Monthly Archives: July 2023

A laboratory-based alcohol challenge was then used to establish an individual’s LR

The contemporary anthropological approach to childhood is strongly influenced by child standpoint theory that aims at an account of society from where children are socially positioned and in which they are not passive social “others” but agentive participants in social life, hence co-constructors of social knowledge and by extension of knowledge generated by research. In particular, anthropologists have taken up the idea that “children have agency and manifest social competency” . Guided by these concerns, we will focus specifically on self-cutting among a group of adolescents who have been psychiatric inpatients; by attending to experience and subjectivity articulated in the youth’s own voices, we will come to understand self-cutting as a crisis of agency enacted on the terrain of their own bodies. There is scant literature on how young people conceive and understand mental health , let alone experiential accounts of adolescent mental illness from the standpoint of the child . In addressing the experience of cutting among a clinically defined and diagnosed group of youth, our stance is not to fall prey to accepting a false dichotomy between ethnographic and clinical sensibilities; that a young person is following a regimen of psychotropic medication is as much an ethnographic as a clinical fact, and that a young person lives in a fragmented family environment may have clinical as well as ethnographic implications. Self-cutting can be understood as a troubling symptomatic behavior or as a creative struggle for agency and may exhibit elements of both pathological obsession and ritual transformation, but in either case it is an enactment of a vexed relation between body and world.This discussion is based on SWYEPT,plant growing rack our study of youth in New Mexico who were inpatients in the state’s flagship Children’s Psychiatric Hospital at the University of New Mexico . New Mexico is a state whose total population according to the 2010 United States Census was 2,059,179.

In 2010, according to the US Census Bureau’s categories, by race the largest population proportions were designated “white” and American Indian/Alaska Native , with 23 federally recognized Indian tribes in the state comprising various groups of Pueblos, Navajos, and Apaches; other racial categories were minimally represented. By ethnicity, Hispanics or Latinos accounted for the largest single block , while among non-Latinos the largest blocks identified themselves as generically white or American Indian . New Mexico is one of the poorest states in the nation. According to the US Statistical Abstract, as of 2008 the median household income was $43, 508 or 44th among the 50 states, and the proportion of persons living below the poverty level was 17.1% or 5th in rank among the states. New Mexico ranks as one of two states within the United States hardest hit by child poverty, with the rate of 30% in New Mexico . Relatedly, home foreclosures have also been inordinately high. Along with poverty comes a serious drug problem, with parts of the state severely afflicted by heroin and methamphetamine use, and the presence of violent gangs, with one anti-gang website listing 178 in the Albuquerque area. The SWYEPT study examines cultural meaning, social interaction, and individual experience among adolescent patients and their families, with the long-term goal of producing knowledge of broad use to those concerned with the treatment of adolescents suffering from mental illness in the context of significant cultural differences. The aspects of this knowledge include: types of problem, illness, or psychiatric disorder experienced by afflicted adolescents; trajectories of adolescent patients from the community into treatment and back into the community; patient experience of therapeutic process and family response to that process; alternative and complementary resources brought into play by families on behalf of patients; difference between the experience of afflicted adolescents and that of counterparts who have not been diagnosed or treated for emotional disturbance. Notably for present purposes, ours was not explicitly a study of self-cutting or self-harm, but cutting emerged within the ethnographic interviews as a theme deserving of the particular attention we devote to it here.

We recruited participants for the study with the assistance of three clinicians at Children’s Psychiatric Hospital who referred to us patients aged 12–18 they judged as not so severely cognitively disabled or developmentally impaired as to be unable to participate in interviews and not so emotionally fragile or clinically vulnerable that their participation would be unduly stressful. We obtained informed consent from youth and their parent or primary guardian based on these referrals, recognizing the ethical responsibility of respecting the vulnerabilities of individual patients and the need for continued rapport in the relationship between therapists and families, as well as the importance of our respect as researchers for the clinical expertise of the referring therapists. All participants entered the project as inpatients at CPH. Assisted by a team of graduate student ethnographers and clinically trained diagnostic interviewers, we conducted ethnographic interviews covering life history and experience with illness and treatment with the young people and their primary parent/guardian three times at approximately six months’ intervals.During this period, we also conducted the child version of the Structured Clinical Interview for DSMIV , a clinician-administered research diagnostic interview , the Adolescent Health Survey , and the Youth Self Report and Child Behavior Check List for children and their parent/guardian respectively. Although initial interviews occasionally took place in the hospital, it was rare for a participant still to be there at the time of the second and third ethnographic interviews. Yet it was not always the case that they were at home, since it was not uncommon for them to be placed instead at another treatment facility of in-treatment foster care. This often led us far afield from the hospital in Albuquerque, such that our ethnography ranged across the entire state of New Mexico and occasionally beyond. In this respect, our work was not strictly speaking a clinical ethnography in the sense of ethnography primarily situated in a clinical context that focuses on the institutional cultural milieu and interactions among patients and staff . Our focus was instead on the experience and subjectivity of the troubled youth along their trajectory back to their families, back again to the hospital, to other institutions, or to treatment foster care.

Whenever possible we conducted interviews in participants’ homes both for their convenience and so that interviewers could conduct ethnographic observation of the domestic environment and neighborhood setting. Our primary ethnographic locus was thus the family rather than either the clinic or the community, following the methodological premise that families are the principal formative inter subjective locus for adolescents and for the mentally ill, no less for mentally ill adolescents . Given these caveats, our work could be described as clinical ethnography in a different sense, insofar as it synthesizes clinical and ethnographic sensibilities and approaches . This means not only a balanced attention to diagnostic profile and life experience, but recognition that narrative data generated by diagnostic and ethnographic interviews can be complementary by identifying different kinds of experientially relevant events and themes . The participants constituted an ethnically diverse group including New Mexican Hispanics and Latinos of Mexican descent, Anglo-Americans, and Native Americans. While an ethnically diverse group of youths whose economic and residential conditions vary, the life situations of most are shaped by features of structural violence . Of the 47 adolescents who participated in the research, 57% reported having cut or harmed themselves at some time, comparable to 61% among adolescents hospitalized for psychiatric problems in a previous study by DiClemente, Ponton, and Harley in another North American location. This rate can be understood against the background of a reported rate of 1–4% of self-injurious behavior in the general population ,2 tier grow rack while the rate among adolescents has been placed by various researchers as ranging between 1 and 39% . Let us now take a closer look at cutting among several of these young people in order to get a sense of how they talk about it and what it means to them, its place in the overall configuration of their experience, and the similarities and differences among them that might allow us to characterize cutting as a crisis of agency.SWYEPT participants represent a wide range of diagnostic profiles from a clinical standpoint and a diversity of life experiences from an ethnographic standpoint , but our purpose here is to present a series of vignettes that summarize the range of experiences and utterances centered around the phenomenon of cutting. Lacking space to present full case studies, we briefly examine how they describe their own cutting behavior and what that behavior means in the context of their troubled lives and in the constitution of their subjectivity. We have selected these instances and interview excerpts based on the young person’s relative ability and/or willingness to elaborate on how cutting has been a part of their lives. Each profile includes the biographical and ethnographic context of the young person’s experience, their diagnostic and functional status, medication history, their own experiential commentary, and a brief interpretative commentary. We first met Maria, a Hispanic 17-year-old female, when she was living in a ranch style home in a lower-income neighborhood that was bustling with the activities of her extended family and infant son.

During the course of the study, she later lived in an apartment with her son, boyfriend and mother, moving again two years later into a very small apartment with her toddler. Maria was the youngest of three daughters to a single mother with multiple boyfriends and father figures. She bore the physical and emotional marks of a major arm injury in mid-childhood from a car accident in which her extremely drunk mother was driving, as well as enduring severe and catastrophic stressors related to abuse, neglect, and sustained psychosocial instability in her early life. While Maria is close to her older sisters, they were not a significant source of personal or financial support and held an anti-psychiatric opinion about how Maria did not need medication. She relayed that she had to “grow up fast” since her mother had severe problems with alcohol. Indeed, her mother’s alcohol abuse severely affected their relationship. Maria was sexually assaulted at the age of 11 by her mother’s ex-boyfriend, which disturbed her greatly; she marks this as a time of pain and confusion. She grew up believing her adoptive father was her biological father, but when Maria was 15, her father went to fight in Iraq. While in Iraq, he wrote her two letters saying that she was not his biological daughter, and he was getting remarried and could not support her financially or otherwise. She said she was devastated by this, by the fact that he would “cut me out of his life.” Maria responded by cutting on herself. In this instance, we have a patent metaphoric and literal alignment of psycholinguistic and palpablebodily expression. These events have created major emotional and psychiatric challenges for Maria. When Maria began the study, she had been admitted for a suicide attempt and ongoing postpartum depression. Prior to being admitted, she had an eating disorder, along with self-harming and abusing cannabis for two years. Her SCID diagnosis shows mood disorder due to a general medical condition, postpartum major depressive disorder, brief psychotic disorder related to postpartum depression, separation anxiety disorder, PTSD, alcohol abuse, cannabis dependence, and an eating disorder.For Maria, cutting was an intended if fraught means of communication in the face of the emotional pain of abandonment. This was not the first time she cut; her practice began at age 11 following the sexual assault by her mother’s boyfriend. In the narrative excerpt above, her motivation was explicit and her logic clear when her father proved unresponsive to her telephone call. In semiotic terms, cutting was a concrete bodily hurt that stood as a sign, the object of which was her emotional hurt, and the interpretant of which was her need for emotional connection. Along with bulimia that resulted in weight loss and “attention from guys,” it formed a complex related to self-esteem and the need for intimacy from males in the context of a close but troubled relationship with a mother marked by alcoholism.

Odds ratios and 95% confidence intervals are shown for significant comparisons

In our studies, immuno regulatory effects on human monocyte-derived DC were observed at lower THC concentrations , more akin to peak levels that occur in the blood of marijuana smokers , and had no effect on cell recovery or surface staining by Annexin-V. Instead of apoptosis, we observed broad-ranging effects of THC on the expression of MHC class II and costimulatory molecules, and the capacity for antigen uptake and IL-12 production. Furthermore, DC that had been exposed to THC during their in vitro differentiation were impaired in their capacity to activate T cells – including both CD4+ and CD8+ responders. T cell proliferation and the acquisition of a memory/effector phenotype were both impaired as was the release of Th1 cytokines. These effects of THC on the capacity for monocyte-derived DC to stimulate T cells are almost identical to the direct effects of THC on T cell activation , suggesting a coordinated immuno regulatory effect. It is interesting that other immuno suppressive factors, including IL-10 and TGF-β3, share this capacity to act in a coordinated manner on both DC and T cells . As is the case with IL-10–/– knockout mice , CB1–/–/CB2–/– double-knockout mice exhibit elevated levels of activated T cells and respond to antigen challenges by producing a higher number of activated effector cells and stronger IFN-γ responses . Collectively,vertical marijuana growing systems these findings suggest an intrinsic role for endocannabinoid signaling as a homeostatic regulator of T cell activation. There are a number of critical features that develop during the transition from monocytes into DC that enable them to activate antigen specific T cells .

Among these are high levels of antigen expression in the context of cell-surface MHC, the upregulation of adhesion and costimulatory molecules, and the elaboration of immuno stimulatory cytokines. Our studies suggest that cannabinoid receptor activation impacts on all of these. Exposure to THC during the differentiation of monocyte-derived DC impaired antigen uptake and prevented the normal upregulation of MHC class II. These findings are consistent with earlier reports by McCoy et al. , where THC was found to impair the presentation of whole hen egg lysozyme, which required uptake and processing, but not the presentation of its immuno dominant peptides, which bound directly to existing cell surface MHC. Dendritic cells that present antigen in the absence of adequate costimulatory molecules cannot fully activate T cells and may contribute to the development of T cell anergy . The inhibitory effects of THC on the expression of CD40, CD86 and other costimulatory molecules likely contributed to the failure of THC-DC to stimulate T cell proliferation. Finally, the relative production of IL-10 and IL-12 by DC plays a central role in their capacity to activate either Th1 or Th2 responses. In our studies, THC-DC produced only limited amounts of IL-12 but normal levels of IL-10. Lu et al. reported a similar suppressive effect of THC on the expression of MHC and costimulatory molecules and on production of IL-12 by mouse bone marrow-derived DC that had been infected with Legionella pneumophila. While these findings add to other compelling evidence that cannabinoids can exert important immuno suppressive effects, clinical evidence that marijuana smoking significantly impairs immune function in humans is limited. One explanation may be that inhaled THC never produces sufficient systemic levels, or that exposures may not be sustained for a sufficient period of time. to mediate immuno suppressive effects . Another explanation may be that the effects are short-lived or counterbalanced by the presence of other immune regulatory factors.

