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While many effective antidepressant drugs treat major depressive disorder (MDD), many patients still suffer from residual depressive/anxiety symptoms, poor sleep, cognitive dysfunction, suicidality, or the lack of significant response. Translational or experimental medicine approaches are required to promote or terminate programs for objective data-driven results. This review will discuss translational paradigms that are agnostic with respect to indication such as target occupancy and are especially useful for antagonists/inhibitors. However, there is less certainty regarding required target occupancy for agonists or positive allosteric modulators (PAMs). Thus a range of functional biomarkers are needed including polysomnography (PSG), measuring biasing of emotional response, cognition, impulsivity, and a speculative discussion on microRNAs (miRs). A number of different examples will be described for how these types of biomarkers can be applied to drug development where the most pressing decision is whether to invest $15–20 million on a Phase 2 proof-of-concept (PoC) trial. These biomarkers may also support clinical meaningful differentiation.

Aims The EURO-ENDO registry aimed to study the management and outcomes of patients with infective endocarditis (IE). Methods and results Prospective cohort of 3116 adult patients (2470 from Europe, 646 from non-ESC countries), admitted to 156 hospitals in 40 countries between January 2016 and March 2018 with a diagnosis of IE based on ESC 2015 diagnostic criteria. Clinical, biological, microbiological, and imaging [echocardiography, computed tomography (CT) scan, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)] data were collected. Infective endocarditis was native (NVE) in 1764 (56.6%) patients, prosthetic (PVIE) in 939 (30.1%), and device-related (CDRIE) in 308 (9.9%). Infective endocarditis was community-acquired in 2046 (65.66%) patients. Microorganisms involved were staphylococci in 1085 (44.1%) patients, oral streptococci in 304 (12.3%), enterococci in 390 (15.8%), and Streptococcus gallolyticus in 162 (6.6%). 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 518 (16.6%) patients and presented with cardiac uptake (major criterion) in 222 (42.9%) patients, with a better sensitivity in PVIE (66.8%) than in NVE (28.0%) and CDRIE (16.3%). Embolic events occurred in 20.6% of patients, and were significantly associated with tricuspid or pulmonary IE, presence of a vegetation and Staphylococcus aureus IE. According to ESC guidelines, cardiac surgery was indicated in 2160 (69.3%) patients, but finally performed in only 1596 (73.9%) of them. In-hospital death occurred in 532 (17.1%) patients and was more frequent in PVIE. Independent predictors of mortality were Charlson index, creatinine > 2 mg/dL, congestive heart failure, vegetation length > 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated. Conclusion Infective endocarditis is still a life-threatening disease with frequent lethal outcome despite profound changes in its clinical, microbiological, imaging, and therapeutic profiles.

Strengthening and expanding of production capacity during the last 20 years have led to a need for modernisation in control centres like control rooms and dispatching. However, the use of new I&C technologies induced an explosion of information and new functions, which are available at these workplaces. However, hand in hand higher demands in performance of operators occurred, which finally influenced even the reliability and safety of controlled processes. To cope with this situation, it requires not only responsible control system design, but also implementation of ergonomic aspects in operators' interface design, in working station construction and in parameters of the control centre environment. Pressure in applications of approach with respect to human factors and needs (so called Human-Centred Design) has grown significantly stronger in recent years. This issue has made its way into discussion held by ergonomists, engineers and operation management, and it induces many specific questions. Th...

Background Graze eating is defined as repetitive, unplanned eating of small amounts of food throughout the day. Little consensuses exist regarding whether graze eating, like binge eating disorder (BED), is characterized by feelings of loss of control (LOC). Furthermore, little is known about how patients who graze eat with and without LOC differ psychologically. Objectives The present study seeks to better characterize graze eating by examining differences between graze eating with LOC (+LOC) and without LOC (–LOC) among presurgical bariatric patients. Setting A large, Midwestern academic medical center. Methods The sample consisted of 288 adult bariatric surgery candidates (mean age 45.8, standard deviation [SD] 12.57) who underwent a presurgical psychological evaluation. Graze eating, BED, and other mental health diagnoses were evaluated using a semistructured interview. Participants were also administered the Minnesota Multiphasic Personality Inventory–2–Restructured Form (MMPI-2-RF) and binge eating scale (BES). Data were collected using a retrospective chart review. Results Among the 33% (n = 95) of the sample who reported preoperative graze eating, 32% (n = 30) also endorsed LOC. Graze eating, particularly with LOC, was associated with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnoses of anxiety disorders and BED, and multiple measures of internalizing dysfunction on the MMPI-2-RF. Conclusions Bariatric surgery candidates who graze eat experience a greater degree of overall distress and psychopathology including anxiety and depression. The minority who experience grazing+LOC appear to have even greater risk of psychopathology. Moreover, there appears to be significant overlap with BED. Future research should explore whether these 2 maladaptive eating patterns benefit from similar treatment.

