana. While here is one retired occupational therapist in Ghana, Dr. Osei conservatively requests for twenty. In actuality, every mental health unit should have an occupational therapist, so the ideal number would be around 200. Hence, in Table 7 I averaged 20 and 200 to get a more accurate estimate of the amount needed. Furthermore, there are only 600 Psychiatric Nurses presently working when there should be at least 3,000 in order to care for most of Ghana’s mentally ill.

Psychiatric Nurses train at either Pantang or Ankaful, and complete one year of general nursing and two years of specialized psychiatric nursing. Clinical psychologists are regrettably not even recognized by Ghana’s Ministry of Health, and any clinical psychologists working at a Psychiatric Hospital have to be listed under another title on the payroll.Seven psychiatrists are working at the Accra Psychiatric Hospital when there should not be less than 30 psychiatrists. Dr. Osei referred to this number as his “dream figure. Table 8 presents other current and proposed numbers of staff. Although there are no trained psychiatric social workers, there are two generic social workers employed by the hospital. The hospital also has two volunteers who help feed and bathe the children in the children’s ward. There should be two security workers in every ward and some more patrolling the hospital, which led to the suggested fifty. Because of the lack of security, many patients escape by jumping over a wall, exiting through a ceiling, or simply walking out of the front entrance. Also, there is typically one incident involving a worker being injured or killed by a patient per year. While some nurses declared that a patient killed another nurse early in 2011, Dr. Osei said that the most recent incident was someone who was blinded in one eye after being hit by a patient. Many of the staff is forced to work at the hospital through either a nursing program or the national service requirement. The staff is terribly limited due to a combination of factors revolving around money and stigma. There are poor working conditions and the little pay reduces any incentive. For a 600-person workforce there are only 28 accommodation units, so most employees are dissuaded because they have to find their own housing closer to the hospital, or pay for transportation into the workplace from their home. As a result, many nurses have confirmed interest in moving to a different country in order to work in a more amicable and rewarding environment, which would further diminish the number of psychiatric nurses the Health Ministry has managed to train. In 2010, the staff strength of Pantang Hospital numbered 524, with two psychiatrists, one clinical psychologist, three medical assistants, three pharmacists, 260 psychiatric nurses, two welfare officers, 34 ward assistants, one bio-statistician, one biomedical scientist, eight occupational therapists, and zero occupational therapists. Dr. Dzadey suggests that the minimum number of psychiatrists the hospital should have is five, around one psychiatrist per two wards and one in OPD, but ideally, the number should be ten so that each ward has its own psychiatrist. In order to gradually reach that ten, the hospital can aim for five permanent psychiatrists and five training or rotating psychiatrists. The one present clinical psychologist overwhelmingly offers counselling, family therapy, individual therapy, and behavioural therapy to all of the hospital’s outpatients and inpatients.

Due to this unfathomable ratio of one psychologist to around 17,265 patients, the quality of therapy and frequency of contact is low, and Dr. Dzadey proposed that there should be a minimum of three clinical psychologists. Preferably, there should be one in every ward, and one in the outpatient department, which would add up to an idyllic number of 10 clinical psychologists. Dr. Dzadey commended the use of physical therapy and recommends that the hospital should also hire at least four physical therapists;currently, there is none. Ghana’s only occupational therapist retired two years ago, but luckily, a temporary occupational therapist came from VSO, Voluntary Service Overseas, and helped train some future occupational therapist assistants to continue her year-long work. However, there should be at least three permanent occupational therapists. The two welfare officers in charge of tracing and contacting the families of patients and organizing repatriation with appropriate CPNs are also severely overworked, which leads to patients staying longer than expected. Dr. Dzadey advises that there should be a minimum of one nurse to five patients. This would result in an average of 275 psychiatric nurses working solely in the wards whereas there are only 260 currently working in either the wards, psych OPD, and/or general OPD. Table 9 shows a clearer representation in the gaps of human resource at the hospital. A person with an acute case is expected to stay at the Accra Psychiatric hospital for two weeks but usually ends up staying for one to three months, while a person with a major case usually stays for about two years though some stay for twenty or thirty years. Inpatients stayed at the Pantang hospital for an average of 63.2 days while vagrants, geriatric patients, and paupers lived in the wards for an average of 173.9 days. These hospitals have a problem with patients overstaying their welcome because there is not enough manpower to frequently evaluate each patient’s progress, the courts do not come for them, or the patients live very far from the hospital. In some cases, the families forget to inquire about their relatives or refuse to pick them up due to the hospital’s distance from their village, or the families can no longer be reached . Moreover, the associated stigma results in a great deal of patients being abandoned by their families upon admittance into the psychiatric hospital. A heartbreaking pattern common to the children’s ward is parents giving spurious phone numbers and addresses to the hospital so that they can no longer be contacted in reference to their child. On average, only 20% of patients at the Accra Psychiatric Hospital have relatives who care enough to occasionally visit and how they are doing; this mainly occurs for those suffering from minor cases. For many years and still to this day, countless Ghanaians believe that supernatural, evil forces or spirits, bewitchment, or planted juju cause mental illness. The executives of Mind Freedom find that most Ghanaians believe that the mentally ill cannot be productive in a society and that the reason they are mentally ill is because they are cursed or have offended a deity. The three noted that this perception cuts across all levels of age, education, and location. This assumption varies little between age and inhabited region, but sometimes varies in education level, with less schooled individuals often placing more blame on super natural forces while the more educated tend to hold more positive attitudes towards the mentally ill .