The study of purified cells in vitro culture does not adequately replicate the complex environment that occurs during an immune challenge in vivo. In this study we hypothesized that the processes of DC activation and cytokine exposure that occur in response to an infectious challenge might modulate the impact of THC. Exposing DC and THC-DC to heat-killed and fixed SAC for 18– 24 h enhanced their capacity for Tcell activation; an effect that was more pronounced with THC-DC than with control DC. Adding IL-12 and IL-15 to the DC:T cell co-culture also enhanced T cell activation and proliferation, but these effects occurred equally with control and THC-DC. Furthermore, these cytokines promoted T cell proliferation and cytokine production even in the absence of stimulation by DC . However, the addition of IL-7 to DC:T cell co-cultures had a dramatic effect on T cell proliferation, maturation and cytokine production that was restricted in part to co-cultures containing THC-DC. These studies suggest that the immuno regulatory effects of THC might be counterbalanced by thepresence of a combination of DC activating signals and the production of cytokines by other cell types present in the local immune environment. In summary, our experiments demonstrate that human monocytes express functional cannabinoid receptors, even if they are not detectable on the cell surface, and that exposure to THC alters their capacity to differentiate into immuno stimulatory DC with prominent effects on antigen uptake and presentation, expression of costimulatory molecules, and production of IL-12. The end result is the generation of DC that fail to stimulate T cell proliferation or promote maturation into functional effector/memory T cells. While the effects are relatively potent when studied in isolation in vitro, there may be a number of immunoregulatory factors that could counteract or moderate the impact of cannabinoid exposure in vivo. The functional role that marijuana smoking has on host immunity and the response to immune challenges in vivo remains to be clarified.Mobile technologies have the potential to revolutionize treatment programs for adolescent substance users. Current practices center on cognitive-behavior altherapies in which youth engage in group therapy, and which rely on retrospective assessments to self-monitor and identify relapse triggers.

Cell phones expand the feasibility and reach of ecological momentary assessment ; events are recorded in near real-time as they occur to elicit ecologically-valid data, reduce reliance on autobiographical memory and reduce recall biases . Mobile technolo-gies also enable ecological momentary interventions , for example, as tested in cell phone-based smoking cessation interventions for youth . Before EMI can be fully realized in supporting drug treatment, a greater degree of granularity is needed in understanding daily behaviors, social contexts, and internal states in order to optimize the personalization inherent in EMI. To date, most information on substance use and contextual factors has been captured through retrospective assessments. Cell phone-based EMA studies in treatment settings are crucial for EMI development, particularly for adolescents given the prevalence of substance use problems, especially in Latino youth, and the high use of cell phones in adolescents’ daily routines . Higher levels of alcohol and drug use across multiple categories have been shown for Latino youth in the 8th and 10th grades compared to African American and Caucasian youth . Moreover, Latino youth with substance use disorders are less likely to receive treatment than White adolescents . In this vein, we pilot tested CEMA of alcohol, marijuana, and other drug use in a sample of mostly Latino youth in outpatient substance abuse treatment. We previously reported high compliance rate for completing CEMA reports . Here we explore contextual factors that were assessed along with AOD use in order to fill gaps in the literature related to the context in which adolescent AOD use occurs. We highlight practical applications of our findings for the development of EMI. Our pilot study tested different CEMA strategies that would likely be used in a treatment setting, including prompted daily recall and event-based reporting. As a secondary aim, we examine if context related to AOD use that is reported during daily recall differs from context reported through event-based reporting. To the best of our knowledge, this has not been explored in prior studies. First, we summarize AOD-related contextual factors that have been evaluated in prior adolescent studies and that are evaluated in our study. We hypothesize similar findings in our sample,vertical rack system grow although we do so with caution. Prior research has mostly focused on social contextual factors ; this study makes a valuable contribution to the literature by giving equal attention to other contextual factors and affect. Moreover, prior findings are not generally based on Latino youth and are mostly based on retrospective assessments. Findings from EMA studies are specified as such.Numerous studies have shown associations between AOD use in adolescents and AOD use in their peers , as well as peer socioeconomic characteristics . What warrants further study are nuances in types of peer relations that relate to AOD use.

For example, minority youth reported alcohol and marijuana use “among young people they knew”, relative to other substances in a qualitative study . Similarly, a study of young Australians found the majority of drinking episodes to occur with “close friends” .Alcohol and marijuana use have been more frequently reported by youth on weekends versus weeknights and after school relative to time periods before or during school . This is in line with the notion that alcohol is easier to detect and more limited to nighttime and weekend parties as reported by youth in qualitative interviews . It has also been noted that youth use alcohol and marijuana to attenuate sleep problems and sleep disturbances from other substances, such as stimulants used to increase daytime alertness .Youth were recruited from an adolescent outpatient substance abuse treatment setting in a large U.S. city from 2010 to 2011. All youth were in the treatment program because they exhibited some degree of impairment in school, social, or family environments. Eligible youth were: 1) between the ages of 12–18, 2) enrolled in treatment with an expected duration of at least a month, 3) able to use a cell phone, and 4) English speaking in order to fill out the CEMA . Youth who were 18 years old signed a consent form while younger youth signed assent forms and parental consent was also obtained. Participating youth received a $15 gift certificate for completing a baseline assessment. Over the course of the study, participants received $25 per week and 500 free cell phone minutes per month. Study procedures were approved by the Institutional Review Board of the University .Assignment to a CEMA strategy was based on anticipated AOD use; youth who were newly enrolled in treatment were more likely to be assigned to EBA than remaining strategies because they were anticipated to have more AOD use events to report. Youth participated in multiple one-month CEMA periods and were rotated through different assessment strategies so that the likelihood of repeating the same assessment strategy was low. During the last two assessment periods, youth could also be assigned to a combination assessment strategy in which youth received EoDA and were also asked to initiate EBA whenever they engaged in AOD use. A total of 28 youth were enrolled. Eleven youth were initially enrolled and followed for one month with four youth assigned to EoDA, three youth assigned to EBA, and four youth assigned to RA. After the initial assessment period, youth could participate in three more month-long assessment periods with month-long breaks in between assessment periods. Six new youth were enrolled during the second assessment period, three youth during the third assessment period, and eight youth were enrolled during the last assessment period. Half of the participants participated in two or more month-long CEMA periods . Four youth participated in all four possible assessment periods.We present descriptive statistics for contextual factors, affect, and cravings by types of AOD. There was a high degree of overlap between reported use of alcohol and both marijuana and other drugs in the same reports. We categorize AOD use in a hierarchical fashion as use of alcohol only, use of marijuana and no other drugs, and use of other drugs. Use of marijuana and other drugs includes reports where alcohol use was also reported. Assessment questions for daily reports shared similar wordings, time frames, and results. In a parallel fashion, assessment questions for in-the-moment reports also shared similar properties and led to similar results. Results on daily reports and results on in-the-moment reports are grouped together for presentation. Percentages for context, affect, and cravings are compared between CEMA when AOD use was and was not reported, where possible. Specifically, comparisons are made for affect and cravings reported during EoDA and for context, affect, and cravings reported during in-the-moment RA. Comparisons are conducted through random-effects logistic regression with random effects for each participant.Models are fit in SAS software version 9.4 through the GLIMMIX procedure.

The fun and na2 mutants interact both additively and synergistically in different tissues

In wild-type plants, BES1 is in the nucleus in a BR inducible manner. When crossed to the bri1::RNAi line, the localization is no longer nuclear. BR insensitivity in this RNAi line was further supported by the presence of BR deficient phenotypes such as short, thickened leaves, shortened stature, and decreased auricle, phenotypes that were observed in Oryza sativa bri mutants. The bri1::RNAi line was also observed to have shortened internodes, especially those between the ear and tassel, and twisting in the leaves. The twisting was sometimes so extreme that leaves had to be removed to access the tassel since they clasped it and prevented it from growing out.Mutants in BIN2 were first identified in Arabidopsis thaliana as semi-dwarf plants that were not rescued by exogenous BR. The bin2 mutant phenocopied classical BR knockout mutants, but was found to contain a gainof-function mutation in the causative gene, rather than a loss of function like bri1 or deetiolated1. Loss of function in BIN2 gives a constitutive response to BR, which manifests in A. thaliana as long wavy petioles and narrow leaves. BIN2 is a serine /threonine kinase of the Glycogen Synthase Kinase- 3 family that phosphorylates BR transcription factors to tag them for degradation in the absence of BR. Thus, when BIN2 is knocked down, the plant is unable to degrade BR transcription factors in the absence of BR and therefore constitutively responds to BR. Maize has at least 10 GSK3 like kinases that were identified by BLAST, 8 of which are expressed in leaf tissue. All 8 of the GSK3 like kinases expressed in leaf tissue were knocked down by the RNAi line created by Dr Kir, so despite the possibility of functional redundancy among these genes,vertical grow factory the knockdown of BIN2 activity is likely to be real. While BR knockouts are usually associated with shorter plants, the constitutively BR responding bin2::RNAi line had an unexpectedly shorter stature than normal siblings.

This shortened stature was due to shortened internodes, but the internodes of the tassel were found to be longer in the bin2::RNAi plants. In concurrence with suppression of BIN2 in rice, auricles were larger in the bin2::RNAi maize line, but unlike the rice line, leaf blades were wider and longer, while the rice line had narrower, longer leaves. The maize bin2::RNAi line leaves also had distinctive crenulations along their blades.When considering mutants with pleiotropic phenotypes, it is difficult to ascertain whether we are observing epistasis, additivity, or synergy simply because there may be epistasis for one phenotype, but not for another. Thus it is important to take into account all metrics when evaluating the mutant interactions. Taking each organ in isolation before coming to a synthesis can be a helpful approach. The fun mutant acts additively with na2 to reduce the overall height of the plant by further affecting the tassel and internodes. Since the d5;na2 double mutant also showed additive effects for height, this could point to a role for FUN in the GA pathway. On the other hand, the synergistic interaction between fun and na2 at the auricle would point to FUN’s involvement in the BR pathway. These two data need not be in contradiction – Best et al.’s work clearly showed that the BR and GA pathways impinge on one another, and the FUN protein itself may be involved in this crosstalk. Though there is very mild feminisation in the bri1::RNAi tassel, this is not an originally described phenotype of the bri1::RNAi line75, nor is it common in family AV802 . Further, the metric of branch number does not indicate feminisation in the bri1::RNAi tassel, though bri1::RNAi is slightly shorter which can be considered a feminine inflorescence trait. Lack of feminisation in the bri1::RNAi tassel is surprising since removing BR causes feminisation in the tassel in the na1 and na2 mutants. Combining the bri1::RNAi line with fun leads to more feminisation than fun alone, implying not simple epistasis by the feminised tassel of fun, but rather an enhancement of the very mild feminisation caused by bri1::RNAi.

Similarly, the reduced height phenotype is enhanced in the double mutant . Phenotype enhancement, or additivity, is also observed at the auricle. Though auricle size was not found to be smaller in bri1::RNAi plants in family AV802, a smaller auricle in bri1::RNAi plants has been reported. Thus we can consider the completely absent auricle phenotype observed in bri1::RNAi;fun plants in family AV802, as compared to the bri1::RNAi and fun single mutants of AV802, as an enhancement of the reduced auricle associated with fun. No leaf width phenotype has been reported for bri1::RNAi plants, and fun appears to have simple epistasis of the leaf width phenotype.According to almost all metrics measured, fun is epistatic to bin2::RNAi. The oversized auricle of bin2::RNAi is completely abolished in the double mutant. Since increased leaf angle has been linked to BR hypersensitivity in rice as well as appearing in this bin2::RNAi line, it is reasonable to assume that this monstrous auricle is a product of BR hypersensitivity, and by extension, auricle growth is promoted by BR. The fact that the fun mutation abolishes this auricle growth is strong support for the function of FUN in the BR pathway, downstream of bin2::RNAi. On the other hand, the retention of leaf blade margin crenulations in the double mutant does not fit into this explanation, unless FUN is simply not expressed along the margin, which would be consistent with the Wab1;fun double mutant . The strong feminisation seen in the double mutant is further support for the placement of fun downstream of bin2::RNAi in the BR signalling pathway. BR is known to accumulate in developing anthers, and hence is a hormone associated with masculinity in maize. The fact that loss of normal FUN produces feminisation in the bin2::RNAi background also supports the hypothesis that FUN is in the BR pathway, downstream of BIN2. Taking together these phenotypes and interactions, this analysis supports the hypothesis that fun functions late in BR pathway, perhaps at its intersection with GA. Additivity with na2 for height is observed as with the d5 GAknockout mutant. At the same time fun enhances the feminisation phenotype of BR deficient na2 and acts additively with the BR insensitive bri1:RNAi while abolishing the phenotypes of the hyper-responder bin2:RNAi. Figure 4-11 shows FUN’s tentative placement in the BR pathway.Since addition of JA was unable to fully rescue the feminised tassel of fun plants, FUN is unlikely to be deficient in JA.