Bariatric surgery is the most effective treatment for morbid obesity; however, a subset of patients who undergo this procedure regain weight or achieve suboptimal weight loss results. A large number of studies have examined whether psychological variables play a role in weight loss surgery outcome. Although presurgical psychopathology has been found to be associated with suboptimal results in some studies, this literature is equivocal. These inconsistent findings are reviewed and considered in the context of contemporary models of psychopathology. More specifically, the review focuses on the limitations of atheoretical, descriptive diagnostic systems and examines whether comorbidity within the mood/anxiety disorders, impulse control/substance use disorders and thought disorders can account for the inconsistent findings reported to date. Contemporary models of psychopathology are highlighted and linked to the Research Domain Criteria, which have been advanced by the National Institute of Health. Means for assessing psychological constructs congruent with these models are reviewed. Recommendations are made for standardizing approaches to investigating how psychopathology contributes to suboptimal bariatric surgery outcomes.

Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm.

There is a need for simple, fast, efficient and sensitive methods of analysis for glyphosate and its degradate aminomethylphosphonic acid (AMPA) in diverse matrices such as water, plant materials and soil to facilitate environmental research needed to address the continuing concerns related to increasing glyphosate use. A variety of water-based solutions have been used to extract the chemicals from different matrices. Many methods require extensive sample preparation, including derivatization and clean-up, prior to analysis by a variety of detection techniques. This review summarizes methods used during the past 15 years for analysis of glyphosate and AMPA in water, plant materials and soil. The simplest methods use aqueous extraction of glyphosate and AMPA from plant materials and soil, no derivatization, solid-phase extraction (SPE) columns for clean-up, guard columns for separation and confirmation of the analytes by mass spectrometry and quantitation using isotope-labeled internal standards. They have levels of detection (LODs) below the regulatory limits in North America. These methods are discussed in more detail in the review.

It is not uncommon for patients to report diminished outcomes as a result of spine surgery or a spinal cord stimulator implant. Presurgical psychological evaluations are increasingly used to identify patients at increased risk for such outcomes and use of personality assessment instruments in these evaluations provides incremental information beyond a clinical interview and medical chart review. This investigation explores the psychometric properties of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in a sample of spine surgery patients (

Background The Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) has empirically validated utility in presurgical psychological evaluations of bariatric surgery patients. However, clinicians may prefer shorter, symptom-focused measures. Objectives The purpose of the present study is to evaluate the feasibility and potential administration time savings of a proposed flexible and conditional (FCA) administration of the MMPI-2-RF in presurgical evaluations of bariatric surgery candidates. Setting Bariatric surgery candidates evaluated at a large hospital as well as a private practice in the Midwest. Methods MMPI-2-RF scores were available for a total of 4099 adult bariatric surgery candidates from 2 separate samples. The hospital sample included 911 males and 2430 females. The average BMI was 49.3 kg/m2 (SD = 11.0). The private practice sample included 105 males, 640 females, and 13 individuals who did not report gender. The average BMI was 48.8 kg/m2 (SD = 8.4). The authors used a simulation design in which existing MMPI-2-RF responses were used to simulate an FCA administration. Results The findings indicated that an FCA of the MMPI-2-RF closely approximates the amount of information typically gained from a full administration of the test in the 2 samples of bariatric surgery candidates. Items savings and estimated time savings ranged from 44% to 88% in both samples, depending on the number of conditionally administered scales. Conclusions The present study supports the feasibility of an FCA of the MMPI-2-RF, potentially shortening administration time and reducing patient burden. However, the findings are limited because the accuracy and time savings are based on a simulation, not actual FCA administrations.

Although spine surgery (SS) and spinal cord stimulators (SCSs) can provide significant relief for patients with intractable pain, their effectiveness is variable. Previously, a number of pre-operative psychosocial risk factors have predicted suboptimal outcomes of these procedures. However, recent research has found that “patient activation”—the extent to which patients are engaged and active in their own health care—can predict positive surgical results. The purpose of the current investigation was to determine whether patient activation helps explain associations between established psychosocial risk factors and suboptimal outcomes. Candidates for SS and SCS (n = 1254; 56.3% women, mean age 50.4 years) consented to participate in an outcome study prior to their pre-surgical psychological evaluation. Of those, 46.3% returned self-report measures an average of 180 days (SD = 79.1) post-surgery. Bootstrapped mediation analyses indicated that patient activation mediates numerous associations between psychosocial risk factors and suboptimal outcomes. That is, patients’ involvement in obtaining information, decision making, and their resilience can explain why some patients do not experience adverse surgical results when pre-surgical psychosocial risk factors are present. Pre-surgical psychological evaluations should include examination of patient strengths in addition to psychosocial risk factors, so that treatments can be appropriately individualized and the most effective surgical results obtained.

