Hemp Growing

For each setting, the vape pen was operated until approximately 100 mg of VEA had been consumed; this consumption was typically achieved within 10–20 puffs. In instances where more puffs were required, the vape pen was allowed to rest at 20 puffs for 10–20 minutes to prevent overheating of the battery. Condensed emission products were dissolved in 1 mL of ACN, with 10 μL of 1, 3, 5-TCB solution added to each sample as an internal standard for chemical analysis. Emissions were analyzed immediately after collection or stored at -80˚C to prevent any aging effects.To determine the impact of the device on the degradation of e-liquids, pure pyrolysis of VEA oil was simulated using a tube furnace reactor system . The schematic of the set up for these experiments is shown in S2 Fig in S1 File. An alumina crucible containing 100 mg of VEA standard oil was weighed, and then placed into a high temperature quartz tube furnace capable of reaching temperatures as high as 1200˚C. The tube furnace was initially set to 23˚C, then ramped to each temperature setting at a rate of 10˚C min-1, and then held at the target temperature for 75 minutes to allow for VEA oil to be evenly heated. Inert argon gas was flowed through the system at a rate of 0.18 L min-1 to carry the VEA pyrolysis products into cold trap apparatus kept at -40˚C. After 75 minutes, the tube furnace was programed to return to room temperature before the alumina crucible was removed and re-weighed to determine the amount of VEA that was consumed. Pyrolysis products condensed in the cold trap were dissolved in 1 mL of ACN and concentrated to 100 μL using a gentle N2 gas stream. Then, 10 μL of 1, 3, 5-TCB solution was added to each sample as an internal standard for chemical analysis.Large molecular weight and non-polar degradation products were analyzed by directly injecting 2 μL of sample into an Agilent J&W DB-5MS column for separation. A solvent delay of 6 min was used; the GC was initially set to 60˚C for 1 min, then ramped to 150˚C at a rate of 3˚C min-1, held at 150˚C for 2 min, ramped to 310˚C at a rate of 20˚C min-1, and then held at 310˚C for 5 min.

Smaller molecular weight,outdoor cannabis grow polar degradation products were analyzed by directly injecting 2 μL of sample into a Rtx-VMS fused silica column . A solvent delay of 6 min was used. The GC was set to 35˚C for 1 min, ramped to 240˚C at a rate of 10˚C min-1, and held 4 min. The detailed procedures for the operation of GC/MS can be found in a previous publication.Degradation products were identified using the NIST 2008 mass spectral database. Compounds with probability 50% and match factor scores 800 were considered as good matches. For compounds that were suspected to be present in our spectra but could not be identified using the NIST library due to lack of available standards, Quantum Chemistry Electron Ionization Mass Spectrometry was used to simulate theoretical EI mass spectra of molecules.The detailed procedures for QCEIMS calculations can be found in the supporting information. Peak abundances were normalized to the 1,3,5-TCB internal standard for quantification.Fig 1 shows the temperature profiles of the e-cigarette coil and VEA oil in the cartridge operated at each voltage setting. Peak coil temperature at each voltage setting was fairly consistent between each measurement with no significant increase after consecutive use, which agrees with previous reports. Though the starting temperature after 1 min of rest increased slightly with subsequent measurements, the starting temperature never exceeded 33˚C. In contrast, the temperature of the oil in the cartridge increased with each subsequent measurement until seeming to plateau. The peak temperatures of both the coil and the oil were then taken and plotted as a function of voltage, as shown in Fig 2. Coil temperature showed a strong positive linear relationship with applied voltage , whereas oil temperature increased linearly with voltage until 41˚C , where the peak temperatures at 4.3 and 4.8 V do not significantly differ. This is likely due to the specific heat capacity of VEA; at higher voltages. Visible discoloration to the oil and wick could be seen during temperature measurements, indicating that the specific heat capacity of the oil in the cartridges may have been exceeded and part of the stored VEA may have been transformed before it is vaped .The total ion chromatographs obtained from GC/MS analysis of VEA vaping emissions produced at each temperature setting are shown in Fig 3. Overall, clear temperature dependent degradation of VEA vaping emissions can be seen as the amount and abundance of degradation products substantially increases with increasing coil temperature.

Analysis of the GC/MS results revealed 19 compounds that were able to be tentatively identified based on consistent NIST MS spectral library match scores of 800 or greater. One other compound, 1-pristene, was not found in the NIST library and thus was identified based on comparison with previously reported mass spectra and a mass spectrum generated with the QCEIMS program that found signature fragments of m/z 266, 111, and 126, which are consistent with our results . A summary of the identified compounds and chemical information identified from PubChem can be found in the supporting information . Many of the products described here, such as phytol, 2,3,5-trimethyl-1,4-benzenediol and 2-hydroxy-4-methoxy-3,6-dimethyl benzaldehyde, have not been previously detected from VEA vaping to our knowledge. An isomer of 2,3,5-trimethyl-1,4-benzenediol has also recently been identified as a substantial VEA degradation product at temperatures 220˚C. Authentic standards were purchased for 2-methyl-1-heptene, phytol, and 2,3,5-trimethyl-1,4-benzenediol to confirm identities of observed products . Other compounds, such as vitamin E, DQ, DHQ, 1-pristene, and 3,7,11-trimethyl-1-dodecanol, have been consistently identified as VEA decomposition products . Several products, such as DHQMA or ketene, that have been previously reported in VEA vaping emissions could not be found in our spectra, likely due to the limitations of the emission collection and analysis method described in section 3.4. A heat map of the mass fractions of degradation products generated at each temperature is shown in Fig 4. Products that contribute to the majority of the observed VEA degradation were separated from the total heat map to better visualize the change in each concentration as a function of temperature. VEA, 1-pristene, and 3,7,11-trimethyl- 1-dodecanol were found to be the most dominant vaping emission products at all of temperature settings, while other compounds, such as duroquinone, durohydroquinone, and 2-methyl-1-heptene steadily increase in concentration as temperature increases. Furthermore, certain compounds including 2,3,5-trimethyl-1,4-benzenediol, 2,6-dimethyl-1,6-heptadiene, 3,7-dimethyl-1-octene, and 3-methyl-1-octene are not produced in concentrations above the detection limit of our instrument until 322˚C, which suggests a potential risk that users who operated vaping devices at lower temperatures would not be exposed to. However, while most identified compounds appear to increase in concentration as temperature increases, phytol and 2,6,10-trimethyl-dodecane are produced at detectable levels at 176 and 237˚C but cannot be found at higher temperatures.

Another recent study has also detected production of phytol when vitamin E were heated in a microchamber/thermal extractor at 250˚C . It is possible that at these compounds are stable at lower temperatures but begin to break down into degradation products themselves as the temperature increases. Another important pattern to note is the increase in compounds that may pose a risk of oxidative damage to lungs, such as DQ and 2,3,5-trimethyl-1,4-benzenediol, at higher concentrations. While not investigated in this study, prior research has shown that increased temperature may result in the enhanced emission of carbonyl-containing compounds when vaping e-liquids containing propylene glycol and glycerin. Thus, vaping VEA at greater temperature settings may also carry the risk of exposure to highly electrophilic molecules and subsequent oxidative lung injury. In order to better understand the interactions between temperature and the generated emission products, a Pearson correlation analysis was performed . Overall,vertical grow system all but four of the identified compounds were strongly correlated with temperature . Compounds such as DQ, 1-pristene, 2-methyl-1-heptene, 2-hydroxy-4-methoxy-3,6-dimethyl benzaldehyde, and 2,6-dimethyl-1,6-heptadiene, were very well correlated with temperature , indicating a strong increase in concentration as temperature increases. VEA and phytol, in contrast, were strongly anti-correlated with temperature , while VE and 2,6,10-trimethyl-dodecane were moderately anti-correlated with temperature . In addition, VEA was found to be weakly to strongly anti-correlated with all degradation products excepting phytol and VE, which demonstrate a strong positive correlation . These results support our analysis of the mass fractions, indicating that as temperature increases, thermal decomposition of VEA is heightened. Further analysis of the correlations between degradation products shows that phytol is strongly anti-correlated with all VEA degradation products with the exception of 2,6,10-trimethyl-dodecane, which was found to have a strong positive correlation with phytol . Phytol was also found to be strongly correlated with VEA , likely because as more VEA was evaporated during the vaping process, the greater the chance of degradation into phytol. These relationships further suggest that while some degradation products may be stable at high temperatures, phytol may further decompose into shorter-chain alcohols, alkanes, and alkenes and enhance the production of VEA vaping emission products. Phytol is known both as a precursor for the synthesis of VE and vitamin K12, as well as a byproduct of chlorophyll degradation . Inhalation of aerosolized phytol has previously been shown to induce lung injury in exposed rats. In addition, phytol is a long chain alkyl alcohol compound, meaning that it has the potential to induce damage to the membrane of cells in a biological system. Overall, the toxicity of phytol raises questions about the safety of vaping not only VEA but cannabis-containing vape products that may result in phytol production.

These results clearly indicate that the product distributions of VEA vaping emissions are highly dependent on the operating temperature of the vape pen. As a result, the exposure for vape users operating the same e-cigarette products at different temperatures may differ significantly.Previous reports of VEA pyrolysis indicate that VEA begins to degrade starting at ~200–240˚C. However, our results clearly demonstrate degradation of VEA and formation of products such as DQ at 176˚C, indicating that the device itself may play a larger role in the decomposition of VEA than initially anticipated. Previous study in our lab has also found substantial formation of DQ at 218˚C–several hundred degrees lower than what has been predicted. To further understand if the device itself may impact the thermal degradation of VEA, pure pyrolysis of VEA oil was carried out using a tube furnace reactor. After 75 minutes, the average mass loss of VEA heated at 176, 237, 322, and 356˚C was found to be 0.11 ± 0.091, 0.37 ± 0.11, 3.7 ± 0.072 and 7.1 ± 0.0016 mg of VEA consumed. At 176 and 237˚C, VEA was fairly stable; substantial consumption of VEA oil was not observed until the two higher temperatures, despite clear consumption at all temperatures during the vaping collection. Fig 6 demonstrates the product distribution of VEA degradation products collected and analyzed using GC/MS. Here, we did not observe substantial thermal decomposition of VEA when heated at 176˚C for 75 minutes, which greatly contrasts with the degradation of VEA at 176˚C for only 4 s during the vaping collection. At 237˚C, the parent VEA molecule was the only detectable emission product, indicating that VEA again did not degrade at this lower temperature, though 237˚C was enough to evaporate VEA so that it could be collected in the cold trap. Degradation products were only detectable from samples collected at 322 and 356˚C, though the number of products and abundance of observed peaks are drastically reduced when compared to the vaping emissions. It should be noted that the tube furnace is capable of heating VEA at more accurate and consistent temperatures than the vape pen itself, which often saw temperature fluctuations that may influence results. The stark difference in product distribution provides evidence that VEA vaping emissions may not be the result of pure pyrolysis alone. Instead, external factors such as the device elements themselves or environmental interactions may play a role in the catalysis of VEA degradation.

Diffusion-weighted MRI of tissues provides a quantitative measure of the apparent diffusion coefficient of water, instead of estimations of water mobility from relaxation measurement that include the influence of translational mobility, composition and other factors . In addition, a spatially resolved map of the apparent diffusion coefficient of water can be obtained, which could help to understand and quantify the development of disorders such as CI within the tissue. MRI has been used to gain insight into early phases of different post harvest physiological disorders before the manifestation of external symptoms . These include core breakdown in pear water core disorder , internal browning and mealiness in apple . There are few reports where MRI was used to detect the early stages of CI in sensitive produce. In persimmon, MR images of cold-stored fruit were distinct from those stored at ambient temperature . In zucchini squash , MRI provided enough data to act as a predictor of where water soaking would occur in the epidermis after the cold-storage. These studies both indicated that MRI has great potential for studying CI in fruit tissues. Tomato is one of the most important horticultural crops both economically and as a genomics, molecular, biochemical, and physiological model for biological processes occurring in fleshy fruits . Like most subtropical fruit, tomato is susceptible to CI. Studies with tomato fruit could leverage existing functional genomics resources to pinpoint the molecular basis of this trait. To our knowledge, MRI has not been used to study CI in this species. We used the dwarf cultivar ‘Micro-Tom’ because it is the functional genomics model for tomato . Its high-density growth, short life cycle and concentrated fruit-set makes it possible to obtain harvests of 500 fruit or more per square meter per year . Because tomato post harvest studies can be hampered by biological variability ,cannabis grow lights the availability of numerous, similarly aged fruit makes Micro-Tom a convenient experimental model for post harvest studies .

