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Its therapeutic use remains controversial due to its potential for craving and abuse, and further study on co-administration with other pharmacotherapies appears promising.Despite that the anti-convulsant medication topiramate has not been approved by the FDA or EMA for AUD treatment, the US Department of Veterans Affairs recommends topiramate as a treatment for AUD, and it has been suggested by the American Psychiatric Association for the pharmacological treatment of patients with AUD. Currently, the specific mechanisms of action of topiramate remain under investigation. However, the drug is thought to inhibit glutamate α-amino 3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptors and L-type calcium channels, as well as enhance the inhibitory activity of GABA. These effects, taken together, work to attenuate dopaminergic activity mesolimbic reward circuits, thereby reducing both alcohol craving and withdrawal symptoms. Preclinically, topiramate was seen to decrease ethanol consumption in rodent models. Clinical studies have found that topiramate reduced craving and alcohol drinking in a sample of 150 participants over 12 weeks, and decreased drinking days, heavy-drinking days, and number of drinks per day in a sample of 85 participants in a 14-week trial. A large, multisite 14-week RCT that enrolled 371 participants with alcohol dependence found reductions in heavy-drinking days and improvements in various self-reported drinking-related outcomes. A meta-analysis including seven RCTs of topiramate for AUD with a total of 1125 participants found that topiramate significantly increased number of days abstinence and decreased heavy-drinking days compared to placebo. Of interest,grow solutions greenhouse this meta-analysis also directly compared effect sizes for topiramate and naltrexone, finding that topiramate was significantly more effective than naltrexone in reducing binge drinking, but not in improving abstinence.

Another recent month-long study of 94 patients that directly compared topiramate and baclofen demonstrated that baclofen was overall more effective and better tolerated than topiramate. The potential of reduced tolerability and significant side effects such as pruritis, paresthesia, anorexia, dysgeusia, dizziness, nervousness, and cognitive impairment, including difculty with concentration and attention, are concerns for the use of topiramate in the treatment of AUD. These cognitive impairments were found to be dose-associated and include impairments in working memory and verbal fuency, as well as mental slowing. Topiramate’s side effects, especially those affecting memory and cognition, present reasons for concern and warrant long-term trials to further investigate these effects. Slow dose titration and ongoing patient monitoring is also recommended. It is worth noting a potential strength of topiramate: the possibility of starting treatment while patients are still actively drinking, allowing topiramate to serve as a harmreduction or abstinence-initiation treatment, rather than only being used to prevent relapse in already detoxifed patients]. Topiramate has already been demonstrably effective in clinical applications across a number of drinking outcomes, but longer-term trials of topiramate are recommended to optimize dose and duration, as well as further exploring side effects.Another anti-convulsant medication, gabapentin, is also suggested by the APA for use in AUD treatment with the goal of reducing alcohol consumption or achieving abstinence. It is thought to modulate GABA activity by indirectly interacting with voltage-gated calcium channels. Preclinical studies of gabapentin’s effects on ethanol consumption have shown mixed results, with some studies finding that gabapentin reduced ethanol intake in alcohol dependent rodents and others finding that it increased self-administration and binge-like drinking. Gabapentin has shown promising results in human laboratory studies and clinical trials.

Gabapentin reduced percent heavy-drinking days and drinks per day, as well as increased percentage abstinent days in a 28-day trial with 60 participants. In another 10-day study with 21 participants, gabapentin significantly delayed return to heavy drinking. In a proof-of-concept one-week human laboratory trial , participants treated with gabapentin showed significant decreases in alcohol craving in comparison to placebo, and a follow-up 12-week RCT with 150 participants found that gabapentin significantly increased abstinence rates and percentage of no heavy-drinking days.For instance, a combination of gabapentin and fumazenil over 39 days in 60 participants increased percentage of abstinent days and delayed time to first heavy-drinking day compared to placebo. This trial also showed an interaction effect with pre-study alcohol withdrawal, such that those with more severe withdrawal symptoms at baseline benefitted more from the treatment during the trial. In combination with naltrexone, gabapentin was also shown to be more effective compared with naltrexone alone in a 6-week trial with 150 participants. A Cochrane review of 25 studies found anticonvulsants, including gabapentin, to significantly reduce both heavy-drinking days and drinks per drinking day in comparison to placebo. Anticonvulsants were also associated with longer time-to-relapse and fewer heavy-drinking days compared to naltrexone. A recent meta-analysis of 7 RCTs with a total of 751 participants found that gabapentin compared to placebo only significantly decreased percent heavy-drinking days, although trend-level effect estimates were shown for other alcohol-related outcomes. In a 16-week RCT with 96 participants, gabapentin improved the percentage of individuals with no heavy-drinking days and increased total abstinence rates over placebo, especially among participants with more severe pre-study withdrawal. However, another recent 6-month multisite RCT of extended-release gabapentin conducted in 346 participants with at least moderate AUD found no effects over placebo for any clinical outcomes including abstinence rate, percent heavy-drinking days, drinks per drinking day, or alcohol craving.

While these findings may be related to potential pharmacokinetic issues relating to the specific formulation of extended-release gabapentin used in the trial, it is also possible that gabapentin may simply be more effective in patients with more clinically relevant and severe symptoms of alcohol withdrawal. The most common adverse events associated with gabapentin treatment are somnolence, dizziness, peripheral edema, and ataxia or gait disorder. Notably, gabapentin does carry the potential for misuse and abuse, particularly in individuals with opioid use disorders; therefore, recommendation of gabapentin to individuals with comorbid substance use disorder should be carefully considered. In summary, gabapentin shows some clinical efficacy, especially in populations with more severe withdrawal symptomology, but more extensive investigation is recommended.Varenicline is a nicotinic acetylcholine receptor agonist that is used for the treatment of nicotine dependence. In rodent models, varenicline was shown to reduce ethanol seeking, intake, and binge-like consumption. Additionally, the combination of varenicline and naltrexone decreased alcohol drinking more effectively than either drug on its own. Clinically,marijuana drying rack varenicline was found to significantly reduce weekly percent heavy-drinking days, drinks per day, drinks per drinking day, and alcohol craving compared to placebo in a 13-week multisite RCT with 200 participants. However, a 12-week RCT found no effect of varenicline over placebo on heavy-drinking days, and a recent 6-week human laboratory study in 47 participants found that varenicline did not significantly attenuate cueinduced alcohol craving relative to placebo. Varenicline appears to be especially relevant to heavy drinking smokers. Approximately 20%–25% of current smokers are estimated to also be heavy drinkers.A human laboratory study with 20 heavy-drinking smokers on varenicline for 7 days found that varenicline significantly reduced the number of drinks consumed and increased the likelihood of complete abstinence in the human laboratory paradigm. Moderator analyses of data collected in the above multi-site trial indicated that varenicline was more efcacious in reducing drinking among smokers who also reduced their cigarette smoking and among individuals with lower severity of AUD, such that that varenicline significantly reduced percent heavy-drinking days and drinks per drinking day in low-severity individuals, while the most severe group showed no differences between varenicline and placebo on drinking outcomes. Findings also indicate that varenicline may be more effective as an AUD treatment in men, as a 16-week RCT with 131 participants found that varenicline combined with medication management decreased percent heavy-drinking days only in men, but improved smoking abstinence in both men and women. Varenicline is well tolerated, suggesting that it may serve as a promising option for AUD treatment, especially in the case of individuals co-using alcohol and nicotine.Aripiprazole is an antipsychotic drug that acts as a partial agonist at the dopamine D2 and 5-HT1A receptors and as an antagonist at the 5-HT2A receptor. Preclinically, aripiprazole has been shown to reduce ethanol-induced place preference and decrease drinking behaviors in mice, as well as reducing alcohol consumption in alcohol-preferring rats. A human laboratory study in 18 healthy participants indicated that aripiprazole affected outcomes related to alcohol consumption , including reducing the euphoric effects of alcohol and increasing sedative effects. In a sample of 30 participants with AUD, aripiprazole compared to placebo, was found to attenuate cue-induced neural activation in the ventral striatum, a region associated with reward. Another recent clinical laboratory study in which 99 participants with AUD took aripiprazole over eight days found that aripiprazole reduced the number of drinks consumed in a bar lab setting, especially among individuals with low self-control, and prolonged the latency to drink in individuals with high impulsivity.

Results from clinical trials of aripiprazole are mixed. A 16-week RCT directly comparing aripiprazole against naltrexone found that the two medications were overall comparable in reducing heavy-drinking days and increasing days of abstinence, although patients treated with naltrexone had reduced craving compared to aripiprazole. A 35-day open-label trial assessing the combination of aripiprazole and topiramate in 13 heavy drinking participants found significant reductions in alcohol use. Additionally, this trial provided no evidence that the side effects of the two medications are additive, indicating that the combination is generally safe and well tolerated. However, another recent five-week study assessing topiramate, aripiprazole, and their combination with 90 participants found that effects on drinking reduction were due to topiramate, while no significant findings were seen for aripiprazole for any outcomes. Another multi-center RCT enrolling 295 participants over 12 weeks found no significant difference between the aripiprazole and placebo groups in percentage of participants completely abstinent from alcohol throughout the study or time to first drinking day; however, the average number of drinks per drinking day was significantly lower for aripiprazole. The aripiprazole group yielded significantly higher discontinuation rates and earlier discontinuation, largely due to adverse events associated with side effects, especially when dosage exceeded 15 mg/day. The most common side effects cited in cases of discontinuation were fatigue, insomnia, restlessness, anxiety, and deficits in attention. Of note, long-term use of antipsychotics like aripiprazole may be associated with more severe adverse effects such as tardive dyskinesia, with risk factors including older age and female sex . In summary, these findings suggest that aripiprazole may be more effective at lower doses and in more impulsive individuals, although larger confirmatory studies are needed to pursue these personalized medicine approaches.Ondansetron is a 5-HT3 antagonist that is used to treat nausea and vomiting. Although the specific mechanism of action remains under investigation, ondansetron may address serotonergic dysfunction common in early-onset AUD, and may reduce alcohol craving via 5-HT3 projections to dopaminergic connections in the midbrain. Preclinically, 5-HT3 antagonism has been shown to block acquisition and maintenance of ethanol self-administration and reduce ethanol-associated dopamine concentration in the nucleus accumbens. Ondansetron was also found to block the development and expression of sensitization to the locomotor stimulant effects of ethanol and reduce voluntary ethanol intake, preference, and withdrawal seizures in rodent models. Clinically, ondansetron may be particularly effective in combination with naltrexone. In an 8-week RCT in 20 participants with early-onset AUD, ondansetron and naltrexone significantly reduced drinks per drinking day and trended towards an increase in percentage of days abstinent. Another combination study in 90 participants after 7 days on ondansetron and naltrexone found that the combination decreased craving for alcohol and ventral striatal activation to alcohol cues. Ondansetron may also be suitable for individuals with biological predisposition to early-onset AUD. In an 11-week RCT of 271 participants, ondansetron was shown to reduce self-reported drinking such that patients with early-onset AUD who received ondansetron reported fewer drinks per day and more days of abstinence compared to placebo. Ondansetron, combined with cognitive behavioral therapy in an 8-week open-label trial comparing effects in early-onset versus late-onset AUD, found that drinks per drinking day and alcohol-related problems were significantly decreased among those with early-onset AUD compared to those with late-onset AUD. Furthermore, in an 11-week study with 253 participants, ondansetron at 4 μg/kg reduced overall craving significantly in participants with early-onset AUD, while a lower dose reduced craving in participants with late-onset AUD. These reductions in craving were also associated with reduced drinking and an increased percentage of abstinent days. Ondansetron is well tolerated with relatively mild side effects including diarrhea, constipation, and headache. Overall, these studies suggest a potential role for ondansetron as an AUD treatment, especially in participants with early-onset AUD and possibly in combination with naltrexone.

Studies comparing DSM-IV and DSM-5 SUD diagnostic criteria have shown increases , no differences , and decreases in prevalence. Increases in SUD prevalences under DSM-5 may relate to the inclusion of ³GLDJQRVWLF RUSKDQV´ in diagnoses² those who meet one or two DSM-IV criteria for dependence, but none for abuse . Nonetheless, concordance of DSM-IV and DSM-5 diagnoses are acceptable, with concordance increasing with severity , suggesting that our findings are likely similar to those resulting had we used DSM-5 criteria. Further research is needed to clarify this issue. GUTS participants are not representative of the U.S. population as they are children of registered nurses and predominantly non-Hispanic White. The prevalence of SUDs in GUTS, however, is comparable to same-aged participants of the NSDUH , as is the distribution of SGMs enrolled in GUTS compared to population-based studies . Additionally, GUTS participants were not enrolled based on their sexual orientation or gender identity. GUTS assessed sexual orientation with a single item tapping both identity and attraction. This limits direct comparisons between our findings and other studies assessing dimensions of sexual orientation separately because research indicates these dimensions have different associations with substance involvement . Further, despite the large sample size, we were limited in our ability to detect within group differences among SGMs. Despite these limitations, our study is strengthened by including multiple SGM subgroups, enabling examination of heterogeneous outcomes that may otherwise be obscured when combining SGM categories. Future research should include more diverse, nationally representative samples to enable examination of interactions between sexual orientation, gender identity,plant growing trays and other sociodemographic factors to further identify higher-risk SGM subgroups.Among the general population, young adults with SUDs experience disproportionate economic and public health burdens and have low utilization of SUD treatment .

