The patient developed bigeminy while in the ED but remained hemodynamically stable and did not have a change in her mental status. Her electrolytes were replaced with oral and intravenous potassium, with improvement of her arrythmia and symptoms. She declined central line placement for more rapid replacement.Random urine electrolytes were obtained after the patient was admitted to the PICU . Nephrology was consulted because these results demonstrated an elevated urine anion gap suggestive of RTA. The patient’s symptoms completely resolved once her electrolytes were repleted. She was found to have positive antinuclear and anti–Sjögren’s-syndrome-related antigen A autoantibodies, leading to the diagnosis of Sjögren’s syndrome, despite a lack of phenotypic features. The patient’s urine anion gap was indeterminate for the etiology of her non-anion gap metabolic acidosis; however, her urine osmolar gap of less than 150 milliosmoles per kilogram suggested type 1 or type 4 RTA as the etiology. This coupled with laboratory findings suggestive of autoimmune disease led to the diagnosis of type 1 RTA. Her RTA was treated with potassium supplementation and alkali therapy to achieve a normal serum bicarbonate concentration. Unfortunately, the patient has not been compliant with her home therapy and has required multiple hospitalizations since her original presentation. Her presentation and urine anion gap strongly suggest toluene toxicity, but the patient repeatedly denied insufflating glue and there is no diagnostic test for toluene.Hyperchloremic,hydroponic stands hypokalemic metabolic acidosis is a condition all emergency providers should be prepared to diagnose and manage.

In this case, the patient presented with a cardiac arrhythmia due to severe hypokalemia. The underlying etiology of the hypokalemia should be sought while simultaneously treating the condition. The initial ED evaluation includes obtaining a basic metabolic panel and a urinalysis. Once it is determined that the patient does not have a serum anion gap, the clinician should consider three broad categories of non-anion gap acidosis and their etiologies: increased acid production; loss of bicarbonate; and decreased renal excretion of acid .Type 1 or distal RTA is a primary problem of urine acidification due to impaired hydrogen ion secretion in the distal convoluted tubules. The underlying etiology in adults is usually autoimmune diseases such as Sjögren’s syndrome or rheumatoid arthritis.In pediatrics, the cause is usually a hereditary gene mutation for either the basolateral chloridebicarbonate exchanger or the apical hydrogenadenosine triphosphatase gene.Lastly, a distal RTA can be iatrogenic due to ifosfamide, a chemotherapeutic analog of cyclophosphamide.Type 2 or proximal RTA is a primary problem of impaired bicarbonate reabsorption leading to increased bicarbonate loss.In adults, the underlying etiology is most commonly proximal tubular toxicity from increased exertion of monoclonal immunoglobulin light chains as seen in multiple myeloma.Type 2 RTAs are seen in Fanconi syndrome , and in patients prescribed carbonic anhydrase inhibitors .In pediatric patients, type 2 RTAs are usually idiopathic, but they can be due to a complication from chemotherapy, cystinosis , or inherited mutations in the KCNJ15 and SLC4A4 genes.The term “type 3 RTA” is rarely used as it is now considered a combination of types 1 and 2. Type 4 RTA is beyond the scope of this discussion. The test of choice when evaluating for a RTA is urine electrolytes so that the clinician can calculate how much ammonium is being excreted.18One of the most populated countries in the Middle East and North Africa region is Iran where over one million people are estimated to use illicit drugs. Moreover, the number of people who inject drugs is estimated to be 280 per 100,000 population, about half of whom are infected with hepatitis C virus and around 13.8% are living with human immunodeficiency virus.

To reduce HIV, HCV, and other blood borne infections among PWID, a comprehensive and innovative harm reduction program has been implemented in Iran. Currently, healthcare facilities including voluntary counseling and testing centers, HR centers for vulnerable women, shelters, prisons, antenatal clinics, and drop-in centers provide onsite or outreach HR services to PWID. These services include but are not limited to opioid agonist therapy by methadone, buprenorphine, or opium tincture, as well as needle and syringe programs , VCT, and free condom distribution. Although buprenorphine maintenance therapy and opium tincture are available in Iran, methadone maintenance treatment programs are more common. MMT programs were initially implemented in pilot projects in 2002; however, they were significantly scaled up in public and private clinical settings from 2003-2007. By September 2014, MMT was offered to PWID at 5744 private centers and 239 public centers supervised by State Welfare Organization, medical sciences universities, or prisons’ organization. As of 2018, over 700,000 participants have received MMT programs in these centers. The cost of MMT services is considerably lower in public centers. OAT in PWID has been associated with several beneficial public health outcomes including decreasing the rate of fatal and non-fatal overdose, reducing the rate of HIV and HCV transmission, lowering the rate of violence, diminishing social costs associated with drug use, increasing PWID’s quality of life, and improving their employment status. For PWID who are less connected to healthcare services, OAT could also represent a gateway to other services such as primary health care, HIV testing and counseling, antiretroviral therapy, and tuberculosis, HCV, and sexually transmitted infections care. Our understanding of the prevalence and patterns of OAT uptake among PWID in Iran is limited. To monitor the impact of OAT programs in prevention of HIV, HCV, and hepatitis B virus , it is crucial to know the current level of OAT uptake among PWID in Iran. In response, we aimed to identify the prevalence and trend of OAT among PWID and determine the factors associated with OAT uptake using the data collected in two national consecutive bio-behavioral surveillance surveys conducted in urban settings across Iran in 2010 and 2014.

Data from the 2010 and 2014 HIV national bio-behavioral surveillance surveys were used to assess the prevalence of OAT uptake among PWID in Iran. As PWID bear the highest burden of HIV on Iran, nation-wide surveys are conducted every few years to help monitor the trend of HIV and its related risk behaviors among this population and inform the national HIV response. The 2010 and 2014 surveys were conducted in 10 geographically diverse cities. Study participants were recruited from shelters, DICs, VCT centers, and street-based venues through outreach efforts. Eligible participants were 18 years or more and self-reported injection drug user for at least once during the previous 12 months. The details of the surveys are previously describe.Our findings showed that as of 2014, less than half of PWID in Iran received OAT in the previous year with significant heterogeneity in OAT uptake across cities. Being ever married, HIV positive, and having a history of incarceration were positively associated with receiving OAT, while using non-opioid drugs were negatively associated with receiving OAT. Moreover, we demonstrated that less than half of the surveyed PWID used OAT in the previous year. Based on the World Health Organization’s definition of high coverage of OAT , Iran falls into the high coverage category. However, there is a high level of disparity for OAT uptake across cities with OAT uptake ranging from 0-75% in different cities. Interestingly,grow table all cities with low OAT coverage were among the less and under developed regions, settings that also have higher rates of child mortality and lower numbers of rehabilitation centers and paramedics in comparison with the rest of the country. Therefore, to reach and maintain the high coverage goal in all regions of the country, allocation of resources regarding the degree of inequality in the distribution of OAT services should be considered in future planning and financing of these services. In addition, addressing and removing the potential barriers to access and use of OAT such as financial barriers, lack of awareness and negative attitudes, worries about methadone’s side effects, and social stigma attached to receiving OAT are integral to increasing the coverage rate of OAT uptake among Iranian PWID. Tackling barriers to OAT access are of particular importance in the context of COVID-19 and future pandemics as accessing such services among PWID is often accentuated during health emergencies. Comparing our results to other countries of the MENA region, the OAT uptake in Iran seems to be higher than most of its neighboring countries. Indeed, the overall OAT provision in MENA is very limited. For example, In 2017, only 7 MENA countries provided OAT which suggests ~ 6% of PWID in the MENA region to be on OAT. However, due to non-random nature of our study sample, these comparisons should be interpreted with caution. The OAT uptake in PWID slightly decreased in 2014 in comparison with 2010. This trend is in opposite direction with the increasing number of facilities that provide OAT services to PWID. Although the observed pattern may be simply due to possible biases in selection of the participants, it might also be due to the recent shift in substance use practices among PWID in Iran and the increase in poly-drug use involving non-opioids among them. Recent studies have shown that methamphetamine use has been increasing among PWID with opioid use disorder.

We also found that compared to PWID who used only opioids within the previous month, those who used only non-opioids and those who used opioids and non-opioids simultaneously, were less likely to have received OAT. Therefore, one possible explanation for the decreasing trend of OAT could be PWID’s increasing tendency toward poly-drug use including stimulants. Following the emergence and increasing supply of synthetic non-opioid drugs including methamphetamines, more PWID tend to use these drugs. On the other hand, the use of methamphetamine in PWID reduces the effectiveness of OAT programs and subsequently leads to lower satisfaction of patients with OAT . These issues are problematic in a way that treatment of PWID who use synthetic drugs has turned into a challenging issue within the last few years. In Iran, there are only a limited number of centers providing treatments for stimulant use disorder. Preliminary studies indicate that the integration of stimulant HR services into opioid HR programs at DICs could be an effective strategy in reducing high-risk behaviors of their clients. Therefore, policies toward the establishment of such centers and providing treatments for stimulant use disorder at DICs should be considered in future policy and planning across the country. Living with HIV was associated with an increased likelihood of OAT uptake, a finding which is consistent with a study conducted in Vancouver, Canada. This may be partly due to the effect of post-test counseling which is freely available for all PWID who undergo HIV testing in Iran. Integration of HIV and substance use services have been shown to improve HIV treatment and care continuum among PWID living with HIV. In our study, having a history of incarceration was positively associated with OAT uptake. This may be due to the establishment of HR programs inside Iran’s prisons. Similar to several international settings, people who use drugs are over represented in prisons across Iran. More than 50% of all Iranian prisoners are being held on drug-related offenses and 70% of them use illicit drugs. When Iran experienced large outbreaks of HIV among incarcerated populations in the early 2000s, HR programs inside prisons were rapidly expanded. As these HR provision and coverage continue to function inside prisons, most PWID with a history of incarceration are likely to have used these services and received OAT during their incarceration period. Previous studies have shown that exposure of prisoners to OAT inside prisons increases their chance of receiving OAT even after their release. Therefore, ensuring the continuation and extension of current strategies of HR inside prisons in Iran is of utmost importance. We acknowledge the limitations of our study. First, social desirability bias may have resulted in over-reporting of OAT uptake and under-reporting of stigmatized and criminalized behaviors such as use of drugs and alcohol. Second, the study was cross-sectional with limited capacity for causal inference. Third, male PWID were over represented in our study sample and our findings may not be generalizable to female PWID in Iran. Fourth, due to non-random selection of the study participants and the possible role of selection bias, the findings might not necessarily represent OAT uptake among all PWID in Iran. Fifth, our data was collected in late 2014 and was delayed in getting published due to several contextual and logistical complexities; therefore, it might not provide a realistic picture of the current status of OAT uptake among PWID in Iran. Lastly, differences in sampling strategy between two study rounds including recruiting participants from different facilities and sites cannot be ruled out as unmeasured confounders, and therefore, comparison between the two rounds should be made with caution.

Nevertheless, pharmacological inhibition of anandamide amidohydrolase activity which can be achieved by using a number of covalent inhibitors with varying degrees of selectivity does not appear to affect the uptake of radioactive anandamide, at least when this is measured over brief time intervals . These findings indicate that, in the short-term, anandamide hydrolysis does not provide the driving force for anandamide transport. Importantly, however, they do not rule out an involvement of anandamide amidohydrolase in the long-term biodisposition of anandamide: it is conceivable, in fact, that anandamide transport into cells may be transiently driven by passive sequestration in lipid storage sites, as it may happen with free fatty acids , followed by a step of enzymatic hydrolysis. If this hypothesis is correct, prolonged inhibition of amidohydrolase activity would result in the intracellular accumulation of unmetabolized anandamide, and may eventually compromise its transmembrane transport and biodisposition. Thus, drugs that block anandamide amidohydrolase activity may cause long-term modififications of anandamide homeostasis, which might in turn be exploited therapeutically in an approach analogous to that used with monoamino oxidase inhibitors . To summarize, the biological actions of anandamide may be terminated by two temporally distinct, but functionally linked mechanisms. A high-affinity transporter protein may combine with extracellular anandamide and remove it from its sites of action by facilitated diffusion. Inside cells, anandamide may betemporarily collected in lipid stores to be then disposed of by enzymatic hydrolysis .Pharmacological experiments with cortical neurons in culture indicate that 2-AG formation is mediated by the PLC/DAG lipase pathway.