Furthermore, we have previously characterized Micro-Tom fruit physiological response to a range of post harvest chilling temperature-time combinations , and used this information to design a metabolomics investigation of CI. This has established a baseline with this cultivar for the further CI studies we exploit here. The specific objective of this study was to determine if MRI could detect some of the earliest physiological changes that accompany CI in tomato fruit. Current methods of assessing the occurrence and severity of CI are: time consuming , destructive , or occur only after the activation of secondary, downstream events . These methods are time-proven and are indispensable, but there is a need for non-destructive methods with equivalent or better sensitivity to those currently used. MRI potentially offers such advantages and could be an important complementary tool for studying incipient CI. We show that MRI can provide spatio-temporal resolution of chilling induced changes in MicroTom tomato fruit prior to development of downstream symptoms.Chilled fruit were removed from 0 ◦C and allowed to slowly warm to 20 ◦C before CO2 and ethylene production were measured.These jars were sealed for 1 h and a 1-mL sample of the head space was withdrawn using a syringe and its CO2 concentration was measured with an infrared gas analyzer as previously described . Ethylene production was measured from a 2.5 mL sample of the head-space using a Gas Chromatograph equipped with a flame ionization detector. These two samples were taken within 30 s of each other from the same jar.Each fruit was cut into four radial segments, cleaned of adhering locular tissue, washed for 5 s in running tap water, blotted dry, and one segment was placed in each sector of a 4-sectored Petri dish under aseptic conditions. The dishes were placed in plastic tubs lined with wet paper towels and loosely covered with aluminum foil. The tubs were held at 12.5 ◦C for 18 h to produce ‘aged’ tissue, i.e., to allow the tissue to overcome the wound-induced alterations in membrane permeability . After transferring to room temperature for 1 h, the four aged segments from each Petri dish were put into a 50 mL plastic centrifuge tube containing 20 mL of an aqueous solution of 0.2 M mannitol.

Preliminary experiments determined that 0.2 M was isotonic for these excised radial segments The conductivity of the bathing solution was measured with an Extech Model 480 digital conductivity meter every 5 min for 30 min and then less frequently for 180 min with gently shaken between readings. After 3 h the tubes were capped, frozen at −20 ◦C and warmed to room temperature and frozen and thawed twice before the total conductivity of the solution was measured at room temperature after 1 h of shaking. Ion leakage was expressed as percent of total and plotted over time. The linear increase in ion leakage from 0.5 to 2.0 h was used to calculate the rate of ion leakage .The aim of this study was to examine the extent to which MRI could detect changes in chilled Micro-Tom tomato fruit. Based on our previous data using Micro-Tom , fruit were stored at 0 ◦C in the dark for 0 , 1, or 2 weeks, and the fruit that were chilled for 2 weeks were held for 1 week at 20 ◦C. The onset of CI was evaluated using changes in respiration, ethylene evolution and ion leakage . One week of chilling increased all of these indicators to levels that were maintained during an additional week of cold-storage . In fruit transferred to 20 ◦C after 2 weeks of chilling, the rate of respiration returned to that of the pre-chilling levels, ion leakage remained at the same elevated levels and ethylene production continued to increase. A sustained rise in ethylene production upon warming after chilling is characteristic many chilling sensitive tissue . MRI provided data that allowed the spatial resolution of the internal changes in chilling-induced fruit that were not available using conventional methods. ADC maps of an equatorial section of a tomato are shown in Fig. 1a. These heat maps indicate changes in water mobility, which increased during and after chilling; presumably because of chilling-induced disintegration of membrane integrity. After chilling at 0 ◦C for one week, the amount of voxels in the entire fruit in the yellow-red range increased compared with that of the non-chilled fruit . This general trend continued during two weeks of cold storage .

However, when these fruit were transferred to 20 ◦C, the number of yellow-red voxels throughout the slice decreased in the pericarp, but less so in the center of the fruit. Quantitative data better illustrate differences among tissues . When compared with the pericarp,cannabis grow tent the inner tissues showed higher signal frequencies at greater ADCs after 2 weeks refrigeration followed by room temperature storage relative to the controls . D-values were calculated for the whole fruit in order to make comparisons with ethylene and respiration data obtained from whole fruit. These values were higher in one week-chilled fruit compared with other storage periods . After two weeks at 0 ◦C and with further storage at 20 ◦C, the D-values were similar to the control . An increase after 1 week of chilling was also observed in carbon dioxide, ethylene evolution, and ion leakage . However, while these criteria remained higher than those in the non-chilled control fruit, the D-values declined relative to those in the control . The mean D-values of distinct spatial regions of the fruit were then calculated. No changes from the control were recorded in the pericarp after chilling for 1 or 2 weeks at 0 ◦C . However, after an additional week of storage at 20 ◦C, D-values decreased to levels observed in the non-chilled control. This may be indicative of the ability of marginally chilled tissue to repair the chilling-induced physiological damage that accumulated during chilling when warmed to non-chilling temperatures . There was little correspondence between changes in these D-values and changes in membrane ion leakage values; which were both derived from pericarp tissue . Ion leakage increased after cold exposure while Dvalues did not. There was some variability in pericarp ADC-values as mentioned earlier; cold-stored fruit varied compared to those reconditioned at 20 ◦C . Even when percent membrane permeability in the pericarp was considered over shorter time intervals, e.g., 15, 25 min, etc., changes due to chilling were still asynchronous with pericarp D-values . For the interior columella and locular tissues, the D-values increased after 1 week of chilling and remained at this elevated level for the remainder of the storage period . This response was significantly different from that of the pericarp. When the controls were compared to fruit kept in the cold for 1 and 2 weeks, D-values for interior tissue correlated reasonably well with changes in respiration and ethylene production . However the inner fruit D-values showed an identical pattern to changes in ion leakage, which is a destructive assessment of pericarp changes . This suggests two possibilities: that each individual assay acts as a proxy for similar underlying biological processes, but that they each encapsulate some divergent mechanisms, or that in response to cold, the pericarp and inner fruit may be modulated in different temporal time frames with varying amplitudes.Membrane disintegration and the subsequent physiological changes in chilled fruit may promote higher water mobility detected as increased D-values. Interpretation of these data suggest that the sensitivity and responsiveness to chilling differs between the pericarp and core tissues. This may arise due to the physical distance from the epidermis to the fruit center. An endogenous temperature gradient may be imposed across the fruit creating an inherent delay in the response and any subsequent adaptation to cold, between pericarp and core tissues. Although this possibility cannot be ruled out, the relatively small diameter of Micro-Tom fruit should minimize this effect.

Of more importance may be the heterogeneous nature of the fruit tissues. Differences in their physiochemical properties and functionalities could produce different biological outcomes to chilling. The realization that fruit responses to cold are asynchronous should inform our view when designing and interpreting data from experiments to study chilling injury. The aim of the experiments described here was to explore basic fruit post harvest biology using MRI and thereby gain new insight into CI.While not fast enough for commercial use,the MRI scan time of 27 min were still much faster than the more than 3 h needed to measure respiration, ethylene evolution and ion leakage. In addition to being faster, MRI also provides spatially resolved data. A long-term goal would be to refine this technology to enable its practical application as an economical, robust and rapid on-line detector of post harvest disorders in packinghouses or even along the supply chain. This would allow each stakeholder to have better control over produce quality. Examining the response of different cultivars that vary in fruit size, pericarp thickness, ratio of columella to locular tissues, and sugar to acid content, and to a variety of low temperature in cubations will also be necessary to facilitate MRI’s adoption in commercial settings.Tomato is the world’s second largest vegetable crop rich in nutrients. Tomato fruit development includes three stages. The first stage is characterized by an increase in cell number and starch accumulation, followed by cell enlargement with starch degradation and soluble sugar accumulation in the second stage. Fruit ripening is the last stage, associated with the accumulation of soluble sugars, carotenoids, organic acids, and volatile organic compounds in fruits. The chlorophyll accumulation and photosynthetic activity of green fruits influence the nutritional components and flavor of ripening tomato fruits. Some genes have been reported to affect chlorophyll accumulation, chloroplast development and fruit quality. As negative regulators, DE-ETIOLATED 1/high pigment 2 and UV-DAMAGED DNA-BINDING PROTEIN 1/ high pigment 1 are involved in chloroplast formation and chlorophyll accumulation in tomato fruits. The tomato GOLDEN2-LIKE transcription factors SlGLK1 and SlGLK2 play an important role in chloroplast formation and chlorophyll accumulation.Evidence suggests that the SlGLK2 gene is predominantly expressed in fruits and that the latitudinal gradient of SlGLK2 expression influences the production of unevenly colored tomato fruits. Over expression of the APRR2- LIKE gene, the closest homolog of SlGLK2, increased the size and number of chloroplasts and enhanced chlorophyll accumulation in green tomato fruits.

However, during follow-up the ICBT group had relatively greater increases in percent-network abstinent, and greater decreases in mean-network drug use and percent-network using drugs. Effects of group, time, and group x time were not statistically significant for self efficacy or the remaining social network variables. Overall the two treatment groups had few differences on process variables, with the exception of social network drug use. Finally, the effect of time was negative and statistically significant for controlled context , indicating an overall decrease over time in the proportion of time spent in controlled contexts, a trend that did not differ between treatment groups. We then examined whether self-efficacy and social network variables prospectively predicted post-treatment alcohol and drug use. Separate HLMS for each process variable tested associations with substance use outcomes , controlling for previously mentioned covariates. Each time-varying predictor was lagged and decomposed into two distinct variables to disaggregate between-person and within-person effects on PDD and PDDRG. Social network variables were substance-specific, with network drinking predicting PDD and network drug use predicting PDDRG. Results of these models are displayed in Table 10. With one exception , all between-person effects were statistically significant. Moreover, individuals with social networks characterized by lower mean use and a lower percentage of regular users had lower PDD and PDDRG during follow-up, and those with greater percent-network abstinent from drinking had lower PDD. For within-person effects, greater mean network drinking and greater percent-network drinking predicted PDD, indicating that fluctuations from the person- mean in these variables predicted drinking in the next 3 months. We then determined whether the amount of time spent in controlled contexts was associated with post-treatment substance use.

These HLMs tested the time-varying effect of controlled context on concurrent PDD and PDDRG, controlling for identical covariates as previous models. The results, displayed in Table 10,cannabis drying racks indicate that a greater proportion of time spent in controlled contexts was associated with significantly lower PDD and PDDRG during these same periods. At month 18 veterans with 0% days controlled had an estimated PDD of 18.19. Estimated PDD was lower for those at the mean of controlled context , and even lower for those 1 standard deviation above the mean . These results confirmed that the percentage of time spent in controlled contexts was significantly and negatively associated with frequency of current substance use. Final models included interactions between lagged process variables and controlled context, to test hypotheses that percent-days in controlled context would moderate the effects of lagged process variables on PDD and PDDRG. As displayed in Table 10, between-person effects for each social network drinking variable interacted significantly with controlled context to predict future PDD. Also, between-person effects for mean network drug use and percent-network regularly using drugs interacted with controlled context to predict future PDDRG. As displayed in Figure 1, social network effects on future PDD and PDDRG were weaker when time in controlled context was high. Controlled context did not significantly moderate self efficacy or within-person effects. Overall, these results indicate that social network characteristics of veterans with substance dependence and MDD predicted future drinking and drug use, but these predictive effects were weakened when veterans lived in controlled contexts for extended periods of time. Prior studies of determinants of post-treatment substance use have not typically focused on individuals with SUDs and co-occurring psychiatric disorders, despite high rates of these co-occurring disorders in many clinical settings . Co-occurring MDD is particularly common, and individuals with SUD and MDD typically have poorer outcomes following treatment and may receive less benefit from therapeutic mechanisms of change . Because they represent a large proportion of patients receiving substance dependence treatment and have a greater risk of poor outcomes, it is critically important to examine determinants of post-treatment substance use within this population.

In a sample of veterans who had received group outpatient psychotherapy for substance dependence and MDD, we examined self-efficacy and network substance use, the effects of controlled contexts, and their interaction in the prediction of post-treatment drinking and drug use. In this sample with substance dependence and MDD, individuals with greater self-efficacy had lower future drinking and drug use during the year following treatment. Self-efficacy has predicted post-treatment use across various substances and treatment settings , and our study extends these findings to patients with substance dependence and MDD. By separating the between-person and within-person components of self-efficacy, we demonstrated that generally maintaining higher self efficacy was protective against future substance use, while time-specific fluctuations in self-efficacy were less critical. Prior studies with this sample revealed that baseline self efficacy predicted time to relapse and self-efficacy increased significantly during treatment . Our results were encouraging in finding that during the year following treatment, self-efficacy did not decrease significantly and continued to predict substance use. Moreover, post-treatment self-efficacy was similar between ICBT and TSF, suggesting that self-efficacy can be sustained similarly following cognitive-behavioral or professionally-led, 12-step based interventions, replicating prior research . Our results support the value of abstinence self-efficacy for patients with substance dependence and MDD, and provide a strong rationale for investigating factors related to increasing self-efficacy within this population. Substance-specific social network variables were also predictive of post-treatment substance use. For both alcohol and drugs, future frequency of use was lower for individuals who generally had 1) lower average network use and 2) a lower proportion of regular users in their network. Furthermore, having a network with a greater density of non-drinking individuals predicted lower future drinking.

