Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

BACKGROUND: Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. AIMS: We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). METHOD: Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF. RESULTS: Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD. CONCLUSIONS: These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?

Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT1A BPND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT1A BPND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT1A BPND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.

Influences of dopaminergic system dysfunction on late-life depression.

Deficits in cognition, reward processing, and motor function are clinical features relevant to both aging and depression. Individuals with late-life depression often show impairment across these domains, all of which are moderated by the functioning of dopaminergic circuits. As dopaminergic function declines with normal aging and increased inflammatory burden, the role of dopamine may be particularly salient for late-life depression. We review the literature examining the role of dopamine in the pathogenesis of depression, as well as how dopamine function changes with aging and is influenced by inflammation. Applying a Research Domain Criteria (RDoC) Initiative perspective, we then review work examining how dopaminergic signaling affects these domains, specifically focusing on Cognitive, Positive Valence, and Sensorimotor Systems. We propose a unified model incorporating the effects of aging and low-grade inflammation on dopaminergic functioning, with a resulting negative effect on cognition, reward processing, and motor function. Interplay between these systems may influence development of a depressive phenotype, with an initial deficit in one domain reinforcing decline in others. This model extends RDoC concepts into late-life depression while also providing opportunities for novel and personalized interventions.

Nd:YAG Laser Capsulotomy: Efficacy and Outcomes Performed by Optometrists.

SIGNIFICANCE: An increasing number of optometrists are performing Nd:YAG laser capsulotomy procedures; however, there is limited published information on the outcomes of these procedures. PURPOSE: This study aimed to assess the efficacy and safety of capsulotomy procedures performed by optometrists. METHODS: Subjects diagnosed with posterior capsule opacification causing reduced vision and subjective visual complaints were recruited for this study. A baseline examination was performed to ensure that the subjects met all the necessary criteria. The procedure was performed by a licensed doctor of optometry at six different clinics, and each subject was monitored for visual outcome and any potential complications. RESULTS: Subjects' Snellen visual acuity improved from an average of 20/40 to 20/23 ( P < .001) with no complications of increased intraocular pressure, inflammation, visually significant lens pitting, macular edema, or retinal detachment. Of 78 subjects who responded to a post-procedure survey, 77 (99%) reported subjective improvement in vision after capsulotomy. CONCLUSIONS: Based on the outcomes of this study, YAG laser capsulotomies are effective treatments to improve patient vision that can be safely and effectively performed by optometrists.

Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior.

BACKGROUND: The serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior. METHODS: [11C]CUMI-101 positron emission tomography imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high risk for mood disorder or suicidal behavior on the basis of having a first- or second-degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk individuals were subdivided into the following groups: high risk resilient having no mood disorder or suicidal behavior (n = 29); high risk with mood disorder and no suicidal behavior history (n = 31); and high risk with mood disorder and suicidal behavior (n = 25). Groups were compared with healthy volunteers without a family history of mood disorder or suicidal behavior (n = 34). Participants underwent the Trier Social Stress Task (TSST). All participants were free from psychotropic medications at the time of the TSST and PET scanning. RESULTS: We observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all participants and BPp in a subset of the sample) and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within the high risk with mood disorder and suicidal behavior group, lower BPp binding (ß = -0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (ß = 9.25, 95% CI [3.27,15.23], P = .004) were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes. CONCLUSIONS: 5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how hypothalamic-pituitary-adrenal axis function influences such risk.

Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder.

Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT1A) autoreceptors regulate brain-wide serotonin neuron firing and are positioned to assert large-scale effects on negative emotion. Here we investigated the relationship between raphe 5-HT1A binding and brain-wide network dynamics of negative emotion. 22 healthy-volunteers (HV) and 27 medication-free participants with MDD underwent positron emission tomography (PET) using [11C]CUMI-101 (CUMI) to quantify 5-HT1A binding in midbrain raphe nuclei and functional magnetic resonance imaging (fMRI) scanning during emotionally negative picture viewing. Causal connectivity across regions responsive to negative emotion was estimated in the fMRI data using a multivariate dynamical systems model. During negative picture viewing, MDD subjects demonstrated significant hippocampal inhibition of amygdala, basal-ganglia, thalamus, orbital frontal cortex, inferior frontal gyrus and dorsomedial prefrontal cortex (IFG, dmPFC). MDD-related connectivity was not associated with raphe 5-HT1A binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT1A binding. Correlation between hippocampal 5-HT1A binding and the hippocampal inhibition network was specific to MDD but not HV. MDD and HV groups also differed with respect to the correlation between raphe and hippocampal 5-HT1A binding which was more pronounced in HV. These findings suggest that increased hippocampal network inhibition in MDD is linked to hippocampal serotonergic dysfunction which may in turn arise from disrupted linkage in raphe to hippocampus serotonergic circuitry.

Highly variable suicidal ideation: a phenotypic marker for stress induced suicide risk.

Suicidal behavior (SB) can be impulsive or methodical; violent or not; follow a stressor or no obvious precipitant. This study tested whether childhood trauma, affective lability, and aggressive and impulsive traits predicted greater SI variability. We also assessed whether affective lability, aggressive or impulsive traits explain childhood trauma's effects on SI variability and whether those with highly variable SI respond to stressful events with increases in SI. Finally, we assessed variable SI's trajectory over 2 years. Depressed participants (n = 51) had ecological momentary assessments (EMA) over 7 days at baseline, 3, 6, 12, 18, and 24 months. SI variability was assessed using the square Root of the Mean Square of Successive Deviations. Mixed Effects Models were fit as appropriate. Childhood trauma was associated with subsequent aggression. Physical abuse predicted both aggression and affective lability as well as SI variability, but not impulsivity. In two-predictor models, physical abuse's effect on SI variability was no longer significant, when controlling for the effect of higher aggression and impulsivity. Those with high SI variability exhibited greater increases in SI after stressors compared with those with less variability. We did not find that SI variability changed over time, suggesting it might be trait-like, at least over 2 years. Variable SI predisposes to marked SI increases after stressful events and may be a trait increasing risk for impulsive SB, at least over 2 years.

Diffusion tensor imaging brain structural clustering patterns in major depressive disorder.

Using magnetic resonance diffusion tensor imaging data from 45 patients with major depressive disorder (MDD) and 41 healthy controls (HCs), network indices based on a 246-region Brainnetcome Atlas were investigated in the two groups, and in the MDD subgroups that were subgrouped based on their duration of the disease. Correlation between the network indices and the duration of illness was also examined. Differences were observed between the MDDS subgroup (short disease duration) and the HC group, but not between the MDD and HC groups. Compared with the HCs, the clustering coefficient (CC) values of MDDS were higher in precentral gyrus, and caudal lingual gyrus; the CC of MDDL subgroup (long disease duration) was higher in postcentral gyrus and dorsal granular insula in the right hemisphere. Network resilience analyses showed that the MDDS group was higher than the HC group, representing relatively more randomized networks in the diseased brains. The correlation analyses showed that the caudal lingual gyrus in the right hemisphere and the rostral lingual gyrus in the left hemisphere were particularly correlated with disease duration. The analyses showed that duration of the illness appears to have an impact on the networking patterns. Networking abnormalities in MDD patients could be blurred or hidden by the heterogeneity of the MDD clinical subgroups. Brain plasticity may introduce a recovery effect to the abnormal network patterns seen in patients with a relative short term of the illness, as the abnormalities may disappear in MDDL .

Bipolar disorder and the gut microbiome: A systematic review.