For SGM young adults, these issues may be even more persistent, with one study finding that less than 4% of the 14-20% of SMs needing treatment actually accessing treatment . Specific barriers to treatment among SGMs include a lack of targeted interventions, differences in coping strategies and psychiatric comorbidities, discrimination within healthcare settings, lack of provider knowledge about SGM health needs, and lack of insurance . Consequently, increasing access to treatment alone may be insufficient to address SGM SUD disparities. Efforts should also focus on bolstering the provision of culturally tailored, SGM affirming treatment which promotes resilience, coping, and wellness. Further, given high co-morbidity with other mental disorders, interventions are needed which integrate psychological and SUD treatment .Though not known as a primarily neurodegenerative disease, human immunodeficiency virus infection has been linked to cognitive impairment as well as cerebral metabolic changes. HIV has been shown to cause significant impairments of varying severity in higher order brain functions . Currently, a set of research diagnostic criteria have been proposed to categorize HAND into three conditions: asymptomatic neurocognitive impairment, HIV-associated mild neurocognitive disorder, and HIV-associated dementia . Neuropsychological deficits in attention and learning have the highest prevalence in HIV+ patients ; as HIV disease progresses from early to later stages, executive functioning, information-processing speed, and motor functioning are associated with the greatest decline .Structural and functional brain imaging has revealed loss of gray and white matter volumes, increased white matter abnormality, and changes in perfusion and glucose metabolism associated with HIV . One indication of neuronal injury is reduced N-acetylaspartate , a putative marker of neuronal health and integrity, on magnetic resonance spectroscopy imaging .

Increased HIV viral load and decreased CD4+ T-cell counts have been associated with decreased levels of NAA in the frontal white matter, frontal gray matter, and basal ganglia regions, suggesting that HIV infection may result in loss of neuronal integrity . Even when asymptomatic, persons with HIV infection may have decreased NAA levels in the basal ganglia region . With advanced ARV regimens, HIV infected individuals are living longer and in better health now than before. Paradoxically, HAND remains prevalent. For example, a recent study by the CHARTER group reported that 40–50% of people in HIV care, with the majority receiving HAART , have neurocognitive impairments . While the reasons for HAND persistence are unclear, one possibility is that certain coexisting factors might increase the brain’s vulnerability to HIV injury. Among such comorbidities, traumatic brain injury is commonplace. Since TBI still remains as a largely unexplored condition within the HIV population, we were interested in its potential effects in HIV-infected people. TBIs involve disruption of normal brain function that can be caused by a physical insult to the head, subjecting it to sudden acceleration and deceleration forces . The incidence of new TBIs each year in the United States is 2 million, which is approximately 35 times greater than the incidence of new HIV infection per year . The high prevalence of TBI in the general population suggests that TBI may be a common comorbidity in HIV+ persons that requires further investigation. The prevalence of HIV+ patients who have suffered from at least one TBI has not been reported systematically. However, in the 1,599 cases studied in the CHARTER program at the University of California, San Diego, approximately 21% reported head injury. Following a traumatic brain injury, people can experience a wide range of impairments in the cognitive, emotional, physical, and psychosocial domains and interactions amongst them . People with moderate to severe TBI history can experience a range of cognitive deficits, with one of the most prevalent being difficulty in applying optimal strategies for learning and memory . MRS studies have confirmed that TBI patients also evidence lower NAA levels .

Mild traumatic brain injury patients have also been shown to exhibit a 12% deficit in WBNAA , suggesting a loss in neuronal health following a head injury . To explore the possibility that TBI might enhance the effects of HIV on the brain, we performed comprehensive neuropsychological assessments with HIV-infected persons who did and did not have histories of TBI. We hypothesized that neurocognitive function in those with TBI would be worse than in those without, particularly in areas of cognition that have been implicated in each etiology—that is, working memory, attention, and executive function. We also performed a nested study on a subset of cases to examine changes in brain metabolites via MRS. Since HIV and TBI are each associated with decreases in NAA levels, we hypothesized that people with both HIV and TBI would evidence greater NAA reductions, suggestive of more neuronal injury.For the neuropsychological study, we selected from the HIV participants with negative TBI history those that matched the HIV+TBI+ on the demographic characteristics of age, sex, education, and ethnicity,as well as on HIV-associated characteristics of current antiretroviral status, antiretroviral history, nadir CD4,rolling grow tables plasma HIV viral loads, CSF HIV viral loads, AIDS or non-AIDS classification, and presence of hepatitis C infection. Wide Range Achievement Test–Third Edition Reading scores were also used as added matching criteria to ensure general intellectual equivalence across the groups . This resulted in a sample of 590 HIV+TBI– and 110 HIV+TBI+ participants whose characteristics are summarized in Table 1.Participants were also compared for potential differences in depressive symptoms and substance abuse, as these can have independent effects on neuropsychological performance. Depressive symptoms were assessed using the Beck Depression Inventory . Participants were also given a Composite International Diagnostic Interview , which permits diagnosis of participants with mood disorders according to the Diagnostic and Statistical Manual of Mental Disorders–Fourth Editioncriteria . The mood disorders specifically assessed for CHARTER participants included major depressive disorder and dysthymia. The CIDI was also used to diagnose a substance use abuse or dependency disorder, and we define “history of substance use disorder” as any individual who met criteria for substance abuse or dependency, either currently or in the past. Data were also gathered on current use of prescription medications with psychotropic effects, including antidepressants, sedatives, and opioid analgesics.The results of this study indicate that HIV-infected participants who report substantial TBI, defined as a history of loss of consciousness greater than 30 minutes or complicated by neurological symptoms persisting more than 2 weeks after the injury, were significantly more impaired in working memory and executive functioning than the HIV+ TBI– group.

Consistent with our neuropsychological test results, the HIV+TBI+ group also reported more neurocognitive problems, including memory and sensory complaints. From our MRS subset, we found that HIV and TBI together were associated with decreased NAA in the frontal gray matter and basal ganglia brain regions when compared to HIV participants without TBI. Our results are consistent with studies that have showed decreased levels of NAA associated with HIV alone and TBI alone; they also suggest greater reduction in neuronal integrity in those regions among the HIV+TBI+ group . Our groups were well equated on many factors that could have independently contributed to worse NP performance or metabolite changes. These matching factors included age, education, race/ethnicity, reading proficiency, and several HIV disease and treatment characteristics, including nadir CD4 count.

Though individuals within the HIV+TBI+ group were somewhat more likely to be male , our use of gender-adjusted norms available for most of the neuropsychological tests make it unlikely that gender influenced the results. Furthermore, a study on neuropsychological performance in mild TBI patients revealed no statistically significant differences between male and female patients . The groups also had equivalent levels of depressive symptoms as well as current and past diagnoses of MDD, dysthymia, or both. Substance disorders were also comparable, with the exception of alcohol disorders, which were about 10% higher in the HIV+TBI+ group. However, analyses taking alcohol disorder diagnosis into account did not reveal any systematic effect for alcohol on CNS outcomes. From these data, we believe it is accurate to say that a history of more than minimal TBI in the setting of HIV is associated with mild enhancement of neurocognitive symptoms and signs, as well as more evidence of metabolite change in the brain. At the same time, the effect sizes for neuropsychological performance are surprisingly small , given that these were more than minimal injuries by history. The effect sizes on reported cognition were somewhat higher and were not explained by differences in mood. This, coupled with the more robust effect on the metabolite NAA in the MRS sub-study, opens the possibility that TBI may be associated with more lingering brain effects than are being captured by neuropsychological testing. Our data are also consistent with another study that demonstrated that people who are HIV+TBI+ have significantly greater number of symptoms associated with mild TBI than do an HIV+TBI– group. The authors used the TIRR symptom checklist, which included the cluster of 25 symptoms specific to mild TBI that were higher in those with previous head injuries . Though the authors were the first to state the importance of recognizing the functional impact of TBI within the HIV population, our report has further explored what the impact is through analysis of neuropsychological tests, spectroscopy information, depressive symptoms, alcohol and drug abuse, and biological markers of HIV infection and AIDS disease. Although the effects of TBI on HIV neurocognitive outcomes have not received wide attention, there are indications that history of TBI can amplify the effects of other neurological diseases. For example, traumatic brain injury appears to increase the risk of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease . Persisting difficulties with abstraction associated with alcoholism may also be amplified by head injury history .Reduction in NAA is consistent with neuronal injury associated with TBI leading to a disruption of neuronal mitochondrial activity, which subsequently leads to cognitive compromise. The lower NAA levels may also be compatible with the common neural injury mechanism of increased excitotoxicity: TBI alone could potentiate large fluxes of calcium that induce apoptosis in neurons associated with cognition . TBI has also been associated with inflammation . However, given that in the MRS sub-study there were no significant differences between HIV+TBI+ and HIV+TBI– in levels of myoinositol and choline, metabolites indicative of inflammation, it appears that an inflammatory process may not be linked to the TBI-associated cognitive worsening that follows. Instead, the patterns in our data suggest that persistent neuronal injury may be a factor.

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, 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 association between 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 ,gardening rack 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 .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, specifically severity 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. It was demonstrated that individuals at CHR report significantly more trauma and bullying than healthy controls. Further, those CHR subjects who experienced past trauma and bullying are more likely to have increased levels of depression and anxiety and a poorer sense of self. Importantly, higher levels of total childhood trauma were demonstrated to be associated with lower global role functioning . Second, Perkins et al. identified a multiplex blood assay that reliably distinguished participants at clinical high risk for psychosis from unaffected comparison subjects and predicted which CHR subjects are likely to transition to an acute psychotic disorder, confirming that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis .

The classifier included 15 analytes , demonstrating that unique profiles of inflammatory plasma analytes can be used to differentiate between patient and control groups. Finally, Walker et al. demonstrated evidence of heightened cortisol secretion in CHR individuals also indicating nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. Thus, adding to accumulating evidence regarding role of HPA activity in prediction of conversion to psychosis. However, despite these relevant discoveries, it has yet to be determined whether inflammation may serve as a biological mediator between childhood trauma and CHR clinical outcomes . A robust body of literature supports the hypothesis that exposure to early life stress, such as childhood trauma, may uncover genetic and epigenetic vulnerabilities that influence neurobiological responses to stress, including activation of the HPA-axis and associated immune system response. Further,vertical farming equipment individuals diagnosed with psychosis have a higher prevalence of exposure to childhood trauma, as well as evidence of inflammatory dysregulation. It is therefore reasonable to suggest that experience of maltreatment in childhood may lead to changes in neurobiological response to stress, as measured by markers of inflammation, and that this response is associated with the onset of various mental illnesses in adulthood, including psychosis. However, to our knowledge, no studies to date have evaluated the relationships between childhood trauma, inflammation, and clinical outcomes in individuals at clinical high risk for psychosis. Thus, the research question that guided this study is as follows: Is a history of childhood trauma linked to a pro-inflammatory phenotype in individuals at clinical high risk for psychosis?Exploratory Factor Analysis was used to explore whether highly correlated networks of inflammatory markers could be identified from the 117 analytes in the present study. EFA was chosen over Confirmatory Factor Analysis , as there is no defined theory regarding the number of factors or which factors theories might best fit an a-priori model of inflammatory networks. In order to limit the potential subjectiveness of EFA, we completed a systematic application of theoretical principles to latent variables, factor reduction, and construction . Firstly, the data was analyzed to determine suitability for factor analysis. A correlation matrix will be used to display the relationships between variables for inspection of correlation coefficients over 0.3. Hair J, Anderson RE, Tatham RL, and WC. categorized these loadings using another rule of thumb as ±0.30=minimal, ±0.40=important, and ±.50=practically significant. If no correlations go beyond 0.30, then factor analysis will be reconsidered, only inflammatory markers known to be associated with childhood trauma from existing research will be used in subsequent analyses. Kaiser-Meyer-Olkin Measure of Sampling Adequacy and Bartlett’s Test of Sphericity was used to assess the suitability of the respondent data for factor analysis. The KMO index is recommended when the cases to variable ratio is less than 1:5. The KMO index ranges from 0 to 1, with 0.50 considered suitable for factor analysis . Further, the Bartlett’s Test of Sphericity should be significant for factor analysis to be suitable to utilize .

