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ROI selection was limited to one due to insufficient power to detect incremental model improvement with multiple ROIs

To address this gap in the literature and to further integrate neuroimaging and human laboratory paradigms for AUD, the current study examines whether alcohol taste cue-induced ventral striatum activation predicts subsequent oral alcohol self-administration in the laboratory. These secondary analyses are conducted in a within-subjects design whereby the same participants completed an fMRI cue-reactivity task followed by an alcohol-self administration task . As striatal activation is thought to underlie craving responses , we hypothesized that those with greater ventral striatum activation would consume their first drink faster than those with lower activation. Similarly, as previous research has demonstrated that mesolimbic activity predicts real-world heavy drinking, we hypothesized that ventral striatum activation would also be positively associated with the total number of drinks consumed during the self-administration paradigm. For the taste cues paradigm, information regarding image acquisition parameters and preprocessing steps are available in Supplementary Materials and are derived from the primary manuscript . The main contrast of interest was the difference in activation corresponding to alcohol taste delivery and water delivery across the two task runs , for each within-subject medication condition. Consistent with previous studies examining relationships among ventral striatum activity, subjective response to alcohol, and drinking behavior , an anatomical bilateral ventral striatum region of interest was defined using the Harvard-Oxford atlas in standard MNI space and was transformed into participants’ respective native space using FSL’s FLIRT . This ROI was selected because ventral striatum is most consistently elicited in alcohol cue and taste reactivity paradigms, as well as most frequently associated with behavioral measures and treatment response .The mean contrast estimate values were extracted from this region for each subject and used in mixed models for group-level analysis . The self-administration paradigm yielded two outcome measures: latency to first drink ,cannabis grower and total number of drinks consumed during the session . To examine the relationship between alcohol taste-induced neural activation and self-administration, multilevel mixed poisson and cox proportional hazard models were the primary analyses for total number of drinks and latency to first drink, respectively.

Frailty models were fitted using a penalized partial likelihood approach available in SAS 9.4 . Primary analyses examined effects of variables of interest, including medication condition , alcohol consumption , and OPRM1. Due to concerns of over parameterization given the limited sample size, additional covariates of interest were individually included in separate models to determine whether main effects of ventral striatum would be altered. Alpha corrections were not utilized in this exploratory study due to limited sample size and constrained power. Tests of proportional hazards are included in Supplementary Materials and Figures S1a-S1d. Survival plots for latency to first drink, controlling for covariates within the final model , were generated to further explore ventral striatum activation in predicting latency to first drink. Of note, a dichotomous median-split ventral striatum variable was created for ease of visualization of these relationships, but ventral striatum activation was included as a continuous variable in all models.The distribution of latencies to first drink was non-normal. Across medication conditions, 52% of individuals refrained from drinking throughout the paradigm, 29% consumed a drink within the first three minutes of the paradigm, and 19% of individuals consumed their first drink at some point during the remainder of the session. Cox regressions for latency to first drink indicated a significant effect of ventral striatum activation, Wald χ2 = 2.88, p = 0.05, such that those with lower ventral striatum activation exhibited longer latencies to first drink . Significant covariates included medication condition, Wald χ2 = 5.99, p = 0.01, such that naltrexone was associated with longer latency to first drink. OPRM1 was also significant, Wald χ2 = 3.31, p = 0.03, such that Asn40Asn homozygotes exhibited shorter latency to first drink. Other covariates of interest were not associated with latency to first drink . There were also no interactions of medication X gender on self-administration outcomes. This study examined the relationship between alcohol cue-induced ventral striatum activation and alcohol self-administration in the laboratory. Results from this heavy-drinking sample of East Asians indicated that higher ventral striatum activation was associated with a shorter latency to first self-administered drink. Similarly, ventral striatum activation was positively associated with the total number of drinks consumed during the self-administration paradigm in this sample.