OBJECTIVES: The microbiome is a rapidly advancing biomedical frontier with relevance for psychiatric illness. The gut microbiota interact with the central nervous system bidirectionally through the gut-brain axis and generate substances that may influence host metabolism, including short-chain fatty acids such as butyrate. Understanding gut microbiota in bipolar disorder (BD) may suggest new disease markers and treatment approaches. METHODS: A PubMed search was performed on January 7, 2020 using terms "bipolar AND (microbiome OR microbiota)", for articles in English in which the study population included a distinct BD group and the gut microbiota/microbiome was assessed. RESULTS: Thirteen articles met the inclusion criteria. In four of five studies that reported on group comparisons with respect to diversity, lower α-diversity was observed in BD relative to healthy controls (HC). The most convergent taxonomic finding was that in four studies, one particular clade distinguished gut microbiota between BD and HC: family Ruminococcaceae, genus Faecalibacterium, and species Faecalibacterium prausnitzii. Members of this clade, known for butyrate production, were reduced in BD relative to HC in three studies but elevated in a fourth. Additionally, genera Bacteroides or Bacteroides-Prevotella group species were elevated in BD in two studies but lower in a third. CONCLUSIONS: Despite few studies and modest sample sizes, salient findings suggest that low α-diversity and dysbiosis with respect to abundance of Faecalibacterium and Bacteroides may characterize BD in both a trait and state-dependent fashion. Decreased richness and butyrate production also foster inflammation, which may be a hitherto unrecognized part of the pathophysiology underlying BD.

Identification of temporal condition patterns associated with pediatric obesity incidence using sequence mining and big data.

BACKGROUND: Electronic health records (EHRs) are potentially important components in addressing pediatric obesity in clinical settings and at the population level. This work aims to identify temporal condition patterns surrounding obesity incidence in a large pediatric population that may inform clinical care and childhood obesity policy and prevention efforts. METHODS: EHR data from healthcare visits with an initial record of obesity incidence (index visit) from 2009 through 2016 at the Children's Hospital of Philadelphia, and visits immediately before (pre-index) and after (post-index), were compared with a matched control population of patients with a healthy weight to characterize the prevalence of common diagnoses and condition trajectories. The study population consisted of 49,694 patients with pediatric obesity and their corresponding matched controls. The SPADE algorithm was used to identify common temporal condition patterns in the case population. McNemar's test was used to assess the statistical significance of pattern prevalence differences between the case and control populations. RESULTS: SPADE identified 163 condition patterns that were present in at least 1% of cases; 80 were significantly more common among cases and 45 were significantly more common among controls (p < 0.05). Asthma and allergic rhinitis were strongly associated with childhood obesity incidence, particularly during the pre-index and index visits. Seven conditions were commonly diagnosed for cases exclusively during pre-index visits, including ear, nose, and throat disorders and gastroenteritis. CONCLUSIONS: The novel application of SPADE on a large retrospective dataset revealed temporally dependent condition associations with obesity incidence. Allergic rhinitis and asthma had a particularly high prevalence during pre-index visits. These conditions, along with those exclusively observed during pre-index visits, may represent signals of future obesity. While causation cannot be inferred from these associations, the temporal condition patterns identified here represent hypotheses that can be investigated to determine causal relationships in future obesity research.

Neural predictors and effects of cognitive behavioral therapy for depression: the role of emotional reactivity and regulation.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for many patients suffering from major depressive disorder (MDD), but predictors of treatment outcome are lacking, and little is known about its neural mechanisms. We recently identified longitudinal changes in neural correlates of conscious emotion regulation that scaled with clinical responses to CBT for MDD, using a negative autobiographical memory-based task. METHODS: We now examine the neural correlates of emotional reactivity and emotion regulation during viewing of emotionally salient images as predictors of treatment outcome with CBT for MDD, and the relationship between longitudinal change in functional magnetic resonance imaging (fMRI) responses and clinical outcomes. Thirty-two participants with current MDD underwent baseline MRI scanning followed by 14 sessions of CBT. The fMRI task measured emotional reactivity and emotion regulation on separate trials using standardized images from the International Affective Pictures System. Twenty-one participants completed post-treatment scanning. Last observation carried forward was used to estimate clinical outcome for non-completers. RESULTS: Pre-treatment emotional reactivity Blood Oxygen Level-Dependent (BOLD) signal within hippocampus including CA1 predicted worse treatment outcome. In contrast, better treatment outcome was associated with increased down-regulation of BOLD activity during emotion regulation from time 1 to time 2 in precuneus, occipital cortex, and middle frontal gyrus. CONCLUSIONS: CBT may modulate the neural circuitry of emotion regulation. The neural correlates of emotional reactivity may be more strongly predictive of CBT outcome. The finding that treatment outcome was predicted by BOLD signal in CA1 may suggest overgeneralized memory as a negative prognostic factor in CBT outcome.