According to this hypothesis, illustrated in Fig. 3, PLC activity may catalyze the cleavage of a membrane phospholipid producing 1,2-diacylglycerol,indoor grow shelves which may be converted to 2-AG by DAG lipase activity. Thus 2-AG may be an intermediate component of a well known and ubiquitous enzymatic pathway that generates sequentially three distinct signaling molecules: 1,2-diacylglycerol, 2-AG, and arachidonic acid . Two of these molecules, 1,2-diacylglycerol and arachidonic acid, serve a host of regulatory functions, most of which have no apparent relationship with cannabinoid signaling. The question arises, therefore, of what biochemical checkpoints may be in place to control the traffic of these widely different messenger molecules. For several reasons, the consecutive reactions catalyzed by DAG lipase and monoacylglycerol lipase are likely to be essential. It is generally thought that the second messenger effects of 1,2-diacylglycerol, which include protein kinase C activation, are terminated by its conversion to phosphatidic acid, catalyzed by DAG kinase . This suggests that the presence of an active DAG lipase may be a critical factor in determining whether 2-AG will be formed under given circumstances, i.e., that a high DAG lipase/DAG kinase ratio may be characteristic of cells that have the need to produce substantial amounts of 2-AG from 1,2-diacylglycerol. Yet, the ability to generate 2-AG is not sufficient to conclude that a cell may use it as a signaling molecule. In platelets, for example, 2-AG is produced in large quantities but it is also immediately converted to arachidonic acid by monoacylglycerol lipase activity . This very short life span suggests that 2-AG may serve primarily as an intermediate in arachidonate release . In neurons, by contrast, 2-AG appears to escape immediate metabolism and to accumulate in response to Ca21 -mobilizing stimuli . Is such accumulation the consequence of a specific regulation of DAG lipase, DAG kinase, and monoacylglycerol lipase activities? The molecular characterization of neuronal DAG lipase and monoacylglycerol lipase should be instrumental to answer this question.

The dependence of anandamide and 2-AG formation on neural activity suggests that endogenous cannabinoids may be released from neurons in vivo and may contribute to the control of behavior. This possibility has not been confirmed directly yet, but finds support in pharmacological experiments with the CB1 antagonist SR141716A. The administration of SR141716A to naı¨ve animals causes a series of effects that may be accounted for by the reversal of an endogenous cannabinoid tone. For example, SR141716A produces hyperalgesia , arousal , memory improvement , anxiety-like responses , and increased acetylcholine release . Unfortunately, the inverse agonist properties of SR141716A and the current lack of biochemical information on the modalities of endogenous cannabinoid release in vivo make these pharmacological data difficult to interpret. One notable exception may be the pronociceptive effect of SR141716A administration in skin. The high levels of anandamide found in this tissue suggest that local CB1 receptors may be activated by the native ligand at least under certain conditions . An alternative experimental approach may be provided by the anandamide uptake inhibitor AM404. If this drug acts effectively in vivo, as initial studies appear to suggest, it may cause the accumulation of endogenous anandamide at its sites of action, and produce a selective ‘‘hypercannabinoid state’’ that should be reversed by CB1 receptor antagonists.Research has found persistent variation in SUD risk by sex. In the general population, men experience single and co-occurring SUDs at higher levels than women . Among SMs, however, sex differences are typically reduced or even reversed, with greater sexual orientation disparities among adult women compared to men, and especially elevated rates among bisexual women . Nonetheless, studies have rarely tested whether sex modifies relationships between sexual orientation and SUDs by including interaction terms in statistical models. Prevalence of SUDs tends to peak around age 25 and declines with age . Research examining SUDs among SMs, however, suggests a slower agenormative decline .

Rarely have researchers compared sexual orientation or gender identity disparities in SUDs among individuals older than 25 years with those in younger age groups. Knowledge of how the magnitude of sexual orientation and gender identity differences in SUDs vary by birth sex and age can help identify subgroups in need of interventions. This study analyzed data from the longitudinal Growing Up Today Study when participants were aged 20-35 to estimate sexual orientation and gender identity differences in probable SUDs. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were used to assess past 12-month nicotine dependence, alcohol abuse/dependence, drug abuse/dependence, any SUD, and co-occurring multiple SUDs . Because research demonstrates sex differences in associations between sexual orientation and substance outcomes , we estimated statistical interactions between 1) sexual orientation and birth sex, and 2) gender identity and birth sex, and present birth-sex-stratified estimates. We hypothesized that SGMs would be more likely than non-SGMs of their same birth sex to meet criteria for SUDs, and that sexual orientation differences would be larger among participants assigned female at birth compared to those assigned male. Additionally, we estimated statistical interactions between 1) sexual orientation and age, and 2) gender identity and age. We hypothesized that sexual orientation and gender identity differences in SUD risk would be larger in older versus younger periods. Among participants meeting criteria for a past 12-month drug use disorder, we examined associations of sexual orientation and gender identity with past 12-month specific drug use.Sexual orientation.Past 12-month nicotine dependence, alcohol abuse/dependence, and drug abuse/dependence were assessed in 2010 and 2015-2017 with questions adapted from the National Survey on Drug Use and Health corresponding to DSM-IV criteria for SUDs . We coded responses as evidencing or not evidencing symptoms of dependence and abuse , classifying participants as having probable substance dependence if they endorsed 3 or more of 7 dependence symptoms and as having probable abuse if they endorsed at least 1 of 4 abuse symptoms. We then created 4 SUD variables: nicotine dependence , alcohol use disorder , drug use disorder ,indoor garden table and co-occurring multiple SUDs . GUTS questionnaires cover multiple health-related topics. Thus, to reduce participant burden, questions assessing drug use disorder for marijuana and other drugs were combined into a single set of questions. Drug use. Past 12-month use of marijuana, cocaine, heroin, MDMA/ecstasy, LSD/mushrooms, methamphetamine, amphetamines, and nonmedical use of prescription benzodiazepines, painkillers, sleeping pills, and stimulants were assessed in 2010 and 2015- 2017. Inhalants was assessed in 2010. Covariates. Race/ethnicity , region of residence , cohort , and age at the time of SUD assessment were included in analyses as potential confounders.Analyses were stratified by birth sex . Unadjusted prevalences of past 12-month SUD outcomes were examined for each sexual orientation and gender identity subgroup. We estimated multi-variable associations of SGM statuses with SUDs using generalized estimating equations with exchangeable correlations structure to account for non-independence of sibling clusters and repeated measures among individuals . When exchangeable correlation structure did not yield convergence for three models estimating drug type , we used independence correlation structure. For nicotine dependence, binary logistic regression estimated adjusted odd ratios . For alcohol use disorders, drug use disorders, and co-occurring SUDs, multi-nomial logistic regression estimated AOR. To test whether birth sex modified relationships between sexual orientation and SUDs and gender identity and SUDs, we included sexual-orientation-bysex and gender-identity-by-sex interaction terms.

To test whether age modified relationships between sexual orientation and SUDs and gender identity and SUDs, we included sexualorientation-by-age and gender-identity-by-age interaction terms stratified by birth sex. To estimate sexual orientation and gender identity differences in past 12-month use of specific drugs, we used binary logistic regression. In these analyses, we combined LGB participants into one category due to small sample sizes. In all models, CH and cisgender participants were referent groups. Corresponding 95% confidence intervals and p-values were estimated. Multi-variable models adjusted for age, race/ethnicity, cohort, region of residence, and birth sex . All analyses were performed with SAS software, version 9.4, with a significance level of 0.05.Table 3 presents the multi-variable associations of sexual orientation, gender identity, and other covariates with SUDs among participants assigned female at birth. The odds of evidencing each SUD and co-occurring multiple SUDs were greater among all SM groups compared to CHs.Table 4 presents the multivariable associations of sexual orientation, gender identity, and other covariates with SUDs among participants assigned male at birth. All SM groups had elevated odds for nicotine dependence and one SUD compared to CHs. MHs also had elevated odds of alcohol dependence, drug abuse and dependence, and having 2 or more SUDs. Gay men also evidenced elevated odds for alcohol abuse and dependence, drug dependence, and having 2 or more SUDs compared to CHs. GMs had significantly higher odds of alcohol dependence than their cisgender peers. Like patterns observed among participants assigned female, associations between gender identity and SUDs were frequently smaller than associations of sexual orientation with SUDs.Table 5 presents the prevalence and multi-variable associations of sexual orientation and gender identity with past 12-month drug use among participants evidencing a drug use disorder, stratified by birth sex. Regardless of sexual orientation and gender identity, marijuana was the most prevalent drug reported. Among participants assigned female, LGBs were more likely than CHs to report using MDMA/ecstasy and LSD/mushrooms and GMs were more likely than their cisgender counterparts to report using LSD/mushrooms. Among those assigned male, LGBs were more likely than CHs to report using methamphetamine and inhalant and GMs were more likely than cisgender peers to report using heroin, amphetamines, inhalants, and non-medical use of prescription painkillers. No differences were found between MH and CH in the prevalence of types of drugs used.Our study quantified sexual orientation and gender identity differences in SUD risk during young adulthood, when SUD prevalence in the general U.S. population is high . We examined SUDs based on DSM-IV criteria including nicotine dependence, alcohol abuse and dependence, drug abuse and dependence, and multiple co-occurring SUDs. Aligning with previous literature , we found that SM status was associated with greater odds of past 12-month SUDs among young adults assigned female, and to a lesser extent among those assigned male. Co-occurrence of 2 or more SUDs in the past 12-months was also more common among SMs compared CHs, aligning with previous studies of lifetime SUD co-occurrence . Contrary to our hypothesis, age-related declines in SUD prevalence were largely similar across sexual orientation and gender identity groups. This finding may be due, in part, to our sample age range and age periods compared in analysis . Previous studies have shown differential age-related declines in alcohol problems between SMs and heterosexuals and noted the largest sexual orientation differences in ages 40 or older . An analysis of representative U.S. data showed declines in the prevalence of tobacco and alcohol disorders among SMs between ages 26-35 but increases in prevalence between the mid-30s to mid-40s .

A primary candidate for the role of endogenous cannabinoid substance anandamide has been identified recently . Like D 9 – tetrahydrocannabinol, anandamide binds with high affinity to cannabinoid receptors, reduces contractions in mouse vas deferens, and modulates the activities of adenylyl cyclase and voltagedependent ion channels in neurons and other cells . Moreover, anandamide elicits, in vivo, a series of behavioral responses typical of cannabinoid drugs . Although the pharmacological properties of anandamide are beginning to be well understood, we still lack essential information on the biochemical mechanisms underlying the biogenesis of this signaling molecule. Two such mechanisms have been proposed. Anandamide may be synthesized through the energy-independent condensation of ethanolamine and arachidonate . This reaction, however, requires pH optima and substrate concentrations that are unlikely to be found in neurons. Also, various lines of evidence indicate that condensation of ethanolamine and arachidonate may result from the reverse reaction of “anandamide amidohydrolase,” an enzyme activity involved in anandamide breakdown . An additional mechanism of anandamide formation, suggested by experiments carried out in cultures of rat brain neurons, is via the phosphodiesterase-mediated cleavage of a phospholipid precursor, N-arachidonoyl phosphatidylethanolamine . For this mechanism to be considered plausible,trim tray pollen two necessary conditions should be fulfilled. First, the occurrence of N-arachidonoyl PE in adult brain tissue should be demonstrated. Second, the enzyme pathway that is responsible for the biosynthesis of N-arachidonoyl PE should be identified.