Objective Pituitary adenoma MRI T2 signal intensity associates with tumor characteristics including responsiveness to somatostatin analogs (SSAs). These analyses determined whether baseline T2 signal intensity predicts response to primary medical treatment with long-acting SSA. Design Post hoc analyses of the prospective multicenter, open-label, single-arm PRIMARYS study in which patients with treatment-naïve GH-secreting pituitary macroadenomas received fixed-dose lanreotide autogel (120 mg) every 4 weeks for 48 weeks. Methods Associations were investigated between adenoma T2-signal hypo/iso/hyperintensity and treatment responses at week 48/last visit: hormonal control (GH ≤2.5 μg/L and IGF-1 normalization); tumor response (tumor volume reduction (TVR) ≥20%); separate GH/IGF-1 control and change from baseline in GH/IGF-1 and tumor volume. Results Adenomas were hypointense at baseline in 50/85 (59%) patients using visual assessment. Of these, 40% achieved hormonal control and 76% achieved a tumor response. Significant univariate associations arose for hypo- vs isointensity with tumor response and achievement of GH ≤2.5 μg/L, but not IGF-1 normalization or overall hormonal control. In multivariate analysis, tumor response was six times more likely for hypo- vs iso-intense tumors (= 6.15; 95% CI: 1.36–27.88). In univariate change-from-baseline analyses, hypo- vs isointensity was associated with greater TVR and IGF-1 reduction but not change in GH. In multivariate analysis, IGF-1 decreased by an estimated additional 65 μg/L (P = 0.0026)) for hypo- vs isointense. Conclusions Patients with hypointense vs isointense GH-secreting macroadenomas had greater reductions in IGF-1 following primary treatment with lanreotide autogel and were more likely to achieve tumor response. Assessment of T2 signal intensity at baseline may help to predict long-term responses to primary treatment with SSAs.

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts cortisone to cortisol and participates in the regulation of glucocorticoid levels in tissues. 11β-HSD1 is expressed in the liver, kidney, adipose tissue, placenta, and brain. 11β-HSD1 is a target for treatment of depression, anxiety, posttraumatic stress disorder, and also against age-related cognitive function and memory loss. In this study, we evaluated the radiotracer

Background The Binge Eating Scale (BES) is a widely-used self-report measure of binge eating severity. Hood et al. [1] reported a 2-factor structure for the BES in a sample of bariatric surgery candidates, with factors labeled feelings/cognitions and behavioral manifestations. The present study aims to replicate and extend the factor structure obtained by Hood et al. [1] by testing the utility of a bifactor model that removes binge eating severity variance, which the total BES score purports to assess, in another sample of bariatric surgery candidates. Methods Bariatric surgery candidates (n = 517; 71.2% women; mean body mass index=49.50 kg/m 2 ; SD=10.17) were sampled. Twenty-four percent met DSM-IV-TR diagnostic criteria for binge eating disorder. Results Consistent with previous research, a 2-factor structure for the BES was supported; however, the 2 factors were substantially correlated ( r = .89). A bifactor model significantly improved model fit, supporting the presence of a higher-order severity factor accounting for a significant amount of variance. This factor was primarily marked by binge eating severity as demonstrated by associations with number of objective binge eating episodes and DSM-IV-TR diagnosis. In the bifactor model, the feelings/cognitions factor was modestly associated with self-reported mood psychopathology. However, contrary to expectations, the behavioral manifestation factor was not associated with empirically derived behavioral problems. Conclusions The current findings partially converge with those of Hood et al. [1] However, the use of the BES as a 2-factor measure is not recommended at this point because of lack of incremental validity demonstrated by the behavioral manifestation factor. Continued use of the BES as a unidimensional measure of binge eating severity, in conjunction with a comprehensive clinical interview, can provide useful guidance for presurgical treatment recommendations.

Background Presurgical psychological screening is used to identify factors that may impact postoperative adherence and surgical outcomes in bariatric surgery candidates. Minnesota Multiphasic Personality Inventory – 2 Restructured Form (MMPI-2-RF) findings have demonstrated utility for this task. Objectives To explore whether there are clinically meaningful gender, ethnicity, or age differences in presurgical MMPI-2-RF scores and the validity of these scores in bariatric surgery candidates. Methods The sample was composed of 872 men and 2337 women. Ethnicity/race groups included 2,204 Caucasian, 744 African American, and 96 Hispanic individuals. A sample of 165 were not included in the ethnicity/race analyses because they were of another descent. Ages groups included 18–35 year olds (n = 454), 36–49 year olds (n = 1154), 50–64 year olds, (n = 1246), and 65 years old or older (n = 355). Validity data, obtained via a retrospective chart review, were available for a subset patients (n = 1,268) who were similarly distributed. Step-down hierarchical regression analyses were conducted to assess for differential validity. Results Bariatric surgery candidates produced comparable MMPI-2-RF scores in all subsamples, indicating that the test norms generalize across demographic groups. Validity findings were also generally comparable, indicating that MMPI-2-RF scores have the same interpretive implications in demographically diverse subgroups of bariatric surgery candidates. Conclusions The MMPI-2-RF can assist in presurgical psychological screening of demographically diverse bariatric surgery candidates.

