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Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies with response to treatment based on individual genetic makeup. In this chapter, we will discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The continued elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.

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.

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.

The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP).Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines.In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response.These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

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 Linking human genetics and brain imaging data is extremely challenging, among other reasons because both fields suffer from multiple comparison problems. New method ProcessGeneLists (PGL) links genetics and human brain imaging by using genes associated with a disease and calculating a normalized mRNA expression average of those genes in each brain region. Brain regions in which those genes are most co-expressed become regions of interest (ROIs) to perform brain imaging in participants with and without the disease, decreasing multiple comparisons. Once a region is identified as “imaging-relevant”, the genes most responsible for that ROI being highlighted can be genotyped in the imaged sample. This allows to re-analyze imaging data under the light of likely relevant genetics, to study possible brain imaging/gene variant interactions. Results As proof-of-concept, we created two lists of genes expressed in the habenula and the striatum, to verified that PGL would highlight those regions. Next, we used a list of genes likely important in alcohol abuse from the literature, which identified several brain regions previously associated with alcohol abuse such as the striatum, habenula, and hippocampus. Comparison with existing methods To our knowledge there is no current method to obtain brain regions of interest from genetics data. Conclusions Genetics typically asks “which genes are associated with a disease?” while human brain imaging typically asks “which brain regions are associated with a disease?” PGL asks “which genes, via modulation within specific brain regions, are found to be associated with a disease?”.

Eleven triatomine species, the vector for Chagas disease, are endemic in the southern U.S. While traditionally thought to only occur in rural habitats and sylvatic transmission cycles, recent studies provide compounding evidence that triatomines could exist in urban habitats and domestic transmission cycles in Texas. We conducted a study of active and passive surveillance techniques over 3 years (2016-2018) in the City of Houston, Harris County, Texas to determine the presence of triatomines in this metroplex. Active surveillance methods uncovered Triatoma sanguisuga nymphs from two locations in downtown Houston city parks. We also documented the first Trypanosoma cruzi positive kissing bug collected in an urban environment of Harris County, Texas. Our findings provide evidence that triatomines can be found in heavily populated U.S. urban environments, and warrant public health support for expanded triatomine and Chagas disease surveillance in city settings.

Epigenetic processes regulate gene expression independent of the DNA sequence and are increasingly being investigated as contributors to the development of behavioral disorders. Environmental insults, such as stress, diet, or toxin exposure, can affect epigenetic mechanisms, including chromatin remodeling, DNA methylation, and non-coding RNAs that, in turn, alter the organism's phenotype. In this review, we examine the literature, derived at both the preclinical (animal) and clinical (human) levels, on epigenetic alterations associated with anxiety disorders. Using animal models of anxiety, researchers have identified epigenetic changes in several limbic and cortical brain regions known to be involved in stress and emotion responses. Environmental manipulations have been imposed prior to conception, during prenatal or early postnatal periods, and at juvenile and adult ages. Time of perturbation differentially affects the epigenome and many changes are brain region-specific. Although some sex-dependent effects are reported in animal studies, more research employing both sexes is needed particularly given that females exhibit a disproportionate number of anxiety disorders. The human literature is in its infancy but does reveal some epigenetic associations with anxiety behaviors and disorders. In particular, effects in monoaminergic systems are seen in line with evidence from etiological and treatment research. Further, there is evidence that epigenetic changes may be inherited to affect subsequent generations. We speculate on how epigenetic processes may interact with genetic contributions to inform prevention and treatment strategies for those who are at risk for or have anxiety disorders.

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.

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.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).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 .05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele.These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration. (Am J Addict 2018;27:567-573).

Neuroimaging and genetic studies provide distinct and complementary information about the structural and biological aspects of a disease. Integrating the two sources of data facilitates the investigation of the links between genetic variability and brain mechanisms among different individuals for various medical disorders. This article presents a general statistical framework for integrative Bayesian analysis of neuroimaging-genetic (iBANG) data, which is motivated by a neuroimaging-genetic study in cocaine dependence. Statistical inference necessitated the integration of spatially dependent voxel-level measurements with various patient-level genetic and demographic characteristics under an appropriate probability model to account for the multiple inherent sources of variation. Our framework uses Bayesian model averaging to integrate genetic information into the analysis of voxel-wise neuroimaging data, accounting for spatial correlations in the voxels. Using multiplicity controls based on the false discovery rate, we delineate voxels associated with genetic and demographic features that may impact diffusion as measured by fractional anisotropy (FA) obtained from DTI images. We demonstrate the benefits of accounting for model uncertainties in both model fit and prediction. Our results suggest that cocaine consumption is associated with FA reduction in most white matter regions of interest in the brain. Additionally, gene polymorphisms associated with GABAergic, serotonergic and dopaminergic neurotransmitters and receptors were associated with FA.

