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Background: The α1 antagonist doxazosin reduces cocaine use in individuals with cocaine use disorder (CUD) through a functional polymorphism of the α1 adrenoreceptor. The regulatory role of the α1 ...

Pediatric patients are often sedated for magnetic resonance imaging (MRI) scans to ensure images are of diagnostic quality. However, access time for MRIs requiring sedation is often long due to high patient volumes and limited sedation resources. This study examined the effectiveness of an MRI Try Without sedation program to decrease the wait time for obtaining an MRI while simultaneously ensuring diagnostic-quality images. A retrospective chart review was performed on subjects who utilized the MRI Try Without program from April 2014 through June 2015 at a dedicated pediatric institution. Child life specialist preparations and access time (i.e. time from exam ordered to exam completed) were recorded in each patient’s electronic medical record. MRI images were evaluated for image quality by a pediatric neuroradiologist. A total of 134 patients participated in the MRI Try Without program (mean age: 6.9±1.7 years), all of whom received interventions from a child life specialist. The average number of days between when the order was placed and when the MRI was completed using the MRI Try Without program was 15.4±18.5 days, while the third-available appointment for sedation/anesthesia was 46.2 days (standard deviation [SD]±15.7 days). Nearly all patients received a “good” or “very good” image quality determination (87.3%) and only 5 (3.8%) patients were recommended for repeat examination for diagnostic-quality images. Utilization of an MRI Try Without sedation program, with child life specialist interventions, decreased the wait time for obtaining an MRI while still providing diagnostic-quality images.

Microbial biosynthesis of fuels and chemicals represents a promising route for their renewable production. Product toxicity, however, represents a common challenge limiting the efficacy of this approach. Integrated bioprocesses incorporating in situ product separation are poised to help address this intrinsic problem, but suffer their own unique shortcomings. To improve and expand the utility of this versatile bioprocessing strategy, recent innovations have focused on developing more effective separation materials and novel process configurations, as well as adapting designs to accommodate semi-continuous modes of operation. As a result, integrated bioprocesses are finding new applications to aid the biosynthesis of an ever-growing list of bioproducts. Emerging applications, meanwhile, are exploring the further expansion of such designs to interface microbial and chemical catalysts, leading to new and versatile routes for the one-pot synthesis of an even greater diversity of renewable products.

OBJECTIVE: The use of synthetic cannabinoid (SC) products has become popular in recent years, but data regarding their impact on hospital stays are limited. The impact of SC and cannabis use on hospital length of stay and doses of antipsychotics at discharge was assessed in this study. METHOD: The sample consisted of inpatients with discharge diagnoses of bipolar disorder, schizophrenia, or other psychotic disorders. Medical records of patients with self-reported SC use and negative urine drug screens (SC group, n = 77), with cannabis use confirmed by urine drug screen (cannabis group, n = 248), and with no drug use confirmed by urine drug screen (no-drug group, n = 1,336) were examined retrospectively. RESULTS: Length of stay (mean [SD] days) significantly differed (p < .001) among the SC (8.29 [4.29]), cannabis (8.02 [5.21]), and no-drug groups (10.19 [9.08]). Antipsychotic doses (chlorpromazine milligram equivalent doses) also significantly differed (p = .002) among the SC (254.64 [253.63]), cannabis (219.16 [216.71]), and no-drug groups (294.79 [287.85]). Unadjusted and adjusted pairwise comparisons showed that the cannabis group had a shorter length of stay (p < .001) and received lower doses of antipsychotics (p = .003) than the no-drug group. SC users did not differ significantly from the other two groups in either length of stay or doses of antipsychotics. CONCLUSIONS: Our findings suggest that acute SC exposure is not predictive of a more prolonged time for response to antipsychotic medications or of a need for larger doses of these medications compared with cannabis users.

OBJECTIVE: Prior research demonstrated that the δ-opioid receptor (OPRD1) rs678849 variant influences opioid use in African Americans treated with methadone. We examined whether this variant moderated cocaine and opioid use in our clinical cohort of methadone and disulfiram treated recipients. METHODS: Cocaine and opioid co-dependent patients were stabilized for two weeks on methadone and subsequently randomized into groups treated with either methadone+placebo (n = 37) or methadone+disulfiram (250 mg/day, n = 33) for 12 weeks. RESULTS: A drop in cocaine positive urines was found in the OPRD1 CC genotype group compared to T-allele carrier patients treated with methadone+disulfiram (P < 0.0001), but not in the methadone+placebo group. No difference in opioid positive urines were found among each genotype group in either treatment group. CONCLUSION: These findings suggested that rs678849 genotype may predict treatment response of disulfiram for cocaine use in patients with co-occurring opioid and cocaine dependence.

Background The use of smartphones and multimedia messaging service (MMS) continues to increase in day to day orthopaedic clinical practice. However, there is limited evidence to support the safe utilisation of MMS. Objectives The aim of this study was to correlate the performance of MMS imaging to picture archiving and communication systems (PACS) imaging within the setting of diagnosis and management of ankle fractures. Methods The ankle fracture radiograph series of 82 consecutive patients were evaluated by five orthopaedic consultant specialists. A questionnaire regarding diagnosis and preferred management was completed separately for each patient using smartphone and PACS images. Statistical analysis was performed using Intraclass Correlation Coefficient (ICC). Results Ankle fracture diagnosis showed strong to excellent correlation both inter- and intraobserver MMS vs PACS when using the Weber (0.815, 0.988), Anatomical (0.858, 0.988), and AO classification systems (0.855, 0.985). MMS was less reliable than PACS in determining many management options. Conclusion The reliability of ankle fracture classification using MMS image viewing was not significantly different to interpretation on PACS workstations. Smartphone use in ankle fracture classification is supported by this study. Smartphone use was less accurate than PACS in devising management plans and future use should be limited to making only initial plans that must be corroberated with PACS and intraoperative findings prior to definitive fixation.

