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Our research group demonstrated that vitamin A restriction affected meat quality of Angus cross and Simmental steers. Therefore, the aim of this study is to highlight the genotype variations in response to dietary vitamin A levels. Commercial Angus and Simmental steers (n = 32 per breed; initial BW = 337.2 ± 5.9 kg; ~8 months of age) were fed a low-vitamin A (LVA) (1017 IU/kg DM) backgrounding diet for 95 days to reduce hepatic vitamin A stores. During finishing, steers were randomly assigned to treatments in a 2 × 2 factorial arrangement of genotype × dietary vitamin A concentration. The LVA treatment was a finishing diet with no supplemental vitamin A (723 IU vitamin A/kg DM); the control (CON) was the LVA diet plus supplementation with 2200 IU vitamin A/kg DM. Blood samples were collected at three time points throughout the study to analyze serum retinol concentration. At the completion of finishing, steers were slaughtered at a commercial abattoir. Meat characteristics assessed were intramuscular fat concentration, color, Warner-Bratzler shear force, cook loss and pH. Camera image analysis was used for determination of marbling, 12th rib back fat and longissimus muscle area (LMA). The LVA steers had lower (P < 0.001) serum retinol concentration than CON steers. The LVA treatment resulted in greater (P = 0.03) average daily gain than the CON treatment, 1.52 and 1.44 ± 0.03 kg/day, respectively; however, there was no effect of treatment on final BW, DM intake or feed efficiency. Cooking loss and yield grade were greater and LMA was smaller in LVA steers (P < 0.05). There was an interaction between breed and treatment for marbling score (P = 0.01) and percentage of carcasses grading United States Department of Agriculture (USDA) Prime (P = 0.02). For Angus steers, LVA treatment resulted in a 16% greater marbling score than CON (683 and 570 ± 40, respectively) and 27% of LVA Angus steers graded USDA Prime compared with 0% for CON. Conversely, there was no difference in marbling score or USDA Quality Grades between LVA and CON for Simmental steers. In conclusion, feeding a LVA diet during finishing increased marbling in Angus but not in Simmental steers. Reducing the vitamin A level of finishing diets fed to cattle with a high propensity to marble, such as Angus, has the potential to increase economically important traits such as marbling and quality grade without negatively impacting gain : feed or yield grade.
Compare quetiapine+antidepressant (AD) with lithium+AD, and quetiapine monotherapy with lithium+AD in open, rater-blinded treatment.
Patients with treatment resistant depression (Thase et al 1997 stage 1 and 2) with severity of MADRS ≥25 received: quetiapine XR 300mg/day plus AD (SSRIs or venlafaxine) (n=229), lithium (monitored to between 0.6 to 1.0 meq/l) plus AD (n=221) or quetiapine XR alone (300mg/day) (n=225) for 6 weeks. Primary efficacy measure was change from baseline in MADRS total score. The pre-specified non-inferiority limit was 3 points on the MADRS.
Fewer patients discontinued on quetiapine+AD (15.2%) than lithium+AD (20.5%) and quetiapine monotherapy (21.5%). Quetiapine+AD and quetiapine monotherapy, were not inferior to lithium+AD in the primary (per protocol) analysis with a mean difference (97.5%CI) on the MADRS of -2.32 (-4.6 to -0.05) favouring add-on quetiapine and -0.97 (-3.24 to 1.31) favouring quetiapine monotherapy. This mandated superiority testing on the modified ITT population showing no significant difference at endpoint.
In a post hoc analysis discounting multiplicity, quetiapine+AD was significantly more effective than lithium+AD on the MADRS change from baseline, p=0.046. The advantage was observed at day 4 (p=0.007) and persisted throughout. Efficacy was supported by CGI-I (p=0.07). Quetiapine+AD showed a numerically greater advantage over lithium+AD in those with two failed treatments (Stage 2) rather than one (Stage 1).
Quetiapine+AD and quetiapine monotherapy, were non-inferior to lithium+AD in treatment resistant depression. There was an early significant and persistent efficacy advantage on MADRS for quetiapine augmentation compared with lithium augmentation of SSRI or venlafaxine treatment.
The aim of this study was to examine the long-term efficacy and safety of a monotherapy with quetiapine or sodium valproate (VPA) in patients with rapid cycling bipolar disorder.
This open-label trial was conducted at three German centers. A sample of 38 remitted or partly remitted bipolar patients with rapid cycling (quetiapine n = 22; VPA n = 16) were treated with quetiapine or VPA (flexible-dose design) up to 12 months. Analyses were based on the ITT-LOCF principle.
