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America's opioid epidemic has spawned an epidemic of neonatal abstinence syndrome (NAS). Studies have not tested approaches to promoting contraceptive services for women with opioid use disorder (OUD) along with treatment for this disorder. This pilot study examined the promotion of medication for OUD (MOUD) treatment and contraception use, primarily long-acting reversible contraception (LARC), for women with OUD.In Appalachia, a peer-delivered contraception and MOUD promotion intervention was delivered to a sample of 30 women with OUD. Primary outcomes were attendance of initial appointments to receive MOUD and counseling about contraceptive options. Peer recovery coaches also offered to help the women schedule appointments and attend the appointment with them or give them a ride if necessary and requested by the patients.Two-thirds experienced all seven symptoms of opioid dependence. Within 30 days of a brief counseling session, over one-half of the women (56.7%) were referred to MOUD, with all of them initiating treatment within 30 days. Just under one-half of the women (46.7%) were referred to a contraception consultation, with 85.7% of those receiving a LARC implant.Study findings indicate the potential efficacy of a single-session, peer-delivered counseling intervention for linking women with OUD and at high risk of unintended pregnancy to MOUD and to services that provide women with highly reliable contraceptives.This study is unique in exploring the efficacy of linking high-risk opioid-using women to contraceptive options and treatment for MOUD to prevent NAS.

Prior studies have shown communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study. Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech-language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10-question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized. The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment-based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive-communication impairment predict the existence of and/or direction of a discrepancy.

Objective:To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA).Method:Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale – Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy).Results:The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains.Conclusion:The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.

INTRODUCTION: Frontotemporal-dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. METHODS: Using a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995–2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. RESULTS: We identified 35 FTDs cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI 1.3, 4.5); we observed an increased trend over time (B= 0.83, 95% CI 0.54, 1.11, P

Background and aims Opioid agonist therapies (OATs) are highly effective treatments for opioid use disorders (OUDs), especially for pregnant women; thus, improving access to OAT is an urgent public policy goal. Our objective was to determine if insurance and pregnancy status were barriers to obtaining access to OAT in 4 Appalachian states disproportionately impacted by the opioid epidemic. Methods Between April and May 2017, we conducted phone surveys of OAT providers, opioid treatment programs (OTPs), and outpatient buprenorphine providers, in Kentucky, North Carolina, Tennessee, and West Virginia. Survey response rates were 59%. Logistic models for dichotomous outcomes (e.g., patient acceptance) and negative binomial models were created for count variables (e.g., wait time), overall and for pregnant women. Results The majority of OAT providers were accepting new patients; however, providers were less likely to treat pregnant women (91% vs. 75%; p Conclusions We found that OAT providers frequently did not accept any insurance and frequently did not treat pregnant women in an area of the country disproportionately affected by the opioid epidemic. Policymakers could prioritize improvements in provider training (e.g., training of obstetricians to become buprenorphine prescribers) as a means to enhance access to pregnant women or enhancing reimbursement rates as a means of improving insurance acceptance for OAT.

Background Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. Objective To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). Methods Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. Results Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. Conclusion Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

Background Lofexidine is an alpha-2-adrenergic receptor agonist approved in the United Kingdom (UK) for the treatment of opioid withdrawal symptoms. Lofexidine has demonstrated better efficacy than placebo for reducing opioid withdrawal symptoms in patients undergoing opioid withdrawal with less reported hypotension than clonidine. Methods Designed as an FDA registration trial, this 8-day, randomized, double-blind, placebo-controlled, parallel-group study in 264 patients dependent on short-acting opioids evaluated the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid withdrawal. The primary efficacy measures were SOWS-Gossop on Day 3 and time-to-dropout. Secondary endpoints included the proportion of participants who were completers; area under the 5-day SOWS-Gossop – time curve (i.e., AUC 1–5 ), and daily mean SOWS-Gossop, OOWS‐Handelsman, MCGI (subject and rater), and VAS-E scores. Participants received lofexidine HCl 3.2 mg daily in four divided doses or matching placebo on Days 1–5, followed by 2 days of placebo. Results Lofexidine significantly decreased mean Day 3 SOWS scores compared to placebo, 6.32 versus 8.67, respectively, p = 0.0212. Fewer lofexidine patients were early terminators compared to placebo (59 versus 80, respectively); and non-completers in the lofexidine group remained in the study longer than those assigned to placebo (p = 0.0034). Secondary endpoints consistently favored lofexidine. Lofexidine was well tolerated in this trial. Conclusion Lofexidine significantly decreased SOWS scores compared to placebo and demonstrated better retention rates in participants undergoing opioid withdrawal. Lofexidine potentially offers a useful non-opioid alternative to treat opioid withdrawal symptoms.