These social network characteristics have previously predicted drinking outcomes in alcohol-dependent samples , but our study is first to demonstrate these findings in patients with substance dependence and MDD. Social network effects at the within-person level were also predictive of substance use. More specifically, when individuals had increases from their own norm of average network drinking or proportion of regular drinkers, they drank more frequently in the future. It is likely that these interpersonal factors operate in multiple ways to influence future drinking . The presence of alcohol or other drinkers represent conditioned cues that elicit craving or other precipitants to drinking, and associating with drinkers may increase exposure to substances or undermine patients’ sobriety efforts via changes in outcome expectancies. Treatment protocols designed explicitly to change social networks have demonstrated long term efficacy in the treatment of alcohol dependence . These interventions have not been tested in patients with co-occurring psychiatric disoders, and our study suggests these interventions could be effective in patients with substance dependence and MDD. This study also found that post-treatment substance use depended on the level of constraint in the living environment. During follow-up over half of our sample had some time in “controlled contexts” at an average of 39% of days in these environments. As hypothesized, when patients spent a greater percentage of time in controlled contexts defined by limited access to substances or negative consequences for use, they had lower frequency of drinking and drug use. Moreover, controlled context acted as a moderator,cannabis grow tray such that social network influences were more predictive of future alcohol and drug use when the environment did not restricted. Social network effects were attenuated for veterans at the highest levels of controlled context, suggesting these contexts do assist in buffering against the maladaptive influence of substance use within the network. Research indicates that patients with substance dependence and MDD are especially likely to utilize inpatient/residential services . The role of environment is rarely examined in treatment outcome studies, which is surprising given theoretical interest in considering intrapersonal and interpersonal processes within environmental context . Our results suggest the level of constraint in the environment is an important construct to consider in future studies. While some 3 controlled contexts may have resulted from adverse events , the most common contexts utilized were residential sober living facilities. Our results suggest patients with substance dependence and MDD who cannot sustain more protective social networks may benefit most from these constrained environments. While this study has important research and clinical implications, its limitations should be noted. The immediate generalizability of these findings is limited due to the demographic characteristics of this veteran sample, which was heavily comprised of Caucasian males. While this is a common limitation of many clinical trials of treatments for addictive disorders , replication in more diverse samples is needed before broader generalizations can be made. Our social network measure did not capture important features of social support examined in prior studies , such as whether network members were supportive of our patients’ abstinence efforts. Furthermore, network members’ use patterns were reported as perceived by study participants, and may not be a completely accurate assessment of their substance use patterns. While the effects of controlled contexts were in the expected direction, context alone may not fully explain our findings as this variable could be confounded with other unmeasured characteristics that are also strong determinants of abstinence.

While this study identified variables that predict post treatment substance use in adults with co-occurring substance dependence and MDD, underlying mechanisms have not yet been identified, which would explain how patients sustained greater levels of self-efficacy and lower levels of network substance use. As such, it will be important for future studies to explore whether specific processes of treatment assist patients in maintaining greater levels of these proximal variables following the conclusion of formal intervention. Study 3 has been submitted for publication in Alcoholism: Clinical and Experimental Research, as following: Worley, M.J., Tate, S.R., & Brown, S.A. Self efficacy, social networks, and the moderating effects of context following treatment for co-occurring substance dependence and depression. The dissertation author was the primary author of this manuscript under review. Many individuals with alcohol or drug dependence have deficits in neurocognitive abilities such as executive functioning and problem solving , verbal or non-verbal memory , cognitive efficiency , and attention , whether these deficits are due to the neurotoxic effects of substance use, preexisting characteristics, or some combination of both . In clinical settings these deficits are especially prevalent as 30-80% of patients enter treatment with some neurocognitive impairment . Although modest recovery in neurocognition is possible, these changes are often not clinically significant and many deficits do not remit even after periods of extended abstinence . Because neurocognitive impairment is so common and persistent, there is a strong rationale for examining whether impairment relates to treatment outcomes within the substance-dependent population. Another factor that may compound these neurocognitive deficits is the presence of other psychiatric conditions. Comorbid psychiatric disorders are common in the substance-dependent population , especially among patients in treatment settings . Major depression is recognized as the most common Axis I condition, and patients with comorbid MDD typically have poorer outcomes from treatment for alcohol or drug dependence . Importantly, MDD is also associated with deficits in working memory, attention, verbal memory, verbal fluency, and processing speed . Consequently, the joint effects of substance dependence and MDD on cognition may be worse than in either disorder alone, as with comorbid substance dependence and bipolar disorder . Despite the prevalence of comorbid substance dependence and MDD and the deficits associated with both conditions, the effects of neurocognitive impairment in patients receiving treatment for substance dependence and MDD have not previously been examined. Psychological treatments for substance dependence often require patients to learn and retain new information, inhibit prepotent responses, engage in future-oriented behavior, and plan behavioral coping strategies. Theoretically, patients with neurocognitive deficits would be less adept at internalizing and engaging in these skills, leading to poorer outcomes from psychotherapy. Some studies support this hypothesis, as patients with poorer cognitive functioning had greater substance use or lower retention in cognitive-behavioral therapy . However, these effects have not been consistent across studies, as many investigations failed to find associations between neurocognition and substance use during or following treatment . While some methodological differences exist between these studies , it is equivocal whether cognitively-impaired patients have poorer outcomes from substance dependence treatment. An important distinction within this literature is whether neurocognitive impairment is best examined as a direct predictor of outcome, or whether different model specifications are more ideal for testing relations with substance use . This notion is supported by studies demonstrating that impairment does not predict outcomes directly, but impacts substance use indirectly through therapeutic mechanisms of change.

Although early results are promising, integrated treatments are not fully empirically-supported, suggesting that further research examining core therapeutic processes within this patient population is needed. Mediators are intervening variables that statistically explain some association between an independent variable and dependent variable . Within the substance dependence treatment literature, researchers have increasingly stressed the importance of studies that seek to identify the mediators of treatment effects with some noting this needs to be “a first priority” . Within the depression treatment literature a similar movement has occurred in parallel . By gaining a greater understanding of the specific processes involved in treatment, therapies can be improved and disseminated more easily into practice settings . However, the search for treatment-specific mediators has often been less than promising, with theoretically dissimilar therapies often producing equivalent treatment effects or showing no differential change on theory-based mediators, and some recommending a paradigm shift in substance use treatment research . However, even studies of alternative treatments with similar effects on mediators and outcomes can provide useful insight into the common mechanisms of treatments, distinct but similarly effective mechanisms, or some combination of both . Previous studies have found that coping skills , self-efficacy ,and social support were common mechanisms of both cognitive-behavioral therapies and comparison interventions, due to similar levels of these variables across treatments and similar magnitude of associations between mechanisms and outcome. While these “null difference” findings are in some ways disappointing , they identify therapeutic processes that generally predict positive outcomes across different treatments. In other studies self efficacy and coping skills were treatment-specific mediators of cognitive behavioral interventions, because greater levels or change were attained and were predictive of group superior reductions in substance use, suggesting that under certain conditions, certain treatments do elicit differential change on therapeutic process variables.

Some of the more robust treatment-specific mediators have been 12-step attendance and affiliation,cannabis grower with greater increases in these mediators repeatedly found for treatments that explicitly encourage 12-step activities . In addition, change in social support for abstinence has been specific mediator of outcome in treatments designed to change social networks . Mediators of substance use may also relate to other outcomes, as one study found greater 12-step meeting attendance was associated with future drinking but also with lower current depressive symptoms . Amid the questionable efficiency in continued reliance on large-scale randomized controlled trials and scrutiny of these designs, further research in proximal variables that mediate treatment outcomes or predict outcomes across treatment conditions has an important role in the further development of substance dependence interventions. Few studies have examined mediators of outcome in patients with substance dependence and psychiatric disorders, and almost none have involved integrated treatments that simultaneously target both disorders. In naturalistic studies of community based, dual-focus self-help groups, the effects of greater meeting attendance and 12-step affiliation on abstinence were mediated by social support, sociability, internal locus of control, and self-help processes . In an observational study of residential treatment, self-efficacy and social support at baseline predicted psychological distress and substance use at follow-up in patients with substance dependence and mixed psychiatric disorders . In one randomized, controlled study, changes in negative mood expectancies predicted long-term alcohol use in patients receiving adjunctive CBT for depression in patients receiving relaxation training . In a study of our sample of veterans with substance dependence and MDD, self-efficacy predicted time to relapse and frequency of substance use during treatment . None of these studies conducted formal statistical tests for mediation, a necessary criterion for the establishment of an intervening variable as a mechanism of change , along with the temporal precedence. There is initial evidence that therapeutic processes involved in substance use treatment and maintenance of abstinence will translate to those with co-occurring MDD, but this literature is currently lacking in methodologically-sound, longitudinal investigations.

In addition to therapeutic process variables identified in general substance dependence treatment studies, level of negative affect likely plays a large role in the maintenance of substance use for individuals with substance dependence and MDD. Negative affect is frequently a precursor to substance use and is dynamically-linked to alcohol and drug use following treatment . These associations may be even stronger in adults with SUDs and MDD, who likely have stronger urges to “self-medicate” with substances to manage depressive symptoms. In one study comparing SUD-only patients to those with SUDs and psychiatric disorders, those with co-occurring MDD were especially likely to experience depressive symptoms prior to relapse . Furthermore, changes in depression and substance use during treatment and follow-up were strongly correlated in our sample of veterans with substance dependence and MDD In addition to the significance of depression severity as proximal risk factor for substance use, the magnitude of improvement in depression during treatment is a potential mechanism of change for substance use behaviors in this population. Prior research suggests the salutary effects of AA meetings on drinking may be explained, in part, by related improvements in depression . Treatment processes or individual characteristics that relate to depression may be especially potent for patients with SUDs and MDD, but prior studies have not examined these effects during or following outpatient treatment for these co-occurring disorders. Models of post-treatment relapse characterize the mediating variables discussed above as critical proximal determinants of substance use but also emphasize the significance of more “distal” risk variables . As such, investigations of mediating variables should also consider the impact of such distal risks on the therapeutic process.Despite a strong clinical rationale that patients with neurocognitive deficits will have poorer outcomes from psychological treatments, especially those that engage higher-order cognitive functions , most studies examining this hypothesis have yielded weak and inconsistent results .

More recently, two studies have examined more indirect effects of neurocognitive impairment: as a predictor of mediating variables, and as a moderator of their effects on substance use. Interestingly, both studies found that greater impairment was linked to lower self-efficacy during treatment, and that therapeutic effects of self efficacy were weaker for impaired patients . These studies highlight complex interactions between variables at different levels of analysis, which are required to fully elucidate our understanding of individual differences in substance dependence treatment outcome. Neurocognitive effects on therapeutic change mechanisms could be similar or even more pronounced in patients with co-occurring MDD. Neurocognitive features of MDD share many impairments with substance dependence, including deficits in memory , processing speed and executive function . Furthermore, better neurocognitive functioning at baseline has predicted greater reductions in depression for patients with depressive symptoms and hazardous alcohol use . This finding in particular suggests impairment is related to recovery from depressive symptoms, an important determinant of substance use for patients with substance dependence and MDD . A prior study of our sample found better substance use outcomes for veterans with poorer cognitive functioning who received integrated CBT as compared to TSF, a result that was somewhat unexpected given the theoretically greater cognitive demands in CBT . Given these prior findings, determining whether neurocognitive impairment interrupts therapeutic change mechanisms has important implications for clinical practice, but these questions have not been examined in patients with co-occurring substance dependence and MDD. Compared to recently emerging literature examining mediators and moderators of outcome in substance-dependent patients,vertical grow systems for sale there is a paucity of research examining these factors in patients with SUDs and co-occurring psychiatric disorders, who are more costly to treat , at greater risk of suicide , are more disabled , and typically have poorer treatment outcomes . The proposed series of studies will make significant contributions in this area of need by focusing on the largest group of substance-dependent adults with co-occurring psychiatric disorders, those with MDD. Results will assist in delineating the specific processes involved in the reduction of both substance use and depressive symptoms over time in this prevalent, chronically disabled, and costly population. The studies will conduct examinations of mediating processes, to explain associations between predictor variables and outcomes . These studies will examine whether specific proximal variables are common mechanisms of change, by highlighting whether specific intrapersonal processes are predictive of outcome regardless of treatment orientation. In addition, results may show that processes traditionally targeted to improve substance use may generalize to depressive symptoms, which has direct implications for clinical practice. By including outcomes up to one-year post treatment, these studies will seek to identify key processes involved in the long-term maintenance of symptom improvement. In addition, this study may be the first to elucidate pathways through which neurocognitive impairment impacts outcome in patients with substance dependence and MDD, which will have significant implications for the treatment of patients with neurocognitive impairment. Compared to the general population, mood and anxiety disorders occur at higher rates among individuals with substance use disorders , and major depression is the most common comorbid Axis I psychiatric disorder . Comorbid MDD is associated with a more chronic and prolonged course of SUDs , higher rates of disability , greater treatment costs and elevated risk of suicide . The prevalence is even greater among those who receive SUD treatment; in some clinical settings over half of patients have MDD .