A substantial proportion of individuals who undergo surgical procedures to relieve spine pain continue to report significant pain and dysfunction after recovery. Psychopathology and patient expectations have been linked to poor results, leading to an increasing reliance on presurgical psychological screening (PPS) as part of the surgical diagnostic process. The original Minnesota Multiphasic Personality Inventory (MMPI; Hathaway & McKinley, 1943) and the MMPI-2 (Butcher, Graham, Ben-Porath, Tellegen, & Dahlstrom, 2001) were among the measures most commonly used in PPS evaluations and research. This study focuses on the newest version of the test, the MMPI-2-Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008/2011; Tellegen & Ben-Porath, 2008/2011) as a predictor of outcomes for spine surgery candidates. Using a sample of 172 men and 210 women who underwent a PPS, we examined the ability of MMPI-2-RF scale scores to predict early surgical outcomes independent of other presurgical risk factors identified by other means, as well as patients' presurgical expectations. MMPI-2-RF results accounted for up to 11% of additional variance in measures of early postoperative functioning. MMPI-2-RF scales that assess for emotional/internalizing problems, specifically Demoralization, measures of somatoform dysfunction, and interpersonal problems contributed most to the prediction of diminished outcome.

This study examines whether workers' compensation (WC) patients respond more poorly to spine surgery than non-WC patients and whether poorer outcome is associated with individual differences in personality and emotional variables, as assessed by the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF). Three-hundred eighty-two patients underwent presurgical psychological screening that included a diagnostic interview and psychometric testing. Pain level, functional ability, work status, medication use, and emotional distress were assessed at baseline and at an average of 6 months postoperative. WC patients showed significantly poorer response to spine surgery than did non-WC patients on measures of pain level, functional ability, work status, medication use, and emotional distress. MMPI-2-RF scales assessing demoralization, somatic complaints, and low positive emotions were found to be incrementally associated with diminished surgery results.

ObjectiveTo evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40–120 mg/week) in acromegaly.DesignThis is a 28-week, multicenter, open-label, single-arm sequential study.MethodsPatients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40–80 mg once weekly or 40 or 60 mg twice weekly).ResultsIn total, 33 (57.9%) patients had normalized IGF1 following coadministration (PP5×upper limit of normal with normalization after withdrawal).ConclusionsIn patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 (mGlu2/3) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu2 gene profoundly attenuates an effect of 5-HT2A receptor activation using the mouse head twitch response (HTR). MGlu2 and mGlu3 receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity. DOI failed to produce significant head twitches in mGlu2 receptor KO mice at a dose 10-fold higher than the peak effective dose in WT or mGlu3 receptor KO mice. In addition, the mGlu2/3 receptor agonist LY379268, and the mGlu2 receptor positive allosteric modulator (PAM) CBiPES, potently blocked the HTR to DOI in WT and mGlu3 receptor KO mice. Conversely, the mGlu2/3 receptor antagonist LY341495 (10 mg/kg) increased the HTR produced by DOI (3 mg/kg) in mGlu3 receptor KO mice. Finally, the mGlu2 receptor potentiator CBiPES was able to attenuate the increase in the HTR produced by LY341495 in mGlu3 receptor KO mice. Taken together, all of these results are consistent with the hypothesis that that DOI-induced head twitches are modulated by mGlu2 receptor activation. These results also are in keeping with a critical autoreceptor function for mGlu2 receptors in the prefrontal cortex with differential effects of acute vs. chronic perturbation (e.g., constitutive mGlu2 receptor KO mice). The robust attenuation of DOI-induced head twitches in the mGlu2 receptor KO mice appears to reflect the critical role of glutamate in ongoing regulation of 5-HT2A receptors in the prefrontal cortex. Future experiments with inducible knockouts for the mGlu2 receptor and/or selective mGlu3 receptor agonists/PAMs/antagonists could provide an important tools in understanding glutamatergic modulation of prefrontal cortical 5-HT2A receptor function.

5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the β2-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 μM). Epinephrine (0.3–10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3–3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective β2-adrenergic receptor antagonist ICI-118,553 (0.01–1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, β2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears to extend this suppressant action to a Gs-coupled GPCR. Furthermore, the modulation of 5-HT2A receptor activation-induced glutamate release onto mPFC layer V pyramidal neurons apical dendrites by a range GPCRs in rat brain slices appears to results in behaviorally salient effects of relevance when screening for novel CNS therapeutic drugs.

