The marijuana tax revenue makes spending increases more palatable to legislators

Posted on July 31, 2023 by hemp2022

Though cutting proved ineffective in communicating with her stepfather, it was apparently effective in a negative sense by addressing her emotional pain. In this sense for Maria cutting was anagentive practice and bodily technique operating in tandem with bulimia—one technique to take away pain and the other to gain attention—against the background of multiple interpersonal traumas. Finally, she was able to evaluate bulimia as something that worked, but in a bad way. Secrecy and isolation are themes for her even though her mother and aunt discovered her actions and initiated a trajectory of consultation with a school counselor leading to hospitalization; in fact, Maria had already spoken to the counselor before this event without telling her mother. It was her mother’s contact, however, that led the counselor to suggest treatment. Maria insisted that she had not cut herself since leaving the hospital.In a variety of ways, Colorado remains a state in transition. As is the case with many states around the nation, the economy continues to improve from the recession. Demographically, the state is becoming increasingly diverse. According to the census, more than one-fifth of state residents were Hispanic or Latino/a in 2015. Colorado’s population growth of nearly eight percent since 2010 ranks third behind only Texas and North Dakota. Politically, Colorado has been trending blue over the past several election cycles. Some have identified the migration of Californians into Colorado as a contributing factor to the state leaning further in the Democratic direction . The state awarded its Electoral College votes in 2008 and 2012 to the Democratic ticket,4 tier grow rack and the party appears poised to carry the state in 2016. A streak of two consecutive wins for the Democratic Party’s presidential candidates has not happened since Colorado voters supported Franklin Roosevelt in 1932 and 1936. Democrats emerged victorious in the last three gubernatorial elections and won three consecutive elections to the U.S. Senate beginning in 2004.

The state’s march toward blue-state status was interrupted in 2014, however, as Republican Representative Cory Gardner defeated incumbent Democratic Senator Mark Udall in a competitive race. Republican candidates in this election cycle swept three of the remaining four statewide races, and the GOP regained control of one chamber of the state legislature. The single bright spot for Democrats on election night 2014 was the reelection of incumbent Governor John Hickenlooper who narrowly edged out Republican challenger Bob Beauprez. Colorado continues to receive national and international attention over the legalization of recreational marijuana, which has important budgetary implications. Though revenues associated with legalized recreational marijuana have fallen short of early government forecasts, marijuana tax revenue continues to grow steadily. The sale of marijuana to adults over the age of 21 became legal on January 1, 2014. By the end of the year, the state received $44 million in revenue from recreational marijuana. Combined with the preexisting medical marijuana market, the state received $76 million in 2014 .1 Despite an improving economy and a new stream of marijuana tax revenue, legislators remain wary about approving new spending measures. This is partly attributable to uncertainty regarding potential tax rebates mandated by the Taxpayer’s Bill of Rights . In the current legislature, Democrats hold a slim majority in the House, while the Republican advantage in the Senate is by a single seat. An analysis of roll call voting in state legislatures concluded that the Colorado Legislature is among the most ideologically polarized in the nation . Divided government, coupled with greater ideological polarization, has made dramatic changes in spending less likely to be successful. Governor Hickenlooper’s approval rating remains above 50 percent, but he faces a divided legislature and does not enjoy substantial political capital, having barely survived a close reelection . When submitting requests to the Office of State Planning and Budget , departments must outline a strategic plan to accompany their request.

The governor’s budget request is submitted to the legislature in the fall. After consideration by the Joint Budget Committee , the full legislature typically passes the budget in May in time for the start of the fiscal year on July 1. The constitution mandates a balanced budget. Last November, the priorities reflected in Governor Hickenlooper’s proposed budget for the 2015–2016 fiscal year were similar to those in prior budgets drafted by the governor in collaboration with the OSPB. In his accompanying letter to the six-member JBC, the governor emphasized “enrollment and inflation increases for K-12 education, the return of General Fund support for transportation for the first time since FY 2007‒08 pursuant to S.B. 09‒228, increased caseload in the State’s Medicaid program, an anticipated decrease in the federal Medicaid match rate, the continuation of existing capital construction projects, and essential projects for the state’s information technology infrastructure” . Spending in just two areas—K-12 education and health and human services—constitute two-thirds of all proposed General Fund appropriations. Governor Hickenlooper’s budget letter detailed how economic progress in Colorado has outpaced the nationwide recovery. In that sense, the budget reflects a cautious optimism about the state’s economic well being. The Bureau of Labor Statistics reports that Colorado’s seasonally adjusted unemployment rate in December 2014 was just 4.0 percent. Tied for seventh lowest in the country , it is a product of 35 consecutive months of job growth. The national unemployment rate for the same month was 5.6 percent. After a decrease in gross state product in 2009, the state has logged increases averaging about 2.5 percent a year for the past four years, and per capita income levels have increased. Against this backdrop of economic improvement, the governor’s budget includes $26.8 billion in total spending with a General Fund allocation of $10.3 billion. The sums represent spending increases from the prior fiscal year of 7.0 percent in total funds and 9.6 percent from the General Fund . During the recent economic recession, General Fund revenue in current dollars decreased over two consecutive fiscal years. Since the low point of the 2009–2010 when the General Fund fell to $6.4 billion, this number has increased by an average of $0.65 billion over the past four years.2 A March 2015 estimate projected that General Fund revenue was on track to grow by nearly nine percent in the current fiscal year, but contraction in oil and gas industry-related activity is projected to slow revenue gains. The projected General Fund amounts for the fiscal years beginning in 2014 and 2015 are $9.6 billion and $10.3 billion, respectively. One novel aspect of this year’s budget debate is that economic gains are substantial enough that lawmakers will have to consider tax refunds under TABOR.

According to TABOR, which voters ratified in the state constitution in 1992, the state must issue tax refunds if revenues exceed the prior year’s spending after accounting for inflation and population growth. TABOR refunds have not been possible for at least a decade. The governor’s budget includes a rebate forecast in the amount of $167.2 million.3 Legislators may ask voters to forego refunds in lieu of providing spending in a number of areas. The governor’s budget letter outlines several contingency plans where additional legislation or voter approval may be necessary to enact the spending items it includes. The governor’s 2015–2016 budget proposed increasing appropriations from the General Fund for most state departments. Table 1 provides summary data comparing the proposed budget with spending levels from the prior year. The first items discussed in the governor’s budget letter concern education, which is among the governor’s highest priorities. Since Governor Hicken looper previously campaigned for passage of Amendment 66—a tax increase to fund K-12 education— it is not surprising to see his budget propose increases in education funding in the aftermath of its defeat. Put to voters on the 2013 ballot,cannabis grow racks Amendment 66 proposed an approximate 10 percent increase in the tax rate on income up to $75,000 and a 25 percent increase on income beyond $75,000. According to the state, the amendment would have raised taxes by $950 million in the first year following adoption. Despite the fact that supporters of the amendment raised in excess of $10 million to promote the measure, Colorado voters overwhelmingly rejected the tax increase with 64 percent of the electorate voting against it. Following this resounding defeat, the governor’s proposed budget seeks to increase education funding. The defeat of the tax increase to fund education could make more modest increases in education spending more acceptable to Republican legislators. Many Democratic lawmakers who supported the tax increase view the governor’s increase in K-12 spending as all the more necessary. Accordingly, the budget for the upcoming fiscal year increases total spending on K-12 education by 8.1 percent , an increase in per pupil funding of nearly $475 that brings total per pupil funding to about $7,500. Spending on higher education will increase by over $100 million after agreement was reached in 2014 on legislation limiting undergraduate tuition increases to no more than six percent in exchange for greater direct support from the state budget.4 General Fund increases for public institutions of higher education was set at about $75 million. This amount allocated to the governing.The governor’s budget continues to make investments in improving the Department of Corrections. Interest in directing greater funds to this area grew after the murder of Department of Corrections Director Tom Clements in 2013. The new director, Rick Raemisch, has championed meaningful prison reform. After increasing General Fund spending for the department by more than six percent last year, the 2015–2016 budget proposes a more modest increase of 4.0 percent, or nearly $30 million. The department estimates a small increase in the number of offenders housed in its facilities, and greater funding will allow the department to improve operations and facilities, including the addition of 330 beds. The state expects to hire more than 20 full-time employees to better assist people in the criminal justice system with mental health issues. A 1.0 percent provider rate increase is also included in the budget. The only departments with proposed reductions in General Fund spending were Public Health and Environment, Public Safety, and Revenue. Funding requested for the Department of Public Safety is 8.5 percent lower due to the absence of nearly $10 million in funding allocated to purchase aircraft and equipment for an aerial firefighting fleet.

These funds made it into the prior year’s budget after the state experienced one of the most devastating wildfire seasons in its history. Partially filling this void is a proposed additional $2.7 million in funding to go toward two new Colorado Bureau of Investigation forensic labs and a 1.0 percent increase for state community corrections program providers. Funding proposed for the Department of Public Health and Environment is 28 percent lower largely due to the absence of appropriations made last year to help communities recover from widespread flooding that occurred in September 2013. General Fund spending for the Department of Revenue is slated for reduction with the loss of a one-time appropriation of $6.2 million in the prior year’s budget to help the department modernize its operations. These anomalies explain most of the larger cuts in General Fund spending. The budget preserves the status quo in most areas with a few targeted increases.In 2012, when nearly 55 percent of Colorado voters cast ballots in favor of legalizing recreational marijuana use by adults over the age of 21 the state’s counties were nearly evenly divided on the issue. Thirty-three of the 64 counties had a majority voting in favor of legalization, while 31 counties were had more no voters. One of many reasons for the ultimate success of the measure was that localities were given the option to prohibit marijuana business.”A year-end analysis in The Denver Post noted that 23 Colorado counties currently permit marijuana cul-tivation, sales, or both . Within these counties, 53 cities or towns permit recreational marijuana sale. As of March 2015, the state had licensed a total of 341 retail stores to sell marijuana. Including those authorized to sell medicinal marijuana, the number of outlets is over 500 .A study by the Marijuana Policy Group found that the demand for marijuana in the state likely far exceeds prior estimates, although the total amount of tax revenue generated by the first year of legal recreational sales fell short of expectations . Using survey data, the study estimates about 13 percent of Colorado’s population used marijuana at least once in 2010 or 2011.

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The disease burden of alcohol and illicit drug addiction is the highest in the United States

Posted on July 27, 2023 by hemp2022

We examined CEMA by Latino youth in outpatient treatment and highlighted a number of important contextual factors related to AOD use. Better understanding context provides an immediate benefit by informing the development of general EMI content and strategies that use, for example, smartphone geo-location data to trigger in-the-moment interventions. The full capabilities of EMI can be recognized by using context to trigger EMI with content that is appropriate for the context. For example, real time advice delivered by EMI can differ depending on the time of day, location, and presence of peers. Social context appears to be an important contextual AOD-use factor in our study as it has in prior studies. AOD use was most frequently reported with close friends and while hanging out relative to other types of associations and activities, respectively. Alcohol by itself was more frequently reported at a friend’s house while marijuana and other substances were more frequently reported at other locations. Social context has traditionally been self-reported and in turn, difficult to harness in automated applications. However, there are promising developments in providing passive mobile data streams. Many users access social networking sites through their phones that leave digital footprints of social interactions. Phone logs are also recorded and can be accessed as other researchers have done . Social network information can be further refined by combining it with GPS location traces to determine time spent with friends at one of their homes. In our study, AOD use was more frequently reported in the afternoon and nighttime and about half the time on weekends. This is in line with other studies that have found AOD use to bemore common after school hours and on weekends . Alcohol consumption by itself was more frequently reported at night and on weekends relative to marijuana and other substances and warrants closer examination in larger samples.

Temporal information provides a good starting point for actionable EMI information. Date and time stamps can be passively collected without user burden and provide quantifiable information, such as weekend or weekday categories,wholesale vertical grow factories that can be incorporated into classifiers that trigger EMI. Cravings provided useful self-reported data, with strong cravings more frequently reported on AOD use days. Cravings can be categorized in a binary fashion with reporting operationalized as a button on a phone’s desktop for easy access and more frequent reporting. Random prompts can be used throughout the day to query cravings similar to Piasecki et al. . This offers an improvement over our study design in the ability to better understand temporal context for AOD use. Affective states are multi-faceted and more difficult to quantify. Happiness tended to be the most frequently reported affective state across CEMA strategies, but were reported to the same degree when AOD use did and did not occur. Thoughts of wanting to get buzzed were more common for alcohol use alone and thoughts of relaxation were more common for marijuana and other substances. Reports of context, cravings and affect were robust to CEMA reporting strategy, whether reports were based on recall or in the moment. An exception was that marijuana use was most commonly reported in the morning based on recall and only reported in the afternoon based on EBA. In-the-moment RA does not provide a comparison as youth were not prompted in the morning. Further study is needed to see if time-of-day differences in reporting marijuana hold in larger samples. Overall robustness in reporting context is encouraging and suggests that there is flexibility in using different CEMA strategies. Flexibility in assessment is important with youth in consideration of school activities and other events that may make it difficult to implement one assessment strategy. Next steps call for studies with larger sample sizes to examine overlap between contextual factors and explore temporal relationships with AOD use, similar to multilevel analyses by Piasecki et al. that analyzed nicotine use in mostly white youth.