In order to appropriately test and validate this model for AUD, we will use an established, FDA-approved medication. NTX is an opioid antagonist with high affinity for mu-opioid and kappa-opioid receptors. Preclinical studies have shown that opioid antagonists at the muopioid receptor reduce ethanol consumption. In humans, alcohol consumption increases the release of endogenous opioids in the mesolimbic dopamine reward system which contributes to the subjective pleasurable effects of alcohol. Therefore, NTX’s therapeutic benefit as an opioid antagonist is proposed to block these rewarding effects and reduce alcohol consumption. Previous studies of NTX have shown that it reduces drinks per drinking day, alcohol craving, rates of relapse, and the subjective pleasurable effects of alcohol. The effects of NTX appear to be moderated by craving such that higher levels of craving were found to be associated with greater reduction in alcohol consumption. As an established medication for AUD, NTX is an ideal candidate to test the novel practice quit attempt model. To further validate this novel early efficacy model, we will also test a promising medication to treat AUD. Varenicline is a partial agonist at α4β2 and a full agonist at α7 nicotinic acetylcholine receptors, which is FDA-approved for smoking cessation. In preclinical studies, activation of nicotinic acetylcholine receptors reduced ethanol consumption. In human laboratory studies, VAR reduced alcohol self-administration and craving, compared to placebo. In smoking cessation trials, it also reduced alcohol consumption and craving.

Additionally, a multi-site randomized controlled trial of VAR in individuals with AUD found that it reduced drinks per drinking day, alcohol craving,cannabis grow supplies and percentage of heavy drinking days. Together, these studies suggest that VAR is a promising pharmacotherapy for the treatment of AUD. Therefore, including varenicline, a widely studied and promising AUD pharmacotherapy, as a third arm in this study will enable us to further validate this novel alcohol quit paradigm. In designing the current study as a 3-arm trial, we benefit not only from establishing the efficacy of NTX and VAR against placebo, but also from a head-to-head comparison of NTX and VAR in a cost-effective manner. The 3-arm trial design has been selected to overcome weaknesses present in non-inferiority trials where a novel drug is compared to an active control that is the current standard treatment. In active control trials, medication efficacy of the novel drug is determined by demonstrating non-inferiority to the active control, which rests on the critical assumption that the active control has an actual drug effect. However, as there is no placebo control, this assumption cannot be proven; therefore, non-inferiority/equivalence trials lack assay sensitivity, or the ability to distinguish between effective and ineffective treatments. The 3-arm design essentially combines the advantages of placebo and active controlled trials. The placebo arm will allow us to showcase if VAR is an effective or ineffective medication in the context of a good internal standard. Additionally, if neither NTX nor VAR are shown to be superior to placebo, then we can conclude that the practice quit paradigm is not a valid method for screening medications for AUD.The purpose of the current study is to develop and validate this novel model to screen novel compounds and advance medications development. Naltrexone was chosen to evaluate the novel practice quit attempt model as it is one of the few FDA-approved medications AUD.

RCT studies with oral NTX have shown that it reduced drinks per drinking day, alcohol craving, rates of relapse, and the subjective pleasurable effects of alcohol. As such, NTX represents a well-known, well-studied medication that is ideal for testing a novel paradigm. Varenicline is a promising pharmacotherapy for the treatment of AUD. VAR has been shown to reduce alcohol self-administration, consumption, and craving. A recent RCT of VAR in individuals with AUD found that it reduced drinks per drinking day, alcohol craving, and percentage of heavy drinking days. These studies suggest VAR as a potential AUD pharmacotherapy. The addition of VAR as a third arm in the current study will allow us to further validate this novel practice quit attempt model. Additionally, the inclusion of a promising pharmacotherapy allows us to compare the efficacy of two medications head to-head in a cost-effective manner. The 3-arm design of a novel medication , standard treatment , andplacebo allows us to not only establish efficacy of each medication against placebo, but also of the novel medication again the standard treatment. This study design essentially combines the advantages of placebo and active control studies.Participants who are eligible after the physical exam will be randomized to one of three treatment conditions . Urn randomization will be stratified by gender, smoking status , and drinking status . The UCLA Research Pharmacy will manage the blind. The three treatment conditions will not be different in appearance or method of administration. All participants will undergo a week long medication titration period prior to the onset of the practice quit attempt as follows: for the naltrexone condition, 12.5 mg will be taken for the first 3 days, followed by 25 mg dosage from days 4–7.

The target dosage of 50 mg will be ingested days 8–14. As for the varenicline condition, a dosage of 0.5 mg will be taken for the first 3 days followed by an increase to 1 mg for days 8–14. The intended dosage of 2 mg will be taken days 8–14. Each condition will the instructed to take prescribed medication twice per day as detailed in Table 1. On study day 1, participants will report to the laboratory to complete the alcohol CR paradigm and receive their first medication dose under direct observation of study staff. They will receive a 7-day supply of study medication in blister packs with AM and PM dosing clearly distinguished. After reaching the target medication dose at the end of 1 week, participants will come to the laboratory on study day 8 to receive their second, 7- day supply of study medication and to begin the 7-day practice quit attempt. Participants will be asked to take the AM dose of study medication on study day 8 in the lab under direct observation of study staff. During the practice quit attempt,cannabis grow facility participants will complete daily online and phone visits to report on their drinking, mood, and craving for alcohol during the previous day in a daily diary assessment . For each virtual visit, participants will be contacted over the phone by research staff. Participants will first be asked about adverse events and about use of concomitant medications. Research staff will then administer the CIWA-Ar to measure alcohol withdrawal. Next, they will ask participants to report on their past day drinking as well as cigarette and marijuana use. Finally, while participants are still on the phone, research staff will send a link to the DDA . All participants will meet with a trained study counselor briefly after the second cue exposure session on day 14. This brief intervention draws from motivational interviewing and Screening, Brief Intervention, and Referral to Treatment models. It uses the therapeutic stance of motivational interviewing which is collaborative and client-centered. Consistent with the literature on brief intervention, the therapist will seek opportunities to engage in and amplify change talk.