The current investigation aims to predict 3-year postoperative percent total weight loss among a sample of bariatric surgery patients with super-super obesity.Previous research implies that persons with presurgical super-super obesity (body mass index [BMI] ≥60 kg/mCleveland Clinic, BariatricMetabolic Institute, Cleveland, OH.Bariatric surgery candidates (N = 1231; 71.9% female; 65.8% Caucasian) completed a presurgical psychological evaluation and the Minnesota Multiphasic Personality Inventory-2-Restructured Form. Participants with a baseline BMI ≥60 (n = 164) were compared with BMI60 (n = 1067) on psychosocial and demographic factors, the Minnesota Multiphasic Personality Inventory-2-Restructured Form, and in the subset that had surgery (n = 870), percent total weight loss extending to the 3-year follow-up.Patients with a BMI ≥60 were younger, less educated, and more likely to be male compared with lower BMI patients. Patients with a BMI ≥60 had greater psychosocial sequelae as evidenced by being more likely to have a history of sexual abuse, history of psychiatric hospitalization, more binge eating episodes, and higher prevalence of major depression disorder and binge eating disorder. On the Minnesota Multiphasic Personality Inventory-2-Restructured Form, those with BMI ≥60 reported greater demoralization, low positive emotions, ideas of persecution, and dysfunctional negative emotions. After controlling for surgery type, weight loss for individuals with BMI ≥60 did not greatly differ from weight loss in patients with BMI60. Variables predictive of less weight loss at 3 years regardless of presurgical BMI, included being older, having a sexual abuse history, and higher ideas of persecution scores.Although patients with BMI ≥60 evidenced more psychopathology before surgery, findings suggest that the relationship between higher BMI and poorer outcome may better be explained by other co-morbid factors.

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT

Focusing on average weight loss (WL) from interventions provides useful efficacy data but masks large variability across patients. In this study, parameters of weight loss trajectories were determined that differentiated individuals during a 15-week clinical lifestyle intervention.Patients (n = 595) were in a fee-for-service WL lifestyle program with a partial meal replacement diet and lifestyle change counseling. Parameters used in latent class analyses were percent WL (%WL), weight nadir, number of weekly weight gains, maximum weekly percent weight gain, standard deviation of weekly weight changes, linear slope values, and change in slope.Average %WL was 9.73%. Latent class analyses revealed three groups with considerable overlap in %WL ranges but differing significantly on all trajectory parameters (Ps 0.001). Group 1 had the most variable and least successful pattern of weight changes. Group 3 had the least variable and most successful pattern of weight changes. Group 2 fell between the others on all parameters.Emphasis on average WL likely obscures considerable variability in individual courses of weight change. Moreover, patients with similar %WL can have different WL trajectories. Identification of behavioral/physiological characteristics associated with different weight loss trajectories may facilitate the development of more tailored interventions, particularly for trajectories associated with less optimal outcomes.

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

Objective Binge eating disorder (BED) was recently included in the DSM-5. The prevalence rate for BED using the DSM-IV-TR research criteria tends to be higher in bariatric surgery candidates than the normative population; however, no studies have examined how many more bariatric surgery candidates will meet the new, less conservative criteria of DSM-5. We explore the current BED prevalence rate change in a sample of bariatric surgery candidates. Method Data were obtained for 1,283 bariatric surgery candidates. 84 men and 213 women were diagnosed with current BED using DSM-IV-TR research criteria. A semi-structured interview, the binge eating scale (BES), and a Minnesota Multiphasic Personality Inventory—2 Restructured Form (MMPI-2-RF) were given to every patient as part of standard procedures mandated by the facility. Results and Discussion An additional 3.43% (p

This 5-year, prospective registry enrolled 600 lower-risk MDS patients (pts) with transfusional iron overload. Clinical outcomes were compared between chelated and nonchelated pts. At baseline, cardiovascular comorbidities were more common in non-chelated pts, and MDS therapy was more common in chelated pts. At 24 months, chelation was associated with longer median overall survival (52.2 months vs. 104.4 months; p

Presurgical psychological screening of bariatric surgery candidates includes some form of standardized psychological assessment. However, associations between presurgical psychological screening and postoperative outcome have not been extensively studied. Here, we explore associations between presurgical Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) scores and early postoperative Somatic Concerns, Psychological Distress, and Maladaptive Eating Behaviors.The sample consisted of male (n = 238) and female (n = 621) patients who were administered the MMPI-2-RF at their presurgical psychological evaluation and received bariatric surgery. Patients were evaluated at their 1- and 3-month postoperative appointments.Confirmatory factor analysis indicated that three latent constructs-somatic concerns, psychological distress, and maladaptive eating behaviors-were represented by responses to a postoperative assessment and that these constructs could be measured consistently over time. Presurgical scores on MMPI-2-RF scales measuring internalizing dysfunction were associated with more psychological distress at postoperative follow-ups, scores on scales measuring somatization were associated with more postoperative somatic concerns, and scores on scales assessing emotional/internalizing, behavioral/externalizing, cognitive complaints, and thought dysfunction prior to surgery were associated with maladaptive eating behaviors after surgery.In conjunction with a presurgical psychological interview, the MMPI-2-RF provides information that can assist in anticipating postoperative outcomes and inform efforts to prevent them.

Nucleic acids can form efficient hybrid catalysts for asymmetric catalysis upon binding of low-molecular-weight metal complexes. Up to now DNA has been the preferred nucleic acid component, while RNA was largely ignored. It is shown that despite RNA's successful use in ribozymes, RNA is less suited for use in hybrid catalysts for asymmetric catalysis. A common dimethyl bipyridine copper complex does not form highly active and enantioselective hybrid catalysts with RNA due to the absence of synergistic effects between the copper complex and dsRNA.