The small number of participants, low rates of AOD use, and missing data due to non-response made this impractical in our study and are limitations. This hampered our ability to provide subgroup analyses by age and gender; both characteristics are linked to AOD use and context . There is variation in the degree of AOD use across participants that may also relate to context but was impractical to explore in our sample. Caution is also warranted in generalizing our findings for normative samples of AOD users as participants were in a substance abuse treatment program. Lastly, RA occurred once a day after school hours and more closely mimicked EoDA than true RA that typically occurs multiple times a day. Our assessment scheme limited our ability to address the second hypothesis and explore if different assessment methods elicited different types of AOD use-related context. Notwithstanding sample size limitations, our sample is representative of Latino youth in outpatient treatment. We did not see evidence of self-selection to participate in our study; there was a lot of interest to participate. The use of a study phone and free cell phone minutes that accompanied participation provided strong incentives. Enrollment was limited by the number of study phones. Interest in our study highlights an important opportunity to develop substance use interventions for youth through a medium they already use in their daily lives.Spontaneous EBR has become increasingly popular as a putative behavioural marker of endogenous dopamine. Interestingly, most of the past studies that have used sEBR in this capacity have loosely referred to ‘dopamine function’ or ‘dopamine activity’, perhaps reflecting the current dearth of knowledge regarding which specific aspect of the dopamine system correlate with sEBR. Here we tested the hypothesis of a positive relationship between sEBR and striatal dopamine synthesis capacity, based on the proposal that sEBR is positively related to striatal dopamine function , and previous results showing a positive correlation between sEBR and striatal dopamine levels measured in post-mortem monkey brains . Both frequentist and Bayesian statistics, as well as ROI and voxel-wise analyses, argue against the existence of such a positive relationship in our sample and show that, if anything, the evidence is in favour of a negative relationship.

While we prefer to refrain from making speculative interpretations regarding the existence of a negative relationship, given the moderate level of evidence, we believe these data provide a strong cautionary message against the use of sEBR as a positive predictor of pre-synaptic striatal dopamine. Importantly, our data speak specifically to dopamine synthesis capacity and do not preclude correlations of sEBR with other aspects of the dopamine system, including dopamine D2 receptor availability. It has been suggested that sEBR might primarily reflect striatal D2 receptor activity, based on the observation of a positive correlation with D2 receptor availability in monkeys , and the observation that sEBR better predicts D2-mediated punishment learning than D1-mediated reward learning . However, this relationship between sEBR and dopamine D2 functioning has been recently questioned by a PET study which failed to replicate it in humans . Also, such a relationship remains difficult to reconcile with recent findings showing a positive association between dopamine D2 receptor availability and dopamine synthesis capacity , as this would predict a positive relationship between sEBR and dopamine synthesis capacity, in contrast to our results. These inconsistencies certainly call for further research to better elucidate the dopaminergic mechanisms underlying sEBR. This study is not devoid of limitations. First, our sample size is relatively small, although one should note that it is larger than the samples used in many of the psychopharmacological studies that have investigated dopaminergic drug effects on sEBR . In fact, a power analysis performed with GPower3.1 suggests that a sample size of 12 individuals should have been sufficient to replicate with 95% power the positive relationship reported by Taylor et al. between striatal dopamine levels and sEBR in monkeys . In addition,grow rack as argued by Dang et al. , the use of sEBR as a reliable predictor of dopamine function implicitly requires that the positive relationship between these two variables should be strong and thus observable even in small samples. For these reasons, we believe that the preliminary evidence reported here is valuable, even though a replication in a larger sample size is warranted. Another aspect that may be perceived as a limitation is the use of a mixed population of healthy participants and pathological gamblers. While we acknowledge that pathological gamblers are not typical individuals and are characterized, among other things, by elevated striatal dopamine synthesis , we believe that this is not necessarily an issue in the context of the current study. Indeed, our goal was to examine whether individual differences in sEBR and dopamine synthesis were positively related, regardless of the origin of these individual differences. If sEBR is to be used as proxy measure of dopamine levels, it should be insensitive to the underlying causes of individual variations, so that it can be effectively used in both clinical and non-clinical populations. In fact, a large portion of the literature that has led to the hypothesis of a link between sEBR and dopamine function is based on the study of clinical populations characterized by dopamine dysfunctions. Finally, one should note that restricting our analyses to healthy individuals did not affect the results, still showing moderate evidence against a positive correlation.

To conclude, our study does not support the hypothesis of a positive relationship between sEBR and striatal dopamine synthesis, and if anything, provides evidence against it. Even though it is based on a modest sample size and needs to be replicated in a larger sample – which we are currently attempting to do, it warrants caution for future studies that may be tempted to use sEBR as a proxy measure of striatal dopamine synthesis capacity.Misuse of substances is common, can be serious and costly to society, and often goes untreated due to barriers to accessing care. Globally, 3.5 million people die from alcohol and illicit drug use each year. Over 20 million Americans had a substance use disorder in 2018, 73% had an alcohol use disorder, 40% had an illicit drug use disorder, and 13% had both alcohol and illicit drug use disorders. Approximately half of Americans with an SUD had a co-occurring mental illness. Treatment of depression and anxiety, the most common psychiatric comorbidities among patients with SUDs, may reduce craving and substance use and enhance overall outcomes. In 2018, less than 1 in 5 individuals with a SUD received addiction treatment. Alcohol and illicit drug misuse and addiction cost the United States over US $440 billion annually in lost workplace productivity, health care expenses, and crime-related costs. Potential effects on individuals include an array of physical and mental health problems, overdose, trauma, and violence. Web-based interventions and digital health apps may reduce or eliminate common, significant barriers to traditional SUD treatment. Preliminary evidence suggests that digital SUD interventions affect substance use behavior and have the potential to reduce the population burden of SUDs. To date, most digital SUD interventions have been delivered on a web platform, rather than via mobile apps. The widespread use of smartphones makes app-based intervention delivery a viable and scalable medium. In 2019, about 8 out of 10 White, Black, and Latinx adults owned a smartphone. Although lower-income adults were less likely to own a smartphone than higher-income adults, they were more likely to rely on smartphones for internet access. In a 2015 survey, 58% of mobile phone owners reported downloading a health app. Texting is the most widely and frequently used app on a smartphone, with 97% of Americans texting at least once a day. Automated conversational agents can deliver a coach-like or sponsor-like experience and yet do not require human implementation assistance for in-the-moment treatment delivery. As recent meta-analytic work suggests, conversational text-based agents may increase engagement and enjoyment in digitized mental health care, whereas most general mental health care apps face difficulty sustaining engagement with high dropout. Conversational agents can provide real-time support to address substance use urges, unlike traditional in-person frameworks of weekly visits. The scale potential of conversational agents is unconstrained, immediate, and available to users in an instant. Being nonhuman based also reduces perceived stigma.

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The conservation of FUN makes it likely to be an important gene in plant development in general

Posted on July 26, 2023 by hemp2022

Many DELLA mutants are constitutive repressors of the GA response and they have been made famous by the socalled “Green Revolution” which included wheat and rice plants that were dwarfed by their inability to respond to GA. Both D8 and D9 maize mutants do not respond to application of GA3 that causes an increase in height in normal siblings. Neither D8 nor D9 are as short as plants treated with PBZ, nor as short as GA biosynthetic mutants like d1, which suggests there are other GA receptor pathways in addition to D8 or D9 in maize.BLASTing the non-redundant maize genome with the FUN protein found partial homology to a region on chromosome 6, where chromosome 3 is known to have duplicates. This region does not translate into a continuous peptide chain, which could mean that duplicates of this gene are punished by selection. BLAST retrieved closely conserved homologues to FUN across the grasses. With PSI-BLAST it was possible to collect homologues of FUN throughout the Plant Kingdom, including Amborella trichopoda, Rosids, Asterids and nongrass monocots. The resulting tree assembled by MAFFT from these proteins fell into the same distribution as the APG IV phylogeny105, and is therefore assumed to be reliable . Alignment of the diverse family of FUN proteins revealed conserved regions , including one of the regions predicted by NucPred to be involved in nuclear localisation, which may be important to the function of FUN. Though BLASTing of ZmFUN only found one hit in the Brassicales , using the C. papaya gene as a BLAST query returned more Brassicale hits,vertical grow manufacturer allowing the retrieval of an Arabidopsis thaliana homologue. The Brassicales were found to have retained the FRWW, MRLM and KKR motifs, but not the GAKHIL motif . RNA-seq datasets published by Stelpflug et al. tracking different stages of maize development106 showed that the FUN transcript is highly expressed in the developing seed and endosperm.

The next highest peaks were: developing leaves, especially the base; immature and meiotic tassels; and the immature and pre-pollination cob. FUN transcript was detected in all samples examined in Stelpflug et al.’s dataset . Walley et al. collected transcript and protein from 23 developing maize tissues and mapped them to the v4 genome. FUN was also examined in this data set, where the highest transcript reads were found in developing leaves, and were much lower in mature leaves. Endosperm levels were still high, but not as extreme as seen in the dataset of Stelpflug et al. Unfortunately, immature tassels were not sampled, but strikingly, no FUN transcript was detected in mature pollen, unlike all other tissues sampled. Relatively high levels of FUN transcript were found in the female spikelet, as well as some in the silk . The proteomic data mapped to v4 did not return anything for FUN, but mapped to v3, high levels of protein were found in the endosperm and the developing leaves, but not the mature leaf, nor any other tissues sampled . No phosphorylated peptides were detected in any tissue sampled. Since these datasets were highly generalised, a dataset created specifically to query auricle development in maize was also used.A dataset created by Kong et al. compares developing B73 auricles with those of the inbre. B73 has what can be considered normal auricles, while the auricles of 986 are much smaller . Developing auricle tissue was collected at three stages and RNA-seq libraries were made. According to Kong et al.’s dataset, FUN is found at equal levels in the early auricle of both B73 and 986. At mid auricle development, both B73 and 986 drop, but 986 is lower than B73. Both have dropped to low levels by late auricle development . Thus, various RNA-seq datasets were used to give indications of where FUN localised at the macro level. Next, various software were used to predict where FUN localised at the sub-cellular level.The entire FUN protein amino acid sequence was entered into NucPred, an online tool for prediction of nuclear proteins as well as PSORT, which predicts sub-cellular localisation given a protein sequence.

The entire FUN protein sequence was entered into the PSIPRED prediction tool , which runs multiple protein folding and interaction predictions to come to a synthetic prediction for the structure and function of a given protein sequence. NucPred gave the FUN amino acid sequence a score of 0.98 on a scale of 0.1-1, with a score of 1 indicating certainty that the protein is nuclear . The k-NN Prediction provided by the online program PSORT lists FUN as 91.3% likely to be nuclear and 8.7% likely to mitochondrial. FFPred, part of the PSIPRED package, also agreed that FUN is likely to nuclear. FFPred also predicted that FUN is likely to be involved in DNA and RNA interactions, is likely to be involved in cytoskeletal and DNA binding, and has a high percentage of serines and glutmamic acid . DISOPRED, also part of the PSIPRED package, predicted that most of the FUN sequence can be defined as disordered, though the first 50 amino acids of FUN are not predicted to be disordered . In sum, FUN transcript is found in developing leaves and tassels, which fits with the phenotype of the mutant. FUN transcript is also found in developing ears, which is surprising since an ear phenotype was not observed. Higher levels of FUN during leaf development are associated with larger auricles. FUN is predicted to be a disordered protein that localises to the nucleus. Attempts were then made to validate these predictions. Y2H, using the FUN protein as bait, and a cDNA library of immature ears and tassels as prey, retrieved a list of 234 possible interactors. Using the A. thaliana homologues of these proteins in a GO term biological process analysis found enrichment for proteins involved in negative regulation organ, specifically flower, development; and proteins involved in negative regulation of nucleic acid metabolic processes . The A. thaliana homologues were enriched in transcription factor activity and hydrolase activity according to a GO term analysis based on molecular function , and most of these predicted interacting partners were nuclear or cytosol localised. The GRMZM numbers were also run through the GO term analysis prediction software provided by AgriGO and were found to be enriched in GTP and GTPase binding . A table of selected genes returned by the Y2H can be seen in Figure 5-7A. One such gene is ZmDWF1.