If the data is not suitable for factorability analyses, EFA will stop after this step and apriori identified analytes, including Perkins et al. 15-Analyte Index will be used in subsequent correlation and mediation analyses. Otherwise, principal components analysis will be used to extract factors as no priori theory or model exists to guide this analysis . Thirdly, multiple extraction techniques will be used for factor extraction including: Kaiser’s criteria for eigenvalue’s > 1 , the Scree plot test , and parallel analysis . Each of these tests will be performed and extracted factors evaluated to determine the most consistent and parsimonious number of factors. Fourthly, factor rotation will be used in order to maximize high item loadings and minimize low item loadings, therefore producing a more interpretable and simplified solution . Although there are two common rotation techniques: orthogonal rotation and oblique rotation, oblique rotation will be used in order to account for factor correlations, which is more accurate for research involving human behaviors and preferred when data does not meet priori assumptions. Finally, factors will be labeled. The labelling of factors is a subjective, theoretical, and inductive process . Factors will be operationalized and descriptively labelled according to constructs that reflect theoretical concepts in inflammatory research.Mediators can be defined as mechanisms through which one variable might achieve its effects. The 3-step Baron and Kenny mediation analysis was conducted to determine if the mediator is caused by the initial IV and is a cause of the DV , the initial IV loses its significance once the mediator is included in the model. More explicitly, first, simple linear regression was used to confirm the relationship between the independent variable, total childhood trauma, and the dependent variable, psychosis risk symptom severity OR functioning. Second, simple linear regression was used to confirm the relationship of childhood trauma and inflammatory analytes defined in Hypothesis 2a and 3b. Third, a final linear regression was used to confirm the significance of the relationship between the inflammatory analytes and psychosis risk symptom severity, or functioning in the presence of childhood trauma, as well as confirm the insignificance or the relationship between the childhood trauma, psychosis risk symptom severity , in the presence of the mediator . Significant associations from hypotheses 3a and 3b will be used to determine the most reasonable clinical outcomes to be used as dependent variables and inflammatory analytes to be used as mediators in subsequent models.This study sought to examine the associations between childhood trauma, psychosis risk symptoms, functioning, and inflammatory analytes in a sample of 67 CHR subjects and 34 UCs, thus contributing to a growing body of literature examining the effect of early life adversity on later life outcomes in individuals at risk for psychosis and identifying associated biological mechanisms. More specifically, this study sought to examine whether inflammation mediates the relationship between childhood trauma and clinical outcomes in individuals at risk for psychosis. This is one of few studies to explore whether inflammatory analytes mediate the relationship between childhood trauma and psychosis risk symptoms or functioning in CHR subjects, providing important implications for clinical intervention in youth at risk for psychosis by helping to uncover biological mechanisms for therapeutic intervention. However, this is the first study to evaluate this hypothesis using an enhanced sample of CHR subjects.

Results exploring the associations between HIV disease characteristic and global neurocognitive function suggest a significant negative association between estimated duration of HIV disease and global neurocognitive function . Therefore, estimated duration of disease was included as a covariate in the linear regression model for PWH. The number of total drinks was not associated with neurocognition in PWH.In the HIV- group, results indicated significant quadratic effects of total drinks on global function , executive function , learning , delayed recall , and motor skills . We applied the J-N technique to inspect these significant changes in the slope of total drinks on neurocognition as a function of total drinks within the HIV- group . Total drinks demonstrated positive, statistically significant associations with neurocognition at the lower end of “low-risk” drinking . Conversely, total drinks demonstrated negative, statistically significant associations with neurocognition at the higher end of “low-risk” drinking . Although there was a significant quadratic association between total drinks and delayed recall, the negative slope did not reach statistical significance. Finally, to examine potential ongoing neurocognitive effects of lifetime AUD among alcohol abstainers, a Chisquare statistic was calculated. Our study is among the first to examine the curvilinear association between recent “low-risk” alcohol consumption and neurocognition among persons with and without HIV. Among HIV individuals, the association between low-risk drinking and neurocognition expectedly followed an inverted-J shaped pattern, with better neurocognition occurring at intermediate levels of “low-risk” drinking compared to alcohol abstinence and heavier consumption. Specifically, region of significance analyses indicated a positive slope of alcohol consumption on global neurocognitive function when the range of total drinks was zero to 18 drinks,drying marijuana whereas a negative slope emerged when the range of total drinks was 52 to 60 drinks; suggesting a potentially innocuous range between 18 to 52 drinks per month for HIV- individuals.

This global effect was driven by abilities supported by frontal brain regions where alcohol metabolism is thought to be particularly active . Additionally, consistent with our hypotheses, there was no quadratic association between level of low-risk alcohol consumption and neurocognition among PWH. This suggests the presence of other factors that may supersede the potentially beneficial neurocognitive effects of low-risk alcohol consumption in the context of HIV. For example, age was significantly associated with global function, executive function, learning, and delayed recall in PWH, despite using age-adjusted T-scores in analyses. Extant literature suggests that the inverted-J shaped association is not unique to neurocognition, which may point towards possible mechanisms underlying the neuroprotective effect of low-risk alcohol consumption. For example, evidence supports a cardio protective effect of low-risk alcohol consumption including a reduced risk of coronary heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, and all-cause mortality . There is a higher risk among alcohol abstainers and when alcohol consumption is high, and lower risk when alcohol consumption is low . Although our data does not directly measure pathways underlying a potential neuroprotective effect of low-risk alcohol consumption, including its specificity to HIV- adults, several plausible bio-psychosocial mechanisms can be drawn from the extant literature. From a biological perspective, low-risk alcohol use has been linked to increased high-density lipoprotein levels and may carry antithrombotic, antioxidative, and anti-inflammatory effects that benefit the neurovascular unit . Additionally, alcohol may directly enhance learning and executive function via stimulation of acetylcholine in the prefrontal cortex and hippocampus . Considering that alcohol consumption increases HDL cholesterol levels, it has been proposed that the association between HDL cholesterol and lowered risk of coronary heart disease is mediated in part by alcohol-induced increases in HDL cholesterol . Other possible mechanisms underlying the observed beneficial effect of low-risk drinking on neurocognition among HIV- individuals in our sample may involve lifestyle factors and/or indicators of socioeconomic status not measured in the current study. For example, previous research exploring beneficial effects of drinking have suggested that low-risk alcohol consumption may be an indicator of higher socioeconomic status and engagement in a healthier lifestyle that includes better nutrition and physical activity .

Moreover, persons of lower socioeconomic status may not have the means to afford alcohol and be more medically compromised which could lead to voluntary or medically recommended abstinence . In addition, it is also well known that individuals of higher socioeconomic status are less likely to experience negative consequences from alcohol use compared to those of lower socioeconomic status who drink the same amount . It is possible that our sample of HIV- participants were of relatively high socioeconomic status, especially compared to our sample of PWH, as HIV disproportionately affects individuals from lower income areas with fewer resources . Although we examined associations between certain HIV disease characteristics, alcohol use, and neurocognition, PWH face additional bio-psychosocial disadvantages that may explain the lack of beneficial effects of low-risk drinking among this group. Even in the context of low-risk use, the immuno suppressant properties of alcohol may counteract the cardioprotective effects on downstream neurocognitive health among PWH, as immunosuppression leads to greater viral infectivity, replication, and subsequently poorer neuronal integrity . Furthermore, our HIV groups had different proportions of individuals with current and lifetime depression, with significantly higher rates among PWH. Depression is known to have adverse effects on neurocognitive performance in HIV , possibly limiting the expression of potentially beneficial effects of low-risk drinking among our PWH sample. The current study has several limitations. Although we detected effects that remained statistically significant after adjusting for relevant covariates, there could be potential unmeasured health and lifestyle confounders such as disability, social status, and reason for drinking, that may mediate the association between alcohol consumption and neurocognition. Next, our sample of lowrisk drinkers, especially among the HIV- group, had fewer drinkers on the high end of the low-risk drinking range, more alcohol abstainers, and more drinkers on the lower end of the low-risk drinking range. Furthermore, we did not have any method to verify self-reported alcohol abstinence. Despite our skewed sample in terms of levels of alcohol consumption, we still detected robust effects even after adjusting for relevant covariates.

Objectively measured recent alcohol consumption would have reduced the possibility of misreporting alcohol abstinence, drinking quantities, and frequency; however, we believe structured interviews are still clinically relevant given that our timeline follow back was only 30 days prior. Future alcohol consumption research should employ methodologies to capture real time and ecologically valid data, rather than relying on retrospective recall. While the full range of “low-risk” drinking does not have discretely defined cut-points for minimal, light,pruning cannabis and moderate alcohol use, our inclusion of the J-N technique allowed us to identify specific boundaries of recent alcohol consumption in which alcohol confers neurocognitive benefits or risks among HIV individuals. Although these analyses may help clinical efforts at identifying intervals of safe drinking for certain populations, interpretations must caution against the differences in low-risk drinking criteria for men and women. According to the NIAAA criteria for low-risk drinking, we included women who self-report 0-30 drinks in the last 30 days, and men who self-report 0-60 drinks. Therefore, the results of the J-N technique for lower regions of significance are applicable to both men and women, whereas the results in the upper regions of significance are applicable only to men. Future work with equal sample sizes by sex should investigate the associations between recent drinking and neurocognitive function to further adjust for sex differences. In conclusion, our results are consistent with the hypothesis of a curvilinear association between recent alcohol consumption and neurocognition within the range of low-risk drinking and only among HIV- older adults, such that intermediate levels of recent alcohol use were associated with better neurocognition compared to alcohol abstinence as well as lower and higher ranges of low-risk consumption. Among PWH, there were no detected beneficial or deleterious effects of low-risk alcohol consumption on neurocognition, suggesting that other factors that may supersede the neurocognitive effects of low-risk alcohol consumption in the context of HIV. Whereas genetic studies have traditionally ascertained cases for a particular disorder, PBCs may contain individuals who can serve as cases for numerous different disorders. However, several limitations need to be considered. The ascertainment of PBCs, while not focused on a specific diagnosis, is never random and therefore does not represent the general population19. For example, andMe and UKB research participants are more highly educated and have higher SES than the general population. In addition, similar to traditionally ascertained genetic cohorts, current PBCs are overwhelmingly made up of individuals of European ancestry; although MVP is a notable exception. Another limitation of PBCs is that certain disorders are underrepresented; for example, in UKB, the frequency of schizophrenia is lower than the general population, perhaps reflecting the lower rate at which schizophrenia patients volunteered to participate in such a rigorous study. The age of subjects in PBCs is another potential limitation. For example, the use of diagnoses for childhood onset disorders like ADHD and autism have changed dramatically over the past few decades, meaning that older subjects will have a lower than expected prevalence of these diagnoses. In addition, the prevalence of environmental exposures , which modulate the prevalence of many traits and diseases, have changed over time, which may confound various genetic studies. Lastly, privacy and intellectual property concerns restrict the sharing of raw data and even the results obtained from some PBCs, these restrictions impede data sharing. Despite these limitations, PBCs are attractive because they are economical, offer the potential to dramatically increase sample size, provide a much greater diversity of phenotypes, and lend themselves to innovative study designs.In some PBCs, clinical diagnoses are not available. However, self-reported clinical diagnoses may be available.

For obvious reasons, these self-reported diagnoses must be interpreted with caution; however, the strength of the genetic correlation between gold-standard diagnoses and self-reported diagnoses helps to address this concern. For example, self-reported MDD and clinician assigned MDD showed a robust genetic correlation. In other cases, self-reported diagnoses are unavailable, but screening tools can be used to approximate diagnoses. For example, scores from the Alcohol Use Disorder Identification Test , which is as a screening tool for AUD, were available in research participants from 23andMe and UKB. Sanchez-Roige et al24 found that when AUDIT scores were converted into a case control phenotype, they were highly genetically correlated with AUD 25 . These examples demonstrate that, even when clinical diagnoses are not available, there is still significant value in using self-reported information from PBCs for genetic studies of psychiatric disorders.In general, there is a tradeoff between phenotyping depth and sample size . The quest for larger sample sizes has led to the adoption of “minimal phenotyping” where a complex disease or trait may be reduced to a single yes or no question. Minimal phenotyping is sometimes criticized because it implicitly assumes that minimal phenotypes are merely noisy measurements of a true underlying phenotype. Cai et al sought to empirically examine this question by considering both self-reported diagnosis of MDD and clinician measurements of the cardinal symptoms of MDD and found that minimal phenotyping yielded a qualitatively different trait. Another empirical examination of minimal phenotyping used a multivariate framework to evaluate several psychiatric disorders and self-report measures of their cardinal symptoms. That study identified large genetic correlations between some disorders and symptom pairs , but very modest genetic correlations between other pairs . Despite these limitations, robust genetic signals — of something — can be obtained using minimal phenotyping; how useful these signals will be for understanding the pathophysiology of psychiatric disorders is a matter of ongoing debate, but when large, minimally phenotyped datasets exist, it seems natural that they should be analyzed. Regardless of whether diagnoses are made by an expert clinician, a structured interview, or self-report, there is a broader question about whether or not the current diagnostic categories are optimal for genetic research, given that the DSM was never intended to be a research tool. A recent review summarized this issue with the memorable phrase “our genes don’t seem to have read the DSM” . Initiatives such as the National Institute of Mental Health Research Domain Criteria and Hierarchical Taxonomy of Psychopathology provide new ways of classifying psychiatric disorders based on dimensions of observable behavioral and neurobiological measures, rather than diagnostic categories. These approaches have not been universally accepted. Even before RDoC, there was widespread enthusiasm for genetic studies of endophenotypes ; however, studies of endophenotypes flourished in the era of candidate genes, when the necessity of large sample sizes was not generally understood. This may have fostered undue skepticism about the utility of endophenotypes for genetic research.