This paper deals with new UHPFRC (Ultra High Performance Fibre Reinforced Concrete) bridges produced or constructed in 2018 in the Czech Republic. The paper includes a short description of 3 unique pedestrian bridges with load bearing structure made of UHPFRC and 2 steel bridges over the railway track with lost formwork for bridge decks and cornices made of thin UHPFRC slabs. Focus is given on the testing of the material, comparison of test specimens and summary of results from UHPFRC production in real scale. The size effect of control specimen and the results analysis is given in the last chapter. The 3 mentioned unique pedestrian bridges are Footbridge over the Lubina river in city Příbor, Pedestrian and cycle bridge in the vicinity of Black Bridges in city Tábor and Footbridge over Dřetovice stream in Vrapice - a district of Kladno city. Thin panels as permanent lost formwork for two bridges over the railway tracks are in city Přerov. All new UHPFRC structures should be worthy of attention of bridge experts and community of specialists in the field of concrete engineering.

BACKGROUND There is a need for a simple, fast, efficient and sensitive method for analysis of glyphosate and its degradate aminomethylphosphonic acid (AMPA) in diverse matrices such as water, vegetation and soil. RESULTS Aqueous extracts from water, vegetation and soil were passed through reverse-phase and cation-exchange columns and directly injected into a tandem mass spectrometer using only a guard column for separation. Extraction efficiencies from the three matrices were >80% for both glyphosate and AMPA. The method reporting levels (MRLs) for glyphosate in water, vegetation and soil were 3.04 µg L−1, 0.05 mg kg−1 and 0.37 mg kg−1 respectively. AMPA MRLs were 5.06 µg L−1 for water, 0.08 mg kg−1 for vegetation and 0.61 mg kg−1 for soil. CONCLUSIONS A validated, simple and efficient liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for routine analysis of glyphosate and AMPA in water, vegetation and soil that uses minimal sample handling and clean-up will facilitate the additional environmental research needed to address the continuing concerns related to increasing glyphosate use. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Objective Binge Eating Disorder (BED) is among the most common psychiatric disorders in bariatric surgery candidates. The Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) is a broadband, psychological test that includes measures of emotional and behavioral dysfunction, which have been associated with BED behaviors in bariatric surgery candidates; however these studies have lacked appropriate controls. In the current study, we compared MMPI-2-RF scale scores of bariatric surgery patients diagnosed with BED (BED+) with BMI-matched controls without BED (BED–). Method Three-hundred and seven BED+ participants (72.64% female and 67.87% Caucasian; mean BMI of 51.36 kg/m2 [SD = 11.94]) were drawn from a large, database (N = 1304). Three-hundred and seven BED– participants were matched on BMI and demographics (72.64% female, 68.63% Caucasian, and mean BMI of 51.30 kg/m2 [SD = 11.70]). Results The BED+ group scored significantly higher on measures of Demoralization, Low Positive Emotions, and Dysfunctional Negative Emotions and scored lower on measures of Antisocial Behaviors, reflecting behavioral constraint. Optimal T-Score cutoffs were below the traditional 65 T score for several MMPI-2-RF scales. MMPI-2-RF externalizing measures also added incrementally to differentiating between the groups beyond the Binge Eating Scale (BES). Discussion BED+ individuals produced greater elevations on a number of MMPI-2-RF internalizing scales and externalizing scales. Use of the test in conjunction with a clinical interview and other self-report data can further aid the clinician in guiding patients to appropriate treatment to optimize outcome. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2014; 47:315–319)

Psychological comorbidity is common in bariatric surgery candidates. Many multidisciplinary teams incorporate psychometric testing to screen for psychological factors that, if left unattended, may negatively impact surgical results. Here, we report descriptive findings and empirical correlates of Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) scales among of bariatric surgery candidates undergoing a pre-surgical psychological evaluation.The sample consisted of male (n = 324) and female (n = 658) patients seeking bariatric surgery who were administered the MMPI-2-RF at their psychological evaluation. Psychosocial and medical variables were retrospectively coded from the patients' medical records. These criteria included history/current mental health diagnoses and treatments, maladaptive eating behaviors/diagnoses, past/current substance use, abuse history, sleep apnea, and denial of surgery.Descriptive analyses demonstrated similar findings for male and female candidates and replicated previous reports. MMPI-2-RF scales measuring emotional dysfunction were associated with maladaptive eating patterns, a history of Major Depressive Disorder, and previous suicide attempts. Scale scores measuring behavioral dysfunction were associated with current/past substance use and previous physical abuse. MMPI-2-RF scale scores measuring somatic problems were associated with a higher BMI at the time of surgery, sleep apnea diagnosis/adherence, physical/sexual abuse history, active mood disorder, previous mental health diagnoses, and maladaptive eating patterns.The MMPI-2-RF can aid in identifying a broad range of psychological comorbidity among bariatric surgery candidates. When used in conjunction with a pre-surgical psychological interview, it can aid in the assessment of psychological factors relevant to pre-surgical psychological assessment of bariatric surgery candidates.