Studies carried out in the laboratory of Schmid et al. before the discovery of anandamide have reported the occurrence in brain of an N-acyltransferase activity, which catalyzes the formation of other N-acyl PEs by transferring a saturated or monounsaturated fatty acyl group from the sn-1 ester bond of phospholipids to the primary amino group of PE . Is this activity implicated in the biosynthesisof N-arachidonoyl PE? Such a possibility has been raised. Arguing against it, though, is the currently accepted notion that tissue phospholipids contain no arachidonate at the sn-1 position, but rather saturated or monounsaturated fatty acids such as palmitate, stearate, or oleate . In the present study, we have examined the occurrence and biosynthesis of N-arachidonoyl PE in adult rat brain tissue. Using highly sensitive and selective gas chromatography/mass spectrometry techniques, we show that N-arachidonoyl PE and anandamide are constituents of brain lipids. Further, we identify and partially characterize an N-acyltransferase activity in brain that catalyzes the biosynthesis of N-arachidonoyl PE, using as substrates sn-1 arachidonoyl-phospholipids and PE. Even further, we describe a novel brain phospholipid that contains arachidonate at the sn-1 position, and may therefore serve as substrate for such enzyme activity. Finally, we show that stimulation of N-acyltransferase activity satisfactorily accounts for the Ca21 -evoked biosynthesis of N-arachidonoyl PE observed in intact neurons. During the preparation of this manuscript, results very similar to ours were reported in a study by Sugiura et al. .This circumstance suggests that these lipids may be generated exclusively during cerebral ischemia and, as such, may not participate in normal brain function . We examined, therefore, whether N-acyl PEs, and particularly N-arachidonoyl PE, were present in rat brain tissue in which metabolic changes associated with ischemic damage had been prevented by immersing the head of the animal in liquid nitrogen within 2 sec of decapitation . We extracted total brain lipids in methanol/chloroform, fractionated the extracts by column chromatography, and analyzed them by bidimensional HPTLC.

The results of these analyses, illustrated in Figure 1A, indicated that a lipid component with the chromatographic properties of N-acyl PEs is present in the extracts. To confirm this identification and to determine the molecular composition of brain N-acyl PEs, in six additional experiments we digested the lipid fractions containing N-acyl PEs with a bacterial PLD . Under appropriate conditions, this enzyme quantitatively hydrolyzes the distal phosphodiester bond of N-acyl PEs, releasing the corresponding NAEs . The NAEs produced in these digestions were then purifified by a combination of column chromatography and normal-phase HPLC, and analyzed by GC/MS as TMS derivatives. The electron-impact mass spectra of the TMS derivatives of synthetic anandamide and other NAEs are shown in Figure 2. From these mass spectra we chose characteristic ions for analysis by SIM, a technique that provides both high sensitivity and specificity of detection. We observed diagnostic fragments for anandamide , N-palmitoylethanolamine , N-stearoylethanolamine , and N-oleoylethanolamine , which were eluted from the GC at the retention times expected for these compounds . These results indicate that a family of N-acyl PEs, including N-arachidonoyl PE, are normal constituents of rat brain lipids. By comparison with an internal standard, we estimated that an average of 22 6 16 pmol of N-arachidonoyl PE were recovered from 1 gm of wet brain tissue after lipid extraction and purification. The percent composition of brain N-acyl PEs determined in these experiments is illustrated in Table 1.We have shown that small amounts of the putative anandamide precursor, N-arachidonoyl PE, are present in brain tissue. To explore the physiological roles of this lipid, it was first essential to characterize the biochemical mechanisms responsible for its biosynthesis. We examined, therefore, whether N-arachidonoyl PE may be produced de novo in brain subcellular fractions. We solubilized crude particulate fractions and incubated them for 60 min with or without 3 mM CaCl2.

When we analyzed the lipid extracts of Ca21 -containing incubations, we noted a lipid component that comigrated with N-acyl PEs on HPTLC . In contrast, this component was not detectable in Ca21 -free incubations or in incubations of heat-inactivated fractions . These results are in agreement with studies by Schmid et al. indicating the occurrence, in brain tissue, of a Ca21 -activated enzymatic activity that catalyzes the biosynthesis of N-acyl PEs. Was N-arachidonoyl PE also produced in these incubations? To address this question, we partially purifified the N-acyl PEs; digested them with bacterial PLD; and analyzed, by GC/MS, the NAEs produced. In seven experiments, we found components that eluted from the GC at the retention times of anandamide, N-palmitoylethanolamine, N-stearoylethanolamine, and N-oleoylethanolamine. Because the NAEs were present in relatively high amounts , we were able to collect complete mass spectra for each of them . Comparison of these mass spectra with those of synthetic NAEs unambiguously confirmed the identification of these compounds. Consequently, our results demonstrate that brain particulate fractions incubated in the presence of Ca21 produce a family of N-acyl PEs, which include N-arachidonoyl PE. A quantitative account of these findings is presented in Table 3. In addition to N-acyl PEs, the four NAEs identified in brain tissue were also generated in these incubations, as determined by GC/MS analysis .Previous studies with various preparations of neural tissue have suggested that N-acyl PE biosynthesis is mediated by an N-acyltransferase activity, which transfers a fatty acyl group from the sn-1 position of phospholipids to the amino group of PE . To determine whether rat brain tissue contains such activity, we incubated detergent-solubilized particulate fractions in a reaction mixture containing CaCl2 and 1,2-di[14C]palmitoyl PC,cannabis grow set up and identified the radioactive products by HPTLC or reversed-phase HPLC. By either method, we found a major radioactive component that displayed the chromatographic properties of N-acyl PEs, indicating the formation of N-[14C]palmitoyl PE . In contrast, parallel incubations carried out in the absence of Ca21 or with heat-inactivated samples contained no detectable N-[14C]palmitoyl PE . Likewise, we found no N-[14C]palmitoyl PE when we used 1-stearoyl,2- [ 14C]palmitoyl PC as fatty acyl donor . Analysis of additional subcellular fractions of rat brain tissue showed that N-acyltransferase activity is present both in crude particulate fractions and in microsomes, and is enriched in the former . To characterize N-acyltransferase activity further, in three subsequent experiments we applied solubilized particulate fractions to a MonoQ FPLC column and measured the enzyme activity in the eluate. Using an assay buffer that contained 1,2-di[14C]palmitoyl PC, exogenous PE, and CaCl2, we detected one major peak of enzyme activity in association with a UV-absorbing component . Thus, our results confirm that rat brain tissue contains a N-acyltransferase activity that catalyzes the biosynthesis of saturated and monounsaturated N-acyl PEs. We considered that the biosynthesis of N-arachidonoyl PE may proceed through a similar mechanism. To address this possibility, it was first necessary to show that, in brain tissue, an arachidonoyl containing phospholipid may serve as fatty acyl donor in the N-acyltransferase reaction, as recently reported in rat testis . We incubated, therefore, various brain sub-cellular fractions in a reaction mixture containing one of three possible N-acyltransferase substrates, radioactively labeled on arachidonate: 1,2-di[14C]arachidonoyl PC, 1-stearoyl,2-[14C]arachidonoyl PC, and 1-stearoyl,2-[14C]arachidonoyl PE.

We observed formation of N-[14C]arachidonoyl PE with only 1,2-di[14C]arachidonoyl PC . Such N-arachidonoyltransferase activity was ; 10-fold lower than the N-palmitoyltransferase activity we measured by using 1,2-di[14C]palmitoyl PC. In contrast, incubations with 1-stearoyl,2- [ 14C]arachidonoyl PC yielded no N-[14C]arachidonoyl PE , whereas incubations with 1-stearoyl,2-[14C]arachidonoyl PE yielded N-acyl PEs that were radioactively labeled only on the sn-2 acyl ester group, as the PE substrate from which they derived . From these observations, we conclude that N-acyltransferase activity in brain can catalyze the transfer to PE of either saturated or polyunsaturated fatty acyl groups, provided that these groups are esterified at the sn-1 position of phospholipids.It is generally thought that, in brain as well as other tissues, arachidonate is mainly esterified at the sn-2 position of phospholipids . Such selective distribution is in striking contrast with the substrate specificity of brain N-acyltransferase, which argues against the participation of this enzyme activity in the biosynthesis of N-arachidonoyl PE. Studies by Blank et al. and Chilton and Murphy have suggested, however, that small amounts of phospholipid species containing arachidonate at the sn-1 position may occur in non-neural tissues. Accordingly, we examined whether similar phospholipids may also be present in rat brain. The experimental approach we adopted to identify sn-1 arachidonoyl phospholipids in brain tissue is depicted in Figure 9A. We isolated brain phospholipids by column chromatography, and digested them with Apis mellifera PLA2, an enzyme that selectively hydrolyzes the sn-2 fatty acyl ester bond, yielding sn-1 lysophospholipids . We extracted the reaction products and incubated them with Bacillus cereus PLC, which hydrolyzes the vicinal phosphate ester bond of sn-1 lysophospholipids, yielding sn-1 monoacylglycerols. The latter, after conversion to bis-TMS derivatives, are readily resolved by GC, and can be unambiguously identified and distinguished from their sn-2 isomers by their typical retention times and mass spectral properties .We have previously reported that, in rat cortical mixed cultures, biosynthesis of N-acyl PEs is enhanced in a Ca21 -dependent manner by ionomycin, a Ca21 ionophore, or by membranedepolarizing agents . These results suggested that a Ca21 -activated N-acyltransferase activity may catalyze N-acyl PE biosynthesis in intact neurons. This possibility could not be stringently tested, however, because pharmacological inhibitors of this enzyme were not available. The finding that BTNP is an effective N-acyltransferase inhibitor in vitro prompted us to examine its effects on N-acyl PE biosynthesis in intact neurons. In a first series of experiments, we used cortical mixed cultures that had been labeled by incubation with [3 H]ethanolamine. We stimulated the cultures with 1 m M ionomycin and measured the radioactivity associated with N-acyl PEs after TLC purification. As reported, N-acyl[3 H]PE levels in ionomycin-treated cultures were approximately threefold greater than those of untreated controls . This effect was almost completely abolished when the neurons were exposed to 25 m M BTNP . To examine the effects of BTNP on N-arachidonoyl PE biosynthesis, in subsequent experiments we stimulated the cultures, purified the N-acyl PEs, and quantifified them by GC/MS after PLD digestion. We found that the cultures contained 0.82 pmol/ dish of N-arachidonoyl PE when unstimulated, 2.54 pmol/dish when stimulated with ionomycin, and 0.95 pmol/dish when stimulated with ionomycin in the presence of 25 m M BTNP. Together, these results support an essential role for N-acyltransferase activity in the biosynthesis of N-arachidonoyl PE and other N-acyl PEs in situ.Experiments with rat brain neurons in primary cultures have suggested that anandamide formation may result from the hydrolytic cleavage of a membrane phospholipid precursor, N-arachidonoyl PE . In the present study, we have considered three aspects of this hypothetical mechanism that are essential to establish its physiological relevance. First, we have determined whether N-arachidonoyl PE is present in adult brain tissue. Second, we have examined the enzyme activity and lipid substrates that participate in the biosynthesis of N-arachidonoyl PE in vitro. Finally, we have assessed the contribution of this enzyme activity to N-arachidonoyl PE biosynthesis in intact neurons.

Since the literature suggests EI causes neuropsychological sequelae, it is worth using MRI imaging techniques to examine any structural abnormalities and cerebral lesions. Irregularities observed on MRI scans are generally unique to each EI case, however white matter hyperintensities found on fluid-attenuated inversion recovery image sequences are a common factor. The latter three of the case studies cited all report WMH specifically in the cerebral corticospinal tract. EI has also been known to cause hypoxia, which is characterized by cytotoxic edema in the cortex of the central region and the basal ganglia.The average lamppost in a densely populated city, such as New York City, works on a single-phase 120 V/240 V 60 Hz, AC received from a nearby three-phase generator. The patient received an electrical shock after submerging his hands in a puddle on a sidewalk charged with stray voltage from a nearby lamppost. Workers from the electrical company in the area testified that exposed ends of an electrical cable of a lamppost were causing 8 V of stray voltage. Using the information we know about wet skin resistance, we can also assume that the patient’s hand had a resistance of 1000 X, while the patient’s internal body had a resistance of 300 X. Rearranging Eq. , we calculate the current passing through the patient’s hand to be approximately 8 mA, while the current passing through the internal body is approximately 26 mA. However since salt water is more conductive than pure water, this would have potentially lowered the resistivity of the patient’s hand, causing the current passing through his hands to be comparatively higher and thus accounting for the no-let-go phenomenon he experienced. To examine the validity of this approximation,growers equipment we consider the patient’s dog that went into seizure upon stepping in the charged puddle.

