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Serotonin receptors blockade is the major basis for the action of atypical antipsychotic drugs. Genetic factors affecting the density and/or function of serotonergic receptors, transporters and enzymes may therefore affect antipsychotic response. This exploratory study investigates the effect of ten polymorphisms from HTR1A, HTR1D, HTR2A, HTR3A, HTR3B, HTR4, HTR6, SLC6A4, TPH1, TPH2 genes on antipsychotic response in a sample of 289 patients with DSM-diagnosis of schizophrenia. Clinical Response was assessed using Brief Psychiatric Rating Scale (BPRS). Response was determined as 20% reduction improvement of BPRS compared to baseline. Selection of the biological relevant interactions, regardless the phenotype was performed using different statistics strategies regardless the phenotype to investigate epistasis within the serotonin system. the test for relevant interaction selection showed that 5HT4 and 5HT6 can be in epistatic relationship. the single locus analysis of these two receptor polymorphisms showed no significant results and the logistic regression model incorporating both genes, the clinical and demographic variables was not significant. Even this result is not significant, this strategy aimed to investigate the epistatic effect among genes could be useful for finding relevant biological interaction among genetic variants. Furthermore we are currently analyzing the methylation level of HTR2A in responders and non-responders, this epigenetic analysis will be very valuable in adding more information to the classic pharmacogenetic studies.
Methadone, a long-acting opioid agonist commonly used in the treatment of opiate dependence, has been reported to cause QTc interval prolongation, increasing the risk of a fatal cardiac arrhythmia – Torsades-de-Pointes (TdP). This effect seems to be attributable to methadone's inhibitory effect on the cardiac “hERG”-K+ ion channel and is dose-dependent. There is a lack of consensus regarding when to perform an ECG for patients on methadone.
Identifying other TdPPRFs in a cohort of patients receiving ≥ 85 mg (high dose) methadone daily to inform local clinical safety guidelines.
Our outpatient caseload was filtered to select opiate-dependent patients receiving more than 85 mg methadone daily. Primary care summaries and laboratory results databases were analysed for the presence of other TdPPRFs: female sex a documented history of ECG abnormalities, electrolyte imbalance, liver or renal failure, and concomitant use of other QT prolonging medication or stimulants.
Fourteen opiate-dependent patients (10.29% of patients on methadone) were maintained on ≥ 85 mg methadone daily. Gender distribution was F:M = 1:1.8; 64% misused illicit stimulants; 57% were prescribed other QTc prolonging medication and 29% had a documented history of liver/renal failure or electrolyte imbalance. Only 14% had previous ECGs documented in primary care summaries. Of patients on high dose methadone, 85.7% had at least one TdPPRFs present and 64.3% had at least two.
These results demonstrate an increased rate of TdPPRFs in this patient group and highlight the importance of ECG monitoring which ideally should be offered to patients receiving even lower doses of methadone.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Overconsumption of fructose time dependently induces the development of non-alcoholic fatty liver disease (NAFLD). We investigated whether ursolic acid (UA) intake by new-born rats would protect against fructose-induced NAFLD. One hundred and seven male and female Sprague Dawley rat pups were randomly grouped and gavaged (10 ml/kg body weight) with either 0.5% dimethylsulphoxide (vehicle control), 0.05% UA, 50% fructose mixed with UA (0.05%) or 50% fructose alone, from postnatal day 6 (P6) to P20. Post-weaning (P21–P69), the rats received normal rat chow (NRC) and water to drink. On P70, the rats in each group were continued on water or 20% fructose to drink, as a secondary high fructose diet during adulthood. After 8 weeks, body mass, food and fluid intake, circulating metabolites, visceral adiposity, surrogate markers of liver function and indices of NAFLD were determined. Food intake was reduced as a result of fructose feeding in both male and female rats (p < 0.0001). Fructose consumption in adulthood significantly increased fluid intake and visceral adiposity in female rats (p < 0.05) and had no apparent effects in male rats (p > 0.05). In both sexes of rats, fructose had no significant (p > 0.05) effects on body mass, circulating metabolites, total calorie intake and surrogate markers of hepatic function. Fructose consumption in both early life and adulthood in female rats promoted hepatic lipid accumulation (p < 0.001), hypertrophy, microvesicular and macrovesicular steatosis (p < 0.05). Early-life UA intake significantly (p < 0.001) reduced fructose-induced hepatic lipid accumulation in both male and female rats. Administration of UA during periods of developmental plasticity shows prophylactic potential against dietary fructose-induced NAFLD.