These results remained significant after controlling for severity of drinking patterns, OPRM1, and medication condition. Overall, this is the first study to examine whether neuroimaging outcomes of interest can predict responses within laboratory paradigms commonly used in the alcohol literature. This foundational work adds important validity to the hypothesized interplay between neural bases of alcohol craving and behavioral measures of alcohol seeking, namely alcohol self-administration in the human laboratory. These associations contribute to a growing literature on the translational value of neuroimaging paradigms in alcohol treatment, particularly in elucidating potential mechanisms through which self-administration paradigms in AUD research are related to real world alcohol consumption . Such work is aligned with current efforts in behavioral treatments utilizing neuroimaging to study mechanisms of behavior change for substance use disorders; identifying those individuals with severe orbitofrontal cortex deficits, for instance, may be useful in guiding them away from treatments focused on increasing the salience of future negative consequences of substance use . In a similar fashion, adjunctive fMRI has been used to train individuals with substance use disorders through resonance-based breathing to reduce visual processing of drug cues and increase activation in areas implicated in internally directed cognition . Elucidating the translational value of these various experimental paradigms is strongly indicated, as AUD medications can exhibit differential results based on the utilized paradigm and such variability may in turn inform precision medicine efforts. Expanding the study of interexperimental paradigms may also shed light on aspects of alcohol consumption unique to individual paradigms. For instance, a greater understanding of individuals’ experiences in the transition between the first and subsequent drinks may be an important point of clinical interventions when discussing naltrexone use. While the primary aim of this study was not focused on genetic determinants of self-administration, it is notable that genotypes encoding the binding potential of mu-opioid receptors were associated with self-administration outcomes. While it is theorized that individuals with at least one copy of the G-allele for OPRM1 exhibit greater vulnerability to developing AUD, meta-analyses have been mixed, with findings that such an association may not be reliable , are population specific ,or that G-allele confers a modest protective effect on general substance dependence in European ancestry cohorts .

In this study, G-allele carriers of OPRM1 exhibited lower total consumption relative to A-allele carriers at a statistical trend level, as well as slower latency to first drink. This finding is consistent with the primary analyses for this data , which indicated that G-allele carriers of OPRM1 also reported less severe drinking history and lower AUDIT scores compared to Asn40 homozygotes and may, in turn, help to explain these findings. In sum, we accounted for genetic factors in these analyses given their theoretical and practical salience ,growing cannabis outdoors particularly in this population . And while the genetic findings are notable and largely consistent with the literature, the primary focus on the study is on the fMRI to human laboratory association. This is the area in which the present analyses make a substantive contribution to the literature by supporting a long hypothesized, yet rarely tested, association between brain and behavior. Finally, this study identified significant effects of naltrexone in increasing latency to first drink and decreasing total alcohol consumption. Notably, while these contrast the primary study results from which the data are derived the current study is a secondary analysis of a sub-sample of participants who had completed both neuroimaging sessions. While inclusion of VS activation may have helped to improve model fit, the primary study had greater power in order to test pharmacogenetic effects. For these reasons, while it is possible that consideration of neuroimaging outcomes help elucidate AUD pharmacotherapy effects, replication using larger samples is warranted. On balance, this study should be interpreted in light of its strengths and limitations. Strengths included assessment of multiple experimental procedures used in the medication development literature and consideration of multiple psychiatric and genetic predictors of self-administration in the statistical analyses. Another strength is the test of hypothesis at the within subjects level of analysis. As argued by Curran and Bauer , several psychological processes which are inherently within-person processes, such as the relationship between how one’s brain processes alcohol cues and how much s/he wants to drink in the future, are presumed to be explained in between-subjects models, when in fact, within-subject analyses provide a more representative test of the process at hand . Thus, a within-subjects approach represents a more robust, and methodologically adequate, test of the association between brain and behavior. One of the most important limitations of the current study is a constrained sample and power; given the exploratory nature of this study, alpha corrections were not implemented. A limitation of the taste cues fMRI paradigm used in this study is that it was modified to reduce trial duration in order to increase the number of trials for analysis; in contrast to the original task , a whole-brain analysis of the task did not elicit significant clusters of mesocorticolimbic, including ventral striatum, activation. Therefore, replication using other tasks that more strongly elicit ventral striatum activation are needed, both to induce significant enough variability to test medication effects and also to translate such effects into another subsequent experimental modality.