These patients often have greater severity of problems at intake and poorer outcomes from alcohol or drug treatment . Despite high prevalence and evidence that treatment is less effective, few studies have examined treatment processes within this population. Recent research in SUD interventions has increasingly focused on mechanisms of change, defined as the factors that explain how and why treatments work . Studies of mediators, or variables that account for the association between a predictor and outcome , are a core element of this research . However, these factors have rarely been investigated in patients with SUD and comorbid MDD, which hinders the advancement of interventions for this patient population. Some of the most frequently-studied mediators of SUD treatment have been variables related to 12-step involvement, including attendance at 12-step meetings and participation in 12-step activities . In general SUD samples these variables are consistently associated with reduced alcohol and drug use and mediated the effects of 12-step psychotherapies in clinical trials . However, among patients with comorbidity studies of 12-step involvement have yielded inconsistent findings. In some studies, patients with psychiatric comorbidity attended similar levels of 12-step meetings and experienced similar benefits as those without psychiatric conditions , but others found reduced benefits of 12-step involvement for patients with comorbid MDD . Issues inherent to some community meetings, such as attitudes about psychiatric medication, could interfere with participation . In light of the limited existing research, further studies are needed to evaluate the utility of 12-step involvement in this population. A more complete understanding of 12-step variables may be achieved by examining mediators of therapeutic effects. Among patients with MDD one potential mediating variable is depressive symptoms. Affect regulation is frequently described in the 12-step literature , and 12-step involvement may increase exposure to common therapeutic factors that could reduce depressive symptoms . Therapeutic changes in mood could play a key role in substance use outcomes, as negative affect is often implicated in relapse and reductions in depression over time are associated with reduced alcohol and drug use . In a secondary analysis of Project MATCH , lower depression explained the effects of Alcoholics’ Anonymous attendance on future drinking, but this was mostly attributable to AA’s effects on current drinking . The relative role of depression in mediating 12-step involvement could be greater for patients with comorbid MDD. Depressive symptoms are a prevalent precipitant of relapse for these patients , and prior research with this sample found strong correlations between individual changes in depression and substance use . Thus, improvement in depressive symptoms linked to 12-step involvement could be a key process in the reduction of substance use for patients with SUD and MDD. The goal of this study was to examine relations between 12-step involvement, depression, and substance use in patients receiving treatment for comorbid SUD and MDD. Veterans with alcohol or drug dependence and MDD received antidepressant pharmacotherapy and 6 months of group psychotherapy with either Twelve-Step Facilitation or Integrated Cognitive-Behavioral Therapy , a cognitive behavioral treatment that focused jointly on depression and substance use .

The literature varies in its characterization of the risk preference variable, even with the same discrete choice questions. My results are similar whether including the full 4-category variable or the linear adjusted risk tolerance measure. Mis-classification of contraceptive consistency as well as contraceptive method could be a concern. There were some discrepancies between women’s reported percent of contraceptive usage and their method type. For example, there were 13 people who reported 0% use of birth control methods and also reported IUD use. This may result from misinterpretation of the question specifically for women using long acting methods. Or those women may have recently switch to IUDs, or use IUDs for other medical issues. It is challenging to determine if this is an error or an accurate response. There may be similar but less outwardly apparent misclassification across all contraceptive groups. The characterization of sexual behavior is limited in NLSY. Notably, respondents were not asked about sexual activity with a same sex partner in the last year. While the results of number of sexual partners are suggestive, future research on risk preference and sexual risk behavior should include a more comprehensive battery of questions. Potential intention-behavior incongruence may lead to the outcome of unintended pregnancy. Novel epidemiologic studies that include models of decision-making could identify antecedents of unintended pregnancy and develop interventions that may be targeted by individual risk preferences. This work provides an initial examination of the relationship between risk preferences and sexual risk behavior and contraceptive use. The findings merit future research with longitudinal samples to explore measure stability over time and in response to life circumstances. If a relationship between risk preferences and reproductive risk behavior, including number of partners and contraceptive use is reinforced,cannabis growing equipment it should inform our models of etiology of unintended pregnancy and also target behavioral interventions.

The goal of this research was to demonstrate the potential contribution of behavioral economics to our understanding of reproductive choices and behavior. Examining people’s decision-making can tell us not only about their likelihood of experiencing outcomes of interest, but also give information about their overall orientation. Preferences and biases may explain behavior and could be integrated into work on psychosocial predictors of health. The link between measured risk aversion and sexual and reproductive outcomes signal the importance of these measures beyond explaining financial behavior. They may, it appears, have implications for our understanding mechanisms underlying choices that drive reproductive health. This is an important step towards predicting who will be at highest risk of adverse outcomes and potentially develop models for intervention. The economic recession in the U.S. prompted increased interest in economic drivers of fertility. Variation in economic conditions may influence pregnancy intentions as well as contraceptive and sexual behavior, thereby altering risk of pregnancy. Additionally, the economic environment may impact individual decision-making on whether to continue a pregnancy. Understanding how economic uncertainty affects fertility intention and decision-making offers insight into the determinants of unintended pregnancy, spontaneous and induced abortion. Unintended pregnancy reduction is a stated national and international public health priority. Nearly half of pregnancies to women aged 15-44 in the United States are unintended, and 40% of those pregnancies end in abortion. Literature links unintended pregnancy to negative health outcomes for mothers and children, making it a significant public health concern and the target of prevention efforts as part of Healthy People 2020. Unintended pregnancy and pregnancy decision-making result from a multidimensional set of economic, cultural, social, psychological and demographic determinants. While risk of unintended pregnancy extends to the majority of women through their reproductive years, age, income, race/ethnicity, and psychosocial factors are associated with occurrence.

There is an educational gradient in unintended pregnancy, with higher incidence among women with lower levels of education. Women who experience unintended pregnancies are more likely have riskier psychosocial profiles prior to pregnancy, including depression, perceived stress, and low social support . Consequences of unintended pregnancy are substantial. There is some evidence of increased maternal risk behavior during pregnancy among those pregnancies that are unintended, including smoking and drinking. Consequences of unintended births include depression, preterm birth and delays in child development. It is estimated that unintended pregnancies cost the US more than $20 billion per year in expenses for births, abortions and miscarriages. Traditional measures of pregnancy intention measure the degree to which a pregnancy was planned or correctly timed. Unintended pregnancies are defined as pregnancies that are mistimed or unwanted at the time of conception. Intended pregnancies include pregnancies that are wanted at the time of conception or happen later than desired. Literature has critiqued this measure as one-dimensional, while asserting that people may feel a complex and multidimensional set of emotions surrounding pregnancy. In addition pregnancy intentions are dynamic and can change prior to and over the course of a pregnancy. Pregnancy intentions are often retrospectively recalled at the time of conception. This can be problematic as participant’s responses of intentions and desires can change depending on when they are assessed. Despite critiques that standard unintended pregnancy measures may not capture there this nuance, they are useful to identify time trends and risk factors. Researchers have long examined the relationship of the economy to fertility. Most studies find evidence for pro-cyclical effects , meaning slowing fertility in an economic downturn. The literature posits several mechanisms through which a worsening economy could affect fertility. First, an income effect from individual economic hardship causes individuals to rationally postpone or revise fertility plans.Becker , for example, suggests that the income effect leads to a quantity-quality trade off in childbearing decisions. Temporary income decreases may cause delays in childbearing whereas more persistent periods of unemployment may reduce the underlying desire to have children.

The economic environment can affect perception of risk in a population, not only among those directly affected by the experience of, for example, unemployment. Uncertainties in the labor market may affect fertility through anticipation of hardship, making fertility planning more challenging. These mechanisms would also yield a pro-cyclical association between the performance of the economy and fertility. Few studies show evidence of counter-cyclical effects, which assume that as employment opportunities decrease, the opportunity costs of time spent raising children decrease as well. This would promote substitution effects of fertility for employment. The recent economic recession in the United States provides opportunity for understanding mechanisms relating the economy and fertility. The Great Recession in the Unites States officially began in December 2007 and ended in June 2009. Unemployment and foreclosures rapidly increased as consumer confidence declined nationwide. During the Great Recession, the fertility rate decreased from 69.6 births per thousand women in 2007 to 66.4 births per thousand women in 2009, and has continued to decline. Several studies have documented a fertility decline in the United States and Europe from 2007-2011. During that time, state level economic indicators were linked to general fertility declines, as well as heterogeneity within subgroups. Schneider found strongest fertility effects of the economic downturn among women aged 20-24, who experienced lower rates of live birth than expected. Decreases in fertility were attributed to increased economic hardship and economic uncertainty which may have affected changes in contraceptive use, increases in abortion, miscarriage, or shifts in pregnancy intentions. Cherlin attributed a greater decline in fertility for young women to postponement rather than elimination of childbearing. Ananat et al. found birthrate declines among black but not white teens following country level job losses. They inferred that changes could be attributed to abortion or pregnancy avoidance based on the timing in gestation at which point the job losses occur. They hypothesized that black teens may be more vulnerable to job loss or uncertainty than white youth and found that the reductions in black teen births may be due to increased pregnancy terminations, reductions in sexual activity and increased contraceptive use. Much of the above work theorizes that fertility decline is due to rational choice to postpone or abstain from childbearing,cannabis plant growing however the ratio of intended and to unintended births during the Great Recession has rarely been examined. There is limited research on how the economic environment may serve as a determinant of unintended pregnancy and pregnancy outcome. Economic uncertainty or income effects may influence decision making prior to pregnancy, including pregnancy planning, sexual behavior and contraceptive use, and decision-making once a pregnancy has occurred, including the decision to abort. A study of institutional and individual economic measures found perception of job and income insecurity as well as aggregate unemployment rates to be associated with decreases short term childbearing intentions. A recent study by Percheski and Kimbo used the National Survey of Family Growth to investigate the risk of unintended pregnancy among women in the great recession. They exploited statewide indicators of unemployment, foreclosure and consumer sentiment and find reductions in both intended and unintended pregnancy among non-college educated women. They investigated the determinants of the decline, but found little evidence that economic indicators reduced sexual activity or increased contraceptive use . Reductions in births observed during the economic downturn may also have resulted from changes in pregnancy outcomes. While challenging to observe given high rates of fetal loss prior to pregnancy recognition, changes in the proportion of pregnancies that are not carried to term can alter fertility rates. A related body of literature establishes the increase of spontaneous abortion, following economic shocks.

Additionally, work demonstrating the shared correlation of spontaneous abortion and induced abortion suggests a positive relationship in response to economic events. Ananat et al.’s finding that teen fertility decreases following job loss that occurs during the first trimester could be explained by either mechanism. Research on abortion patients finds that economic insecurity is often cited as a reason for the decision. In the current investigation, I focus on two primary research questions: i.) Is national economic uncertainty associated with ratio of pregnancies reported as mistimed or unwanted relative to intended pregnancies; and ii) Is national economic uncertainty associated with the ratio of pregnancies ending in abortions or miscarriages relative to live births? Economic uncertainty, measured by changes in national monthly measures of the economy, captures contextual effects beyond effects among individuals who have experienced job loss or economic change. To investigate the relationship of economic uncertainty and reproductive health outcomes, I use data from the National Survey of Family Growth , combined with and monthly national unemployment data from the National Bureau of Labor statistics and the national consumer sentiment index from the Conference Board. The National Survey of Family Growth is a cross sectional, nationally representative survey administered by the National Center for Health Statistics. The Survey, initiated in 1973, collects data on fertility in the United States and contains detailed questions about sexual behavior, contraceptive use, relationship status and pregnancy.The survey collects data on each pregnancy, retrospectively recalled by participants. It is one of the only national surveys to include questions about pregnancy intention and contraception use at the time that the pregnancy occurred, as well as report of pregnancy resolution. This allows for examination of multiple pregnancies. NSFG includes inverse probability selection weighting based on of PSU, segment, housing unit, and person within selected household sampling procedures My analysis uses the 2006-2010 wave, which includes a national sample of 12,279 women and 10,403 men age 15-44 years living in households in the United States. In person interviews were conducted for a total sample size of 22,682. The interviews averaged 80 minutes in length for women. The response rate was 77% overall—78% for women, 75% for men]. To investigate women’s reproductive health outcomes, I use the pregnancy data file from the 2006-2010 survey of women across the US. The pregnancy file contains information on all of the participants’ past and current pregnancies, including date of conception, ‘wantedness’ at the time of conception, and pregnancy outcome. Therefore pregnancy is the unit of analysis. Economic uncertainty, as measured by the unemployment rate, Index of Consumer Sentiment, and timing of recession was associated with increased ratio of unintended compared to intended pregnancy, and abortion and miscarriage compared to live birth. Among unintended pregnancies, the ratio of mistimed pregnancies appeared more strongly and consistently associated with economic indicators than unwanted pregnancies.

