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Reproductive health researchers and practitioners have documented that perceptions of the risk of pregnancy and of STIs shape sexual and reproductive behavior in addition to pregnancy intention and access to contraceptive methods. These perceptions and behaviors are partly the result of individual tolerance for risk and uncertainty. Tversky and Kahneman instigated a robust area of inquiry by first describing how risk preferences shape choices and behavior. These same theories of how humans make decisions under uncertainty may shed light on differences in reproductive outcomes. Economists concerned with explaining behavior, including wealth accumulation, focus on measures of economic preferences that govern differences in decision-making. These preferences, including the willingness to assume risk, strongly predict financial behavior and outcomes. Analyses that examine how risk preferences may extend beyond financial behavior to explain behavior in other domains, including health, appear less frequently in the literature. A particularly unexplored area of research concerns how risk preferences affect decision-making surrounding reproduction, contraceptive behavior, and sexual risk taking, where intention-behavior inconsistencies are widely acknowledged. This paper tests the hypothesis that the propensity to take risk manifests not only in the financial decisions commonly studied by decision theorists, but also in less-well studied choices that affect reproductive health. I explore whether individual measures of financial risk tolerance predict important reproductive outcomes of sexual and contraceptive behavior using data from the 1997 cohort of the National Longitudinal Survey of Youth . National and international public health priorities include reduction of unintended pregnancy. Defined as pregnancies that are mistimed or unwanted, unintended pregnancies comprised 45% of all pregnancies to women aged 15-44 in the United States in 2011. Half of those pregnancies ended in abortion.

Epidemiologic literature, moreover,cannabis growing supplies reports associations between unintended pregnancy and negative health and mental health outcomes for mothers and children. Women who experience unintended pregnancies also are more likely to report perceived stress, low social support, and depressive feelings.Evidence further suggests a connection between unintended pregnancy and risk behaviors during pregnancy, such as smoking and alcohol drinking. It is estimated that unintended pregnancies cost the US more than $20 billion per year in expenses for births, abortions and miscarriages. Unintended pregnancies, like many health outcomes, are differentially experienced in the population. They concentrate among women of color and low-income women. Young age, low education, previous pregnancies, non-married status, and living in an urban neighborhood, explain some but not all of the concentration of unintended pregnancy among poor and minority women. Nonuse or inconsistent use of contraception is common among women at risk of unintended pregnancy, meaning those sexually active with a stated desire not to get pregnant.Reproductive health literature reports inconsistencies between intention and behavior regarding contraceptive use and pregnancy. A California study following young women who initiated a new method of contraception and who reported not wanting to be pregnant within a year found high rates of discontinuation over the year. An analysis of a nationally representative dataset found that 25% of non Hispanic black women, 16% of Hispanic women, and 14% of non-Hispanic white women did not use contraception despite risk of unintended pregnancy. Additional studies have shown disparities in contraception use for non-Hispanic black and Hispanic women. These differences may result, at least in part, from lack of information about method availability, especially long acting methods. Research on contraceptive attitudes has reported fear of side effects and mismatches of desired method features to selected method features to be a reason for nonuse. Other research suggests that provider biases may also lead to disparities in information: in one such study, providers of contraceptive counseling recommended IUDs to low-income women of color more often than to white women.