OBJECTIVES/HYPOTHESIS Internal auditory diverticula in adults have been found to exist independent of otosclerosis, and in the presence of otosclerosis. We sought to determine the prevalence of internal auditory canal (IAC) diverticula in a pediatric cohort, to assess whether IAC diverticula are a risk factor for hearing loss, and the co-occurrence of otic capsule hypoattenuation. STUDY DESIGN Retrospective review. METHODS A single-site retrospective review of high-resolution temporal bones computed tomography (CT) scans including the presence and size of diverticula and hypoattenuation of the otic capsule. Demographic, imaging, and audiometric data were collected and descriptively analyzed. Bivariate analysis of collected variables was conducted. Comparisons between sides in unilateral cases were also performed. RESULTS 16/600 (2.7%; 95% CI [2.0%, 3.4%]) were found to have IAC diverticula. Six were bilateral. Thirty-one patients (5.2%) were found to have hypoattenuation of the otic capsule. There were no coincident cases of IAC diverticulum and hypoattenuation of the otic capsule. There was no association between the presence of IAC diverticula and age (P = .13). In six patients with unilateral diverticula, pure tone average (P = .42), and word recognition (P = .27) scores were not significantly different when compared to the normal, contralateral side. CONCLUSIONS The prevalence of IAC diverticula in children is lower than the prevalence in adults. IAC diverticula in children likely represent congenital variants of temporal bone anatomy. Similar to adult populations, there is evidence that IAC diverticula in children are likely not an independent risk factor for hearing loss. LEVEL OF EVIDENCE 4 Laryngoscope, 131:E1683-E1687, 2021.

Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 mg) and saline in a randomized order. The subjective effects of cocaine were self-reported using a visual analog scale starting prior to the administration of cocaine (−15 min) or saline and up to 20 min after infusion. Participants were evaluated for methylation of the SLC6A4 promoter region and 5-HTTLPR genotype. A series of ANCOVAs for SLC6A4 methylation (high/low) were run for each of ten subjective and three cardiovascular effects controlling for age, sex [utilizing the sex-determining region Y protein (SRY)], and population structure (determined from ancestry informative markers and STRUCTURE software). Participants with SLC6A4 hypermethylation reported greater subjective response to cocaine for ‘depressed’ relative to participants with SLC6A4 hypomethylation (experiment-wise p =.002). These findings indicate that SLC6A4 methylation moderates the ‘depressed’ subjective effect of cocaine in non-treatment-seeking cocaine-dependent participants.

BACKGROUND AND OBJECTIVES The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory. METHODS A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS). RESULTS The variant allele was associated with increased cocaine-induced subjective ratings for "Drug Effect," "High," and "Depressed." The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (A allele: 47% vs. 34%; AA genotype: 30% vs. 13%; p

The winter wheat (Triticum aestivum L.)–fallow (WF) dryland production system employed in the Central Great Plains has evolved in the past 40 yr to include a diversity of other crops, with a reduction in fallow frequency. Wheat remains the base crop for essentially all cropping systems. Decisions to change a farming system benefit from information about average wheat yields, yield stability, and probabilities of obtaining a specified minimum wheat yield. The objective of this experiment was to quantify wheat yields, yield stability, and the probability of obtaining a specified minimum yield in eight dryland rotational systems varying in cropping intensity. The study was conducted over a 24-yr period at Akron, CO. Yield stability was characterized with six stability measures. The probability of obtaining a yield less than 1500 kg ha⁻¹ was also calculated for each rotation. Wheat yields were greatest in rotations where wheat followed a fallow period and least where wheat followed millet production. Rotations ranked from most stable to least stable wheat production (averaged over the six stability measures) were WF(NT), WF(CT), WMF, WCMP, WCM, WCMF, WM, and WCF. The probability of producing

Background and objectives Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive components of opioid dependence. Methods We studied habenular resting state functional connectivity with related brain structures, specifically the striatum. We compared abstinent psychiatric patients who use opioids (N = 51) to psychiatric patients who do not (N = 254) to identify an endophenotype of opioid use that focused on withdrawal avoidance and aversion rather than the more commonly examined craving aspects of relapse. Results We found that habenula-striatal connectivity was stronger in opioid-using patients. Increased habenula-striatum connectivity was observed in opioid-using patients with the low risk rs16969968 GG genotype, but not in patients carrying the high risk AG or AA genotypes. Conclusions We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use. Scientific significance Our data uncovered a promising brain target for development of novel anti-addiction therapies and may help the development of personalized therapies against opioid abuse. (Am J Addict 2017;26:751-759).

A common dryland rotational cropping system in the semi-arid central Great Plains of the USA is wheat ( Triticum aestivum L.)-corn ( Zea mays L.)-fallow (WCF). However, the 12-month fallow period following corn production has been shown to be relatively inefficient in storing precipitation during the summer months and in some years could leave the soil vulnerable to wind erosion. The objective of this experiment was to determine the effect on system productivity when the fallow period in a WCF rotation was replaced with spring-planted forage triticale ( X Triticosecale rimpaui Wittm.). The 3-yr study was conducted at Akron, CO and Sidney, NE under both dryland and very limited irrigation conditions (to approximate average precipitation during the growing season). Growing season precipitation during the course of the study was above-average in five of the six site-years. Over a wide range of wheat water use (361–591 mm) wheat yields ranged from 1696 kg ha −1 to 5527 kg ha −1 . Wheat yields averaged 17% lower when triticale (T) replaced fallow, primarily because of reductions in water content at wheat planting. Corn yields were unaffected by triticale replacing fallow and ranged from 3159 kg ha −1 to 8085 kg ha −1 . Triticale yields ranged from 2967 kg ha −1 to 6724 kg ha −1 . System productivity as quantified by system net returns was greater for WCT than for WCF when growing season precipitation was above-average resulting in triticale production over 6000 kg ha −1 , but even in drier years net income was not reduced when the fallow phase was replaced with triticale production. A WCT rotation can be recommended over WCF provided that growing season precipitation is not far below average and there is an available market for the triticale forage produced. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. The U.S. Department of Agriculture (USDA) prohibits discrimination in all its programs and activities on the basis of race, color, national origin, age, disability, and where applicable, sex, marital status, familial status, parental status, religion, sexual orientation, genetic information, political beliefs, reprisal, or because all or part of an individual's income is derived from any public assistance program. (Not all prohibited bases apply to all programs.) Persons with disabilities who require alternative means for communication of program information (Braille, large print, audiotape, etc.) should contact USDA's TARGET Center at (202) 720-2600 (voice and TDD). To file a complaint of discrimination, write to USDA, Director, Office of Civil Rights, 1400 Independence Avenue, S.W., Washington, D.C. 20250-9410, or call (800) 795-3272 (voice) or (202) 720-6382 (TDD). USDA is an equal opportunity provider and employer.