Introduction Little is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD). Methods Regional tau and β-amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model. Results Age was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β-amyloid differed little by age. Age showed a stronger association with tau than volume and β-amyloid in all cortical regions. Age was not associated with cognitive performance. Discussion Age is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.

Background Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA). Objective This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles. Methods We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses. Results We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups. Conclusions LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.

Methadone and buprenorphine are highly effective and commonly prescribed for the treatment of opioid use disorder. Both medications are also efficacious for the treatment of pregnant women with this disorder. In one third of states, however, Medicaid reimbursement will cover the cost of buprenorphine, but not methadone, to treat opioid use disorder in pregnant women. This commentary will explore the clinical and policy rational and consequences of this policy, with the opinion that this approach is guided by political expediency rather than sound clinical research. The commentary will focus on the pharmacological management of prescription opioid dependence during pregnancy in Tennessee, one of the states that restrict Medicaid coverage of pregnant women to buprenorphine. Tennessee is also relevant in that this state ranks second nationally in the rate of prescriptions written for opioid pain relievers; in contrast to injection opioid use in urban populations, opioid addiction in rural and southeastern regions of the US is characterized by use of non-injection prescription opioids. Until recently, most research-based recommendations for the management of opioid use disorder during pregnancy have derived from studies of women using opioids intravenously. The lack of research in non-injection opioid-using pregnant women may partially explain why policy rather than scientific evidence guides Medicaid reimbursement. It is hoped that future research in pregnant women addicted to prescription opioids will clarify which opioid addicted pregnant women have better outcomes with buprenorphine or methadone treatment and these findings, in turn, will inform Medicaid reimbursement.

Background Methadone and buprenorphine are recommended to treat opioid use disorders during pregnancy. However, the literature on the relationship between longer-term effects of prenatal exposure to these medications and childhood development is both spare and inconsistent. Methods Participants were 96 children and their mothers who participated in MOTHER, a randomized controlled trial of opioid-agonist pharmacotherapy during pregnancy. The present study examined child growth parameters, cognition, language abilities, sensory processing, and temperament from 0 to 36 months of the child’s life. Maternal perceptions of parenting stress, home environment, and addiction severity were also examined. Results Tests of mean differences between children prenatally exposed to methadone vs. buprenorphine over the three-year period yielded 2/37 significant findings for children. Similarly, tests of mean differences between children treated for NAS relative to those not treated for NAS yielded 1/37 significant finding. Changes over time occurred for 27/37 child outcomes including expected child increases in weight, head and height, and overall gains in cognitive development, language abilities, sensory processing, and temperament. For mothers, significant changes over time in parenting stress (9/17 scales) suggested increasing difficulties with their children, notably seen in increasing parenting stress, but also an increasingly enriched home environment (4/7 scales) Conclusions Findings strongly suggest no deleterious effects of buprenorphine relative to methadone or of treatment for NAS severity relative to not-treated for NAS on growth, cognitive development, language abilities, sensory processing, and temperament. Moreover, findings suggest that prenatal opioid agonist exposure is not deleterious to normal physical and mental development.

We compared fitness-for-duty assessment findings of physicians who subsequently engaged in suicidal behavior and those who did not.Assessments of 141 physicians evaluated at the Vanderbilt Comprehensive Assessment Program were retrospectively compared between those who later either attempted (n = 2) or completed (n = 5) suicide versus the remainder of the sample.Subsequent suicidal behaviors were associated with being found unfit to practice (86% vs. 31%, P.05), being in solo practice (71% vs. 33%) and chronically using benzodiazepines (57% vs. 11%, Fisher's Exact Test, P.05).Being found unfit for practice may trigger a cascade of adverse social and financial consequences. Those engaged in solo practice may be particularly vulnerable due to isolation and lack of oversight by supportive colleagues. Finally, chronic benzodiazepine use may impair resilience due to associated brain dysfunction. Although these characteristics must be investigated prospectively, our observations suggest that they may be important signals of increased risk for suicidal behavior in physicians. The intense stress associated with medical practice and the relatively high rates of suicidal behavior among physicians make it important to be able to identify physicians who are at risk, so that appropriate preventive actions can be taken.