It is important to note that many substances detected in the plant samples were not detected in the blood or urine samples. Some examples include 5-Fluoro-NNEI 2’-naphthyl isomer, 5-fluoropentylindole, NM-2201 and NPB-22. There are multiple explanations for these findings. The patient may have used SC products that were not included in our plant samples and therefore would not be associated with the urine and blood samples. It is also possible that the metabolites of the compound were not in the database or that the level was below the LC TOF detection limits. Furthermore, the metabolite may have been metabolized to a common XLR metabolite that was detected, or the drug had already been eliminated from the body.However, the study has a number of important limitations. First, the selection of patients was based on the judgment of our ED team and toxicologists based on abnormal vital signs, subjective history from the patient, presentation of decreased mental status and clinical judgment. Many intoxicated patients may have been evaluated and treated without being included in the study. In addition, patients may have had altered mental status for reasons other than SC intoxication and may have been erroneously included in the study because their ED arrival was associated with other patients with SC intoxication. Although there were 141 visits, several patients with recurrent intoxications were included as multiple visits in the study. The SC samples were provided by patients, but it should not be assumed that the specific sample was necessarily the cause of their intoxication. Furthermore, the samples were collected anonymously,curing cannabis without designation to a specific patient, and therefore we were unable to identify which of the patients presenting with bradycardia tested positive for certain compounds.

This significantly diminished our ability to conclude that certain types of SC are associated with more profound presentations of bradycardia and psychomotor depression. Lastly, the majority of the patients presented from a large, nearby psychiatric center. The patients often presented as groups, possibly due to simultaneous drug use with the same sample. This patient population tends to have multiple comorbidities, and members may be taking neuroleptic medications that may increase the opportunity for interactions with the cannabinoids. This is a population with an increased risk of substance use, and therefore the results of our case series cannot necessarily be extrapolated to other populations.More than one-quarter of a million women in the United States are currently living with HIV , and many women living with HIV fare poorly on the HIV Care Continuum . In 2015, only 50% of WLHIV were retained in care and 48% achieved HIV viral suppression . Despite the broad availability of effective antiretroviral medications, WLHIV also experience high rates of morbidity and mortality compared to the general population . Trauma is increasingly recognized as a near-universal experience among WLHIV and as a key contributor to HIV acquisition, morbidity, and mortality. Defined as “an event, series of events, or set of circumstances that is experienced by an individual as physically or emotionally harmful or threatening and that has lasting adverse effects” , trauma can include childhood and/or adult physical, sexual, or emotional abuse or neglect, as well as sociostructural violence such as racism, sexism, homophobia, transphobia, xenophobia, or living in a community where violence is common. People living with HIV experience disproportionately high rates of trauma , including rates of childhood sexual abuse that are more than twice the rates among the general population. Trauma exposure in PLHIV is associated with nonAIDS related deaths , and is predictive of experiencing later violence . It is also closely associated with mental health disorders including depression, PTSD, and anxiety , as well as with increased HIV-risk behavior, including substance use disorders . HIV diagnosis is itself often highly traumatic . Among PLHIV, trauma and substance use often function syndemically, as “epidemics interacting synergistically and contributing, as a result of their interaction, to excess burden of disease in a population” . The syndemic of violence/trauma, substance use, and HIV has been identified as one of the main drivers of HIV infection and of poor health outcomes among women living with HIV . Research has consistently shown high rates of substance use among people living with HIV, and rates that are higher than among the general population . Substance use has also been shown to have a negative impact on HIV treatment adherence and virologic suppression .

The link between trauma and health outcomes has led to calls for increased attention to trauma in health care by advocates and government leaders, including the U.S. Preventive Services Health Task Force, the Institute of Medicine, and the Agency for Healthcare Research and Quality . While an emerging literature describes interventions to address trauma and PTSD among PLHIV , no prospective study has evaluated the impact of a comprehensive model of trauma-informed health care delivery on health outcomes. To address this gap, we initiated implementation of a model of traumainformed health care in one clinic serving WLHIV in the San Francisco Bay Area. As part of this effort, we are conducting a broad evaluation of the impact of TIHC on patient health outcomes. Here we report results of baseline data analyses, examining the association of trauma with physical, behavioral, and social health indicators, with particular attention to quality of life and undetectable viral load. We then consider how the results of the investigation serve to inform efforts within health care settings to improve outcomes. Women were recruited from the waiting room during regular clinic hours on two half-days each week. Researchers approached patients in the waiting room, briefly explained the purpose of the study and, if a patient was interested, met with her in a private room. At that time, the researchers reviewed consent documents, explained the study procedures including data abstraction from the electronic health record , and answered any questions. Individuals were eligible to participate if they self-identified as cisgender or transgender women who were 18 years of age or older, were currently receiving primary HIV care at the clinic,cannabis dryer and were English-speaking and cognitively able to complete the interview. If the patient was eligible and willing, she signed a general consent form and an EHR data abstraction consent form. Following consent, the researcher conducted the interview by reading each question aloud and marking responses in a survey booklet. At the end of the interview, the participant received a $25 gift card in appreciation of her time. Most interviews took 30-45 minutes to complete. After the interview, researchers abstracted relevant data from the participant’s EHR. This study was designed as a broad evaluation and, as such, was exploratory in nature. Thus, data were collected on a wide variety of constructs. Two women living with HIV who were not clinic patients or study participants reviewed and provided input on the measures used in the interview. Demographics. We asked participants for general demographic information. Based on observed distributions, we dichotomized race into white women and women of color; and dichotomized education into more than a high school education or not. We dichotomized housing into stable or not; individuals who self-identified as being homeless, living in a car or vehicle, or having lived in a location for fewer than 6 months were characterized as unstably housed.

We also used the Household Food Security Survey , a validated two-item instrument that measures experiences of food insecurity in the past year . Trauma was measured in three ways. First, we measured childhood trauma using the Adverse Childhood Experiences instrument, which counts 10 types of abuse, neglect, and household dysfunction experienced before the age of 18 . A cut-off of 4 is commonly used, and prior research has shown that individuals who experienced 4 or more ACEs have significantly greater risk for later poor health outcomes. We also measured lifetime trauma using the validated checklist from the Trauma History Screen to measure exposure to 14 potentially traumatic events from childhood to the present time . Finally, we asked whether participants had experienced recent trauma based on two questions about sexual coercion and abuse, threats, and victimization in the past 30 days. In our analysis, we found both ACEs and recent trauma to be highly correlated with the Trauma History Screen. For this reason, and because the THS covers both childhood and recent trauma, we use the THS for our analysis. Empowerment was measured using the Empowerment Scale, a 28-item scale developed with members of self-help communities . Social Support was measured using the 4-item Social Support Survey , a shortened version of the original Medical Outcomes Study Social Support Survey . Participants self-reported whether they were currently on HIV antiretroviral medications. Thirty-day HIV medication adherence was self-reported, based on a validated six-point scale , dichotomized into good 30- day adherence or not . We asked participants whether they had disclosed their HIV status to anyone. Of those who had disclosed, we asked, “On a scale of 1-10, how open or ‘out’ are you about your HIV status?” Those who said that they had not disclosed to anyone were given a score of 0. HIV Stigma was measured using the Sayles Stigma Scale , a 28-item instrument that measures internalized stigma through questions about how often certain items happen or are true because of their HIV. PTSD symptoms were measured using the PTSD Checklist for DSM-5 , a 20-item instrument to assess symptom criteria for PTSD . A score of 33 or above indicates a provisional diagnosis of PTSD. Depression symptoms were assessed using the Patient Health Questionnaire- 9, a validated nine-item patient-reported measure of depression symptoms that maps to DSM diagnostic criteria . A score of 10 or above is considered to be indicative of at least moderate depression. Anxiety symptoms were assessed using the Generalized Anxiety Disorder scale , a 7-item self-report scale to measure symptom severity. A score of 10 or above indicates at least moderate anxiety. Substance use was measured in three ways. Alcohol use was assessed using the short Alcohol Use Disorders Identification Test , a 3-item screen to identify individuals who may be hazardous drinkers or who have alcohol use disorders . The instrument provides a raw numerical score ; an indicator of binge drinking; and a diagnostic of AUD . Drug use was measured using one question from the Alcohol, Smoking and Substance Involvement Screening Test asking about substance use in the past three months. We dichotomized this into any non-prescribed drug use in the past 3 months, and a similar variable of “hard” drug use that excludes marijuana. Drug abuse was measured using the Drug Abuse Screening Test 10 , which yields a score range of 0-10. A score of 3 or greater indicates at least a moderate level of drug abuse. Quality of Life was measured using the five-item WHO-Five, developed cross culturally by the World Health Organization . The instrument measures self-reported quality of life over the past two weeks in the areas of mood, physical vitality, and interest in life. A score below 13 indicates poor quality of life . Mental well-being was measured using the seven-item Short Warwick Edinburgh Mental Well being Scale, which focuses on emotions and mental functioning , and yields a score of 7-35. Undetectable viral load. For participants who consented to having data abstracted from their electronic health record , we abstracted HIV viral load and CD4 counts. Data were abstracted only if the person had had a test within the past year, and the most recent test result was used.For the analysis, we focused on undetectable viral load as the outcome of interest. Patient-Provider relationship was measured using the Engagement with Health Care Provider scale , a 13-item instrument in which clients rate their interactions with their providers on a scale of 1 “always” to 4 “never”. Responses are summed to get a total score of 1-52, with lower scores indicated greater engagement. Appointment Adherence. We abstracted EHR data to examine appointment adherence as a proxy for engagement in care. Appointment adherence is the percentage of scheduled clinical appointments that were actually attended in the six months prior to the study visit. First, we generated descriptive statistics to summarize the baseline data. Second, we used bivariate linear and logistic regression analysis to examine relationships between trauma and various indicators of health. Third, we used bivariate linear and logistic regression analysis to examine factors that are associated with the two outcomes of interest: quality of life and undetectable viral load.

Several studies have reported positive correlations, such as drinks per week , monthly binge drinking days , and AUDIT scores . Although the exact reasons for this discrepancy are unclear, we speculate that two factors may be relevant. The first is that the APT used in our study is different from other studies in terms of its instruction about framing the hypothetical drinking context, which will be discussed more in the study limitations later. Briefly, our generic description of the drinking situations may be insufficient to allow participants to imagine their typical drinking scenarios thus that they could not accurately report their alcohol demand. The other possible reason might be differences between study populations. Unlike previous studies , our participants were treatment seeking, and thus their motivation of quitting/reducing drinking and smoking may have changed how they responded in these purchase tasks. Besides the difference of motivations, our participants were more dependent on alcohol than the undergraduate samples tested previously —the average AUDIT score in our sample was almost twice that of theirs. Similarly, all of our participants had a diagnosis of AUD, while only about 50% who were dependent or abusing alcohol in the study by Amlung et al. . Additionally, our participants were also heavy smokers and importantly, several studies found that smoking resulted in higher demand for alcohol than nonsmoking . Thus, smoking may have resulted in a higher and more uniform alcohol use demand, masking a possible linear relationship between dependence and demand. Consistent with this possibility, we did not find any relationships between alcohol demand and alcohol misuse diagnoses. Although this possibility exists,rolling grow table future studies evaluating this population will help address whether heavy smoking can indeed mask the relationship between alcohol dependence measures and alcohol demand indices. The positive correlations between alcohol and cigarette demand indices suggest that those who had higher demand for alcohol tended to have higher demand for cigarettes too.