Variations of the Monetary Incentive Delay task that administer beer may be particularly useful in disentangling whether anticipation, relative to receipt, of alcohol taste are differently discriminant in predicting self-administration Relatedly, the taste cues paradigm was limited to the choice of red or white wine, which did not always correspond with participants’ drink of choice; while this correspondence was not a significant covariate in self-administration outcomes, administering drink of choice may increase external validity of the imaging task. Another potential weakness is that medication effects from the primary manuscripts were null; future studies are needed to corroborate that medication effects are consistent across paradigms, particularly in identifying significant such effects. An additional warranted question is whether such consistency of medication effects in laboratory studies would translate directly to clinical outcomes and treatment-seeking populations. Lastly, the “priming dose” that preceded the self-administration period was higher than the usual 0.03 g/dl reported in the literature. While the higher priming dose of alcohol in this study did not suppress alcohol self-administration, it may be interpreted differently in that participants were seeking to self-administer to reach high levels of BrAC, perhaps binge-like levels. If that was the case, results would remain highly relevant and consistent with recent efforts to phenotype binge-drinking in the human laboratory . Limitations notwithstanding, the present findings provide proof-of-concept that neuroimaging and laboratory paradigms may be closely linked. Further, neuroimaging may be a useful tool to explore in greater detail how different paradigms are related to real world consumption behavior. Future studies are warranted to replicate the current results and to identify, refine, and implement translational paradigms in AUD research.In the European Union and the United States, 3,4-methylenedioxymethamphetamine is currently a schedule I controlled substance . The interest in MDMA use in psychiatry has solidified and is growing following publications of results from multiple controlled trials including a Phase 3 study for MDMA assisted therapy for post-traumatic stress disorder . MDMA’s psychoactive properties are due to multiple mechanisms that modulate monoamine neurotransmission, including release and reuptake of serotonin, dopamine and norepinephrine . Proposed therapeutic mechanisms of MDMA may include increased ability to confront upsetting memories, supporting fear-extinction learning and increased interpersonal closeness . Adverse events observed in controlled trials included transient hypertension, muscle tightness, decreased appetite, nausea, hyperhidrosis and feeling cold . Serotonin syndrome is a potentially life-threatening condition resulting from serotonergic over-activity at synapses of the central and peripheral nervous systems usually involving serotonergic medications . SS manifests itself through a range of mild to severe symptoms. Mild symptoms include akathisia and tremors, and severe symptoms include hyperthermia and muscular rigidity, which can be life-threatening .

The primary gear type for shrimp fisheries is trawl gear

We estimated a potentially clinically significant 89-g increase in birth weight among infants born to mothers using wood-fueled chimney stoves compared with those born to mothers using open fires. These results are similar to those of four other studies that assessed the relationship between birth weight and maternal exposures to HAP . Unlike previous studies, however, ours introduced a standardized, improved chimney stove, assessed stove conditions on a weekly basis, and measured personal CO exposures among pregnant women every 3–6 months. In a recent meta-analysis of five studies, which included the present findings, Pope et al. estimated a reduced mean birth weight of 95.6 g and a 38% increase in LBW among women exposed to HAP compared with women who used cleaner stoves during pregnancy . Previous studies compared only birth weight outcomes and maternal report of fuel type. A Zimbabwean study of 3,559 newborns showed that infants born to clean fuel users weighed 175 g more than did infants born to mothers who used wood, straw, and dung as fuel . In a study of 1,771 newborns in Guatemala, Boy et al. reported that infants born to women using cleaner-fuel stoves versus wood-fuel stoves weighed 63 g more, on average, whereas infants born to women using wood-fueled improved stoves were 32 g heavier, on average, than were those born to women using open fires. Some of the improved stoves in that study were poorly maintained or repaired, which may have biased the estimate toward the null. A study of 634 infants in Pakistan found a non-significant decrease in birth weight in infants born to women using wood fuel compared with infants born to natural gas users . Although this last estimate is similar to that observed in the RESPIRE trial,cannabis grower supplies all the study women from RESPIRE used wood-fueled stoves. At present, in these rural, poor communities of Guatemala, an improved wood stove is the only viable, low-cost option.