41 % of the patients with quetiapine and 50 % with VPA completed the trial. According to the Clinical Global Impression Scale responder rates tended to be higher for quetiapine than for VPA: i.e. 43 % vs. 25 % (depression), 48 % vs. 36 % (mania), and 43 % vs. 19 % (improvement in both mania and depression). There were no differences found between the treatment groups evaluating the HRSD, MADRS and YMRS. In contrast, Life Chart Method data showed that patients being treated with quetiapine had significantly less depressive days than patients on VPA whilst they did not differ in the number of days with manic symptoms. The incidence of adverse events, especially of orthostatic dysregulation and sedation was higher in the quetiapine group.
Quetiapine may be more effective than VPA regarding depressive symptoms and as effective as VPA in the treatment of manic symptoms in the long-term treatment of rapid cycling bipolar disorder. The side effect profile of quetiapine tends to be less favorable than the one of VPA.
Investigate effects of adjunct extended release quetiapine fumarate (QTP-XR) on sleep disturbance and quality in patients with MDD and inadequate response to antidepressant (AD) therapy.
Data were pooled from two (D1448C00006/D1448C00007) 6-week, double-blind, randomised, placebo (placebo+AD)-controlled studies of adjunct QTP-XR (15 0 mg/day and 300 mg/day). Primary endpoint: MADRS total score change versus placebo+AD. Secondary endpoints (post hoc): change from randomisation in MADRS item 4 (reduced sleep), HAM-D items 4, 5 and 6 (early-, middle- and late-insomnia), sleep disturbance factor (HAM-D items 4+5+6) and sleep quality (PSQI global score). MADRS total score change in patients with baseline HAM-D sleep disturbance factor score > = 4 or < 4 (high and low sleep disturbance, respectively) was evaluated.
919 patients received adjunct QTP-XR: 150 mg/day (n = 309), 300 mg/day (n = 307), placebo+AD (n = 303). At Week 6, adjunct QTP-XR (both doses) reduced MADRS item 4, HAM-D sleep disturbance factor, HAM-D items 4, 5 and 6 and PSQI global scores from baseline versus placebo+AD (p < 0.001). In patients with baseline HAM-D>=4 (n = 226, 215 and 210, respectively) adjunct QTP-XR (both doses) improved (p< 0.01) MADRS total score versus placebo+AD from Week 1 onward. In patients with baseline HAM-D< 4 (n = 83, 92, 93, respectively) adjunct QTP-XR (both doses) improved (not statistically significantly) MADRS total score versus placebo+AD at Week 6.
Adjunct QTP-XR significantly restored sleep and improved sleep quality in patients with MDD and inadequate response to AD. Significant improvement in depressive symptoms was demonstrated with adjunct QTP-XR in patients with MDD and high baseline sleep disturbance. AstraZeneca funded.
Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.
The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.
There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.
These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.
Self-ratings of psychotic experiences might be biased by depressive symptoms.
Data from a large naturalistic multicentre trial on depressed inpatients (n = 488) who were assessed on a biweekly basis until discharge were analyzed. Self-rated psychotic symptoms as assessed with the 90-Item Symptom Checklist (SCL-90) were correlated with the SCL-90 total score, the SCL-90 depression score, the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale 21 item (HAMD-21) total score, the Montgomery Åsberg Depression Rating Scale (MADRS) total score and the clinician-rated paranoid-hallucinatory score of the Association for Methodology and Documentation in Psychiatry (AMDP) scale.
At discharge the SCL-90 psychosis score correlated highest with the SCL-90 depression score (0.78, P<0.001) and with the BDI total score (0.64, P<0.001). Moderate correlations were found for the MADRS (0.34, P<0.001), HAMD (0.37, P<0.001) and AMDP depression score (0.33, P<0.001). Only a weak correlation was found between the SCL-90 psychosis score and the AMDP paranoid-hallucinatory syndrome score (0.15, P<0.001). Linear regression showed that change in self-rated psychotic symptoms over the treatment course was best explained by a change in the SCL-90 depression score (P<0.001). The change in clinician-rated AMDP paranoid-hallucinatory score had lesser influence (P = 0.02).
In depressed patients self-rated psychotic symptoms correlate poorly with clinician-rated psychotic symptoms. Caution is warranted when interpreting results from epidemiological surveys using self-rated psychotic symptom questionnaires as indicators of psychotic symptoms. Depressive symptoms which are highly prevalent in the general population might influence such self-ratings.
Previous findings suggested that electrodermal hyporeactivity has a high sensitivity (up to 97%) and high raw specificity (up to 98%) for suicide.
To evaluate prevalence, sensitivity and specificity of electrodermal hyporeactivity for suicide and suicide attempt, with and without death intent and with violent method or not, in adult patients with a primary diagnosis of depression.