Misperception of pregnancy risk may also result in reduced contraceptive use and subsequent unintended pregnancy regardless of knowledge of available methods. A study of family planning patients found, for example, that underestimation of the likelihood of conception predicted unprotected sex. Foster et al. found that nearly 46% of women engaged in unprotected intercourse in the past three months underestimated the risk of conception.A study of women seeking abortion services found that the majority of women had an inaccurately estimated the risk of pregnancy prior to conception. Structural and psychosocial factors also affect unintended pregnancy risk. Relationship factors, including reproductive coercion, drive contraceptive decision-making and ability to use contraception even in contexts where pregnancy is not desired. A qualitative study exploring determinants of inconsistent use found that eroticism of unprotected sex and the risk of conception was a powerful explanatory factor. Additionally many women, particularly young, poor, and uninsured women, lack access to reproductive healthcare. Micro economists have long attempted to explain differences in choices given equal information. Much of this work falls under the rubric of “behavioral economics,” the study of decisional biases and preferences. Primary questions in the field include: what leads people to behave in ways inconsistent with intentions? Given that differences in information alone unlikely explain differences among groups in unintended pregnancy, looking to behavioral economics for suggestions of other determinants seems warranted. Risk preferences, frequently studied in social science, are strong determinants of financial decision-making, including investment and savings. While elicitation methods vary, a common approach to assess preferences includes a series of questions assessing willingness to take gambles with lifetime income. People willing to take fewer gambles are generally deemed risk averse and those more willing to take gambles are risk tolerant. Behavioral economists have argued that risk preferences in humans arise from loss aversion or the tendency to risk more to avoid a loss than to realize a gain even if the prospective losses and gains are equal.

The argument has garnered credibility in comparison to a standard economic model, which assumes “rational agents” who make choices to maximize utility and who would, therefore, exhibit indifference in choices between equal loss and gain.One seminal study found that a measure of financial risk tolerance predicted risk behavior including smoking and drinking. Barky validated the now widely used measure of risk preferences in a nationally representative sample in the Health and Retirement Study . Risk aversion has also been linked to cancer screening behavior , smoking, heavy drinking, obesity, and non-use of a seat belt. Despite results from the above studies, and the widely-held belief that loss aversion and risk preferences affect choices under uncertainty, surprisingly little attention has been paid to these measures as determinants of sexual and reproductive behavior. In the best example of this limited literature, Schmidt hypothesized that when the risk of pregnancy appears highly uncertain, risk preferences help explain variability in timing of childbearing . She found risk tolerance correlated with earlier childbearing at young ages and earlier timing of marriage. She suggested that the association between early childbearing and increased risk tolerance may be a product of less contraceptive use, although she did not directly test this connection. With exception, much work argues that risk preferences vary with age, income and gender. Gender differences in risk aversion, with females expressing greater aversion, have been hypothesized to arise from different reproductive investment strategies. A few studies have shown that risk tolerant women more likely delay marriage,cannabis indoor growing indicating the apparent importance of risk tolerance to demographic behavior. Schmidt found that the effect of risk tolerance on fertility timing varied by marital status, such that for both married and unmarried women, higher risk tolerance predicted early birth at young ages. Among married women it was also associated with delayed fertility later in life. In this paper, I ask whether propensity to risk-taking in financial decisions affects reproductive behavior. Using data from the 1997 cohort of the National Longitudinal Survey of Youth , I examine several outcomes relevant to reproductive health: sex with high-risk partners, number of sex partners, consistency of contraception use, and effectiveness of contraceptive method. I conduct stratified analyses for contraceptive consistency and effective method use among unmarried and non-cohabitating women and among married or cohabitating women. Number of sexual partners. Respondents were asked the number of partners they had sexual intercourse with since the last interview. As this variable was highly right-skewed, I truncated responses above five to greater than or equal to five partners. Consistent contraceptive use. I derived a measure of consistency of contraceptive use from several questions in the survey. Respondents are first asked the number of times they had sex and then the number of times they used a condom or other birth control. If they could not recall the number, they were asked the proportion of the time that they used a method.