Together, the combination of evidence-based practices and principles applied to AUD, coupled with the experience of change in the context of study participation, is expected to result in an opportunity for health behavior change .Criteria for discontinuing or modifying allocated interventions are at the discretion of the study physicians or principal investigator. One week after beginning the medication, physicians will speak with the participant via phone call to check for any adverse events. If reported, participant may either undergo a dose-reduction or termination. Participants will also have the option to voluntarily discontinue all medication at any point. All severe adverse events will be reported to relevant reporting entities immediately.Adherence to interventions is facilitated by dividing the medication into separate blister packs for two distributions, the daily virtual visits during the practice quit attempt period, and a completion bonus. The separation of the study medication into two blister packs, each a 7-day supply, will motivate participants to come back to the laboratory for the second supply, and reduce the chance of them misplacing the medication at the start of the study. During the practice quit attempt period, the participants will be asked to send pictures of their blister packs to the study staff after completion of the daily phone visits. This will allow the study staff to count the medication for compliance. Additionally, a completion bonus will be given out to participants on the last day of the study if they have completed at 7 out of the 8 in-person and virtual visits. This is to motivate participants to complete all daily phone visits and online assessments .Participants will be recruited from the community through online and newspaper advertisements, as well as campaigns on multiple social media platforms .Targeted recruitment will also take place through a lab database of previous study participants who agreed to be contacted for future studies.Data are collected at the behavioral eligibility screening visit, the randomization visit , at each of the daily phone visits during the practice quit attempt period , and at the in-person study visits . All staff personnel will be trained on any relevant assessment procedures and inter-reliability will be monitored continuously by the primary investigator. For the drinking outcomes , data will be collected via participant self-report through the Timeline Follow back. The Alcohol Urge Questionnaire will be used in the CR paradigm to measure craving. The AUQ is an 8-item scale in which participants will rate their present experience of alcohol craving on a 7-point Likert scale. The AUQ has demonstrated high test-retest reliability, high internal consistency, and construct validity in human laboratory studies.Self-report measures will be directly completed through an electronic data capture electronic case report forms system, Qualtrics. Timeline Follow back data will be entered by research staff into excel in order to generate daily drink averages based on standard drink calculations. All other data will be entered by research staff onto SPSS. Data will be held on a secure server at the University of California, Los Angeles. Appropriately qualified personnel designated by the PI will monitor data entry and ensure that missing data are addressed as soon as possible after detection. All Timeline Follow back data will be double-checked by research staff to ensure validity. Excel will also be formulated to detect and notify in the case of any abnormal values.Participants will be given a 24-h telephone number to reach the study physician to discuss side effects, and physician office hours will be available as needed. Adverse events, including signs of sickness, will be collected in an open-ended format and coded using a systematic assessment for treatment emergent events format at each study visit . Vital signs will be monitored at the beginning of each in-person study visit. Alcohol withdrawal will be monitored at each visit through administration of the CIWA-Ar, and any significant withdrawal, as indicated by a score of 10 or more on the CIWA-Ar, will be reported to the study physician immediately. In the event that significant medical problems are encountered, the study blind will be broken and appropriate medical treatment will be provided.The PI will designate appropriately qualified personnel to periodically perform quality assurance checks at mutually convenient times during and after the study. These monitoring visits provide the opportunity to evaluate the progress of the study and to obtain information about potential problems. The monitor will assure that data are accurate and in agreement with any paper source documentation used, verify that subjects’ consent for study participation has been properly obtained and documented, confirm that research subjects entered into the study meet inclusion and exclusion criteria, verify that study procedures are being conducted according to the protocol guidelines, monitor review AEs and SAEs, and assure that all essential documentation required by GCP guidelines are appropriately filed. At the end of the study, they will confirm that the site has the appropriate essential documents on file and advise on storage of study records.Alcohol use disorder is a chronic condition with both high relapse and low treatment rates.

Secondary antisera from ThermoFisher Scientific included Alexa Fluor 594 antirabbit IgG , Alexa Fluor 488 anti-mouse IgG and Alexa Fluor 488 anti-guinea pig IgG all used at 1:1000 dilutions. An epifluorescence microscope with a 63× PlanApo objective and ORCA-ER camera was used to capture image z-stacks, through a depth of 2 μm in 0.2 μm z-steps, from the DG outer molecular layer and CA1 stratum radiatum. For slice experiments, 1 z-stack was captured from each of 6 sections per slice. For behavioral/brain studies, 3 z-stacks were captured per section from 3 to 4 spaced sections within a given septo-temporal span of hippocampus . Immunolabeling for the synaptic vesicle protein SYN and for the excitatory synapses postsynaptic scaffold protein PSD-95 served as markers for the presynaptic and postsynaptic compartment, respectively. The incidence and density of immunolabeling for the phosphoprotein co-localized with these compartment markers were then evaluated using wide- field epifluorescence microscopy and fluorescence deconvolution tomography as described elsewhere . Briefly, images within each z-stack were processed for iterative deconvolution and then used to construct a 3-dimensional montage of the sample field. Automated systems were then used to normalize background density, identify immuno labeled elements within the size and eccentricity constraints of synapses, and quantify those double-labeled. Elements were considered double-labeled if there was any overlap in the field labeled with the 2 fluorophores as assessed in 3D.Male Long–Evans rats were handled for 6 sessions, 2 sessions per day, and prior to odor discrimination training. Procedures for animal handling, training, and testing were adapted from Martens et al. as described in detail elsewhere . Sessions of ten 30 s trials on a given odor pair were repeated up to twice daily until rats reached a success rate of 80% correct at which point they were considered to have acquired the odor discrimination task.