This brassinosteroid synthesis protein was found to have a synergistic interaction in double mutant analysis with fun . Another gene implicated in the brassinosteroids pathway was BSL1 that is known as an inhibitor of BRI1. The strongest confidence hit for the Y2H as an interactor for FUN was tubulin, butthis may be a false positive due to the high concentration of this protein in a cell.In order to test the idea that FUN is nuclear-localized, I carried out a transformation experiment using Nicotiana benthamiana. The entire FUN protein was fused to an N terminus YFP as described in Methods. The FUN-YFP fusion was found to localise to the nucleus in transformed N. benthamiana pavement cells. This result was observed in two separate transformations. Though not all nuclei in the samples were found to fluoresce under YFP excitation, this is likely due to imperfect transformation efficiency and is normal in this kind of experiment109. 25 nuclei expressing YFP were photographed and many more observed during the course of this experiment; YFP expression was not observed in any other sub-cellular regions. In order to confirm that the YFP expression was nuclear, the leaves were also examined under 405nm excitation. Since the leaves had been infiltrated with DAPI prior to examination,vertical grow marijuana system this caused the DNA to fluoresce. YFP fluorescence was shown to overlap with this DAPI fluorescence . As further confirmation, the sample was also examined under bright field and the YFP fluorescence was thus seen to overlap with clearly visible nuclei . This was observed at the microscope, as well as by overlapping micrographs using ImageJ. Close inspection of individual transformed nuclei revealed a nuclear speckle pattern . In order to make an antibody to the FUN protein, the purified protein has to be injected into a living animal and the antibody produced must then be purified. To this end, the third exon of FUN was amplified by primers 53xF/R and cloned into pENTR. Recombining with pDEST17 was unsuccessful. I hypothesised that FUN may be toxic, which would explain why the expression plasmid would not grow, though pENTR would grow, so bacteria were grown at lower temperatures. This was also unsuccessful, so a smaller fragment out of the exon was used, amplified from cDNA with primers An2F/R . This 600bp fragment was successfully cloned into pDEST17. Interestingly, the other fragments attempted that contained the conserved GAKHIL motif did not clone into pDEST17 under the conditions used, which could imply a toxicity of this domain, since all fragments that did not contain the GAKHIL motif were successfully cloned.The newly made plasmid pDEST17-An2F/R was then cloned into Rosetta cells and grown into a 100ml culture overnight. This culture was used to spike 1 litre of fresh LB. After 4 hours of growth at 37°C this culture reached 0.42 OD600nm and 200μl of 1M IPTG were added. This culture was then shaken at room temperature for 5 hours and spun at 8000 RCF for 15 minutes at 4°C. The resulting pellet was resuspended in 75ml of lysis buffer . This was spun at 12000 RCF for 15 minutes and the supernatant co-incubated with 2.5ml of 50% Ni++ beads in EtOH slurry.

The beads were spun and washed several times using wash buffer and were finally eluted using elution buffers at pH 4.4, 3.8 and 3twice each. Most protein was recovered from the second pH 4.4 and first 3.8 elutions as measured by nanodrop. These samples were then run on an SDS gel and the correct size band was observed for An2F/R samples, but nothing was observed for An1F/R. Thus the protein produced by plasmid pDEST17-An2F/R was purified. It was then resuspended in 6M urea by dialysis in a side-A-lyser cassette and sent to Cocalico for injection into guinea pigs. Test-bleeds and pre-bleeds were returned from the company. The pDEST17- An2F/R protein product was blotted onto nitrocellulose and incubated in 2ml of PBS with 2μl of test-bleed or 2μl of pre-bleed for 2 hours before washing and incubating in PBS and anti-Guinea Pig Alkaline Phosphotase fusion antibody. Finally this was incubated in NETN and NBT/BCIP to give an output of purple colour if the antibody is reacting to the protein . Later, second bleeds were returned by the company, and this dot-blot process was repeated, along with the sera from another antibody as a control . Thus, it was confirmed that the guinea pigs were producing appropriate antibody. In order to purify the terminal bleeds, a GST-tagged version of the protein was made. The pENTR-An2F/R was therefore combined with pDEST-15, transformed into Rosetta cells and induced and spun down as for the pDEST17- An2F/R purification step. This pellet was resuspended in NETN and put through a French press twice at ~1000lbs of pressure before 2x 20s of sonication to shear DNA. Triton X-100 was then added to 0.5%. This cell lysate was then spun at 12,000 RCF for 15mins and the supernatant was added to 2ml of 50% glutathione-sepharose beads equilibrated in 10ml NETN. After co-incubation during which the GST-tagged protein should bind to the beads, the beads are spun down and washed several times with 0.2M Borate pH8. The washed beads are then transferred to a column and cross-linked to the beads using DMP solution before washing with 0.1M glycine-Cl pH2.5 to remove non-covalently linked molecules and a final wash with 1xTBS . The terminal bleeds were thawed and 1/10 volume 10xTBS was added. This TBS-serum was then incubated in a column containing beads bound to GST for 30min at 4°C. Thus any antigens specific to GST that might be in the guinea pig sera would bind to these beads and the eluate from this column should be free of such contaminants. This eluate was incubated in the column described in the preceding paragraph and incubated at 4°C for 1 hour. Thus any antibodies specific to the FUN fragment should bind to these beads.

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The dogma of evolutionary theory states that change must occur by incremental mutations

Posted on July 25, 2023 by hemp2022

A historical theory for why imperfect flowers might be beneficial was that it could promote out crossing. Clearly a dioecious species is an obligate out crosser, since the male and female flowers exist on separate plants. However, it is not so clear that this would be true for monoecious plants. It was hypothesised that if monoecy were to promote out crossing inherently, monoecious plants would not have to rely on other costly mechanisms to promote out crossing such as molecular self-incompatibility . Studies have not shown this to be the case, indeed monoecy is just as common in self-compatible species as it is it in SI species5 , though of course this does not rule out the possibility that avoiding self-fertilisation could still be a factor in the evolution of imperfect flowers, especially for dioecious plants. Instead of making a theory and trying to find data to support it, it is more fruitful to look at the natural world and make a theory to explain it. For this, we might ask: “what kinds of plants are likely to bear imperfect flowers?”. Analysis of large datasets has shown that species with imperfect flowers are likely to be viniferous or woody, wind-pollinated plants with small green flowers, and for dioecious plants, the bearing of fleshy fruits2 . One theory proposed by Bertin to explain enrichment in wind-pollinated plants is the relatively low cost of their flowers allows for monoecy to develop. Monoecy is more expensive than perfection because a plant with unisexual flowers will have to produce two sets of flowers where asingle perfect flower would suffice, thus Bertin argues, it is only when flowers are relatively cheap that monoecy can be permitted. Bertin’s theory does not explain why monoecy might be desirable, instead it merely states why it might not be punished. Since monoecy is not uncommon in plants, there must be some kind of advantage. Again, we should turn to direct observations of the natural world to explain this. As we have seen,vertical grow bench wind pollinated plants are more likely to evolve monoecy than insect pollinated. Indeed, all gymnosperms are wind pollinated and can be thought of as dioecious or monoecious since they bear micro- and macrostrobili.

When we consider the flowers of a wind pollinated angiosperm tree such as hazel, the benefit of the separation of the sexes becomes immediately apparent. The benefit is specialisation. Male hazel inflorescences hang from the branch; their primary role is in dispersal of gametes and their hanging habit allows for the efficient dispersal of pollen by the wind. On the other hand, the primary role of female flowers is the reception of gametes – female hazel flowers fulfil this end by having tentacle like protrusions that catch pollen from the air. Insect pollinated plants have no such need for specialisation – in fact they need the same insects to visit both the male and female flowers. While Bertin’s theory may explain how monoecy is permitted, the advantages bestowed by specialisation explains how it can become fixed. It has further been proposed that pistils that are separated from stamens might be more effective in being pollinated because they avoid “pollen interference”. Self-pollen could clog the tip of the pistil, stopping pollen from other plants from reaching into the stigma. It could also begin to grow down into the stigma and even if it is stopped at the micropyle the pollen tubes could partially or completely block the micropyle, again interfering with fertility mechanistically. This would be especially true for wind-pollinated plants that produce copious amounts of pollen that fills the surrounding environment, fitting with the observation that wind pollinated plants are more likely to have imperfect flowers. Despite the elegance of this theory, it remains to be confirmed, and studies in gynodioecious Plantago maritimax and representatives from the Lamiaceae8 failed to find evidence for an female advantage due to lack of interference from self-pollen. Finally, the potentially high cost of female flowers has been suggested as a driver towards imperfection. Hermaphroditic flowers must produce nectar, petals, sepals etc., stamens, ovules and fruits and seeds. A male flower must produce a + b, while a female flower must produce a + c + d. Even if the fruits and seeds are aborted at some stage, there is still the cost of their inception, for example the monoecious Cucumis spp. make fairly large prefruits on their female flowers long before pollination. When fruit and seeds are especially large , unisexual flowers can allow a plant to produce pollen without committing large reserves of resources to ovules, fruits and seeds.

As we shall see, andromonoecy is more common than gynomonoecy, which fits with this theory.If our starting point is a perfect flower as seen in most angiosperms and the basal Amborella trichopoda and Magnoliidae, and the unisexual flower is the derived state what are the intermediary steps from hermaphroditic flowers to a monoecious or dioecious species? Protogyny and protandry, androand gynomonoecy, along with andro- and gynodioecy, present themselves as intermediaries between perfection and monoecy or dioecy. Almost all of these states have been shown experimentally to be intermutatable. Once these states arise, they can remain environmentally plastic, or become fixed: in monoecy by the evolution of strict developmental pathways; and in dioecy by the evolution of autosomal sex determining loci or true sex chromosomes.One of the first steps towards unisexual flowers is thought to be the temporal separation of male and female function in hermaphroditic flowers6,9 . This separation is most often thought of as a strategy for promoting outcrossing and/or reducing pollen interference. The temporal separation of the sexes allows them to begin evolving as separated pathways, and can eventually lead to true unisexual flowers.C. bulbosum is an annual from the Apiaceae common by riversides in Europe. The plants are andromonoecious – bearing both hermaphroditic and male flowers in their umbelliferous inflorescences. Andromonoecy is common in the Apiaceae, and appears to have evolved multiple times from dioecy within this group. Some Apiaceae are protandrous , highlighting the role this sexual form may play in the evolution of andromonoecy. C. bulbosum has been shown to respond to damage and pollination restriction by increasing its ratio of hermaphroditic to male flowers in order to ensure seed set. Thus, this plant is able to respond to environmental cues by changing its sex ratios to enhance reproductive success. Andromonoecy is thought to be a more common first step towards monoecy than gynomonoecy because the benefits of avoiding commitment to female flowers is more obvious, as discussed above.In androdioecious populations, both hermaphroditic and male plants exist.

It has been proposed that in such a situation, the population will naturally tend toward true dioecy because hermaphroditic flowers cannot compete with the high pollen production of exclusively male flowers and will therefore tend to become more female. While this has not been shown experimentally, the inverse has. By removing all male plants from a population of M. annua, pollen production by the hermaphroditic plants was shown to increase over 3 generations as compared to the control group12, implying that the hermaphroditic flowers are compensating for a lack of pollen. This implies that the hermaphrodites in the wild, unmanipulated populations are restricting their pollen production and perhaps also enhancing female function as a response to the males in their population. This may mean that M. annua is providing us with a snapshot in evolutionary time of a species on its way towards evolving dioecy .Gynomonoecy, where plants bear female and hermaphroditic flowers, is a very rare sexual state. In a survey of Occupied Palestine, Sinai and Jordan, only 0.4% of plants were listed as gynomonoecious. Further,vertical grow cannabis most gynomonoecious plants are of the Asteraceae, where female ray florets surround perfect disc florets. It is not likely that the femininity of these ray florets underlies their evolution and maintenance – rather it seems that these are specialised flowers that serve as pollinator attractors. Overall, gynomonoecy has been understudied as a sexual system in plants, partially due to its rarity and partially because it is not thought to be important as a sexual system. Gynomonoecy does appear in domesticated species such as cultivars of Spinacia olearacea, which is usually monoecious, showing that gynomonoecy represents a possible route between sexual systems in plants .Given the rarity of gynomonoecious species, it is perhaps surprising that gynodioecious species are so prevalent. Perhaps specialising as female on a separate plant is more beneficial than doing so on the same plant. Further, Given the rarity of gynomonoecious species, it is perhaps surprising that gynodioecious species are so prevalent. Perhaps specialising as female on a separate plant is more beneficial than doing so on the same plant. Further, Monoecy in Zea mays is rigidly controlled with an apical male inflorescence and axillary female inflorescences. This is not simply a relic of domestication – teosinte also bears its female inflorescences laterally to its male inflorescences. Likely, this spatial separation and elevation of the male tassel enhances the specialisation of these inflorescences. Monoecy does not have to follow this strict habit though. In Cucumis spp. the flowers alternate unpredictably between male and female along the shoot. Another vine, Freycinetia funiculari, preferentially makes male flowers early in its life before switching to female flowers later in development.