Combining the frequency of intercourse and condom or birth control use questions allowed me to create a percent condom or birth control variable. This is variable categorized into nonuse , inconsistent use , and perfect consistent use . I recoded anyone that reported sterilization as a consistent user even if they reported a lower birth control usage percent. Contraceptive method type. Respondents were asked: “ thinking of all the times that you have had sexual intercourse since the last interview, how many of those times did you or your sexual partner or partners use a condom or female condom?” if they replied 1 or greater, I coded them as using condoms. The following question assessed additional contraceptive use asking which “one of these methods did you or your partner use most often, either with or without a condom or female condom?” Respondents could select one of the following: withdrawal , rhythm , spermicide , diaphragm , IUD , morning after pill , birth control pills, Depo-Provera or injectables, Norplant, patch or ring , cap or shield , had vasectomy or tubal ligation, or no other method. Since the questions were asked separately, condom use could be in addition to or in absence of other contraception use. Contraceptive method effectiveness. I grouped contraceptive methods together based on typical use pregnancy prevention effectiveness rates using categories of low effectiveness , medium effectiveness , and high effectiveness . Participants were coded as medium effectiveness with condoms only if condoms were reported as the only method. Confounding variables were selected a priori based on literature as characteristics that would affect both risk aversion and sexual behavior and included: age, race/ethnicity, education, religion, marital status, parity, insurance, poverty. Age serves as an important control variable, as both risk aversion and fertility intention and contraceptive behavior change with age. Age was assigned at year of risk preference measurement and ranges from 26-32. Race/ethnicity information was recorded at entry into the cohort in 1997. Respondents self-reported race ethnicity, which I divided into Hispanic, non-Hispanic white, non-Hispanic black, and mixed race/other. For multivariable models, I dropped the mixed race/other respondents due to positivity concerns. Education influences risk perception as well as fertility timing and method choice. Risk aversion has been shown to decrease with later schooling and age. I categorize educational attainment into the following categories: some high school, high school degree, some college, and college degree or higher. In addition to age, reproductive history is an important predictor of current reproductive behavior. I therefore include a control for parity . Unintended pregnancy may carry different meaning in the context of being partnered and not partnered. While there is evidence that partnership may affect risk preference and also sexual behavior, I would not expect a different relationship of risk preferences to high risk sex by partnership status. Partnership status can be thought of as an effect modifier to the relationship between risk preferences and contraceptive behavior. Additionally relationship context and power may influence ability to use contraception. Marital status is categorized as: never married/not cohabitating, never married/cohabitating, currently married, and widowed, separated or divorced. While each wave of NLSY97 contains detailed information on contraceptive method use and type, no wave measures pregnancy intention. I cannot, therefore, attribute nonuse to wanting pregnancy or use to wanting to avoid pregnancy. I attempt to indirectly assess intention through fertility expectations. First I include a measure of fertility expectations assessed with the following question: “In five years, what is the percent chance that you will have child?” Respondents report a range of 0-100%. I code ‘don’t know’ responses as 50%. While expectations may differ from intention, they have been shown to access the same construct .

Specifically, we assessed aspects of the informed consent content that participants found most and least informative, and explored whether this differed by HIV serostatus. We also examined the efficacy of our informed consent process by assessing whether participants thought the information presented was consistent with what they experienced during the study.Participants enrolled in ongoing studies at the HIV Neurobehavioral Research Program completed a questionnaire regarding their experience with the informed consent process. The questionnaire was administered to participants immediately after enrolling as well as after completing their study visit.All participants who came to the HNRP between May 5, 2017 and July 11, 2017 were invited to complete the consent questionnaire. One participant declined due to the paperwork burden of the primary study in which they were enrolled. The participants who chose to enroll in the present study were enrolled in a wide variety of both cross-sectional and longitudinal studies ranging in complexity and length of assessment that involved completion of self-report measures , neuropsychological testing, and participation in clinical trials designed to test the efficacy of new drugs for improving cognition and physical outcomes among PWH.A recruiter from the HNRP was responsible for presenting the informed consent information for this study to our existing HNRP participants. On average, recruitment staff have been with the HNRP for 9.8 years and have an established professional relationship with study participants. Our recruitment staff adhere to a standardized informed consent process as follows. A recruiter sits across from the participant in a quiet screening room to ensure privacy during the consenting process. Typically, only one recruiter is present with one participant, unless particular expertise is needed from additional staff. In this case,pots for cannabis plants and with the participant’s permission, another recruiter may be brought in to assist and offer additional information.