Background and Objectives Despite the dramatic increase in the use of buprenorphine for the treatment of opioid dependence, clinical outcomes of this treatment approach continue to need evaluation. This study examines factors associated with relapse and retention during buprenorphine treatment in a sample of opioid dependent outpatients. Methods In a retrospective chart review of 62 patients with opioid dependence, relapse was determined by self-report, urine toxicology screens, and by checking the state controlled substance monitoring database. Data was analyzed using two-way tests of association and logistic regression. Results Patients with comorbid anxiety disorders, active benzodiazepine use (contrary to clinic policy), or active alcohol abuse, were significantly more likely to relapse. Patients who relapsed were also more likely to be on a higher buprenorphine maintenance dose. Conclusion This study identifies relapse risk factors during buprenorphine treatment for opioid dependence. Future research is needed to determine whether modifying these factors may lead to improved treatment outcomes. (Am J Addict 2014;23:62–67)

Background and Objectives: How best to measure the occurrence of adverse events during a randomized clinical trial is an issue that has not been adequately examined in the research literature. Focus of this study was on the examination of the relative frequency of occurrence of adverse events directly recorded during the conduct of the trial compared to an indirect determination of adverse events derived from data collected as part of the trial. Methods: A secondary analysis of nonserious adverse events that occurred in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study was undertaken. MOTHER was a randomized clinical trial of methadone versus buprenorphine in 175 opioid-dependent pregnant women. Results: The two methods of recording adverse events failed to agree on where differences in the frequency of occurrence of adverse events between the medication conditions might exist. Moreover, indirect assessment indicated all participants had experienced at least one adverse event, yet indirect coverage of adverse events was incomplete. Conclusions: Findings suggest indirect examination of occurrence of adverse events should be cautiously undertaken, because indirect assessment of adverse events makes no distinction between what might be simply typical variation in behavior rather than systematic changes in behavior attributable to study condition, and lacks coverage of the full spectrum of adverse events. Scientific Significance: Contemporaneous direct measurement of adverse events likely yield reasonably valid estimates of the rate of occurrence of the adverse events, while indirect measu-rement of adverse events may not be sufficiently reliable. (Am J Addict 2012;21:S1–S4)

Aims This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk and longer-term developmental effects. Methods Within each outcome area, findings are summarized first for the three randomized clinical trials and then for the 44 non-randomized studies (i.e. prospective studies, case reports and series and retrospective chart reviews), only 28 of which involve independent samples. Results Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiological suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. Conclusions While buprenorphine produces a less severe neonatal abstinence syndrome than methadone, both methadone and buprenorphine are important parts of a complete comprehensive treatment approach for opioid-dependent pregnant women.

Aim To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. Design A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. Setting Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. Participants Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. Measurements Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. Findings Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps

Aims To examine the relationship of anxiety and depression symptoms with treatment outcomes (treatment discontinuation, rates of ongoing use of illicit drugs and likelihood of preterm delivery) in opioid-dependent pregnant women and describe their use of psychotropic medications. Design and setting Secondary data analysis from a randomized clinical trial of treatment for opioid dependence during pregnancy. Participants A total of 175 opioid-dependent pregnant women, of whom 131 completed treatment. Measurements Symptoms of anxiety and depression were captured with the 15-item Mini International Neuropsychiatric Interview (MINI) screen. Use of illicit drugs was measured by urine drug screening. Preterm delivery was defined as delivery prior to 37 weeks' gestation. Self-reported use of concomitant psychotropic medication at any point during the study was recorded. Findings Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment [adjusted odds ratio (OR) = 4.56, 95% confidence interval (CI): 1.91–13.26, P = 0.012], while those reporting only depression symptoms were less likely to discontinue treatment (adjusted OR = 0.14, 95% CI: 0.20–0.88, P = 0.036) compared to women who reported neither depression nor anxiety symptoms. No statistically significant between-group differences were observed for ongoing illicit drug use or preterm delivery. A majority (61.4%) of women reported use of concomitant psychotropic medication at some point during study participation. Conclusions Opioid agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation.