At each study site at least 100 patients with a primary diagnosis of depression, also in remission, will be recruited. Depressive symptomatology will be evaluated through the Montgomery-Asberg Depression Scale. Previous suicide attempts will be registered and the death intent of the worst attempt will be rated according to the first eight items of the Beck Suicide Intent Scale. The risk of suicide will be assessed according to rules and traditions at the centre. The EDOR Test (ElectroDermal Orienting Reactivity) will be performed. Two fingers are put on gold electrodes. Through headphones a moderately strong tone is presented now and then during the test. Sensors located within the electrodes are able to register the electrodermal response to those tones, measuring the skin conductance (i.e. electrodermal activity from sweat gland activity). Each patient will be followed up for one year for actions of intentional self-harm that require medical care and for suicide. The death intent will also be rated.
It is expected that the EDOR test detects a previously unknown neuropsychological dysfunction that is independent of the depressive state and can predict suicidality with a high sensitivity and specificity.
Functional magnetic resonance imaging (fMRI) studies in schizophrenia found altered brain activation patterns during Theory of Mind (ToM) task performance in the so-called ToM-network, recently focusing on over- rather than under-activation. Even though most fMRI-studies applied tasks that might gradually activate the ToM-network, no study so far has investigated the time-course of ToM-performance. Some of the varying activation results might thus be due to time-course of performance.
Our aim was to investigate neural activation over time in schizophrenia compared with a healthy control sample.
Using a block design in fMRI, we presented a sophisticated paradigm that depicts moving geometrical shapes interacting in social patterns. 14 patients with schizophrenia and 15 healthy controls participated in the study. Functional activation patterns were investigated for the first and second half of the videos separately.
Both groups activated brain areas related to the ToM-network during performance of ToM videos as compared to a baseline condition. Most importanly, schizophrenia patients showed activation in ToM-related brain areas only in the second part, while healthy controls activated the ToM-network in the first part of the video presentation.
Results confirm recent findings of an increased activation in ToM-related brain areas in schizophrenia. Moreover, patients activated ToM-related brain areas later than healthy controls. This delay might be due to a general cognitive slowing, symptom-related inhibition of cognition-associated processes or specific delay in task processing. As this is the first study to investigate this time-course of ToM, more research is needed to classify results.
Neuroprotective effects of lithium have been well documented in tissue cultures and animal models. The evidence for lithium related neuroprotection in human subjects is limited and inconsistent, likely due to methodological heterogeneity.
To investigate the effects of lithium on brain chemistry and structure, we recruited bipolar patients selected for substantial illness burden and varied the exposure to lithium by using strict inclusion criteria.
We obtained 1.5T magnetic resonance imaging data from 27 bipolar patients with at least 2 years of ongoing lithium treatment (Li group), 16 subjects with < 3 months lifetime exposure to lithium >2 years ago (non-Li group) and 21 healthy controls. Patient groups had to have at least 10 years of illness and 5 episodes.
The non-Li group had significantly lower hippocampal volumes (t = 4.68,corrected p < 0.05) and prefrontal cortex N-acetyl aspartate (NAA) levels (t = −2.91,corrected p < 0.05) than controls, who showed comparable hippocampal volumes and NAA levels to the Li treated subjects. Duration of illness was negatively associated with NAA levels only in the non-Li, but not the Li group.
Among patients selected for substantial illness burden, only those with no or minimal lifetime Li exposure had significantly lower prefrontal NAA levels and hippocampal volumes than controls. Patients with at least 2 years of ongoing Li treatment showed no such changes, despite substantial burden of illness. These findings provide indirect support for neuroprotective effects of lithium and negative effects of illness burden on brain chemistry and structure in patients with bipolar disorders.
Nested data arise frequently in clinical research. The nesting might be hierarchical, such as patients nested within clinicians, or it might be longitudinal, such as repeated assessments over time nested within individuals. As articulated in this chapter, whenever and however nesting occurs, it is necessary to account for the statistical dependence of observations within units when analyzing the data. Further, it is important to determine the level(s) of the data at which predictors exert their effects. Multilevel models are a particularly popular and useful approach for addressing these issues. We thus describe these models in detail, illustrating the application of multilevel models in clinical research via two examples. The first example considers nesting of siblings within families and demonstrates the importance of separating within- versus between-family effects. The second example focuses on the application of multilevel models with repeated measures to evaluate within-person change over time. Additionally, we provide a brief survey of other approaches to the analysis of nested data (e.g., cluster-robust standard errors, generalized estimating equations, fixed-effects models).
First rank symptoms (FRS) of schizophrenia have been used for decades for diagnostic purposes. In the new version of the DSM-5, the American Psychiatric Association (APA) has abolished any further reference to FRS of schizophrenia and treats them like any other “criterion A” symptom (e.g. any kind of hallucination or delusion) with regard to their diagnostic implication. The ICD-10 is currently under revision and may follow suit. In this review, we discuss central points of criticism that are directed against the continuous use of first rank symptoms (FRS) to diagnose schizophrenia.