This co-demand pattern is consistent with a recent study which revealed the same positive correlations among a similar sample of heavy drinking smokers . Moreover, by conducting hierarchical multiple regression analyses, their study found that smoking had a positive impact on the alcohol demand, but not the other way around . Their finding may help explain the relative higher demand for alcohol than for cigarettes among treatment-seeking smokers with AUD in the present study, because our participants were more dependent on nicotine than those non-treatment seeking heavy drinking smokers in their study —the relatively higher level of smoking in our sample may have resulted in greater alcohol demand in an asymmetric fashion. An important study factor that should be taken into account is the differential alcohol and smoking satiation statuses among the participants. Although our participants were instructed to complete the hypothetical purchase tasks in a general context, we cannot rule out the possibility that the reported demand patterns may have been influenced by their alcohol and smoking statuses. Previously, we speculated that the special characteristics may have caused the null correlations between alcohol demand and alcohol related measures. Unlike other alcohol-related measures, alcohol withdrawal scores were correlated with alcohol demand metrics, which support the possibility that alcohol deprivation status may have indeed increased the reported demand for alcohol among our participants who experienced more alcohol withdrawal, consistent with a previous study which showed the increased cigarette demand among nicotine-deprived smokers . In the current study, we also found that cigarette demand metrics were positively correlated with smoking withdrawal, which suggests an increased demand for cigarettes due to smoking deprivation. However, the exact effects of alcohol deprivation on alcohol demand are more speculative with the current study design , which can be examined in future studies that contrast the alcohol demand metrics between deprived and satiated patients with AUD.

The study has the following limitations. First, the APT and CPT were administered separately, with each having no assumption of allocating limited resources to the other. Although our findings suggested that alcohol had higher demand than cigarettes using the single-commodity tasks , we do not have direct evidence that alcohol is preferred if both drugs are considered in the same context. Such relative preference between two co-used drugs can be best captured by a cross-commodity task wherein the consumption patterns for both drugs are examined simultaneously. Using the cross-commodity paradigm, researchers have found a complex interplay between cannabis and alcohol use with nontrivial proportions of the study sample showing patterns of complementarity, substitution, and independence . However, in a different cross-commodity study involving marijuana and tobacco cigarettes, researchers found an independent demand pattern between these two drugs . These studies suggest the manipulation robustness of using the cross-commodity paradigm in substance use research to simultaneously study couse of drugs. More importantly, this paradigm provides a better ecological validity by placing participants in a more realistic context with their access to both drugs while having limited shared resources. Future studies should consider using this cross commodity paradigm to better capture the demand for alcohol and cigarettes among smokers with AUD, which may shed light on developing personalized treatments based on relative demand patterns between alcohol and cigarettes. Second, to make the participants have similar contexts for the APT and CPT, the APT’s instruction used the same contextual description as the CPT’s, and differences in the current APT’s instructions from previous studies may have affected participants’ ability to report their alcohol demand with ecological validity. Previous studies have generally assessed alcohol demand under contexts in which alcohol is likely to be consumed . Similarly, time parameters such as duration of access and weekend vs. weekday have been shown to impact alcohol demand. Third, per protocol requirements, participants were abstinent from alcohol to have proper cognitive functionality to complete the visits, but they could smoke ad libitum.

Thus, differences in alcohol deprivation and smoking satiation may have affected the demand for alcohol and cigarettes. Alcohol appeared to have higher relative reinforcing efficacy than cigarettes among adult smokers with alcohol use disorder, as evidenced by their greater demand for alcohol than for cigarettes, although it is possible that acute substance status may play a role in modulating the demand for alcohol and cigarettes. A two-factor structure was identified for both alcohol and cigarette demand curves, and the differential loadings of demand indices in the current population of heavy drinking smokers and other less dependent younger samples assessed previously suggest a distinct demand pattern for smokers with AUD. As an important future direction of the present study,indoor plant table hierarchical multiple regressions analyses of multiple purchase tasks should be conducted to provide a deeper understanding of cross substance demand for alcohol and cigarettes among treatment seeking smokers with AUD.Health care reform in the United States has had major implications for people with substance use disorders , including greater opportunities to enroll in private insurance coverage, increased access to services, and changes in health care costs . The Affordable Care Act established state insurance exchanges to promote and offer health coverage, and mandated SUD and psychiatric disorder treatment as essential benefits. Practitioners expected these ACA mandates, implemented in 2014, to increase access to care . Following ACA implementation in 2014, the overall number of individuals living without insurance dropped . Evidence suggests a positive impact of the ACA on both SUD and psychiatry coverage , including an increase in insurance choices . The number of individuals with identified SUDs enrolled in health plans increased . But access to services remains a major concern , and much is still unknown regarding how ACA-associated enrollment through insurance exchanges and cost-sharing structures are associated with access to and use of SUD treatment and other health services in this complex patient population. SUD treatment initiation and retention are key clinical goals for SUD patients . Specific characteristics of the ACA, such as enrollment via new state insurance exchanges and increased patient cost sharing via higher deductibles, may influence treatment differentially for people with SUDs who may be new enrollees . Patient cost sharing may adversely impact both initiation and retention. If SUD treatment and psychiatry services are viewed as discretionary and less essential than primary care, they may be especially vulnerable to cost-sharing mechanisms . A previous evaluation of SUD patients enrolled in the same California healthcare system found that compared to a pre-ACA enrollment cohort with SUDs, post-ACA SUD patients had more psychiatric and medical conditions and greater enrollment in high-deductible plans. Although this prior work did not examine patterns of health service utilization, the findings suggest that newly enrolled patients post-ACA may have greater clinical needs as well as increased financial obstacles to accessing services . It is important to not only evaluate SUD treatment initiation and retention over time following implementation of the ACA, but also to evaluate how factors related to the ACA may influence utilization of other health services. The current study aimed to extend what is currently known about the consequences of healthcare reform by examining the potential relationship of ACA exchange enrollment and high deductible health plans to trends in health service utilization in a cohort of individuals who were newly enrolled in a healthcare system and had a documented SUD. We examined factors associated with utilization as conceptualized by the Andersen model of healthcare utilization , which proposes that utilization is determined by predisposing need and enabling factors .

We hypothesized that psychiatric comorbidity would be associated with greater use of health services, and that members with higher deductibles would be less likely to initiate SUD and psychiatry treatment but would have higher emergency department and inpatient utilization than those without deductibles. As with earlier studies , which indicate that SUD diagnosis is often precipitated by a critical event such as an ED visit, we expected that post diagnosis utilization would be highest in the period immediately following diagnosis but would likely decrease over time, although trajectories would vary by type of utilization. Knowing how these factors are associated with use of healthcare can be highly informative to future healthcare reform and behavioral health services research. Kaiser Permanente Northern California is an integrated healthcare system serving approximately 4 million members . The membership is racially and socioeconomically diverse and representative of the demographic of the geographic area . SUD treatment is provided in specialty clinics within KPNC, which patients can access directly without a referral.Treatment sessions take place daily or four times a week, depending on severity, for nine weeks . Treatment in psychiatry includes assessment, individual and group psychotherapy, and medication management . KPNC is not contracted to provide SUD care or intensive psychiatry treatment for Medicaid patients and those patients are referred to county providers. The University of California, San Francisco and Kaiser Permanente Northern California Institutional Review Boards approved the study and approved a waiver of informed consent. We identified common chronic medical conditions , many of which are known to be associated with SUDs using ICD-9/10 codes recorded within the first year after initial enrollment. Conditions included asthma, atherosclerosis, atrial fibrillation, chronic kidney disease, chronic liver disease, chronic obstructive pulmonary disease, coronary disease, diabetes mellitus, dementia, epilepsy, gastroesophageal reflux, heart failure, hyperlipidemia, hypertension, migraine, osteoarthritis, osteoporosis and osteopenia, Parkinson’s disease or syndrome, peptic ulcer, and rheumatoid arthritis. Patients with chronic medical conditions utilize more health services than patients without such conditions , which may influence their decision to choose a plan with a lower deductible if given an option , so we included this covariate to control for confounding. Deductibles are features across different benefit plans, including commercial plans, but are more common in ACA benefit plans. The individual deductible limit is the amount the individual must pay out of-pocket for health expenses before eligibility for health plan benefits. At KPNC, there are many types of benefit plans that include deductibles. Patients with deductible plans that do not include SUD as a covered benefit are responsible for bearing the cost of those services until their deductible is reached, and/or the accumulating cost of copays for multiple visits as part of the SUD care model. We did not include type of insurance as a covariate due to its collinearity with deductible limits and enrollment via the ACA exchange .

As an example of synthetic control, pH dependent conformation of histidine-rich peptides has led to larger nanocrystals of Cu0 at pH 7–10 than at pH 4–6 . Plants produce ascorbic acid for many functions and rhizospheres often contain the breakdown products of ascorbic acid, which facilitates electron transfer during mineral weathering.Fungi, which proliferate over plants and bacteria in metal-contaminated soils, can stabilize excess copper by extracellular cation binding or oxalate precipitation , but mechanisms probably also require enzymes, thiol-rich proteins and peptides, and antioxidants . The formation of electron-dense Cu granules within hyphae of arbuscular mycorrhizal fungi isolated from Cu- and As-contaminated soil suggests that fungi also can produce nanoparticulate copper. Some copper reduction possibly occurred in response to the European heat wave of the summer of 2003 . Elevated expression of heat shock protein HSP90 and metallothionein genes has been observed in hyphae of an arbuscular mycorrhizal fungus in the presence of 2 × 10–5 M CuSO4 in the laboratory . This suggests that a single driving force can trigger a biological defense mechanism that has multiple purposes. Thus, reduction of toxic cations to native elements may increase as rhizosphere biota fight metal stress and stresses imposed by elevated temperatures expected from global warming.Laboratory evidence has shown that plants , fungi , bacteria ,rolling grow table and algae can transform other more easily reducible metals, including Au, Ag, Se , Hg, and Te, to their elemental states both intra and extracellularly.

When mechanisms have been proposed, they typically have involved enzymes; however, ascorbic acid was implicated when Hg2+ was transformed to Hg0 in barley leaves . Theoretically all of these metal cations could be transformed by a reducing agent weaker than ascorbic acid . However, binding appears to stabilize cationic forms in the absence of a sufficiently strong reductant such as ascorbic acid. Processes used in materials synthesis that were developed with biochemical knowledge might yield clues to other possible, but presently unknown, biologically mediated reactions in different organisms.The discovery of nanoparticulate copper metal in phytore mediated soil may shed light on the occurrence of copper in peats. Native copper likely forms abiotically in the reducing acidic environments of Cu-rich peat bogs . However, swamps by definition are more oxidizing with neutral to alkaline pHs, and they may be ideal sites for biotic formation of metallic Cu nanoparticles. For example, in swamp peats near Sackville, New Brunswick, Canada, copper species unidentifiable by XRD were dissolved only with corrosive perchloric acid , suggesting they may have been nanoparticulate metal formed by active root systems of swamp plants. If swamp peats evolve to bog peats the Cu reduction mechanism could convert to autocatalysis on the initial nanocrystals . The addition of peats that either act as templating substrates or contain nanoparticulate copper could enhance the effectiveness of using wetlands plants for phytoremediation.In contrast to harvesting hyperaccumulators, the oxygenated rhizosphere would become an economic source of biorecycled copper, and rhizosphere containment would prevent copper from entering the food chain via herbivores, limiting potential risks to humans.Despite schizophrenia being a debilitating disorder affecting 1% of the population, there are no extant biomarkers to aid the clinician in identifying this disorder.

Studies predict the genetic risk to be up to 80%,but despite strenuous research efforts the genes and polymorphisms found to be associated with schizophrenia account for very little of the genetic risk. Environmental risk such as urbancity,migrant status,childhood maltreatment,prenatal infections,cannabis use and maternal vitamin D defificiency also contribute to schizophrenia susceptibility. However, not all individuals exposed to environmental risk develop schizophrenia.This observation suggests that interaction between susceptibility genes and environmental factors may better account for schizophrenia. DNA methylation has been identified as a key mechanism for environmental regulation of gene expression.DNA methylation is an epigenetic modification that is essential for normal human development via regulation of gene function. DNA methylation results in the addition of a methyl group on the cytosine of CpG dinucleotides, which can then be inherited through cell division. These cytosine modifications can affect gene expression by altering the binding of transcription factors to promoter regions or changing mRNA processing. DNA methylation studies of the brain and peripheral tissue have previously been reported for schizophrenia. However, to our knowledge, no study has published results from an Illumina Infinium HumanMethylation450 Bead chip in the brain tissue of patients with schizophrenia. Studies to date have typically been performed in peripheral tissues and have been limited to the analysis of CpG islands in the promoter regions. A recent DNA methylation study analysed 27 578 CpG sites in peripheral blood cells from 18 patients with schizophrenia and 15 normal controls.This study revealed 603 CpG sites that had significantly different DNA methylation levels between schizophrenia and controls. Among these genes were HTR1E, COMTD1 and SLC6A3, which have previously been found to be associated with schizophrenia. An epigenetic study of monozygotic twins discordant for schizophrenia identified a number of loci differentially methylated in peripheral blood.Selected gene promoters have also been analysed for differential DNA methylation in the brain tissue from small numbers of patients with schizophrenia.