On the following day, trained rats were either given 10 training trials on a novel odor pair or transported to but not placed in the test apparatus,cannabis plant growing and killed immediately thereafter for tissue harvest .The CB1R is found on axon terminals throughout the brain including the field of LPP termination in the outer molecular layer of the DG . We confirmed CB1R localization to glutamatergic terminals in the rat LPP field and then compared the effects of cannabinoid receptor agonist WIN 55,212–2 on synaptic physiology in the S–C and LPP projections. In accord with prior work , WIN caused a rapid and pronounced depression of S–C fEPSPs in CA1 that was accompanied by an increase in paired-pulse facilitation and the expected severe impairment of LTP . Very different results were obtained in the LPP: WIN had no effect on baseline fEPSPs or on paired pulse facilitation . Voltage-clamp recordings also detected no effect on EPSCs in the LPP . In contrast to these results for glutamatergic responses in the LPP, WIN produced the canonical depression of IPSCs elicited by single pulse LPP stimulation . We next asked if, despite the lack of effect on baseline responses, WIN influences the machinery that produces the ECBdependent potentiation of the LPP using stimulation that is near threshold for induction. WIN more than doubled the magnitude of lppLTP under these conditions . These results suggest that activation of CB1Rs in the LPP preferentially engages signaling mechanisms leading to potentiated transmission as opposed to the more commonly observed depression of release. CB1R signaling through ERK1/2 effects phosphorylation and degradation of the vesicular protein Munc18-1 leading to reductions in transmitter release . In accord with this, using dual immunofluorescence and FDT , we found that treatment with WIN increased levels of phosphorylated Munc18-1 S241 co-localized with the presynaptic marker SYN in the S–C terminal field: WIN caused both a rightward shift in the pMunc18-1 immuno labeling intensity frequency distribution and increased numbers of terminals with dense pMunc18-1 immuno reactivity . In the same slices, WIN had no effect on presynaptic pMunc18-1 immuno labeling in the LPP terminal field .

The above results indicate that WIN-initiated CB1R signaling at LPP terminals is biased “away from” the ERK1/2-to-Munc18-1 cascade through which ECBs suppress neurotransmitter release and toward a route that promotes plasticity. They also raise the question of whether signaling to Munc18-1 and release suppression in CA1 is engaged by normally occurring patterns of physiological activity. Blocking the CB1R with the inverse agonist AM251 had no effect on S–C fEPSPs elicited by single pulses . Thus, we tested for an effect using short trains of low-frequency gamma stimulation. This pattern occurs routinely in hippocampal and entorhinal fields in behaving animals and is thought to be associated with processing of complex information . Within-slice comparisons were made between responses collected before and after 40 min perfusion of vehicle or 5 μM AM251. In CA1, S–C responses to low gamma stimulation showed the rapid, within-train frequency facilitation described in prior work . AM251 did not affect baseline responses but clearly enhanced S–C response facilitation during the gamma train . Effects of AM251 were greatest in later portions of the train, as anticipated for contributions of “on-demand” ECB production. Very different results were obtained for the LPP. Within-train facilitation was less pronounced in the LPP than in the S–C system, and this effect was not altered by AM251 . These findings are consistent with the hypothesis that CB1R signaling leading to a depression of transmitter release is more readily engaged in the S–C projections than in the LPP.The above results were unexpected because prior studies showed that physostigmine causes a suppression of excitatory transmission in the LPP and other hippocampal pathways that is blocked by AM251 .Therefore, we tested if physostigmine increases hippocampal 2-AG levels, as anticipated, and then used the FDT technique employed above to determine if it also triggers Munc18-1 S241 phosphorylation in the LPP. Infusion of physostigmine elicited a marked increase in slice levels of 2-AG but not other lipids ; it also produced a reliable increase in SYN+ terminals with dense concentrations of pMunc18-1 in both LPP and S–C fields.