Despite limitations of a small sample size, possible birth weight measurement error due to delay between time of birth and time of measurement, exposure mis-classification, other unmeasured exposures to wood smoke , and air pollution reductions primarily restricted to the third trimester, we identified a potentially clinically significant, but not statistically significant, difference in birth weight. Because of possible exposure misclassification among women who received their stove days before birth, we created an exposure variable indicating whether women had a stove in use for at least 60 days before delivery. This reduced the stove group from 69 to 34 births, introduced uncertainty into the model, and thus reduced our power to detect an effect from stove type with an estimated 63 g increase . Because of the heavy demands on field personnel to meet the primary aims of the RESPIRE trial, we were not able to assess newborn gestational age at the home deliveries and are thus not able to state what proportion of LBW was due to preterm birth. In 2009, the primary author trained 10 local traditional birth attendants who work in the communities that previously participated in RESPIRE. Using a cell-phone notification system, traditional birth attendants notified us of home deliveries. Within a 2-week period, we evaluated within 48 hr of birth 22 live newborns who were delivered at home. Preliminary analysis of estimated mean gestational age assessment using the New Ballard scale was 36.1 weeks . We estimated the lowest gestational age at 32 weeks, with an instrument margin of error of ± 2 weeks. We plan to conduct future studies to extend training in gestational age assessment using validated methods such as the New Ballard scale. A further limitation of the present study was the small number of maternal CO exposure measurements. A recent systematic review of 41 studies in industrialized countries examined the effect of a range of ambient air pollutants on adverse birth outcomes; 13 studies looked at CO and LBW . Although averaging times and exposure during pregnancy intervals varied across the studies, significant estimated effects on birth weight were reported for CO as low as 1–2 ppm in the third trimester based on in single-pollutant ambient models . These levels were lower than the 48-hr personal CO concentrations among the pregnant women in RESPIRE, including the stove group. Another limitation is the lack of information on diet and maternal weight gain during pregnancy. Chronic under nutrition was marked among the participating mothers and is reflected in their short stature. In this study, 2.0% of non-pregnant women were below the standard reference cutoff of 18.5 kg/m2 for maternal under nutrition.

This is comparable with the 2002 Guatemalan maternal–child health national survey, which found maternal under nutrition to be 1.9% for women of reproductive age . Our study has several strengths. This study of HAP exposure and birth weight is the first to explore a trimester effect with the use of improved stoves, although few women were observed starting from the first or the second trimester. Differential exposure was limited primarily to the third trimester and after stove construction. The velocity of fetal growth is largest during the third trimester, so limiting smoke exposures during this period is crucial . We observed a non-significant mean increase of 106 g in infant birth weight among the 52 women who used the chimney stove in the third trimester compared with women who used open fires throughout their pregnancy. Dejmek et al. estimated that newborns whose mothers were exposed to ETS throughout their pregnancy weighed 53 g less , on average, than those whose mothers were unexposed to ETS. In the same study, women who were moderate cigarette smokers during the third trimester had children whose birth weight averaged 130 g less than that of children born to mothers who never smoked. Our estimate falls within a plausible range for this third-trimester exposure period. A further strength of our study is the low prevalence of active tobacco smoke and ETS exposure. In other studies measuring the impact of solid fuels used for cooking, LBW could potentially be attributed in part to unmeasured tobacco exposures if smoking is common. In Pakistan, Siddiqui et al. found that 15% of the study women smoked during pregnancy. Among women enrolled in RESPIRE, only one woman stated that she was a former smoker, and among the 26% of women who reported a smoker in the house, only one or two cigarettes were smoked per day. Weekly visits made by trained fieldworkers ensured that the chimney stove was functioning as intended. During the RESPIRE trial, the chimney stove reduced kitchen air pollution by approximately 90%. Among all 529 women monitored during the 2-year trial, arithmetic mean personal exposures over 48 hr were reduced by 54%, from 4.8 ± 3.6 ppm to 2.2 ± 2.6 ppm, in the chimney-stove group . Among pregnant women, CO was 39% lower among women who used the cook stove compared with open-fire users.

