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1.  Opioid Dependence during Pregnancy: Relationships of Anxiety and Depression Symptoms to Treatment Outcomes 
Addiction (Abingdon, England)  2012;107(0 1):74-82.
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 controlled trial of treatment for opioid dependence during pregnancy.
175 opioid-dependent pregnant women, of whom 131 completed treatment.
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.
Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment (adjusted OR = 4.56, 95% 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.
Opioid-agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation.
PMCID: PMC4315620  PMID: 23106929
2.  Caudate responses to reward anticipation associated with delay discounting behavior in healthy youth 
Choices requiring delay of gratification made during adolescence can have significant impact on life trajectory. Willingness to delay gratification can be measured using delay discounting tasks that require a choice between a smaller immediate reward and a larger delayed reward. Individual differences in the subjective value of delayed rewards are associated with risk for development of psychopathology including substance abuse. The neurobiological underpinnings related to these individual differences early in life are not fully understood. Using functional magnetic resonance imaging (fMRI), we tested the hypothesis that individual differences in delay discounting behavior in healthy youth are related to differences in responsiveness to potential reward.
Nineteen 10 to 14 year-olds performed a monetary incentive delay task to assess neural sensitivity to potential reward and a questionnaire to measure discounting of future monetary rewards.
Left ventromedial caudate activation during anticipation of potential reward was negatively correlated with delay discounting behavior. There were no regions where brain responses during notification of reward outcome were associated with discounting behavior.
Brain activation during anticipation of potential reward may serve as a marker for individual differences in ability or willingness to delay gratification in healthy youth.
PMCID: PMC3932556  PMID: 24309299
adolescent; reward; fMRI; delay discounting; intertemporal choice; delayed gratification
3.  Predictive Factors for Relapse in Patients on Buprenorphine Maintenance 
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.
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.
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.
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.
PMCID: PMC3922612  PMID: 24313243
4.  Norms from the Georgia Centenarian Study: Measures of verbal abstract reasoning, fluency, memory, and motor function 
We previously presented normative data from a relatively large, population-based sample (n = 244) of centenarians and a reference group of octogenarians (n = 80) for several brief, global neurocognitive tasks adapted for use for older adults with physical and sensory limitations (Miller et al., 2010). Here, we present additional normative data on several domain-specific tasks from these samples from Phase III of the Georgia Centenarian Study, including measures of verbal abstract reasoning, fluency, memory, and motor function. Expected age differences were demonstrated across all cognitive measures, and, consistent with our previous findings, centenarians showed a stronger association between age and performance. Normative tables are presented unweighted as well as population-weighted, and stratified by age and education level. These findings offer a unique contribution to the literature on cognitive aging, as normative performance in this age group is understudied and largely unavailable to clinicians and researchers.
PMCID: PMC4281023  PMID: 23379531
5.  Fetal Assessment before and after Dosing with Buprenorphine or Methadone 
Addiction (Abingdon, England)  2012;107(0 1):36-44.
To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal well-being.
A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial.
Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women.
81 of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation.
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.
Significant group differences were found for number of FHR accelerations, non-reactive NST, and BPP scores (all Ps < 0.05). There were no significant group differences before time of dosing. Significant decreases (all Ps < 0.05) occurred from pre- to post-dose assessment for mean FHR, FHR accelerations, reactive NST, and fetal movement. The decrease in accelerations and reactive NST were only significant for fetuses in the methadone group and this resulted in a significantly lower likelihood of a reactive NST compared to fetuses in the buprenorphine group.
Buprenorphine compared with methadone appears to result in less suppression of mean fetal heart rate, fetal heart rate reactivity, and the biophysical profile score after medication dosing and provide support for the relative safety of buprenorphine when fetal indices are considered as part of the complete risk-benefit ratio.
PMCID: PMC4277183  PMID: 23106925
fetal; opiates; biophysical profile; heart rate; tbc
6.  Effect of HCV status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication 
Addiction (Abingdon, England)  2012;107(0 1):91-97.
To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on methadone or buprenorphine.
Participants were randomized to either methadone or buprenorphine maintenance. Blood chemistry tests, including liver transaminases and HCV status, were determined every four weeks 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.
Six United States sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women.
n = 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study.
ALT, AST, and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. Hepatitis C (HCV)-positive subjects exhibited higher transaminases at all time points compared to HCV-negative subjects, regardless of medication condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained.
Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women.
PMCID: PMC4268861  PMID: 23106931
7.  Predicting Treatment for Neonatal Abstinence Syndrome in Infants Born to Women Maintained on Opioid Agonist Medication 
Addiction (Abingdon, England)  2012;107(0 1):45-52.