A study done by Woodbury investigated the stimulus parameters needed to induce electroshock seizures on rats, and found that at 60 Hz AC, the current needed to promote seizures was 17.7 mA. This is extremely similar to the current needed, 16 mA, to induce the no-let-go phenomenon in the average male. Thus we can assume with substantial confidence that the current passing through the patient’s hand was roughly around 16 mA AC.At age 10, the patient was treated for meningitis. One week after the electrical injury, the 37-year-old patient received a brain MRI that reported no abnormalities. Six years after the injury, the patient had another brain MRI, which was sent to our laboratory. Since the cavitation of his right lateral ventricle is prominent on T1 multi-planar reconstruction and T2 FLAIR MRI sequences , it is highly probable that this particular abnormality was not derived from the patient’s childhood meningitis, otherwise it would have been observed by his former radiologist. MRI DTI analysis done on adult meningitis reports increased FA values in cortical regions, while analysis done on neonatal meningitis reports increased FA values in leptomeningeal regions and decreased FA values in periventricular white matter regions. However, to date, there are no studies that report white matter abnormalities found in adults with childhood meningitis, or studies that have assessed high diffusion anisotropy sequelae in patients with a history of meningitis.At the time of the neuropsychological exam, the patient was taking multiple medications that could have potentially affected cognitive performance. An investigation of these potential effects was conducted. Depressed patients treated with Bupropion scored similarly to normal, healthy controls on neuropsychiatric tests that assessed verbal memory, visual memory, finger tapping, and symbol digital coding. On the dominant finger-tapping test, our patient scored in 5th percentile, while on the coding subtest, he scored in the 10th percentile. The patient’s visual and verbal memory scores were average. In a study that assessed the neuropsychiatric effects of Hydrocodone, subjects that had taken hydrocodone performed 10% worse than the mean on the motor performance test, while no variance was found on simple and complex reaction time tests. Our patient scored in the 2nd percentile on the motor and processing speed index. In a study done on 38 patients taking Clonazepam, 8 patients experienced behavioral side effects while 30 patients did not.

The mean absolute discrepancy between VIQ and PIQ of the 8 patients was 17.5 points, while the discrepancy between VIQ and PIQ of the 30 patients who did not experience behavioral side effects was 6.5 points. Our patient’s VIQ and PIQ difference was 20 points. No study has been done on the effects of memantine on cognitive behavior for patients without Alzheimer’s disease , but for patients with AD, memantine improved language and memory scores in comparison to a placebo group. Gonzalez measured the effects of cannabis on cognitive performance by determining overall indexes of neuropsychological performance and running individual neuropsychological tests . Habitual cannabis users performed 1/5th a standard deviation worse than controls in overall index scores, and had performed significantly worse on memory tests. The patient’s performance on memory tests and his full scale IQ were rated average. No effects of melatonin on neurocognitive performance were found. No effects of gabapentin on neurocognitive performance were found.The patient shows significant increase in the right lateral ventricle volume on quantitative volumetric analysis, which can also be seen in his T1 MPR and T2 FLAIR MRI image sequences . This right-sided volumetric increase would also be consistent with the 20-point discrepancy of the VIQ and the PIQ since the right side of the brain is more closely associated with the PIQ and the left side of the brain is more closely associated with VIQ. The increased right-sided lateral ventricle would also be consistent with the more prominent right-sided ROIs found on MRI DTI analysis such as right-sided posterior internal capsule, external capsule and arcuate abnormalities. Right-sided abnormalities in areas such as the posterior internal capsule, shown in Fig. 1, would also be compatible with the chronic neuropathy in his left arm since the right side of the brain regulates the left side of the body. Reisner noted that delayed myelopathy after electrical injury has been established in the literature, and that possible mechanisms include glutamatergic hyper stimulation leading to oxidative stress.Common psychiatric problems, including conduct disorder, depression and anxiety, are important risk factors for alcohol and marijuana use in adolescence. The consistent link between common psychiatric problems and substance use has led researchers and practitioners to suggest that by intervening early in adolescence to treat psychiatric disorders, we could reduce substance use problems by late adolescence. However, two key questions need to be answered before we can conclude that intervening on psychiatric problems will be an effective strategy to reduce substance use in adolescence.

First, do adolescents who exhibit an increase in their psychiatric problems exhibit a subsequent increase in their substance use? Longitudinal studies provide consistent evidence that youth with higher levels of psychiatric problems are more likely to engage in substance use during adolescence 3. Etiologic theories to explain this comorbidity are based on causal pathway models, in which conduct disorder, depression, and anxiety result in substance use. Frequent explanations for these relationships are that children and adolescents with conduct disorder gravitate towards social environments that facilitate problem behaviors such as substance use and that drugs like alcohol and marijuana are used to self-medicate or alleviate persistent symptoms of sadness and anxiety. However, existing studies have primarily examined whether youth with higher levels of psychiatric problems are more likely to use and abuse substances ,plant benches rather than examining whether adolescents tend to increase their level of substance use during periods when their psychiatric problems increase . The latter approach represents a more direct examination of the self-medication hypothesis, where adolescents increase their substance use in an attempt to manage emerging psychiatric problems. Few longitudinal studies have examined the association between intra-individual changes in mental health problems and substance use. By examining within-individual change, causal inference is enhanced because selection effects and all factors that vary between individuals are ruled out as potential confounds. It also provides a better indication of whether treating an adolescent’s psychiatric problems could potentially lead to a reduction in his substance use. The second key question is: Are there sensitive periods during adolescence when psychiatric problems play a particularly strong role in shaping substance use? Cerdá and colleagues found no evidence that there was a sensitive period in which acute and chronic psychiatric problems were more strongly related to the onset of alcohol and marijuana use from childhood to late adolescence. Specifically, both recent and cumulative conduct disorder problems were associated with earlier alcohol and marijuana use onset in a cohort of boys followed from ages, whereas cumulative, but not recent, depression problems were associated with earlier alcohol use onset. However, there was no particular age of substance use initiation when psychiatric problems mattered the most. In contrast, Maslowsky and colleagues 10 and Gibbons and colleagues 11 found evidence indicating that early conduct problems were a stronger predictor of alcohol and marijuana use in late adolescence than conduct problems in middle adolescence. However, these three studies focused on between-individual differences in psychiatric problems and substance use. Therefore, it is unclear whether there is a specific developmental period during adolescence when youth are more likely to escalate their drug and alcohol use in response to emerging psychiatric problems.

One way to effectively address these two key questions is to use longitudinal data to examine whether youth tend to increase the frequency of their substance use after they experience an increase in their psychiatric problems, and test whether this association changes across development. This type of within-person change analysis eliminates the possibility that time-stable individual differences such as genotype, race/ethnicity, personality traits, family history of psychiatric problems and substance dependence, and parenting problems can explain the association between changes in psychiatric problems and substance use across adolescence. Hence, it controls for all unmeasured time-invariant confounders. In addition, measured time-varying confounders can also be included as control variables . Using this approach, researchers have shown that change in alcohol abuse or dependence and nicotine dependence in early adulthood predicted change in major depression in a birth cohort in New Zealand. Additionally, increasing frequency of cannabis use was associated with concurrent increasing depression problems in four Australasian birth cohorts. But to our knowledge, no research has used this approach to establish the directionality of the relationship between common psychiatric problems and substance use: that is, to evaluate whether an increase in conduct disorder, depression and anxiety problems leads to a subsequent increase in alcohol and marijuana use; an increase in alcohol and marijuana use leads to a subsequent increase in conduct disorder, depression and anxiety; or a reciprocal relationship exists between psychiatric problems and substance use. Thus, the aims of the present study are to address the following questions: do adolescents experience an increase in the frequency and quantity of their alcohol and marijuana use following an increase in conduct disorder, depression, and anxiety problems? Are there specific periods during adolescence when increases in these mental health problems are more strongly related to escalations in substance use than others? We examine these questions in a longitudinal urban sample of males followed from ages 13 to 19, with yearly measures of psychiatric problems and substance use quantity and frequency. To establish the directionality of these associations, we examine both whether increases in alcohol and marijuana follow increases in conduct disorder, depression, and anxiety, and whether increases in conduct disorder, depression, and anxiety follow increases in alcohol and marijuana use. Data are from the youngest cohort of the Pittsburgh Youth Study. This sample has been described in depth elsewhere.Briefly, participants included first-grade boys enrolled in 31 public schools in Pittsburgh in 1987-1988.The screen involved assessing the boys’ conduct problems using ratings collected from the parents, teachers, and the boys themselves. Boys whose composite conduct problem scores fell within the upper 30th percentile, together with an approximately equal number of participants randomly selected from the remaining end of the distribution, were selected for longitudinal follow-up . The sample is predominantly Black and White with 3% Asian, Hispanic, and mixed-race. Participants were assessed annually or semi-annually, depending on the measure, for thirteen years.

Experiencing intense emotions may have led individuals with substance use problems to be deeply affected by both positive and negative pandemic-related changes. Additionally, perceiving greater personal growth was associated with lower likelihood of struggling with responsibilities at home and lower likelihood of avoiding large gatherings. Participants who perceived personal growth may be a subset whose daily lives were less strongly affected by the pandemic. Study data are cross-sectional, and causal pathways cannot be determined. There may be bidirectional relationships between substance use problems and pandemic-related mental health symptoms and stressors. While pandemic-related stress may have worsened mental health symptoms and substance use, it is also plausible that individuals with preexisting mental health symptoms and more substance use problems were negatively impacted by the pandemic than those with milder symptoms. Longitudinal research is needed to fully understand how substance use and pandemic-related circumstances may impact one another. The study was exploratory and was intended to be hypothesis-generating rather than hypothesis-confirming. Results are also subject to recall bias, as all measures were self-reported. Participants may have had difficulty accurately reporting their substance use and mental health symptoms from the past two weeks. Data were not collected on general life stressors unrelated to the pandemic. Individuals with high levels of stress may have experienced more pandemic-related stressors, mental health symptoms, and substance use problems. Lastly, the sample was predominantly non-Hispanic white. People of color are at increased risk of contracting and experiencing complications from COVID-19 . Moreover, Hispanic and Black individuals were more likely to report increased substance use than non-Hispanic white or Asian adults, potentially due to increased stress.

All participants were enrolled in a clinical trial, were not experiencing severe medical problems from their substance use, owned smartphones,pot for growing marijuana and were proficient in English. Hence, findings may not generalize to more impoverished, medically complicated, or diverse groups. Future research into pandemic-related stressors and substance use should aim to recruit a more diverse sample. Smoking and alcohol misuse often co-occur. In the United States, the prevalence of nicotine dependence among individuals with alcohol dependence is 45.4%, while the prevalence of any alcohol use disorder among adults with nicotine dependence is 22.8% . These co-dependent individuals have more difficulty quitting smoking . An outstanding problem among those with substance use disorders is their disproportionate valuation of the drug and their disproportionate allocation of resources to obtaining the drug compared to participating in other daily activities . This imbalance between drug-related vs. regular activities reflects reinforced drug consumption patterns , and the differences in how drugs and non-drug reinforcers exhibit differential reinforcement strengths can be operationalized using a concept known as Relative Reinforcing Efficacy . One validated laboratory approach to measuring the RRE of drugs is hypothetical purchasing tasks, which assess changes in drug purchase and consumption as a function of increasing drug price . The consumption pattern can yield the demand curve modeled by Q = Q0∗10k , an exponentiated version of the classic equation by Hursh and Silberberg . Q represents consumption at price C; Q0 represents consumption at or near price zero, α represents the rate of change in demand elasticity, and k is the span of consumption values in log units. Other demand indices derived from the demand curve include: break point , Omax , and Pmax . Pmax also indicates the price at which the slope of the demand curve becomes <-1, indicating a shift from relatively inelastic demand where changes in consumption is resistant to increases in price to relatively elastic demand.