Time preferences are related to health investment and health status and self-reported health. Several studies characterize addictive behaviors, including cigarette smoking, alcohol consumption and illicit drug use, as a special case of discounting. A review of gambling and substance use studies found consistent evidence that high rates of discounting are associated with a range of addictive behaviors with adverse health consequences.Discount rates have also been linked to alcohol dependence, alcohol abuse disorder, and moderate levels of alcohol use, including heavy social drinking. These effects are seen early in life, as discounting is positively correlated with age of first alcohol use and number of passed out episodes among adolescents. Illicit drug use also shows a consistent relationship, with higher discount rates among heroin and opioid-dependent individuals compared to non-drug users. Discount rates have also been studied in relationship to eating behavior and obesity, and may be closely related to food rewards among children. There are mixed results of monetary discounting and BMI in adults.The trade offs between longer-term goals and immediate rewards of unprotected sex fit a discounting framework. A qualitative study exploring determinants of inconsistent contraceptive use found that eroticism of unprotected sex and misunderstanding the risk of conception was a powerful explanatory factor. In one of the only articles to propose the connection between contraceptive use and behavioral economic interventions, Stevens and Berland note the connection of present-biased preferences to long acting reversible contraceptive use. They suggest that present bias in use of LARC could be leveraged by reducing the actual or perceived costs of obtaining LARC methods, such as higher cost if insurance is unavailable and discomfort of the procedure, in favor of long term benefits . While these types of changes to clinical encounters make intuitive sense based on behavioral economics,indoor cannabis grow system no research directly links delay discounting to contraceptive method choice. However, literature about other reproductive and sexual decisions may offer insight into the connection with contraceptive use. Individual decision-making is also shaped by perception of risk. Prospect theory describes decision-making in the context of risk.

The theory posits that people take greater risks to avoid loss than to realize gain even if the loss and gain are equal. It has gained credibility in the arena of health decision-making in comparison to the standard economic model, which assumes people are rational agents who make choices to maximize utility. Risk preferences are frequently studied in social science and are established as strong determinants of financial decision-making, including investment and savings. Risk preferences are generally measured as willingness to take gambles with income.People willing to take fewer gambles are generally deemed risk averse and those more willing to take gambles risk tolerant. Prospect theory also described lossaverse behavior in the context of risk, where individuals are more sensitive to potential losses than gains. A few studies have examined risk preferences and health behaviors. Anderson found that an experimental measure of risk aversion was negatively associated with several health behaviors, including smoking, heavy drinking, obesity, and non-use of a seat belt. A seminal study in the Health and Retirement Study found that an economic measure of risk tolerance predicted risk behavior including smoking and drinking. Loss aversion has also been linked to reduced cancer screening behavior among those with chronic disease who would be most sensitive to health losses. Willingness to accept risk has intuitive connection to sexual and reproductive health behaviors. The consequences of sexual and reproductive behavior, including unintended pregnancy to STI transmission, are probabilistic rather than certain. Thus an individual’s tolerance for risk may affect their willingness to engage in unprotected sex. Although it is clear that individual decision-making affects sexual and reproductive health behaviors, including contraceptive method choice, consistency of condom use, number of sexual partners, and use of substances while engaging in sex, literature exploring the connection of discounting and risk tolerance has emerged only recently. This systematic scoping review examines the literature suggesting how two decisional preferences from behavioral economics, temporal discounting and risk tolerance, may influence sexual and reproductive behavior. The review seeks to contribute to the literature on sexual and reproductive health by assessing the state of the evidence available and offering suggestions for future work.

Descriptions from the 20 included articles are displayed in Table 1. Sixteen studies utilized cross-sectional designs, three were longitudinal, and one embedded within a randomized trial. Four of the studies tested correlations between the preference measure of interest and one or more health behaviors and did not control for confounding variables, making causal assessment of findings difficult. Participants were recruited from university courses or psychology labs, general populations or subgroups of the general population clinical samples, Facebook, or MTurk. Overall 10 studies focused on adolescents or young adults. These studies noted that adolescents are a particularly important subgroup to study in the context of sexual risk behavior, as they have heightened risk of STI and also unintended pregnancy. Five papers focused on college students above 18. Three studies included general samples of young people including 16-24 year old Swiss young adults, 18-24 year olds from urban centers, and 14-30 year olds from and medical and STI clinics. Two studies included even younger samples of Appalachian youth aged 10-17 at recruitment, and 10-12 year olds in Philadelphia. Three studies focused on sexual risk behavior among men who have sex with men. One study included only male heterosexual college students, 21-32, and another only heterosexual women from the PSID. Four studies required hazardous alcohol or substance use dependence for eligibility.The dependent and independent variables of interest as well as the results are summarized in Table 2. The majority of the articles examined delay or probability discounting while only three assessed a measure of risk tolerance. Earlier studies of discounting and sexual behavior used survey measures of monetary discounting: a trade off between present and future monetary rewards. More recently,cannabis grow equipment in recognition of domain specific preferences, discounting measures have been developed for discounting relating to sexual rewards. There is a further distinction between delay discounting and probability discounting, of both money and sex. Probability discounting tasks entail choices between smaller sooner rewards and delayed uncertain rewards. The reviewed articles can be divided into those that use measures of monetary discounting, sexual discounting, or both. Studies that assessed monetary discounting most often used the Monetary Choice Questionnaire , a 27-item measure involving choices between smaller immediate rewards and larger delayed rewards developed by Kirby.

One study used the MCQ but added a time perspective measure to assess future uncertainty. Chesson used a three-item hypothetical payoff measure. One study included probability discounting of money in addition to delay discounting.Sexual delay discounting tasks were used in several studies. Participants were asked to consider 60 photographs of people and to rank who they most want to have sex with, least want to have sex with, who is most likely to have an STI and least likely to have an STI. The chosen photos were then shown to participants to assess willingness to wait for condom-protected sex with a higher ranked partner versus immediate unprotected sex as a form of sexual delay discounting. Both studies found that sexual discounting differed as a function of the stated partner characteristics. Darioitis found that youth discounted significantly more with partners they ‘most want to have sex with’ and partners whom they thought were ‘least likely to have an STI.’ The sexual probability discounting tasks extend this same logic as the delay tasks, but instead of a delay they use varying chances of engaging in sex with the preferred partner. One study modified the SDDT for use with MSM. Two studies included both measures of monetary and sexual discounting. Johnson and Bruner were the first to find evidence of sexual domain specificity, as they not find evidence of monetary discounting with HBRS measure. Lawyer proposed another specification of the sexual discounting task. This task did not use hypothetical partner images, but instead asked participants about a trade off between more minutes of the sexual activity with some delay or fewer minutes immediately. The study used several scales that are validated in sexuality research and correlated with behavior. Sexual delay and probability discounting were associated with the measure of sexual excitability, but not with other non-sexual measures. Additionally monetary discounting was not associated with sexual outcomes, lending support to the domain specificity of sexual discounting. In the three articles focusing on risk tolerance, each used a different measure. Brobdeck used a risk preference and hedonism scale from the Trier Integrated Personality Inventory developed by Becker. Schmidt used a measure of hypothetical gambles over lifetime income that is modeled after the Health and Retirement Study in the PSID. Szrek et al employed four risk-taking propensity measures, including the a general measure of risk-taking propensity derived from a one-item survey question , a risk aversion index calculated from a set of incentivized monetary gambles , a measure of risk taking derived from an incentive compatible behavioral task—the Balloon Analog Risk Task , and a composite score of risk-taking likelihood in the health domain from the Domain-Specific Risk Taking scale.

Seventeen of the 20 articles evaluated the effect of discounting or risk tolerance on sexual behavior and outcomes. Of these, seven examine these relationships in the context of substance use. The sexual discounting task was repeatedly associated with sexual behavior. All studies assessed self-report of sexual risk behavior, and Chesson also included laboratory measures of STIs. Daugherty and Base, included a measure of sociosexual orientation , a measure of degree to which individual is more comfortable engaging in sexual behaviors without mental or emotional commitment. Lawyer examined sexual excitability rather than self reported behavior. Johnson and Bruner examined HIV risk behaviors, finding a significant relationship between greater discounting and history of high-risk sex. Dariotis and Johnson extended these findings from older high-risk sample to a sample of youth, finding that the four components of the SDT were negatively correlated with several reported sexual behaviors, including number of lifetime risky sexual partners. In addition, they found that less favorable attitudes towards risk were correlated with lower discounting, or preference for postponed protected sex under the ‘most want to have sex with’ and ‘least likely to have an STI’ components. Jarmolowizc applied the SDT task to promiscuity, finding that number of sexual partners selected on discounting task was related to higher rates of delay discounting, which was predictive of sexual behavior. Collado et al. examined sexual delay discounting and self-reported STI risk sex behaviors, HIV knowledge and STI risk perception among college students. They found that higher values of each of the four SDT measures were associated with self-reported risk behaviors. Hermann et al. extended the SDT to men who have sex with men and found discounting of condom protected anal intercourse to be hyperbolic, meaning that participants discounted using condoms as delays to CPAI increased. Steeper discounting of CPAI was associated with unprotected anal intercourse, substance use, not having been tested for HIV, sex under the influence of substances. One study examined risk tolerance, and argued that risk taking is domain specific, comparing four risk propensity measures with health risk behavior including sexual risk behavior. The found the Dohmen measure of general risk propensity was positively correlated with sexual risk behavior along with problem drinking and seat belt use. A risk aversion index calculated from a set of incentivized monetary gambles and the BART, and the DOSPERT scale were each uncorrelated with sexual risk behavior. Adolescence is a critical period for sexual behavior, as risk behavior emerges and peaks during the period . In one of the few studies to have self-reported data along with laboratory measures of STIs, higher discount rates were associated with ever having sexual intercourse, sexual intercourse before age 16, and ever having gonorrhea or chlamydia, controlling for demographics among a sample of adolescents and young adults.They did not find significant association of discount rates with unprotected sex or HSV-2 testing or infection. Khurana enrolled 10-12 year olds and examined the role working memory on adolescent early sexual initiation two years later and potential meditational pathways of impulsivity.

We then use two approaches for computing the semantic similarity between them: cosine similarity computed between average token embeddings, and BERTSCORE , which involves computation over BERT token embeddings of the tweet and misconception to obtain an F1-score-like measurement that we use as a similarity score. For the cosine similarity approach, we experiment with both non-contextualized and contextualized word embeddings. For non-contexualized word embeddings we use 300D GloVe trained on 2014- Wikipedia and Gigaword embeddings . For contexualized embeddings we use a pretrained BERT-LARGE model. However, Since BERT is not trained on COVID-19-related text we also use COVID-Twitter-BERT1 which uses domain-adaptive pretraining on 160M tweets about COVID-19. For sake of brevity, we will append the suffix to models that use COVID-Twitter-BERT instead of spelling out the full model name.We present the performance of similarity models in Table 4.1. Average embedding, both with GloVe and BERT embeddings, perform the worst . Although information retrieval based approaches, TF-IDF and BM25, considerably outperform the average embedding techniques, BERTSCORE captures the similarity as accurately as well. Domain adaptation, however, further improves the embedding-based similarity techniques, improving average BERT embeddings to be as good as others, while making BERTSCORE much more accurate than all other techniques. Thus we see that using domain adaptation and BERTSCORE are both important for performing accurate misconception retrieval.We illustrate the differences in the similarity models using example predictions in Table 4.2. The first example provides a challenging case of retrieval that requires taking both COVID-19 knowledge and contextual information into account, and thus only the BERTSCORE model is able to retrieve the correct misconception. The second example primarily requires domain knowledge that ‘coronavirus’ and ‘Sars-cov-2’ are very similar,vertical cannabis and only domain-adapted models are able to score the correct misconception highest.

The last example shows when contextual embeddings outperform non-contextual embedding . Due to the lack of adequately large datasets for stance detection with pairs of sentences , we cannot use existing datasets to train models for our setup. However, since classes in misinformation detection correspond to those in natural language inference and fact verification, tasks with much larger training datasets, we instead experiment with zero-shot learning on these tasks. The COVID-19 Health Risk Assessment task released after the pandemic started, also allowed us to experiment with few-shot learning by combining it with COVID-19 tweet-misonception pairs annotated for stance by researchers at the UCI School of medicine. Standard evaluation metrics like we have used above can overestimate the real world performance of NLP models, and do not reveal enough information about situations where the models are failing or how to fix them. To evaluate our stance detection models more rigorously we use the matrix of linguistic capabilities and test types provided by Check List for behaviour testing of NLP models. We evaluate our best zero- and few-shot models: BERTSCORE + SBERT trained on MNLI and CH+PA respectively. We test the following linguistic capabilities: Robustness , Negation, Vocabulary, NER , Temporal , and SRL . We perform three types of types: Minimum Functionality Tests , which are simple ’sanity checks’ of targetted capabilities; Invariance Tests consisting of perturbations which should not change model output; and Directional Expectation Tests For all tests, we use the COVID-19 misconceptions from COVIDLIES. For MFTs we construct simple tweets based on perturbations of the misconceptions, eg. introducing a simple typo: Salt water → wtaer protects from coronavirus. From the results of the tests in 4.5 we see that that there are linguistic capabilities that the zero-shot model is more competent at than the few-shot model and vice versa. Notably, the few-shot model is more robust to typos and positive paraphrases possibly because it is trained on informally written content . However, an alarming incompetency of the few-shot model is when the constructed tweet is identical to the misconception— the output should obviously be Agree, which the zero-shot model is able to correctly predict 100% of the time, while the the few-shot model only 91.9% of the time .