Microbial systems have been widely studied and exploited through genetic engineering to address industrial needs and societal challenges. However, owing to their complexity, singular approaches often do not yield desired or optimal results, pushing researchers to explore combinatorial strategies. With advances in synthetic biology, various methods can readily be employed to generate large and comprehensive libraries. To serve as tractable tools, however, this capability necessitates the development of high-throughput screening (HTS) techniques to identify the best performing strain and/or those carrying the desired trait. Owing to their miniaturization, time efficiency, potential for automation, and so on, HTS enables comprehensive exploration of diverse experimental landscapes. Herein, we review the recent and novel HTS approaches and applications in the realm of microbial biotechnology.

Background and Objectives There is significant variability in severity of neonatal abstinence syndrome (NAS) due to in utero opioid exposure. Our previous study identified single nucleotide polymorphisms (SNPs) in the prepronociceptin (PNOC) and catechol-O-methyltransferase (COMT) genes that were associated with differences in NAS outcomes. This study looks at the same SNPs in PNOC and COMT in an independent cohort in an attempt to replicate previous findings. Methods For the replication cohort, full-term opioid-exposed newborns and their mothers (n = 113 pairs) were studied. A DNA sample was obtained and genotyped for five SNPs in the PNOC and COMT genes. The association of each SNP with NAS outcomes (length of hospitalization, need for pharmacologic treatment, and total opioid days) was evaluated, with an experiment-wise significance level set at α

Background and objectives Disulfiram has been beneficial in treating cocaine addiction in several studies. Patients with two SLC6A3 (DAT1) rs28363170 10-repeat alleles who have with genetically high dopamine transporter (DAT) levels may benefit from increased dopamine levels resulting from disulfiram treatment. Methods After stabilization for 2 weeks on methadone, 70 cocaine and opioid codependent patients were randomized into disulfiram and placebo groups for 12 weeks of treatment. We genotyped the SLC6A3 (DAT1) 40 bp 3'-untranslated region variable number tandem repeat variant and evaluated its role in moderating disulfiram efficacy for cocaine dependence. Results Among the 10,10-repeat genotype group, cocaine-positive urines dropped from 78% to 48% and from 80% to 75% among the 9-repeat carrier group in the disulfiram group (P = 0.0001, with an effect size of 0.09). No difference was observed in cocaine-positive urines in the placebo group between the 10,10-repeat genotype and the 9-allele carrier patients. Conclusions and scientific significance We found that patients with genetically higher DAT levels had better treatment outcomes with disulfiram pharmacotherapy of cocaine dependence than those with lower DAT levels. (Am J Addict 2019;28:311-317).

Variants in three genes coding for components of the serotonergic system, the tryptophan hydroxylase 1 (TPH1) rs1799913, serotonin transporter (SLC6A4) 5-HTTLPR, and serotonin receptor 2A (HTR2A) rs6311, were evaluated for association with suicidal ideation (SI) and with recovery from SI in a psychiatric inpatient population. Five hundred and eighty-two adult inpatients, including 390 patients who had SI, collected from December 2012 to April 2016 were assessed. SI recovery, calculated as change in SI between the first two-week period after admission and weeks 5 and 6, was appraised for association with the three variants. In this preliminary study, both TPH1 and 5-HTTLPR genotypes were associated with recovery (TPH1: recessive model, increased recovery with AC genotype, P = 0.026; additive model, increased recovery with AC genotype, P = 0.037; 5-HTTLPR: recessive model, increased recovery with AC, P = 0.043). When patients with comorbid alcohol use disorder (AUD) were removed, given that TPH1 has been associated with alcoholism, the associations of those recovered from SI with TPH1 rs1799913 remained significant for the additive (increased recovery with AC, P = 0.045) and recessive (increased recovery with C-carriers, P = 0.008) models, and with 5-HTTLPR using the dominant model (increased recovery with S′S′, P = 0.016). In females, an association of SI recovery with TPH1 rs1799913 was found using a recessive model (increased recovery with C-carriers, P = 0.031), with 5-HTTLPR using additive (increased recovery with L′S′, P = 0.048) and recessive (increased recovery with S′S′, P = 0.042) models. Additionally, an association of SI with TPH1 rs1799913 was found in females using both additive (increased risk in AC, P = 0.033) and recessive (increased risk in C-carriers, P = 0.043) models, and with 5-HTTLPR using a recessive model (increased risk in S′S′, P = 0.030). This study provides evidence that variation in the TPH1 and serotonin transporter genes play key roles in moderating recovery from SI during treatment in an inpatient psychiatric clinic.

Importance Treating patients with opioid use disorder (OUD) and traumatic brain injury illustrates 6 neurobiological principles about the actions of 2 contrasting opioid analgesics, morphine and fentanyl, as well as pharmacotherapies for OUD, methadone, naltrexone, and buprenorphine. Observations This literature review focused on a patient with traumatic brain injury who developed OUD from chronic morphine analgesia. His treatment is described in a neurobiological framework of 6 opioid action principles. Conclusions and Relevance The 6 principles are (1) coactivation of neuronal and inflammatory immune receptors (Toll-like receptor 4), (2) 1 receptor activating cyclic adenosine monophosphate and β-arrestin second messenger systems, (3) convergence of opioid and adrenergic receptor types on 1 second messenger, (4) antagonist (eg, naltrexone)–induced receptor trafficking, (5) genetic μ-opioid receptor variants influencing analgesia and tolerance, and (6) cross-tolerance vs receptor antagonism as the basis of OUD pharmacotherapy with methadone or buprenorphine vs naltrexone.