Research using the alcohol purchase task has found alcohol demand to be associated with alcohol use. For example, college students with recent heavy drinking exhibited greater intensity, Omax, and break point than recent lighter drinkers , and the APT’s reliability and validity was further confirmed among college students . Importantly, heavy drinking smokers exhibited greater Omax, Pmax, and break point for alcohol compared to heavy drinking nonsmokers , suggesting that smoking may increase the demand for alcohol. Research using the cigarette purchase task has suggested that cigarette demand indices are associated with smoking behaviors. Nicotine dependence severity was positively associated with the break point, intensity, Pmax, and Omax among young light smokers and among moderately heavy smokers . Cigarette demand is also related to psychiatric conditions among smokers. For instance, it was shown that smokers with schizophrenia reported higher intensity, consumption, and expenditure than smokers without schizophrenia . Researchers have further studied the latent structure of the demand indices to identify higher-level factors in the RRE domain that potentially better explain drug use behaviors. Two latent factors, labeled Persistence and Amplitude, have been identified for different drugs, including marijuana , alcohol , and cigarettes . The Persistence factor was found to consist of break point, Omax, Pmax, and elasticity. Higher levels of break point, Omax, and Pmax, and lower elasticity values were associated with higher Persistence scores, reflecting more persistent demand for the studied drug. However, the Amplitude factor appears to be more heterogeneous. The demand index that loads to this factor is the intensity, and thus it may reflect the maximum possible amount acquired and consumed by users, but other demand indices, such as Omax and elasticity ,were found to load on the Amplitude factor. While many studies have evaluated the RRE of alcohol and cigarettes separately, most were conducted in nonclinical samples, particularly among younger college students.

Smokers with alcohol use disorder represent a special population known to be more treatment resistant because of their dual dependency . Recently, there have been several attempts studying the demand for alcohol and cigarettes among populations with concurrent use of alcohol and cigarettes. For instance, it was found that smokers showed greater demand for alcohol than nonsmokers among a college student sample . Extending these results from university settings to communities, Amlung et al. provided further evidence of increased demand for alcohol among smokers compared to nonsmokers. Recently,container for growing weed in a larger community sample of non-treatment seeking heavy drinking smokers, Green et al. found that alcohol and cigarette demand indices were positively correlated and more importantly, they found that compared to alcohol-related dependence measures, smoking-related measures accounted for more variance in alcohol demand’s Persistence factor, suggesting that smoking may play a reinforcing role in increasing alcohol demand among non-treatment seeking heavy drinking sample. These three studies have provided important insights for the interrelationships between the demand for alcohol and cigarettes, shedding light on developing interventions for alcohol and tobacco co-dependence. To complement these findings, we evaluated the demand for alcohol and cigarettes among treatment-seeking smokers with AUD, a clinical population that has not been examined previously. Specifically, the current study used the APT and CPT to examine the baseline demand for alcohol and cigarettes among smokers with AUD enrolled in a clinical trial for the concurrent treatment of AUD and smoking. We aimed to compare the alcohol and cigarette demand indices and their latent factor structures and examine each drug’s demand metrics’ relationship with the dependence severity of alcohol and nicotine. The final data set had data from 99 participants with 96 sessions of APT and 98 sessions of CPT data. All data analyses were conducted using SAS . To compare the demand indices between APT and CPT, we conducted one-sample paired t-tests in SAS with a two-sided alternative. For these tests, a significance level of 0.01 was set to adjust for multiple comparisons involving five separate demand metrics . To identify the latent factors for the demand curve indices, we conducted principal component analyses with the oblique rotation, which allowed the estimation of multi-factorial solutions with correlated factors . The scree plot for clear discontinuities between succeeding factors was used for factor retention . A loading of 0.32 was considered to load significantly on a given factor . To examine the correlations between various dependence variables and demand indices, we conducted bivariate correlation analysis. The correlation analysis also included factor scores, which were computed from the five demand indices using the regression method. Our finding that participants had higher Omax and elasticity in the APT than in the CPT suggests that they were willing to allocate more economic resources toward alcohol than cigarettes and were less sensitive to the price escalation of the alcohol than that of cigarettes. These results suggest that alcohol had relatively greater RRE than cigarettes among smokers with alcohol use disorder. Our results were consistent with an earlier study among alcohol-dependent individuals . They used a multiple-choice questionnaire to assess the crossover point between drug and monetary values and found that the crossover point for the monetary option was higher for a drink than for a cigarette, suggesting that alcohol had greater RRE than cigarettes did among a similar population. The greater values of Omax and lower elasticity scores in the APT than those in the CPT suggested that smokers with AUD had greater demand for alcohol than cigarettes.

Consistent with difference in elasticity between alcohol and cigarette demand, our findings support the notion that smokers with AUD were more resistant to the price elevation in terms of reducing their alcohol consumption compared with their cigarette consumption. Notably, greater and more sustained demand for alcohol may be related to one’s smoking status per se, as previous research showed that heavy drinking smokers reported greater alcohol demand than heavy drinking nonsmokers . Although our participants reported lower intensity of alcohol than that of cigarettes, this difference in intensity may reflect the inherent difference in characteristics between alcohol and cigarettes, such as packaging and consumption patterns specific to the products. The relative difference in intensity between alcohol and cigarettes demand, as well as their relative difference in baseline consumption patterns is consistent with previous research using a similar sample—heavy drinking smokers . Our PCA suggested a robust two-factor latent structure for the APT that accounted for 80.65% of the variance. This finding is consistent with previous research that identified a two-factor solution for marijuana , alcohol , and cigarettes . Moreover, consistent with these studies, the first factor includes break point, Omax, Pmax, and elasticity for both alcohol and cigarette demands. These four indices reflect the sensitivity to the increasing prices of alcohol and cigarettes. Thus, this factor indicates the persistence of alcohol and cigarette use behaviors among this population. The second factor has been commonly referred to as Amplitude , which reflects individuals’ consumption levels when the cost was minimum. This factor was mainly attributable to the intensity index. However, previous research identified differential contributions from a second demand index. Three studies found extra loading from Omax , one study found elasticity , and one found no extra indices . Unlike these studies, we found that the Amplitude factor had extra loading from the break point and Pmax, although three studies found similar non-significant negative loadings from Pmax . These results highlight the heterogeneity of the second factor, despite the consistent loading from intensity. For the cigarette demand’s PCA, we replicated a two-factor . Overall, the loadings to the first factor were similar to our findings with the APT’s PCA. However, the Persistence factor accounted for 52.55% of the variance in alcohol demand vs. 46.67% of the variance in cigarette demand, which suggests that smokers with AUD are characterized by higher persistence use of alcohol than cigarettes, consistent with the differences of Omax and elasticity between APT and CPT. Perhaps the most interesting finding with the cigarette demand’s PCA was the second factor. This factor pattern is unique because it has been partially reported. For example, Bidwell et al. and O’Connor et al. reported Omax, while González-Roz et al. reported elasticity to load to the second factor. Except for the same factor loading to the second factor, the loading from the other four demand indices have a complementary pattern . These differential loading patterns highlight the heterogeneity of the Amplitude factor, and distinct latent factors may contribute to the observed differential demand for alcohol and cigarettes. We found that cigarette demand indices were significantly correlated with FTND scores, baseline smoking rate, and smoking withdrawal . These positive correlations have been reported in several studies , and suggest that smokers who were more dependent on nicotine have more demand for cigarettes.

The ethnographic evaluation is guided by the Consolidated Framework for Implementation Research. The CFIR assesses five domains of interventions, outer settings, inner settings, provider characteristics, and participant characteristics. The evaluation includes pre- and post intervention in-depth interviews with key informants who participate in the study and ethnographic observation with participants in their daily activities at the clinics and in the community settings.Participants are recruited from the methadone clinics in Hanoi and Ho Chi Minh City —the two largest urban settings in Vietnam. As of March 2021, there are 23 methadone clinics in HCMC and 18 in Hanoi, treating 5047 and 4655 patients, respectively. Criteria for selecting clinics include number of patients, estimated prevalence of methamphetamine use, availability of human resources to implement study interventions, and space for intervention activities. Ten clinics in each city will be randomly selected from those that meet the criteria.An investigator will stratify participants by HIV status and randomize them into two front line interventions using REDCap, as shown in Fig. 1. She will send the allocation results to the site research assistants who will then inform providers at the study clinics. This is an open-label study so unblinding does not occur. Participants and their counselors, research assistants, and data managers are aware of participants’ assignment of intervention. Participants will receive two individual sessions of motivational interviewing with their counselors before they get into the frontline interventions and, in week 13, before the adaptive strategies start. These sessions would boost participants’ motivation for intervention and provide them with greater details of the upcoming intervention activities.

In each selected clinic,cannabis grow equipment a physician, two counselors, and one nurse will participate in the study as intervention providers. The physician will ensure referral to HIV and psychiatric services when necessary; two counselors will run motivational interviewing, group education sessions, and Matrix meetings; the nurse will collect urine twice a week and conduct contingency management based on the UDS results. Before the start of the intervention, to ensure the accuracy,integrity, and fidelity to the EBIs, all intervention staff at methadone clinics will receive didactic training on the theory behind the approach, evaluate their comprehension of the concepts within and behind the approach, watch a video of a Master Behavioral Counselor conducting intervention sessions and discuss the details of the session, and conduct at least two pilot intervention instances. All intervention sessions, except contingency management, will be audio-recorded, transcribed, and coded to ensure intervention fidelity. Intervention staff who have lower levels of intervention integrity or who have significant drift will be provided detailed feedback and supervision until there is parity with other staff.Sample sizes were chosen to compare primary outcomes based on first-stage randomization into one of two groups: high intensity or low intensity front line interventions. Sample size calculations are conducted in PASS 2008 for a two-group comparison of binary outcomes, a power of 80%, a 5% alpha level, and a conservative attrition rate of 20%. Using estimates from our prior work, we anticipate base rates of 80 to 90% for substance use and 60 to 70% for viral suppression. Based on these assumptions and a proposed sample of 200 HIV-positive participants , we can detect randomization group differences of 20% or more for binary outcomes, such as substance use and viralload suppression.

We can detect even smaller group differences for substance use outcomes in the proposed sample of 400 HIV-negative participants and the combined sample of HIV-positive and HIV-negative participants. If estimated outcome probabilities are similar between first-stage randomization groups at 12 weeks, we will pool 12-week results for even greater power in evaluating second-stage randomization differences.Different datasets collected from different sources will be linked through a unique identification code using RED Cap for quantitative data. Data will be uploaded in real-time from the 20 study clinics onto our database. The study data manager will assess transferred data for completeness, query sites regarding any inconsistencies, and code merged data files for analysis. For qualitative data, field notes written on site are expanded and recorded electronically within 24 h. After removing all personal identifiable information, the research team will upload password-protected transcripts on a secured database. The transcripts will be uploaded into Atlas.ti software to organize data and facilitate analysis.We will use a time-varying mixed-effects model that will be fitted to the participants’ common outcome measures over time. The unadjusted model will include indicators of first-stage and second-stage intervention conditions, time of the assessment , and intervention indicators-by-time interaction terms. An additional interaction term of the two intervention indicators will be included to account for any interaction effect between the first and the second stage interventions. The adjusted model will include patients’ socio-demographic characteristics, drug use history, HIV-serostatus, and location as fixed effects. The mixed effects models will include a participant-level random effect to account for repeated observations of each participant, as well as a clinic-level random effect to account for the nested nature within the clinics. We will conduct subgroup analyses among HIV positive and HIV-negative participants.