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.
n = 131 infants born to opioid dependent mothers, 129 of which were available for NAS assessment.
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.
53% of the sample (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin reuptake inhibitors (SSRIs), vaginal delivery, and higher infant birth weight predicted higher peak NAS scores. Higher infant birth weight 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.
Maternal weight at delivery, estimated gestational age, infant birth weight, 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.
PMCID: PMC4268864  PMID: 23106926
8.  Cannabis cue-induced brain activation correlates with drug craving in limbic and visual salience regions: Preliminary results 
Psychiatry research  2013;214(2):122-131.
Craving is a major motivator underlying drug use and relapse but the neural correlates of cannabis craving are not well understood. This study sought to determine whether visual cannabis cues increase cannabis craving and whether cue-induced craving is associated with regional brain activation in cannabis-dependent individuals. Cannabis craving was assessed in 16 cannabis-dependent adult volunteers while they viewed cannabis cues during a functional MRI (fMRI) scan. The Marijuana Craving Questionnaire was administered immediately before and after each of three cannabis cue-exposure fMRI runs. FMRI blood-oxygenation-level-dependent (BOLD) signal intensity was determined in regions activated by cannabis cues to examine the relationship of regional brain activation to cannabis craving. Craving scores increased significantly following exposure to visual cannabis cues. Visual cues activated multiple brain regions, including inferior orbital frontal cortex, posterior cingulate gyrus, parahippocampal gyrus, hippocampus, amygdala, superior temporal pole, and occipital cortex. Craving scores at baseline and at the end of all three runs were significantly correlated with brain activation during the first fMRI run only, in the limbic system (including amygdala and hippocampus) and paralimbic system (superior temporal pole), and visual regions (occipital cortex). Cannabis cues increased craving in cannabis-dependent individuals and this increase was associated with activation in the limbic, paralimbic, and visual systems during the first fMRI run, but not subsequent fMRI runs. These results suggest that these regions may mediate visually cued aspects of drug craving. This study provides preliminary evidence for the neural basis of cue-induced cannabis craving and suggests possible neural targets for interventions targeted at treating cannabis dependence.
PMCID: PMC3904759  PMID: 24035535
drug abuse; functional MRI; addiction
9.  Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates 
Addiction (Abingdon, England)  2012;107(0 1):53-62.
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.
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 (methadone = 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.
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-exposed infants (36 versus 59 hours postnatal, respectively).
The profile of neonatal abstinence syndrome 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.
PMCID: PMC4165073  PMID: 23106927
Buprenorphine; incidence; in utero; methadone; neonatal abstinence syndrome; profile; severity; signs; treatment initiation
10.  PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma 
The New England journal of medicine  2014;370(11):1008-1018.
Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.
In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.
The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).
In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; number, NCT01282424.)
PMCID: PMC4039496  PMID: 24450858
11.  Induction of Pregnant Women onto Opioid-agonist Maintenance Medication: An Analysis of Withdrawal Symptoms and Study Retention 
Drug and alcohol dependence  2013;132(0):329-334.
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, p<0.001]. 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.
PMCID: PMC3732530  PMID: 23523131
pregnancy; opioid dependence; buprenorphine induction; CINA; opioid withdrawal; methodone induction
12.  Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B Cell Lymphoma 
Cancer discovery  2013;3(9):1002-1019.
Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemo-resistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTIs) reprogrammed chemo-resistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemo-resistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was performed evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk newly diagnosed DLBCL patients. The combination was well tolerated and yielded a high rate of complete remission. Pre and post azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.
PMCID: PMC3770813  PMID: 23955273
Non-Hodgkin lymphoma; epigenetic; DNA methylation; DNMT inhibitor; chemoresistance
13.  Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas 
Genome Biology  2014;15(8):432.
Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.
We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events.
Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0432-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4158101  PMID: 25123191
14.  Increasing pregnancy-related use of prescribed opioid analgesics 
Annals of epidemiology  2013;23(8):498-503.
To quantify the prevalence of prescribed opioid analgesics among pregnant women enrolled in Tennessee Medicaid from 1995 to 2009.
Retrospective cohort study of 277,555 pregnancies identified from birth and fetal death certificates, and linked to previously-validated computerized pharmacy records. Poisson regression was used to estimate trends over time, rate ratios and 95% confidence intervals.