BACKGROUND: The α(1) adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine β-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DβH’s conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DβH levels. METHODS: This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DβH levels from the DBH CC genotype, and 27 with lower DβH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N=47) or placebo (N=29), and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. RESULTS: Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41% from baseline in the CT/TT group with low DβH and NE levels, as compared to no net reduction in the CC genotype group with normal DβH and NE levels. CONCLUSIONS: The DBH polymorphism appears play an important role in CUD patients’ response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

Aromatic compounds represent a broad class of chemicals with a range of industrial applications, all of which are conventionally derived from petroleum feedstocks. However, owing to a diversity of available pathway precursors along with natural and engineered enzyme 'parts', microbial cell factories can be engineered to create alternative, renewable routes to many of the same aromatic products. Drawing from the latest tools and strategies in metabolic engineering and synthetic biology, such efforts are becoming an increasingly systematic practice, while continued efforts promise to open new doors to an ever-expanding range and diversity of renewable chemical and material products. This short review will highlight recent and notable achievements related for the microbial production of aromatic chemicals.

Although it represents a promising biofuel, n-butanol production by conventional batch fermentation is limited as a result of its cytotoxic effects. To address this limitation and facilitate semi-continuous fermentation, in situ n-butanol removal has proven to be an effective approach. Exploiting the phenomena of solvent extraction, adsorption, or vaporization, numerous integrated bioprocess configurations have been developed to facilitate selective n-butanol recovery. The objective of this review is to provide a broad overview of different technology options and process configurations to this end, highlighting notable achievements and recent developments. In each case, relevant design considerations critical for improving key production metrics will be discussed, with particular emphasis given to studies that, as a result of relieved product toxicity, have successfully demonstrated further enhanced n-butanol production through semi-continuous operation.

a b s t r a c t Crop water production functions (CWPFs) are often expressed as crop yield vs. consumptive water use or irrigation water applied. CWPFs are helpful for optimizing management of limited water resources, but are site-specific and vary from year to year, especially when yield is expressed as a function of irrigation water applied. Designing limited irrigation practices requires deriving CWPFs from long-term field data to account for variation in precipitation and other climatic variables at a location. However, long-term field experimental data are seldom available. We developed location-specific (soil and climate) long-term averaged CWPFs for corn (Zea mays L.) using the Root Zone Water Quality Model (RZWQM2) and 20 years (1992-2011) of historical weather data from three counties of Colorado. Mean CWPFs as functions of crop evapotranspiration (ET), ET due to irrigation (ETa-d), irrigation (I), and plant water supply (PWS = effective rainfall + plant available water in the soil profile at planting + applied irrigation) were developed for three soil types at each location. Normalization of the developed CWPF across soils and climates was also developed. A Cobb-Douglas type response function was used to explain the mean yield responses to applied irrigations and extend the CWPFs for drip, sprinkler and surface irrigation methods, respectively, assuming irrigation application efficiencies of 95, 85 and 55%, respectively. The CWPFs developed for corn, and other crops, are being used in an optimizer program for decision support in limited irrigation water management in Colorado. © 2014 Elsevier B.V. All rights reserved.

OBJECTIVE The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure. METHODS Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40 mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Ratings of subjective effects were normalized to baseline, and saline infusion values were subtracted. Data were analyzed using repeated measures analysis of variance. DNA from the participants was genotyped for the DAT1 intron 8 (rs3836790) and 3'-untranslated region (rs28363170) variable number of tandem repeats. RESULTS Participants were mostly male (∼80%) and African American (∼70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3'-untranslated region (9,9 and 9,10) exhibited greater responses to cocaine for 'high', 'any drug effect', 'anxious', and 'stimulated' (all P-values

Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure has significant variability of severity. Preliminary studies have suggested that epigenetic variation within the μ-opioid receptor (OPRM1) gene impacts NAS. We aimed to determine if DNA methylation in OPRM1 within opioid-exposed mother-infant dyads is associated with differences in NAS severity in an independent cohort. Full-term opioid-exposed newborns and their mothers (N = 68 pairs) were studied. A DNA sample was obtained and then assessed for level of DNA methylation at 20 CpG sites within the OPRM1 promoter region by next-generation sequencing. Infants were monitored for NAS and treated with replacement opioids according to institutional protocol. The association between DNA methylation level at each CpG site with NAS outcome measures was evaluated using linear and logistic regression models. Higher methylation levels within the infants at the -18 (11.4% vs 4.4%, P = .0001), -14 (46.1% vs 24.0%, P = .002) and +23 (26.3% vs 12.9%, P = .008) CpG sites were associated with higher rates of infant pharmacologic treatment. Higher levels of methylation within the mothers at the -169 (R = 0.43, P = .008), -152 (R = 0.40, P = .002) and +84 (R = 0.44, P = .006) sites were associated point-wise with longer infant length of stay. Maternal associations remained significant point-wise for -169 (β = 0.07, P = .007) and on an experiment-wise level for +84 (β = -0.10, P = .003) using regression models. These results suggest an association of higher levels of OPRM1 methylation at specific CpG sites and increased NAS severity, replicating prior findings. These findings have important implications for personalized treatment regimens for infants at high risk for severe NAS.

Background and Objectives Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. Methods Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. Results and Conclusions The genetic variability of μ-, δ- and κ-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. Scientific Significance Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction. (Am J Addict 2015;24:15–23)

Synthetic cannabinoid (SC) products have gained popularity as abused drugs over the past decade in many countries. The SCs broadly impact psychological state (e.g., mood, suicidal thoughts and psychosis) and physiological functions (e.g., cardiovascular, gastrointestinal and urinary). This review is about the effects of SCs on psychotic symptoms in clinical settings and the potentially relevant chemistry and mechanisms of action for SCs. Induction of psychotic symptoms after consuming SC products were reported, including new-onset psychosis and psychotic relapses. The role of SCs in psychosis is more complex than any single chemical component might explain, and these effects may not be a simple extension of the typical effects of cannabis or natural cannabinoids.