Though failure to correct the feminised phenotype was more obvious in the first application of JA family AV920 still showed a failure to rescue by JA application when branch number is considered. AV920 was not ideal for this experiment because the fun plants in this family were not heavily feminised. This could have been due to the fact that they were grown in the winter greenhouse – greenhouse grown fun plants have been observed to be less feminised than those grown in the field, and the winter greenhouse is particularly sub-optimal for growing corn. Further these plants were the fun-2 allele, which has not been adequately characterised,vertical grow indoor but may have lower feminisation severity than the original fun-1 allele. Finally, the genealogy of these plants contains a recent cross to Mo17, which may have reduced the severity of the phenotype , as well as the fact that some of the fun plants were heterozygous for ts1 . Nevertheless, JA application to fun and ts1 plants in family AV920 did not refute the original experiment showing that JA is unable to fully rescue the feminised tassel phenotype of fun plants. ts1 and fun can be considered additive in their effects on feminisation of the tassel. Double mutant tassels were more heavily feminised than either double mutant, supporting the hypothesis that ts1 and fun are in different pathways. The lack of lower floret abortion in the tassel of ts1 and ts1;fun plants compared to successful lower floret abortion in fun plants further supports the hypothesis that fun is not deficient in JA since JA is required for lower floret abortion in the ear. The loss of silks in the sk1;fun further refutes the hypothesis that FUN is involved in the production of JA. A JA biosynthetic mutant would be expected to retain silks in combination with sk1, as previously shown with ts1 and ts 2. The retention of feminised traits in the form of glabrous, thickened glumes in the double mutant implies an additive interaction – the fun mutation is still causing aspects of feminisation in the tassel, though the lack of functional SK1 cannot protect the silk from abortion by the action of JA. Branch loss in both sk1 and fun, and the additivity in the double is a complex set of observations. Though branch loss is a feminine trait since the ear is branchless and tassels are branched, the sk1 mutant also has branch loss. sk1 is presumably high in JA due to the loss of the SK1 gene that is responsible for JA degradation. This high JA allows silk abortion, and so would seem to be a masculine characteristic. Paradoxically, this loss of functional SK1 is also associated with the feminine trait of less branching in the tassel, implying a role for JA in branch inhibition during tassel development. Since there is an additive interaction between the sk1 and fun mutations, and addition of JA to developing fun tassels lead to tassels that resembled the sk1;fun double mutant tassels, the hypothesis of FUN being outside of the JA pathway is supported.If we consider JA and BR as masculinising hormones in Zea mays, GA can be thought of as a feminising hormone. In the 50s, Nickerson showed that application of GA directly to the whorl during tassel development was sufficient to induce feminisation of the terminal inflorescence.

In the early 80s it was shown that developing ears have GA levels two orders of magnitude higher than in developing tassels. The d1 mutant in maize was shown to block steps in the GA biosynthesis pathway and when the gene was cloned it was found to be a GA3 oxidase that catalyses the final step in bio-active GA synthesis. While the most striking phenotype of d1 is its tiny stature, more pertinent to this discussion is its ear phenotype, dubbed “anther ear”. Without the presence of GA, the anthers of the ear do not arrest and instead grow out to produce bisexual flowers in the ear while the flowers of the tassel are normal. As such it is perhaps erroneous to call GA a simple feminising hormone – rather it is a male killer hormone. The mRNA coding for D1 protein was shown by in situ to accumulate in stamen primordia of the developing ear which undergo cell cycle arrest and ceases growth early in its development. d1 mutant plants do not undergo this stamen primordia arrest in the ear. Since the fun mutant was feminised in the tassel, we made crosses to GA mutants and applied paclobutrazol which is an antagonist of the GA pathway and has applications as a plant growth retardant and fungicide. PBZ blocks the entkaurene oxidation step of GA biosynthesis, and thus plants treated with this compound are unable to produce GA. PBZ has been used to investigate the role of GA in maize, and to elucidate the nature of dwarf mutants in the GA pathway. The dominant D9 mutant was obtained from the maize stock centre and is similar to the D8 maize mutant96, which both bear similarities to the biosynthetic d1 mutant. D8 and D9 are both dwarf, have increased tillering, and display varying degrees of anther ear. All the D8 alleles described have anther ear, while D9 displays full anther ear in some backgrounds, but in others it develops anthers up to the point that they are visible with a magnifying glass96. The D8 locus on chromosome 1 encodes a DELLA protein, and D9 has been shown to encode a duplicate of this protein located on chromosome 5. DELLA proteins are part of the Gibberellic Acid signalling pathway, and act to repress the GA response.

Additional repurposed medications show clinical effectiveness for the treatment of AUD

A translational study examining GET73-alcohol interactions found that neither 30 nor 100 mg/kg GET73 administered in rats potentiated alcohol-induced intoxication. Additionally, GET73 administered both in the presence and absence of alcohol was well tolerated in two samples of 14 and 11 participants, with no severe adverse events and no difference in adverse events. A Phase I clinical trial in two samples of 48 and 32 participants found that both single doses and repeated ascending doses of GET-73 were safe and well tolerated. Another inpatient human laboratory study conducted by the same group confirmed the safety and tolerability of GET73 such that no serious or severe adverse events occurred when GET73 was co-administered with alcohol. Co-administration also did not affect the pharmacokinetics of either GET73 or alcohol. However, GET73 also had no effect on alcohol cue-induced craving or self-administration, warranting additional research. A clinical trial of the effects of GET73 on magnetic resonance spectroscopy measures of glutamate and GABA levels in individuals with AUD was recently completed ; however, the results have not yet been posted, and another trial, which includes a free-drinking bar lab component, is ongoing .In comparison to the drawbacks presented by GABAB agonists like baclofen and SMO, positive allosteric modulators at this receptor present a potential alternative. By binding to a different, non-competitive allosteric site on the GABAB receptor, PAMs allow endogenous GABA, binding at its original orthosteric site, to retain its potency and efficacy, reducing the risk of tolerance development and side effects. A number of PAMs have been studied as potential pharmacotherapies for AUD,vertical garden grow system and have demonstrated reductions in alcohol-associated behaviors and ethanol self-administration in preclinical models.

When directly contrasted against baclofen, a GABAB PAM had a better profile, with dose-dependent reduction of relapse-like alcohol drinking and with no signs of sedation. One such novel GABAB PAM, ASP8062, appears particularly promising as it has been shown to significantly increase the affinity and efficacy of endogenous GABA binding in human and rat GABAB receptors in vitro and with oral administration in an in vivo rodent model of fibromyalgia, demonstrating the ability of oral formulated ASP8062 to cross the blood-brain-barrier. ASP8062 has recently progressed to clinical development. Two Phase I clinical trials with a combined total of 112 participants evaluated single ascending doses and multiple ascending doses of ASP8062, respectively. These studies found that ASP8062 was well tolerated in humans, with no evidence of drug effects on safety, cognition, drug withdrawal, or suicidal ideation. One additional clinical trial, assessing the safety and efficacy of ASP8062 for alcohol use disorder , is currently underway. Overall, ASP8062, and GABAB PAMs in general, appear to be well tolerated in humans and decrease alcohol self-administration in animals. These agents present a potential pathway to better utilize the GABAergic system and reduce the side effects seen with GABAB agonists.Ghrelin, a peptide produced by endocrine cells primarily in the stomach, is thought to regulate growth hormone secretion, food intake, and glucose homeostasis. Ghrelin is also thought to play a role in AUD. Ghrelin signaling is required for stimulation of the reward system by alcohol, and higher ghrelin levels are associated with higher self-reported measures of alcohol craving. In human laboratory studies, intravenous ghrelin administration has been shown to increase the urge to drink, increase alcohol self-administration, and modulate brain activity in regions involved in reward processing and stress regulation. Preclinical studies with ghrelin receptor antagonists have shown reductions in alcohol conditioned place preference, alcohol intake and preference, and alcohol-elicited nucleus accumbens dopamine release in rodents.

PF-5190457 is a ghrelin receptor inverse agonist that inhibits GHS-R1a constitutive activity as well as blocking its activation by ghrelin. In a preliminary clinical study in 12 heavy-drinking individuals, PF-5190457, compared to placebo, reduced alcohol craving and cue-reactivity to alcohol. Additionally, when administered in combination with alcohol, PF-5190457 was safe and well-tolerated with no drug-alcohol interactions. This was the first clinical study of a GHS-R1a inverse agonist in a sample of heavy alcohol drinkers. PF-5190457 may increase somnolence, heart rate, and lower blood glucose concentrations, although clinical results indicate that these side effects were not exacerbated by alcohol co-administration and in general PF-5190457 is well tolerated. In summary, preclinical and early clinical evidence support additional research toward investigating PF-5190457 as a pharmacological approach to treat AUD.Cannabidiol , one of the main compounds found in Cannabis sativa, has shown promise as a novel therapeutic to treat AUD. CBD is nonintoxicating and has diverse pharmacological effects throughout the central nervous system, including functioning as a negative allosteric modulator of CB1 and CB2 receptors, and blocking anandamide update and inhibiting enzymatic hydrolysis. CBD may also interact with non-endocannabinoid signaling systems, including the serotonergic system and the opioidergic system, among others. Preclinical studies have shown that CBD reduces alcohol administration, decreases motivation for alcohol, reduces relapse-like behavior, and improves withdrawal symptoms in animals exposed to chronic alcohol. Evidence in healthy individuals demonstrates that CBD is well tolerated, does not interact with the subjective effects of alcohol, and has no abuse liability. Two recent studies investigated signals for potential efficacy of CBD as a treatment for heroin use disorder and cannabis use disorder. Regarding heroin use disorder, acute CBD reduced cue induced craving for heroin and reduced anxiety in a sample of 42 abstinent individuals, which was maintained one-week following the last CBD exposure. The cannabis use disorder study found that CBD was more efficacious at reducing cannabis use than placebo in a sample of 48 subjects.

In both clinical samples, CBD was well tolerated and not associated with serious adverse events. CBD is currently being evaluated as a potential treatment for AUD, AUD with comorbid PTSD, and alcohol withdrawal in AUD in three clinical trials . In brief, preclinical evidence and clinical evidence in other substance use disorders indicate the promise of CBD as a novel therapeutic for AUD.This qualitative literature review discusses the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD. This information is summarized in Table 1. As of 2018, the APA recommends acamprosate and naltrexone for the treatment of AUD and suggests gabapentin and topiramate for patients with the goal of reducing alcohol consumption or achieving abstinence, while disulfram is suggested for achieving and maintaining abstinence only. Similarly, while not included in the APA’s recommendations, aripiprazole and mifepristone are associated with drinking reduction, while baclofen shows association with abstinence and mixed results with drinking reduction.Some of these appear to have particular promise in specific cases, such as varenicline’s use for nicotine and alcohol co-users , baclofen for individuals with liver disease, and aripiprazole for more impulsive individuals. Novel agents such as GET73 and ASP8062 have also reduced alcohol intake in preclinical studies. In summary, while currently approved medications are somewhat effective,vertical greenhouse growing there remains a crucial need to develop new and improved pharmacotherapies for AUD. Novel and repurposed agents show significant promise as treatments that may improve upon currently approved pharmacotherapies. Medication development has been identified as a critical priority for AUD research. While considerable progress has been made in this field, there are a number of areas which require our attention to realize the benefit of AUD pharmacotherapy. First, despite the prevalence of AUD, the rate of seeking treatment for AUD remains very low. In order for anyone to benefit from the advances in medication development reviewed herein, the treatment gap must be closed. This will require engagement at multiple levels, from prevention to public education about AUD and the available treatments. Researchers and clinicians can help in these efforts by reducing stigma surrounding AUD and other substance use disorders by choosing appropriate language to describe these disorders and the people who are affected by them. A related issue is the need to improve access to FDA approved pharmacotherapies for AUD. A recent analysis of the 2019 National Survey on Drug Use and Health found that only 1.6% of people with a past-year AUD received an evidence-based medication to treat their AUD. Medication use was associated with living in a large metropolitan area, use of the emergency department, and receiving mental health care, indicating that these services and residing in an urban environment appear to increase access to evidence based medications. There is also a great need to improve the education of physicians and clinicians on the availability of evidence-based treatments for AUD. Ongoing efforts in this area are underway by the American Society of Addiction Medicine and the American Academy of Addiction Psychiatry, as well as by the National Institute on Alcohol Abuse and Alcoholism.