For the HIV positive subgroup, the specific outcomes of interest include HIV viral load suppression and adherence to antiretroviral treatment, and specific outcomes for HIV-negative subgroup include frequency of HIV testing and HIV seroconversion. Substance use will be the common outcomes in models including participants of both HIV statuses.The qualitative analysis team will read and provide a narrative summary for each transcript. A code book will be developed based on these summaries. Memo-writing and code-refining will be conducted throughout the analysis. Iterative analyses assess convergence of patient, provider and organizational dimensions on study measures, and the context of the policy subsystems, cross system interactions, and resource allocation.We will first describe the extent and patterns of missingness within each variable and check for associations between missing and observed data to determine the mechanism of missingness, which could be missing completely at random, missing at random, or missing not at random. Missing data will then be handled using multiple imputation. Appropriate imputation techniques will be chosen for the type of missing data and the statistical tools employed . For sensitivity analysis, we will conduct analyses with and without multiple imputations. All participants will be analyzed on an intent-to-treat basis where the study outcomes are examined based on the random intervention assignment and not on the actual intervention received or adherence to the intervention.There is no planned interim analysis as the behavioral therapies used in this trial have no known serious adverse events and are consistently more efficacious than control conditions in treatment-seeking participants. The effect sizes of the behavioral therapies in this trial are in the moderate range. Furthermore, any interim analysis and decision to stop the trial would likely be based on under powered data and susceptible to error.Our data monitoring committee is composed of members of the Data and Safety Monitoring Board for Addiction Medicine of the University of California – Los Angeles. These members are not connected to the study in any way. The DSMBAM is independent from the National Institute on Drug Abuse —the sponsor of this study. The DSMBAM meets quarterly to monitor subjects’ progress in the trial and considers whether adverse social harms differentially accrue by condition. Although there are no prospective stopping rules for this trial,horticulture rack the DSMBAM is within its charge to review aggregate data, request statistical tests of differences in social or other harms, and then advise changes in intervention type or intensity if statistically significant differences emerge in adverse events by condition. Prior to each meeting, the study team will submit a performance report including all reports of SAEs for DSMBAM’s consideration. After each meeting, recommendations will be made in writing to the principal investigators.Hanoi Medical University and the staff in the STAR-OM study provide oversight of financial management. The Vietnam teams and US teams maintain frequent communication via emails and bi-weekly online meetings to report updates on the study progress, discuss scientific aspects of the study, and troubleshoot issues when they arise. The teams in Hanoi and HCMC meet online once weekly and in-person quarterly during monitoring visits to discuss the study conduct. We submit annual research progress reports to the Ethics Committee of Hanoi Medical University.

Any protocol amendments need to get ethical approval before implementation. The UCLA Addiction Medicine Data Safety Monitoring Board independently review our data and data management twice a year.Adverse events in this trial are defined as medical issues that do not require hospitalization. Serious adverse events are defined as life-threatening events such or other events that have a negative impact on participants’ life such as incarceration or compulsory drug rehabilitation. The clinic staff will communicate information about adverse events and serious adverse events to the study team right after they are informed by participants or participant families. The study coordinators in Hanoi and HCMC are responsible to report adverse events within 7 days and serious adverse events within 24 h on REDCap with the time of onset, seriousness, duration, and outcomes. The principal investigator will decide what serious adverse events need to be reported to the Ethics Committee.Prior to participation in the trial, the participant will be informed about the research. Participants will complete a short questionnaire about the study objectives and main activities to show how they understand the study. Research assistants will provide more explanation based on the results of the questionnaire. If participants agree to join the study, they will sign a consent form. Each participant will be assigned a unique identifier at the time of screening. Participant data will be linked to this identifier only. Participant personal identifiable information is stored in a separate locked cabinet to which only responsible study staff have access. All study staff sign a confidentiality agreement to non-disclosure of participant information. We make extra efforts to ensure nodisclosure of drug use information to anyone other than participants and the study staff.Between July and October 2020, we conducted 4 focus group discussions of a convenience sample of participants from four methadone clinics in the downtown and suburbs of Hanoi and HCMC to inform intervention content and refinement. Respondents reported information on local taxonomy and patterns of methamphetamine use, triggering situations, methampheta minerelated sexual risks, motivations for seeking treatment, and perceived acceptability of the adaptive interventions. The pilot implementation lasted 12 weeks from November 2020 through February 2021. It identified issues to be addressed before the full implementation. At the conclusion of the pilot, we conducted 2 FGD with patients and 1 FGD with providers participating in the pilot to gauge their feedback about the interventions.With the cut-off point of ASSIST ≥ 4 and methamphetamine-positive UDS as originally proposed, there were 26 and 52 eligible participants in two pilot clinics in Hanoi and HCMC, respectively . For the pilot implementation, we randomly recruited 42 participants with ASSIST score ≥ 4 or methamphetamine-positive UDS. After the front line intervention, 16 participants were non-responders and randomized into adaptive interventions. At least 50% of the original sample must transition to the adaptive phase for sufficient statistical power. Thus, we decided to recruit more participants with severe use of methamphetamine, as evidenced in both ASSIST score ≥ 10 and methamphetamine-positive UDS. Furthermore, to recruit enough participants for the front line intervention phase, given most other clinics are smaller than the two pilot ones, we decided to use ASSIST score “OR” UDS instead of “AND” to increase the pool of potential participants. We kept the criterion of methamphetamine-positive UDS to compensate for participants with lower ASSIST scores due to desirability bias.The STAR-OM study is among the first studies to evaluate different combinations of EBIs for methamphetamine use among methadone patients in low-and-middle-income countries. The study will provide effectiveness and cost-effectiveness evidence for scaling up these interventions. The SMART design assesses different treatment strategies for participants who respond differently to front line interventions. The combination of trial and ethnographical study will provide insights on factors at multiple levels that need to be considered in decision making.As the interventions will be delivered by methadone providers at methadone clinics, they can be readily implemented if the trial demonstrates they help.

Most of the THC-containing products used by the patients were obtained from friends, family, school, dealers, or off the street. Interestingly, most of the patients used universal “vape pens” for which prefilled THC cartridges can be used, as opposed to the closed pod devices sold for proprietary nicotine containing products . Use of devices with a tank designed to be filled with nicotine-containing liquid or THC oil was reported by 18 patients, and 14 reported aerosolizing THC concentrates by “dabbing,” a process involving vaporizing extracts of a concentrate that has been placed on a hot surface.Although the CDC investigation suggests that a clue to the vaping lung injury epidemic lies in the Dank Vapes products, the causative agent remains unknown. Public health investigators in New York State suggested that vitamin E acetate added as a thickening agent to THC-containing extracts, including Dank Vapes , may be responsible for lung injury, after 34 samples of extracts used by injured patients all contained it . However, other extracts tested used by cases in other states have not confirmed the universal presence of vitamin E acetate . Because virtually all THC containing extracts are oily, lipoid pneumonia also has been suggested as the responsible pathophysiology , and some but not all BAL fluid from patients has shown the presence of lipidladen macrophages . It is important to note that some patients with lung injury only used nicotine-containing products . Triantafyllou and colleagues describe several possible mechanisms by which vaping can lead to acute lung injury . The common vehicles of the nicotine-containing extracts are propylene glycol and glycerin, which have been shown to induce airway remodeling . Nicotine vapor itself has been shown to induce macrophage activation , and flavoring additives, including the known respiratory toxin diacetyl, lead to the generation of byproducts that directly injure the airway epithelium . It is really no surprise to anyone with a background in in halational toxicology that when chemically complex extracts are heated to the point of aerosolization and vaporization,cannabis grow facility toxic agents will be generated . A recent paper from the Mayo Clinic that described the pathological examination of lung biopsies from 17 patients with vaping associated lung injury reported findings more consistent with airway-centered chemical pneumonitis from one or more inhaled toxic substances, rather than lipoid pneumonia .

Although the CDC, in concert with state public health officials, feverishly works to find the “bad actor or actors” in vaping extracts, it has also taken steps to warn the public of the dangers of vaping, especially of THC-containing extracts. The CDC recommends that current users consider refraining from using e-cigarette, or vaping, products, particularly those containing THC . The agency also recommends that youth and young adults not use e-cigarettes or vaping products and that these products not be bought off the street or modified in any way. The negative publicity surrounding e-cigarettes has caused the company with the largest share of the market, JUUL, to stop all advertising, end internet sales of flavored e-cigarettes, and drop its well-funded political campaign to skirt San Francisco’s legislative ban on sales of e-cigarettes. JUUL’s CEO recently resigned, to be replaced by an executive from Altria, the tobacco company that owns 35% of JUUL. The tragic epidemic of lung injury due to vaping was preventable. If the U.S. Food and Drug Administration had taken a more proactive approach to regulation of e-cigarettes as electronic nicotine delivery devices similar to nicotine patches or gum, there would likely have been much less use by America’s youth. Data from the 2019 Monitoring the Future Survey conducted annually by the National Institute on Drug Abuse showed a doubling of the percentage of teens who reported vaping, with 25% of high school seniors reporting use in the last month. Rather than take regulatory action that could have protected the nation’s youth, the FDA abdicated its responsibility and let corporate profits come before public health. A cardinal tenet of environmental health is the precautionary principle that holds when a new product is developed that may have the potential for harm, it should be tested carefully for toxicity before being widely marketed. The FDA was made aware of the potential harm of inhaling vapors of nicotine-containing aerosols but allowed tobacco company–funded companies like JUUL to market flavored e-cigarette pods, which has led to the nicotine addiction of thousands of children.

There is a powerful lesson here. Ignore the precautionary principle at society’s peril. Lives have been lost through this ignorance.HIV infection is a global pandemic and the population is growing due to successful treatment with highly active antiretroviral therapy. Although rates of HIV have been reduced in the United States among most groups as a result of successful public health efforts , sexual risk behavior and subsequent acquisition and/or spread of HIV and other sexually transmitted infections are still of concern among men who have sex with men as well as drug using populations. Thus, it is evident that, despite research and efforts to understand and curb sexual risk behavior within these vulnerable populations, additional work employing novel approaches are needed. Sexual risk behaviors can be viewed as a composite of numerous behaviors that collectively make-up a complex behavioral phenotype. As with most complex phenotypes, sexual risk behavior is heterogeneous and several factors contribute to the variance that can be observed from one individual to another. To date, a majority of work examining risk factors for sexual risk behavior phenotypes have primarily focused on psychosocial factors and/or other complex/heterogeneous behavioral phenotypes such as substance use behaviors as indicators for current or future sexual risk behavior. Ultimately these indicators, upon sufficient replication, become candidates for public health interventions that aim to prevent and reduce sexual risk behaviors. However, the trouble with many of these candidates is that they are too proximal to sexual risk behaviors and often cooccur, making it difficult to disentangle temporal precedence and ultimately limit prevention efforts. One relatively novel approach is to examine intermediate phenotypes or endophenotypes such as neurocognitive factors as well as biological factors. These factors are more distal to the onset of sexual risk behavior and thus are potentially more advantageous candidates for identifying vulnerable individuals and informing prevention efforts for sexual risk behavior. Studies in literature examining neurocognitive and biological factors as indicators for sexual risk behaviors are limited. In fact, only two studies to date have examined neurocognitive factors and none to our knowledge have examined biological factors as potential indicators. Although this paucity of research is surprising given previous work linking both neurocognitive and genetic indicators to other health related behaviors, research has established the dopminergic system as a common link between neurocognitive functioning and sexual behavior.