During the study period, 29% of pregnant women filled a prescription for an opioid analgesic. From 1995 to 2009, any pregnancy-related use increased 1.90-fold (95% CI = 1.83, 1.98), first trimester use increased 2.27-fold (95% CI = 2.14, 2.41), and second or third trimester use increased 2.02-fold (95% CI = 1.93, 2.12), after adjusting for maternal characteristics. Any pregnancy-related, first trimester, and second or third trimester use were each more likely among mothers who were at least 21 years old, white, non-Hispanic, prima gravid, resided in non-urban areas, enrolled in Medicaid due to disability, and who had less than a high school education.
Opioid analgesic use by Tennessee Medicaid-insured pregnant women increased nearly 2-fold from 1995 to 2009. Additional study is warranted in order to understand the implications of this increased use.
PMCID: PMC3888316  PMID: 23889859
Opioids; Pregnancy; Prescription
15.  A Comparison of Cigarette Smoking Profiles in Opioid-Dependent Pregnant Patients Receiving Methadone or Buprenorphine 
Nicotine & Tobacco Research  2013;15(7):1297-1304.
Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study.
A sample of opioid-maintained pregnant patients (18–41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition.
Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (β = −0.08, SE = 0.05, p = .132).
Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women.
PMCID: PMC3682847  PMID: 23288871
16.  Consistency and Timing of Marital Transitions and Survival During Midlife: the Role of Personality and Health Risk Behaviors 
Marital status is associated with survival.
The aims of this study are to evaluate marital history and timing on mortality during midlife, test the role of pre-marital personality, and quantify the role of health risk behaviors.
Cox proportional hazard models were run with varying classifications of marital history and sets of covariates.
In fully adjusted models compared to the currently married, lifetime marital history predicts premature mortality with never married at 2.33 times risk of death and ever married at 1.64 risk of death. Midlife marital history shows that not having a partner during midlife (hazard ratio (HR)= 3.10 formerly married; HR=2.59 remaining single) has the highest risk of death. Controlling for personality and health risk behaviors reduces but does not eliminate the impact of marital status.
Consistency of marital status during midlife suggests that lack of a partner is associated with midlife mortality.
PMCID: PMC3644000  PMID: 23299546
Marital history; Midlife mortality; Longitudinal study; UNC Alumni Heart Study
18.  Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke 
Neurology  2013;80(17):1546-1550.
The usefulness of the implantable loop recorder (ILR) with improved atrial fibrillation (AF) detection capability (Reveal XT) and the factors associated with AF in the setting of unexplained stroke were investigated.
A cohort study is reported of 51 patients in whom ILRs were implanted for the investigation of ischemic stroke for which no cause had been found (cryptogenic) following appropriate vascular and cardiac imaging and at least 24 hours of cardiac rhythm monitoring.
The patients were aged from 17 to 73 (median 52) years. Of the 30 patients with a shunt investigation, 22 had a patent foramen ovale (73.3%; 95% confidence interval [CI] 56.5%–90.1%). AF was identified in 13 (25.5%; 95% CI 13.1%–37.9%) cases. AF was associated with increasing age (p = 0.018), interatrial conduction block (p = 0.02), left atrial volume (p = 0.025), and the occurrence of atrial premature contractions on preceding external monitoring (p = 0.004). The median (range) of monitoring prior to AF detection was 48 (0–154) days.
In patients with unexplained stroke, AF was detected by ILR in 25.5%. Predictors of AF were identified, which may help to target investigations. ILRs may have a central role in the future in the investigation of patients with unexplained stroke.
PMCID: PMC3662328  PMID: 23535493
19.  Profiles of Cognitive Functioning in a Population-Based Sample of Centenarians Using Factor Mixture Analysis 
Experimental aging research  2013;39(2):125-144.
Background/Study Context
The goal of the study was to identify and characterize latent profiles (clusters) of cognitive functioning in centenarians and the psychometric properties of cognitive measures within them.
Data were collected from cross-sectional, population-based sample of 244 centenarians (aged 98-108, 15.8% men, 20.5% African-American, 38.0% community-dwelling) from 44 counties in Northern Georgia participating in the Georgia Centenarian Study (2001-2009). Measures included the Mini-Mental State Examination (MMSE), Severe Impairment Battery (SIB), Wechsler Adult Intelligence Scale-III, Similarities sub-test (WAIS), Finger Tapping, Behavioral Dyscontrol Scale (BDS), Controlled Oral Word Association Test (COWAT), and Fuld Object Memory Evaluation (FOME). The Global Deterioration Rating Scale (GDRS) was used to independently evaluate criterion-related validity for distinguishing cognitively normal and impaired groups. Relevant covariates included directly assessed functional status for basic and instrumental activities of daily living (DAFS), race, gender, educational attainment, Geriatric Depression Scale Short Form (GDS), and vision and hearing problems.