Aims To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine- exposed infants. Design, setting and participants Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined. Measurements For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (metha- done = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition. Findings Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine- exposedinfants(36versus59hourspostnatal,respectively).Conclusions Theprofileof neonatalabstinencesyndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome.

Aims To characterize infections and compare obstetric outcomes in opioid-dependent pregnant women who participated in a randomized clinical trial comparing agonist medications, methadone and buprenorphine. Design Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites. Setting Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women. Participants Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. Measurements Obstetric, infectious and other maternal medical complications captured by medical records, physical examination, blood tests and self-report. Neonatal medical complications captured by medical records. Findings Hepatitis C was the most common infection (32.3%), followed by hepatitis B (7.6%) and chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetric complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions. Conclusions Buprenorphine appears to have an acceptable safety profile for use during pregnancy.

Aims The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current—and single most comprehensive—research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine. Methods The MOTHER study design is outlined, and its basic features are presented. Conclusions At least seven important lessons have been learned from the MOTHER study: (i) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (ii) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment, patient populations and hospital practices that, in turn, differentially impact recruitment rates, treatment compliance and attrition; (iii) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (iv) staff turnover needs to be addressed with a proactive focus on both hiring and training; (v) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (vi) timely tracking of data in a multi-site trial is both demanding and unforgiving; and (vii) complex multi-site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results.

Aim To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. Design and Setting Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters. Participants A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. Measurements Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms. Findings Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS. Conclusions Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.

Aim To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on metha- done or buprenorphine. Design Participants were randomized to either methadone or buprenorphine maintenance. Bloodchemistrytests,includinglivertransaminasesandhepatitisCvirus(HCV)status,weredeterminedevery4weeks and once postpartum. As part of a planned secondary analysis, generalized mixed linear models were conducted with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as the dependent variables. Setting Six US sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women. Participants A total of 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study.Findings ALT, AST and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. HCV-positive subjects exhibited higher transami- nases at all time-points compared to HCV-negative subjects, regardless of medication (all Ps < 0.05) condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained (P < 0.05). Conclusions Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women.

Opioid alkaloids have been used medicinally for centuries as analgesics, for their antidiarrheal and antitussive properties, and as hypnotics. Opioids were initially derived from the poppy plant (Papaver somniferum) by the ancients of the Mediterranean Basin. Written records of the medicinal uses of opioids date to before the time of Hippocrates (460–377 BC). Paracelsus prescribed opium in a medicinal drink of wine and spices in the 16th century. Sir William Osler, the renowned Canadian physician of the late 1800’s remarked that opium was “God’s own Medicine”. Opioids are considered superb medications by modern physicians, who widely prescribed them still and for the most part without significant adverse consequences. Yet there is a “dark side” to opioids for those who develop dependence on these drugs (1). Opioids have significant dependence liability because of compelling biphasic central effects, behavioral activation at low doses and sedation at higher doses, accompanied by allostatic neuroadaptation of the CNS, leading to use of rapidly escalating doses. These dynamics may be amplified in persons having altered dopamine receptors in the limbic system, suggesting a possible genetic association (2). Dependent individuals may be unable to stop compulsive self-administration of opioids, in part because of these plastic changes in the brain akin to learning and memory that are highly resistant to modification. Synaptic alterations in neurons of the reward and limbic circuits may irreversibly modify emotions and responses to the environment, thereby permeating the behavioral repertoire of the addict. Accordingly, it may be impossible for most actively dependent individuals to live a fulfilling life simply because so much of their effort becomes devoted to activities necessary to obtain illicit opioids, use them, and recover from their use. Indeed, some individuals who have been dependent on opioids may never be able to return to a normal emotional life without intensive ongoing therapeutic support that allows the acquisition of new learning and more effective coping. The goal of the psychiatrist is to assist the opioid dependent patient to achieve recovery from an opioid-focused life, to help the individual to live a full and balanced life that is no longer fixated on drugs. Those who addictively use opioids often develop complications, less from opioid use per se than from a life outside the law, a direct consequence of their involvement with illicit drugs. The life and exceptional achievements of Dr. William Halsted, first chief of Surgery at Johns Hopkins Hospital, suggests that chronic opioid use may not necessarily be incompatible with a productive life. (Halsted turned to daily morphine use in a futile attempt to “cure” his cocaine dependence, contracted via self-administration of cocaine during research studies to develop a surgical anesthetic. Halstead had ready, unrestricted access to inexpensive, high-grade morphine, so he