As predicted,vertical grow system physostigmine effects on both projections were dramatically reduced in slices prepared from Munc18-1+/− mice relative to those from wild types although the mutation had no effect on the input/output curve or paired-pulse facilitation in the LPP . A recent study showed that the locally synthesized neurosteroid pregnenolone reduces both CB1R signaling through ERK1/2 and neurotransmitter release suppression normally mediated by the ECB receptor . We tested for this effect in hippocampus beginning with the pronounced fEPSP depression produced by CB1R activation in the S–C system: treatment with 10 μM pregnenolone prevented the synaptic response depression elicited by WIN . Pregnenolone was similarly effective in the LPP where it blocked actions of physostigmine on presynaptic pMunc18-1 immuno reactivity and synaptic transmission . These findings point to the conclusion that the pregnenolone/ CB1R/Munc18-1 system, as found in the S–C projections, is present in the LPP although it is not engaged by either the CB1R agonist WIN or repetitive afferent activity. There remains the possibility, however, that it is activated by the short high-frequency gamma trains used to induce lppLTP and participates in subsequent stabilization of the potentiated state of LPP terminals. We conducted multiple tests of this argument. Pregnenolone at the concentration that eliminates physostigmine effects on transmission and pMunc18-1 immuno reactivity in CA1 had no detectable effect on lppLTP induced by near threshold stimulation . Conventional stimulation trains failed to influence Munc18-1 phosphorylation in LPP terminals and induction of lppLTP was fully intact in Munc18-1+/− mice . Considered together with evidence that lppLTP is both 2-AG and CB1R-dependent , the present results suggest that potentiation in the LPP involves a second CB1R signaling pathway that has not been evaluated in work using physiological activation of hippocampal synapses. Finally, the results obtained with pregnenolone afforded a means for testing if increases in 2-AG content produced by physostigmine promote lppLTP in the absence of the response suppression associated with Munc18-1 phosphorylation. We tested this intriguing point and found that physostigmine more than doubled the magnitude of lppLTP induced by threshold level stimulation . This result is consistent with our earlier observation that reducing 2-AG breakdown, and thereby increasing hippocampal slice 2-AG levels, with the monoacylglycerol lipase inhibitor JZL184 similarly augments lppLTP .Prior results showed that lppLTP is blocked by presynaptic actions of latrunculin A , a toxin that selectively blocks the assembly of actin filaments. This raises the possibility that the CB1R promotes lppLTP via actions on actin regulatory signaling, an idea in alignment with evidence that CB1R initiates actin reorganization in dissociated cells and rapidly activates both FAK and the small GTPase RhoA in N18TG2 neuroblastomacells . FAK is a non-receptor tyrosine kinase that mediates integrin effects on the actin cytoskeleton throughout the body .

Other experiments found that CB1R acting through FAK initiates actin remodeling in pancreatic cells resulting in enhanced insulin release . Accordingly, we used FDT to test if WIN activates FAK, via Y397 phosphorylation, in LPP terminals . WIN produced a pronounced rightward skew in the immunofluorescence intensity-frequency distribution for pFAK Y397 co-localized with SYN . RhoA and its downstream effector, ROCK2, represent a primary route whereby FAK signals to actin . In the LPP terminal field, WIN increased levels of pROCK S1366 co-localized with SYN but not with the postsynaptic density marker PSD-95 . In the same hippocampal slices, WIN increased presynaptic pROCK levels in CA1 but this effect was substantially smaller than that in the LPP. We quantified the regional difference by converting the data into cumulative probability curves and then subtracting the WIN treatment values at each density bin for each slice from the mean curve for the vehicle group. The rightward shift in pROCK immuno labeling produced by WIN was over 2-fold greater in the LPP than in CA1 . In all, the CB1R agonist WIN had a much greater effect on Munc18-1phosphorylation in CA1 than in the LPP and a much greater effect on markers of actin signaling in the LPP than in CA1. We conclude from this that the CB1R response to WIN is biased toward different signaling streams in the 2 projections. We further tested if CB1R signaling to ROCK is more prominent in the LPP than in CA1 using physostigmine to elevate 2-AG levels and signaling. Physostigmine produced a reliable increase in presynaptic pROCK in the LPP that was blocked by CB1R antagonism but had no reliable effect on presynaptic pROCK levels in CA1 of the same hippocampal slices . A similar pattern of results was obtained in an analysis of the most densely pROCK immunoreactive terminal boutons . Collectively, these results describe a CB1R-FAK-ROCK route by which 2-AG generated and released during high-frequency stimulation could facilitate presynaptic cytoskeletal changes required for production of stable lppLTP. In accord with this proposal, high-frequency bursts of LPP stimulation caused a rightward shift in the density frequency distribution of presynaptic pFAK in slices harvested 2 min after stimulation.Together, these results describe a second CB1R signaling pathway in LPP terminals that, unlike the ERK1/2-Munc18-1 route, is directly involved in the production of lppLTP.An important question raised by the above results is why activation of FAK and ROCK by pharmacological CB1R stimulation, augmented lppLTP but did not by itself induce potentiation. One possibility is that electophysiological stimulation of the LPP engages elements that are not downstream from CB1R activation but nonetheless are required for shifting LPP terminals into the enhanced release state. We tested if integrin class adhesion proteins, which co-operate with CB1R in actin regulatory signaling in cultured cells , fill this critical role. Integrins are dimeric transmembrane adhesion receptors for extracellular matrix and cell surface proteins that are expressed throughout the brain by neurons and glia . In hippocampus the majority of integrins contain the β1 subunit and β1 integrins have been localized to both pre- and postsynaptic compartments . We previously demonstrated that, in hippocampal slices, infusion of β1 neutralizing antisera disrupts activity-induced actin polymerization and LTP in field CA1 . Here, we tested if similar treatments influence potentiation in the LPP. Treatment with anti-β1 had no effect on baseline LPP responses but caused a near complete suppression of lppLTP . In contrast, neutralizing anti-αV integrin left potentiation intact .

A murine model also suggested inhaled VEA may cause EVALI-like lung injury,but the underlying mechanism remains to be determined. The age range of cases and deaths is broad, and the e-cigarette use patterns are diverse, although 75% of EVALI patients were young Caucasian males and an overwhelming majority admitted to THC vaping. While VEA from THC vaping has been most commonly and consistently linked to EVALI cases, the spectrum of usage patterns and clinical manifestations suggest a possible role of multiple toxicants from unregulated products. Chemical analysis of counterfeit cartridges obtained from EVALI patients demonstrated the presence of several toxicants including volatile organic compounds, semi-volatile hydrocarbons, silicon conjugated compounds, terpenes, pesticides, and metals, which were not found in medical-grade THC cartridges.The typical symptoms of EVALI include dyspnea, chest pain, cough, fever, and fatigue. Additionally, many of the EVALI patients also presented with nausea and vomiting and other gastrointestinal symptoms. Chest radiography of most cases was abnormal; images typically showed ground-glass opacities in both lungs.Four radiographic patterns were identified in EVALI patients including acute eosinophilic pneumonia, diffuse alveolar damage, organizing pneumonia, and lipoid pneumonia.Histological analysis of lung biopsies showed patterns of acute fibrinous pneumonitis, diffuse alveolar damage, or organizing pneumonia.EVALI patients may have slightly different phenotypes and have been diagnosed with acute respiratory distress syndrome, lipoid pneumonia, and pneumonitis. Patients have been treated with antibiotics and glucocorticoids,and the steroidal treatment has been shown to improve symptoms and lung function.