The dopminergic system has been shown to be involved in sexual arousal, motivation and the subsequent rewarding effect of sexual behavior . Furthermore, DA in the human brain, specifically in the prefrontal cortex , has been shown to be necessary for proper cognitive functioning to occur and high or low levels of DA in this brain region are known to contribute to individual cognitive differences in humans. The PFC is of particular importance when examining risk behavior in that executive functions such as decision-making, planning, self-monitoring as well as behavior initiation, organization, and inhibition are largely dependent on PFC integrity. Impairment in executive functioning may result in difficulties in assessing relationships between a person’s current behavior and future outcomes; thereby resulting in choices and/or responses on the premise of immediate rewards versus long term consequences and an ultimate potential increase in the likelihood for participation in sexual risk behaviors. Thus,cannabis grow system mechanisms responsible for maintaining a dopamine balance within the brain and in particular the PFC would appear to be good biological candidates for further exploration of an association between executive dysfunction and sexual risk behavior. One such candidate is catechol-O-methyltransferease which is a mammalian enzyme involved in the metabolic degradation of released dopamine, particularly in the PFC. Of particular interest to this study is a common polymorphism involving a Val to Met substitution at codon 158. The Val allele of the COMT Val158Met polymorphism is 40% more enzymatically active than the Met allele. Thus, carriers of the Met allele metabolize dopamine at a less efficient rate, resulting in higher levels of dopamine in the synapse and ultimately an escalation in dopamine receptor activation. This differentiation of dopamine receptor activity dependent on COMT genotype has led to several investigations into the relationship between COMT and executive dysfunction in which the Val allele has been putatively linked to poor performance on executive functioning tasks. However, to our knowledge no work has examined the relationship between COMT and sexual risk behavior; albeit studies of similar behaviors such as novelty seeking, reward dependence, as well as affective arousal and regulation have demonstrated significant relationships. Given the aforementioned paucity of research in the current literature addressing the contribution of genetic and neurocognitive factors on sexual risk behavior, the primary aim of this study was to examine the main effects of executive functioning as well as the main effects of the COMT Val158Met polymorphism on sexual risk behavior among a ethnically diverse population of men with and without METH dependence and/or HIV infection. Within this aim, we hypothesized that the highly active COMT Val/Val genotype and its putatively associated deficits in executive functioning would be independently associated with sexual risk behaviors. In addition, as a result of previously mentioned research that has demonstrated an association between COMT genotype and executive functioning we also explored the potential interaction effects of COMT and executive dysfunction on sexual risk behavior.Participants were volunteers evaluated at the HIV Neurobehavioral Research Center at the University of California in San Diego as part of a cohort study focused on central nervous system effects of HIV and methamphetamine.

The current study comprised 192 sexually active non-monogamous men with and without methamphetamine dependence and/or HIV infection . Men were classified as non-monogamous if they stated they had “no current partner” at time of assessment. Monogamous men were excluded because unsafe sexual behavior within a monogamous relationship is less risky than in non-monogamous relationships. All participants underwent a comprehensive characterization procedure that included collection of demographic, neuromedical, psychiatric as well as neuropsychiatric information. HIV serological status was determined by enzyme linked immunosorbent assays plus a confirmatory test. Lifetime METH dependence was determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders Version IV . However, participants were not actively using other substances, with the exception of cannabis and alcohol. Potential participants were excluded if they met lifetime dependence criteria for other drugs, unless the dependence was judged to be remote and episodic in nature by a doctoral level clinician. Alcohol dependence within the last year was also an exclusion criterion. All participants were seronegative for hepatitis C infection. Additional information for each participant was collected as it relates to current depressed mood as well as lifetime diagnosis of Major Depression Disorder and/or Bipolar Disorder I or II. Current depressed mood was assessed utilizing the Beck Depression Inventory-I and MDD and Bipolar Disorder were ascertained using the SCID-IV. Information was also collected to determine lifetime dependence on sedatives, cannabis, opioids, cocaine,hallucinogens, and alcohol, using the SCID-IV. For METH+ participants, additional information was collected regarding age at first use, years of use, and days since last use of METH; whereas for HIV+ participants, HIV RNA plasma copies was ascertained as part of a larger neuromedical evaluation. All participants gave written consent prior to enrollment and all procedures were approved by the Human Research Protection Program of the University of California, San Diego and San Diego State University.Executive functioning was determined as part of a larger comprehensive battery of tests covering seven ability domains . The executive functioning domain deficit score, of particular focus in this study, was made up of perseverative responses on the Wisconsin Card Sorting Test; errors on the Halstead Category Test, which measures abstraction and cognitive flexibility; and time to complete the Trail Making Test part B, reflecting ability to switch and maintain attention between ongoing sequences.

However, in the present context, we must also see agency as a fundamental human process that is no less fundamental for being challenged by illness . Specifically, self-cutting is a crisis in the agentive relation between adolescent bodies and the surrounding world, or put another way, a crisis of their bodily being in the life-world that they inhabit. In understanding embodiment as an indeterminate methodological field, this relationship between body and world is defined by three modes or moments of agency: the intentionality of our bodies in acting on the world or being-toward-the-world, the reciprocal interplay of body and world embedded in a habitus, and the discursive power of the world upon our bodies to establish expectation and shape subjectivity . To be precise, approaching the interpretation of cutting from the standpoint of agency in these troubled adolescents’ body-world relationship has the immediate effect of shifting interpretive attention from the wounded flesh to the relation between the active hand of the cutter and the self-inflicted wound. It is then not just a matter of the pain, the relief, or the blood that originates at the violated boundary between self and world, and the concomitant breach in bodily integrity. In the first mode of agency, regardless of the implement used to cut with, the cutter’s hand is an agent of self, and the opening of the wound and flow of blood are an emanation of personhood into the world. Cutting is a form of active being toward-the-world whether understood as a form of projecting outward or as a kind of leaking and draining into the world. This mode of agency is epitomized in the statements of identity such as “I am a cutter.” In the second mode or moment of agency, hand and flesh together instantiate the reciprocal relationship of body and world.

The cutting hand interpellates the part of the animal and material world that is one’s very own body,cannabis grow equipment and that precise fragment of the world responds with the opening of the flesh . In this way cutting highlights the simultaneity of body as both self and other. The flow of blood marking not only the violation of a boundary but the opening between body and world. The reciprocity between body and world is highlighted in the simultaneous infliction of pain and the granting of relief. The cutter’s body is also the locus of an anguished subjectivity that elicits the application to itself by an agentive hand ambivalently cruel and kind, of an otherwise inert implement from the material world, whether it is a razor blade or a piece of glass. In the third mode of agency, both hand and flesh are no longer part of an inviolate self but conscripts of the world’s oppressive agency, and one’s body may as well not be one’s own but just a body, any body, “the” body as an object rather than a subject. The cutter’s hand is now the hand of the other, the wound is world-inflicted, and structural violence is incorporated at the most intimate bodily level. That is, it is inflicted by an anonymous oppressive world or the world dominated by the cruelty of others, and one’s flesh becomes an inert object alienated not only from self hood but from the trajectory of a possible life, isolated from others and immersed in the immediacy of present pain and unproductive bodily transformation. We must take care to distinguish what is specific to each young person and what is fundamental to their bodily experience in the account we have just given. Attending to the immediate life worlds of individual youth reminds us that each has a distinct experience of cutting under distinct circumstances. Gender, ethnicity, and socioeconomic status matter to define these circumstances, while family relations and especially family instability are particularly insistent and frequent themes.

Insofar as all the youth we have discussed were psychiatric inpatients, they can be counted among the more extreme instance of adolescent self-cutters, while exhibiting varied diagnostic profiles, levels of functioning, regimes of psychiatric medication, and phases of treatment and recovery. The combination of individual uniqueness and shared extremity across their situations has allowed us to elaborate a multilayered crisis of agency in the relation between body and world and highlights the existential profundity of cutting as a function of its mute immediacy in practice. The possibility for this kind of embodied existential analysis is that cutting is not an idiosyncratic occurrence but a culturally patterned act. Yet it cannot be accounted for just because other kids do it, and this is why it has been important to examine it in the lives of afflicted adolescents rather than simply as an element in the ethnography of “Emo” culture. The interpretive point is that the trajectory of our argument from experiential specificity on the individual level to the fundamental human process of agency does not define the ends of a continuum. We must instead understand the extraordinary conditions of suffering as simultaneous with the enactment of fundamental human process, because the relation between body and world is always embedded in a specific instance, and each specific instance points to our shared existential condition of embodiment. Identifying the wounded flesh as locus of agency at the intersection of body and world as we have done brings to the fore a particular configuration of relations between self as active and passive, strategy and symptom, subjectivity and subjectivation. The moment of cutting is a fulcrum or hinge between the self as agent or as patient, with an intended pun on the medical sense of patient.

From the standpoint of individual experience, cutting in the first sense is a strategy that is part of the self as agent, while in the second sense it is a symptom that is part of a disease process. As a cultural phenomenon, cutting in the first sense exhibits the body as existential ground of culture and wellspring of agentive subjectivity , while in the second sense cutting identifies the body as a site at which cultural practice and structural violence are inscribed and have the effect of subjectivation . In this respect, the distinction between subjectivation and subjectivity in the cut/cutting body is substantively parallel to the distinction between symptom and strategy in the afflicted person. Perhaps the analysis we have presented suggests that self-cutting may indeed be sufficiently complex to serve as the core of a distinct diagnostic category and too problematic with respect to agency to be defined as a symptom in the ordinary sense. Whether or not this proves to be the case, the existential complexity to which we have pointed is precisely what one would expect by bringing attention to bear on cutting as a crisis of agency with its locus at the intersection of body and world. Despite viral suppression on combination antiretroviral therapy , people with HIV suffer from depressed mood and chronic inflammation. Depression is the most common psychiatric comorbidity in HIV . Depressed PWH show poorer medication adherence ,cannabis drying racks lower rates of viral suppression , greater polypharmacy , poorer quality of life and shorter survival . A sub-type of treatment-resistant depression in the general population is associated with chronic inflammation . The potential clinical significance of this is high, since the anti-inflammatory TNF-alpha blocker tocilizumab and other drugs such as the antibiotic minocycline, the interleukin 17 receptor antibody, brodalumab, and the monoclonal antibody, sirukumab, have been shown to be effective treatment for this depression sub-type , but these have not been studied in the context of HIV. Inflammation is associated with greater symptom severity, differential response to treatment, and greater odds of hospitalization in patients with major depressive disorder . Chronic inflammation persists in virally suppressed PWH and predicts morbidity and mortality . There also is an extensive literature on showing that depression correlates with markers of inflammation and immune activation in PWH , but most of these studies were performed in individuals who were not virally suppressed. We hypothesized that inflammation in virally suppressed PWH would be associated with poorer mood.HIV disease was diagnosed by enzyme-linked immunosorbent assay with Western blot confirmation. HIV viral load in plasma was measured using commercial assays and deemed undetectable at a lower limit of quantitation of 50 copies/ml. CD4 T cells were measured by flow cytometry and nadir CD4 was assessed by self-report. Inflammatory biomarkers measured in blood plasma at the 12-year follow-up visit using immuno assays were neopterin, soluble tumor necrosis factor alpha type II , d-dimer, interleukin-6 , C-reactive protein , monocyte chemoattractant protein type I , soluble CD14 and soluble CD40 ligand . We selected these markers based on previous studies linking them to depressed mood . Biomarkers were measured only at the 12-year follow-up visit, and correlations were assessed with BDI-II at the same visit, and secondary at the initial visit.Current mood at baseline and 12-year follow-up was assessed using the Beck Depression Inventory -II . Lifetime major depressive disorder and substance use disorders were assessed using the computer-assisted Composite International Diagnostic Interview , a structured instrument widely used in psychiatric research. The CIDI classifies current and lifetime diagnoses of mood disorders and substance use disorders, as well as other mental disorders.