Background: Alcohol dependence is associated with neurocognitive deficits related to neuropathological changes in structure, metabolism, and function of the brain. Impairments of motor functioning in alcoholics have been attributed to well-characterized neuropathological brain abnormalities in cerebellum. Methods: Using functional magnetic resonance imaging (fMRI), we studied in vivo the functional connectivity between cerebellar and cortical brain regions. Participants were 10 uncomplicated chronic alcoholic patients studied after 5 to 7 days of abstinence when signs of withdrawal had abated and 10 matched healthy controls. We focused on regions of prefrontal, frontal, temporal, and parietal cortex that exhibited an fMRI response associated with nondominant hand finger tapping in the patients but not in the controls. We predicted that fronto-cerebellar functional connectivity would be diminished in alcoholics compared with controls. Results: Functional connectivity in a circuit involving premotor areas (Brodmann Area 6) and Lobule VI of the superior cerebellum was reduced in the patients compared with the controls. Functional connectivity was also reduced in a circuit involving prefrontal cortex (Brodmann Area 9) and Lobule VIII of the inferior cerebellum. Reductions in connectivity were specific to fronto-cerebellar circuits and were not found in other regions examined. Conclusions: Our findings show a pattern in recently abstinent alcoholic patients of specific deficits in functional connectivity and recruitment of additional brain regions for the performance of a simple finger-tapping task. A small sample, differences in smoking, and a brief abstinence period preclude definitive conclusions, but this pattern of diminished fronto-cerebellar functional connectivity is highly compatible with the characteristic neuropathological lesions documented in alcoholics and may reflect brain dysfunction associated with alcoholism.

Background: Chronic alcohol-dependent patients (ALC) exhibit neurocognitive impairments attributed to alcohol-induced fronto-cerebellar damage. Deficits are typically found in complex task performance, whereas simple tasks may not be significantly compromised, perhaps because of little understood compensatory changes. Methods: We compared finger tapping with either hand at externally paced (EP) or maximal self-paced (SP) rates and concomitant brain activation in ten pairs of right-hand dominant, age-, and gender-matched, severe, uncomplicated ALC and normal controls (NC) using functional magnetic resonance imaging (fMRI). Results: Mean tapping rates were not significantly different in ALC and NC for either task, but SP tapping variances were greater in ALC for both hands. SP tapping was more rapid with dominant hand (DH) than non-dominant hand (NDH) for both groups. EP and SP tapping with the non-dominant hand demonstrated significantly more activation in ALC than NC in the pre and postcentral gyri, inferior frontal gyrus, inferior parietal lobule, and the middle temporal gyrus. Areas activated only by ALC (not at all by NC) during NDH tapping included the inferior frontal gyrus, middle temporal gyrus, and postcentral gyrus. There were no significant group activation differences with DH tapping. No brain regions activated more in NC than ALC. SP tapping in contrast to EP activated fronto-cerebellar networks in NC, including postcentral gyrus, anterior cingulate, and the anterior lobe and vermis of the cerebellum, but only parietal precuneus in ALC. Conclusions: These findings with NDH finger tapping support previous reports of neurocognitive inefficiencies in ALC. Inferior frontal activation with EP in ALC, but not in NC, suggests engagement of regions needed for planning, organization, and impulse regulation; greater contralateral parietal lobe activation with SP in ALC may reflect right hemispheric impairments in visuospatial performance. Contrasting brain activation during SP and EP suggests that ALC may not have enlisted a fronto-cerebellar network as did NC but rather employed a higher order planning mode by recruiting parietal lobe functions to attain normal mean finger tapping rates. Elucidation of the compensatory neural mechanisms that allow near normal performance by ALC on simple tasks can inform functional rehabilitation of patients in recovery.