Perspective on the Development of a Large-Scale Clinical Data Repository for Pediatric Hearing Research.

The use of "big data" for pediatric hearing research requires new approaches to both data collection and research methods. The widespread deployment of electronic health record systems creates new opportunities and corresponding challenges in the secondary use of large volumes of audiological and medical data. Opportunities include cost-effective hypothesis generation, rapid cohort expansion for rare conditions, and observational studies based on sample sizes in the thousands to tens of thousands. Challenges include finding and forming appropriately skilled teams, access to data, data quality assessment, and engagement with a research community new to big data. The authors share their experience and perspective on the work required to build and validate a pediatric hearing research database that integrates clinical data for over 185,000 patients from the electronic health record systems of three major academic medical centers.

Cortisol Stress Response and in Vivo PET Imaging of Human Brain Serotonin 1A Receptor Binding.

BACKGROUND: Abnormalities in the hypothalamic-pituitary-adrenal axis, serotonergic system, and stress response have been linked to the pathogenesis of major depressive disorder. State-dependent hyper-reactivity of the hypothalamic-pituitary-adrenal axis is seen in major depressive disorder, and higher binding to the serotonin 1A receptor is observed as a trait in both currently depressed and remitted untreated major depressive disorder. Here, we sought to examine whether a relationship exists between cortisol secretion in response to a stressor and serotonin 1A receptor binding throughout the brain, both in healthy controls and participants with major depressive disorder. METHODS: Research participants included 42 medication-free, depressed subjects and 31 healthy volunteers. Participants were exposed to either an acute, physical stressor (radial artery catheter insertion) or a psychological stressor (Trier Social Stress Test). Levels of serotonin 1A receptor binding on positron emission tomography with [11C]WAY-100635 were also obtained from all participants. The relationship between [11C]WAY-100635 binding and cortisol was examined using mixed linear effects models with group (major depressive disorder vs control), cortisol, brain region, and their interactions as fixed effects and subject as a random effect. RESULTS: We found a positive correlation between post-stress cortisol measures and serotonin 1A receptor ligand binding levels across multiple cortical and subcortical regions, independent of diagnosis and with both types of stress. The relationship between [11C]WAY-100635 binding and cortisol was homogenous across all a priori brain regions. In contrast, resting cortisol levels were negatively correlated with serotonin 1A receptor ligand binding levels independently of diagnosis, except in the RN. There was no significant difference in cortisol between major depressive disorder participants and healthy volunteers with either stressor. Similarly, there was no correlation between cortisol and depression severity in either stressor group. CONCLUSIONS: This study suggests that there may be a common underlying mechanism that links abnormalities in the serotonin system and hypothalamic-pituitary-adrenal axis hyper-reactivity to stress. Future studies need to determine how hypothalamic-pituitary-adrenal axis dysfunction affects mood to increase the risk of suicide in major depression.

Resting-state amplitude of low-frequency fluctuation is associated with suicidal ideation.

BACKGROUND: Identifying brain activity patterns that are associated with suicidal ideation (SI) may help to elucidate its pathogenesis and etiology. Suicide poses a significant public health problem, and SI is a risk factor for suicidal behavior. METHODS: Forty-one unmedicated adult participants in a major depressive episode (MDE), 26 with SI on the Beck Scale for Suicidal Ideation and 15 without SI, underwent resting-state functional magnetic resonance imaging scanning. Twenty-one healthy volunteers (HVs) were scanned for secondary analyses. Whole brain analysis of both amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF was performed in MDE subjects to identify regions where activity was associated with SI. RESULTS: Subjects with SI had greater ALFF than those without SI in two clusters: one in the right hippocampus and one in the thalamus and caudate, bilaterally. Multi-voxel pattern analysis distinguished between those with and without SI. Post hoc analysis of the mean ALFF in the hippocampus cluster found it to be associated with a delayed recall on the Buschke memory task. Mean ALFF from the significant clusters was not associated with depression severity and did not differ between MDE and HV groups. DISCUSSION: These results indicate that SI is associated with altered resting-state brain activity. The pattern of elevated activity in the hippocampus may be related to how memories are processed.