Some of these genes include RELN, COMT, SOX10 and HTR2A.An earlier study of 12 000 CpG islands in the frontal cortex of 35 schizophrenia and 35 controls revealed differential DNA methylation in genes associated with glutamatergic and GABAergic pathways.Apart from the present study, the only extant study using a 450 000 genome-wide methylation array was performed in leukocytes from patients with schizophrenia.DNA methylation analysis of schizophrenia has been more widely performed in peripheral tissue, because it can be readily obtained from living patients. The epigenetic profile differs in the brain compared with the peripheral tissue; however, some regions may have common patterns,which would make these regionsideal as potential biomarkers for schizophrenia. Some of the genes found to be differentially methylated in peripheral tissue of schizophrenia patients include HTR1A, HTR2A,BDNF,GRM2,GRM5 and COMT.Brain tissue from the Human Brain and Spinal Fluid Resource Centre, CA, USA,indoor plant table was obtained in order to examine tissue involved in the etiology of schizophrenia. We analysed this tissue in a genome-wide methylation study of schizophrenia. We report significant differences in methylation status in brain tissue from schizophrenia patients compared with that from controls. In addition, unsupervised clustering analysis revealed two distinct groups corresponding to schizophrenia and controls. Results of future epigenetic studies hold great promise of a schizophrenia biomarker and treatment, as epigenetic processes can be reversed.The results of the clustering indicate that the methylation profiles in those with schizophrenia are a heterogeneous group. There were some profiles that were consistently deemed distinct from the controls, whereas there were others that were not found to be significantly dissimilar. Twelve samples in particular tended to exhibit the former trait. When comparing these two potential subgroups of those with schizophrenia, we can see that the two subgroups exhibit no obvious difference in characteristics . Thus, there is potential for methylation arrays to be used to detect differences within these two potential subgroups. Differential methylation analysis between the two schizophrenia subgroups indicated that there were 73 222 probes that were differentially methylated . Of those probes, 6681 were promoter-associated and 2006 were both promoter-associated and located at a CpG island. After adjusting for age and PM1, 56 001 probes were found to be differentially methylated , 4779 being promoter-associated and 1238 both promoter-associated and located at a CpG island. The abundance of differentially methylated probes suggests significant groupings within the schizophrenia methylation profile. By contrast, a history of completed suicide or the presence of another psychiatric disorder revealed no significant differences in methylation.Differential DNA methylation in schizophrenia has been reported in several studies to date, although most of these studies involve the use of non-functional tissues such as blood. In this study, we analysed DNA methylation status in brain tissue, the primary tissue of pathology in schizophrenia, employing a genome-wide methylation array with very extensive coverage of the potential methylation sites in the human genome. After adjusting for age and PMI, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. When we compared the differentially methylated gene list with past studies using peripheral leukocyte samples, we found a high concordance rate, particularly for genes previously found to be associated with schizophrenia. Of the 589 genes Nishioka et al.11 found to be differentially methylated in peripheral blood cells from patients with schizophrenia, we were able to replicate 99 of these in the brain tissue. This shows promise for the use of non-invasive tissue such as blood or saliva to be used as a future diagnostic indicator of schizophrenia.

We are aware of only one other study that used the 450 Illumina array in schizophrenia, although peripheral leukocytes were analysed rather than the brain tissue.That study identified 10 747 differential DNA methylation sites in medication free subjects.One of the genes they identified was RAI1, which has altered DNA methylation in the present study as well as an earlier schizophrenia study using the brain tissue.Other genes found to be differentially methylated in both the leukocyte study and the present brain tissue study includes HDAC4, GFRA2 and GDNF. The leukocyte study did not replicate COMTD1 and HTR1A that were found to be differentially validated from a previous study in the peripheral tissue.However, we report that these genes are differentially methylated in the brain. Although we were able to validate many of the previously identified CpG sites, experimental validation using an alternative method, such as pyrosequencing, would also confirm our results. Functional significance of genes found to be differentially methylated should also be tested by gene expression. Unsupervised clustering of the top 3000 most variable probes revealed two distinct groups after adjusting for age and PMI. Cluster 1 comprised 88% patients with schizophrenia and 12% controls, whereas cluster 2 comprised 27% patients with schizophrenia and 73% controls. To our knowledge, this is the first report of DNA methylation profiling that is able to significantly differentiate between those with schizophrenia and control subjects. Although Nishioka et al.was able to identify site specific DNA methylation changes in patients with schizophrenia, they were unable to discriminate between controls and schizophrenia patients using unsupervised clustering.DNA methylation patterns differ in brain cells compared with peripheral tissues such as blood,and this may explain the lack of separation reported by Nishioka et al.Although some genes may have the same epigenetic profiles in peripheral and brain tissue, a more comprehensive list of tissue-specific genes may be required to differentiate controls from those with schizophrenia. Another reason may be the analysis of fewer CpG sites in the previous study. This is potentially important, as a DNA methylation signature across the whole genome is required to identify the most important differentially methylated probes. The results of our clustering analysis will need to be confirmed in an independent brain tissue cohort. Clustering analysis also revealed two subgroups within schizophrenia. It is possible that these two subgroups have specific symptomatology that warrants further investigation in a sample set with a comprehensive clinical history. After adjusting for age and PMI, DTNBP1, COMT and DRD2 were found to be differentially methylated between the two schizophrenia subgroups. Interestingly, these are genes that we have previously found to be associated with schizophrenia.A recent study has found significant DNA methylation changes in the early stages of development and suggest that aberrant DNA methylation during the transition from the fetal to the postnatal period of development could be critical for the pathogenesis of schizophrenia.Genes that are differentially methylated from fetal to neonatal life stage include DRD2, NOS1, SOX10 and DNMT1, all of which have been previously found to be associated with schizophrenia. We also found DNMT1, NOS1 and SOX10 to be differentially methylated in brain tissue from patients with schizophrenia. However, after adjusting for age and autolysis, DRD2 was not differentially methylated. The main limitation of our study was that patients were not free of antipsychotic medication, and antipsychotic medication has been shown to influence DNA methylation.

Recently, peripheral blood monocyte expression of CCR2 has been shown to predict HAND in combination ART – era HIV cohorts. Elevated levels of CCL2 expression have also been observed in non HIV-positive samples. In patients with mild cognitive impairment and Alzheimer’s disease, higher levels of CSF CCL2 correlated with lower cognitive scores. The presence of elevated CCL2 in HIV-positive patients with neuroinflammation, predictive power of monocyte CCR2 for HAND and elevations of CCL2 in non HIV positive patients with neurocognitive deficits suggests that CCL2 may have a critical role in the neuropathogenesis of HAND and other noninfectious dementing disorders. A number of studies have examined genetic variation in the CCL2 gene and identified single nucleotide polymorphisms to be associated with HIV-disease progression and neurocognitive functioning over time. Individuals with an A to G polymorphism in the CCL2 enhancer region, annotated as rs1024611 , have higher CCL2 levels in serum, plasma and CSF than individuals without the A to G polymorphism. Increased CCL2 expression from the – 2578G allele has also been investigated in pathologic conditions and was found to be associated with higher incidences of tuberculosis, breast cancer and atherosclerosis, suggesting that the SNP is involved in chronic inflammatory conditions . Among HIV-infected individuals, homozygosity for the -2578G allele was associated with accelerated disease progression, enhanced leukocyte recruitment to tissues and a 4.5-fold risk for HIV-associated dementia. In a study examining the -2578G allele in a cognitively impaired population, elderly patients with senile dementia due to Alzheimer’s disease, CCL2 serum levels were significantly higher in patients who carried at least one G allele, whereas the highest levels of CCL2 were present in patients carrying two G alleles. The -2578G allele has also been reported to be associated with diminished performance in working memory over time in HIV infected individuals. The HIV-positive group who did not carry the -2578G allele improved at a faster rate in working memory than the HIV-positive group who carried the -2578G allele,microgreen flood table but not faster than the HIVnegative groups.

However, direct associations between the CCL2 rs1024611 SNP and HIV-disease progression have not been consistent across studies , suggesting that there may be intermediate mechanisms that mediate the association between CCL2 genotype, host immune responses and neurocognitive outcomes. Although CCL2 expression in both plasma and serum has been linked to neurocognitive impairment, the purpose of the current study was to elucidate interrelationships between CCL2 genotype at the rs1024611 SNP, CCL2 levels in CSF, expression of other neuroinflammatory markers in the CSF. In addition, we considered plasma viral load, CD4þ cell count and neurocognitive performance in our analysis of HIV-infected individuals. We hypothesized that HIV-positive carriers of the CCL2 -2578G allele would exhibit high levels of CCL2 expression in CSF, and that elevated levels of CCL2 would be associated with higher concentrations of other proinflammatory markers in CSF, higher neurocognitive deficit scores, higher HIV viral load and a lower CD4þ T-cell count in blood plasma. We also hypothesized that accounting for CSF levels of CCL2 would explicate the relationship between CCL2 genotype and cognition.The cohort that was examined consisted of 145 HIV infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom CCL2 genotyping and CSF samples were available. The NNTC is a multi-centre consortium engaged in a longitudinal study of adults with HIV/AIDS. The four participating clinical centres in the United States were The National Neurological AIDS Bank located in Los Angeles, California, USA; the Texas NeuroAIDS Research Center located in Galveston, Texas, USA; the Manhattan HIV Brain Bank located in New York, New York, USA; and the California NeuroAIDS Tissue Network located in San Diego, California, USA. Participants are administered a comprehensive battery of psychometric measurements that include tests of neuropsychological function and self-report instruments that estimate past and current substance and psychiatric illness. Neurological examinations, lumbar puncture for CSF collection and laboratory tests were conducted for plasma HIV viral load and plasma CD4þ lymphocyte count. The following were the inclusion criteria in the current study: at least 18 years of age, fluent in the English language, at least sixth grade education, able to provide informed consent. All participants had cognitive symptoms of sufficient severity to warrant a HAND diagnosis. Exclusion criteria were as follows: no history of CNS opportunistic infections , no history of traumatic brain injury, no history of learning disability or other developmental disorders and no other major neurologic syndromes .

Genotyping was conducted on a subset of NNTC participants as part of a previously reported study. Peripheral blood mononuclear cells and/or frozen tissue samples were shipped to the University of California Los Angeles Biological Samples Processing Core from the four NNTC sites for DNA extraction.Sample purity was determined via OD 260/280. Extracted DNA was then sent to the UCLA Genotyping Core for genotyping. Prior to genotyping, the samples were checked for concentration by Quant-iT ds DNA Assay kit and for quality by agarose gel. DNA amplification by PCR was performed on 96 and 384-well plates on GeneAmp PCR System 9700 thermal cyclers . Genotypes were determined using the allelic discrimination assay on an Applied Bio-systems 7900 Taqman instrument analysed with SDS2.3 software. Data then underwent error-checking and data-cleaning, including control checks, duplicates checks and checking for Hardy–Weinberg equilibrium. Each genotype was evaluated independently according to a number of quality parameters. Data from cases with genotyping success rate of less than 75% were removed. [Note that brain tissue had poorer genotyping success rate than PBMCs ]. For the CCL2 rs1024611 SNP, haplotype analysis has shown that the rs1024611G polymorphism is associated with allelic expression imbalance of CCL2 and the allele containing -2578G is preferentially transcribed. Within this sample, only 5% of participants were homozygous for the – 2578G allele ; therefore, consistent with previous reports, we combined GA and GG genotypes for statistical analyses to test the hypothesis that carriers of the -2578G allele would express higher levels of CCL2 and greater neurocognitive deficit than noncarriers containing the -2578A allele .Global neurocognitive functioning was determined with a comprehensive battery of neuropsychological measures that included the Trail Making Test , Hopkins Verbal Learning Test, Brief Visuospatial Memory Test, Paced Auditory Serial Addition Test, Wisconsin Card Sorting Test-64 Card Version, Grooved Pegboard, Letter-Number Sequencing, Digit Symbol Test, Controlled Oral Word Association Test and Symbol Search . Validated standard approaches were used in transforming raw scores into standardized T scores and deficit scores. A Global Deficit Score was calculated on the basis of averaging individual test deficit scores.