Mild traumatic brain injury (mTBI) occurred in 15–30% of Veterans returning from Iraq and Afghanistan. We examined whether DNA methylation of the apolipoprotein E (APOE) gene promoter region or plasma ApoE protein levels are altered in mTBI. APOE promoter region DNA methylation, APOE genotype, and plasma ApoE concentration were determined in 87 Veterans with or without mTBI who were recruited from 2010-2014. Plasma ApoE concentration was found to be associated with Posttraumatic Stress Disorder (PTSD) symptom severity ratings by hierarchical linear regression (p = .013) and ANCOVA (p = .007). Hierarchical linear regression revealed that plasma ApoE concentration was associated with APOE-e4 genotype status (p=.022). Higher ApoE plasma levels were found in e3/e3 Veterans than in APOE-e4 carriers (p = .031). Furthermore, plasma ApoE concentration was associated experiment-wise with DNA methylation at CpG sites -877 (p = .021), and -775 (p = .014). The interaction between APOE-e4 genotype and having a PTSD diagnosis was associated with DNA methylation at CpG site -675 (p = .009).

Synthetic cannabinoid products have become popular and have led to an increased number of patients presenting to emergency departments and psychiatric hospitals. The purpose of this study was to evaluate the impact of synthetic cannabinoid use at admission on length of stay and doses of antipsychotics at discharge in individuals with bipolar disorder, schizophrenia and other psychotic disorders. We retrospectively examined medical records of 324 inpatients admitted from January 2014 to July 2015. We found that synthetic cannabinoid use predicted length of stay and antipsychotic dose using structural equation modeling. Further, the association of synthetic cannabinoid use with length of stay was partly mediated by antipsychotic dose. These associations were independent of specific diagnosis. In conclusion, patients with bipolar disorder, schizophrenia, or other psychotic disorders who reported synthetic cannabinoid use at admission had shorter length of stay and received lower doses of antipsychotics, irrespective of clinical diagnoses.

Objective This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. Methods Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. Results Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5-HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. Conclusion These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants.

Paul A. Heidenreich, MD, MS, FACC, FAHA, Chair Nancy M. Albert, PhD, CCNS, CCRN, FAHA Paul S. Chan, MD, MSc, FACC Lesley H. Curtis, PhD T. Bruce Ferguson, Jr, MD, FACC Gregg C. Fonarow, MD, FACC, FAHA P. Michael Ho, MD, PhD, FACC, FAHA Corrine Jurgens, PhD, RN, ANP-BC, FAHA Sean O’Brien

Objective Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants with NAS outcomes. Study design DNA samples from cord blood or saliva were analyzed for 86 infants who were being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with $2 medications, and length of hospital stay. We adjusted for covariates and multiple genetic testing. Results Sixty-five percent of infants required treatment for NAS, and 24% required $2 medications. Hypermethylation of the OPRM1 promoter was measured at the � 10 CpG in treated vs nontreated infants (adjusted difference d = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the � 14 (d = 4.9% [95% CI, 1.8%-8.1%], P =. 003),� 10 (d =5 .0% [95% CI, 2.3-7.7%],P = .0005), and +84 (d = 3.5% [95% CI, 0.6-6.4], P = .02) CpG sites in infants requiring $2 medications, which remained significant for � 14 and � 10 after multiple testing correction. Conclusions Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing. (J Pediatr 2014;165:472-8).

The Glashaus is considered a significant exemplar of early modernist architecture and is generally accepted as having had Expressionist origins. However, current research has revealed that the design origins of this important building are not fully understood. While the historical record acknowledges the contributions of the bohemian poet Paul Scheerbart and the art critic Adolf Behne, the role of the Glashaus’ architect, Bruno Taut, has been moderated. In an attempt to rectify this situation this article proposes that the design origins of the Glashaus can be found in a strong architect-client interaction. It is argued that the Glashaus’ client, the Deutsche Luxfer Prismen Syndikat under the directorship of Frederick Keppler, exerted a significant influence on its design. In order to showcase the glazed products of Luxfer in the best manner possible, Keppler insisted that the design feature a glazed dome, electric lighting, a fountain as well as a cascade. Given the detailed stipulations of this brief, Taut had few options other than to offer interpretations of precedent that derived from the Victoria regia lily and Gothic proportioning. By expounding this architect-client relationship, this article expands our understanding of the Glashaus, and reinvigorates our understanding of this important early example of modern architecture.

We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals.This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine.Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P

The use of automated methods to estimate fractional vegetation cover (FVC) from digital photographs has increased in recent years given its potential to produce accurate, fast and inexpensive FVC measurements. Wide acceptance has been delayed because of the limitations in accuracy, speed, automation and generalization of these methods. This work introduces a novel technique, the Automated Canopy Estimator (ACE) that overcomes many of these challenges to produce accurate estimates of fractional vegetation cover using an unsupervised segmentation process. ACE is shown to outperform nine other segmentation algorithms, consisting of both threshold-based and machine learning approaches, in the segmentation of photographs of four different crops (oat, corn, rapeseed and flax) with an overall accuracy of 89.6%. ACE is similarly accurate (88.7%) when applied to remotely sensed corn, producing FVC estimates that are strongly correlated with ground truth values.

Advances in neuromedicine have emerged from endeavors to elucidate the distinct genetic factors that influence the changes in brain structure that underlie various neurological conditions. We present a framework for examining the extent to which genetic factors impact imaging phenotypes described by voxel-wise measurements organized into collections of functionally relevant regions of interest (ROIs) that span the entire brain. Statistically, the integration of neuroimaging and genetic data is challenging. Because genetic variants are expected to impact different regions of the brain, an appropriate method of inference must simultaneously account for spatial dependence and model uncertainty. Our proposed framework combines feature extraction using generalized principal component analysis to account for inherent short- and long-range structural dependencies with Bayesian model averaging to effectuate variable selection in the presence of multiple genetic variants. The methods are demonstrated on a cocaine dependence study to identify ROIs associated with genetic factors that impact diffusion parameters.