Development and evaluation of a multimodal marker of major depressive disorder.

This study aimed to identify biomarkers of major depressive disorder (MDD), by relating neuroimage-derived measures to binary (MDD/control), ordinal (severe MDD/mild MDD/control), or continuous (depression severity) outcomes. To address MDD heterogeneity, factors (severity of psychic depression, motivation, anxiety, psychosis, and sleep disturbance) were also used as outcomes. A multisite, multimodal imaging (diffusion MRI [dMRI] and structural MRI [sMRI]) cohort (52 controls and 147 MDD patients) and several modeling techniques-penalized logistic regression, random forest, and support vector machine (SVM)-were used. An additional cohort (25 controls and 83 MDD patients) was used for validation. The optimally performing classifier (SVM) had a 26.0% misclassification rate (binary), 52.2 ± 1.69% accuracy (ordinal) and r = .36 correlation coefficient (p < .001, continuous). Using SVM, R2 values for prediction of any MDD factors were <10%. Binary classification in the external data set resulted in 87.95% sensitivity and 32.00% specificity. Though observed classification rates are too low for clinical utility, four image-based features contributed to accuracy across all models and analyses-two dMRI-based measures (average fractional anisotropy in the right cuneus and left insula) and two sMRI-based measures (asymmetry in the volume of the pars triangularis and the cerebellum) and may serve as a priori regions for future analyses. The poor accuracy of classification and predictive results found here reflects current equivocal findings and sheds light on challenges of using these modalities for MDD biomarker identification. Further, this study suggests a paradigm (e.g., multiple classifier evaluation with external validation) for future studies to avoid nongeneralizable results.

Kappa opioid receptor binding in major depression: A pilot study.

Endogenous kappa opioids mediate pathological responses to stress in animal models. However, the relationship of the kappa opioid receptor (KOR) to life stress and to psychopathology in humans is not well described. This pilot study sought, for the first time, to quantify KOR in major depressive disorder (MDD) in vivo in humans using positron emission tomography (PET). KOR binding was quantified in vivo by PET imaging with the [11 C]GR103545 radiotracer in 13 healthy volunteers and 10 participants with current MDD. We examined the relationship between regional [11 C]GR103545 total volume of distribution (VT ) and diagnosis, childhood trauma, recent life stress, and, in a subsample, salivary cortisol levels during a modified Trier Social Stress Test (mTSST), amygdala, hippocampus, ventral striatum and raphe nuclei. Whole-brain voxel-wise analyses were also performed. [11 C]GR103545 VT did not differ significantly between MDD participants and healthy volunteers in the four a priori ROIs (p = 0.50). [11 C]GR103545 VT was unrelated to reported childhood adversity (p = 0.17) or recent life stress (p = 0.56). A trend-level inverse correlation was observed between [11 C]GR103545 VT and cortisol area-under-the curve with respect to ground during the mTSST (p = 0.081). No whole-brain voxel-wise contrasts were significant. Regional [11 C]GR103545 VT , a measure of in vivo KOR binding, does not differentiate MDD from healthy volunteers in this pilot sample. Future studies may examine KOR binding in subgroups of depressed individuals at increased risk for KOR abnormalities, including co-occurring mood and substance use disorders, as well as depression with psychotic features.

Utilization of the Tablet Application Proband in Pedigree Construction and Assessment.