Although this is a new field,cannabis flood table where initial cross-sectional epidemiological studies have demonstrated several limitations, adolescents who vaped have been found to be more likely to try cigarettes than non-smoking non-vaping youth.For example, a cross-sectional analysis of PATH study data indicated an association between e-cigarette use and self-reported wheeze,and an analysis of data from 402 822 never-smoking participants in the behavioral risk factor surveillance system indicated an association between self-reported asthma and e-cigarette use intensity.It is important to recognize that the above studies were observational in nature, and the chronology of e-cigarette use and disease development are often not clear, so more evidence is needed that will further clarify the cause-effect relationship between e-cigarette use, cardiopulmonary disease, and cerebrovascular events. Regardless, these publications serve as an impetus for future research into the causative and mechanistic relationships between e-cigarette use and cardiopulmonary disease risk.E-cigarettes have been proposed as an effective strategy to quit conventional cigarette smoking, but they have not been approved for this purpose in the USA or elsewhere. To date, the clinical trials that have been carried out do not address the question of effectiveness in the “real world”, that is, does the availability of e-cigarettes in the marketplace decrease smoking at the population level. Instead, clinical trials have compared the delivery of nicotine by an e-cigarette to other modalities of nicotine delivery. The most recent review on this topic concluded: “The evidence is inadequate to infer that e-cigarettes, in general, increase smoking cessation. However, the evidence is suggestive but not sufficient to infer that the use of e-cigarettes containing nicotine is associated with increased smoking cessation compared to the use of e-cigarettes not containing nicotine, and the evidence is suggestive but not sufficient to infer that more frequent use of e-cigarettes is associated with increased smoking cessation compared with less frequent use of ecigarettes”.

To predict the relative dangers of second- and third-hand e-cigarette exposures, an understanding of the degree to which ecigarette use might lead to an increase in ambient nicotine and particulate matter, and the degree to which nicotine and other e-cigarette constituents deposit on surfaces, will be critical. Since there are no side stream aerosols from e-cigarettes, unlike combustible cigarettes, secondhand e-cigarette exposure is almost exclusively from user exhalation. Thus, it remains unclear and somewhat controversial as to what level of additional particulate matter, vapor phase, and nicotine emissions are released into the environment from e-cigarettes. Some of this uncertainty may relate to variability in device design and liquid composition. However, several studies have demonstrated ecigarette use by individuals can contribute to worse indoor air quality, including release of toxicants and particulate matter.For example, indoor e-cigarette use can generate fine particulate matter in high concentrations during natural use conditions in indoor environments, as well as an increase in particle numbers and concentrations of 1,2-propanediol, glycerin, and nicotine.Increased levels of 1,2-propanediol, diacetin,cannabis grow supplier and nicotine were also measured by gas chromatography from one exhaled e-cigarette puff. E-cigarettes containing nicotine-free solutions may have higher particulate levels than those containing nicotine. However, these particles dissipate much more quickly than cigarette smoke particles and further studies will be needed to fully understand the risk of second and third-hand exposures. Measurable nicotine levels have been detected in samples from hard surfaces and cotton surfaces exposed to e-cigarette emissions.Recent developments in detection strategies by use of auto fluorescence have further elucidated e-liquid deposition topography. One study found that for each 70-mL aerosol puff, 0.019% of the aerosolized e-liquid was deposited on hard surfaces.

These studies may also be an overestimate when compared to real-life scenarios because aerosol puffs were directly administered to the observed surfaces and were not inhaled and exhaled prior to surface deposition. However, in an attempt to provide a better model of surface deposition, deposition as a result of inhaled and exhaled e-cigarette aerosol was performed.This study found no significant increase in surface nicotine levels following 80 puffs per participant. The authors noted these results may not indicate a lack of risk for third-hand exposure, since they did not account for gradual accumulation on surfaces over time. Together, these results indicate that potentially hazardous e-cigarette emissions, including PG/VG, nicotine, and heavy metals may be deposited on household surfaces as a result of typical vaping behavior. Furthermore, they suggest a potential risk for third-hand exposure which could serve as a public health concern. However, more studies are needed to better understand the risk of vaping for second and third-hand exposures.In assessing the public health impact of e-cigarette use, there is an implicit comparison to alternative or counterfactual scenarios; in the case of e-cigarettes, the comparison is to the hypothetical situation of a world lacking e-cigarettes. There are established methods for quantitative risk assessment that are widely used for public health decision-making, such as the four-element paradigm set out in the 1983 National Research Council Report generally referred to as “The Red Book”. The elements include: hazard identification, that is, is there a risk?; exposure assessment, that is, what is the pattern of exposure?; dose-response assessment, that is, how does risk vary with dose?These four elements have general applicability to characterizing the impact of ecigarettes in terms of the prevalence of nicotine addiction and its profile across groups in the population and the associated additional burden of disease. Population impact is quantitatively assessed using conceptual models that capture an understanding of the relationships between independent and modifying factors and their outcomes. Models are implemented using statistical approaches and evidence-based estimates of the values of parameters at key steps in the model, for example, the rate of initiation of use of tobacco products with e-cigarettes present . This approach was used by the FDA’s Tobacco Products Scientific Advisory Committee to estimate the impact of menthol-containing tobacco products.