A possible explanation for why this happens is that the tweets in COVID-Hera tend to repeat the headlines or claims they are paired with verbatim, even in the refute/rebutscategory. Both models failed spectacularly at NER tests when perturbing country names and numbers in misconceptions to construct tweets, i.e., they always fail to predict No Stance in these cases. For INV and DIR tests we randomly sample 45 misconception-tweet pairs per class from COVIDLIES that both models are able to correct the label for. For INV tests we perturbed tweets in ways that should not lead to output changes, and for DIR tests perturbations were to induce a specific label switch. INV tests were more successful than DIR tests for both models . In the social sciences, there have been recent efforts to quantify COVID-19 misin formation on social media , as well experimental efforts to prevent propagation of misinformation . At the same time, members of the NLP community have been working on developing tools for the automatic detection of COVID-19-related misinformation online. Serrano et al. detect YouTube videos spreading conspiracy theories using features of user comments, and Dharawat et al. classify tweets by the severity of health risks associated with them. McQuillan et al. study the behaviour of COVID-19 misinformation networks on Twitter using mapping, topic modeling, bridging centrality, and divergence. Penn Medicine launched a chat bot to provide patients with accurate information about the virus , and a crowd sourced chat bot, Jennifer, is also available to answer questions about the pandemic . We are the first to frame COVID-19 misinformation detection as a two-stage task of misconception retrieval and pairwise classification of stance, and add to this body of work by providing a dataset and benchmark models for automated identification of misinformation.There are several datasets for misinformation detection with binary veracity labels , for example, Fake NewsNet consisting of news articles, Some Like It Hoax consisting of Facebook posts, and PHEME containing twitter threads. Misinformation detection is also closely related to fact-checking since both tasks aim to assess the veracity of claims. FEVER is a dataset of claims and evidence pairs with Supported, Refuted or Not Enough Info labels to facilitate research in automated fact checking.

This is similar to Emergent , a stance classification dataset consisting of rumored claims and associated news articles with labels of For, Against, or Observing the claim. Stance detection is also the focus of the Fake News Challenge 1 consisting of pairs of news article headlines and body texts with Agrees, Disagrees, Discusses, and Unrelated labels. Our proposed models for detecting misinformation by using classififiers fall within the framework of detecting misinformation using content features . Other approaches include using crowd behaviour , reliability of the source , knowledge graphs , or a combination of these approaches . Adapting these techniques to COVID-19 misinformation is a promising direction for future work. The ongoing COVID-19 pandemic has been accompanied by a corresponding ‘infodemic’ of misin formation about the virus. It is important to develop tools to automatically detect misinformation online, especially on social media sites where the volume and speed of the spread are high. However, rapidly evolving information and novel language make existing misinformation detection datasets and models ineffective for detecting COVID-19 misinformation. In this work, to initiate research on this important and timely topic, we introduced COVIDLIES, a benchmark dataset containing known COVID-19 misconceptions accompanied with tweets that Agree, Disagree, or express No Stance for each misconception, annotated by experts.We evaluate a number of approaches for this task, including common semantic similarity models for retrieval,cannabis hydroponic set up accurate models trained on a variety of NLI datasets, and domain adaptation by pretraining language models on a corpus of COVID-19 tweets. We demonstrate domain adaptation significantly improves results for both sub-tasks of misinformation detection. We also show that it is feasible to detect the stance of tweets towards misconceptions using both zero-shot and few-shot settings. We showed that few-shot learning slightly improves stance detection when evaluating using standard aggregate performance metrics. However, further behaviour testing using CheckList leaves an unclear picture of which setting is better. Both settings have considerable scope for improvement. Future work will involve exploring improved performance on stance detection, preferably without reliance of methods that require a large amount of data collection since they are not quickly available in an emerging crisis. We plan to continually expand our annotated dataset by including posts from other domains such as news articles and Reddit, and misconceptions from sources beyond Wikipedia, such as Poynter . We invite researchers to build COVID-19 misinformation detection systems and evaluate their performance using the presented dataset.Chemotherapy-induced nausea and vomiting can be classified into three categories: acute onset, occurring within 24 h of the initial chemotherapy administration; delayed onset, occurring 24 h to several days after the initial treatment; and anticipatory nausea and vomiting . Anticipatory nausea develops in response to chemotherapy treatments, in which cytotoxic drugs are delivered in the presence of a novel context . Developing in approximately 30% of patients by their fourth treatment , AN has traditionally been understood in terms of classical conditioning. After one or more treatment sessions, a conditional association develops between the distinctive contextual cues of the treatment environment and the unconditioned stimulus of chemotherapy treatment that results in the unconditioned response of post-treatment illness experienced by the patient. Subsequent exposure to the treatment environment results in the patient experiencing a conditioned response of nausea and/ or vomiting before initiation of chemotherapy treatment. Once it develops, AN has been reported to be especially refractive to anti-emetic treatment . The evaluation of potential treatments for AN would be accelerated by the establishment of a reliable rodent model of nausea.

Although rats are incapable of vomiting, they display characteristic gaping reactions when exposed to a flavoured solution previously paired with lithium induced nausea. In fact, this gaping reaction in the rat requires the same orofacial musculature as that required for vomiting in other species . Only drugs that produce emesis in species capable of vomiting produce conditioned gaping in rats, although many non emetic drugs produce conditioned taste avoidance . Furthermore, anti-emetic drugs interfere with the establishment of conditioned gaping reactions elicited by a nausea-paired flavor, presumably by interfering with the nausea . Conditioned gaping in rats appears to be a selective index of conditioned nausea. Not only are flavor cues capable of eliciting conditioned gaping reactions when paired with lithium chloride – induced nausea in rats, but recently Limebeer et al. have demonstrated that re-exposure to LiCl-paired contextual cues also elicit conditioned gaping reactions in rats. This paradigm more closely resembles that reported to produce AN in chemotherapy patients. Rats were injected with LiCl or saline before placement in a vanilla-odor laced chamber with lights and texture different than their home cage on each of four trials, separated by 72 h. To equate both groups for experience with illness, the rats in group unpaired were injected with LiCl and those in group paired were injected with saline 24 h after each conditioning trial but were then simply returned to their home cage. When the rats were returned to the conditioning context, 72 h after the final conditioning trial, rats in group paired showed the conditioned gaping reaction, as a measure of AN. Although classical anti-emetic treatments such as the 5- hydroxytryptamine-3 antagonist, Ondansetron , effectively reduce unconditioned nausea and vomiting, they are ineffective in the alleviation of conditioned nausea once it develops in humans . Indeed, OND also did not suppress the conditioned gaping reactions displayed during re-exposure to the LiCl-paired context . Further more, using the emetic species, Suncus murinus as an animal model for AN, pre-treatment with a dose of OND that was shown to alleviate acute vomiting , did not reduce the display of conditioned retching reactions during re-exposure to a nausea-paired context . Thus, although OND has proven effective in the reduction of acute post-treatment nausea and vomiting, it does not appear to relieve conditioned nausea when it does develop.The psychoactive component in marijuana— delta-9-tetrahydrocannabinol —has been shown to interfere with the expression of vomiting in shrews and ferrets and conditioned gaping reactions elicited by a lithium-paired flavor in rats .

In the present review, I outline recent progress made in these directions, specifically focusing on endocannabinoid deactivation, and discuss some of the challenges lying ahead.Anandamide was the first endocannabinoid sub stance to be isolated and structurally characterized . Its formationinneural cells is thought to require two enzymatic steps, which are illu strated in Fig. 1. This reaction, which is mediated by a unique D-type phospholipase , produces anandamide and phosphatidic acid, which is recycled to produce other glycerol-containing phospholipids. The cellular stores of NAPE are small, but canbe refilled by an N-acyltransferase activity, which catalyzes the intermolecular passage of anarachidonic acid group from the sn-1 positionof phosphatidylcholine to the head group of phos phatidylethanolamine . Incultures of rat cortical neurons, NAT activity is controlled by two intracellular second messengers: Ca2+, which is required to activate the enzyme, and cyclic 30 , 50 -adeno sine monophosphate , which stimulates protein kinase A-dependent protein phosphorylation and, via an unknown mechanism, enhances NAT activity . Although separate enzymes cata lyze the syntheses of anandamide and NAPE, the two events are likely to occur simultaneously because Ca2+- stimulated anandamide production is often accompanied by denovo formationof NAPE . Anandamide synthesis can be elicited in vitro by a variety of agents that elevate intracellular Ca2+ levels. For example, the Ca2+ ionophore ionomycin stimulates [ 3 H]anandamide formation in cultures of ratstriatal and cortical neurons labeled by incubation with [ 3 H]ethanolamine . In the same neurons, Ca2+-dependent [3 H]ana ndamide production may be elicited by the glutamate receptor agonist, kainate, by the K+ channel blocker 4- aminopyridine, and by membrane-depolarizing con centrations of K+ ions .

Depolarizationof neural cells was also shown to evoke Ca2+-dependent anandamide release in vivo . Along with Ca2+ entry,vertical grow shelf activation of certain G pro tein-coupled receptors can also initiate anandamide generation. Administration of the dopamine D2-recep tor agonist quinpirole causes a profound stimulation of anandamide synthesis in the rat basal ganglia, which is prevented by the D2 antagonist raclopride . Importantly, cocaine elicits a similar response , suggesting a role for anandamide in the actions of these psychostimulant drugs. The ability of the anandamide transport inhibitor AM404 to reduce D2 agonist induced hyperactivity, discussed below, further sup ports this possibility .The biological elimination of anandamide proceeds through two successive steps of high-affinity transport into cells, followed by intracellular degradation . Brain neurons and astrocytes in culture internalize anandamide through a process that fulfills all key requirements of a carrier-mediated transport. Plots of the initial rates of [3 H]anandamide internalization in rat brain neurons and astrocytes in culture yield apparent Michaelis constants that are consistent with a saturable process and are comparable to the KM values of brain amine or amino-acid transporters . Moreover, neurons and astrocytes in culture internalize [3 H]anandamide, along with a select group of structurally related compounds, in a stereoselective manner . Evenfurther, [3 H]ana ndamide internalization can be inhibited by drugs that have no effect on the uptake of non-cannabinoid lipid mediators such as fatty acids and eicosanoids . Nevertheless, anandamide is internalized in a Na+- and energy-inde pendent manner , a feature that differentiates this lipid mediator from most conven tional neurotransmitters.The prototype of this class of drugs, the arachidonate derivative AM404 , has provided important information on the properties of anandamide transport, not only aiding the in vitro characterization of this process, but also helping to reveal its possible functions in animals. Importantly, the partial cannabimetic profile exhibited by this agent in vivo suggests that anandamide transport might provide a useful tar get in disease conditions in which the endocannabinoid system is hypofunctional . Evidence indicates that one such condition could be opiate withdrawal, which is markedly reduced in rodents by administering AM404 . These theories have been hindered by the fact that the putative transport system responsible for anandamide internalization is still uncharacterized at the mol ecular level.

In fact, the presence of such a system has been recently questioned, based on the observation that [ 3 H]anandamide uptake in certain cell lines is saturable at longer , but not at shorter incubationtimes . This finding has been interpreted to suggest that fatty-acid amide hydrolase —a key enzyme of intracellular anandamide degradation, described in a subsequent section—may be responsible for the saturation of uptake noted at longer incubation times . However, the result may also be explained on purely technical grounds, as the high concentration of serum albumin used in the experiments of Glaser and collaborators was previously shown to prevent [3 H]anandamide internalization . Consistent with this interpretation, recent stu dies have provided additional evidence for the existence of an anandamide transport system independent of FAAH . In particular, one of these studies has shown that cultures of cortical neurons isolated from the brain of FAAH null mice internalize anandamide as efficiently as do neurons that express normal levels of the enzyme. The same study also demonstrated that the transport inhibitor AM404 is equally effective at reducing anandamide internalization in neurons of FAAH-null and wild-type mice. These results indicate that FAAH does not pro vide the driving force for anandamide uptake or serve as a target for AM404. Invivo experiments further support this conclusion, showing that AM404 not only enhances the actions of exogenous anandamide in FAAH-null mice, but acts more effectively in this mutant strain than it does in control animals. This implies that AM404 is not in fact a FAAH inhibitor, as it has been proposed , but a FAAH substrate. In support of this idea, it was found that membranes prepared from the brains of normal mice rapidly hydrolyze AM404, whereas those prepared from mice that lack FAAH are unable to carry out this reaction.The fact that FAAH is not directly involved in anandamide internalization raises the question of what mechanism provides the driving force for this process. One possibility is that an intracellular protein may sequester anandamide at the membrane, driving its internalization and facilitating its movement to the mitochondria and the endoplasmic reticulum, where FAAH is primarily localized . If selective for anandamide, such a protein might participate in the transport process as well as serve as a target for transport inhibitors. This hypothetical model is consistent with fatty acid transport into cells, which is also thought to require the cooperation of membrane transporters and intracellular fatty-acid binding proteins .AM404 increases endogenous anandamide levels in brain tissue and peripheral blood of rats and mice . This effect is accompanied by a series of behavioral responses that, though blocked by the CB1 antagonist rimonabant , are clearly distinguishable from those of direct cannabinoid agonists.