Postponing growth of female flowers makes sense because of the greater resource investment required, especially for vines which may spend years beneath the canopy waiting for full sun. Charles worth and Charles worth briefly discuss the evolution of monoecy. They argue convincingly that monoecy must evolve from hermaphroditism through a series of at least two mutations, through the intermediary steps of gyno- or andromonoecy. Charles worth and Charles worth further postulate that these genes would have no tendency to be linked, unlike the mutations leading to dioecy which must be linked. Confirmation of this theory comes from Erin Irish’s work in stacking the maize mutations of the tasselseed and dwarf class. The tasselseed mutants fail to abort the silk in the male tassel, rendering them female; and the dwarf mutants restore perfection to the female flowers. Together these two mutations change the monoecious maize plant into a plant that bears only perfect flowers. Singly, the dwarf mutants in Zea mays and the CmACS7 mutant in Cucumis sativus are capable of changing these monoecious plants to andromonoecious plants, showing this rote of evolution of monoecy . The Cucumis sativus mutant CmWIP1 represents a change from monoecy to gynodioecy suggesting a route from monoecy to dioecy. Monoecy is able to convert to dioecy, as shown by the high number of monoecious families containing nested dioecious species but I believe it would be a mistake to consider monoecy merely a stepping stone to dioecy. Unlike dioecy, monoecy allows plants to retain their ability to be both mothers and fathers, but allows specialisation of floral forms that is so crucial for wind pollinated plants. From a human perspective, monoecy has been a powerful tool in the genetic manipulability of Zea mays, allowing both hybrid crops and extensive genetic research in the modern era .As we have seen, gyno- and androdioecy lead towards dioecy. When plants in a population become sex specific, there is an evolutionary pressure for hermaphrodites to specialise in the other direction thereby producing a dioecious population. Dioecy can also evolve from monoecy, as predicted by dioecious species nested within monoecious evolutionary groupings9 . Simple dioecy is not the end of the road – it can become more and more fixed and derived as evolutionary time proceeds. It is thought that at first dioecy is characterised by simple sex determining regions in the genome. These will often be clustered on a single autosome as is the case in Populus balsamifera. In this species, an SDR has been described on chromosome 1917. This region includes 13 genes, one of which is a paralogue of methyltransferase1 . Another gene within the region is a cytokinin signaling gene PbRR9 and methylation of this gene is predictive of sex of the tree21. P. balsamifera is therefore a less derived dioecious species which still relies on epigenetic modifications for its sex determination loci that reside on autosomes.

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Tolerance to baclofen may also develop with chronic administration

Posted on July 24, 2023 by hemp2022

Not all individuals with AUD consider abstinence to be a goal of their recovery; only 2–6% of goals set in patient-driven treatment center on attaining alcohol abstinence. Non-abstinent recovery, including reductions in drinking and heavy drinking in particular , has been recognized to have health and societal value and has gained traction as a treatment target . Indeed, non-abstinent AUD recovery has been shown to be sustainable for up to 10 years following treatment. Despite growing recognition of the benefits of harm reduction, however, the most commonly prescribed pharmacotherapy to treat AUD remains disulfram, a medication advised strictly for abstinence. Furthermore, the heterogeneity of AUD suggests that it will be unlikely that one single medication will be effective for all individuals with an AUD. Therefore, there is a pressing need for the development of novel, diverse, and effective pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. The focus of the current review is to summarize pharmacotherapies for AUD with a clinical perspective. Specifically, this review provides a brief overview of currently approved medications and identifies new and repurposed agents “on the horizon” for which evidence indicates a potentially effective application toward AUD treatment.The following sections examine pharmacotherapies approved or in-development for AUD. Medications were selected for this qualitative review by considering gaps in existing review articles and the expertise of all authors; information was gathered via qualitative PubMed literature searches. This review is organized into sections based on drug approval status, namely approved medications, rolling vertical grow racks repurposed medications, and novel agents. Within each medication section, we examine the basic mechanism of action, evaluate preclinical research testing the efficacy of the medication in mitigating alcohol-related behaviors in animal models, and review clinical findings from human laboratory studies and randomized controlled trials where available.

We also examine the tolerability and potential personalized applications of each drug by identifying populations in which the drug may be particularly effective, and indicate treatment targets . This information is summarized in Table 1. We conclude by discussing future directions for the development of pharmacological treatments and precision medicine for AUD.This section briefly describes medications currently approved by agencies in many countries including the US FDA and EMA for the treatment of AUD: disulfram, acamprosate, and naltrexone , as well as nalmefene, which is EMA-approved. This section also reviews baclofen and sodium oxybate, which are medications approved for AUD treatment by agencies in European countries but not by the FDA or EMA. As many of these pharmacotherapies have been extensively discussed in the literature, our review of these medications primarily focuses on clinical trials and recent meta-analyses.Disulfram, the first medication FDA-approved for AUD treatment , is an aldehyde dehydrogenase inhibitor that acts by blocking the metabolism of alcohol, increasing acetaldehyde concentration. Acetaldehyde, a toxic metabolite of ethanol, produces an alcohol-induced aversive response, characterized by nausea, vomiting, sweating, flushing, and heart palpitations. Unsurprisingly, these unpleasant effects give disulfram a relatively poor adherence rate. Disulfram may also act on dopamine systems, as its major metabolite inhibits the enzyme dopamine betahydroxylase , which aids in metabolizing dopamine into noradrenaline. Serum DBH activity is associated with withdrawal symptoms, and disulfram has been shown to reduce serum DBH levels. A meta-analysis of 22 RCTs found that disulfram saw increased success rates compared to placebo in open-label studies only—blinded trials yielded no statistical significance between disulfram and placebo. However, while these findings do not appear to support the use of disulfram for treating AUD, this outcome may be due to placebo effects. Research showed that placebo-treated individuals showed decreases in cue-reactivity to alcohol stimuli in a sample of 38 participants, and experiencing an acetaldehyde reaction did not necessarily improve treatment response in a sample of 46 participants . Instead, a patient simply being aware of a potential adverse reaction appears to be enough to influence drinking behavior.

Disulfram ingestion under supervision saw significantly better success rates compared to non-supervised treatment, suggesting that supervised administration of disulfram may still have a place in treating individuals struggling to attain sobriety, and unsupervised disulfram may also be helpful for individuals highly motivated for abstinence. However, adherence management issues limit the utility of disulfram in the treatment of AUD, and the disulfram-ethanol interaction can sometimes present as a medical emergency. Therefore, disulfram is only recommended in the maintenance of abstinence; using this medication to reduce drinking is not advised.While the specific mechanisms through which acamprosate works to treat AUD remain under investigation, it is thought to act on the glutamatergic system as an N-methyl-d-aspartic acid receptor partial co-agonist. This may reduce neuronal hyperexcitability, a phenomenon that occurs in acute withdrawal and protracted abstinence from alcohol. A meta-analysis of 27 RCTs with a total of 7519 participants found that acamprosate treatment reduced risk of abstinent patients returning to any drinking, but did not reduce rates of binge drinking. A number of trials have also found that acamprosate did not show a significant beneft over placebo. In particular, a large scale trial , which compared acamprosate, naltrexone, and behavioral therapies, both individually and combined with each other, against placebo , found that acamprosate had no significant effect on drinking in comparison to placebo, either alone or in combination with naltrexone and/or behavioral intervention. Placebo effects in this trial may explain some of these negative outcomes, as might differences in trial design and patient characteristics: COMBINE required 4 days of pre-trial abstinence while European trials with positive outcomes were typically conducted in inpatient populations requiring complete detoxifcation. Overall, however, a Cochrane meta-analysis of 24 RCTs with 6915 participants found that acamprosate significantly reduced the risk of any drinking and increased cumulative duration of abstinence. Acamprosate is generally well tolerated and may also have neuroprotective effects. As chronic alcohol abuse is associated with neuronal changes related to NMDA receptors, this neuroprotection may be particularly important in AUD treatment.

Acamprosate is recommended for the achievement and maintenance of complete abstinence, rather than for the reduction of drinking or prevention of relapse in the event of drinking. It is FDA-approved for abstinence maintenance in AUD patients who are abstinent when beginning treatment.Naltrexone, the best-studied of these three commonly approved medications, was originally approved to treat opioid use disorder. Naltrexone is an antagonist of the mu opioid receptor . By attenuating alcohol-induced opioidergic activity in the mesolimbic dopamine system, opioid antagonists like naltrexone, modulate the rewarding effects of alcohol , thereby reducing alcohol consumption. In 1994, the FDA approved oral naltrexone to treat alcohol dependence after two independent 12-week trials, which included 97 and 70 participants, respectively, found that naltrexone significantly decreased drinking days and relapse rates. Additional recent trials demonstrate that naltrexone reduces the rewarding effects of alcohol, alcohol craving, drinks per drinking day, and relapse rates, strengthening the initial findings. Extended-release injectable naltrexone , administered once monthly by a medical professional, may be beneficial for individuals who are more sensitive to naltrexone’s adverse side effects or have difficulty adhering to oral medication. A six-month multisite trial of 380 mg injectable naltrexone in 624 patients with alcohol dependence found significant reductions in heavy-drinking days versus placebo . However, evidence for naltrexone remains mixed. Another RCT reported no significant differences between naltrexone and placebo , and that the clinical utility of naltrexone was limited by its adverse effects. Additionally, clinical trials of naltrexone often yield modest effect sizes. A meta-analysis of 53 naltrexone RCTs with a total of 9140 participants found naltrexone to significantly reduce both the risk of return to any drinking and return to binge drinking; however, both of these associations were modest in magnitude. Oral and injectable naltrexone show similar decreases in likelihood of binge drinking and both are generally well tolerated,vertical cannabis grow racks with fairly mild side effects. Importantly, however, naltrexone does block the therapeutic effects of opioid analgesics and can precipitate opioid withdrawal in patients who have developed physical dependence to opioids; therefore, individuals who are prescribed naltrexone for AUD must be monitored for opioid use and withdrawal. Of note, naltrexone is contraindicated for patients with acute hepatitis or liver failure, and should be “carefully considered” in patients with acute liver disease, potentially limiting its use in the alcohol-associated liver disease population. In summary, naltrexone appears to have a moderate effect on the reduction of alcohol use.Nalmefene works in a similar manner to naltrexone as an antagonist at the mu and delta opioid receptor, but is also a kappa opioid receptor partial agonist. Via its kappa agonist activity, particularly centered in dopaminergic nucleus accumbens circuitry, nalmefene may reduce motivation for self-administration and withdrawal-induced alcohol consumption. Nalmefene was approved by the EMA in 2013 for the reduction of alcohol consumption among patients with AUD.

Approval followed findings from three multicenter 6-month clinical trials enrolling 604, 667, and 718 individuals, respectively, in which participants took the medication or placebo on an as-needed basis. In these trials, nalmefene decreased total alcohol consumption and heavy-drinking days. However, the drug’s approval based on these studies has received criticism due to limited evidence of efficacy, especially as these trials were conducted only against placebo rather than an active medication comparison. A more recent meta-analysis of the efficacy of nalmefene, which included fve RCTs , found that participants treated with nalmefene had 1.65 fewer heavy-drinking days per month than participants treated with placebo after 6 months. Studies indicate that nalmefene is associated with more adverse events and study dropouts compared to placebo, and the most frequently reported of these are dizziness, nausea, vomiting, insomnia, and headache. Overall, while nalmefene may reduce heavy-drinking rates, its effects on other outcomes remain small-to-moderate, and study withdrawals related to adverse events are common in nalmefene trials. However, similar to naltrexone, this medication may appeal to patients with goals of reducing alcohol consumption and those reluctant to engage in abstinence based treatment.Baclofen acts on the γ-amino butyric acid system as a GABAB agonist. It was approved for treatment of AUD in France in 2018 and has been used of-label for AUD for over a decade in other countries, especially other European countries and Australia. Clinical trials of baclofen have produced mixed results. A recent meta-analysis of 12 RCTs showed that baclofen in comparison to placebo was associated with higher abstinence rates; however, it did not increase abstinent days or decrease craving, heavy drinking, depression, or anxiety. Another meta-analysis of 13 RCTs indicated that baclofen was associated with longer time to relapse and a larger percentage of abstinent patients. Furthermore, greater alcohol use at baseline was correlated with a greater treatment effect. In contrast, however, another recent meta-analysis of 12 RCTs with 1128 total participants found no significant differences between baclofen and placebo in primary or secondary outcomes of interest ; however, baclofen did increase depression and adverse effects including sedation and vertigo. Baclofen’s significant adverse side effects include drowsiness, sedation, headache, vertigo, confusion, perspiration, muscle stiffness and/or abnormal movements, slurred speech, and numbness.Additionally, dose and sex may moderate baclofen tolerability and response; escalation of dosage in response to developing tolerance can increase sedative side effects, which affect women significantly more than men at the same dose. Importantly, cessation or reduction in dose can precipitate potentially life-threatening withdrawal syndrome. The variability in baclofen’s effectiveness seen across studies may be partially explained by high baclofen pharmacokinetic variability seen among individuals with AUD. This heterogeneity is an important factor to take into account when considering baclofen as an AUD treatment . Of note, there is also some evidence that baclofen might be particularly useful in treatment of AUD among individuals with liver disease. In summary, baclofen seems to effectively promote abstinence; however, it shows mixed results regarding its clinical effects on non-abstinence outcomes , significant adverse side effects, and inter-individual variability in response. As such, baclofen as a treatment of AUD—as well as its optimal dosage—continues to be debated.Sodium oxybate , the sodium salt of gamma-hydroxybutyrate , has been utilized as a medication for a number of disorders. SMO is approved in Italy and Austria for the treatment of AUD. SMO acts on the GABA system both directly as a GABAB partial agonist and indirectly through GHB-derived GABA. A Cochrane meta-analysis of 13 RCTs with a total of 649 participants found that SMO was effective compared to placebo in the treatment of alcohol withdrawal syndrome and in preventing relapses in previously detoxifed participants, and that SMO was more effective than naltrexone and disulfram in maintaining abstinence.Another recent meta-analysis found that SMO, compared to placebo, increased abstinence rates by up to 34% in a sample of 711 participants with very high drinking risk levels.