Many medical institutions have converted to a digital model for record keeping due to the Health Information Technology for Economic and Clinical Health Act. This Act provides incentives to health care systems to accelerate and encourage the adoption of electronic health record (EHR) systems. The pedigree as a tool in medicine provides an efficient method to assess and represent an individual's health and family health risks that may otherwise not be apparent in the medical record in a clearly identifiable way (Schuette, J. L., & Bennett 2009). Many clinicians continue to construct pedigrees using pen and paper method despite findings of improved identification of at risk patients with similar electronic intake tools (Arar et al. in Personalized Medicine 2011 8:523-32). The goal of this study was to explore the patient and practitioner experience with electronic pedigree programs using Proband, an application developed at The Children's Hospital of Philadelphia for genetic counselors to construct pedigrees during genetic counseling sessions directly on iPads. The first part of this study looked at the patient experience and assessed time to take the pedigree and the impact of using an electronic pedigree tool on the relationship between participant and genetic counselor. This involved 50 participants and was compared with the traditional paper method of taking a pedigree. There was no statistical significance found between the two different mediums in accuracy, speed, and rapport with provider. The second part of the study assessed the usability of Proband by ten genetic counselors. Overall, the application received a system usability score of 90/100 with a majority (7/10) of counselors agreeing that they would use this application in their clinic. The positive outcome of this study encourages future work to assess the impact and usability of programs on a larger scale as they continue to integrate into current electronic health records.

Positron emission tomography quantification of serotonin transporter binding in medication-free bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5-HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [(11)C]DASB, we compared 5-HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). EXPERIMENTAL DESIGN: 5-HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of VT/fP (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. PRINCIPAL OBSERVATIONS: 5-HTT binding (VT/fP ) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BPF*, BPP*, and BPND*) indicated lower binding in BD compared with HV across these six regions of interest (BPF*: P = 0.047; BPP*: P = 0.032; BPND*: P = 0.031). 5-HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. CONCLUSIONS: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [(11)C]DASB. We do not find evidence of abnormal 5-HTT binding in bipolar depression using our primary outcome measure, VT /fP . However, we did observe lower 5-HTT binding in BD with alternative outcome measures that are frequently used with [(11)C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted.

Randomized clinical trial of two oral care regimens in reducing and controlling established dental plaque and gingivitis.

PURPOSE: To evaluate the efficacy of a test regimen (TR) integrating the use of a commercially available triclosan, PVM/MA copolymer, and sodium fluoride containing toothpaste, an alcohol-free, fluoride-free cetylpyridinium chloride (CPC) mouthwash, and a manual toothbrush with cheek and tongue cleaner compared to a negative control regimen (NCR) integrating a commercially available 0.76% sodium monofluorophosphate toothpaste, a manual toothbrush and a fluoride-free and alcohol-free non-antibacterial mouthwash in the reduction and control of established plaque and gingivitis after 4 weeks of product use. METHOD: A 4-week, two-cell, double-blind, parallel-group, randomized clinical study was conducted in Cedar Knolls, New Jersey, USA. Recruited subjects were randomly assigned to two regimens: (1) a commercially available toothpaste containing triclosan, PVM/MA copolymer, and 0.243% sodium fluoride, a manual toothbrush with cheek and tongue cleaner, and commercially available mouthwash containing 0.075% CPC in a fluoride-free and alcohol-free base (TR), or (2) a commercially available 0.76% sodium monofluorophosphate toothpaste, a manual toothbrush with rounded/polished bristles, and a fluoride-free and alcohol-free non-antibacterial mouthwash (NCR). Subjects were examined for dental plaque and gingivitis. Gingival, Gingival Severity, Gingival Interproximal, Plaque, Plaque Severity and Plaque Interproximal Index scores were calculated. For regimen comparison, independent t-test and ANCOVA analyses were performed. RESULTS: 130 subjects were screened; 120 enrolled; and 115 subjects completed the randomized clinical trial (RCT). After 4 weeks of product use, subjects using TR exhibited statistically significant (P < 0.001) reductions of 22.3%, 27.8% and 20.4% in mean Gingival, Gingival Severity and Gingival Interproximal Index scores, respectively, as compared to subjects using NCR. After 4 weeks of product use, subjects using TR exhibited statistically significant (P < 0.001) reductions of 28.2%, 60.7% and 27.6% in mean Plaque, Plaque Severity and Plaque Interproximal Index scores, respectively, as compared to subjects using NCR.