The consent process involves conveying study information to a prospective participation and usually requires approximately 30-minutes, but the time can vary depending on the complexity of the study. During the informed consent process, the recruiter gives the prospective participant a copy of the “Experimental Subjects Bill of Rights” to review, which is required by California state law when enrolling in biomedical research that involves medical experimentation. The recruiter explains the HNRP’s privacy practices and data confidentiality procedures, including that participants’ identifying information is stored securely and separately from information collected for the study and only specific research staff have access to that information. Next, the recruiter reviews each paragraph of the IRB approved study consent document with the prospective participant. At the end of each consent section, the recruiter asks if the prospective participant has any questions or concerns. Across studies hosted by the HNRP, the consent documents contain language required by the IRB, standard HNRP practices, and study specific information resulting in documents that range from 4 to 17 pages. Lastly, participant’s knowledge of the study is tested with a validated assessment tool , which is used to evaluate understanding of the study purpose and procedures, including possible risks and benefits.In research studies, it is the responsibility of the researcher to ensure that the consent process is implemented correctly. While decisional capacity questionnaires are common, particularly in populations with higher risk of impaired decisional capacity, it is not common practice to solicit feedback from participants with regard to the informed consent process. Research participants at the HNRP, a research center with multiple years of working with PWH and dedicated research staff with experience taking potential research participants through the consent process, found the consenting process, on average, to be extremely informative and extremely consistent with what they did during the study. This indicates that the traditional informed consent process involving a face-to-face discussion with a prospective research participant combined with a written consent document can be successful. Additionally, several different themes were endorsed as “most important” and the most common answer for what was “least important” was that everything was important.

This would indicate that although some participants do not find all portions of informed con sent to be useful, some participants do; including the goals of the study, procedure, risks, and information about protection of confidentiality. This may also suggest the consenting process should be tailored to individual participants, and participants should be able to choose how much additional information they are provided beyond the required information. We did not observe differences in response to any of the questions by HIV status. Unfortunately, there is little research examining what PWH value most from research study participation, the informed consent process in general, or in comparison to HIV-negative persons to compare with our findings. One review examining barriers to participation in HIV drug trials found societal discrimination and distrust of researchers, among other things , were barriers to participation . Based on this review, as well as historical and ongoing stigma toward PWH, confidentiality may be something PWH highly value in research studies. However, in this study, we did not observe HIV serostatus differences in proportion of participants reporting confidentiality to be “most important.” The majority of PWH participants who filled out the consent questionnaire have been in multiple studies at the center and, on average, have completed more study visits than HIV-negative participants. The center is also actively involved within the community. Therefore, participants prior experience with the center may have had a higher level of trust going into the informed con sent process, which may have influenced their responses. Additionally, confidentiality is likely valued by many individuals regardless of HIV status, which also may be why we did not observe any difference by HIV serostatus. While this study adds valuable insights into informed con sent literature, there are limitations. First, the center in which this study took place is an established community research facility with highly trained staff experienced both working with this study population and consenting participants. Studies without these resources, trained staff,cannabis flood table or established study enrollment practices may have difficulty with establishing the practices described in this study. Second, participants in the study were already willing to come in for the research study, so their responses may not accurately reflect what the general population values from the informed con sent process or what aspects of the informed consent process may persuade individuals that are not willing to participate in research. Moreover, we were unable to examine responses by other variables of interest due to sample size restrictions.