Poland currently has a traditional budget system that is primarily based on organisational units and control of inputs. But Poland is in the process of introducing a new budget system, the performance-based budgeting system, in order to improve public finance management and strengthen allocative and operational efficiency, multi-year budgeting, and transparency and accountability. Poland faces hard choices on how to harness the advantages of performance management while minimising the costs in terms of organisational capacity and funding. This article assesses the reform process to date, examines cross-cutting institutional, technical, and strategic issues, and provides a series of recommendations for each stage of the budget process: budget preparation, approval and execution, and reporting, accounting and audit. JEL classification: H500, H610, H830 Keywords: Poland, budget process, performance budgeting system, performance-based budget, PBB, public finance management, allocative efficiency, operational efficiency, multi-year budgeting, transparency, accountability

Under the Health Information Technology for Economic and Clinical Health (HITECH) Act, passed as a part of the American Recovery and Reinvestment Act of 2009, the US Congress implemented new regulations to encourage the adoption of electronic health records (EHRs). The federal government will expend up to $27 billion in incentive payments to physicians and hospitals to increase adoption and implement "meaningful use" of EHRs. Otolaryngologists may receive as much as $44,000 under Medicare or $63,750 under Medicaid as part of this law. In July 2010, the US Department of Health and Human Services announced final rules to support "meaningful use." This commentary discusses recommendations from the American Academy of Otolaryngology--Head and Neck Surgery Medical Informatics Committee for implementing "meaningful use" of EHRs to improve safety, quality, and efficiency of patient care and receiving incentive payments as defined by these new regulations.

In this review, we highlight many recent developments in nanotechnology of critical relevance to microbial bioenergy synthesis. Nanoparticles, nanotubes, nanofibres, and nanoporous materials, are each being utilised in powerful ways as tools for feedstock processing, genetic engineering, and biofuel harvesting, as well as in bioelectrochemical systems. As materials and techniques continue to mature, nanomaterials will become a truly integral part of the bioenergy sector. Sustainable bioenergy production will ultimately be achieved through interdisciplinary efforts that continue to bridge the gap between these traditionally distinct fields of study. Dans cette etude, nous avons presente plusieurs nouveautes en matiere de nanotechnologie qui sont cruciales pour la synthese bioenergetique microbienne. Les nanoparticules, les nanotubes, les nanofibres et les materiaux nanoporeux servent efficacement d'outils pour le traitement des produits de depart, le genie genetique, les biocarburants, ainsi que pour les systemes bioelectrochimiques. Avec le developpement des materiaux et des techniques, les nanomateriaux feront partie integrante du secteur des bioenergies. On pourra atteindre une production bioenergetique durable grâce a des efforts pluridisciplinaires qui permettent de combler le fosse existant entre ces domaines d'etude traditionnellement differents.

Objective To determine the scope of wrong-site sinus surgery. Study Design Electronic mail survey. Setting E-mailed via the American Academy of Otolaryngology–Head and Neck Surgery's weekly newsletter. Subjects and Methods Members were asked about wrong-site sinus surgery in an 11-item survey. Results A total of 455 members responded (response rate 19.8%). Forty-two (9.3%) have heard of a case of wrong-site sinus surgery occurring. Twenty-one cases were analyzed; of these, 10 (48%) implicated radiographic error, and the Universal Protocol was followed in one third. In seventeen reports (81%), there was disclosure to the family, one case with delayed disclosure; there was no disclosure in three cases. Sixty-one percent (n = 266) are concerned about operating on the wrong sinus or side. Forty-nine percent (n = 216) routinely use a checklist preoperatively. There is large variation in site marking for sinus surgery. Sixty-five percent (n = 282) routinely review the computed tomography scan prior to surgery. Conclusion Approximately 10 percent of survey respondents know of a case of wrong-site sinus surgery occurring; the majority of respondents are concerned about a wrong-sinus or wrong-sided surgery occurring in their practice. Otolaryngologists should be vigilant regarding the potential for inverted computed tomography images; there should be national efforts to address this latent systems defect. Surgeons should be trained in understanding the role of and engaging in disclosure and in other techniques that are of greatest support to the patient. Consideration of sinus-specific checklists should be led by the societies representing sinus surgeons.

The OPRL1 gene encodes the nociceptin/orphanin FQ receptor, which plays a role in regulating tolerance and behavioral responses to morphine. However, there is limited information on whether variants of OPRL1 are associated with vulnerability to develop opiate addiction. In this study, we examined five variants of OPRL1 and their role in determining vulnerability to develop opiate addiction.We recruited 447 individuals: 271 former severe heroin addicts and 176 healthy controls. Using a 5'-fluorogenic exonuclease assay, we genotyped individuals at five variants in OPRL1. It was then determined whether there was a significant association of allele, genotype, or haplotype frequency with vulnerability to develop opiate addiction.When the cohort was stratified by ethnicity, we found that, in Caucasians but not in African-Americans or Hispanics, the allele frequency of rs6090041 and rs6090043 were significantly associated point-wise with opiate addiction (P=0.03 and 0.04, respectively). Of the haplotypes formed by these two variants, one haplotype was found to be associated with protection from developing opiate addiction in both African-Americans (point-wise P=0.04) and Caucasians (point-wise P=0.04), and another haplotype with vulnerability to develop opiate addiction in Caucasians only (P=0.020).This study provides evidence for an association of two variants of the OPRL1 gene, rs6090041 and rs6090043, with vulnerability to develop opiate addiction, suggesting a role for nociceptin/orphanin FQ receptor in the development of opiate addiction.

Typically, the outcome of biologically engineered unit operations cannot be controlled a priori due to the incorporation of ad hoc design into complex natural systems. To mitigate this problem, synthetic biology presents a systematic approach to standardizing biological components for the purpose of increasing their programmability and robustness when assembled with the aim to achieve novel biological functions. A complex engineered biological system using only standardized biological components is yet to exist. Nevertheless, current attempts to create and to implement modular, standardized biological components pave the way for the future creation of highly predictable artificial biological systems. Although synthetic biology frameworks can be applied to any biological engineering endeavor, this article will focus on providing a brief overview of advances in the field and its recent utilization for the engineering of microbes.