The overall approach was to formulate a conceptual framework, conduct systematic reviews around the framework, and implement an evidence-based statistical model for making estimates related to public health impact. The systematic reviews highlighted those gaps in scientific evidence, pointing to the most critical research needs for strengthening the evidence foundation for potential regulation of menthol. For e-cigarettes, the research priorities identified in this article relate to key evidence gaps that need to be addressed to achieve a greater and more certain understanding of the population impact of ecigarettes.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 non-adherence 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, 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 .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. A modified timeline follow-back interview was used to assess drinking behavior in the last 30 days .

For the CBIs listed that did not mention use of a broad theory , but mentioned using a specific construct or technique, all provided a description of how it was applied in the intervention ; however the amount and quality of information provided about the application of the construct/techniques varied considerable across this group of CBIs.Of the 21 CBIs that mentioned use/application of theory , all but two included at least one measure of a construct associated with the theory. If a CBI mentioned use of a theory, it was more likely to include a measure of specific constructs associated with the theory compared to CBIs that did not mention use of a broad theory. Specifically, of the CBIs, that did not explicitly mention use of a theory, but did include a specific construct, only five included corresponding measures of the theoretical construct . Tables 1 and 2 lists the classification of each CBI and provides a list of the measure associated with the theory, construct or intervention technique.This study identified 100 unique articles covering 42 unique computer-based interventions aimed at preventing or reducing alcohol use among adolescents and young adults.Thus, this review includes a total of 21 new CBIs and 43 new articles. This review is the first to provide an in-depth examination of how CBI’s integrate theories of behavior change to address alcohol use among adolescents and young adults. While theories of behavior change are a critical component of effective interventions that have been developed and evaluated over the past several decades,cannabis equipment attention to the application of theory in CBIs has been limited. We utilized a simple classification system to examine if theories were mentioned, applied or measured in any of the publications that corresponded with the CBIs.

Only half of the CBIs reviewed mentioned use of an overarching, established theory of behavior change. The other half mentioned used of a single construct and/or intervention technique but did not state use of a broader theory. CBIs that were based on a broad theoretical framework were more likely to include measures of constructs associated with the theory than those that used a discrete construct or intervention technique. However, greater attention to what theory was used, articulating how theory informed the intervention and including measures of the theoretical constructs is critical to assess and understand the causal pathways between intervention components/mechanisms and behavioral outcomes . When mentioning the use of a theory or construct, almost all provided at least some description of how it informed the CBI; however, the amount and quality of information about how the theory was applied to the intervention varied considerably. Greater attention to what is inside the “black box” is critical in order to improve our understanding of not only what works, but why it works. While a few articles provided detailed information about the application of theory, the majority included limited information to examine the pathway between intervention approach and outcomes.Some researchers/intervention developers may not fully appreciate how theory can be used to inform intervention approaches. There is an emphasis on outcomes/effectiveness of interventions and less attention is placed on their development. In addition, to our knowledge, there are no publication guidelines/standards for describing the use of theoretical frameworks in intervention studies and the inclusion of this information is often up to individual authors and reviewers. Given the importance of theory in guiding interventions, greater emphasis on the selection and application of theory is needed in publications. The classification system used in this review provided some form of personalized normative feedback and applied it relatively consistently across the CBIs.

Personalized normative feedback is designed to correct misperceptions about the frequency and acceptability of alcohol use among peers. It typically involves an assessment of a youth’s perceptions of peer norms around alcohol attitudes and use followed by tailored information about actual norms. In addition, some interventions have recently incorporated personal feedback to address individual’s motivations to change through assessing and providing feedback on drinking motives or in decisional balance exercises.The widespread use of personalized normative feedback in CBIs may be because it has been widely documented as an effective strategy and because it lends itself readily to an interactive, personalized computer-based intervention. Motivational interviewing was also used in several of the CBIs and is an effective face-to-face counseling technique. In contrast, this technique was applied to CBIs in a number of different ways, such as exercises designed to clarify goals and values, making both the description of how it was applied even more essential to examine differential effectiveness across various CBIs. This study builds on the growing evidence supporting the use of CBIs as a promising intervention approach. We found most of the CBIs improved knowledge, attitudes and reduced alcohol use among adolescents and young adults. In addition, this study suggests CBIs that use overarching theories more frequently reported significant behavioral outcomes than those that use just one specific construct or intervention technique . This finding is consistent with prior studies examining the use of theory in face to-face interventions targeting alcohol use in adolescents. However, it is important to acknowledge the wide variation across the CBIs not only in their use of theory, but in scope, the targeted populations, duration/dosage, and measured outcomes. It is encouraging that even brief/targeted CBIs demonstrated some effectiveness and thus can play an important role in improving knowledge and attitudes, which are important contributors to changes in behavior. There are limitations to this study.