To further improve access to treatments and increase treatment-seeking, there is a need to increase the menu of approved pharmacological treatments towards AUD, especially those that have shown promise internationally. Currently, the FDA only accepts two primary outcomes for Phase 3 trials: abstinence and no heavy-drinking days. These outcomes do not always mirror the goals of patients with AUD for their recovery, which may be better refflected by a harm reduction endpoint. Recent work has found that harm reduction endpoints, including reductions in WHO based drinking levels, are associated with improvements in physical health and quality of life and can be used as efficacy outcomes in clinical trials. The acceptance of these outcomes as clinical trial endpoints could have a substantial impact on the medication development field and ultimately result in a larger pharmacotherapy toolbox for clinicians.Another area of development is the move towards personalized treatment, also referred to as precision medication. AUD is a highly heterogenous disorder, and it unlikely that any medication will work for all individuals with an AUD. As such, there have been efforts to use precision medicine approaches to tailor pharmacotherapies to individuals with different presentations of AUD. Studies have taken several approaches towards personalized treatments, such as pharmacogenetics, sex differences, family history, severity of alcohol withdrawal, drinking phenotypes, and bio-behavioral markers. However, even these efforts may be overly simplistic given the complex nature of AUD. It is likely that personalized treatment approaches will need to account for multiple factors to truly tailor treatments to individual patients. Conversely, the public health significance of the improved efficacy of AUD pharmacotherapy with clinically accessible phenotypes argue for wider dissemination and implementation of precision treatment recommendations identified to date. A final issue to consider is the need to develop treatments for individuals with AUD and comorbid psychiatric disorders and for individuals with AUD and AALD. AUD often co-occurs with other psychiatric disorders, including other substance use disorders, personality disorders, major depressive disorder, anxiety disorders, and PTSD. The development of integrated treatments, including combined behavioral and pharmacological interventions, which simultaneously address AUD and other cooccurring disorders, is difficult due to the complexity of treating multiple disorders and the limited understanding of the underlying mechanisms. However, this is a necessary area of research given the high rates of comorbidity in the AUD population. Treatment options for individuals with AALD are limited; of the FDA-approved medications, only acamprosate can be used without concerns of hepatotoxicity. Of the non-FDA medications that may prove useful in this population, only baclofen has been evaluated in an RCT. There is a clear need to develop additional treatments for this population.Unisexual flowers are the exception in angiosperms; the vast majority of flowering plants bear hermaphroditic flowers that have both pollen producing stamens and ovule-containing ovaries . Nevertheless, a substantial number of angiosperms produce nonhermaphroditic flowers. In a recent data analysis, 5-6% of plant species were found to be dioecious, but 43% of plant families were shown to contain dioecious members. The rarity of dioecy at the species level, coupled with its widespread occurrence across the angiosperm lineage, shows that dioecy must have evolved multiple times. In this chapter, we will first discuss the possible benefits and costs to producing imperfect flowers, before considering the likely routes evolution has taken to produce these floral types, and the molecular mechanisms that underlie the development of imperfect flowers. Through a sequence of case studies, this chapter will detail a likely route that an ancestor bearing perfect flowers could take to arrive in the derived states of dioecy and monoecy, through the intermediary steps of protogyny and protandry; andro- and gynomonoecy; and andro- and gynodioecy .

E-cig vapor also contains chemicals that are not found in cigarette smoke

Approximately 87% of deaths attributable to tobacco smoking occurred among current smokers. Only 6% of global deaths attributable to smoking occurred among individuals who had quit smoking for at least 15 years. This underscores the significant health benefits of smoking cessation, especially when achieved earlier in life and soon after the initiation of smoking. Chemical analyses of e-cig vapor have revealed the presence of some of the same toxicants and carcinogens as those found in cigarette smoke, including carbonyl compounds, volatile organic compounds, free radicals, and heavy metals, albeit mostly at substantially lower concentrations.The latter likely arise from the mixing and heating of humectants [e.g., propylene glycol and glycerol ; PG/VG] and flavorings present in e-liquid. Overall, the reduced levels of toxicants and carcinogens in e-cig vapor are consistent with the fact that e-cigs, unlike traditional cigarettes, do not “burn” tobacco to produce in halable materials. This has led to the perception that e-cig use/vaping is safe or less harmful than tobacco smoking. Whilst the lower levels of toxicants and carcinogens in e-cig vapor may imply mitigated health risk, they cannot, however, equate to no risk. In fact, exposure to many of the same constituents of e-cig vapor, at various concentrations, has been associated with a wide range of cardiovascular-, immune-related , and respiratory diseases, and cancer . Emerging data indicate that e-cig use may adversely affect the pulmonary and cardiovascular systems. Also, limited evidence exists on the potential of e-cigs to cause carcinogenic effects. To date, clinical studies have primarily investigated the acute effects of vaping. By design,movable vertical growing solutions epidemiologic studies have explored the “association” of e-cig use with disease outcomes. So, the “causal” relationship between vaping and disease pathology remains largely unknown.

Currently, determining the long-term health consequences of vaping is a top research priority. Of utmost importance is the long-term effects of vaping, especially among adolescents whose developing brains are more susceptible to influences on learning, memory, and attention. Future well-defined controlled experimental studies are needed to establish the mechanisms by which chronic vaping may lead to adverse health consequences in humans. These investigations are expected to identify the constituent of e-cig vapor, which are of most relevance to disease development. Though it is generally accepted that e-cig use exposes the users to fewer and lower levels of toxicants and carcinogens as compared to smoking, the net public health effect of vaping continues to be debated. The scientific community, regulatory authorities, and the general public are faced with competing views on the health risks or benefits of vaping. On the one hand, proponents of e-cigs advocate for: “harm reduction” potential of vaping, especially for smokers who are unable/unwilling to quit; and utility of vaping for smoking cessation. On the other hand, opponents argue against the adoption of an alternative tobacco product whose long-term health effects are yet to be determined. To reach a consensus, more conclusive scientific evidence will be needed; the available data favor the stance that vaping is likely to be less harmful than smoking, with the caveat that it may still pose a health risk on users, which would otherwise be eliminated if neither product were used. On June 22, 2009, with broad bipartisan support from Congress, President Obama signed into law the Family Smoking Prevention and Tobacco Control Act , also known as “Tobacco Control Act”. The FSPTCA granted FDA immediate authority and unprecedented power to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, smokeless tobacco, and any other tobacco products that the agency, by regulation, deems to be subject to the law . On August 8, 2016, when FDA’s “Deeming Rule” took effect, many of the regulatory and statutory requirements that had been in place for manufacturers of the originally regulated tobacco products since passage of the FSPTCA in 2009, became applicable to the deemed products, including e-cigs and all other electronic nicotine delivery systems , cigars, pipe tobacco, nicotine gels, hookah tobacco, and any future products meeting the statutory definition of “tobacco product.”

The applicable statutory provisions include the requirement that deemed products that meet the definition of a new tobacco product must receive premarket authorization from the FDA to be legally marketed. The premarket authorization requires a Premarket Tobacco Product Application for any new tobacco product seeking an FDA marketing order. In the deeming rule and subsequent guidance documents, FDA stated that it intended to defer enforcing the premarket review requirements, for a period of time, with respect to “deemed” new tobacco products that were on the market as of the effective date of the deeming rule. This policy did not extend to deemed new tobacco products that entered the market after the rule’s effective date . Under a federal court order, manufacturers of deemed new tobacco products that were on the market as of the deeming rule’s effective date, were required to submit premarket review applications by September 9, 2020. Following the court order, FDA accelerated its planning and preparation to receive a large number of applications by the premarket application deadline. Accordingly, the agency received thousands of submissions, representing more than 6.5 million products by the set deadline. Per the court order, products for which applications were submitted by the deadline of September 9, 2020, could generally remain on the market for up to a year from the date of the application—or until September 9, 2021, at the latest—pending FDA review, although FDA retains enforcement discretion. Over the last year, FDA has worked to review thousands of PMTAs, representing products from roughly 500 companies. The vast majority of the PMTAs are for ENDS products. Under the PMTA pathway, manufacturers or importers must demonstrate to the FDA that permitting the marketing of the new tobacco product would be “appropriate for the protection of the public health,” among other things. That statutory standard requires the FDA to consider the risks and benefits to the population as a whole, including users and non-users of tobacco products. The FDA’s review of PMTAs includes assessment of a tobacco product’s components, ingredients, additives, toxicological profile, and health effects, as well as its manufacturing, packaging, and labeling processes, and data from consumer perception research , and the applicant’s description of marketing plans for the product.

When reviewing PMTAs for ENDS products, FDA’s task is to follow the direction Congress provided in the law by taking into account the increased or decreased likelihood that existing users of tobacco products will stop using such products, as well as the increased or decreased likelihood that those who do not use tobacco products will start using such products. In making this determination, the impact of such products on youth initiation and use is a critical consideration. So far, the FDA has issued ruling on over 96% of the PMTAs submitted on or before the September 9, 2020 deadline, including 295 marketing denial orders for more than 1,089,000 flavored ENDS products. Products subject to a MDO for a premarket application may not be introduced or delivered for introduction into interstate commerce. If the product is already on the market, the product must be removed from the market or risk enforcement. On October 12, 2021, the FDA granted permission to R.J. Reynolds to market its Vuse Solo closed ENDS device and two accompanying tobacco-flavored e-liquid pods with a nicotine strength of 4.8%, which approximates the nicotine content of a pack of cigarettes. The FDA simultaneously issued MDOs for ten other flavors submitted under Vuse Solo but declined to state which ones. RJR is the second-largest tobacco company in the United States , and a wholly owned subsidiary of Reynolds American Inc., after merging with the U.S. operations of British American Tobacco in 2004 . In a statement announcing the decision,multi tier vertical growing the FDA said that “The authorized products’ aerosols are significantly less toxic than combusted cigarettes based on available data.” The statement concluded that “For these products, the FDA determined that the potential benefit to smokers who switch completely or significantly reduce their cigarette use, would outweigh the risk to youth, provided the applicant follows post marketing requirements aimed at reducing youth exposure and access to the products”. The FDA’s decision came on the heels of the 2021 NYTS report showing an estimated 2.06 million U.S. middle and high school students as current users of e-cigs, with Puff Bar, Vuse, and Juul among the most popular brands. In its decision, the FDA stated that it was aware that 10% of high school students who used e-cigs, named Vuse as their favorite brand in the 2021 NYTS. Vuse has become the fastest-growing e-cig brand, accounting for over 26% market share in the top five markets, being the market leader in Canada, the UK, France, and Germany. In the United States, Vuse continues to outperform other brands, becoming the second largest and fastest growing player in the market in 2021. Currently, Vuse owns 33% of the market share in the United States whereas Juul owns 40%. The FDA’s decision to grant marketing orders for Vuse Solo and accompanying e-liquid pods marks a milestone in vaping regulations as this is the first time ever that a set of vaping products gets clearance from the agency. The cleared products can now be mass marketed and sold legally in the United States.

As expected, the watershed decision by the FDA to green light Vuse Solo vaping products has been praised by the industry as well as proponents of e-cigs for harm reduction. Simultaneously, there have been swift and harsh criticisms of the decision by many experts in public health and medicine and numerous healthcare advocacy groups. As the FDA continues its premarket reviewing of the remaining PMTAs for ENDS products, including major brands such as Juul, and while teens’ favorite products, specifically Puff Bars , are being ordered off the market, Vuse is expected to continue its growth momentum owing to its “first-mover” advantage and industry leading FEELM ceramic coil. Alcohol use disorder is a highly prevalent, chronic, relapsing condition characterized by an impaired ability to stop or control alcohol use despite clinically significant impairment, distress, or other adverse consequences. It is the most common substance use disorder: in 2016, 100.4 million people globally were estimated to have an AUD. This disorder represents a significant public health concern. The WHO estimates that alcohol consumption is responsible for 5.9% of all deaths and 5.1% of global disease burden. Alcohol use and misuse is thought to contribute to over 200 related diseases and health conditions globally, including cardiovascular disease, cancer, liver cirrhosis, and injuries. AUD is also often comorbid with other substance use disorders, major depressive disorder, bipolar disorder, and other psychiatric disorders. In the USA alone, AUD is estimated to contribute to about 88,000 deaths each year. An estimated 44.6 million adults per year in the USA suffer from AUD, and 93.4 million adults in the USA will meet or have met AUD criteria at some point in their life.Furthermore, the economic burden of AUD is estimated to be approximately $250 billion across the USA. Although AUD is an important public health concern, the disorder remains severely under treated with only 7% of adults with AUD in the USA and less than 10% in Europe receiving pharmacotherapy and/or psychotherapy treatment. Furthermore, the lag between the age at which AUD onsets and the age of first AUD treatment has been estimated to be eight years on average. Pharmacotherapies have seen limited use in the treatment of AUD, partially due to lack of addiction treatment training for medical professionals, lack of awareness regarding medication options , reluctance to prescribe and take medications, perceived low efficacy of medication, and stigma surrounding treatment. Indeed, only three pharmacotherapies are approved by the US Food and Drug Administration for use in AUD treatment. These medications are disulfram , acamprosate, and naltrexone. The European Medicines Agency similarly recognizes only these same three medications, as well as nalmefene, as established pharmacotherapies for AUD. These medications are only modestly effective and are under-utilized in treatment. A study conducted in 2019 found that only 1.6% of adults in the USA with past-year AUD received evidence-based AUD pharmacotherapies. Treatment outcomes for AUD differ widely across patients and medications. While abstinence may be desirable, it is infrequently obtained, such that only 16% of individuals in treatment for AUD achieve abstinence. Furthermore, evidence does not support abstinence as the only approach in the treatment of AUD.