Widespread concerns have been raised regarding the need to develop sustainable processes for the production of fuels from renewable resources. While bioethanol production processes have been studied and successfully developed at industrial scales, its inferior fuel properties (e.g., lower energy density and higher hygroscopicity) relative to higher chain alcohols have directed recent interest towards producing C3-C10 alcohols, a more challenging prospect than bioethanol production. Metabolic engineering enabled by systems biology and synthetic biology is an enabling technology in such efforts, and many research examples show great promise for addressing current issues, including engineering enzymes and pathway flux, enhancing cofactor and precursor availability, and improving hosts’ tolerance to toxic biofuel products. In this chapter, we discuss the challenges and research efforts towards engineering microbes for optimized production of alcohol-based biofuels, with an emphasis on C3-C10 alcohols produced via central metabolism. Section 1.1 begins with a general introduction and compares relevant properties of different fuels. Section 1.2 discusses two categories of alcohol-producing pathways in detail, including both fermentative (i.e., acetone-butanol-ethanol pathway called the ABE pathway) and non-fermentative (i.e., Ehrlich pathway linked with amino acid metabolism; and reverse β-oxidation pathway). In Section 1.3 , engineering strategies to improve higher alcohol production are reviewed, which include (1) enhancing the function of enzymes and pathways as well as cofactor and precursor availability, and (2) addressing product toxicity. Section 1.4 covers successes and challenges towards commercialization of higher alcohol-based biofuels, giving some examples of successful commercialization and current issues and topics such as product separation, host choice, and alternative feedstocks. Section 1.5 concludes this chapter with an outlook on the future of higher alcohol biofuel production.

Purpose The glutathione (GSH) antioxidant system has been shown to play an important role in the maintenance of good health and disease prevention. Various approaches have been used to enhance GSH availability including diet, nutritional supplementation, and drug administration, with minor to moderate success. Exercise training has evolved as a new approach. The purpose of this study was to investigate the effects of aerobic exercise training (AET), circuit weight training (CWT), and combined training (AET + CWT) on general adaptations, and resistance to acutely induced oxidative stress, as assessed by changes in the GSH antioxidant system. Methods Eighty healthy sedentary volunteers participated in the study who were randomly assigned to four groups: control (no exercise); AET, CWT, and AET + CWT. Exercise training programs were designed to simulate outpatient cardiac rehabilitation (40 min × 3 days × 6 weeks). Venous blood sampling was taken at rest and post maximal graded exercise test (GXT). A new improved spectrophotometric venous assay analysis technique was used. A mixed model repeated measures analysis of variance design was used with t-tests for preplanned comparisons evaluated at Bonferroni-adjusted α levels. Results Effectiveness of the exercise training programs was demonstrated by significant between-group (exercise group versus control) comparisons. AET, CWT, and AET + CWT showed significant pretraining-posttraining increases in resting GSH and glutathione-glutathione disulfide ratio (GSH:GSSG), and significant decreases in GSSG levels ( P Conclusion This study represents the first longitudinal investigation involving the effects of multiple modes of exercise training on the GSH antioxidant system with evidence, suggesting the GHS:GSSG ratio as the most sensitive change marker. The significant findings of this study have potential clinical implications to individuals involved in cardiac and pulmonary rehabilitation. Eur J Cardiovasc Prev Rehabil 14:630-637 © 2007 The European Society of Cardiology

This volume of the Advances in Agricultural Systems Modeling series presents 14 different case studies of model applications to help make the best use of limited water in agriculture. These examples show that models have tremendous potential and value in enhancing site-specific water management for different soils and climates, and evaluating cropping system sustainability over the longer term, when model results are integrated with the available field measurements in experimental studies. Here we summarize applications of 11 system models commonly reported in the literature for agricultural water management along with those presented in this volume. These 11 models vary greatly in simulating agricultural system components for water balance related processes (the differences in crop growth and N balance processes were even greater among models), which need to be kept in mind when reading about the applications of each model. A sensor-based automated irrigation scheduling system is presented. Finally, we summarize further needs for experimental data and model improvements to enhance future water management applications. Abbreviations: ABA, abscisic acid; AgMIP, Agricultural Model Inter-Comparison and Improvement Project; APEX, Agricultural Policy Environmental eXtender model; APSIM, Agricultural Production Systems Simulator; CGMS, Crop Growth Monitoring System; CSM, cropping system model; CWPF, crop water production function; DSS, decision support system; DSSAT, Decision Support System for Agrotechnology Transfer; EPIC, Environmental Policy-Integrated Climate; ET, evapotranspiration; IRT, infrared thermometer; NCP, North China Plain; PALMS, Precision Agricultural Landscape Modeling System; PSA, plant–soil–atmosphere; RZWQM2, Root Zone Water Quality Model; STICS, Simulateur mulTIdisciplinaire pour les Cultures Standard; SWAP, Soil Water Atmosphere Plant; TSEB, two-source energy balance; WOFOST, WOrld FOod STudies; WUE, water use efficiency. L.R. Ahuja (laj.ahuja@ars.usda.gov), Liwang Ma (Liwang.Ma@ars.usda.gov), S.A. Saseendran (Saseendran. anapalli@ars.usda.gov), USDA-ARS, Agricultural Systems Research Unit, 2150 Centre Ave., Bldg. D, Ste. 200 Fort Collins, CO 80526. *Corresponding author. Q.X. Fang, Agronomy College, Qingdao Agricultural University, Changcheng Rd. 700, Chengyang District, Qingdao, Shandong, China, 266108 (fangqx@igsnrr.ac.cn). Robert J. Lascano, USDA-ARS, Wind Erosion and Water Conservation Research Unit, Cropping Systems Research Laboratory, 3810 4th St., Lubbock, TX 79415 (robert.lascano@ars.usda.gov). David C. Nielsen, USDA-ARS, Central Plains Resources Management Research Unit, 40335 County Rd. GG, Akron, CO, 80720-0400 (david.nielsen@ars.usda.gov). Enli Wang, CSIRO Land and Water, Christian Laboratory, Clunies Ross St., Black Mountain ACT 2601, Australia (Enli.Wang@csiro.au). Paul D. Colaizzi, USDA-ARS, Conservation and Production Research Lab., P.O. Drawer 10, 2300 Experiment Station Rd., Bushland, TX 79012-0010 (Paul.Colaizzi@ars.usda.gov). doi:10.2134/advagricsystmodel5.c15 Published December 5, 2014

Substance use disorders have significant personal, familial, and societal consequences. Despite the serious consequences of substance use, only a few therapies are effective in treating substance use disorders, thus highlighting a need for improved treatment practices. Substance use treatment response depends on multiple factors such as genetic, biological, and social. It is essential that each component is represented in treatment plans. The dopaminergic system plays a critical role in pharmacotherapy for the addictions and an understanding of the role of variation of genes involved in this system is essential for its success. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines. A computerized literature search was conducted using PubMed and Scopus (all databases). Articles published up to April 2015 that examined the role of dopaminergic gene variation in the pharmacotherapy of alcohol, opioid, and cocaine substance use disorders were reviewed. Search terms were dopamine, gene, polymorphism, substance abuse, treatment, and response. Polymorphisms of the DRD2, ANKK1, DAT1, DBH, and DRD4 genes have been found to moderate the effects of the pharmacotherapy of alcohol, opioid, and cocaine substance use disorders. The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapy intervention for substance use disorders. More studies are needed to confirm and extend these findings.