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.

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.

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.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.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.We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use.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).

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).

Background Four of the most consistently replicated variants associated with mood disorder occur in genes important for synaptic function: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and DGKH (rs1170191). Aims The present study examined associations between these candidates, mood disorder diagnoses, cognition, and fronto-limbic regions implicated in affect regulation. Methods and materials Participants included 128 individuals with bipolar disorder (33% male, Mean age = 38.5), 48 with major depressive disorder (29% male, Mean age = 40.4), and 149 healthy controls (35% male, Mean age = 36.5). Genotypes were determined by 5′-fluorogenic exonuclease assays (TaqMan®). Fronto-limbic volumes were obtained from high resolution brain images using Freesurfer. Chi-square analyses, bivariate correlations, and mediational models examined relationships between genetic variants, mood diagnoses, cognitive measures, and brain volumes. Results Carriers of the minor BDNF and ANK3 alleles showed nonsignificant trends toward protective association in controls relative to mood disorder patients (P = 0.047). CACNA1C minor allele carriers had larger bilateral caudate, insula, globus pallidus, frontal pole, and nucleus accumbens volumes (smallest r = 0.13, P = 0.043), and increased IQ (r = 0.18, P

Evidence indicates that individuals with the 5-HTTLPR variant short/short genotype have increased sensitivity to both positive and negative perceptions of perceived social support. The aim of this study was to evaluate this association among Veterans in the context of mild traumatic brain injury (TBI). As part of a larger TBI center, we performed a cross-sectional study of 67 OEF/OIF/OND Veterans (41 with TBI and 26 controls without TBI) who completed the questionnaires and consented to genetic testing. The primary measures included the Connor-Davidson Resilience Scale (CDRISC) and the Perceived Limitations in community participation subscale of the Community Reintegration of Service Members Instrument (CRIS-PL). Both 5-HTTLPR genotype and TBI status were independently associated with the CRIS-PL (p = .009 for genotype, p = .001 for TBI) and the CDRISC (p = .015 for genotype, p = .003 for TBI) scores. This study suggests that both the 5-HTTLPR genotype and TBI status independently, in an almost equal but opposite direction, influence resilience and perceived limitations to social participation. Further, resilience appears more sensitive to perceived limitations in Veterans carrying an S′S′ genotype than in L′ carriers, but only in the context of having sustained a TBI. While having a TBI appeared to increase a Veteran's sensitivity to social stress, the Veteran's who were L′ allele carriers with a TBI fared the worst, with lower resilience and more perceived limitations for community participation compared to L′ carrier Veterans without a TBI or Veterans with the S′S′ genotype regardless of TBI status.

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

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.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 .003 and point-wise level of α .05. SNP associations in a combined cohort of n = 199 pairs (replication cohort plus 86 pairs previously reported), were also examined.In the replication cohort, mothers with the COMT rs4680 G allele had infants with a reduced risk for treatment with two medications for NAS (adjusted OR = .5, p = .04), meeting point-wise significance. In the combined cohort, infants with the PNOC rs4732636 A allele had a reduced need for medication treatment (adjusted OR 2.0, p = .04); mothers with the PNOC rs351776 A allele had infants who were treated more often with two medications (adjusted OR 2.3, p = .004) with longer hospitalization by 3.3 days (p = .01). Mothers with the COMT rs740603 A allele had infants who were less often treated with any medication (adjusted OR .5, p = .02). Though all SNP associations all met point wise and clinical significance, they did not meet the experiment-wise significance threshold.We found differences in NAS outcomes depending on PNOC and COMT SNP genotype. This has important implications for identifying infants at risk for severe NAS who could benefit from tailored treatment regimens. Further testing in a larger sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants with NAS. (Am J Addict 2017;26:42-49).