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The study also revealed additional findings regarding BUP dose and treatment retention

Posted on July 21, 2023 by hemp2022

Other findings of the study are also consistent with prior literature, including higher dose related to longer retention, use of other drugs associated with lower retention, and opiate use during treatment negatively related to dose for both groups. The unique contribution of the present study is that these findings were confirmed with this randomized trial conducted in community treatment programs in the U.S.First, approximately 25% of the BUP participants dropped out within first 30 days of treatment, suggesting a critical period calling for special efforts in retaining these participants. Second, of those who remained in treatment, positive opiate urine results were significantly lower among BUP relative to MET participants during the first 9 weeks of treatment. This finding confirms the advantage of BUP requiring a much shorter time for induction than MET. Third, there was a linear positive relationship between BUP dose and the treatment completion rate, suggesting the benefit of dosing greater than the common practice of a maximum dose of 16mg. However, even with the highest BUP dose level of 30–32mg allowed in this trial, the retention rate was less than the rate in the MET group , and approximately 30% of the participants continued opioid use. Besides additional strategies focusing on retaining BUP participants beyond 30 days of treatment, these findings suggest that participants may yet fare better with BUP doses higher than the 32mg used in this study. Given the generally high safety profile of BUP and the lack of any significant side effects and other adverse effects at the high dose range observed in this study, we believe with proper monitoring safety will not be a clinical concern in such an effort.Finally, the study has identified additional participant characteristics predicting dropout, including being young, Hispanic, and concomitant use of heroin or other drugs such as cannabinoids,grow cannabis cocaine or amphetamine during treatment. Treatment programs may consider paying special attention to patients with these characteristics to prevent dropout. It should be noted that our finding on cannabinoids is in contrast to most prior studies that have found no effect of the use of cannabis on methadone treatment outcomes including treatment retention.

A potential explanation for this discrepancy may be that strains of marijuana available more recently, when the current study was conducted, have been deliberately bred to have high concentrations of delta-9-tetrahydrocannabinol making them much more potent and potentially more destabilizing for patients on opioid maintenance therapy. The study has several limitations. There were limited measures of participant motivation and program and community characteristics that are likely to influence treatment retention. Reasons for dropout were coarsely recorded; although the data did indicate that many more BUP participants simply discontinued their treatment. A qualitative study of this sample has suggested that BUP participants reported negative physical reactions or did not like BUP,being previously familiar with MET, and thus dropped out.The findings must also be taken in the context of an open-label, unblinded clinical trial. Despite these limitations, the study revealed several important findings as discussed earlier. Given the linear trend of higher BUP dose related to increased retention, future studies should investigate if BUP doses greater than 32mg should be considered to increase retention, and perhaps to further reduce opioid use during treatment. One study which examined BUP doses of 24–56mg/d among 650 patients showed a retention rate over 92% at 30 months and, similar to the present investigation, decreasing rates of illicit substance use at the higher doses.In research or clinical practice, BUP is often prescribed at a dose of 16mg or lower, as BUP is an opioid partial agonist with a ‘ceiling effect’ for respiratory depression and in previous human laboratory studies, higher doses of BUP revealed a flattening out of the dose-effect curve, i.e. increasing doses do not result in greater changes in subjective measures or respiratory rate.A recent review article indicates that the risk of respiratory depression associated with BUP is lower than with other opioids including methadone.It appears that the current common practice of prescribing at a dose of 16mg per day and not to exceed 32mg maximum is driven by the ceiling effect observed and a few PET scan studies showing high mu receptor occupancy as well as concerns about diversion.However, these studies were based on small samples and do not take into account inter-individual variation and the other potential non-mu effects of BUP.

History has taught that for about 20 years it was common to have MET dose ceilings of 40mg per day, but it is now well established that this is inadequate to maintain the necessary plasma concentrations to be effective; the effective range is between 60mg and 120mg or higher per day for most patients.The current study suggests the possibility of BUP at a dose of 32mg or higher having a potential impact on improving treatment retention and outcome. Thus, further investigations of the safety, efficacy, and clinical utilities of higher doses of BUP should be considered. The high dropout rates at the early phase of BUP treatment suggest the need for early interventions to prevent dropout. It is possible that more intensive psychosocial support could help, although studies to date indicate little benefit to increased counseling for patients treated with buprenorphine.An alternative approach as propounded by Kakko et al. and demonstrated efficacious in a randomized trial is prompt, early transfer to MET of patients who do not quickly stabilize on BUP.A more widespread introduction of contingency management into opioid treatment programs could also help to optimize retention and outcomes for both BUP and MET.Finally, heroin-assisted treatment is used in several European countries with success, particularly for people with opioid dependence who continue intravenous heroin while on methadone maintenance or who are not enrolled in treatment.BUP retention may also be improved with take-home doses as permitted by regulation and as standard in office-based practice supervised by physicians, which obviates the need for daily attendance in clinic for dosing. As described earlier, the trial was conducted among community methadone maintenance programs and thus may not be optimal for delivering BUP treatment. The nine clinics were all federally licensed opioid treatment programs that have provided treatment with methadone for many years. All staff and most participants had previous experience with MET, and participants came to these programs for methadone treatment. Because BUP was delivered within these methadone maintenance programs, all programs delivered BUP following the same rules and regulations for methadone prescription ,indoor cannabis grow system precluding the flexibility and individualization possible in office-based treatment that may help to retain some patients.The differential retention of males by medication condition has no definitive explanation and deserves future investigation. Since opioids suppress the hypothalamic-pituitary-gonadal axis leading to lower testosterone levels, it may be that BUP, as a partial agonist, does so less than MET, and thus males find BUP more tolerable in that regard.

In conclusion, the study findings suggest the need to investigate the use of higher medication doses, particularly for BUP, address continued use of opiate and other drugs such as cocaine, amphetamines, and cannabinoids, and further study and identify factors/ strategies influencing BUP retention, particularly during the first 30 days of treatment in order to help in efforts to improve engagement and retention in opioid treatment programs.The cannabinoid system has an important impact on liver-related fibrosis, steatosis, regeneration, and portal hypertension. Endocannabinoid ligands are ubiquitous and interact with cannabinoid receptors 1 and 2, which have high affinity for tetrahydrocannabinol , the psychoactive mediator of marijuana. Under physiologic conditions, hepatic expression of CB1 and CB2 is weak or absent. However, both receptors are up-regulated in a variety of liver diseases, including alcoholic and nonalcoholic liver disease, liver fibrosis, chronic hepatitis C, primary biliary cirrhosis, and hepatocellular carcinoma. Limited studies have examined the impact of THC use and liver fibrosis progression, with conflicting results. Some cross sectional studies have shown evidence of increased fibrosis, and other longitudinal studies of relatively short duration suggest no impact on fibrosis progression. Data are lacking on the influence of long-term THC use on liver-related outcomes such as fibrosis in human immunodeficiency virus /hepatitis C virus –coinfected individuals. For this reason, we sought to examine the impact of THC use on liver fibrosis progression in a well-characterized cohort of women coinfected with HIV and HCV.The Women’s Interagency HIV Study is a prospective, multi-center, longitudinal observational cohort of adult women infected with HIV or at high risk of acquiring HIV, described in detail elsewhere. Approximately 30% of HIV-infected women enrolled were coinfected with HCV prior to enrollment in WIHS. A total of 4137 women have been enrolled in the first 3 enrollment cohorts . All women gave informed consent at entry, and the study was approved by each center’s institutional review board. Patients are seen in follow-up every 6 months, where detailed sociodemographic, medical, and behavioral data are collected through structured interviews, physical examination, and biologic specimen collection. As of visit 37 , a total of 790 women with HIV/HCV coinfection at baseline had enrolled in the WIHS into cohorts 1 and 2, and were included in our analysis. HIV infection was confirmed by positive HIV enzyme-linked immunosorbent assay and a confirmatory Western blot, and HCV infection was defined as a positive result for serum HCV RNA at entry into the study. THC use is prevalent in the WIHS; 14% of participants regularly use marijuana, and 6% report daily use. Liver biopsy is not performed as part of the WIHS observational study. However, noninvasive markers of liver fibrosis, aspartate aminotransferase to platelet ratio index , and FIB-4 have been validated in this cohort.Sociodemographic data including age, ethnicity, race, and past substance use were collected at entry into WIHS. Biologic specimens were collected at visits every 6 months with testing for liver enzymes, renal function, complete blood count, CD4 count, and HIV RNA load. HIV RNA was measured using the isothermal nucleic acid sequence–based amplification method with a lower limit of detection of 80 copies/mL.

Highly active antiretroviral therapy was defined by the contemporaneous US Department of Health and Human Services guidelines. Second- or third-generation enzyme immunoassays were utilized for HCV antibody detection and confirmed by documenting HCV RNA seropositivity and by reverse transcription polymerase chain reaction . Hepatitis B was tested within the first year of enrollment and was defined as hepatitis B surface antigenemia. Data including body mass index, history of hypertension, diabetes, and insulin resistance were collected. Diabetes was defined as any fasting glucose measurement of >126 mg/dL, hemoglobin A1c measured at ≥6.5%, or self-report of taking antidiabetic medication.Discrete variables were summarized using frequency and percentages; continuous variables were summarized using mean and standard deviation for normally distributed data, and median and interquartile range for non-normally distributed data. Comparisons between THC use groups were made using the χ2 or Fisher exact tests for categorical data and analysis of variance or Kruskal–Wallis tests for continuous data. The cumulative probability of progression to advanced fibrosis was estimated using the Kaplan–Meier method and compared by THC use category with the log-rank test. All analyses were 2 tailed, with P < .05 considered statistically significant. Risk of progression to advanced fibrosis was evaluated separately for FIB-4 and APRI outcomes using Cox proportional hazards regression. Hazard ratios and 95% confidence intervals were calculated from the models. To account for the fact that patients must remain alive to enter the study, age at study entry was treated as a left-truncated variable with age used as the time scale. Patients were followed until their first visit with significant fibrosis or were censored at the date of last fibrosis measurement for those not progressing to the event. Factors with a univariable P < .1 and THC use were evaluated in the multi-variable model. The model was selected by backward elimination with P > .05 for removal from the model. The final model included 2 additional variables: biologically relevant HCV RNA and evaluate whether long-term THC exposure impacted fibrosis progression. We also conducted sub-analyses in participants with at least mild fibrosis to evaluate whether the presence of some fibrosis is a prerequisite for THC to modulate fibrosis progression. Data were analyzed using SAS software version 9.4 .

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Outliers were determined as values greater than 3 standard deviations from the grand mean

Posted on July 20, 2023 by hemp2022

The objective of the current study was to assess everyday functional ability in four groups of individuals stratified based upon their HIV status and history of METH dependence, using the UPSA-2 to assess the individual and interactive effects of HIV and METH dependence on specific and essential domains of everyday functioning. We hypothesized that participants with both HIV infection and a history of METH dependence would have lower scores on the UPSA-2 than subjects with either condition alone and non-infected non-METH dependent comparison subjects. A secondary aim was to assess to what extent performance on the UPSA-2 measures would correlate with HIV illness features , and METH use characteristics within our HIV+ and METH-dependent participants, respectively. This investigation was a component of the Translational Methamphetamine AIDS Research Center , which is a multi-project center grant focused on translational approaches to understanding the combined effects of HIV and methamphetamine dependence on brain structure and function. The UCSD Human Research Protections Program approved the study. All human participants in the TMARC cohort were included. Participants were stratified by HIV and METH dependence status into one of four groups: HIV−/METH− , HIV−/METH+ , HIV+/METH− , and HIV+/METH+ . HIV infection was determined by Enzyme-linked immunosorbent assay and a confirmatory Western blot. The presence and history of METH use disorders were determined via the DSM-IV criteria for METH abuse and dependence as assessed by the Composite International Diagnostic Interview Version 2.1 [CIDI; ]. Participants who met criteria for both lifetime METH dependence and METH abuse or dependence within the past 18 months were included in the two METH+ groups. Potential participants were excluded if they reported histories of psychosis or significant medical or neurological conditions known to affect cognitive functions.

To minimize the confounding effects of acute drug use ,cannabis vertical farming participants who tested positive for METH or any other illicit drugs were also excluded. In the first domain, comprehension and planning skills were assessed by having participants read a fictional article about the opening of a theme park and then described the activities at the park and planned a trip to the recreational facility. Financial ability was evaluated by a counting change task and having the subjects identify important aspects of a utility bill. Communication skills were assessed through role-playing tasks that asked participants to use telephone to schedule a medical appointment. The Transportation domain involved reading and interpreting a generic bus route and planning the use of a public bus system. Household skills were assessed by requiring preparation of a shopping list for a specific cooking task based on food items presented in a mock pantry. Finally, for the Medication Management domain, participants were required to organize a medication routine where they were asked to role-play how they would take a number of different medications over the course of a single day. Administration of the UPSA-2 requires about 30 minutes. Each of the UPSA-2 domains generates a raw score that is converted to a domain score ranging from 0 to 20 points. The 6 domain scores are summed to create a total UPSA-2 score up to a maximum of 120 points, with higher scores indicating better performance. For the purpose of examining the UPSA-2 measures in relation to HIV disease characteristics and METH use patterns, participant characterization data were drawn from the TMARC parent study. Selected HIV disease-related variables included current and nadir CD4+ T-cell counts, plasma viral loads, and self-reported duration of HIV infection. Self reported METH use characteristics were collected using a comprehensive timeline follow back procedure and included age of first use of METH, days since last use of METH, total days of METH use, and total quantity of METH used.UPSA-2 total and sub-scale scores were examined for outliers, normality of distribution, and homogeneity of variance. In order to preserve the relative value of these data points and retain power, outliers were truncated to within 3 standard deviations of the mean, per published methods . A total of ten outliers were truncated .