To evaluate the effect of opioid receptor genes and dopamine system genes polymorphisms on treatment outcomes of opioid dependence with implantable and oral naltrexone.Authors carried out a randomized double-blind, double-dummy, placebo-controlled clinical trial. Three hundred and six patients with opioid dependence were randomized into 3 equal treatment groups. The first group received implantation of 1000 mg naltrexone every 2 months during 6 months + oral naltrexone placebo; the second group - placebo implant every 2 months + oral naltrexone (50mg/day) and the third group - placebo implant + oral naltrexone placebo. It was genotyped polymorphisms in the following genes: mu-opioid receptor (OPRM1), kappa-opioid receptor (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (DAT1).Regardless of treatment several polymorphisms of these genes were associated with high risk of relapse: an allele L (2R) DRD4 120bp (p=0.05; OR (95% CI)=3.3(1.1-10.1)); an allele С DRD2 NcoI (р=0,051; OR (95% CI)=2,86 (1,09-7,52)); the genotype 9.9 DAT VNTR 40bp (р=0,04; OR (95% CI)=1,4 (1,3-1,5)); on the contrary, (СС+СТ)-(ТТ)) variants of OPRK1-DRD2Ncol increased a chance to complete treatment program (р=0,004; OR (95% CI)=7.4 (1.8-30.4)), Kaplan-Meier survival analysis (р=0,016). The probability of completing treatment program by the carriers of these variants was higher in the oral naltrexone group (p=0.016), lower in the double placebo group (p=0.015), but did not influence on treatment outcomes in the naltrexone-implant group.Naltrexone-implant is a highly effective medication for treatment of opioid dependence and its effectiveness exceeds that of oral naltrexone and placebo. The study has shown the joint influence of opioid receptor genes and genes of dopaminergic system on treatment outcomes of opioid dependence. Genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.Цель исследования - выявить влияние полиморфных вариантов генов опиоидной и дофаминовой систем на эффективность противорецидивной терапии опийной наркомании имплантируемой и пероральной лекарственных форм налтрексона. Материал и методы. Было проведено двойное слепое рандомизированное плацебо-контролируемое исследование с двойной маскировкой. 306 больных опийной наркоманией были рандомизированы в 3 группы по 102 человека в каждой. Больным 1-й группы назначались имплант 1000 мг налтрексона (3 имплантации с интервалом 2 мес, всего на 6 мес) и таблетки плацебо, больным 2-й группы - плацебо-имплант и пероральный налтрексон (50 мг в сутки), больным 3-й группы - двойное плацебо (имплант и таблетки). Генотипирование больных проводили по следующим вариантам полиморфизма генов: опиоидных рецепторов типов мю (OPRM1) и каппа (OPRК1), фермента катехол-орто-метил-трансферазы (COMT), дофаминовых рецепторов 2 (DRD2) и 4 (DRD4) подтипов, фермента дофамин-бета-гидроксилазы (DBH), белка - трансмембранного переносчика дофамина (SLC6A3, DAT1). Результаты. Было установлено, что вне зависимости от вида противорецидивной терапии ряд полиморфных вариантов повышает риск рецидива зависимости: аллель L (2 повтора по 120 н.п.) DRD4120bp (р=0,05; OR (95% ДИ)=3,3(1,1-10,1)); аллель С DRD2NcoI (р=0,051; OR (95% ДИ)=2,86 (1,09-7,52)); генотип 9,9 DATVNTR40bp (р=0,04; RR (95% ДИ)=1,4(1,3-1,5)); напротив, варианты полиморфизма (СС+СТ)-(ТТ)) по сочетанию генов (OPRK1-DRD2Ncol) повышают вероятность завершения программы лечения (р=0,004; OR (95% ДИ)=7,4 (1,8-30,4)), анализ выживаемости Каплана-Мейера (р=0,016). В группе перорального налтрексона носители этих же вариантов (OPRK1-DRD2Ncol) имели более высокую вероятность завершения программы лечения (р=0,016), однако эффект был обратным в группе двойного плацебо (р=0,015) и не проявлялся вообще в группе с имплантом налтрексона (р=0,33). Заключение. Имплант налтрексона является высокоэффективным препаратом для лечения опийной наркомании, превосходящим по эффективности пероральный налтрексон и плацебо-имплант. По результатам генотипирования вероятно выявление потенциальных респондеров при терапии пациентов, что может повысить эффективность лечения.

Drug addiction is a serious disease with damaging effects on the brain and physical health. Despite the increase in the number of affected individuals, there are few effective pharmacological treatment options for substance use disorders. The study of the influence of an individual's genetic features on the treatment response may help to identify more efficacious treatment options. This systematic review focuses on the serotonergic system because of its relevant role in mood and impulse control disorders, and its contribution to the development and maintenance of drug use disorders. In particular, we examine the role of serotonergic genes in the response to pharmacotherapy for alcohol, cocaine and nicotine addiction. Current evidence suggests that genetic variability of the serotonergic biosynthesis enzyme tryptophan hydroxylase 2 (TPH2) and the serotonin transporter (SLC6A4) genes mediates the efficacy of several addiction treatments, such as ondansetron and disulfiram, and the antidepressants bupropion, nortriptyline and sertraline.

There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability.Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated.SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level.These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.