There are several limitations to the study presented here that should be noted

An isomer of 2,3,5-trimethyl-1,4-benzenediol has also recently been identified as a substantial VEA degradation product at temperatures 220˚C. Authentic standards were purchased for 2-methyl-1-heptene, phytol, and 2,3,5-trimethyl-1,4-benzenediol to confirm identities of observed products . Other compounds, such as vitamin E, DQ, DHQ, 1-pristene, and 3,7,11-trimethyl-1-dodecanol, have been consistently identified as VEA decomposition products. Several products, such as DHQMA or ketene, that have been previously reported in VEA vaping emissions could not be found in our spectra, likely due to the limitations of the emission collection and analysis method described in section 3.4. A heat map of the mass fractions of degradation products generated at each temperature is shown in Fig 4. Products that contribute to the majority of the observed VEA degradation were separated from the total heat map to better visualize the change in each concentration as a function of temperature. VEA, 1-pristene, and 3,7,11-trimethyl- 1-dodecanol were found to be the most dominant vaping emission products at all of temperature settings, while other compounds, such as duroquinone, durohydroquinone, and 2-methyl-1-heptene steadily increase in concentration as temperature increases. Furthermore, certain compounds including 2,3,5-trimethyl-1,4-benzenediol, 2,6-dimethyl-1,6-heptadiene, 3,7-dimethyl-1-octene, and 3-methyl-1-octene are not produced in concentrations above the detection limit of our instrument until 322˚C,cannabis grow system which suggests a potential risk that users who operated vaping devices at lower temperatures would not be exposed to. However, while most identified compounds appear to increase in concentration as temperature increases, phytol and 2,6,10-trimethyl-dodecane are produced at detectable levels at 176 and 237˚C but cannot be found at higher temperatures.

Another recent study has also detected production of phytol when vitamin E were heated in a micro-chamber/thermal extractor at 250˚C. It is possible that at these compounds are stable at lower temperatures but begin to break down into degradation products themselves as the temperature increases. Another important pattern to note is the increase in compounds that may pose a risk of oxidative damage to lungs, such as DQ and 2,3,5-trimethyl-1,4-benzenediol, at higher concentrations. While not investigated in this study, prior research has shown that increased temperature may result in the enhanced emission of carbonyl-containing compounds when vaping e-liquids containing propylene glycol and glycerin. Thus, vaping VEA at greater temperature settings may also carry the risk of exposure to highly electrophilic molecules and subsequent oxidative lung injury. In order to better understand the interactions between temperature and the generated emission products, a Pearson correlation analysis was performed . Overall, all but fourof the identified compounds were strongly correlated with temperature . Compounds such as DQ, 1-pristene, 2-methyl-1-heptene, 2-hydroxy-4-methoxy-3,6-dimethyl benzaldehyde, and 2,6-dimethyl-1,6-heptadiene, were very well correlated with temperature , indicating a strong increase in concentration as temperature increases. VEA and phytol, in contrast, were strongly anti-correlated with temperature , while VE and 2,6,10-trimethyl-dodecane were moderately anti-correlated with temperature . In addition, VEA was found to be weakly to strongly anti-correlated with all degradation products excepting phytol and VE, which demonstrate a strong positive correlation . These results support our analysis of the mass fractions, indicating that as temperature increases, thermal decomposition of VEA is heightened. Further analysis of the correlations between degradation products shows that phytol is strongly anti-correlated with all VEA degradation products with the exception of 2,6,10-trimethyl-dodecane, which was found to have a strong positive correlation with phytol .

Phytol was also found to be strongly correlated with VEA , likely because as more VEA was evaporated during the vaping process, the greater the chance of degradation into phytol. These relationships further suggest that while some degradation products may be stable at high temperatures, phytol may further decompose into shorter-chain alcohols, alkanes, and alkenes and enhance the production of VEA vaping emission products. Phytol is known both as a precursor for the synthesis of VE and vitamin K12, as well as a byproduct of chlorophyll degradation. Inhalation of aerosolized phytol has previously been shown to induce lung injury in exposed rats. In addition, phytol is a long chain alkyl alcohol compound, meaning that it has the potential to induce damage to the membrane of cells in a biological system. Overall, the toxicity of phytol raises questions about the safety of vaping not only VEA but cannabis-containing vape products that may result in phytol production. These results clearly indicate that the product distributions of VEA vaping emissions are highly dependent on the operating temperature of the vape pen. As a result, the exposure for vape users operating the same e-cigarette products at different temperatures may differ significantly.Previous reports of VEA pyrolysis indicate that VEA begins to degrade starting at ~200–240˚C. However, our results clearly demonstrate degradation of VEA and formation of products such as DQ at 176˚C, indicating that the device itself may play a larger role in the decomposition of VEA than initially anticipated. Previous study in our lab has also found substantial formation of DQ at 218˚C–several hundred degrees lower than what has been predicted. To further understand if the device itself may impact the thermal degradation of VEA, pure pyrolysis of VEA oil was carried out using a tube furnace reactor.At 176 and 237˚C, VEA was fairly stable; substantial consumption of VEA oil was not observed until the two higher temperatures, despite clear consumption at all temperatures during the vaping collection.

Fig 6 demonstrates the product distribution of VEA degradation products collected and analyzed using GC/MS. Here, we did not observe substantial thermal decomposition of VEA when heated at 176˚C for 75 minutes, which greatly contrasts with the degradation of VEA at 176˚C for only 4 s during the vaping collection. At 237˚C, the parent VEA molecule was the only detectable emission product, indicating that VEA again did not degrade at this lower temperature, though 237˚C was enough to evaporate VEA so that it could be collected in the cold trap. Degradation products were only detectable from samples collected at 322 and 356˚C, though the number of products and abundance of observed peaks are drastically reduced when compared to the vaping emissions. It should be noted that the tube furnace is capable of heating VEA at more accurate and consistent temperatures than the vape pen itself, which often saw temperature fluctuations that may influence results. The stark difference in product distribution provides evidence that VEA vaping emissions may not be the result of pure pyrolysis alone. Instead, external factors such as the device elements themselves or environmental interactions may play a role in the catalysis of VEA degradation. The cartridge used in this study is a newer THC cartridge that contains a ceramic heating element, a nichrome filament wire, a fibrous wick/insulation wrap through which oil was delivered to the heating element, and a stainless steel air flow tube and heating element housing that the oil remained in direct contact with. The emission of metals during the vaping process has been documented in several prior studies, but the interaction between VEA and the metal components of the vape device are still being investigated. Saliba et al. recently found that interaction between a metal heating element and PG greatly decreased the temperature required to observe PG thermal decomposition. Certain metals such as stainless steel, which is present in the cartridge used in this study,cannabis grow lights resulted in a nearly 300˚C reduction in required temperature compared to pure pyrolysis, highlighting a clear interaction between the PG decomposition and the device itself. Furthermore, a study by Jaegers et al. found that pyrolysis alone in an anaerobic environment was not able to induce thermal degradation of PG and VG at low temperatures , despite previous studies observing degradation at temperatures as low as 149˚C during vaping. However, when heated in an aerobic environment, thermal decomposition was observed at 133 and 175˚C, both without and with the addition of metal oxides Cr2O3 and ZrO2, suggesting that oxidation is a key process during vaping. In combination with the results shown here, evidence highly suggests that pure pyrolysis alone may not be the only pathway for VEA degradation. During the vaping process, not only may VEA come into direct contact with metals that are present in the filament wire or stainless-steel body, but VEA must also come into contact with molecular oxygen in ambient air. These interactions may promote VEA degradation at temperatures lower than predicted under pure pyrolysis conditions. Ultimately, it is then possible that compounds such as DQ or ketene may be able to form at lower temperatures than what is theoretically calculated if these interactions are considered.However, further study is required to fully understand the effects of the e-cigarette device and vaping environment on the degradation of e-liquids.First, this study presents a range of decomposition products that were identified using a -40˚C cold trap and GC/MS analysis.

Approximately 40% of the mass of VEA consumed by the vape pen could be attributed to the compounds identified here. However, compounds with high vapor pressure, such as ketene, that have been previously reported from VEA pyrolysis may not have been efficiently captured using the cold trap method described in this study. This method is expected to better traps particle-phase compounds that are able to condense at -40˚C and are stable enough to transfer from the cold trap to collection vials at room temperature and is unable to capture highly volatile or reactive VEA vaping emission products. For example, ketene, which is expected to form during VEA pyrolysis, has an estimated boiling point of -56˚C and, as a result, was not expected to be observed in our collection. Furthermore, highly volatile and/or reactive compounds such as ketene and various low molecular weight carbonyl-containing species, etc., often require additional derivatization methods that were not used in this study to be observed using GC/MS. This study was also only able to identify compounds with mass spectra that could be found in the NIST mass spectral library. While PubChem currently reports over 111 million unique chemical structures, the NIST library used in this study contains MS fragmentation patterns for only 242,466 compounds. As such, a large portion of the TIC for each collection could not be matched to a known compound . Furthermore, several peaks were observed that were believed to be co-elution of two or more products, which prevented clear analysis of the fragmentation patterns. Several identified products, such as VEA, may also have multiple isomeric forms that have only slight differences in their retention times and mass spectra that the NIST library matching program is unable to account for. In the case of VEA, all peaks were assumed to be and quantified as the same α form, but it is possible for VEA to exist in α, β, γ, or δ forms. This may be true for other structures identified in this study. The use of QCEIMS to identify products that cannot be found in the NIST database, such as 1-pristene, is a potential avenue for further identification of vaping product emissions, though its use for non-target analysis is limited if the researcher does not have a proposed structure in mind to simulate fragmentation. While this study was able to account for ~40% of the mass consumed by the pen during the vaping process, the remaining mass is likely attributable to these uncaptured volatile or reactive products, as well as degradation products that were captured, but unable to be identified at this time. Finally, the vaping topography used in this study was adapted from previous literature on nicotine vaping and optimized for capture of particles in the cold trap system. Real-word nicotine vape users have been reported to inhale between 50–80 mL/puff at greater flow rates than used in this study, whereas parameters for THC-vaping have not been well-characterized at this time. The production yields of VEA degradation products reported in this study could consequently differ for those who vaped at higher flow rates. The temperature dependence of product distribution, however, remains true.This is the first large scale randomized trial that provides the opportunity to compare the treatment retention of participants on buprenorphine and methadone in community treatment programs in the U.S. The results demonstrate that those treated with BUP were more than 50% less likely to remain in treatment for 24 weeks than those receiving MET. This finding is consistent with other controlled trials or observational studies, even including studies that focused on special populations such as pregnant patients.19

The only exception is that GMs assigned male evidenced elevated odds for alcohol dependence

This study was embedded within a larger longitudinal birth-cohort study and therefore limited by attrition. It is possible that mothers who chose to participate in the study and to continue for multiple assessments may have differed from those who did not, although retention since age 9 was around 95%. Given limitations, results should be replicated among diverse populations, as well as other samples of Mexican-origin youth. Lastly, the study was limited to youth who had no gang involvement because of risk for violent responses to the TSST. This criterion may have attenuated associations, as gang members often show greater substance use . Substance use disorders affect more than 20 million individuals in the United States annually, increasing risk for psychiatric disorders, chronic diseases, and disruptions to social, family, and work lives . SUD prevalence peaks during young adulthood , with co-occurrence of multiple SUDs also common during this time period, which increases clinical severity and complicates treatment . Previous research has established that, compared to completely heterosexual and cisgender individuals , sexual and gender minorities engage in greater substance use beginning in adolescence and extending throughout life .Even fewer have examined more serious SUD outcomes by sexual orientation or gender identity or have focused on SUDs during young adulthood . The present study addresses these gaps by examining associations between SGM statuses and past 12-month prevalence of SUDs in a community cohort of U.S. young adults. SGM disparities in SUDs persist because SGMs use substance to cope with SGM-related minority stressors,cannabis grow system including self-stigma and interpersonal and structural-level discrimination . Disparities may also be driven by differences in substance use norms within SGM communities . For example, research indicates that sexual minorities perceive greater availability of substances and have more tolerant use norms than do heterosexuals .

Additionally, gender minority youth may perceive less risk associated with substance use than cisgender youth .Research has found persistent variation in SUD risk by sex. In the general population, men experience single and co-occurring SUDs at higher levels than women . Among SMs, however, sex differences are typically reduced or even reversed, with greater sexual orientation disparities among adult women compared to men, and especially elevated rates among bisexual women . Nonetheless, studies have rarely tested whether sex modifies relationships between sexual orientation and SUDs by including interaction terms in statistical models. Prevalence of SUDs tends to peak around age 25 and declines with age . Research examining SUDs among SMs, however, suggests a slower agenormative decline . Rarely have researchers compared sexual orientation or gender identity disparities in SUDs among individuals older than 25 years with those in younger age groups. Knowledge of how the magnitude of sexual orientation and gender identity differences in SUDs vary by birth sex and age can help identify subgroups in need of interventions. Research on how gender identity is associated with SUD risk is severely lacking, with available studies using small, subgroup samples . Studies also frequently lack cisgender comparison groups, preventing quantification of gender identity differences. This study analyzed data from the longitudinal Growing Up Today Study when participants were aged 20-35 to estimate sexual orientation and gender identity differences in probable SUDs. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were used to assess past 12-month nicotine dependence, alcohol abuse/dependence, drug abuse/dependence, any SUD, and co-occurring multiple SUDs . Because research demonstrates sex differences in associations between sexual orientation and substance outcomes , we estimated statistical interactions between 1) sexual orientation and birth sex, and 2) gender identity and birth sex, and present birth-sex-stratified estimates.