Patients with major depressive disorder (MDD) display cognitive deficits in acutely depressed and remitted states. Childhood maltreatment is associated with cognitive dysfunction in adults, but its impact on cognition and treatment related cognitive outcomes in adult MDD has received little consideration. We investigate whether, compared to patients without maltreatment and healthy participants, adult MDD patients with childhood maltreatment display greater cognitive deficits in acute depression, lower treatment-associated cognitive improvements, and lower cognitive performance in remission.
Healthy and acutely depressed MDD participants were enrolled in a multi-center MDD predictive marker discovery trial. MDD participants received 16 weeks of standardized antidepressant treatment. Maltreatment and cognition were assessed with the Childhood Experience of Care and Abuse interview and the CNS Vital Signs battery, respectively. Cognitive scores and change from baseline to week 16 were compared amongst MDD participants with (DM+, n = 93) and without maltreatment (DM−, n = 90), and healthy participants with (HM+, n = 22) and without maltreatment (HM−, n = 80). Separate analyses in MDD participants who remitted were conducted.
DM+ had lower baseline global cognition, processing speed, and memory v. HM−, with no significant baseline differences amongst DM−, HM+, and HM− groups. There were no significant between-group differences in cognitive change over 16 weeks. Post-treatment remitted DM+, but not remitted DM−, scored significantly lower than HM− in working memory and processing speed.
Childhood maltreatment was associated with cognitive deficits in depressed and remitted adults with MDD. Maltreatment may be a risk factor for more severe and persistent cognitive deficits in adult MDD.
The National Project on Achievement in Twins (NatPAT) began in 2017 as part of the third funding cycle of the Florida Learning Disabilities Research Center, a program project grant funded by the Eunice Kennedy Shriver National Institute of Child Health and Development. NatPAT will have a nationally representative sample of elementary school-aged twins in the United States. The overall goal of the project is to uncover salient factors, including genetic and environmental influences, which contribute to the co-development of reading and math performance during the critical developmental period of elementary school. Here we present the specific aims, methods and materials, and future directions of the project.
Individuals experiencing different medical conditions, as well as healthy volunteers, may often be interested in trial participation, and researchers similarly need to find participants to advance medical knowledge. The ResearchMatch (RM) Trials Today clinical trial searching tool leverages clinicaltrials.gov data to enable potential participants to look for trial opportunities relevant to their situation. To facilitate expanded use of this tool, we undertook a national digital public awareness campaign to increase awareness of Trials Today among members of the general public.
The awareness campaign promoted Trials Today using Facebook and digital banner messages in 2017, encompassing nine cities across the USA. The digital strategy was complemented by print media in several outlets. We employed descriptive statistics to summarize campaign metrics and site usage data during the campaign.
The campaign was successful in increasing visits to Trials Today, with 142,303 sessions logged during its run, as compared to pre-campaign data indicating 104,688 total sessions during the entire 2-year period since the site’s inception. The city-specific click-through rate for all digital impressions, combining Facebook and banner messaging, ranged from 0.50% to 1.09%, resulting in a cost-per-click range of $0.69–$1.15. In addition, visitors conducted 29,697 searches and viewed individual trial records 173,512 times.
The public awareness campaign was successful in increasing use of the RM Trials Today clinical trial searching tool. Our findings support the value of digital media messaging as a cost-effective vehicle for promoting clinical trial awareness, especially for chronic ailments.