Important functional interactions between the metabotropic glutamate 2 (mGlu2) and 5-hydroxytryptamine2A (5-HT₂A) neurotransmitter receptors have been established based on electrophysiological, biochemical and behavioral evidence. Over the last several years, dimerization between 5-HT₂A and mGlu2 receptors has been proposed to account for the functional cross-talk between these two receptors in the prefrontal cortex. The pros and cons for the existence of a heteromeric complex between 5-HT₂A and mGlu2 receptors will be reviewed here. First, the fundamental criteria needing to establish evidence for heteromeric complexes will be reviewed. Then, the in vitro evidence for and against heteromeric complexes between 5-HT₂A and mGlu2 receptors will be discussed in regard to physical and functional interactions. Finally, the data with native in situ mGlu2 and 5-HT₂A receptors will be discussed with respect to whether heteromeric complexes or a simple functional interaction between two distinct GPCRs based on brain network activity is the more simple explanation for a range of in vivo data.

Objective Studies have demonstrated that negative affect increases prior to food intake in individuals diagnosed with an eating disorder. Mindfulness has been supported empirically to treat experiential avoidance stemming from anxiety. Thus, the current objective in this study is to empirically compare mindfulness vs. thought suppression invention during a food exposure in both clinical and nonclinical samples. Method In a 2 (Group: clinical vs. nonclinical) × 2 (Intervention: mindfulness vs. distraction) counterbalanced within treatment design, the current investigation sought to determine the differential effectiveness of a brief mindfulness intervention vs. a brief distraction intervention in women diagnosed with AN and BN in a clinical and nonclinical sample during a food exposure. Results Results indicated that the eating disorder group reported a significant increase in negative affect after the mindfulness intervention as compared to the distraction intervention, whereas the nonclinical group reported a significant decrease in negative affect after the mindfulness intervention as compared to the distraction intervention. Discussion Preliminary findings suggest that clinicians may want to proceed cautiously when using mindful eating in those with severe eating disorders during the early stages of food exposure. Limitations and future directions are discussed. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013; 46:582–585)

Group II metabotropic glutamate (mGlu) receptor agonists were efficacious in randomized clinical research trials for schizophrenia and generalized anxiety disorder. The regional quantification of mGlu(2) and mGlu(3) receptors remains unknown. A selective and structurally novel mGlu(2/3) receptor agonist, 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY459477) was tritiated and the distribution of mGlu(2) and mGlu(3) receptors was studied in transgenic mice lacking either mGlu(2), mGlu(3) or both receptors. LY459477 is an agonist with 1-2 nM potency for rodent and human mGlu(2) and mGlu(3) receptors. The functional selectivity of LY459477 was demonstrated by over 640-fold selectivity and the displacement binding selectivity was greater than 320-fold for all glutamate receptors except mGlu(6) (∼230-fold). More than 1000-fold selectivity was demonstrated for all non-glutamate receptors known to be targeted by antipsychotic drugs. Like atypical antipsychotic drugs, LY459477 reversed in vitro electrophysiological effects of a serotonergic hallucinogen and behavioral effects of phencyclidine or amphetamine. There was virtually no binding of [(3)H]LY459477 to any brain region in mice with a deletion of both mGlu(2) and mGlu(3) receptors. Regions enriched in mGlu(2) receptors included the medial prefrontal cortex, select hippocampal regions, the medial mammillary nucleus, the medial habenula, and the cerebellar granular cell layer. Regions enriched in mGlu(3) receptors were the dorsolateral entorhinal cortex, the hippocampal CA1 field, the piriform cortex, the substantia nigra, the thalamic reticular nucleus, and primary sensory thalamic nuclei. These findings suggest [(3)H]LY459477 should be a useful tool to further define the role of mGlu(2) and mGlu(3) receptors throughout the brain with respect to major neuropsychiatric syndromes. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

ABT-384 is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1), the enzyme that regenerates cortisol in several tissues. Two clinical studies of ABT-384 were undertaken to assess its safety, pharmacokinetics, target engagement, and pharmacologic effects in healthy subjects. Single doses from 1 to 240 mg, and multiple doses from 1 to 100 mg once daily for 7-14 days, were administered to healthy adults. Multiple doses from 10 to 100 mg once daily for 21 days were administered to elderly subjects. A total of 103 subjects received at least 1 dose of ABT-384. A maximum-tolerated dose was not defined in either study. The pharmacokinetic profiles of ABT-384 and its active metabolite support once daily dosing. Analysis of urine cortisol metabolites demonstrated full hepatic HSD-1 inhibition with regimens from 1 mg daily, and confirmed in vitro target selectivity. Pharmacologic effects included increases of adrenocorticotrophic hormone levels, cortisol production and androgen and estradiol levels. ABT-384 has a wide therapeutic index relative to full hepatic target engagement which is relevant for indications such as diabetes and metabolic syndrome. Its therapeutic index for other potential indications such as Alzheimer's disease remains to be established.