For example, administra tion of AM404 into the cerebral ventricles of rats decreases exploratory activity without producing cata lepsy and analgesia, two hallmarks of direct CB1 receptor activation. Inaddition, AM404 reduces two characteristic effects caused by activationof D2 family receptors: the yawning response elicited in mice by low doses of the D1/D2-receptor agonist apomorphine; and the stimu lationof locomotor activity evoked inrats by the D2- receptor agonist quinpirole . These effects are observed at doses of AM404 that selectively target anandamide transport and produce only mild hypokinesia when the drug is administered alone . The results of this study,cannabis grow indoor which have been  confirmed in several subsequent reports , demarcate the pharmacological profifile of AM404 from those of direct-acting cannabinoid drugs. This distinction may result from the ability of AM404 to enhance ananda mide signaling in an activity-dependent manner, caus ing anandamide to accumulate in discrete regions of the brain and only when appropriate stimuli initiate its release. Pharmacological activationof D2 receptors may represent one such stimulus, suggesting that blockade of anandamide transport might offffer an inno vative strategy to correct abnormalities associated with dysfunction in dopaminergic transmission. Initial tests of this hypothesis have shownthat systemic adminis tration of AM404 normalizes movement in sponta neously hypertensive rats , an inbred line in which hyperactivity and attention defificits have been linked to a defective regulation of mesocorticolimbic dopamine pathways .FAAH was first identifified as an amide hydrolase activity present in rat liver tissue, which catalyzes the hydrolysis of the fatty-acid ethanolamides palmitoy lethanolamide and oleoylethanolamide . That anandamide serves as a substrate for this activity was first suggested onthe basis of biochemical evidence and later demonstrated by molecular clon ing, heterologous expression and generation of FAAH null mice by homologous recombination . FAAH belongs to a group of enzymes known as ‘amidase signature family’ and catalyzes the hydrolysis not only of anandamide and other fatty-acid ethanola mides, but also of primary amides such as oleamide and even of fatty-acid esters such as 2-AG . Elegant site-directed mutagenesis and X-ray diffffraction studies have demonstrated that this unusually broad substrate preference is due to a novel catalytic mech anism involving the amino-acid residue lysine 142. This residue may act as a general acid catalyst, favoring the protonation and consequent detachment of reaction products from the enzyme’s active site . Three serine resi dues that are conserved in all amidase signature enzymes also may be essential for enzymatic activity: serine 241 may serve as the enzyme’s catalytic nucleophile, while serine 217 and 218 may modulate catalysis through an as-yet-unidenti- fified mechanism .

Electron microscopy experiments in the rat and mouse brain have shown that FAAH is predominantly, if not exclusively localized to intracellular membrane com partments, particularly to the endoplasmic reticulum and the mitochondria . Although FAAH appears to be the predominant route of anandamide hydrolysis in the brain, other enzymes are likely to participate in the breakdown of this endocannabinoid in peripheral tissues. An acid amide hydrolase activity catalytically distinct from FAAH has beencharacterized inhumanmega karyoblastic cells and shown to be highly expressed in the rat thymus, lungs and intestine .The search for small-molecule inhibitors of intra cellular FAAH activity has led to the emergence of sev eral potent and selective agents, which include substituted sulfonyl flfluorides , alpha-keto-oxazolopyridines an d carbamic acid esters . The latter were identifified during structure– activity relationship studies aimed at determining whether esters of carbamic acid such as the insecticide carbaryl inhibit FAAH activity. It was found that, although carbaryl is ineffective in this regard, variations in its template result in significant inhibitory potencies. Fur ther structural optimizations yielded a group of highly potent inhibitors, a representative example of which is provided by the compound URB597 . Kinetic and dialysis experiments indicate that URB597 interacts non-competitively with FAAH, which is suggestive of anirreversible or slowly revers ible associationwith the enzyme. Importantly, URB597 has no notable effect on CB1 or CB2 binding, ananda mide transport, or rat brain monoglyceride lipase , a cytosolic serine hydrolase that catalyzes the hydrolysis of the second endocannabinoid, 2-arachido noylglycerol  . Following administration to rats in vivo, URB597 produces profound, dose-dependent inhibition of brain FAAH activity. After injection of a maximal dose of compound , FAAH inhi bitionis rapid , persistent and asso ciated with a 3-fold increase in brain anandamide levels. Furthermore, the inhibitor intensififies and pro longs the effects produced by exogenous anandamide, yet it elicits no overt cannabinoid-like actions when administered alone; for example, it does not cause hypothermia, hot-plate analgesia, or hyperphagia .Although URB597 does not display a typical canna binoid profifile in live animals, it exerts several pharma cological effects that might be therapeutically relevant. One such effect, the ability to reduce anxiety-like beha viors inrats, was demonstrated intwo distinct experi mental models: the elevated ‘zero maze’ test, and the isolation-induced ultrasonic emission test . The ‘zero maze’ consists of an elevated annular platform with two open and two closed quad rants and is based on the conflflict between an animal’s instinct to explore its environment and its fear of open spaces where it may be attacked by predators . Benzodiazepines and other clinically used anxiolytic drugs increase the proportion of time spent in, and the number of entries made into, the open com partments. In a similar fashion, URB597 elicits anxio lytic-like responses at a dose that corresponds to those required to inhibit brain FAAH activity. Moreover, these effects are prevented by the CB1-selective antagonist rimona bant. Analogous results were obtained in the ultrasonic vocalizationemissiontest, which measures the number of stress-induced vocalizations emitted by rat pups removed from their nest .

It is possible that participants in our study were obtaining care in safety‐net primary care settings with CCMs. Alternatively, the reduced odds of unmet need amongst those who had regular care providers could reflect other factors that we did not measure. For example, having a regular care provider may be a marker for increased system engagement and reduced barriers to any type of care. Those who seek primary care may be more organized, knowledgeable about safety‐net service availability, and have more access to transportation and other enabling resources. . Having a case manager was associated with less mental health and substance use treatment need. In the case management brokerage model, case managers help people navigate care systems and provide a linkage to services. In the clinical case management model, case managers serve as care providers and may provide both mental health and substance use services directly . In some models, such as intensive case management, case managers provide both brokerage and direct services . It is possible that the association between having a case manager and decreased odds of unmet need for both mental health and substance use services is a result of reverse causality; treatment programs may assign a case manager. We found that participants who first became homeless at age 50 or older had a higher odds of unmet substance use treatment need. Those with late onset homelessness had led more “typical” lives, with a higher likelihood of having been continuously employed and having been married or partnered . They were less likely to have had early onset of substance use problems, thus, they may have developed substance use problems more recently. These individuals may have been less aware of safety‐ net resources in general or resources for substance use treatment in particular. Spending time in jail/prison in the past 6 months was associated with reduced unmet substance use treatment need. It is possible that participants initiated substance use treatment while incarcerated. However, most incarceration settings do not provide adequate treatment services. 

Alternatively, as a condition of release,hydroponic racks participants may have been required to engage in substance use treatment.By giving medication‐assisted treatments, such as buprenorphine for opioid use disorder and naltrexone for alcohol use disorder in primary care settings, primary care providers can begin to address this unmet need . However, there is a need for greatly expanded substance use services. Our study has several limitations. We did not use a full psychiatric diagnostic interview. However, screening measures are important empirical tools for the referral of individuals to mental health treatment, especially when integrated care is available . We did not ask participants where they received mental health services, thus we cannot determine whether they received care colocated with primary care, or treatment in mental health specific settings.Historical descriptions of the stimulatory effects of Cannabis sativa on feeding are now explained by the ability of its psycho active constituent 9 -tetrahydrocannabinol to interact with CB1 cannabinoid receptors . Both THC and the endogenous cannabinoid anan damide  promote overeating in partially satiated rats . Moreover, THC increases fat intake in laboratory animals and stimulates appetite in humans . The selective CB1 receptor antagonist SR141716A counteracts these effects and, when administered alone, decreases standard chow intake and caloric consumption , presumably by antagonizing the actions of endogenously released endocan nabinoids such as anandamide and 2-arachidonoylglycerol . These results suggest that endocannabinoid substances may play a role in the promotion of food intake, possibly by delaying satiety. It is generally thought that the hyperphagic actions of cannabinoids are mediated by CB1 receptors located in brain circuits involved in the regulation of motivated behaviors . Thus, infusions of anandamide in the ventromedial hypothalamus were shown to promote hyperphagia , whereas the anorectic effects of leptin were found to be associated with a decrease in hypothalamic anandamide levels . Nevertheless, evidence suggests that cannabinoids also may promote feeding by acting at periph eral sites. Indeed, CB1 receptors are found on nerve terminals innervating the gastrointestinal tract , which are known to be involved in mediating satiety signals that originated in the gut .

To test this hypothesis, in the present study we have examined the impact of feeding on intestinal anandamide accumulation, the effects of central versus peripheral systemic administration of cannabinoid receptor agonists on feeding behavior, and the effects of sensory deafferentation on cannabinoid-induced hyperphagia.Animals. Male Wistar rats were housed individually with food and water available ad libitum, except when restriction was required. All animal procedures met the National Institutes of Health guidelinesfor the care and use of laboratory animals and the European Commu nities directive 86/609/EEC regulating animal research. Surgery. For intracerebroventricular injections, stainless steel guide cannulas aimed at the lateral ventricle were implanted in the rats. The animals were anesthetized with equithesin and placed in a David Kopf Instruments stereotaxic instrument with the incisor bar set at 5 mm above the interaural line. A guide cannula was secured to the skull by using two stainless steel screws and dental cement and was closed with 30 gauge obturators . The implantation coordinates were 0.6 mm posterior to bregma,2.0 mm lateral, and 3.2 mm below the surface of the skull. These coordinates placed the cannula 1 mm above the ventricle. Aftera7d post surgical recovery period, cannula patency was confirmed by gravity flow of isotonic saline through an 8-mm-long, 30 gauge injector inserted within the guide to 1 mm beyond its tip. This procedure allowed the animals to become familiar with the injection technique. Chemicals. Capsaicin was purchased from Sigma , and cholecystokinin octapeptide sulfated , R–methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl) methanone monomethanesulfonate , and 1,4-dihydro-3–5H-pyrrolo[3,2-b]pyridin-5- one were obtained from Tocris Cookson . N-pip eridino-5–1–4-methylpyrazole-3- carboxamide was a gift from Sanofi Recherche . Anandamide and oleoylethanolamide were synthesized in the laboratory . Capsaicin was dissolved in 5% Tween 80, 5% propyleneglycol, and 90% saline. All other drugs were dissolved in dimethylsulfoxide and administered in 70% DMSO in sterile saline. HPLC/mass spectrometry analyses. Anandamide was solvent-extracted from tissues, fractionated by column chromatography, and quantified by HPLC/mass spectrometry with an isotope dilution method, as described previously . Drug treatments. Capsaicin was administered subcutaneously  in rats anesthetized with ethyl ether.

The total dose of capsaicin was divided into three injections . Control rats received vehicle injections. Experiments were performed 10 d after capsaicin treatment in rats that had lost the corneal chemosensory reflex , and showed enhanced water intake 10 d after capsaicin treatment.For intracerebroventricular administration, the obturator was removed from the guide cannula and an 8 mm injector that was connected to 70 cm of calibrated polyethylene-10 tubing was lowered into the ventricle. The tubing was then raised until flow began, and 5l of drug solution was infused over a 30–60 sec period. The injector was left in the guide cannula for an additional 30 sec and then removed. The stylet was immediately replaced. Animals were tested 5 min after injections. The intracerebroventricular cannula placements were evaluated after each experiment by dye injection. Only rats with proper intracerebroventricular placements were included in the data analysis. Food intake studies. The effects of drugs on feeding behavior were analyzed in animals deprived of food for 24 hr and habituated to handling or in partially satiated animals . To this end, 48 hr before testing,indoor garden table the bedding material was removed from the cage and a small can containing food pellets was placed inside the cage for 4 hr. The animals were then food-deprived for 24 hr, with access to water ad libitum. The animals were returned to their home cage 15 min after drug administration; there, a can with a measured amount of food and a bottle containing 250 ml of fresh water were placed. Food pellets and food spillage were weighed at 60, 120, and 240 min after starting the test, and the amount of food eaten was recorded. At the end of the test, the amount of water consumed was also measured. For partial satiation of animals, 24 hr food-deprived rats were allowed to eat from the can for 1 hr. The can was replaced and intake was recorded. Fifteen minutes after drug injections, the food was again presented, and the amount consumed was recorded hourly for the next 4 hr. Open-field test. Motor behaviors in the open field were studied in an opaque open field as described previously . The field was illuminated using a ceiling halogen lamp regulated to yield 350 lux at the center of the field. Rats were habituated to the field for 10 min the day before testing. On the experimental day, the animals were treated and placed in the center of the field, and locomotor activity and rearing and grooming behavior were scored for 5 min at 5, 30, 60, and 120 min after drug injection. Behavior was scored by trained observers who were unaware of the experimental conditions. Statistics. Statistical significance was assessed by one-way or multi-factorial ANOVA, as required. After a significant F value, post hoc analysis was performed. Calculations were done using the BMDP statistical package .We first investigated whether starvation and refeeding affect anandamide content in intestinal tissue, where various intrinsic signals modulating food intake, such as CCK and OEA , are generated. As shown in Figure 1, food deprivation was accompanied by a seven fold increase in anandamide content in the small intestine, an effect that was reversed on refeeding. In contrast, no such increase was observed in brain or stomach tissues . The change in intestinal anandamide did not result from the inhibition of anandamide degradation. Indeed, fatty acid amidohydrolase activity, which catalyzes the deactivating hydro lysis of anandamide, was not affected by the feeding status .The small intestine produces both anandamide, which stimulates food intake , and OEA, which inhibits food intake by acting on peripheral sensory fibers . However, the intestinal levels of the two compounds appear to be reciprocally regulated. Thus, the OEA content decreases , whereas the anandamide content increases during starvation. To examine the possible interaction of these fatty acid ethanolamides on feeding, we studied whether OEA blocks AEA-induced hyperphagia and whether blockade of CB1 receptors with a low, sub-threshold dose of SR141716A potentiates the inhibitory actions of OEA on food intake.