As discussed previously,vertical grow shelf many articles did not explicitly describe how theory was applied in the CBI. It is therefore possible that the theoretical pathways for the intervention were further developed than we have noted, and possibly included in other documents, such as logic models and/or funding applications; however, such information is not readily accessible and was outside the scope of this review. Thus, lack of mention of the name of a theory or construct or its application does not mean that the intervention did not integrate the theory in the intervention, only that the article did not provide information about its application. Thus, due to variations in the described use of theory along with the wide range of CBIs, it was not possible to draw comparisons about the relative effectiveness of CBIs according to the theory used.This review spanned articles published between 1995 and 2014. During this period, CBIs to address health issues have been rapidly evolving due to major advancements in technological innovations . These advancements coupled with greater interest and investments from federal agencies and philanthropic foundations.Electronic cigarettes are battery-powered devices that aerosolize e-liquids, which typically contain propylene glycol and vegetable glycerin , nicotine, flavors, and stabilizers/humectants such as triacetin.Although it is well known that combustible cigarettes cause multiple cardiovascular and pulmonary diseases, the effects of e-cigarettes on health have only begun to be studied. Alarmingly, there has been a rapid increase in e-cigarette use among adolescents and young adults, who could potentially be exposed to e-cigarette aerosols for decades if their use is lifelong.Indeed, the US Surgeon General concluded that the use of e-cigarettes among youth and young adults has become a major public health concern.A recent European Respiratory Society task force concluded that since the long-term effects of e-cigarettes are unknown, it is not clear whether they are in fact safer than tobacco and based on current knowledge, their negative health effects cannot be ruled out.In the USA, the Family Smoking Prevention and Tobacco Control Act of 2009 gave the Food and Drug Administration the power to regulate tobacco products. While e-cigarettes were not covered in the original act, the FDA has clarified its position with its “deeming” rule, and since 2016, has begun to exert its regulatory authority over e-cigarettes and other noncombustible products. In 2020, in response to the growing popularity among youth, the FDA issued a policy to limit the sales of some flavored e-cigarette products.As the FDA adheres to a public health impact standard, evidence on adverse health effects of e-cigarettes will be a consideration to impact on future sales of e-cigarettes and e-cigarette liquids. Such a regulation will likely be contingent upon their observed health effects, as well as effects on nicotine addiction.

In addition, the recent emergence of acute and severe e-cigarette, or vaping, product use-associated lung injury across the US underscores the need, complexity, urgency, and importance of basic and clinical research on the health effects of e-cigarettes, particularly focused on cardiopulmonary systems.With regard to public health impact and cardiopulmonary health, availability and use of e-cigarettes might benefit those who switch from combustible cigarettes to e-cigarettes, that is, harm reduction. However, the potential benefits from the use of these products are uncertain: they deliver a poorly defined, highly variable, and potentially toxic aerosol that may have adverse effects, which may be dependent on patterns of age, reproductive status, health of the user, and use. In addition, there are major public health concerns surrounding the availability of e-cigarettes for children, adolescents, and young adults.Nicotine addiction is of particular concern and the use of e-cigarettes is positively associated with increased risk of use of combustible cigarettes.These issues complicate the question of how e-cigarettes might impact cardiopulmonary health and are explored further in the later sections of this review. Recognizing the potential health impact of e-cigarettes when they first emerged, particularly impacting the heart and lung, the Division of Lung Diseases and the Division of Cardiovascular Sciences at the NIH’s National Heart, Lung, and Blood Institute conducted a workshop in the summer of 2015 entitled “Cardiovascular and Pulmonary Disease and the Emergence of E-cigarettes”, to identify key areas of needed research as well as opportunities and challenges of such research. The workshop was organized around a framework recognizing that the public health impact of e-cigarettes would be influenced by a complex network of factors in addition to direct health and biological effects, including device characteristics, chemical constituents , aerosol characteristics, and use patterns. In response to the significant gaps and research areas highlighted at the workshop, NHLBI subsequently directed research funding to projects aimed at understanding the cardiopulmonary health effects of e-cigarettes and inhaled nicotine. Funded investigators met in 2018, 2019, and 2020 to discuss their results, findings in the larger field, and remaining scientific questions. The focus of this review is the result of discussions recognizing a need for further understanding of cardiopulmonary health effects of e-cigarettes that occurred at these NHLBI-supported workshops and investigator meetings. This review takes a holistic view of e-cigarette use and cardiopulmonary health, with a major focus on the USA. A summary of the current understanding of the multitude of factors that ultimately affect health, including policies, behaviors, emissions, and biological effects associated with e-cigarette use, is provided herein, with the ultimate goal of identifying key research gaps that remain in the field. E-cigarettes inhabit a rapidly changing marketplace and an evolving pattern of use that typically precedes scientific exploration. Following a PubMed search for relevant literature using “e-cigarette” and/or “cardiopulmonary” and/or “pulmonary”, and/or “cardiovascular disease” as search terms, we break down the pertinent fields to uncover critical research questions that will better enable an understanding of how e-cigarettes affect cardiopulmonary health at an individual and community level.E-cigarettes are highly variable in design, and are comprised of a battery, a reservoir for holding the e-liquid, a heating element, an atomizer, and a mouthpiece. The first generation of e-cigarettes were similar in size and shape to combustible cigarettes. First-generation devices typically used a prefilled nicotine solution cartridge that directly contacted the heating element. Many second-generation devices were penshaped; some included refillable cartridges, while others were closed systems that held only prefilled sealed cartridges. Third generation devices were called “mods” since they are easily modified. They were more diverse, and featured customizable atomizers, resistance coils, and larger-sized batteries capable of heating made-to-order e-liquids to higher temperatures to create more aerosol and potentially deliver more nicotine.Fourth generation devices were smaller and some resembled familiar items such as USB drives. Their sleek design and ease by which they can be concealed from parents and teachers have contributed to their growing popularity in school-age children. These e-cigarettes operate at lower wattages than third generation devices.