Bariatric surgery is a viable treatment option for patients with extreme obesity and associated medical comorbidities; however, optimal surgical outcomes are not universal. Surgical societies, such as the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend that patients undergo a presurgical psychological evaluation that includes reviewing patients' medical charts, conducting a comprehensive clinical interview, and employing some form of objective psychometric testing. Despite numerous societies recommending the inclusion of self-report assessments, only about 2/3 of clinics actively use psychological testing-some of which have limited empirical support to justify their use. This review aims to critically evaluate the psychometric properties of self-report measures when used in bariatric surgery settings and provide recommendations to help guide clinicians in selecting instruments to use in bariatric surgery evaluations. Recommended assessment batteries include use of a broadband instrument along with a narrowband eating measure. Suggestions for self-report measures to include in a presurgical psychological evaluation in bariatric surgery settings are also provided. (PsycINFO Database Record

Background Psychosocial factors contribute to poorer weight loss outcomes following bariatric surgery; however, findings on associations between preoperative psychiatric diagnoses, psychological testing, and weight loss are inconsistent. Objectives Examine associations between presurgical psychiatric diagnoses derived from a semi-structured clinical interview and test scores from the Minnesota Multiphasic Personality-Inventory−2 – Restructured Form (MMPI-2-RF) and 5-year Body Mass Index (BMI) outcomes. Setting Cleveland Clinic Bariatric and Metabolic Institute Methods 446 consecutively consented patients who underwent a Roux-en-Y gastric bypass (RYGB) at least 5 years prior were included in the study. A majority were women (74.2%) and Caucasian (66.2%). Patients' mean presurgical BMI was 49.14 kg/m 2 [SD = 9.50 kg/m 2 ]. Psychiatric diagnoses were obtained from a presurgical, semi-structured clinical interview and all participants were administered the MMPI-2-RF at their presurgical evaluations. BMIs were collected at 4 postoperative time points across a 5-year trajectory. This prospective design utilized latent growth curve modeling. Results Older patients evidenced a slower rate of BMI reduction over time. A presurgical diagnosis of Binge Eating Disorder predicted higher BMIs at the 5-year outcome. Scores on MMPI-2-RF measures of emotional and behavioral dysfunction domains incrementally predicted poorer weight loss outcomes. Conclusion Preoperative indicators of psychopathology, notably indicators that are dimensional in nature, are important in predicting postoperative outcomes. Closer follow-up with patients who evidence presurgical psychological factors, both before and after surgery, may help improve outcomes.

The origin of modern psychopharmacology can be traced to the discovery of the first clinically efficacious antipsychotic drug, chlorpromazine, in 1952. Following this watershed advance, several additional antipsychotic agents of the same (i.e., phenothiazine) class, as well as others derived from the butyrophenone scaffold (e.g., haloperidol, 1958), were discovered and widely utilized in the treatment of schizophrenia patients. Arvid Carlsson and his colleagues were the first to show that antipsychotics of both the phenothiazine and butyrophenone classes acted via blockade of dopamine (DA) receptors [1]. This hypothesis was further refined over a decade later by observations that all antipsychotic drugs potently block dopamine D2-like receptors [2, 3]. Interest in moving to mechanisms of antipsychotic action other than dopamine D2

Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT(2A) and the metabotropic glutamate receptor mGlu(2) has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT(2A)-mGlu(2) heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT(2A)-mGlu(2) heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu(2) formed complexes with 5-HT(2B) and mGlu(5) but not 5-HT(2C) indicating that complex formation is not specific to the 5-HT(2A)-mGlu(2) pair. We studied the functional consequences of the 5-HT(2A)-mGlu(2) heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu(2) agonists, antagonists and PAMs, or 5-HT(2A) hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT(2A) agonists induced signaling through G(q/11), but not G(i) and thus did not lead to modulation of intracellular cAMP levels. In membranes of the medial prefrontal cortex [(3)H]-LY341495 binding competition of mGlu(2/3) agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT(2A)-mGlu(2) heterocomplex.

In vivo translational imaging techniques, such as positron emission tomography and single-photon emission-computed tomography, are the only ways to adequately determine that a drug engages its target. Unfortunately, there are far more experimental mechanisms being tested in the clinic than there are radioligands, impeding the use of this risk-mitigating approach in modern drug discovery and development. Pharmacological magnetic resonance imaging (phMRI) offers an approach for developing new biomarkers with the potential to determine central activity and dose selection in animals and humans. Using phMRI, we characterized the effects of xanomeline on ketamine-induced activation on blood oxygen level-dependent (BOLD) signal. In the present studies, xanomeline alone dose-dependently increased the BOLD signal across several regions of interest, including association and motor and sensory cortical regions. It is noteworthy that xanomeline dose-dependently attenuated ketamine-induced brain activation patterns, effects that were antagonized by atropine. In conclusion, the muscarinic 1/4-preferring receptor agonist xanomeline suppressed the effects of the N-methyl-D-aspartate channel blocker ketamine in a number of brain regions, including the association cortex, motor cortex, and primary sensory cortices. The region-specific brain activation observed in this ketamine challenge phMRI study may provide a method of confirming central activity and dose selection for novel antipsychotic drugs in early clinical trials for schizophrenia, if the data obtained in animals can be recapitulated in humans.