Main effects of HIV, METH, and their interaction on UPSA-2 performance were examined for the Total Score and sub-scale scores using Univariate Analysis of Variance . Three between-subjects factors were entered into the models, as well as their interaction: METH status , HIV status , and education level . Years of education was selected a priori as an additional between-subjects factor given the difference in education among the groups, the significant relationship between education and UPSA scores , and previous reports of a significant relationship between education and UPSA scores . Planned contrasts were conducted on the four groups. When other demographics were associated with the sub-scales, those factors were included in the analysis to account for their effects . Pearson’s correlation coefficients were used to assess the relationship among UPSA-2 scores and HIV disease characteristics as well as METH use features. An independent samples test was used to assess difference in UPSA-2 scores between participants with and without a detectable plasma viral load. The HIV viral load measure and METH use measures were significantly positively skewed; log transformations of those variables were thus entered into the analyses. All analyses were performed using SPSS 20. Significance values were set at p < .05, and effect sizes were calculated using partial Eta-squared and Cohen’s d.See Table 1 for demographic information and HIV and METH features. The groups did not differ by age or ethnicity, but a greater proportion of the HIV−/METH− group were women. The HIV−/METH+ group had significantly fewer years of education and lower scores on the Wide Range Achievement Test than the other three groups. Consistent with previous literature , all three risk groups had higher scores on a depression scale, the Beck Depression Inventory , than the HIV−/METH− group. Global Deficit Scores , a gross index of neurocognitive deficits , were lower in the HIV−/METH− group but not significantly different among the three risk groups. Participants in the METH groups had a higher prevalence of lifetime substance use disorder than the METH-negative groups. Ten participants had a positive urine toxicology for cannabis; these participants did not have significantly different UPSA-2 scores than the remainder of the cohort. Better-educated participants performed better on the Financial and Communication sub-scales , with a trend toward Medication Management and Comprehension sub-scales . Thus, education level was included as a between-subjects factor in the analyses.

Higher WRAT-4 scores were positively correlated with higher scores on the Medication Management, Financial, Communication, Transportation, and Household Management scales . Given that WRAT-4 performance is an index of premorbid verbal intelligence, which in turn is highly dependent on education level, including education in the analyses was intended to account for the group differences in premorbid intelligence as reflected by both education and WRAT-4 scores. Men and women did not differ on most UPSA-2 measures although women performed better than men on the Communication sub-scale. The analysis involving Communication was thus repeated with gender as a between-subjects factor in a univariate ANOVA to account for its influence. The two HIV+ groups did not differ on any HIV illness features,cannabis drying racks and the two METH+ groups did not significantly differ on self-reported METH use history and characteristics. Approximately 70% of the HIV+ subjects reported current use of ART medications ; this proportion did not differ in the METH− vs. METH+ groups nor did the groups significantly differ on duration of ART treatment. All participants were taking a nucleoside reverse transcriptase inhibitor ; 56% were also on a protease inhibitor ; 33% were on a non-nucleoside reverse transcriptase inhibitor ; 15% were on an integrase inhibitor ; and 6% were on an entry inhibitor . A small proportion of participants on ART had a detectable plasma viral load; these participants were equally distributed in the two METH groups.People with METH dependence evidence difficulty with tasks of daily living , as do those with HIV infection , and in combination these risk factors result in an additive effect on self-reported everyday functioning . However, the combined effect of METH dependence and HIV has not previously been investigated with the use of performance-based functional measures that are likely a better reflection of an individual’s actual real-world functioning than self-report. We expected that there would be an additive deleterious effect of METH and HIV given previous findings of worse neurocognitive impairment in dually-affected participants. Contrary to our hypotheses, people with both HIV infection and METH dependence showed impairment on a performance-based measure, the UPSA-2, which was equivalent to that evidenced by individuals with either condition alone. It is important to note that the three risk groups performed comparably and it is unclear why having two risk factors did not result in disproportionately worse performance relative to those with single risk factors.

The lower level of education in the HIV−/METH+ group does not account for the findings, nor does use of ART. The number of individuals with a detectable viral load despite ART use, which may reflect sub-optimal adherence to ART but may also indicate non-responsivity to ART, was not different in the two HIV groups. We were likely under powered to detect effects of ART non-adherence and differential effects of specific ART regimens. Although Blackstone and colleagues did observe additivity of HIV and METH on a composite measure of everyday functioning that was largely comprised of self-reported information , the present findings are consistent with an earlier report of a lack of additive effect of METH and HIV on self-reported measures of functioning . Our group and others have previously observed an additive effect of METH and HIV on neurological and neurocognitive functions , but the current results are consistent with findings based on other neurobehavioral and neuroimaging markers. For example, additive effects of HIV and METH were not observed for behaviors associated with frontal systems dysfunction, including sensation-seeking, impulsivity/disinhibition, and apathy; moreover, a similar pattern of results was observed for impulsivity/disinhibition such that an HIV-by-METH interaction revealed an effect of METH among HIV-negative participants but not in the HIV-positive group . There is also some neuroimaging evidence that the combination of these two conditions mitigates brain changes that are seen in HIV infection or METH dependence alone . Additionally, though not assessed in the current study, age may be relevant. Although some cognitive functions such as impulsivity and risky decision making may decrease with age in the general population , a recent study found that older HIV+ individuals with a history of METH dependence did have substantially poorer functioning than younger participants, possibly suggesting increased vulnerability to combined risk factors in the context of aging. The average age of the current sample was just 40 years thus we could not examine the effects of aging. Studies are in progress to further investigate the impact of aging on cognition and functioning in METH and HIV. An alternate reason that the dual-risk group does not appear to have worse everyday functioning than either risk group alone may be the fact that METH users who must manage their HIV disease face challenges of everyday living when compared to their METH– dependent, HIV-negative counterparts that force them to develop skills that would detected by the UPSA-2. For example, they must navigate the medical system in order to obtain and maintain healthcare—relevant tasks would include transporting themselves to medical appointments, managing extensive and sometimes complex medication regimens, and other challenges that could negatively impact treatment adherence . Therefore, participants in this group may be relatively “practiced” at meeting the demands of everyday living. Social factors may be relevant; e.g., having an HIV-positive partner could result in the modeling of adaptive health behaviors such as medication adherence and drug abstinence . A comparison of the demographic, HIV illness features, and METH use features of the current dually-affected cohort and the relevant cohort in the Blackstone et al. study suggests a somewhat more cognitively intact and healthier group in the current study with higher WRAT-4 scores, more education, higher CD4 counts, higher prevalence of ART use, and less METH use compared to the Blackstone et al. participants.

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Exaggerated emotion reactivity to stress has been related to poorer health

Posted on July 19, 2023 by hemp2022

These results indicate that METH may not only hinder brain development and The present study examined how differences in the stress response related to substance use in a sample of Mexican-origin youth growing up in a low-income region with high levels of adversity . Using a longitudinal study design, we tested whether differences in HPA axis reactivity and emotion and recovery to stress at age 14 were associated with use of alcohol, marijuana, and cigarette use by age 14 ; use of alcohol, marijuana, cigarettes, and vaping of nicotine by age 16; and onset of alcohol, marijuana, and cigarette use between ages 14 and 16. Finally, we tested whether associations between stress reactivity, stress, recovery, and substance use varied by poverty status and sex. Substance use greatly increases during adolescence, as the percentage of students who have used an illicit drug doubles from 8th to 10th grade, and nearly half of students report using at least one substance by 12th grade . Although experimentation is common in adolescence, youth who use alcohol, tobacco, and marijuana earlier in adolescence are at higher risk for psychopathology and substance use disorders in adulthood . Previous research has also consistently found that use of alcohol and marijuana by ages 14 and 16 specifically are related to poorer adjustment and higher use later in adolescence and adulthood . Risk is particularly high for Latinx adolescents, who show higher lifetime use of varied substances by 8th grade and by 12th grade compared to White and Black youth, and tend to begin using cigarettes, alcohol, and other drugs at earlier ages than other ethnic minorities . Furthermore, prior research suggests that Mexican American adolescents, specifically, are more likely to have initiated substance use by the eighth grade than non-Latinx and other Latinx youth . People generally respond to stress by showing increased negative emotion, decreased positive emotion, and activation of the HPA axis, a biological system especially sensitive to social-evaluative stressors .However,cannabis grow kit inability to mount a response or showing blunted reactivity to stress may suggest disengagement and has also been related to poorer well-being .

Dampened reactivity and recovery following stress have also been related to poorer health including depression and externalizing problems . Individuals can show blunted rather than exaggerated stress reactivity and recovery for many reasons . Individuals who experience chronic or repeated stress may initially show heightened emotional and biological stress reactivity and recovery, and these responses may habituate and show a blunted profile over time . Therefore, whereas unpredictable, acute stressful life events may promote a profile of exaggerated reactivity to stress, living in adversity can serve as a chronic stressor and consequently can promote inflexibility of psychobiological systems over time, such that individuals are incapable of responding to acute stressors . Indeed, youth and adults who experience more adversity generally show blunted rather than enhanced cortisol and heart rate reactivity to acute stress , as well as reduced activation of neural regions involved in threat such as the amygdala . It has been posited that individuals who experience high levels of adversity may be inclined to disengage from stressors, which can attenuate psychobiological reactivity and recovery . Lastly, low reactivity may result from socialization from peers and parents . For instance, youth who experience adversity may interact with deviant peers or bullies who prompt them to be less responsive to stress and may be socialized by parents to be less affected by daily stressors . Just as heavy substance use can dysregulate HPA axis function , dysregulation of the HPA axis may also contribute to substance use risk. Youth with blunted HPA axis reactivity to stress may lack physiological inhibitory control, such that they may be less inhibited by the social consequences of risk-taking compared to adolescents who show greater cortisol reactivity to stress . Alternatively, adolescents with chronic under arousal may be generally more inclined to pursue risky behaviors to promote physiological arousal . Youth may not show cortisol reactivity to a stressor because they are not sensitive to that stressor, or because they have already become elevated in anticipation of a stressor .

That is, certain youth may be more responsive to the threat such that they already show elevated levels of cortisol prior to stress onset and consequently show no further elevation in cortisol thereafter. Both blunted cortisol reactivity and anticipatory cortisol have been associated with more frequent substance use later in adolescence, especially among youth with difficulties in emotion regulation . Dysregulation of HPA axis function may similarly promote risk for lifetime substance use during adolescence. Adolescents with higher basal cortisol had earlier onset of substance use, although cortisol was not assessed following stress , and blunted cortisol secretion in anticipation of a laboratory task has been linked to greater substance use in pre-pubertal boys . Given the potential for bidirectional associations between HPA axis function and substance use, longitudinal studies are needed to disentangle whether HPA axis reactivity to and recovery from stress relate to risk for substance use onset during adolescence. Specifically, it is well-established that heavy substance use—as opposed to substance use initiation or less frequent substance use—can dysregulate physiology , so researchers may be best positioned to examine the role of physiology on substance use risk during adolescence when youth are initiating substance use but have not yet engaged in heavy substance use. In addition to cortisol reactivity, emotion reactivity to stress may relate to substance use. There are several emotion-related risk factors for substance use and substance use disorders in both adults and adolescents, including greater negative emotions, emotional lability, and emotional dysregulation . Although it is well-established that emotions influence frequency of substance use among users, it remains unclear whether emotion reactivity to stress relate to adolescents’ risk for substance use initiation. Emotion reactivity to stress often includes increases in negative emotions of both high arousal and low arousal and decreases in positive emotion, and each form of emotional change can have unique implications for health . Youth with exaggerated and dampened stress reactivity and recovery with respect to emotion may be particularly at risk for earlier onset of substance use, especially for Mexican-heritage adolescents, who experience culturally-specific stressors .