We hypothesized that SGMs would be more likely than non-SGMs of their same birth sex to meet criteria for SUDs, and that sexual orientation differences would be larger among participants assigned female at birth compared to those assigned male. Additionally, we estimated statistical interactions between 1) sexual orientation and age, and 2) gender identity and age. We hypothesized that sexual orientation and gender identity differences in SUD risk would be larger in older versus younger periods. Among participants meeting criteria for a past 12-month drug use disorder, we examined associations of sexual orientation and gender identity with past 12-month specific drug use.Our study quantified sexual orientation and gender identity differences in SUD risk during young adulthood, when SUD prevalence in the general U.S. population is high . We examined SUDs based on DSM-IV criteria including nicotine dependence, alcohol abuse and dependence, drug abuse and dependence, and multiple co-occurring SUDs. Aligning with previous literature , we found that SM status was associated with greater odds of past 12-month SUDs among young adults assigned female, and to a lesser extent among those assigned male. Co-occurrence of 2 or more SUDs in the past 12-months was also more common among SMs compared CHs, aligning with previous studies of lifetime SUD co-occurrence . Contrary to our hypothesis, age-related declines in SUD prevalence were largely similar across sexual orientation and gender identity groups. This finding may be due, in part, to our sample age range and age periods compared in analysis . Previous studies have shown differential age-related declines in alcohol problems between SMs and heterosexuals and noted the largest sexual orientation differences in ages 40 or older . An analysis of representative U.S. data showed declines in the prevalence of tobacco and alcohol disorders among SMs between ages 26-35 but increases in prevalence between the mid-30s to mid-40s . We uniquely examined how GM status is related to risk for SUDs. This is an important contribution as studies assessing SUDs by gender identity are limited and typically focused on substance use instead of abuse . In contrast to findings related to sexual orientation, we did not find consistent evidence of greater prevalence of SUDs among GMs after accounting for sexual orientation in statistical models.This lack of evidence, however, should be interpreted with caution considering small numbers of GM participants in GUTS and previous evidence indicating their disproportionate substance use .

Additional studies quantifying associations between gender identity and SUDs are needed.Among the general population, more people assigned male at birth report probable SUDs than do people assigned female at birth . In contrast, we found SMs assigned female generally had similar or higher levels of SUDs compared to SMs assigned male, and sexual-orientation differences were larger in assigned females than assigned males. One reason is that comparisons between SM and CH women will yield relatively large effect sizes because CH women have the lowest levels of SUDs of all groups defined by sexual orientation and birth sex. Beyond this explanation, there is little insight into why SM women are at especially elevated risk, though some have proposed that SM women are at greater risk for minority-specific stressors and mood disorders, resulting in greater risk for SUDs .Among participants with a drug use disorder,marijuana grow system we found that some subgroups of SGMs had elevated odds of reporting use of certain drugs compared with CHs and cisgender participants. Studies examining sexual orientation or gender identity differences in drug use among individuals with drug use disorders are rare; however, cross-sectional studies with participants of the NSDUH found that SM adults were significantly more likely than heterosexuals to report past-year marijuana and other drug use . This indicates that SGMs may be more likely to use different substances than non-SGMs, which has implications for screening, intervention, and treatment . The DSM-IV defined separate criteria for substance abuse and dependence, whereas in the updated DSM-5, abuse and dependence are combined into a single SUD diagnosis . Studies comparing DSM-IV and DSM-5 SUD diagnostic criteria have shown increases , no differences , and decreases in prevalence. Increases in SUD prevalences under DSM-5 may relate to the inclusion of ³GLDJQRVWLF RUSKDQV´ in diagnoses² those who meet one or two DSM-IV criteria for dependence, but none for abuse . Nonetheless, concordance of DSM-IV and DSM-5 diagnoses are acceptable, with concordance increasing with severity , suggesting that our findings are likely similar to those resulting had we used DSM-5 criteria. Further research is needed to clarify this issue. GUTS participants are not representative of the U.S. population as they are children of registered nurses and predominantly non-Hispanic White. The prevalence of SUDs in GUTS, however, is comparable to same-aged participants of the NSDUH , as is the distribution of SGMs enrolled in GUTS compared to population-based studies . Additionally, GUTS participants were not enrolled based on their sexual orientation or gender identity. GUTS assessed sexual orientation with a single item tapping both identity and attraction. This limits direct comparisons between our findings and other studies assessing dimensions of sexual orientation separately because research indicates these dimensions have different associations with substance involvement . Further, despite the large sample size, we were limited in our ability to detect within group differences among SGMs. Despite these limitations, our study is strengthened by including multiple SGM subgroups, enabling examination of heterogeneous outcomes that may otherwise be obscured when combining SGM categories. Future research should include more diverse, nationally representative samples to enable examination of interactions between sexual orientation, gender identity, and other sociodemographic factors to further identify higher-risk SGM subgroups.

Among the general population, young adults with SUDs experience disproportionate economic and public health burdens and have low utilization of SUD treatment . For SGM young adults, these issues may be even more persistent, with one study finding that less than 4% of the 14-20% of SMs needing treatment actually accessing treatment . Specific barriers to treatment among SGMs include a lack of targeted interventions, differences in coping strategies and psychiatric comorbidities, discrimination within healthcare settings, lack of provider knowledge about SGM health needs, and lack of insurance . Consequently, increasing access to treatment alone may be insufficient to address SGM SUD disparities. Efforts should also focus on bolstering the provision of culturally tailored, SGM affirming treatment which promotes resilience, coping, and wellness. Further, given high co-morbidity with other mental disorders, interventions are needed which integrate psychological and SUD treatment .Methamphetamine dependence commonly accompanies HIV infection, typically because of behaviors during drug use that increase the risk of viral transmission . While each of these conditions by themselves often have negative effects on the individual’s cognition and functional behaviors, there is also evidence that the combined effect of HIV infection and heavy METH use may have additive effects, e.g., resulting in worse neuronal injury , compounded damage to frontostriatal circuits , and more profound neuropsychological impairment than either condition alone. Neuropsychological deficits, particularly those that are frontally-mediated, are thought to substantially impact everyday functional ability, i.e., the ability to engage in vital tasks of daily living . For people living with HIV, an added demand is adherence to an antiretroviral therapy regimen. Although HIV and METH dependence have each been associated with worse performance on tasks of everyday functioning , the combined effects of HIV infection and heavy drug use on the ability to carry out tasks of daily living have not been widely studied [but see ] but are important to understand given the high co-occurrence of these two conditions and the potential adverse implications for medication adherence and other important functional behaviors. Parsing the relationships among HIV illness, METH use characteristics, and everyday functioning may help inform treatment decisions. For example ART seems to reduce the severity of HIV-associated neurocognitive disorders , however some antiretroviral medications do appear to have neurotoxic effects . Furthermore, there are limitations in the operationalization of everyday functioning in previous investigations. Many studies of everyday functional ability, including those conducted in HIV and substance dependence have used self-report measures that ask the individual to rate how well they perform activities of daily living. We and others have proposed that reliance on self-report is problematic especially during the study of conditions with known cognitive impairment. Performance based functional measures, such as the UCSD Performance Based Skills Assessment , are useful in that they divide everyday function into specific components and have high reliability and validity , e.g., comprehension and planning abilities, financial skills, knowledge in use of transportation and managing the household, and the extent to which individuals can internalize and plan to take a complex daily regimen of medications.

Astrocytes and proliferative neural progenitor cells did not yield many significant pathways

In addition, our experiment found that cerebral organoids may be used to model neuroinflammation. This is an unexplored avenue of research and may warrant the use of organoids to study neurological diseases associated with neuroinflammation. Previous findings related to METH research on brain development were done with mice models and found that prenatal METH exposure in mice has led to a decrease in bodily growth, learning capabilities, and increased aggressive behavior. These observations are behavioral and cannot be observed through our experiment. In mice, METH has also been known to promote neuroinflammation and neurodegeneration, which is consistent with our results. Human brain organoid models show the same results, strengthening the claims that neuroinflammation and neurodegeneration are likely consequences of METH exposure.Alternatively, the neuroinflammation and neurodegeneration that we found may also be due to the lack of microglia in our cerebral organoids. Currently, organoids produced from human induced pluripotent stem cells lack microglia which are an integral part of the brain’s immune system. These cells play a key role in maintaining the brain’s homeostasis and development. Therefore, it is important to consider how microglia’s role is altered in METH treatment as well. Recently, there have been advancements in organoid research and it is possible that they may contain endogenous microglia or microglia may be added via a co-culture. It would be beneficial to test the effects of the same drugs with cerebral organoids that have microglia incorporated for a more holistic understanding of the effects of METH treatment on the developing brain. Moreover, as organoid research develops, it be may interesting to try the same experiment on whole-brain organoids that have been vascularized,cannabis growing supplies which may be a better model because it is even more similar to the developing brain. In THC, we saw that our organoids represented a diverse array of neural cell types found in the developing brain .

Due to the discrepancy in cell counts per organoid, we decided to focus on cell types that had more even counts in our data when comparing THC and control organoids. Thus, there were three clusters of interest GFAP+ astrocytes, proliferative neural progenitor cells, and neurons that had more even cell counts .When looking at neurons, we decided to focus on neural sub-types to see if THC treatment was causing any changes there. Clustering the neuronal population again revealed a population of glutamatergic, GABAergic, and an unidentified cluster of SOX11+ and MEIS2+ cells . Pathways related to neurogenesis were found to be up-regulated as a result of THC treatment with some notable genes including NEUROD2 and NEUROD6 . These genes are associated with neurogenesis and were up-regulated in THC glutamatergic neurons, suggesting that THC treatment is affecting this neuronal sub-type in some way, perhaps by leading to its preferential differentiation towards glutamatergic fate via NEUROD6. THC glutamatergic neurons also expressed CNR1 at a higher level than control organoids . Typically, CB1 expression has been shown to decrease as a result of chronic THC exposure, however, we see an increase in CNR1 especially in glutamatergic neurons further suggesting THC may be altering this neuronal subset. The cluster of cells that did not express some of the key glutamatergic markers, does express NEUROD2, NEUROD6, and CNR1 which may indicate that this population may also differentiate into glutamatergic neurons. These findings suggest that THC treatment may lead to differentiation into glutamatergic neurons in the developing brain. These results, however, are based on a small population of cells and would need to be functionally validated in vivo to confirm that this phenomenon does occur.

The field of single-cell RNA-sequencing analysis is constantly evolving. Recently, new tools and packages have been made to address the issue of ambient RNA. A new package by the name of DecontX has recently been used to remove the ambient RNA contamination before downstream analysis, so this may a novel way to address the problem of contamination that we faced in the THC dataset48. In the future, it may also be interesting to explore other single-cell analysis techniques to see if results differ. We use Chromium, a 10x single-cell RNA-sequencing technique, which sequences from just the 3’ end of RNA, however, there are many other methods such as Smartseq2 which provide full-length transcripts49. Full-length transcript may allow for increased sensitivity and a higher level of detail about each cell. This increased sensitivity may provide more information about more minute changes in gene expression. All in all, this study has provided valuable insights into the effects of METH and THC on the developing brain via cerebral organoids, a topic that is difficult to study otherwise. This model and the results of this experiment may be used to properly advise pregnant women about the effects of METH and THC use on fetal brain development. Substance use emerges and greatly increases across adolescence, and early substance use and more frequent use are risk factors for substance use disorders in adulthood . In 2018, the percentage of students who had used an illicit drug doubled from 8th to 10th grade, and nearly half of students reported using at least one substance by 12th grade. High substance use in adolescence has been reliably linked with substance use problems and addiction in adulthood . Converging evidence from cross-sectional and prospective studies has indicated that earlier use of alcohol, tobacco, and marijuana during adolescence is a risk factor for more problematic substance use and substance use dependence . Furthermore, youth who engage in substance use broadly have more problems with respect to academics, social function, psychopathology, and the legal system both throughout adolescence and during adulthood . Therefore, it is important to identify youth at heightened risk for substance use. Although stress and distress are consistent risk factors for substance use, few studies have examined whether stress reactivity is related to substance use among adolescents.