Background Opioid addiction, whether to opiates such as heroin and morphine, and/or to non-medical use of opioids, is a major problem worldwide. Although drug-induced and environmental factors are essential for the liability to develop opioid addiction, the genetic background of an individual is now known also to play a substantial role. Methods The overall goal of this article is to address the common and specific liabilities to addiction in the context of approaches to studies of one addiction, opioid addiction. Literature on identifying genetic variants that may play a role in the development of opioid addiction was reviewed. Results A substantial number of genetic variants have been reported to be associated with opioid addiction. No single variant has been found in any of the reported GWAS studies with a substantial effect size on the liability to develop heroin addiction. It appears that there is a complex interaction of a large number of variants, some rare, some common, which interact with the environment and in response to specific drugs of abuse to increase the liability of developing opioid addiction. Conclusions In spite of the inherent difficulties in obtaining large well-phenotyped cohorts for genetic studies, new findings have been reported that are being used to develop testable hypotheses into the biological basis of opioid addiction.

Dynorphins, the endogenous ligands for the κ opioid receptor, are implicated in neuropsychiatric disorders through modulation of basal and stimuli-induced dopaminergic, glutamatergic, and serotonergic tones. Expression of the prodynorphin gene (PDYN) is critical for rewarding properties of drugs of abuse and stress-induced responses. Epigenetic factors, such as DNA methylation, play an important role in modulation of gene expression.We analyzed DNA methylation patterns of three CpG-rich regions of PDYN, a CpG island, and cluster A in the proximal promoter, and cluster B in coding exon 4, by bisulfite sequencing of DNA from the caudate and anterior cingulate cortex from post-mortem brain of 35 individuals (22 HIV seropositive), and in peripheral blood mononuclear cells from 21 of these individuals.We found remarkably similar patterns of methylation across CpG sites in these tissues. However, there were tissue-specific differences in methylation levels (P=0.000001) of the CpG island: higher levels in peripheral blood mononuclear cells (82%) than in the brain tissues, the caudate (62%), and the anterior cingulate cortex (44%). But there was higher PDYN expression in the caudate than in the anterior cingulate cortex. In contrast, cluster A near the transcription start site is hypomethylated.This DNA methylation profile of the PDYN gene is typical for primary responsive genes with regulatory elements for both basal and tissue-specific transcription. Our findings provide a rationale for further studies of the role of other epigenetic factors in the regulation of PDYN expression in individuals with psychiatric and neurological disorders.

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.

OBJECTIVES We have used genome-wide association studies to identify variants that are associated with vulnerability to develop heroin addiction. METHODS DNA from 325 methadone stabilized, former severe heroin addicts and 250 control individuals were pooled by ethnicity (Caucasian and African-American) and analyzed using the Affymetrix GeneChip Mapping 100 K Set. Genome-wide association tests were conducted. RESULTS The strongest association with vulnerability to develop heroin addiction, with experiment-wise significance (P=0.035), was found in Caucasians with the variant rs10494334, a variant in an unannotated region of the genome (1q23.3). In African Americans, the variant most significantly associated with the heroin addiction vulnerability was rs950302, found in the cytosolic dual specificity phosphatase 27 gene DUSP27 (point-wise P=0.0079). Furthermore, analysis of the top 500 variants with the most significant associations (point-wise P< or =0.0036) in Caucasians showed that three of these variants are clustered in the regulating synaptic membrane exocytosis protein 2 gene RIMS2. Of the top 500 variants in African-Americans (point-wise P< or =0.0238), three variants are in the cardiomyopathy associated 3 gene CMYA3. CONCLUSION This study identifies new genes and variants that may increase an individual's vulnerability to develop heroin addiction.

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.

The μ-opioid receptor is the site of action of many endogenous opioids as well as opiates. We hypothesize that differences in DNA methylation of specific CpG dinucleotides between former severe heroin addicts in methadone maintenance treatment and control subjects will depend, in part, upon ethnicity. DNA methylation analysis of the μ-opioid receptor gene (OPRM1) promoter region was performed on African-Americans (118 cases, 80 controls) and Hispanics (142 cases, 61 controls) and these were compared with a similar Caucasian cohort from our earlier study. In controls, a higher methylation level was found in the African-Americans compared with the Hispanics or Caucasians. Significant experiment-wise differences in methylation levels were found at the −25 and +12 CpG sites in the controls among the three ethnicities. The overall methylation level of the CpG sites were significantly higher in the former heroin addicts when compared with the controls (point-wise P = 0.0457). However, in the African-Americans, the degree of methylation was significantly decreased experiment-wise in the former heroin addicts at the +12 CpG site (P = 0.0032, Bonferroni corrected general estimating equations). In Hispanics, the degree of methylation was increased in the former heroin addicts at the −25 (P < 0.001, experiment-wise), −14 (P = 0.001, experiment-wise), and +27 (P < 0.001, experiment-wise) CpG sites. These changes in methylation of the OPRM1 promoter region may lead to altered expression of the μ-opioid receptor gene in the lymphocytes of former heroin addicts who are stabilized in methadone maintenance treatment.