Global inequity in access to and availability of essential mental health services is well recognized. The mental health treatment gap is approximately 50% in all countries, with up to 90% of people in the lowest-income countries lacking access to required mental health services. Increased investment in global mental health (GMH) has increased innovation in mental health service delivery in LMICs. Situational analyses in areas where mental health services and systems are poorly developed and resourced are essential when planning for research and implementation, however, little guidance is available to inform methodological approaches to conducting these types of studies. This scoping review provides an analysis of methodological approaches to situational analysis in GMH, including an assessment of the extent to which situational analyses include equity in study designs. It is intended as a resource that identifies current gaps and areas for future development in GMH. Formative research, including situational analysis, is an essential first step in conducting robust implementation research, an essential area of study in GMH that will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in low- and middle-income countries (LMICs). While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions.
There is renewed interest in the inverse association between psychiatric hospital and prison places, with reciprocal time trends shown in more than one country. We hypothesised that the numbers of admissions to psychiatric hospitals and committals to prisons in Ireland would also correlate inversely over time (i.e. dynamic measures of admission and committal rather than static, cross-sectional numbers of places).
Publicly available activity statistics for psychiatric hospitals and prisons in Ireland were collated from 1986 to 2010.
There was a reciprocal association between psychiatric admissions and prison committals (Pearson r=−0.788, p<0.001), an increase of 91 prison committals for every 100 psychiatric hospital admissions foregone.
Penrose’s hypothesis applies to admissions to psychiatric hospitals and prisons in Ireland over time (dynamic measures), just as it does to the numbers of places in psychiatric hospitals and prisons in Ireland and elsewhere (static, cross-sectional measures). Although no causal connection can be definitively established yet, mentally disordered prisoners are usually known to community mental health services. Psychiatric services for prisons and the community should be linked to ensure that the needs of those currently accessing care through prisons can also be met in the community.
We report a rapid combustion synthesis method for producing band gap tunable gallium zinc oxynitrides, a material of interest for water splitting applications. By varying the ratio of zinc and gallium, we can tune the band gap from 2.22 to 2.8 eV. Furthermore, nitrogen can be incorporated up to nearly 50% via replacement of oxygen without the need for high temperatures or an additional ammonolysis step. X-ray photoelectron spectroscopy (XPS) and EDX analysis suggests a preferential segregation of Zn to the surface of the as-synthesized particles, though the surface Ga/Zn molar ratio in the as-synthesized particles is correlated with the Ga/Zn molar ratio of the precursor materials. Photoelectrochemical measurements show that the oxynitride powders are photoactive under both AM1.5 and visible-only (λ > 435 nm) irradiation. Hydrogen and oxygen were both evolved in half-reaction experiments under simulated AM1.5 irradiation without externally applied bias, although addition of an OER catalyst did not enhance the rate of oxygen formation, suggesting that intra- and interparticle recombination are significant.
In an effort to optimize patient outcomes, considerable attention is being devoted to identifying patient characteristics associated with major depressive disorder (MDD) and its responsiveness to treatment. In the current study, we extend this work by evaluating whether early change in these sensitivities is associated with response to antidepressant treatment for MDD.
Participants included 210 patients with MDD who were treated with 8 weeks of escitalopram and 112 healthy comparison participants. Of the original 210 patients, 90 non-responders received adjunctive aripiprazole for an additional 8 weeks. Symptoms of depression and anhedonia were assessed at the beginning of treatment and 8 weeks later in both samples. Reward and punishment sensitivity were assessed using the BIS/BAS scales measured at the initiation of treatment and 2 weeks later.
Individuals with MDD exhibited higher punishment sensitivity and lower reward sensitivity compared with healthy comparison participants. Change in reward sensitivity during the first 2 weeks of treatment was associated with improved depressive symptoms and anhedonia following 8 weeks of treatment with escitalopram. Similarly, improvement in reward responsiveness during the first 2 weeks of adjunctive therapy with aripiprazole was associated with fewer symptoms of depression at post-treatment.