Adolescents show neurobiological development, and substances can influence one’s neurobiology by altering neural reward circuitry to promote substance dependence and addiction . This substance-induced neural rewiring may be most notable during adolescence, as adolescents experience neurodevelopment and already show increased reward sensitivity relative to children and adults . Excessive substance use can also reduce executive function and attentional control . These deficits may cause youth to struggle with academics,cannabis indoor growing and academic motivations and school engagement provide an important buffer for substance use . Substance use can also manifest in social changes which further promote dependence and risky behavior. For instance, substance use has been linked with increases in impulsivity and sensation seeking and greater involvement with deviant peers during adolescence . Because youth cannot legally acquire substances, youth may need to identify deviant peers to obtain access, and identification with deviant peers can promote further substance use . In this way, early substance use can prompt youth to engage with others who promote delinquent behaviors and poorer adjustment . Adolescents may use substances for varied reasons related to stress. For instance, common motives include to enhance their social and emotional well-being, to reduce distress, and to conform to peer pressure . Just as substances can influence emotion, emotional states can influence adolescents’ inclination to engage in substance use. For instance, substance use is higher on days when individuals experience higher levels of positive emotion as well as negative emotion . Similarly, daily experiences can also influence one’s proclivity for substance use. Daily stressors are generally followed by increased negative emotion and decreased positive emotion, and people turn to substances to mitigate these emotional responses. This may be particularly the case during adolescence, a period when youth experience more frequent stressors in varied domains as well as enhanced reactivity to stress relative to children and adults . Further, adolescents experience greater variability and intensity in emotion relative to adults, such that stressful experiences may be especially distressing . Heightened emotional responses with reduced capacity for regulation can contribute to increased psychopathology broadly during adolescence, including substance use . In addition to emotional responses, stress is followed physiological changes from biological systems that naturally respond to stress. Physiological responses often do not correspond to self-reported emotion, and profiles of psychological and physiological responses together or interactions between systems can impart unique information about adolescents’ experiences with stress . Two physiological systems that may aid in the identification of at-risk youth are the hypothalamic pituitary adrenal gland axis and the autonomic nervous system. Adolescents become more sensitive to social stress following pubertal onset, and the HPA axis is sensitive to social-evaluative stress . The two branches of the autonomic nervous system—the sympathetic nervous system and parasympathetic nervous system —jointly alert the body to threat, and they have also been found to relate to impulsivity and emotion regulation, traits relevant for substance use . People with blunted SNS activity tend to be more impulsive and people with blunted PNS reactivity have poorer mental health and self-regulation . Although blunted activity across all systems is linked substance use, limited work has examined whether individuals with dysregulation across systems are at greater risk for substance use. Limited work has assessed how stress responses reactivity can relate to substance use and behavioral problems concurrently and prospectively.

However, among youth with depression, conduct problems, or no psychiatric condition, Brenner and Beauchaine have found that greater increases in SNS activity in response to reward were associated with delinquency, both externalizing and internalizing problems, and anxiety and depressed mood . Moreover, they found that lower SNS reactivity to reward predicted greater alcohol use four and six years later among middle school children . Yet, no work has assessed links between psychophysiological responses and substance use in middle or late adolescence. Although substance use often begins in mid-adolescence and increases in frequency during late adolescence, limited work has examined associations between stress responses and substance use onset and frequency in adolescence. Early identification of at-risk youth is imperative as earlier substance use is linked with greater severity of use in adulthood . Therefore, this dissertation investigated how stress responses relate to lifetime substance use in middle adolescence among youth with high adversity backgrounds and frequency of substance use in late adolescence among a community sample across middle and late adolescence . Associations between emotional and cortisol reactivity to stress at age 14 and lifetime substance use at ages 14 and 16 were assessed in Study 1, as well as differences in associations by gender and poverty status. Associations between SNS and PNS reactivity to stress, as well as profiles of responses across the two systems, at age 14 and substance use at ages 14 and 16 will also be assessed in Study 2. In both studies, sensitivity analyses were limited to adolescents who had never used substances by age 14 to determine whether stress responses were related to use versus initiation specifically. These studies will highlight whether stress reactivity can prospectively predict substance use onset and have utility for identifying at-risk youth. In contrast, Study 3 assessed whether daily emotional reactivity, as opposed to acute reactivity, related to substance use count and frequency of alcohol and marijuana use in late adolescence, as well as whether associations differed by gender. By better understanding pathways that contribute to heightened predisposition for adolescent substance use and which groups of adolescents are at heightened risk for substance use, treatments can be tailored to address aspects of stress regulation among specific populations of at-risk youth. Substance use initiation greatly increases across adolescence . Youth with greater internalizing and externalizing problems tend to show high risk for substance use, and differences in the activation of to two key stress response systems—hypothalamic pituitary adrenal axis and emotion—have been related to both . However, limited research has examined whether differences in the biological and psychological responses to stress, with respect to changes in cortisol secretion and emotions following stressor onset and across a recovery period, relate to substance use among adolescents, especially those at heightened risk for substance use.

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Neither model showed significant mediating effect of inflammation on the relationship between childhood trauma and clinical outcome due to lack of association between inflammation and childhood trauma. Thus, we can conclude that childhood trauma and the 15-Analyte Index may have additive effects in predicting SOPS positive and GAF, and that the effects of total childhood trauma on clinical outcomes is not mediated by inflammatory processes. These results have several possible explanations. It is possible that the lack of association between childhood trauma and inflammation was due to the inability to account for severity of childhood trauma experienced. Thus, with a measure of severity of childhood trauma, perhaps the relationship between total severity/chronicity of trauma experienced would be associated with Cortisol, CRP, IL-6, TNF-a, or the 15-Analyte index. However, it is also possible that the individual analytes included in the 15-analyte index are uniquely and independently predictive of SOPS positive symptoms and GAF, thus childhood trauma may not be associated with those specific inflammatory analytes irrespective of the childhood trauma indices used. Several studies cite the significant relationships between inflammation, childhood trauma, and in first episode psychosis ,but no studies to our knowledge to date have evaluated the mediating effect of inflammation on the relationship between childhood trauma and clinical outcomes in CHR subjects to date.Lastly, we explored the effect of psychosis-risk conversion status and trauma history on inflammation, psychosis risk symptom severity, and functioning in CHR. Group stratification revealed that there were no significant differences between CHR-C and CHR-NC groups in total trauma,vertical growing rack meaning that CHR individuals who progressed to psychosis from an at-risk state did not demonstrate higher total trauma as compared to CHR subjects that did not progress to psychosis.

MANCOVA revealed significant between groups differences in SOPS P, GAF, and the 15-Analyte Index. Post-Hoc analyses using Bonferroni correction revealed that CHR- CTrauma subjects with a history of childhood trauma demonstrated significantly higher SOPS positive symptom scores than CHR- CNoTrauma, and CHR- NCTrauma, CHR- NCNoTrauma subjects. Given that criteria for conversion to psychosis is based on increased scores in the SOPS Positive scale, total childhood trauma may be an important independent variable associated with increased baseline SOPS positive symptoms and help identify a category of individual who are highest risk for conversion to psychosis. Further, CHR-CTrauma demonstrated lower GAF as compared to CHRNCNoTrauma subjects, whereas CHR- CNoTrauma did not demonstrate differences in GAF scores compared to either group of CHR-NC subjects. This again may imply that history of childhood trauma may be an important independent variable associated with increased baseline global functioning and thus help identify a category of clinical high-risk subjects who demonstrate the lowest global functioning. Finally, the 15-Analyte index did not differ between CHR-CTrauma and CHR-CNoTrauma subjects but did differ between CHR-NCTrauma and CHR-NCNoTrauma groups. Given that higher scores on the 15-Analyte index are associated with higher SOPS overall symptoms, lower global functioning, and lower social/role functioning, this finding may be interpreted to mean that CHR subjects with any history of trauma may demonstrate a unique population of subjects with worse clinical outcomes who would benefit most from early intervention. There are several possible limitations of this study that may explain the non-significant association between history of childhood trauma and pro-inflammatory cytokines . While sample size was adequate to detect small to medium between subjects’ effects, due to employing multiple between-subjects comparisons, risk for Type I error was increased.

Future research may consider use of open public data sets or consortium efforts in order to pool resources and maximize recruitment of sufficient samples to conduct analyses that require a large sample of subjects, such as exploratory factor analyses of inflammatory analytes. Further, measurement of childhood trauma in this study prevents evaluation of the effect of chronicity and severity of trauma to be evaluated. Future studies should consider use of the non-abbreviated Childhood Trauma Questionnaire: CTQ, in order to capture severity and chronicity of each individual sub-type of trauma endorsed. A review by Schafer and Fisher determined that instruments assessing childhood trauma, such as the CTQ, that were originally developed for the general population are also appropriate for use among people with psychosis. However, the use of self-report measures of childhood trauma is additionally prone to bias, particularly when subjects are under the age of 18. Thus, in order to prevent bias in reporting, future studies should employ use of informants that may be able to verify experience of childhood trauma in order to increase reliability of reporting. Moreover, inflammatory analytes and childhood trauma were only evaluated from one time point. Due to the age range of the at-risk sample , this might mean that ongoing changes in inflammatory analytes and additional trauma experiences that occurred during the course of the study, were not captured. Ongoing sampling of childhood trauma on inflammation must be evaluated across time in order to establish more reliable measures of these dynamic processes. The use of cross-sectional data for mediation analyses is limited, as temporal precedence cannot be established thereby preventing implications to be drawn regarding the causal effect of childhood trauma or inflammatory markers on clinical outcomes. While a study by Simpson et al. demonstrated that self-report measurement of childhood trauma in a first episode psychosis sample remained stable and consistent across multiple time points, they found that severity of trauma reported did fluctuate across multiple assessments.

If unable to collect multiple biological samples from different time points, implementation of a stress test design with blood marker sampling would allow for testing the impact of trauma on stress reactivity and inflammatory response during the course of one visit. Additionally, the validation of inflammatory markers in psychosis is ongoing; therefore, selection of specific markers of inflammation to measure at various phases of illness is not well established, nor is there a clear understanding of what inflammatory analytes may be differentially impacted by environmental stress as compared to disease progression. Measuring a large panel of serum markers of inflammation is preferable, but studies must be well-powered in order to establish reliable effects. Evaluating profile networks of inflammatory analytes is needed to understand the dynamic activation and suppression of analytes and provide a clearer understanding of immune system regulation as a whole, as compared to understanding of single analytes. Measurement of single inflammatory analytes provides only a small snapshot of a much larger and more complex picture that is the immune system. Finally, this study lacked assessment of variables known to affect inflammatory analyte levels, namely body mass index . While this study controlled for the effects of antipsychotic, antidepressant, tobacco, and cannabis use, BMI is highly associated with inflammation and thus may have confounded findings in inflammatory analytes. Taken together these results confirm existing research that individuals at CHR for psychosis demonstrate higher total childhood trauma as compared to unaffected comparison subjects and that history of childhood trauma is associated with increased positive psychosis-risk symptoms and worse global functioning. However, total childhood trauma was not associated with inflammation in this sample, thus analyses of the mediating effect of inflammatory analytes in the relationships between childhood trauma and clinical outcomes was non-significant. Instead,cannabis vertical grow this study suggests that total childhood trauma and inflammatory analytes independently predict positive psychosis risk symptoms and lower global functioning; thus, these independent effects are additive. These findings confirm the importance of assessing for childhood trauma and blood-based inflammation in at-risk subjects as a means to identify individuals who may be at the highest risk for poor clinical and functional outcome. Childhood trauma and inflammation may seem difficult variables to target through existing evidence-based psychotherapy interventions. However, there is a growing body of research that supports the use of complementary and alternative medicine psychosocial interventions that may effectively target these factors in psychosis. The goal of research of CAM in psychosis is to replicate results from studies conducted in the general population demonstrating that the use of mind-body interventions reduces reactivity to stress and chronic inflammation. For example, research Breines et al. demonstrated that higher levels of “self-compassion,” defined by Neff as “the attitude of treating oneself with kindness and non-judgmental understanding,” are associated with reduced IL-6 response in reaction to stress. More importantly, it has been demonstrated that self-compassion is not a “trait,” but rather a modifiable and alterable “state.” Cognitively-Based Compassion Training is a meditation-based program derived from Tibetan Buddhist mind-training that has been demonstrated to enhance empathy and compassion for oneself and others. Research on CBCT in medically stable populations by Pace et al. reveals 6 weeks of compassion meditation training reduced stress-induced immune responses in a stress-test design. Further, Pace et al. demonstrate that strength of reduction in immune response was not mediated by time spent meditating, indicating that benefits of compassion training are not dependent on long hours of practice. This is very relevant to the application and effectiveness of such techniques in children or adolescents, particularly those currently experiencing mental health concerns, given that it would be impractical to expect children with mental health concerns to engage in lengthy meditation practice. In fact, Pace et al. demonstrated the feasibility of CBCT in not only adolescents, but those in foster care with a history of early life adversity.