Therefore, research is needed to determine whether emotion reactivity to stress and recovery from stress is related to substance use and the emergence of substance use among these youth.The impact of stress reactivity and recovery on substance use during adolescence may vary by sex. Adolescents’ motivations for substance use differ by sex . Male youth tend to be more motivated to use substances for social enhancement whereas female adolescents are more motivated to use substances to cope with negative emotion and stress . Further, female adolescents show higher comorbidity between substance use and depression relative to male adolescents,cannabis grow supplies suggesting that emotion and stress may be particularly tied to female adolescents’ substance use . Therefore, although male adolescents tend to show earlier and more frequent substance use relative to female adolescents , substance use may be particularly related to the stress response among female adolescents. Indeed, prior research regarding youth who have used substances by age 16 in this cohort of Mexican-origin adolescents has found that greater cortisol reactivity relates to earlier age of initiation of alcohol use for girls, whereas blunted cortisol reactivity was related to earlier initiation of marijuana use only for boys with less advanced pubertal status . It is critical to disentangle whether differences in stress reactivity and recovery precede substance use across the sexes.Poverty status may also moderate associations between responses to stress and substance for two reasons. First, early life adversity including poverty status has been found to influence psychobiology such that youth who experience early life adversity, including youth below the poverty line, tend to show profiles of blunted cortisol responses to stress . Because these youth are already at heightened risk for blunted cortisol responses, the association between these responses and substance use may be stronger among these youth. Second, poverty status may influence adolescents’ propensity for substance use. Youth below the poverty line may experience earlier exposure to substance use and substance-related crime, more targeted marketing of substances, and lower parental involvement . They may also be more motivated to use substances for reasons beyond stress, such as due to boredom, sensation seeking, and pursuit of enhancing effects in order to compensate for a lack of pleasurable substance-free daily activities . Poverty status may similarly influence the types of substances that adolescents use. Whereas cigarette use is more common among youth with lower socioeconomic status, marijuana, alcohol, and vaping are generally more prevalent among more affluent youth, potentially due to differences in cost, availability, and social norms . As a result, associations between stress reactivity and recovery and certain substances may differ by poverty status. The present study investigated whether adolescents’ HPA axis and emotion responses to the Trier Social Stress Test , a validated paradigm for eliciting social-evaluative threat, were related to the use of various substances among Mexican-origin youth growing up in a low income, high-risk agricultural setting . Responses to a social stressor were selected because adolescents tend to be particularly responsive to social threats, compared to younger children and adults , and youth often use substances in peer contexts to reduce social stress or enhance social experiences.

In line with prior research highlighting how people vary in the types of emotions they experience in response to stress , we examined changes in three emotions following stress: anger, sadness, and happiness. Discrete emotions have different functional purposes and have unique impacts on cognitions and judgments . Therefore, rather than aggregating across emotions, we assessed unique effects of each emotion. We tested whether stress reactivity and recovery related to substance use among adolescents at heightened risk for substance use, in line with previous studies that have examined substance use initiation in high-risk samples . Most prior studies examining stress responses and substance use have been conducted in the context of adult substance users or with cross-sectional designs . Therefore, we employed a longitudinal design to disentangle whether dampened psychobiological stress reactivity and recovery at age 14 precede the emergence of substance use initiation by age 16. Models examined whether differences in adolescents’ HPA axis and emotion reactivity and recovery to the TSST at age 14 were related to a) use of substances by age 14, b) use of substances by age 16, and c) emergence of substance use between ages 14 and 16, excluding youth who had already used by age 14. Given the high levels of adversity in this sample, dampened psychobiological stress reactivity and recovery were predicted to be associated with use of alcohol and marijuana among these youth, in line with previous research . Although not previously tested with use of cigarettes and vaping, we examined whether dampened psychobiological reactivity and recovery would similarly relate to these substances which are also commonly used in adolescence. Finally, models examined whether associations between HPA axis and emotion stress reactivity and recovery and substance use differ by sex and poverty status. Given that female adolescents may be more inclined than male adolescents to use substances to reduce negative emotion , we predicted that associations between dampened stress reactivity and recovery and substance use would be stronger for female adolescents than male adolescents. Because poverty status can promote profiles of dampened reactivity and can influence the types of substances that youth use , we tested whether associations differ by poverty status.Adolescents provided four 1-2 mL saliva samples via passive drool throughout the task. They provided the first sample after spending over two hours in the laboratory environment, during which they completed benign surveys, and then resting in the lab for 10 min. The second sample was collected immediately after the TSST was completed, roughly 15 min. after TSST onset. The third sample was collected 30 min. after TSST onset, and the fourth and final sample was collected 60 min. after TSST onset. This sampling procedure was similar to previous administrations of the TSST .

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Binge drinking in the past year was measured using standard cutoffs

Posted on July 18, 2023 by hemp2022

Evidence based psychotherapies for trauma that include focus on stress management and interpersonal effectiveness such as Skills Training in Affect and Interpersonal Regulation , may be particularly meaningful for CHR subjects who have a history of childhood trauma. Schafer and Fisher demonstrated the effectiveness and tolerability of STAIR for individuals at clinical high risk for psychosis with history of childhood trauma. However, there has been little research evaluating the effectiveness of evidence-based trauma-focused treatments in this complex population. Studies evaluating the effectiveness of trauma focused interventions may include individuals with psychosis as only a small sub-sample of participants included in the research, but co-occurring psychosis spectrum disorders are often included as exclusionary criteria in evaluation of trauma-focused treatments for individuals with a history of trauma . As previously discussed, compassion training, such as CBCT, may represent a unique category of psychosocial intervention that helps to improve stress reactivity in youth who have experienced early life adversity . Moreover, PoehlmannTynan et al. demonstrated when parents completed 8-10 weeks of CBCT their children demonstrated reduced cortisol, indicating that compassion training for parents may have cascading effects of cumulative stress on their children. Although difficult to achieve, prevention of the occurrence of childhood trauma would be an ultimate goal. Varese et al. maintain that if childhood trauma was removed from the population entirely, the number of individuals presenting with psychosis would be reduced by 33%. Thus, assessment of childhood trauma is an essential first step toward not only early intervention in,cannabis vertical grow racks but also ultimately prevention of psychosis spectrum disorders.Approximately 1 in 10 transitional age youth between the ages of 18 to 24 experience homelessness every year in the United States , representing 3.5 million youth annually.

Prior research has consistently demonstrated an increased prevalence of mental health disorders among this population, including high rates of depression, anxiety, substance use and post-traumatic stress disorder. Overall, the lifetime prevalence of psychiatric conditions among youth experiencing homelessness is twice that of their stably-housed peers. Further, unstably housed TAY experience high rates of co-occurring substance use disorders with either anxiety, or affective disorders including major depressive disorder or bipolar disorder, a phenomenon known as dual diagnosis. Among homeless TAY with multiple comorbid psychiatric conditions, major depressive disorder is the most common diagnosis, affecting anywhere from 41% to 73% of these individuals. Studies have also demonstrated that suicidal ideation and attempt are markedly higher among unstably housed TAY. For instance, 40% to 80% of homeless youth report suicidal ideation, and 23% to 67% report at least one prior suicide attempt. In San Francisco, one study found that the mortality rate among homeless TAY was 10-fold higher than stably-housed, age-matched peers, largely due to increased deaths from suicide and conditions associated with severe substance use disorder. The causes of homelessness among many TAY include violence and abuse, including physical, sexual or emotional abuse experienced in homes of origin. Following the onset of homelessness, many TAY continue to encounter victimization and abuse. For instance, one study found that 83% of youth reported one or more instances of physical or sexual victimization while living on the streets, which contributes to poor mental health outcomes. Experiences of violence and victimization vary by sexual orientation. For instance, lesbian, gay, bisexual or transgender youth are more likely to face sexual victimization and harassment from police compared to their counterparts, increasing their vulnerability to developing mental health disorders such as anxiety, PTSD and depression. Further, other homeless LGBT TAY report higher rates of depression and suicidality compared to their heterosexual and cisgender peers. While the high prevalence of various mental health disorders among unstably housed TAY is well-established in the literature, few studies to our knowledge have employed a syndemic approach to understand how the co-occurrence of anxiety, PTSD symptoms and poly substance use impact depression. Originally conceived in the early years of the HIV/AIDS pandemic by Merrill Singer, Syndemic Theory is a model for conceptualizing how two or more co-occurring health conditions can interact synergistically within a specific population and social context to mutually increase the overall burden of deleterious health outcomes.

Notably, the term ‘syndemics’ is not a synonym for comorbidities, but rather a phenomenon that develops under the co-occurrence of various adverse socio-structural conditions which in turn increases the risk of developing negative health outcomes. Since its conception, Syndemic Theory has been widely applied in medical, anthropological, and public health research to better understand the impact of disease clustering. Leveraging this framework to understand the synergistic effects of anxiety, PTSD and poly substance use on depression among unstably housed TAY may help inform service delivery methods to improve the overall health of this marginalized population.To address this knowledge gap, we studied marginally housed and homeless TAY between the ages of 18 and 24 in San Francisco, California to identify the prevalence and correlates of being at risk of clinical depression. Additionally, we employed a syndemics framework to examine whether the co-occurrence or clustering of multiple adverse psychosocial factors, including symptoms of moderate or severe anxiety, symptoms of PTSD and polysubstance use, had a synergistic effect on being at risk of clinical depression among high risk youth. We hypothesized that the prevalence of being at risk of clinical depression would be high and associated with a greater number of syndemic factors. As such, this study fills an important gap in research on how syndemic experiences fuel inequalities in psychological and socio-behavioral outcomes among marginally housed and homeless TAY in San Francisco, CA.We utilized baseline data from a Substance Abuse and Mental Health Services Administration funded study designed to assess mental health, substance use and HIV risk behaviors among marginally housed and homeless TAY at Larkin Street Youth Services in San Francisco, CA. Participants were considered eligible if they were: 1) between the ages of 18 and 24, and 2) clients of Larkin Street Youth Services. Larkin Street Youth Services is a community based organization that provides a wide variety of services, including housing, case management, education and employment training programs, and medical care for marginally housed and homeless youth in San Francisco.From May 2017 through April 2018, 100 TAY were recruited from various Larkin Street Youth Service sites, including transitional housing sites, one of which was designed for youth living with HIV, and drop in-centers.

Recruitment strategies involved posting recruitment flyers, giving presentations at community meetings for Larkin Street clients,commercial marijuana vertical growing and coordinating closely with Larkin Street staff to recruit participants.Surveys were administered by trained interviewers with extensive experience working with high-risk TAY. All interviews were conducted in a private setting and lasted approximately 90 minutes. Data were collected using a computer assisted survey information collection method administered on iPads. Participants received a $30.00 drugstore gift card for their participation. Participation in the survey had no bearing on individuals’ ability to obtain services at Larkin Street.Data on age in years, race/ethnicity and gender were collected. Sexual orientation was measured by creating a dichotomous variable for those who identified has being heterosexual versus gay, lesbian, bisexual, or pansexual . Participants were asked to describe where they live by selecting one of the following responses: 1) In my own apartment, 2) In a relative’s home, 3) In a group home, 4) In a campus/dormitory housing, 5) In a foster care, 6) homeless or in a shelter, and 7) other. From these responses, a categorical measure of housing stability was created with the following categories; stably housed , unstably housed and homeless or living in a shelter. Data on ever having been incarcerated for three or more days and self-reported HIV serostatus were also collected.Symptoms of post-traumatic stress disorder in the past month were assessed via the 20-item PCL-5. Total scores range from 0–80, and a standard cutoff of 33 was used to create a dichotomous measure of PTSD symptoms. We used the Generalized Anxiety Disorder 7-item , to measure symptoms consistent with anxiety in the past two weeks. Total scores range from 0–21 and designated cutoffs for minimal , mild , moderate and severe were used to create a categorical measure of symptoms of anxiety. A dichotomous measure of symptoms of moderate or severe anxiety was created for those with scores of 10 or greater. We measured any exposure to traumatic events prior to the age of 18 using the Adverse Childhood Experiences instrument. Traumatic events assessed included experiences of emotional, physical and sexual abuse. A cutoff of 4 or more was used to create an indicator variable for greater adverse childhood experiences . These instruments were not used as diagnostic tools, they were used to evaluate the presence of symptoms consistent with the mental health conditions assessed to decide whether further psychiatric evaluation was needed.Drug and alcohol use were assessed using the NIDA-Modified ASSIST. Participants were asked if they used any of the following drugs: cannabis, cocaine, prescription stimulants, methamphetamine, inhalants, sedatives, hallucinogens, street opioids, prescription opioids or other drugs in the past three months . Consistent with prior research on poly substance use and syndemics, polysubstance use was defined as using three or more of the drugs listed above in the past three months .