Findings highlight the predictive utility of early change in reward sensitivity during antidepressant treatment for major depression. In a clinical setting, a lack of change in early reward processing may signal a need to modify a patient's treatment plan with alternative or augmented treatment approaches.
The appeal of ketamine – in promptly ameliorating depressive symptoms even in those with non-response – has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives – derived from evidence and clinical experience – and to consider strategies for future investigations.
We sought to identify and review published studies that discuss the ethical considerations, from a physician’s perspective, of managing a hunger strike in a prison setting.
A database search was conducted to identify relevant publications. We included case studies, case series, guidelines and review articles published over a 20-year period. Non-English language publications were translated.
The review found 23 papers from 12 jurisdictions published in five languages suitable for inclusion.
Key themes from included publications are identified and summarised in the context of accepted guidelines from the World Medical Association. Whilst there seems to be an overall consensus favouring autonomy over beneficence, tensions along this fine balance are magnified in jurisdictions where legislation leads to a dual loyalty conflict for the physician.
Heightened reactivity to unpredictable threat (U-threat) is a core individual difference factor underlying fear-based psychopathology. Little is known, however, about whether reactivity to U-threat is a stable marker of fear-based psychopathology or if it is malleable to treatment. The aim of the current study was to address this question by examining differences in reactivity to U-threat within patients before and after 12-weeks of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT).
Participants included patients with principal fear (n = 22) and distress/misery disorders (n = 29), and a group of healthy controls (n = 21) assessed 12-weeks apart. A well-validated threat-of-shock task was used to probe reactivity to predictable (P-) and U-threat and startle eyeblink magnitude was recorded as an index of defensive responding.
Across both assessments, individuals with fear-based disorders displayed greater startle magnitude to U-threat relative to healthy controls and distress/misery patients (who did not differ). From pre- to post-treatment, startle magnitude during U-threat decreased only within the fear patients who received CBT. Moreover, within fear patients, the magnitude of decline in startle to U-threat correlated with the magnitude of decline in fear symptoms. For the healthy controls, startle to U-threat across the two time points was highly reliable and stable.
Together, these results indicate that startle to U-threat characterizes fear disorder patients and is malleable to treatment with CBT but not SSRIs within fear patients. Startle to U-threat may therefore reflect an objective, psychophysiological indicator of fear disorder status and CBT treatment response.
Many medications administered to patients with schizophrenia possess anticholinergic properties. When aggregated, pharmacological treatments may result in a considerable anticholinergic burden. The extent to which anticholinergic burden has a deleterious effect on cognition and impairs ability to participate in and benefit from psychosocial treatments is unknown.
Seventy patients were followed for approximately 3 years. The MATRICS consensus cognitive battery (MCCB) was administered at baseline. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Ability to benefit from psychosocial programmes was measured using the DUNDRUM-3 Programme Completion Scale (D-3) at baseline and follow-up. Psychiatric symptoms were measured using the PANSS. Total antipsychotic dose was measured using chlorpromazine equivalents. Functioning was measured using the Social and Occupational Functioning Assessment Scale (SOFAS).
Mediation analysis found that the influence of anticholinergic burden on ability to participate and benefit from psychosocial programmes was completely mediated by the MCCB. For every 1-unit increase on the ACB scale, change scores for DUNDRUM-3 decreased by −0.27 points. This relationship appears specific to anticholinergic burden and not total antipsychotic dose. Moreover, mediation appears to be specific to cognition and not psychopathology. Baseline functioning also acted as mediator but only when MCCB was not controlled for.
Anticholinergic burden has a significant impact on patients’ ability to participate in and benefit from psychosocial treatment programmes. Physicians need to be mindful of the cumulative effect that medications can have on patient cognition, functional capacity and ability to benefit from psychosocial treatments.