In line with previous reports,seedling grow rack the results of this study showed that carriers of the -2578G allele had significantly higher levels of CCL2 in CSF. In addition, higher CCL2 expression was correlated with neurocognitive deficit score, higher levels of other proinflammatory markers in CSF, higher plasma viral load and lower CD4þ lymphocyte counts. We did not observe a significant interaction between CCL2 genotype at rs1024611 and neurocognitive deficit score, suggesting that carrying the -2578G allele alone does not appear to effect cognition. Instead, the findings suggest that increased expression of CCL2, modulated by CCL2 genotype, influences neurocognitive test performance. As expected, there was a strong correlation between CCL2 genotype and CCL2 expression, which led to the investigation of whether CSF CCL2 expression was acting as a moderating variable to the effects of CCL2 genotype on cognition. This suggests that the -2578G genotype results in a more reactive immune response, and increased viral load results in higher concentrations of CCL2 than normal, resulting in neurocognitive dysfunction. After controlling for CCL2 expression, the association between genotype and cognition emerged, indicating that CCL2 genotype has an effect on cognition, which may be moderated by CCL2 expression. Using plasma viral load to further probe the relationship between CCL2 genotype on cognition in the context of HIV infection, we found that in the presence of high viral load, the CCL2 -2578G allele was associated with greater CCL2 expression and neurocognitive deficit. Although plasma viral load was used as a surrogate for CSF viral load , these results suggest that as HIV infection persists, carrying the – 2578G allele will lead to worse cognitive outcomes . The results also suggest that carrying the CCL2 -2578G allele and thereby expressing higher levels of CCL2 may contribute to or support a pro-inflammatory state in the CNS. We found that CSF CCL2 was associated with increased sCD14, sIL-6Ra, IL-2, IL-6, BAFF and sTNFR2. However, we are unable to determine whether increased CCL2 expression is a consequence of an already established pro-inflammatory state or if induction of CCL2 drives the pro-inflammatory immune response. Interestingly, in addition to CCL2, we found that BAFF and sTNFR2 correlated with cognitive performance; however, CCL2 was the only marker that was associated with CCL2 genotype. These results suggest that BAFF and sTNFR2 may also play an important role in neuroinflammation and cognitive impairment among HIV-infected individuals. B-cell activating factor , a cytokine that is a member of the TNF super family, plays a critical role in mediating B-cell differentiation, activation and survival to generate efficient B-cell responses [30]. Within the CNS, BAFF is expressed by microglia and astrocytes, with recombinant BAFF inducing secretion of inflammatory markers, IL-6 and TNF-a, and IL-10, highlighting BAFF’s contribution to the inflammatory response [31]. Consistent with our results, elevated levels of BAFF in CSF from patients with inflammatory neurological diseases, including HIV, have been reported to be significantly higher than in patients with nonin- flammatory neurological diseases. These findings highlight the importance of controlled BAFF expression for an efficient B-cell response, which is a contributing factor in HIV disease progression.

Increased CSF BAFF may be indicative of neuroinflammation and may be important in the persistence of HIV within the CNS. TNFR2 is a receptor for TNF-a, a key regulatory cytokine in the inflammatory response, and upon binding, induces a signalling cascade to promote cell survival. TNFR2 is expressed by lymphocytes , microglia, oligodendrocytes, astrocytes, endothelial cells, myocytes, thymocytes and mesenchymal stem cells. Soluble TNFR2 can be generated via shedding from the cell surface and may act as a scavenger in a protective capacity by sequestering TNF-a to reduce TNF mediated inflammation. TNFR2 signalling in neurologic disorders and cognitive impairment has been examined and increased levels of sTNFR2 have been reported in CSF and plasma from patients diagnosed with bipolar disorder, mild cognitive impairment and AD compared with healthy controls. Increased staining for TNFRs has also been demonstrated in brains of individuals with HIV encephalitis and other opportunistic infections, and one report has described an association of plasma sTNFR2 with HIV-associated cognitive abnormalities. These results suggest that increased sTNFR2 expression in CSF may serve as a marker of the neuroinflammatory response to HIV and may play an important role in HIV neuropathogenesis and neurocognitive impairment. Our results indicate that individuals carrying the CCL2 – 2578G allele expressed higher levels of CCL2 in CSF and correlational analyses demonstrated that increased CCL2 was associated with increased pro-inflammatory markers, including sCD14, sIL-6Ra, IL-2, IL-6, BAFF and sTNFR2, in addition to greater cognitive deficit. These results are in line with previous studies reporting that increased levels of CCL2 are associated with a faster rate of cognitive decline. Furthermore, the CCL2- CCR2 axis was recently reported to be a critical signalling pathway in HAND, with CCR2 on CD14þCD16þ monocytes serving as a peripheral biomarker for HAND. Overproduction of cytokines in the CNS may allow for HIV-infected cells to persist in the brain despite antiretroviral therapy treatment . As stated previously, CCL2 expression was also correlated with plasma viral load. This is of particular clinical importance because the failure to adequately suppress viral replication may result in repeated BBB insults that further contribute to peripheral immune cell migration into the CNS. This is an area that requires further investigation and has the potential to inform therapeutic interventions. Owing to the cross-sectional nature of the current study, we cannot determine whether the expression of CCL2 is a precursor, consequence or simply correlative to cognitive status. It is possible that elevations in CCL2 expression in CSF may signal other inflammatory processes or genetic influences that were not evaluated in the current study.

One study was excluded from the depression meta-analysis because it assessed aggregate data on crashes, crash deaths, and depression. Effect estimates showed some heterogeneity , hence a random effects model was used. A funnel plot from the six studies did not indicate any major publication bias. Pooled data from the six studies indicate that depression nearly doubles the risk of involvement in a car crash .Two studies , Rapoport et. al were excluded from the antidepressant use meta-analysis because event data could not be extracted. Effect estimates showed some heterogeneity , hence a random effects model was used. The random effects and the fixed effects model estimates were close.Pooled data from the eight studies show that antidepressant use may increase the risk of car crash involvement by 40% .Depression and antidepressants have mental and physical effects with the potential to adversely affect the ability to operate a motor vehicle. Depression, in addition to psychomotor retardation, is often associated with suicidal ideation and intent, increasing the potential for both unintentional and self-harm related motor vehicle crashes . The studies reviewed, conducted mainly in developed countries, found associations between depression and crashes. Though estimates are hampered by the variation in study population and study design, depression was generally found to approximately double the risk of crash risk. Antidepressants have numerous side effects that include drowsiness, hypotension, suicidal ideation, dizziness,rolling benches canada decreased seizure threshold, nausea, and anxiety. These may individually and combined have the potential to interfere with driving abilities. Studies of the effects of antidepressants as a class and driving found a modest increase in crash risk, with OR ranging from 1.19 to 1.90 for crashes, and 3.19 for fatal crashes.

The effect varied by type of antidepressant, with significant variation between studies, but averaged about 1.4 times the crash risk in meta-analysis. Antidepressants have potentially conflicting contributions to motor vehicle crashes in relieving the effects of depression and suicide while posing side effects that may affect driving. While the benefits of antidepressants outweigh their potential risks, prospective studies are needed to better understand the risk of antidepressants and depression on motor vehicle crashes. Of the seven studies included in this analysis assessing the effects of depression, only three included information on antidepressants. However, no comparison of depression scores, medications use, and crash risk in given individuals was reported. Equally, the studies of the effects of antidepressants did not assess the current or past levels of depression. Future studies are needed to control for these interactions. In addition to the effects of the drugs when taken alone, antidepressants can interact with numerous classes of medications primarily due to their inhibition of metablism of other drugs that are cleared through the cytochrome P-450 system of enzymes. Drug interactions may be especially important in impairing attention and cognition when antidepressants are combined with drugs that also have sedative properties, such as benzodiazepines and tricyclic antidepressants . Among antidepressants and their active metabolites, norfluoxetine and fluvoxamine have significant inhibitory effects on CYP 3A4 isoenzyme, which is the most abundant CYP enzyme found in the human body . Fluoxetine and fluvoxamine have been reported to reduce metabolism of multiple drugs, specifically the triazolobenzodiazepines . By blocking the metabolism of these benzodiazepines, the serum concentrations of the benzodiazepines may increase and have increased side effects . It should be recognized that although in vitro affinities of antidepressants for the respective isoenzymes can be very helpful for predicting potentially dangerous drug combinations, there is wide variability between patients and their susceptibility for these interactions. Much of this variability can be attributed to genetic polymorphisms. The strengths of this review include that 17 of the studies reported used large population-based databases, and 14 included detailed crash analysis, increasing the validity of their findings. Also included were studies from across a number of developed countries, with well designed studies that met the inclusion criteria.

The studies included in this review have several limitations. The criteria for determination of depression ranged from self-report to claims-based diagnostic codes. In determining the effects of depression and antidepressants, it is difficult to distinguish effects of depression from effects of drugs. The distinction is hampered by the retrospective methodology of the majority of the studies. Additionally, antidepressants are often prescribed with other psychotropic medications, increasing the potential for crashes due to both drugs, as has been demonstrated in several studies . Due to the limitation of these studies, the extent to which antidepressants mitigate the effects of depression remains unknown. However, the larger association of depression with crash risk, vs. the use of antidepressants, suggests that treatment of depression is likely to reduce the risk. In the management of depression the risk-benefit ratio fo treatment should be considered, as well as the side effect profile when medications are being considered.Cocaine popularity in the United States has rebounded in the past 5 years after many years of decline. Annual deaths by cocaine increased 200% from 2012 to 2017, making cocaine the leading non-opioid cause of drug overdose death in the US. At the same time, cocaine’s user base has expanded with more people trying cocaine for the first time. From 2012 to 2017, the number of people using cocaine for the first time in the past year increased by 57%. In 2017, 6.2% of people in the US aged 18–25 reported using cocaine in the past year, compared to 0.6% for heroin. Historically, patterns of cocaine use differed from those of other illicit drugs in that cocaine has been used almost exclusively in social settings, especially to indicate high social status. Cocaine possesses the unique reputation of being the “rich man’s speed,” a symbol of affluence flouted by celebrities and artists and the object of aspiration for others. The glamorization of cocaine’s bodily effects and an underestimation of its dangers likely also influenced public perception of cocaine. A 1977 Newsweek story on cocaine reported “Among hostesses in the smart sets of Los Angeles and New York, a little cocaine, like Dom Perignon and Beluga caviar, is now de rigueur at dinners”. Although the impression of cocaine is that it gives the user strength and vigor, its actual use is harmful.

In a study ranking the danger of drugs, cocaine received the highest harm ratings and notably scored highest in the “social harm” category. Furthermore, epidemiological evidence on cocaine has shown it to be a highly addictive and widely abused drug specifically among young people .Its attractiveness among the public has been arbitrated by popular media, including coverage of celebrity drug activities associating the drug with high society. In these ways, references to cocaine in the media and popular culture portrayed real-world behaviors of cocaine use. There is reason to believe that popular culture today is again capturing real-world trends around a renewed interest in cocaine. Although cocaine’s reputation waned during the 1980s War on Drugs government crackdown, other forms of popular media such as the music industry continue to relay information about cocaine. Major artists today frequently mention cocaine and other drugs extensively in their songs,flood table particularly in the context of glamour, wealth, and sociability. For instance, studies analyzing popular music and videos have found drugs to be a dominant theme with one study reporting that 33.3% of top-charting songs portrayed substance use with an average of 32.5 drug references per hour. Considering that 90 percent of Americans regularly listen to music with an average listening time of 32.1 h per week, this means Americans on average are exposed to 54 explicit references to drugs every day. A growing body of research supports that drug mentions in popular media may be linked with substance use, including for smoking, alcohol, and cannabis. A qualitative study found that an underground form of hip-hop music called “screw” is a strong reinforcer of codeine syrup use; respondents named “media modeling” as the foremost reason for the popularity for syrup usage. A content analysis of another genre of music, popular country music, found that lyrics were more likely to describe women in association with alcohol use and sex in the 2010’s compared to earlier decades, confirming the known association between alcohol use and sexual assault in this genre. However, the majority of these studies on substance use in song lyrics have been descriptive and limited in the scope of songs analyzed. For instance, Primack et al.conducted a content analysis of 279 songs for drug-related content in the single year of 2005 to determine degree of drug exposure for music listeners. Hall, West, and Neeley analyzed time trends of alcohol, tobacco, and other drugs in 1100 songs over 50 years, an average of only 22 songs per year. Herd performed a qualitative analysis of the social context surrounding 341 rap songs. While these studies describe important findings regarding drug exposure in song lyrics, trends over time, and qualitative content analysis, none were specific to cocaine nor quantified the effect size of drug exposure in song lyrics with drug use behavior. Additionally, all studies compiled song titles from ranked lists, most commonly the Billboard Top-100, thereby skipping over thousands of popular songs that did not make the list.