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction, by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in non-coding regions of the genes encoding the mu (OPRM1; rs510769, rs3778151), kappa (OPRK1; rs6473797), and delta opioid receptors, (OPRD1; rs2236861, rs2236857 and rs3766951), the neuropeptide galanin (GAL; rs694066), the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multi-locus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction that is worthy of future study.

The mu-opioid receptor is the site of action of opiates and opioids. We examined whether there are differences in cytosine:guanine (CpG) dinucleotide methylation in the OPRM1 promoter between former heroin addicts and controls. We analyzed methylation at 16 CpG dinucleotides in DNA obtained from lymphocytes of 194 Caucasian former severe heroin addicts stabilized in methadone maintenance treatment and 135 Caucasian control subjects. Direct sequencing of bisulfite-treated DNA showed that the percent methylation at two CpG sites was significantly associated with heroin addiction. The level of methylation at the -18 CpG site was 25.4% in the stabilized methadone-maintained former heroin addicts and 21.4% in controls (p=0.0035, generalized estimating equations (GEE); p=0.0077, t-test; false discovery rate (FDR)=0.048), and the level of methylation at the +84 CpG dinucleotide site was 7.4% in cases and 5.6% in controls (p=0.0095, GEE; p=0.0067, t-test; FDR=0.080). Both the -18 and the +84 CpG sites are located in potential Sp1 transcription factor-binding sites. Methylation of these CpG sites may lead to reduced OPRM1 expression in the lymphocytes of these former heroin addicts.

The tryptophan hydroxylase 2 gene (TPH2) was resequenced at the 5′ upstream, coding, and 3′ downstream regions, including all 11 exons in 185 subjects. Twenty-three novel and 14 known variants were identified. In a cohort of 583 consecutively ascertained subjects, including normal volunteers and those with specific addictive diseases, six common TPH2 and one TPH1 variant were genotyped. Allele frequencies of three TPH2 variants and the TPH1 variant varied significantly among the four ethnic groups within the control subjects. Of these subjects, 385 who met heroin addiction or control criteria and were of Caucasian, African-American, or Hispanic ethnicity were examined for potential association with vulnerability to develop heroin addiction. At the two locus genotype level in Hispanics, the TPH1 rs1799913 variant was found to significantly interact with the TPH2 rs7963720 variant and heroin addiction (P = 0.022), and with the TPH2 rs4290270 variant and heroin addiction (P = 0.011). In the African-American group, a significant association of a specific TPH2 haplotype with heroin addiction also was found (SNPHAP, P = 0.004; PHASE P = 0.036).

Background and Purpose During the aging process, older adults may experience a loss of strength and power, which then may lead to functional limitations and disability. The purpose of this study was to examine how impairments in lower-extremity strength and power are related to functional limitations and disability in community-dwelling older adults. Subjects Thirty older adults (age [X̅±SD], 77.3±7.0 years; 25 women and 5 men) with mild to moderate functional limitations participated in this study. Methods Lower-extremity strength, peak power, power at a low relative intensity, and power at a high relative intensity were measured with a pneumatic resistance leg press. Functional limitations and disability were assessed with the Short Physical Performance Battery (SPPB), the Six-Minute Walk Test (SMWT), and the Late Life Function and Disability Instrument (LLFDI). Results All measures of strength and power were related to functional limitations. Peak power demonstrated the strongest relationships with SMWT, the SPPB gait speed subscale, and the LLFDI functional limitation component. Power at a high relative intensity demonstrated the strongest relationships to the SPPB total score and the SPPB sit-to-stand subscale score. All measures of strength and power were indirectly related to the LLFDI disability component. Discussion and Conclusion Older adults should focus on increasing and maintaining lower-extremity strength and power across a range of intensities in order to decrease functional limitations and disability.

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

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.