Background: Alcoholics Anonymous (AA) members represent an important and relatively understudied population for improving our understanding of alcohol dependence recovery as over 1 million Americans participate in the program. Further insight into coffee and cigarette use by these individuals is necessary given AA members’ apparent widespread consumption and the recognized health consequences and psychopharmacological actions of these substances. Methods: Volunteers were sought from all open-AA meetings in Nashville, TN during the summer of 2007 to complete a questionnaire (n = 289, completion rate = 94.1%) including timeline followback for coffee, cigarette, and alcohol consumption; the Alcoholics Anonymous Affiliation Scale; coffee consumption and effects questions; the Fagerstrom Test for Nicotine Dependence (FTND); and the Smoking Effects Questionnaire. Results: Mean (±SD) age of onset of alcohol consumption was 15.4 ± 4.2 years and mean lifetime alcohol consumption was 1026.0 ± 772.8 kg ethanol. Median declared alcohol abstinence was 2.1 years (range: 0 days to 41.1 years) and median lifetime AA attendance was 1000.0 meetings (range: 4 to 44,209 meetings); average AA affiliation score was 7.6 ± 1.5. Most (88.5%) individuals consumed coffee and approximately 33% of coffee consumers drank more than 4 cups per day (M = 3.9 ± 3.9). The most common self-reported reasons for coffee consumption and coffee-associated behavioral changes were related to stimulatory effects. More than half (56.9%) of individuals in AA smoked cigarettes. Of those who smoked, 78.7% consumed at least half a pack of cigarettes per day (M = 21.8 ± 12.3). Smokers’ FTND scores were 5.8 ± 2.4; over 60% of smokers were highly or very highly dependent. Reduced negative affect was the most important subjective effect of smoking. Conclusions: A greater proportion of AA participants drink coffee and smoke cigarettes in larger per capita amounts than observed in general U.S. populations. The effects of these products as described by AA participants suggest significant stimulation and negative affect reduction. Fundamental knowledge of the quantitative and qualitative aspects of coffee and cigarette consumption among AA members will enable future research to discern their impact on alcohol abstinence and recovery.

Background: Fine and gross motor dysfunction in chronic alcoholic patients is prevalent, but not extensively studied. Brain autopsy studies of brain regions involved in motor movements indicate cerebellum and frontal lobes are particularly sensitive to alcohol-induced damage, in contrast to motor cortex. Methods: Using functional magnetic resonance imaging (fMRI), we compared the pattern of activation of the cerebral cortex and cerebellum during repetitive, self-paced dominant (DH) and nondominant (NDH) index finger tapping in eight uncomplicated alcohol-dependent patients after approximately 2 weeks of abstinence and in nine normal controls. Results: Whereas alcoholic patients tapped significantly more slowly than normal controls, a greater percentage of pixels were activated in the ipsilateral cortex during DH tapping. Furthermore, alcoholics tapped significantly less efficiently (tapping rate divided by percent pixels activated [weighted by pixel intensity] in a given region of interest [ROI]) than normal controls in every ROI examined while using DH, but only in ipsilateral hemi-cerebellum using NDH. Finally, the alcohol-dependent patients did not demonstrate the greater mean pixel activation, percentage activated pixels, and lesser activation efficiency in the ipsilateral cortex during NDH compared to DH tapping that was observed in the normal control group. Conclusions: These findings are compatible with motor inefficiency and compensatory alterations of cortical-cerebellar circuits. Further studies are needed to determine whether these deficits recover with prolonged abstinence and how they relate to cognitive inefficiency throughout the clinical course of alcoholism.

This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol-related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and Functional reorganization of the brain in alcoholism: neuroimaging evidence, by John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf Pfefferbaum, and Edith V. Sullivan.

Background Proton magnetic resonance spectroscopy may elucidate the molecular underpinnings of alcoholism-associated brain shrinkage and the progression of alcohol dependence. Methods Using proton magnetic resonance spectroscopy, we determined absolute concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline (Cho)-containing compounds and myo-inositol (mI) in the anterior superior cerebellar vermis and frontal lobe white matter in 31 alcoholics and 12 normal controls. All patients were examined within 3 to 5 days of their last drink. Patients who did not relapse were again studied after 3 weeks and 3 months of abstinence by using an on-line repositioning technique that allows reliable localization of volumes of interest (VOIs). Results At 3 to 5 days after the last drink, frontal white matter metabolite concentrations were not significantly different from those of normal controls, whereas brain tissue in the VOI was reduced. Cerebellar [NAA] and [Cho] and brain and cerebellar volumes were decreased, but [Cr], [mI], and VOI brain tissue volume were not significantly different. Eight patients relapsed before 3 weeks (ER), 12 relapsed between 3 weeks and 3 months (LR), and 11 did not relapse (NR) during 3 months. Cerebellar [NAA] was reduced only in ER patients, despite the fact that ER patients drank for significantly fewer years and earlier in life than LR or NR patients. After 3 months, in the 11 continuously abstinent patients, cerebellar [NAA] and brain and cerebellar volumes increased; cerebellar [Cho], [Cr], and [mI] and VOI brain tissue did not change significantly. Conclusions Decreased [NAA] and [Cho] in cerebellar vermis indicate a unique sensitivity to alcohol-induced brain injury. Cerebellar [NAA] increased with abstinence, but reduced [Cho] persisted beyond 3 months. Further studies are needed to determine whether low cerebellar [NAA] is a risk factor for, or consequence of, malignant, early-onset alcoholism.