The literature suggests that grain number largely determines and as such limits yield in barley. Many of the reported studies were conducted in relatively low-yielding environments and it is unclear if grain number is also a limiting factor in high-yield potential climates. Nor is it known with certainty what physiological or morphological traits must be targeted in order to increase grain number. A detailed programme of assessments was carried out on replicated field plots of a two-row spring barley variety (Hordeum vulgare L. cvar Quench) at three sites (Carlow, Wexford and Cork) in Ireland from 2011 to 2013. Plots were managed for high yield potential as per current best farm practice. Destructive sampling and in-field assessments were carried out at approximately weekly intervals from emergence onwards to gather growth, development and yield component data. Across nine site/seasons, grand means of 8·52 t/ha for yield, 18 419 for grain number/m2 and 46·41 mg for mean grain weight were achieved. Grain number/m2 accounted for most of the variation in yield and ear number/m2 accounted for most of the variation in grain number/m2. Early-season maximum shoot number/m2 had little influence on harvest ear number/m2. The period over which final ear number was determined was more flexible than the literature suggests, where the phases of tiller production and senescence varied considerably. Significant post-anthesis re-tillering occurred following the initial phase of shoot mortality at two out of nine site/seasons, but this appeared to contribute little to yield. Yield was positively associated with the proportion of shoots surviving from an early season maximum to a mid-season minimum (R2 = 0·62). Shoot size and weight at the beginning of stem extension had the largest influence on shoot survival, indicating that crop condition and hence growth and development pre-stem extension may be more important for shoot survival than growth and development during the stem extension period. Achieving high shoot numbers of adequate size and weight at the beginning of stem extension may be an appropriate target for establishing a high-yield potential crop.
Cognitive dysfunction is common in major depressive disorder (MDD) and a critical determinant of health outcome. Anhedonia is a criterion item toward the diagnosis of a major depressive episode (MDE) and a well-characterized domain in MDD. We sought to determine the extent to which variability in self-reported cognitive function correlates with anhedonia.
A post hoc analysis was conducted using data from (N=369) participants with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)-defined diagnosis of MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. The IMDCP is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Canada, and the Cleveland Clinic, Cleveland, Ohio. Measures of cognitive function, anhedonia, and depression severity were analyzed using linear regression equations.
A total of 369 adults with DSM-IV-TR–defined MDD were included in this analysis. Self-rated cognitive impairment [ie, as measured by the Adult ADHD Self-Report Scale (ASRS)] was significantly correlated with a proxy measure of anhedonia (r=0.131, p=0.012). Moreover, total depression symptom severity, as measured by the total Montgomery–Åsberg Depression Rating Scale (MADRS) score, was also significantly correlated with self-rated measures of cognitive dysfunction (r=0.147, p=0.005). The association between anhedonia and self-rated cognitive dysfunction remained significant after adjusting for illness severity (r=0.162, p=0.007).
These preliminary results provide empirical data for the testable hypothesis that anhedonia and self-reported cognitive function in MDD are correlated yet dissociable domains. The foregoing observation supports the hypothesis of overlapping yet discrete neurobiological substrates for these domains.
This work considers debris disks whose spectra can be modelled by dust emission at two different temperatures. These disks are typically assumed to be a sign of multiple belts, but only a few cases have been confirmed via high resolution observations. We derive the properties of a sample of two-temperature disks, and explore whether this emission can arise from dust in a single narrow belt. While some two-temperature disks arise from single belts, it is probable that most have multiple spatial components. These disks are plausibly similar to the outer Solar System's configuration of Asteroid and Edgeworth-Kuiper belts separated by giant planets. Alternatively, the inner component could arise from inward scattering of material from the outer belt, again due to intervening planets. For either scenario, the ratio of warm/cool component temperatures is indicative of the scale of outer planetary systems, which typically span a factor of about ten in radius.