However, CO levels were high even among chimney-stove users. In these communities, there are other important sources of smoke exposure, and certainly there are exposures to other copollutants in wood smoke besides CO. Roughly 85% of the population uses a wood-fired steam bath for 30–45 min several times a week . Temazcal use could have a much greater effect on LBW than kitchen exposures. Data presented here did not incorporate these significantly elevated exposures, because women were asked to remove their CO tubes before entering the temazcal to bathe,dry rack cannabis because high-humidity conditions would interfere with the accuracy of the tube measurement. These extreme, acute CO exposure levels affect the entire population of temazcal users and could contribute to the high incidence of LBW observed in the RESPIRE population . In this study, however, women who had the chimney stove in use during pregnancy and those who used the open fire were equally exposed to the temazcal . We observed a strong association with season, with a significantly higher average birth weight among children born during the cold season compared with children born during the rest of the year. We anticipated potentially higher exposures to CO during the cold season, when household members typically sit around the fire for warmth. However, we found no seasonal differences in measured maternal CO exposures . It is possible that higher birth weight during the cold season is attributable to increased food availability during the harvest period, which occurs in the months preceding the cold season. Increased fetal weight may be attributable to improved nutrition during the second trimester and third trimester, when fetal weight gain accelerates, although this cannot be verified from our data. Rao et al. found evidence of a seasonal energy stress effect among Indian women in rural farming communities. Women who had higher maternal caloric intake during the second and third trimesters, which coincided with the winter harvest season, were found to have heavier newborns than did women whose second and third trimesters coincided with summer and monsoon seasons . Women in the RESPIRE trial not only face chronic malnutrition but also experience seasonal stress that acutely affects infant birth weight. A final strength of this study is the intensive, weekly household surveillance that was employed during RESPIRE. This increased our ability to weigh infants born at home soon after birth. Our LBW prevalence was 22.4%, almost double the national reported prevalence of 12% . The national LBW rate includes urban populations, typically characterized by higher socioeconomic status, better access to medical care, and cleaner cooking fuels.The premise of this study is that an increasing number of the world’s fisheries are producing or exceeding their maximum yield, while the world demand for seafood increases. Global per capita seafood consumption has increased steadily from 9.9 kg in the 1960s to 19.2 kg per capita in 2012 .

This skyrocketing demand in conjunction with population growth and increased fishing efficiency has led to over exploitation of many marine fish stocks. Technological advancements have made accessible areas that were once too remote or too deep to be exploited. Commercial fishing involves deploying hundreds of miles of nets and dragging various apparatus along bottom habitats. A side effect of this is environmental damage throughout ocean ecosystems, much of which is unobservable and immeasurable . Fishery management authorities have started adopting ecosystem-based management approaches, understanding that fish populations depend upon habitat integrity . Many fisheries stipulate gear restrictions and limited access, but enforcement, efficacy, and consideration of economic and social factors all vary on a case-by-case basis. Despite increased efficiency, fleet size, and access, wild capture fisheries’ annual production has stabilized to 1990 levels, varying up and down about three percent since 1998 . The relative consistency of wild catch over the past two decades, accompanied by the periodic dramatic stock collapse, such as the anchoveta crisis in 1998 and today’s California sardine fishery closure, suggests wild-capture marine food fish production may be at capacity. Yet to date, seafood production has risen to meet demand, outpacing world population growth twofold in annual growth rates since the 2000s. This has been made possible by the aquaculture industry, which has been growing rapidly in the past few decades: aquaculture contributed to 5 percent of seafood production in 1962, and an impressive 49 percent in 2012 . From some perspectives, aquaculture is a means to contribute to global food security while alleviating pressure on wild stocks and preventing environmental damage from impactful fishing gear. But to others, farmed seafood comes with its own variety of health and environmental risks, and is neither an adequate nor sustainable substitute for its wild counterpart.In regards to U.S. seafood consumption, shrimp is the most consumed product, weighing in at 1.9 kg per year consumed by the average American . Despite this popularity, we remain dependent upon foreign production for upwards of 90% of shrimp products. In 2015 the U.S. imported almost 1.3 billion pounds of shrimp, valued at over $5.4B . The aquaculture industry continues expand, and import data prove shrimp is a top priority for the U.S. However, ecosystem-based assessments of commercial fisheries particularly malign shrimp fisheries.Certain types of trawls earn the highest rank among fishing gear in terms of physical and biological habitat damage . Also, trawling for small species leads to massive amounts of bycatch: roughly five pounds of non-target species per pound of shrimp in the U.S. fisheries.