Consistent with other research on syndemics, a composite syndemic score ranging from 0–3 was created by summing dichotomous measures of; moderate or severe anxiety, PTSD symptoms and poly substance use. We selected these factors based on a priori hypotheses related to broader mental health disease clustering and their confirmed association with the outcome of interest . Factors that were not significantly associated with being at risk of clinical depression in bivariate analyses were not included the syndemic score. A nominal syndemic variable was also created to identify those with zero, one, two or three syndemic factors.We used descriptive statistics to describe the study sample and examine the prevalence of various mental health factors, substance use and sociodemographic characteristics. We generated frequencies, percentages and depending on distributional assumptions for continuous data means, standard deviations or medians and interquartile ranges . We calculated pairwise correlation coefficients and corresponding p-values to estimate the level of clustering among the syndemic factors included in this study and to ensure they are true syndemic factors. Then, we examined the prevalence of being at risk of clinical depression by number of syndemic factors . We also graphed one’s depression score by the number of syndemic factors .We used modified Poisson regression with robust error variances to estimate the relative risk of being at risk of clinical depression by various sociodemographic, mental health, substance use and syndemic factors. Per Zou and colleagues recommendation, this method was used to yield more precise estimates including, smaller confidence intervals. Each primary exposure that was significantly associated with being at risk of clinical depression at the bivariate level including: symptoms of moderate or severe anxiety, symptoms of PTSD, polysubstance use, the composite syndemic score and the nominal syndemic variable, was explored further in multi-variable Poisson regression models. As recommended by Westreich and colleagues,each primary effect measure was modeled separately in order to yield total effect estimates and avoid multicollinearity. Multivariable models controlled for the following correlates of depression: age in years, gender, race/ethnicity and sexual orientation. Interactions were tested between each primary exposure and sexual orientation. All analyses were performed using Stata 16.1.Among a total of 100 participants, the average age was 22 , 67% were male, 38% were Multiracial, 28% were Black, 22% were White and 12% identified as other or declined to state their race/ethnicity. Over half identified as gay, bisexual or pansexual, 13% were unstably housed and 50% were homelessness. Nearly a quarter were living with HIV and almost a third had ever been incarcerated for at least three days . The median CESD score was 25.3 and 74% met symptom criteria for clinical depression evidenced by having a score of 16 or greater. Anxiety symptoms ranged from 23%with minimal, 26% with mild, 25% with moderate, 25% with severe and 51% with moderate or severe anxiety symptoms. The mean PCL-5 score was 54.6 and 80% had a PCL-5 score of 33 or greater which is indicative of probable PTSD . The mean ACEs score was 5.8 and 77% had an ACEs score of 4 or more which is indicative of significant abuse, neglect and/or household dysfunction .

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The influence of inflammation on the HPA-axis stress response is well-established

Posted on July 17, 2023 by hemp2022

It is known that early life experiences have a profound effect on the developing brain. Optimal development of some brain functions is actually experience-dependent, meaning that input from external stimuli during critical periods of neural development are essential for appropriate neurological development and absence of sufficient input can have deleterious effects . However, this dynamic and synergistic process, while critical for development, also leaves the developing brain vulnerable to influence by negative external stimuli. Thus, the experience of stressful life events, such as childhood trauma, during critical periods of development has been shown to influence the development of neural systems, specifically those involved in response to stress/threat . Yet, the experience of stress does not unequivocally lead to maladaptive consequences, as we know that not all individuals who experience childhood trauma go on to develop physical or mental illnesses. However, the experience of early life stress may uncover biological vulnerabilities in some individuals causing modulation of typical neurobiological stress response, creating life-long patterns of emotionality, behavioral, and physiological responding . While this review will not discuss the role of epigenetics in development of mood disorders, it is important to briefly reference findings from animal model research which demonstrate that experience of early life stressful events, such as maternal separation or neglect, differentially affects neuronal development , mRNA expression and even cortisol reactivity due to differential expression of underlying epigenetic vulnerabilities . One neurological system is critical to the understanding of how environmental stimuli impact biological stress response: the hypothalamic-pituitary-adrenal axis. The HPA-axisis responsible for the release of glucocorticoids in the brain that signal activation of coordinated autonomic, neuroendocrine, metabolic, and immune system responses . Importantly, the HPA axis is highly responsive to environmental adversities both in childhood and in adulthood . Experience of early life stress is implicated in modulation of HPA-axis functioning ,cannabid vertical grow racks with experience of trauma affecting not only the expression of stress induced hormones , but also increasing reactivity to acute stress, and decreasing recovery of cortisol following acute stress .

The responsiveness of the HPA-axis is determined by the ability of glucocorticoids to regulate the release of additional stress hormones, providing return to homeostasis once the perceived stress or threat has subsided . Findings are inconsistent as to whether childhood trauma or early life stress leads to exclusively hyper-activation versus hypo-activation of HPAaxis glucocorticoid release , but nonetheless, dysregulation of HPA- axis has been associated with the development of both mental and physical illnesses, including increased risk for cardiac disease, diabetes, obesity, and autoimmune disorders . In fact, the overlap between physical and mental illness resulting from exposure to childhood trauma and HPA-axis dysregulation , has led to the exploration of the role of the immune system as an underlying mechanism in psychopathology, as inflammation is involved in the pathogenesis of many of the aforementioned medical disorders associated with childhood trauma and HPA-axis dysregulation . Research on the impact of childhood trauma on inflammation has established a dosedependent relationship between number of childhood traumas and elevations/reductions in levels of many inflammatory markers, including IL-6 and Creactive protein . Moreover, cytokines and other markers of inflammation are known to be potent activators of the central HPA-axis stress response . Inflammatory cytokines, including tumor necrosis factor-α , interleukin-1β and interleukin-6 can stimulate the HPA-axis independently, or in combination . Further, IL-6 plays a major role in the immune stimulation of the HPA-axis, particularly in times of chronic inflammatory stress . Replicated studies have demonstrated that cytokines such as IL-1, IL-6, TNF-α and IFN-α, activate the HPA-axis by increasing levels of corticotrophin releasing hormone , adrenocorticotropic hormone and cortisol .Thus, the HPA-axis is not only modulated by childhood trauma, but it is a powerful modulator of inflammatory activity, and is in turn modulated by inflammatory processes.

Both inflammation and HPA-axis activation are mechanisms by which the body protects itself from threat. The immune system plays a critical role in the body’s response to injury and infection as it simultaneously prevents the proliferation of pathogens, while also promoting tissue survival, repair, and recovery through regulated circulation of inflammatory markers . Relevant to the discussion of mood disorders, immune system response is associated with behavioral alterations in mood, sleep, energy, cognition, and motivation. Animal models provide evidence that induction of a “pro-inflammatory state” leads to patterns of behaviors in mice, termed “sickness behaviors” that resemble depressive symptomatology and include: lethargy, decreased appetite, decreased interest in exploring, decreased sexual activity, and increased time spent sleeping . In humans, increases in depressive symptoms have been observed in conjunction with administration of immuno-therapies, such as vaccinations , lipopolysaccharides , interferon , and interleukin-2 . Further, an increased prevalence of mood symptoms is present in a variety of inflammatory conditions including auto-immune diseases, cardiovascular diseases, diabetes, obesity, and metabolic syndrome, as well as benign inflammatory conditions including asthma and allergies . As a result of these associations, there has been an increased interest in exploring the relationship between inflammation and development of various forms of psychopathology. Research on inflammation in individuals diagnosed with MDD has repeatedly shown increased incidence of mood symptoms and episodes associated with elevated levels of Creactive protein , TNF-α, IL-1β, IL-2 and IL-6, in peripheral blood . Further, increased severity of depressive symptoms has been associated with higher levels of inflammatory markers in a dose-dependent manner . Similarly, research on inflammation in individuals diagnosed with BD has repeatedly shown increased incidence of mood symptoms and episodes associated with elevated levels of CRP, TNF-α, IL-1β, IL-2 and IL-6, and decreased BDNF . Acute elevations in inflammatory markers have also been shown to occur during depressive and manic episodes, with marker concentrations peaking during mood episodes and dropping during euthymic periods .Impairment of HPA-axis functioning has been shown to occur within the CHR population .

A limited number of studies have explored differences in levels of plasma inflammatory analytes between CHR and HC groups, as the primary study aim . Stojanovic et al. reported that levels of plasma IL-6 were significantly higher in CHR subjects as compared to HC subjects. Zeni-Graiff et al. later replicated the IL-6 results, additionally reporting that levels of IL-17 were significantly lower in CHR subjects as compared to HC subjects. Karanikas et al. report significantly higher levels of IL-4 in CHR as compared to HC subjects. Focking et al. report that individuals identified to be at “ultra-high risk” for developing a psychotic disorder, demonstrate elevations in baseline levels of plasma IL12/23p40 compared to healthy controls and that elevations of this marker were associated with transition to a psychotic disorder. Finally, Yee, Lee, and Lee report significantly higher levels of serum BDNF in CHR subjects as compared to healthy controls, although the elevation was not predictive of transition to psychosis. Thus, there appears to be evidence of increased levels of several inflammatory analytes in individuals at heightened risk for psychosis, but how these elevations compare to elevations of inflammatory analytes across later phases of psychotic illness remains unclear. Further, CHR groups tend to be rather heterogenous, with 20–35% of CHR individuals developing full psychotic symptoms over a 2-year period , so it is unclear whether these early finding are specific to psychosis risk or general psychopathology and environmental factors.Although research on levels of inflammatory plasma analytes in FEP subjects has been more prolific, it is also more inconsistent. A recent systematic review aggregated 59 studies of cytokine levels in early psychosis subjects,commercial marijuana vertical growing reporting evidence for significantly higher levels of circulating cytokines, IL-6, IL-1b, IL-2, IL-4, IL-10, TNF-α, and IL-8, in FEP as compared to HC groups. However, these results were not consistent across studies, with additional evidence from several studies demonstrating these findings only in drug naive subjects, no significant differences or suppression of analytes in FEP compared to HC subjects . As will be discussed, the effect of antipsychotic medication on inflammatory analytes is an important variable that has been inconsistently examined in current inflammatory research. Additionally, there have been few studies investigating levels of chemokines between FEP and HC subjects, with only one study examining MCP-1 in FEP subjects . Martínez-Cengotitabengoa et al. examined the associationbetween MCP-1 and cognition in FEP subjects, reporting that MCP-1 was strongly associated with learning and memory, consistent with findings that MCP-1 is associated with cognitive deficits in Alzheimer disease and HIV dementia . More research is needed to explore the role of chemokines in early psychosis, particularly if these analytes are associated with cognitive decline and other relevant impairments in psychotic illness. More consistently, levels of BDNF have been reported to be significantly reduced in drug naïve FEP subjects, as compared to HC subjects . Importantly, Toll and Mane discuss that studies reporting reductions in FEP levels of BDNF compared to HC subjects have been predominantly conducted in drug-naïve FEP patients as compared to studies reporting no alterations in FEP levels of BDNF compared to HC subjects have been conducted in medicated patients. These results are consistent with previous meta-analyses in drug-naïve schizophrenia groups , as well as subsequent studies, which additionally report that levels of BDNF are generally reduced in drugnaïve FEP patients and appear to be associated with learning capacity and cognition ; however, reductions in BDNF have not been reported to be associated with psychotic symptom severity nor predictive of conversion to psychosis . Despite inconsistent findings, several studies have demonstrated the clinical relevance of inflammatory plasma analytes in psychosis groups, through successful development of blood based protein biomarker multiplexed immuno assays that either discriminate individuals with a psychotic disorder from HC subjects or reliably predict which CHR individuals will go on to develop a psychotic disorder.

In unmedicated FEP subjects, Schwarz et al. identified inflammatory, oxidative stress, and HPA signaling serum proteins that were uniquely altered in FEP subjects. Chan et al. established a biomarker panel with high discriminatory power to differentiate CHR individuals who would later be diagnosed with schizophrenia versus a diagnosis of bipolar disorder.Associations between inflammatory plasma analytes, psychotic symptoms severity, and functioning has been well studied in patients with chronic psychosis , but less extensively in FEP and CHR subjects. In schizophrenia groups, higher levels of pro-inflammatory cytokines TNF-α and IL-6 have been associated with higher levels of depressive symptoms, greater physical comorbidities, such as arthritis, reduced executive functioning, and lower self-rated mental well-being, suggesting that these markers are clinically relevant . Similarly, plasma levels of chemokines MCP-1, MIP-1β, Eotaxin-1, and MDC have been observed to not only be higher in patients with schizophrenia compared to healthy controls, but also significantly associated with increased levels of sub-clinical depressive symptoms, worse self-rated mental well-being, and greater overall severity of typically mild medical illnesses . Very few studies have evaluated the effect of childhood trauma on inflammation in psychosis. In a sample of individuals with chronic schizophrenia subjects, Dennison, McKernan, Cryan, and Dinan provide evidence that individuals with a history of childhood trauma show significantly higher levels of TNF-a and IL-6 as compared to subjects without a history of trauma and healthy controls. In fact, both Dennison et al. and Di Nicola et al. demonstrated that levels of TNF-a were correlated with history of childhood trauma, specificallyseverity of the trauma in psychosis subjects. Hepgul et al. , reports that levels of CRP were significantly higher in first episode psychosis subjects with a history of childhood trauma as compared to those without a history of childhood trauma and healthy controls. Chase et al. demonstrated that childhood trauma, through its effects on IL6, may be a risk factor for schizophrenia. This is consistent with the meta-analysis conducted by Baumeister, Akhtar, Ciufolini, Pariante, and Mondelli , demonstrating that CRP, IL-6, and TNF-a were markedly elevated in individuals with a history of childhood trauma versus those without. Finally, Mondelli et al. conducted research on cortisol awakening response in first episode psychosis and established that history of childhood sexual trauma is associated with blunted cortisol awakening response. Authors purport that this finding helps to explain the association between HPA-axis abnormalities and excess psychological stress in first episode psychosis subjects. Importantly, no studies to our knowledge have sought to examine the relationship between childhood trauma, inflammation, and clinical outcomes in CHR subjects.However, results from the North American Prodrome Longitudinal Study 2 have established several important findings regarding the relationship between childhood trauma and inflammation independently on clinical outcomes in CHR subjects. Firstly, Addington et al. evaluated the relationship between childhood trauma and clinical outcomes in CHR subjects.

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