Results suggest two distinct classes of cognitive performance in this centenarian sample. Approximately one-third of the centenarians show a pattern of markedly lower cognitive performance on most measures. Group membership is independently well-predicted (AUC=.83) by GDRS scores (sensitivity 67.7%, specificity 82.4%). Membership in the lower cognitive performance group was more likely for individuals who were older, African Americans, had more depressive symptoms, lower plasma folate, carriers of the APOE ε4 allele, facility residents, and individuals who died in the two years following interview.
In a population expected to have high prevalence of dementia, latent subtypes can be distinguished via factor mixture analysis that provide normative values for cognitive functioning. The present study allows estimates for normative cognitive performance in this age group.
PMCID: PMC3579538  PMID: 23421635
20.  Restoring professionalism: the physician fitness-for-duty evaluation☆ 
General hospital psychiatry  2013;35(6):659-663.
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.
PMCID: PMC3923266  PMID: 23910216
Professionalism; Medical ethics; Fitness for duty; Fitness to practice; Disruptive behavior; Physician health and wellness; Comprehensive psychiatric assessment; Psychiatric diagnosis
21.  Predicting pKa for proteins using COSMO-RS 
PeerJ  2013;1:e198.
We have used the COSMO-RS implicit solvation method to calculate the equilibrium constants, pKa, for deprotonation of the acidic residues of the ovomucoid inhibitor protein, OMTKY3. The root mean square error for comparison with experimental data is only 0.5 pH units and the maximum error 0.8 pH units. The results show that the accuracy of pKa prediction using COSMO-RS is as good for large biomolecules as it is for smaller inorganic and organic acids and that the method compares very well to previous pKa predictions of the OMTKY3 protein using Quantum Mechanics/Molecular Mechanics. Our approach works well for systems of about 1000 atoms or less, which makes it useful for small proteins as well as for investigating portions of larger proteins such as active sites in enzymes.
PMCID: PMC3817581  PMID: 24244915
Proteins; pKa; COSMO-RS; OMTKY3; Quantum mechanics; Implicit solvent; Semi-empirical methods
22.  Impact of retreatment with an artemisinin-based combination on malaria incidence and its potential selection of resistant strains: study protocol for a randomized controlled clinical trial 
Trials  2013;14:307.
Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains.
We embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first-line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection.
Trial registration
NCT01374581 and PACTR201203000351114
PMCID: PMC3849445  PMID: 24059911
Malaria; Artemisinin-based combination treatment; Artesunate-amodiaquine; Artemether-lumefantrine; Quinine; Clindamycin; Randomized trial; Democratic Republic of Congo; Uganda
23.  Successful Recruitment of Centenarians for Post-Mortem Brain Donation: Results from the Georgia Centenarian Study 
Brain donation and neuropathological examination of brain tissues is the only way to obtain definitive diagnostic information on research subjects enrolled in aging studies. We investigated predictors of brain donation in a population-based study of centenarians in Phase III of the Georgia Centenarian Study (GCS).
Sixty-six individuals (mean age = 100.6 years, 91% female, 20% African American) were successfully recruited from the core sample of 244 individuals residing in 44 counties of Northeast Georgia to provide brain donation.
Bivariate (t-tests, chi-square tests) and multivariate analyses (logistic regression) showed no significant differences between donors and non-donors across a wide range of demographic, religious, personality, cognitive and physical functioning characteristics.
We succeeded in recruiting a diverse, population-based sample of centenarians for brain donation. Our findings also suggest that barriers to brain donation reported in other studies may have less impact in these exceptional survivors.
PMCID: PMC3763720  PMID: 24013849
25.  Cancer cachexia: impact, mechanisms and emerging treatments 
Many forms of cancer present with a complex metabolic profile characterised by loss of lean body mass known as cancer cachexia. The physical impact of cachexia contributes to decreased patient quality of life, treatment success and survival due to gross alterations in protein metabolism, increased oxidative stress and systemic inflammation. The psychological impact also contributes to decreased quality of life for both patients and their families. Combination therapies that target multiple pathways, such as eicosapentaenoic acid administered in combination with exercise, appetite stimulants, antioxidants or anti-inflammatories, have potential in the treatment of this complex syndrome and require further development.
PMCID: PMC3684701  PMID: 23097000
Cancer cachexia; Oxidative stress; Antioxidant; Eicosapentaenoic acid; Oxypurinol

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