In this article, we review the diagnosis, classification, and differential diagnosis of problematic hypersexuality. The estimated frequency, morbidity, comorbidity, mortality, and the associated societal issues underscore the necessity for improved recognition, better understanding, and more effective treatment for this disorder. In general, hypersexual behavior does not seem to be evaluated, classified, or monitored in the same manner as other innate behaviors like feeling, thinking, sleep, or eating, despite the fact that hypersexual behavior is among the criteria for several psychiatric disorders. More widespread clinical use of acceptable diagnostic criteria for problematic hypersexuality would further elucidate the relationships among problematic hypersexuality and other psychiatric disorders.

Sexual addictions may be systematically studied using operationalized diagnostic criteria in a variety of studies employing conventional research methodologies such as is being done in the investigations of a variety of Axis I disorders. Although descriptive investigations into the sexual addictions were on par with that of other major mental disorders in the last century, further investigations did not keep pace with that of other mental disorders. Programmatic research into the sexual addictions is poised to be guided by understanding both neurobiological mechanisms involved in sexual behaviors and multicausal, biopsychosocial approaches. A comprehensive understanding of sexual addiction would involve addressing issues in the areas of nosology, epidemiology, family studies, diagnostic criteria, genetics, neurobiology, comorbidity, and empirically based treatments. The authors suggest current research questions and priorities that, when addressed, can contribute to significant advances in the un...

Alcoholism can result in a number of severe consequences to the central nervous system, including Korsakoff's psychosis, delusions, delirium, Wernicke's encephalopathy, and cerebellar degeneration. Many of these disorders have a substantially higher prevalence than had been previously believed. Neuropathologic and neuroimaging studies have been instrumental in identifying the changes undergone by the alcoholic brain and the factors that may contribute to alcohol-induced brain damage. Biologic differences appear to make women especially susceptible to central nervous system insult from alcohol abuse. The damage caused by alcohol may be associated, in part, with thiamine deficiency, neuronal excitotoxicity, and magnesium wasting.

Thiamine deficiency, a frequent complication of alcoholism, contributes significantly to the development of damage in various organ systems, including the brain. The molecular mechanisms that underlie the differential vulnerabilities to thiamine deficiency of tissue and cell types and among individuals are not understood. Investigations into these mechanisms have examined potential variations in thiamine utilizing enzymes. Transketolase is a homodimeric enzyme containing two molecules of noncovalently bound thiamine pyrophosphate. In the present study, we examined a his-tagged human transketolase that was produced in and purified from Escherichia coli cells. Previous findings demonstrated that purified his-transketolase had a Km app for cofactor and a thiamine pyrophosphate-dependent lag period for attaining steady-state kinetics that was similar to transketolase purified from human tissues. Interestingly, the time of the lag period, which is normally independent of enzyme concentration, was found herein to be dependent on the concentration of the recombinant protein. This atypical behavior was due to production in E. coli. Generation of the normal, enzyme concentration-independent state required a cytosolic factor(s) derived from human cells. Importantly, the required factor(s) was found to be defective in a Wernicke-Korsakoff patient whose cells in culture show an enhanced sensitivity to thiamine deficiency.