The results, illustrated in Figure 4A, indicate that pretreatment with OEA inhibits AEA-induced hyperphagia in partially satiated rats, whereas SR141716A and OEA act synergistically to decrease eating in food-deprived animals . The effects were ob served during the 240 min period of testing. The inhibitory actions of combined SR141716A and OEA lasted for at least 24 hr , a prolonged effect that these drugs do not elicit separately.The present results suggest, first, that systemically administered cannabinoid agents affect food intake predominantly by engaging peripheral CB1 receptors localized to capsaicin-sensitive sensory terminals and, second, that intestinal anandamide is a relevant signal for the regulation of feeding. Two observations support the idea that cannabinoid agents modulate feeding through a peripheral mechanism. First, the lack of effect of central administration of cannabinoid antagonists such as SR14116A and 6-iodo-2-methyl-1-[2-ethyl]-[1H]-indol-3-yl methanone on food intake in food-deprived animals and, second, the ability of capsaicin-induced deafferentation to prevent changes in feeding elicited by the peripheral administration of cannabinoid drugs. Moreover, the similar pattern of expression of the early gene c-fos on hypothalamic and brainstem areas regulating food intake after both the peripheral administration of either CB1 agonists and antagonists and the acute administration of peripherally acting satiety modulators such as gastrointestinal hormones or feeding inhibitors such as OEA further support the peripheral actions of cannabinoids on food intake. Finally, the fact that the CB1 receptor antagonist SR141716A was active only after intraperitoneal or oral administration but not after subcutaneous injection further supports this hypothesis. These results do exclude the possibility that peripheral anandamide also modulates feeding by acting on specific hypothalamic areas involved in caloric homeostasis . However, they do suggest that the predominant effects of systemically administered SR141716A are mediated by peripheral CB1 receptors, which may thus represent a potential target for anorexic agents. The concentration of anandamide in intestinal tissue increases during food deprivation, reaching levels that are threefold greater than those needed to half maximally activate CB1 receptors . This surge in anandamide levels, the mechanism of which is unknown, may serve as a short-range hunger signal to promote feeding. This idea is supported by the ability of SR141716A to reduce food intake after systemic but not central administration.

DSM-IV diagnoses for all disorders were made algorithmically from SSAGA information. However for these analyses we also generated a DSM-5 diagnosis for AUD in the following way. Individual alcohol symptoms were queried, starting with symptoms of DSM-IV alcohol dependence and alcohol abuse, adding craving and subtracting legal problems related to alcohol. Onset and offset of each symptom was recorded, making it possible to cluster symptoms that occurred by age. Thus the analyses presented here use DSM-5 AUD as an outcome variable while all other disorders are diagnosed by DSM-IV.Diagnoses of externalizing and internalizing disorders at the baseline interview were also made algorithmically from the SSAGA using DSM-IV. Externalizing disorders included any of the following: ADHD, conduct disorder/antisocial personality disorder, oppositional defiant disorder, drug use disorder . Internalizing disorders included major depression, panic disorder, obsessive-compulsive disorder, social phobia, and agoraphobia.Subjects were divided into groups based on whether they had an externalizing disorder or an internalizing disorder at the time of the baseline interview. The groups were: Externalizing, Internalizing, Both, or Neither. Alcohol use disorder diagnosis was then assessed at each interview period, using the DSM 5 distinctions for Mild AUD , Moderate AUD , and Severe AUD . Subjects with age of onset of AUD prior to age of onset of internalizing/externalizing disorders were excluded from analysis. We also performed a sensitivity analysis in which all subjects with externalizing were compared with all subjects without externalizing; likewise subjects with internalizing were compared with all subjects without internalizing . An externalizing-internalizing interaction term was included in this analysis. Overall, 43.0% of the sample met criteria for a diagnosis of either Mild, Moderate, or Severe AUD by the end of the observation period .

At the time of the baseline interview, 982/3286 subjects had an externalizing diagnosis ; 140/3286 subjects had an internalizing diagnosis , 286 had both and 1878 had neither . All covariates had significant relationships to age of onset in subjects with either mild, moderate, or severe AUD . The association of any comorbid disorder and presence of Alcohol Use Disorder was significant overall ,plant growing stand and there was a significant effect of comorbidity on age of onset as well . Among subjects with an externalizing disorder only at baseline, 515/982 had some type of AUD during the follow-up period. Among subjects with an internalizing disorder only at baseline 66/140 had an AUD. Among subjects with both externalizing and internalizing, 182/286 had an AUD. In comparison, subjects with neither type of disorder had an AUD rate of 34.7% . Figure 1 shows onset of alcohol use disorders in subjects stratified by initial diagnoses of Externalizing disorder, Internalizing disorder, Both, or Neither. Figures 1a–c show onset of mild, moderate, and severe AUDs respectively. For each type of AUD, the relationship with comorbid disorders is significant by Log-rank test and Cox Proportional Hazards . Age of onset comparisons are shown in Kaplan-Meier Plots . Each of these shows significant effects of comorbidity by Log-rank Test . The plots do not include a covariate effect but we have also achieved similar results by the Cox model adjusting for covariate effects . The statistical effect of comorbidity is generally greatest in the development of Severe AUD and least in Mild AUD based on the hazard ratios in the different comorbidity types . The three groups are significantly different from each other in the strength of the comorbidity effect . The sensitivity analysis showed a clear effect of externalizing on age of onset in mild AUD, moderate AUD, and severe AUD . For internalizing, there was an effect in moderate AUD and severe AUD . No statistical interaction was seen between the effect of externalizing and the effect of internalizing. Age of onset distributions are presented for Mild AUD , Moderate AUD , and Severe AUD . The distributions include drinking milestones as well as onset ages for the diagnoses of Mild AUD , Moderate AUD and Severe AUD . As noted above, the study samples are independent of each other for analytic purposes, and are classified according to the most severe disorder that the subject met criteria for during the observation period.

Figure 2 shows drinking milestones in subjects who developed an alcohol use disorder. Figure 2a–c show mean, median, interquartile range, and outliers for subjects with mild , moderate and severe alcohol use disorder. Subjects are classified in a cohort according to the most severe form of disorder they manifested during the observation period. In Figure 2b milestones for the moderate group include the age when they would have been first classified as showing a mild AUD. In Figure 2c milestones for the severe group include the ages when they would have been first classified as showing a mild or moderate AUD. We used ANOVA and i-test to detect the correlation between the onset of drinking milestones in the four diagnostic groups. The mean age of first drink progresses from 16.2 inUnaffected to 14.9 in Mild to 14.4 in Moderate to 12.8 in Severe . The mean age of first regular drinking progresses from 18.8 in Unaffected to 17.5 in Mild to 16.9 in Moderate to 15.7 in Severe . The mean age for meeting criteria for Mild AUD progresses from 18.6 in Mild to 17.4 in Moderate to 16.1 in Severe . The mean age for meeting criteria for Moderate AUD progresses from 19.1 in Moderate to 17.3 in Severe . The age of onset for Severe AUD is 18.5. This age relationship is detailed in Figure 3. Figure 3 represents the onset of alcohol use and alcohol problems in 3286 adolescents observed over a ten year period. It includes 1870 who remained unaffected, 684 who developed mild alcohol use disorder, 415 who developed moderate alcohol use disorder, and 317 who developed severe alcohol use disorder. The ANOVA for onset of first drink among the unaffected, mild, moderate, and severe cohorts shows p < 0.001. The ANOVA for onset of regular drinking among the unaffected, mild, moderate, and severe cohorts shows p < 0.001. The ANOVA for onset age of mild AUD among the mild, moderate, and severe cohorts shows p < 0.001. The t-test for onset age of moderate AUD between the moderate and severe cohorts shows p < 0.001. These data suggest a strong effect of externalizing and internalizing disorders on prevalence and age of onset of Alcohol Use Disorder among adolescents/young adults at risk for the development of AUD on the basis of family history.

Externalizing disorders were clearly associated with an increased risk for AUD and for earlier development of AUD. Internalizing disorders by themselves did not show a significant effect, but in combination with externalizing disorders they were associated with an earlier onset for severe AUD . When we considered all internalizing disorders together a clear effect on onset of moderate AUD was seen as well. By the end of the follow-up period,plant grow table more than 60% of young people with both externalizing and internalizing disorders at baseline had developed alcohol dependence in comparison with about 30% of young people with neither type of comorbid disorder. The effect of comorbidity was stronger in more severe forms of AUD, with a 6-fold increase in risk for Severe AUD among subjects with both externalizing and internalizing disorders compared to subjects with neither form of comorbid disorder. There was also evidence for an earlier developmental course in more severe forms of AUD compared to less severe. Persons with Severe AUD were likely to have their first full drink prior to the age of 13 and be drinking regularly prior to age 16 and experiencing 1–2 alcohol problems by that same age. In contrast young people who did not demonstrate any AUD were likely to have their first drink at 16 and start regular drinking just prior to age 19. Median and mean ages of onset for each type of AUD were 18–19, though the range extended through the follow-up period. Those at greatest risk for an AUD were males of European descent from an alcohol dependent proband family with one or more childhood onset psychiatric diagnoses. Those at least risk were females of African-American ancestry from a non-case family with no childhood onset diagnosis. Limitations of the study include the fact that all analyses are based on self-report and there is no independent corroboration of diagnoses or symptoms. Subjects interviewed in their late 20s may have had more difficulty with accurate reporting of events in early teenage years in comparison to subjects in their mid-teens. Retention rate from baseline interview to two-year interview was 85%, the majority of subjects completed at least four interviews . Families in the COGA study tend to be densely affected and results may not be generalizable to persons with alcohol use disorder in the general population. The subjects were ascertained at 7 University-based clinical sites and the populations studied reflect those sites. The magnitude of these effects was substantial, and this information may be helpful in targeting efforts at education and prevention. In this sample most of the AUD-affected subjects had a comorbid psychiatric disorder at baseline. Many such subjects may come to clinical attention for their childhood-onset disorders and it may be worth educational efforts targeting AUD, especially for those at increased familial risk. It has been argued, though, that more intensive interventions are not likely to be cost- effective at this time . It seems to be of value to continue to try to quantify risk in various clinically and biologically identifiable groups. Polygenic risk scores, especially as they increase in power with data from expanding clinical samples, will likely be of use . It would also be of value to attempt to separate AUD effects from other forms of SUD, since we know that they are highly comorbid in many samples, including the sample studied here. The internet has profoundly altered how individuals obtain information regarding their health, and men’s health is no exception. Although men are less likely than women to pursue preventative health care and more likely to develop chronic cardiovascular and metabolic disease, the rise of online social media platforms may play a role in challenging this disproportion. Men contending with infertility increasingly turn to social media platforms for information, guidance, and discussion with peers. A male factor contributes to nearly 60% of all cases of infertility, yet cultural and societal constructs of masculinity create psycho social barriers to consultation with a physician. Social media platforms enfranchise men to take an active role in understanding causes and treatments for infertility by providing anonymity absent from face-to-face encounters. Although health information online is becoming more readily accessible, it escapes the scrutiny of scientific publication guidelines, allowing for the propagation of non-evidenced-based material. Social media tends to amplify the most sensational content and headlines. Literature assessing the quality of male infertility content available online remains scarce, although a recent review has shown that urological conditions as a whole suffer from a spread of misinformation on social media. Social media analytics tools have emerged that provide detailed, quantitative metrics, but these tools have not yet been applied to content in the male infertility space. Given the proliferation of sensationalism on social media, we hypothesized that content about male infertility shared on social media platforms may be largely inaccurate or misleading. Using a combination of ananalytics tool and a quality rating system, we per formed a quantitative and qualitative analysis of male infertility content shared on social media. These data may inform how men’s health specialists should aproach patient education about male infertility, as well as ways in which they engage with social media in the future.We used the social media analytics tool BuzzSumo to identify the most shared male infertility content from September 2018 through August 2019. BuzzSumo gathers data across the social media platforms Facebook, Pinterest, Reddit, and Twitter to generate a list of article links with the highest online engagement. Engagement is defined as the total number of interactions that users have with a particular article link, including actions, such as “liking,” “commenting,” and “sharing” on social media. Two urologists with advanced fellowship training in male reproductive medicine initially screened a total of 20 search terms related to male infertility using BuzzSumo.