Given cocaine’s fashionable reputation and highly social patterns of use, descriptions of cocaine in music are potentially an indication of increased cocaine initiation and use. However, the epidemiological trends between popular media and cocaine have yet to be studied empirically. This study investigated the relationship between prevalence of drug mentions in music lyrics and epidemiological trends for cocaine. We sought to offer insights on the recent rise in cocaine use incidence and cocaine overdose mortality observed during the first decades of the 21st century with respect to the influence of contemporary music trends on population-based health behaviors.Our study explores the ability of song lyrics to signal epidemiological trends in incidence and mortality of cocaine use. specifically, our results found that an increase in cocaine mentions in song lyrics is associated with increased incidence of cocaine use in the same year and death by cocaine 2 years later. The temporal relationship between cocaine lyrics and incidence of cocaine use and related deaths was confirmed with significant cross correlation in the same year for cocaine use and 2 years for cocaine overdose mortality. The lead time period of 2 years found in this study between lyrics mentioning cocaine and incidence of cocaine and cocaine overdose mortality is supported by epidemiological evidence that the time between initiation of cocaine use and seeking help for addiction is between 1 and 3 years. Musical trends that depict cocaine in lyrics may be an early signal of a rising interest and use of cocaine in the same year. The lag-time period of 2 years between cocaine lyrics and cocaine mortality may indicate that there is an incubation period of 2 years between addiction and fatality. Treatment intervention is critical in this time period to prevent the onset of drug dependence and death. Our results also provide insights into the pathways by which media may influence cocaine use behaviors. In addition to being a measurement tool to estimate cocaine epidemiology, media itself can influence public perceptions of drug use and lead to increased drug use at the population level. Therefore, music about cocaine may not only provide an early signal of cocaine-related behaviors, but it could also act as an exposure that encourages the use of cocaine. Our study did not test the potential dynamic and cyclical relationship between cocaine lyrics and patterns of cocaine use. While cocaine mortality did not appear to estimate future cocaine mentions in song lyrics, further investigation into the influence of cocaine use on song lyrics is warranted. Our study showed growth in slang terminology such as “kilo”, “yayo”, “coco”, and “baking soda” instead of more explicit terms for cocaine such as “coke” and “cocaine” used in older song lyrics. These results may indicate that the current generation has inherited an attachment to cocaine expressed through the development of new slang terms for cocaine. Evidence of this shifting use of cocaine by younger generations is provided by a 2018 United Nations study reporting that settings of cocaine use have branched out from exclusive clubs to include more accessible environments including college parties, concerts, and bars. Furthermore, in the past decade, first time users of cocaine have moved from high income areas to lower income and under resourced neighborhoods.

Thereby it was suggested that increases of brain FAE levels serve a neuroprotective function mediated by CB1-receptors. Oleoylethanolamide does not bind to cannabinoid CBreceptors but to PPAR-a, thereby activating a different neuroprotective mechanism. Sleep deprivation has been hypothesized to represent an oxidative challenge for the brain and that sleep may have a protective role against oxidative damage. While Gopalakrishnan et al. found no change in antioxidant enzymatic activities or increased oxidant production in the brain or in peripheral tissues after prolonged sleep deprivation, other studies suppose that sleep deprivation may result in a condition of oxidative stress including a reduction in glutathione levels in whole brains of rats . Ramanathan et al. showed that prolonged sleep deprivation results in significant decreases in the activity of superperoxide-dismutase in rat hippocampus and brainstem. This effect may be due to the degradation of antioxidative enzymes after prolonged activation during wakefulness, which suggests an alteration in the metabolism resulting in oxidative stress. Even if sleep deprivation might not show extensive effects comparable to cerebral injury or tissue necrosis, FAEs have been shown previously to be elevated during situations of cellular stress and oxidative stress factors are elevated following sleep deprivation . Therefore, in this study,indoor growers we investigated whether the levels of the endogenous PPAR-a agonist oleoylethanolamide and the endocannabinoid anandamide were elevated in CSF and serum of healthy individuals after acute sleep deprivation.

The Ethics Committee of the Medical Faculty of the University of Cologne reviewed and approved the protocol of this study and the procedures for sample collection and analysis. All volunteers gave written informed consent twice at least 1 day prior to each lumbar puncture after extensive introduction into the procedures and goal of this study. The healthy subjects received an allowance for the participation in this trial. All investigations were conducted in accordance with the Declaration of Helsinki. This study was integral to a larger project on endocannabinoid levels in CSF and serum of healthy volunteers and patients suffering psychiatric disorders. As part of that, volunteers were investigated to establish baseline levels of endocannabinoids in a healthy control population . Twenty healthy volunteers with no family history and no clinical indication for any relevant medical, psychiatric or neurological disturbances were included in our study to investigate effects of sleep withdrawal on endocannabinoid levels. Necessary criteria for inclusion were absence of cannabis use within the last year and lifetime cannabis use not exceeding five times. No positive urine drug screening for illicit drugs was accepted at time of the lumbar puncture . Living circumstances for those volunteers selected did not change substantially during this period. Subjects were lumbar-punctured twice during the course of our study using a nontraumatic LP procedure. The first LP was done under regular sleep condition. The second LP took place after 24 h of sleep deprivation about 1 year later to avoid seasonal influences and artificial alterations in cerebrospinal fluid due to a previous LP in the near past. All subjects spent the nights before both LPs at home; sleep quality before the first lumbar puncture was assessed by the self-rating questionnaire for fatigue and for sleep and awakening quality . The night of sleep deprivation was spent in the habitual environment of the volunteers. Alertness was monitored by wrist actigraphy, using the ‘‘Actiwatch2000,’’ a piezoelectric transductor recording a maximum of 240 wrist motions per minute. Actiwatch was given to the volunteers 24 h before the second lumbar puncture. Volunteers showing a mosaic of inactivation at the actiwatch-scan of more than 5 min during the 24-h period were excluded from the experiment.

This approach allowed us to continuously monitor the subjects during the night of sleep withdrawal . Sleep habits in volunteers were assessed for 7 days before sleep deprivation using a sleep protocol to exclude interferences of the sleep rhythm. For sleep deprivation, volunteers were requested to stay awake for one night without consuming any coffee or alcohol during that night; intake of food was allowed. All LPs were done between 10:00 and 12:00 AM, and each time peripheral blood was collected. All samples revealed no pathognomonic cell counts, CSF/serum albumin ratios or oligoclonal bands. Virological and microbiological testing of the CSF was negative in all cases. In all subjects, we measured CSF and serum levels of oleoylethanolamide along with anandamide. To quantify FAEs, CSF aliquots and serum were spiked with 25 pmol of [2 H4]-anandamide and [2 H4]-oleoylethanolamide and prepared for further analysis as described previously . Fatty acid ethanolamides were purified and quantified by isotope dilution high performance liquid chromatography/masss pectrometry using a HP 1100 Series HPLC/ MS system equipped with a octadecylsilica Hypersil column . MS analyses were performed with an electro-spray ion source as previously described . Statistical analyses were performed using SPSS and R software . Because of apparent non-normality of empirical data distributions, location differences in measurements were assessed by Wilcoxon signed rank or rank sum test .Our results show a significant increase of oleoylethanolamide in human CSF after 24 h of sleep deprivation, whereas the levels of the endocannabinoid anandamide remain unaffected. Interestingly, there is no indication for a functional role of anandamide in sleep induction in humans as hypothesized previously . In rats, Murillo-Rodriguez et al. showed that anandamide increases slow wave sleep, which can be blocked by administration of the cannabinoid CB1-receptor antagonist rimonabant, indicating that the endocannabinoid system is involved in sleep regulation . Further, recent data in rats indicate diurnal variations of anandamide and oleoylethanolamide in CSF with maximum values for oleoylethanolamide during the late light phase, decreasing in the dark phase .

This research was done in rats, which are awake in the lights-off period. Translating these results to the human sleep/wake cycle it may be hypothesized that the concentration of oleoylethanolamide in CSF may decrease during daytime and increase during sleep. Given these assumptions, the increase of oleoylethanolamide is not very likely the result of an accumulation, particularly with regard to the very limited extracellular life span of endocannabinoids . As in our study the second lumbar puncture was done at the same time of the day as the first one; circadian rhythms should not confound our results. Oleoylethanolamide is renowned for modulation of feeding, body weight and lipid metabolism, as its levels decrease during food deprivation and increase upon feeding . This should not be a confounder as well, as oleoylethanolamide plays its role as a local satiety hormone in the intestine , and the feeding conditions were not changed before and after sleep-withdrawal in this study. Like anandamide, oleoylethanolamide is synthesized by neurons and other cells in a stimulus-dependent manner and is rapidly eliminated by enzymatic hydrolysis. Oleoylethanolamide binds with high affinity to the PPAR-a,trimming tray a nuclear receptor that is known to regulate several aspects of lipid metabolism and induces satiety by activating PPAR-a . PPAR-a is also involved in neuroprotection through activation of antioxidant and anti-inflammatory mechanisms. It has been shown that pretreatment with the synthetic PPAR-a agonist fenofibrate is neuroprotective against cerebral injury . Furthermore, treatment with PPAR-a agonists as well as monounsaturated and polyunsaturated fatty acids induces an increase in activity of major antioxidant enzymes in the brain . The distribution of PPAR-a receptors in the human brain remains mainly conjectural. Moreno et al. have provided an overview on the distribution of PPARs in the adult rat central nervous system . They reported the highest densities of PPAR-a in the hippocampal dentate gyrus and the granular cell layer of the cerebellar cortex. Furthermore, they observed PPAR expression in previously unreported locations, such as the basal ganglia, the reticular formation, some thalamic, mesencephalic and cranial motor nuclei and the large motor neurons of the spinal cord . This widespread distribution in the CNS also includes brain areas involved in sleep regulation such as the thalamus and the reticular formation. It has been hypothesized that sleep may serve an antioxidant function by removing free radicals or oxygen reactive species produced during waking time and that restoration of antioxidant balance is a property of recovery sleep . However, these protective mechanisms, especially in the brain, are still poorly understood. Interestingly, several studies have found that sleep deprivation is a stressful condition, which is associated with the disruption of various physiological processes . Reduced glutathione levels have been found in different brain regions, such as thalamus and hypothalamus, as well as in different organs of sleep deprived animals . Additionally, markers of generalized cell injury accompanied these decreases and decreased superoxide-dismutase activity has been shown in hippocampus and brainstem after prolonged sleep deprivation . The activation of these components of the antioxidant defense system suggests that sleep deprivation is a stressful condition for the entire body and for the brain in particular.

Activation of PPAR-a in vivo causes an upregulation of the mRNA and protein levels of a number of peroxisome- and nonperoxisome-associated enzymes and structural proteins, including the antioxidant enzymes catalase, superperoxide-dismutase and mediators of the glutathione pathway. In this context, pretreatment with fenofibrate reduces cerebral infarct volume in apolipoprotein E-defificient mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-a-defificient mice, suggesting that PPAR-a activation is involved as a protective mechanism against cerebral injury . We failed to confirm the initially hypothesized increase of anandamide after sleep deprivation questioning its proposed role in sleep induction in humans . This is in line with findings on cannabinoid CB1- receptor gene expression, which is suggested to be modulated by sleep. While sleep rebound significantly increased CB1-receptor protein and decreased respective mRNA, no effects were found following sleep deprivation . Interestingly, according to the product information, the CB1-receptor antagonist rimonabant induces sleep disturbances frequently but also sedation in clinical trials. Several shortcomings might have influenced our somehow preliminary data; first, a randomized, balanced crossover design would have been the ideal design for the trial. Second, EEG recordings might have provided more detailed information on sleep quality instead of an actigraphy for control of sleep deprivation only.More high school students smoked little cigars and cigarillos than cigarettes in 33 US states in 2015. 1 Concern is growing about co-use of tobacco and marijuana among youth, particularly among African-American youth. 2,3 In a 2015 survey, for example, one in four Florida high school students reported ever using cigars or cigar wraps to smoke marijuana. 2 One colloquial term for this is a “blunt.” Adolescent cigar smokers were almost ten times more likely than adults to report that their usual brand offers a flavored variety. 4 Since the US ban on flavored cigarettes , the number of unique LCC flavors more than doubled. 5 Anticipating further regulation, the industry increasingly markets flavored LCCs with sensory and other descriptors that are not recognizable tastes.For example, after New York City prohibited the sale of flavored cigars, blueberry and strawberry cigarillos were marketed as blue and pink, but contained the same flavor ingredients as prohibited products.Among the proliferation of such “concept” flavors , anecdotal evidence suggests that references to marijuana are evident.Cigar marketing includes the colloquial term, “blunt”, in brand names and product labels . Other marketing techniques imply that some brands of cigarillos make it easier for users to replace the contents with marijuana.For example, the image of a zipper on the packaging for Splitarillos and claims about “EZ roll” suggest that products are easily manipulated for making blunts. We use the term “marijuana co-marketing” to refer to such tobacco industry marketing that may promote dual use of tobacco and marijuana and concurrent use . In addition to flavoring, low prices for LCCs also likely increase their appeal to youth.In California, 74% of licensed tobacco retailers sold cigarillos for less than $1 in 2013.Before Boston regulated cigar pack size and price in 2012, the median price for a popular brand of grape-flavored cigars was $1.19.In 2012, 78% of US tobacco retailers sold single cigarillos, which suggests that the problem of cheap, combustible tobacco is widespread.Additionally, the magnitude of the problem is worse in some neighborhoods than others. Popular brands of flavored cigarillos cost significantly less in Washington DC block groups with a higher proportion of African Americans 14 and in California census tracts with lower median household income.For the first time, this study examines neighborhood variation in the maximum pack size of cigarillos priced at $1 or less and assesses the prevalence of marijuana co-marketing in the retail environment for tobacco. School neighborhoods are the focus of this research because 78% of USA teens attend school within walking distance of a tobacco retailer.