Moreover, foster care program adolescents with a history of childhood trauma demonstrated significant reductions in salivary CRP after just 6-weeks of compassion training. Compassion training has not yet been evaluated in CHR population, but there is evidence that adapted mindfulness-based interventions are not only safe and therapeutic for use in chronic psychosis populations, but also may help to decrease individual distress around positive psychosis symptoms, such as auditory hallucinations and delusions . A recent systematic review by Louise, Fitzpatrick, Strauss, Rossell, and Thomas on “third-wave” cognitive behavioral interventions in psychosis, reveals that acceptance-based interventions show moderate effects in reducing depressive symptoms, but no effect in reducing distress around psychosis symptoms or improving functional outcome. Randomized-controlled clinical trials utilizing mindfulness-based interventions for early-psychosis are currently lacking. Nonetheless, these techniques represent a promising category of psychosocial intervention warranting further study as they may modify reactivity to stress and immune response. Other CAM interventions that warrant further study in psychosis populations to target immune response and clinical outcomes include exercise, diet, and cannabidiol. Exercise and diet have been shown to have robust effects on reducing chronic inflammation and improving health outcomes in the adolescents . Research on aerobic exercise in psychosis groups has demonstrated very promising findings, indicating that moderately intense exercises, such as walking or bike riding, may improve positive and negative psychosis risk symptomatology, cognition, and functional outcome . Further, these effects have been replicated in CHR populations . Diet may be another window of opportunity for impacting clinical outcomes and immune response in psychosis. For example, a recently review by Stogios et al. reveals that unmedicated individuals with psychosis demonstrate increased appetite and cravings for fatty foods, which contribute to weight gain and metabolic disturbances known to be associated with higher levels of inflammation. Wu, Wang, Bai, Huang, and Lee revealed that a 6-month combined diet and physical activity program in schizophrenia subjects resulted in reduced BMI, improved metabolic profiles of insulin and triglycerides, as well as improved psychotic symptoms. Cahn, Goodman, Peterson, Maturi, and Mills demonstrated a 3- month mindfulness, diet, and yoga combined intervention resulted in increased levels of BDNF and increased cortisol awakening response in a population of medically stable adults. Research on novel therapeutics, such as cannabidiol , as a potential treatment for psychosis have demonstrated that CBD may not only have neuroprotective, antioxidant, and anti-inflammatory effects, but also improve disease trajectory of psychosis by reducing positive psychosis symptoms, anxiety, and cognitive deficits in first episode psychosis groups . To date, there are no studies evaluating the effects of diet, exercise, CBD, or combined interventions on immune response to stress in CHR psychosis populations; however, there is strong evidence to warrant further study of these interventions in CHR psychosis groups. Finally, therapeutic interventions that are known to improve clinical outcomes for individuals who have experienced childhood trauma may be particularly important in mitigating long term functional impairments in youth at clinical high risk for psychosis. Bendall, AlvarezJimenez, Nelson, and McGorry describe several recommendations to be considered for good, quality, assessment and intervention withing individuals at risk for psychosis endorsing a history of childhood trauma, including, systematic inquiry about childhood trauma for all individuals with psychosis, and development of individualized treatment plan adapted from cognitive behavioral therapy approaches for the treatment of psychosis and trauma, paying particular attention to pacing of treatment and repeated assessment.

History of childhood trauma is also highly prevalent in patients diagnosed with BD

Results are largely consistent with our hypotheses and previous research demonstrating higher rates of psychiatric comorbidity , emotion regulation difficulties, and reward sensitivity in ED-SUD samples. Partially consistent with previous research , our results suggested a trend towards a higher frequency of binge eating in ED-SUD, although there were no differences between ED and ED-SUD groups on purging. Furthermore, patients with bulimic syndromes were not significantly more likely to have a SUD. While this is somewhat inconsistent with previous research , results support examining substance use across ED diagnoses. In contrast, with previous research, we did not find evidence for higher levels of self-harm or BPD symptoms in the ED-SUD group. Previous research supporting increased self harm in ED-SUD has been in adolescent samples , which may also explain this discrepancy. While previous research has found higher cluster B symptoms in ED-SUD , the lack of significant differences between ED and ED-SUD in our sample may be due to the relatively high scores on the BEST in both groups. Indeed, both groups scored similarly to patient samples with BPD .Taken together with previous research, several of these findings have important implications for developing a treatment approach for the ED-SUD population, and provide a rationale for the usefulness of DBT to target these disorders concurrently.Overall, results demonstrating a greater number of comorbid diagnoses for the ED-SUD group support the need for integrated treatment, which is consistent with recent calls from experts within the field . DBT takes a behavioral approach, treating behaviors, regardless of their diagnostic association, according to a specific hierarchy. Given the complexity of ED-SUD cases and the tendency for these patients to vacillate between ED and substance use behaviors over time , an integrated, transdiagnostic approach may be useful in treating both behavioral presentations. Importantly,vertical growing rack we did not find evidence for ED diagnostic differences between ED-SUD and ED only groups, lending further support for a transdiagnostic approach to ED-SUD treatment.

DBT provides a comprehensive framework for effectively working with the multiple comorbidities observed in ED-SUD patients. In particular, the focus on the DBT hierarchy may help address vacillation between ED-SUD and other comorbid symptoms. The DBT hierarchy systematically addresses the most severe and life-threatening symptoms first, to help avoid shifting treatment targets throughout treatment. Additionally, skills generalization may be particularly important in this population. Phone coaching, which is a part of DBT, may be useful in helping patients to generalize skills to multiple behaviors across environments. Regarding specific disorders, the non-statistically significant elevation in the likelihood of PTSD in the ED-SUD group compared to the ED alone group suggests that trauma symptoms may be a relevant treatment target for ED patients generally. Indeed, groups are working to develop protocols for the concurrent treatment of ED and PTSD , while existing trauma protocols are commonly used to treat PTSD in these populations such as the DBT/Prolonged Exposure protocol .Our study shows that ED-SUD patients report significantly greater difficulties with emotion regulation. More specifically, ED-SUD patients in our sample endorsed difficulties with regulating behavior when distressed, engaging in goal directed behavior when distressed, and accessing strategies for feeling better when distressed. Moreover, ED-SUD patients were more likely to already be prescribed a mood stabilizer; thus, despite previous treatment for emotion dysregulation they continued to have difficulty in this area. This is consistent with our hypothesis and points to emotion regulation as a critical treatment target. As previously discussed, DBT was specifically developed to provide education on emotion dysregulation and provide individuals with adaptive emotion regulation skills. Several skills were added to the DBT for SUD model to specifically address the heightened impulsivity reported by ED-SUD patients. These skills include Burning Bridges to persons, places, and things associated with substance abuse and Adaptive Denial of urges for substance use.The present findings that patients with ED-SUD report higher reward sensitivity to highlight the importance of assessing for and addressing temperament in this treatment population.

Reward sensitivity may be an underlying mechanism that drives an individual’s substance use and ED behaviors. For instance, substance use and ED behaviors may be highly rewarding in the moment; hence, patients seek the short-term rewards of addictive behaviors despite their long-term, negative consequences. Furthermore, a potential obstacle to abstinence from ED behaviors and substances of abuse is the non-rewarding aspect of abstinence . Several skills taught in DBT for SUDs target these barriers. Contingency management strategies to reduce cues and access to substances and behaviors , as well as reinforcement of adaptive behavior, are essential to treatment. Specifically, Community Reinforcement , and Abstinence Sampling focus on the reinforcement of healthy behaviors. In conjunction with findings on reward sensitivity, the trend towards the significance of increased punishment sensitivity in this ED-SUD population suggests that for some patients, holding patients accountable to treatment goals and implementing consequences and rewards accordingly may be important for behavior change. For example, using behavioral contracts and administering drug analysis screens to monitor substance use may be helpful. The DBT skill of Pros and Cons may help patients to identifying negative consequences of substance use.The present study has several strengths, including the use of structured clinical interviews to assess diagnoses and an examination of a broad range of constructs theoretically relevant to eating and substance use disorders. As such, this study adds to the limited literature investigating factors characterizing the ED-SUD population. However, there are several limitations worth noting. First, participants were drawn from a treatment-seeking sample presenting at a higher level of care. As such, results may not be representative of individuals with ED-SUD in the broader community. The modest ED-SUD sample size may have limited our ability to detect significant differences between groups. Additionally, the present study did not assess tobacco use or caffeine use disorders, which may also be relevant substances for ED groups, given their association with appetite suppression. Further, although the present sample included males and non-binary individuals, the smaller numbers in these groups limits the generalizability of the results beyond females. Importantly, we did not assess the past history of SUD, so the relative influences of active substance use versus traits underlying substance use on our findings cannot be determined.

Finally, this study reviewed factors that provide a rationale for the applicability of DBT to treat EDs and co-occurring substance use in a cross-sectional study; however, future longitudinal studies and randomized controlled trials are needed to examine outcomes to determine the efficacy of DBT to treat ED-SUDs.Psychoneuroimmunology refers to the study of interactions between behavior, neural and endocrine systems, and the immune system . Alder and Cohen state that the field of psychoneuroimmunology is intended to “emphasize the functional significance” of the relationship between mind and body systems “in addition to” and “not in place of analysis of the mechanisms governing functions within a single system.” This growing field seeks to understand the associations between environmental exposures and neural, endocrine, and immune systems,cannabis vertical grow as well as the consequences of inflammatory responses on human behavior, to allow for new insights into mechanistic pathways that are involved in the development of psychopathology. Thus, identifying the impact of early life adverse experiences, such as childhood trauma, on immune system regulation, and subsequent clinical outcomes, such as functioning, provides important information regarding possible therapeutic targets for early intervention and prevention of psychopathology. Psychiatric illnesses that begin during adolescence and disrupt successful transition into adulthood represent one such category of mental disorders for which primary prevention is key, but therapeutic targets meeting the goal of prevention are lacking. This study seeks to provide rationale for and test the hypothesis that immune system dysregulation may serve as a biological mediator between the experience of childhood trauma and vulnerability for developing psychosis by evaluating associations between childhood trauma, inflammation, and clinical outcomes in a sample of subjects at clinical high risk for psychosis . Childhood trauma is defined as the experience of severe and/or chronic interpersonal stress including abuse or neglect . In the development of a validated childhood trauma assessment tool, the Childhood Trauma Questionnaire , Bernstein et al. defined subcategories of childhood trauma as follows: 1) sexual abuse is defined as sexual activity between a minor child and an adult or older person ; 2) Physical abuse is defined as bodily assault imposed upon a minor by an adult, which resulted in risk or experience of injury; 3) Emotional abuse is defined as verbal assaults on an individual’s sense of worth or well-being, including verbal humiliation, intimidation, or demeaning behavior directed towards a minor by an adult; 4) Physical neglect is defined as the failure of caretakers to provide for a child’s basic physical needs, including food, clothing, shelter, safety, and health care, as well as poor parental supervision if such behavior places a minor’s safety in jeopardy; and 5) Emotional neglect is defined as a failure for a caretaker to provide a minor with appropriate emotional support or validation. Sub-types of trauma differ in prevalence.

The United States Department of Health and Human Services Administration for Children and Families report that the national number of children receiving a child protective services investigation response increased 10.0% percent from 2013 to 2017 , with the national rounded number of victims in 2017 approximated at 674,000 children. Three-quarters of these victims experienced neglect, 18.3 percent physical abuse, and 8.6 percent sexual abuse . However, prevention of childhood trauma extends far beyond mere desire to protect children, as research has established that the consequences of childhood trauma are severe and long-lasting. Firstly, experience of childhood trauma increases risk for medical illnesses such as lung disease, arthritic disorders, cardiac disease, diabetes, and autoimmune disorders . Moreover, the development of medical disorders is found to be directly proportional to the number and magnitude of childhood traumas experienced . Secondly, experience of childhood trauma is associated with significantly increased lifetime risk for developing serious mental illnesses, such as major depressive disorder , bipolar disorder , post-traumatic stress disorder , schizophrenia , as well as personality disorders and substance use disorders . Research on sub-types of childhood trauma and early life stress reveal that physical abuse, sexual abuse, and neglect are associated with the development of mood disorders and anxiety disorders, while emotional abuse is associated with development of personality disorders and schizophrenia . Other studies have identified sub-types of emotional abuse and neglect to be among the most significant predictors of developing a mood disorder in adulthood . Experience of multiple childhood traumas is a significant predictor of increased chronicity of depression, increased suicidal behavior, as well as poor response to antidepressant or combined psychosocial and pharmacological treatment.Incidence of childhood trauma is a significant predictor for severity of manic and depressive symptoms, psychotic symptoms, rapid cycling, greater number of depressive episodes, and increased risk of suicide attempts in individuals diagnosed with BD Importantly, childhood trauma has been reliably shown to be associated with increased risk for developing psychosis later in life . Research on the relationship between childhood adversity and psychosis not only links childhood abuse and neglect to psychotic symptoms, specifically hallucinations, but also indicates that the relationship is causal, with a dose-effect . A large cohort study by , demonstrated that youth who experienced trauma in the first 17 years of life were 2.91 times more likely to have psychotic symptoms at 18 years of age, and those who experienced 3 or more types of childhood trauma were 4.7 times more likely to have psychotic symptoms. Exposure to trauma during childhood is associated with increased emotional and psychotic reactivity to stress in patients diagnosed with psychotic disorders . This increased stress reactivity may represent both an expressed genetic liability, as well as an acquired vulnerability due to exposure to traumatic events. Exposure to childhood trauma may actually sensitize patients with psychosis liability for the later exposure to daily life stress . In fact, Varese et al. , argues the relationship between childhood trauma and psychosis is so significant, that removing childhood trauma from the population would yield a 33% decrease in number of individuals with psychosis. While studies have repeatedly shown that experience of childhood trauma is associated with an increased risk for developing both physical and mental illnesses later in life, the biological mechanisms by which this risk manifests are less explicit .

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