Previous studies investigated the impact of brain-derived neurotrophic factor (BDNF) val66met (rs6265) on hippocampus volumes and neurocognition in bipolar disorders (BD), but the results were not consistent. This study aimed to investigate the effect of BDNF polymorphism on hippocampus volumes and memory performance in well-characterized adult populations diagnosed with type I BD (BD-I) and major depressive disorder (MDD) compared with healthy controls (HC).48 BD-I patients, 33 MDD patients and 60 HC were genotyped for BDNF rs6265 using DNA isolated from white blood cells. Individuals with val/met and met/met genotypes were grouped as met carriers and compared to those with the val/val. Brain segmentations were obtained from structural magnetic resonance imaging (MRI) using the Freesurfer. Memory performance was assessed with the California Verbal Learning Task (CVLT).We found a significant diagnosis effect and marginal interaction between diagnosis and BDNF genotype group for both hippocampus volumes and memory performance. BDNF met allele carrier BD patients had smaller hippocampus volumes and reduced performance on multiple CVLT scores compared to MDD patients and HC.We provide strong evidence for the BDNF val66met polymorphism as a putative biological signature for the neuroanatomical and cognitive abnormalities commonly observed in BD patients.

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.

Hsu MJ, Nielsen DH, Lin-Chan SJ, Shurr D. The effects of prosthetic foot design on physiologic measurements, self-selected walking velocity, and physical activity in people with transtibial amputation. Objective To investigate the physiologic differences during multispeed treadmill walking and physical activity profiles for the Otto Bock C-Walk foot (C-Walk), Flex-Foot, and solid ankle cushion heel (SACH) foot in people with transtibial amputation. Design A repeated-measures design with 3 prostheses. Setting Research laboratory. Participants Eight men with unilateral transtibial amputation. Interventions Not applicable. Main Outcome Measures Physiologic responses (energy expenditure, gait efficiency, exercise intensity, rating of perceived exertion [RPE]) during multispeed treadmill walking (53.64, 67.05, 80.46, 93.87, 107.28m/min) test were analyzed with 2-way repeated-measures analysis of variance (ANOVA). One-way ANOVA was employed to analyze foot-type differences for self-selected walking velocity (SSWV), and steps per day (daily activity). Analysis of covariance was used to analyze foot-type differences with SSWV as the covariable for the physiologic measurements. Results The C-Walk had a trend of improved physiologic responses compared with the SACH; however, no foot-type differences were statistically significant. Compared with the C-Walk and SACH, the Flex-Foot showed no significant differences in energy expenditure and gait efficiency, but significantly lower percentage of age-predicted maximum heart rate and RPE values. Conclusions The energy storing-releasing feet appeared to have certain trends of improved gait performance compared with the SACH; however, not many objective foot-type differences were significantly noted. Further studies with a larger sample size are suggested.

In February 2013, the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) released its list of 5 recommendations of diagnostic and therapeutic interventions that physicians and patients should question, as part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely campaign. This commentary outlines the impetus for the AAO-HNSF to join the campaign, our list of 5 recommendations, how they were developed, and our future involvement with the campaign. The AAO-HNSF's 5 recommendations are (1) don't order a computed tomography (CT) scan of the head/brain for sudden hearing loss, (2) don't prescribe oral antibiotics for uncomplicated acute tympanostomy tube otorrhea, (3) don't prescribe oral antibiotics for uncomplicated acute external otitis, (4) don't routinely obtain radiographic imaging for patients who meet diagnostic criteria for uncomplicated acute rhinosinusitis, and (5) don't obtain CT or magnetic resonance imaging in patients with a primary complaint of hoarseness prior to examining the larynx.

In 2011, the US federal government implemented an oversight program to encourage the adoption and meaningful use of electronic health records (EHRs). Otolaryngologists may receive as much as $44,000 under Medicare or $63,750 under Medicaid as part of this law. To receive this full benefit, otolaryngologists must acquire a certified EHR and demonstrate stage 1 meaningful use requirements by the end of 2012. Furthermore, the Office of the National Coordinator for Health IT intends to advance meaningful use requirements to stage 2 (estimated to go in effect in 2014) and stage 3 requirements. This commentary discusses updated recommendations from the Academy of Otolaryngology-Head and Neck Surgery Medical Informatics Committee for implementing meaningful use of EHRs, receiving incentive payments, and preparing for potential stage 2 and stage 3 requirements.