Induction onto buprenorphine during pregnancy may be more challenging than induction onto methadone. This study explores factors predicting withdrawal intensities and compares trajectories of withdrawal during the induction phase between opioid-dependent women randomly assigned to methadone or buprenorphine.A secondary analysis was conducted on data from 175 opioid-dependent pregnant women inducted onto buprenorphine or methadone subsequent to stabilization on morphine sulfate. ANOVA analyses were conducted to determine differences between mean peak CINA scores by medication and completion status. General linear mixed models were fitted to compare trajectories of CINA scores between methadone and buprenorphine conditions, and between study dropouts and completers within the buprenorphine condition.Both buprenorphine and methadone patients experienced withdrawal categorized as minimal by the CINA scoring system. Significant differences in mean peak CINA scores for the first 72 hours of induction were found between the methadone (4.5; SD=0.4) and buprenorphine conditions (6.9; SD=0.4), with buprenorphine patients exhibiting higher mean peak CINA scores [F (3, 165)=9.70, p0.001]. The trajectory of CINA scores showed buprenorphine patients exhibiting a sharper increase in mean CINA scores than methadone patients [F (1, 233)=8.70, p=0.004]. There were no differences in mean peak CINA scores [F (3, 77)=0.08, p=0.52] or in trajectory of CINA scores [F (1, 166)=0.42, p=0.52] between buprenorphine study dropouts and completers.While mean peak CINA score was significantly higher in the buprenorphine condition than the methadone condition, neither medication condition experienced substantial withdrawal symptoms. Further research on factors related to successful induction to buprenorphine treatment in pregnant women is needed.

We compare findings from 10 years of experience evaluating physicians referred for fitness-to-practice assessment to determine whether those referred for disruptive behavior are more or less likely to be declared fit for duty than those referred for mental health, substance abuse or sexual misconduct.Deidentified data from 381 physicians evaluated by the Vanderbilt Comprehensive Assessment Program (2001-2012) were analyzed and compared to general physician population data and also to previous reports of physician psychiatric diagnosis found by MEDLINE search.Compared to the physicians referred for disruptive behavior (37.5% of evaluations), each of the other groups was statistically significantly less likely to be assessed as fit for practice [substance use, %: odds ratio (OR)=0.22, 95% confidence interval (CI)=0.10-0.47, P.001; mental health, %: OR=0.14, 95% CI=0.06-0.31, P.001; sexual boundaries, %: OR=0.27, 95% CI=0.13-0.58, P=.001].The number of referrals to evaluate physicians presenting with behavior alleged to be disruptive to clinical care increased following the 2008 Joint Commission guidelines that extended responsibility for professional conduct outside the profession itself to the institutions wherein physicians work. Better strategies to identify and manage disruptive physician behavior may allow those physicians to return to practice safely in the workplace.

Objective The purposes of this article are 1) to review federal and state laws relevant to confidentiality in group therapy with impaired physicians and 2) to provide empirical data concerning the actual confidentiality practices and experiences of group therapists treating chemically impaired physicians. Method In the clinical research phase, 25 state medical societies identified 45 rehabilitation centers as those to which the societies preferentially referred chemically impaired physicians. Fifty-one group leaders from 33 of these rehabilitation centers completed the survey questionnaire employed in this project. Results Because of the risk of potentially irreversible social and professional injury, physician patients were exceedingly concerned about breaches of confidentiality. Co-members' infractions most often involved the violator sharing with close friends and family members the name and abuse history of a fellow physician. In contrast, transgressors rarely leaked information about a co-member's drug-related illegal behaviour. Conclusions Chemically impaired physicians would feel safer in sharing secrets in group therapy if more jurisdictions adopted legislation making co-members liable for violating confidentiality. Currently the pertinent body of law is confusing and inconsistent and provides little protection to impaired physicians who enter group therapy. The authors propose ideas for model legislation.

SynopsisA female alcoholic presented with Wernicke's encephalopathy subsequent to administration of diazepam and glucose (without thiamine) for treatment of withdrawal seizures. Nystagmus and cerebellar ataxia quickly resolved when administered thiamine, although severe global amnesia consistent with Korsakoffs syndrome persisted. Magnetic resonance imaging (MRI) revealed infarction of the right temporal lobe with hippocampal atrophy, but no lesions of thalamus or atrophy of mammillary bodies. Positron emission tomography (PET) confirmed decreased cerebral metabolic rates for glucose (CMRglu) in the right temporal lobe corresponding to MRI findings, but also significant metabolic asymmetry of dorsal thalamus, i.e reduced CMRglu in left versus right. This patient is unique in that neuroradiological findings revealed intact mammillary bodies and suggest asymmetrical dysfunctions (structural right temporal and functional left diencephalic) to produce her profound amnesia.