Future studies should aim to assess participants’ preferences with respect to information presented during the informed consent process and how those preferences differ at the individual level. Lastly, not all participants provided responses to every question, particularly the open-ended response questions, which may be due to participants not having feedback to provide or found the open-ended response questions to be burdensome. Asking a more specific question or interviewing participants about what changes they would suggest for improving the informed consent process may have elicited more responses.This study demonstrates that implementing the informed con sent process with trained staff can be successful. Participants reported the experience as both informative and believed what they were told during the consent process was consistent with what they experienced during the study. This is in line with systematic reviews that have found that the most effective way to improve understanding of the informed consent was to have a one-on-one discussion with study participants . This would suggest that IRBs and researchers should be invested in the training of those who implement the informed consent process as well as monitor how the informed consent is presented to research participants. Furthermore, our recommendation to researchers working with PWH is to view the informed consent process as an opportunity to build trust, educate and show a true appreciation for the participants’ time, which will hopefully encourage continued participation in research.There are opportunities to continue to improve the informed consent process, and there have been recent updates to the “Common Rule”, which will influence the presentation of the informed consent moving forward .For example, a recent meta-analysis found that participants’ understanding of portions of the informed consent ranged from 52–76% . Even more discouraging is that Tam et al. found that the proportion of participants who understood the informed consent process has not improved in the past 30years. In hopes of improving informed consent to make it more engaging and understandable, two studies compared a simplified and concise informed consent with a traditional consent form. Both studies reported that participants found the shorter informed consent more engaging, and one study reported that comprehension was equivalent to the standard consent form whereas the other study found improved understanding with the shorter consent form . Another study found that implementing a fact sheet and engaging in a question and answer feedback session improved open-ended questions to assess understanding of the informed consent . Additionally, in a study that compared ways to assess understanding of the informed consent, found that commonly used forced choice or self-report questionnaires may overestimate the level of understanding of the informed consent as recognition of information does not ensure comprehension of information .

Therefore, free-response questions may be a better measure of comprehension indicating that IRBs that review decisional capacity questionnaires and researchers who are trying to improve the informed con sent process must be mindful of how understanding of the informed consent is assessed. As research moves more toward digital studies and trials where the in-person interaction is not feasible, as we are currently facing with the COVID-19 crisis, it will be important to design the consent process that can build upon elements of existing successful consent models. Standards of practice and design features for digital consent, also known as eConsent, are in development. Some groups have begun to create open-source and customizable tools for low-risk, mobile-mediated research , which has been used in patient populations . Digital studies and eConsents are advantageous as they allow for use of multimedia methods , which can be standardized and reviewed by an IRB to ensure that participants are receiving the necessary information. Studies that have examined multimedia methods have shown that they successfully relay information to participants, with some studies reporting that use of video or PowerPoint is related to an increase in engagement and com prehension . Additionally, as more participants want their study results returned to them, digital consent could allow participants to tailor the consent to their personal preferences and select which data they would like access to. However, there are additional considerations when designing eConsent . For example, in a focus group study of patients underrepresented in research, participants overall found eConsent easy to use and interesting; however, minor ity and rural participants raised concerns about accessibility, trust, and confidentiality . We anticipate our findings demonstrating an engaging informed consent process can be adapted for digital deployment for populations that value privacy and confidentiality such as PWH.The way that people make decisions is of fundamental importance to epidemiologists seeking to understand health behavior. Eating, substance use, physical activity and sexual behavior result in differential health trajectories over the life course. The fact that unhealthy behaviors persist despite knowledge of risk has perplexed public health practitioners and led them to consider whether insights might be gleaned from behavioral economics – a field committed to explaining why humans act in ways inconsistent with rational self interest. Sexual and reproductive behaviors are particularly relevant to study in the context of behavioral economics because the results of risky sex have delayed and uncertain consequences to health, such as pregnancies or STI acquisitions. Additionally, reproductive health researchers have long noted that sexual and contraceptive behavior may deviate from women’s stated intentions about pregnancy. The field of behavioral economics is rising in popularity and quickly expanding into public health and social epidemiology. At the intersection of economics and psychology, research in this area attempts to explain human behavior. In particular, behavioral economics arose out of acknowledgement that standard economic utility maximization models poorly explain observed behavior, as people often deviate from purely “rational” choices. If people act differently than we would predict from their apparent preferences, does that make them irrational?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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