Additional assessments measured activities of daily living, disability, employment and quality of life. Quality of life was assessed using the Medical Outcomes Study HIV Health Survey Short Form 36 , a reliable and valid tool for assessing overall quality of life, daily functioning, and physical health . The MOS-HIV contains 36 questions that assess various physical and mental dimensions of health. Items are grouped into two overall categories , with 11 subcategories . These are scored as summary percentile scales ranging from 0 to 100, with higher scores indicating better health. Disability was assessed using the Karnofsy Scale . Dependence in instrumental activities of daily living was assessed with a modified version of the Lawton and Brody Scale that asks participants to rate their current and best lifetime levels of independence for 13 major IADLs such as shopping, financial management, transportation, and medication management . An employment questionnaire asked about job loss, decreases in work productivity, accuracy, and quality; increased effort required to do one’s usual job; and increased fatigue with the usual workload. Neurocognitive function was assessed using a comprehensive, standardized battery described in detail previously . The battery covered 7 cognitive domains known to be commonly affected by HIV-associated CNS dysfunction. The best available normative standards were used, which correct for effects of age, education, sex, and ethnicity, as appropriate. Test scores were automatically converted to demographically corrected standard scores using available computer programs.Demographic and clinical characteristics were summarized using means and standard deviations, median and interquartile ranges or percentages, as appropriate. Log10 transformation was used to normalize the biomarker distributions for parametric analysis. Factor analyses with oblique Equamax rotation were employed to reduce the dimensionality of the biomarkers. Factor analysis is a statistical method used to describe variability among observed, correlated variables in terms of a potentially lower number of unobserved variables called factors. Thus, factor analysis is a method for dimensionality reduction and can help control false discovery.To validate the factors, we examined intercorrelations between the biomarkers assigned to each factor. Pearson’s r and Spearman’s rho were calculated to compare factors with BDIII scores. Secondary analyses evaluated correlations with quality of life , neurocognitive function, and employment status. We used multi-variable linear regression models to test interaction effects. In the absence of an interaction, additive effects were tested. Analyses were conducted using JMP Pro® version 15.0.0 .We found that higher concentrations of a specific panel of markers of inflammation in blood were seen in PWH with worse depression. Additionally, PWH with depressed mood had markedly reduced quality of life and were more dependent in IADLs. In addition, higher inflammation associated with worse scores on numerous life quality indicators. Chronic HIV-associated inflammation and immune dysfunction have emerged as key factors that are strongly linked to non AIDS complications . Our findings confirm those of previous investigations , and extend them by evaluating a more comprehensive panel of biomarkers and more extensive evaluation of impact on daily functioning and quality of life.

Greg Gianforte, Attorney General Austin Knudsen and the state Republican Party did not reply to inquires asking whether they believe ‘socialist rag’ is an appropriate description of the Montana Constitution and whether they believe the document should be replaced.”Montana’s constitution has been in place since 1972, when it was drafted by a truly bipartisan convention and ratified by the voters. It has long been something that Montanans across the political spectrum have been proud of, a document widely taught in public school curriculums across the state. As reported by Dietrich, Montanans must vote on whether they want to replace the 1972 Constitution at least once every 20 years. Votes to call a new convention failed by an 18-82 margin in 1990 and a 41-59 margin in 2010. Provisions exist for amending the constitution as well, and if the Republicans pick up two more legislative seats in the next election they will have sufficient votes in the legislature that would enable them to put amendments on the ballot. Current trends in Montana would make this a good bet to happen. Notably, the 67th Legislature passed a referendum measure to ask Montana voters to change how Montana selects Supreme Court justices, as dictated by the Constitution, from statewide to district elections. This is motivated by the fact that Republicans are unhappy with the current makeup of the court and believe that shifting to districts would allow them, in the words of critics that oppose this change, to gerrymander judicial appointments. As will be detailed below, the policy outcomes in the budget, tax, Medicaid, energy, and mental health illustrate the hard right turn. This hard right turn is also in clear view in a number of “hot button” issue areas that elicited fiery debates in committee and on the floor and attracted substantial media attention during the session. Perhaps the most controversial was the Conceal and Carry Bill. HB 102 significantly expanded the ability to carry concealed weapons in public places. The bill singled out universities explicitly,cannabis grow supplier forbidding them to prevent the carrying of concealed weapons on campus, including classrooms.

The bill passed and was signed into law quite early in the session. However, the Board of Regents challenged the bill in courts as a violation of the Montana State Constitution to be the sole authority governing campuses across the Montana State System. The challenge is still making its way through the courts. As was true in many Republican controlled legislatures across the country, Montana’s Republican caucus also proposed and passed a number of bills signed into law by the governor that imposed new requirements on voters. HB 176 puts an end to Montana’s long-standing tradition of same day registration. SB 169 requires voters without a government issued photo ID or a state concealed carry permit to present two forms of identification to vote at the polls. Students lobbied to allow a school photo ID to serve as a single source equal to the concealed carry permit, but this was rejected by the Republican majority, adding an added tone of political polarization to the bill. HB 530 prohibits people from distributing or collecting mail-in ballots from voters if paid to do so. HB 651 makes it harder to run ballot initiatives in Montana. SB 319, a broad bill revising campaign finance law, “was amended during the final week of the Legislature to include language specifically barring the well-known and liberal leaning MontPIRG from conducting voter registration or signature gathering efforts in campus dorms, dining halls and athletic facilities. It also requires that an optional $5 student fee supporting MontPIRG be presented to students at the University of Montana, where MontPIRG is based, as an opt-in rather than opt-out option.”All of these bills are-as of this writing-being challenged in court. Rs also put forward a number of anti-transgender bills, generating some of the most heated debates of the session. HB 112, which bars transgender women from participating on collegiate women’s sports teams, is being challenged on grounds similar to HB 102 , that it trespasses on the Regent’s mandate.

The Montana legislature, coordinating with the governor’s office, also passed a number of restrictive immigration bills in a state with one of the lowest immigrant populations in the country, leading some critics of the legislation to charge that passing immigration enforcement laws in Montana is a solution in search of a problem. As reported enthusiastically by Brietbart, Montana Gov. Greg Gianforte signed HB 200 into law on March 31, 2021, banning sanctuary cities, which effectively act as safe havens for illegal immigrants across the state, promising “immigration laws will be enforced in Montana.” Montana has no sanctuary cities. There was widespread going into the session amongst unionists the legislature would pass anti-union legislation, including so-called right to work bills. SB 89 would have barred public employers from collecting dues for unions via paycheck withholding. HB 168 would have required annual worker consent for union membership. HB 251 would have required written consent for union due paycheck deductions. Montana unions, including many blue-collar trades workers affiliated with the AFL-CIO, organized and mobilized visibly in the capital. The most compelling speculation for why anti-union Rs in the legislature backed down is that the legislation lacked the backing of the governor, who decided not to pay the political costs anticipated with opposing organized labor in such a frontal attack this session. Observers and participants on both sides of the aisle received clear indications of how the governor and the Republican majorities in both houses had set their policy compasses. Gone was the purple tinge to Montana politics, signaled most significantly by back to back two-term moderate Democratic governors balancing a Republican controlled legislature. While Republican legislative leadership, in the period leading up to the legislative session, rhetorically signaled that they would bring a bi-partisan attitude to the legislative process, no observer I spoke with going into the session took this seriously. However, what did happen during the session to moderate anticipated budget cuts was the infusion of substantial COVID relief funds from the federal government. This allowed the Republican majority to both cut taxes and maintain spending levels.

Bullock was quoted as saying that his budget “does not necessitate any cuts to government programs and services” and that “if the next administration and legislature choose to cut government services, it’ll be based upon ideology, not necessity.”Brooke Stroyke chaired the Gianforte transition team. In an email to journalist Eric Dietrich, she wrote “With state spending increasing by 60% over the last 10 years, Governor-elect Gianforte thinks it’s critical to hold the line on new state spending.” Meanwhile, according to a Montana Free Press analysis of data compiled by the National Association of State Budget Officers, percapita spending by state government, unadjusted for inflation, rose by 42%, to about $6,600 per state resident, between 2008 and 2018. However, it is important to note that about half that increase was driven by portions of the state budget funded by federal dollars, a category that includes the vast majority of the spending resulting from Montana’s expanded Medicaid program. The source of increased state spending was rarely mentioned in Republican stump speeches that often focused on increased state spending as being “runaway” and needing of Republicans to reign it in. Hence, the first order of business by the Republican controlled legislature was to scrap Bullock’s budget proposal.5 Importantly, Governor Bullock’s budget anticipated a drop in general fund revenues of $94 million in fiscal year 2021 but also anticipated a comeback in 2023 collections. Bullock’s budget anticipated ending the biennium with a $251 million-dollar positive balance,cannabis drainage system well above that required by state law. It included modest increases in education and health along with a $499 million-dollar infrastructure package, largely funded with federal dollars. During the 2019 legislative session, Bullock had championed a modest $30 million-dollar investment in early childhood education only to see it go down in flames over disagreements between Republican legislators and the powerful union representing public school teachers, the Montana Federation of Public Employees . This time around, he had reduced his ask to 10 million. In contrast to the Bullock budget proposal, candidate Gianforte released a 16-page glossy pamphlet entitled The Montana Comeback Plan. Nothing in it came as a surprise to those who had followed Gianforte’s career trajectory as a businessman turned politician.6 “Bringing back good jobs” was highlighted in Gianforte’s vision, which is consistent with longstanding Republican hopes to return to Montana’s resource extraction led economy. This is presumably possible by reforming state agencies and in order to “move projects forward.” The campaign took place during the pandemic, which altered the atmospherics considerably. Governor Bullock had instituted a mask order, anathema to most Republican voters and politicians. “We need to get our economy going again and we need to get Montana open for business” was a key line in candidate Gianforte’s stump speech. Gianforte came into office promising to cut 100 million from Bullock’s budget, fulfilling his promise to “hold the line” on spending. This was tempered most importantly by the infusion of COVID funds.

Gianforte’s proposed general fund budget included a 1.66% increase over the next two years — a 2.32% decrease in the upcoming fiscal year and a 3.98% increase in the second. Making good on a widely broadcasted campaign promise, the budget also proposed 50 million in tax cuts . This included lowering the top marginal individual income tax rate from 6.9% to 6.75%. In a press conference announcing the plan, candidate Gianforte also promised to continue this tax cutting exercise in the future. “This is just a first step. As we find greater efficiencies in government and our economy continues to grow, we will continue to cut taxes.” Democrats responded that they wanted any tax cuts directed towards middle- and lower-income Montanans: their bills to make progressive tax reform were all tabled in committee. Gianforte’s budget also proposed eliminating the business equipment tax for roughly 4,000 businesses in the state by raising the exemption from $100,000 to $200,000. As reported by Holly Michels, “Heather O’Loughlin, the co-director of the left-leaning Montana Budget and Policy Center, said Thursday the income tax cut would equate to a reduction of about $1,314 in the tax bill for the top 1% of those in the state, or people that earn $509,000 or more annually. An analysis of the proposal by the center and Institute on Taxation and Economic Policy found that people earning from $40,000-$63,000 would see a reduction of about $14.”One of the more controversial of the new governor’s proposed tax cuts was exempting businesses “that create long-term jobs in Montana” from capital gains taxes from the sale of employee-owned stock. This was particularly controversial given the rather widespread view that this proposal is directly inspired by Gianforte’s displeasure at having to pay this tax himself when he sold Right Now Technologies, located in Bozeman, to Oracle for 1.8 billion. Not surprisingly, progressives to moderates to no small number of principled conservatives cast this as a sweetheart deal for Gianforte and his well-heeled friends. Equally unsurprising is that his defenders argued that this tax cut would attract new investment and thus new and good paying jobs to Montana. Some of the proposals in the governor’s budget did attract bipartisan support. Prominent amongst these was a proposed 25% increase in funding for the program that helps seniors and disabled veterans offset increasing property taxes and a proposed $2.5 million to augment starting pay for public school teachers. Democrats would have favored larger budgetary commitments to both, offset by progressive taxation, but ended up voting for what they could get. Reminiscent of Governor Bullock’s passion for early childhood education, Gianforte has displayed passionate promotion of his Healing and Ending Addiction Through Recovery and Treatment Act. His budget included $23.5 million toward this initiative to be paid for by a combination of leveraging federal dollars and redirecting $6 million from the revenue expected to be generated from taxing the sale of recreational cannabis beginning in January 2023, along with funds from a major tobacco settlement. I say redirected because the recreational marijuana citizen referendum that passed in November 2020 directed all proceeds from taxes to be spent on the protection and expansion of public lands.