We describe the specific circumstances in which Schneider articulated his approach to schizophrenia diagnosis and discuss the relevance of his approach today. Further, we discuss anthropological and phenomenological aspects of FRS and highlight the importance of self-disorder (as part of FRS) for the diagnosis of schizophrenia. Finally, we will conclude by suggesting that the theory and rationale behind the definition of FRS is still important for psychopathological as well as neurobiological approaches today.
Results of a pivotal meta-analysis and other studies show relatively poor sensitivity, yet relatively high specificity for FRS as diagnostic marker for schizophrenia. Several methodological issues impede a systematic assessment of the usefulness of FRS in the diagnosis of schizophrenia. However, there is good evidence that FRS may still be useful to differentiate schizophrenia from somatic causes of psychotic states. This may be particularly important in countries or situations with little access to other diagnostic tests. FRS may thus still represent a useful aid for clinicians in the diagnostic process.
In conclusion, we suggest to continue a tradition of careful clinical observation and fine-grained psychopathological assessment, including a focus on symptoms regarding self-disorders, which reflects a key aspect of psychosis. We suggest that the importance of FRS may indeed be scaled down to a degree that the occurrence of a single FRS alone should not suffice to diagnose schizophrenia, but, on the other hand, absence of FRS should be regarded as a warning sign that the diagnosis of schizophrenia or schizoaffective disorder is not warranted and requires specific care to rule out other causes, particularly neurological and other somatic disorders. With respect to the current stage of the development of ICD-11, we appreciate the fact that self-disorders are explicitly mentioned (and distinguished from delusions) in the list of mandatory symptoms but still feel that delusional perceptions and complex hallucinations as defined by Schneider should be distinguished from delusions or hallucinations of “any kind”. Finally, we encourage future research to explore the psychopathological context and the neurobiological correlates of self-disorders as a potential phenotypic trait marker of schizophrenia.
We describe an algorithm that can fit the properties of the dwarf galaxy progenitor of a tidal stream, given the properties of that stream. We show that under ideal conditions (the Milky Way potential, the orbit of the dwarf galaxy progenitor, and the functional form of the dwarf galaxy progenitor are known exactly), the density and angular width of stars along the stream can be used to constrain the mass and radial profile of both the stellar and dark matter components of the progenitor dwarf galaxy that was ripped apart to create the stream. Our provisional fit for the parameters of the dwarf galaxy progenitor of the Orphan Stream indicates that it is less massive and has fewer stars than previous works have indicated.
A core question in the debate about how to organise mental healthcare is whether in- and out-patient treatment should be provided by the same (personal continuity) or different psychiatrists (specialisation). The controversial debate drives costly organisational changes in several European countries, which have gone in opposing directions. The existing evidence is based on small and low-quality studies which tend to favour whatever the new experimental organisation is.
We compared 1-year clinical outcomes of personal continuity and specialisation in routine care in a large scale study across five European countries.
This is a 1-year prospective natural experiment conducted in Belgium, England, Germany, Italy and Poland. In all these countries, both personal continuity and specialisation exist in routine care. Eligible patients were admitted for psychiatric in-patient treatment (18 years of age), and clinically diagnosed with a psychotic, mood or anxiety/somatisation disorder.
Outcomes were assessed 1 year after the index admission. The primary outcome was re-hospitalisation and analysed for the full sample and subgroups defined by country, and different socio-demographic and clinical criteria. Secondary outcomes were total number of inpatient days, involuntary re-admissions, adverse events and patients’ social situation. Outcomes were compared through mixed regression models in intention-to-treat analyses. The study is registered (ISRCTN40256812).
We consecutively recruited 7302 patients; 6369 (87.2%) were followed-up. No statistically significant differences were found in re-hospitalisation, neither overall (adjusted percentages: 38.9% in personal continuity, 37.1% in specialisation; odds ratio = 1.08; confidence interval 0.94–1.25; p = 0.28) nor for any of the considered subgroups. There were no significant differences in any of the secondary outcomes.
Whether the same or different psychiatrists provide in- and out-patient treatment appears to have no substantial impact on patient outcomes over a 1-year period. Initiatives to improve long-term outcomes of psychiatric patients may focus on aspects other than the organisation of personal continuity v. specialisation.
Research demonstrates the importance of nutrition for early brain development. Few studies have examined the effectiveness of multiple micronutrient powders (MNP) on child development. This study examined the impacts of home fortification with MNP on motor and mental development, executive function and memory of children living in Bihar. This two-arm cluster-randomised effectiveness trial selected seventy health sub-centres to receive either MNP and nutrition counselling (intervention) or nutrition counselling alone (control) for 12 months. Front-line health workers delivered the intervention to all households in study communities with a child aged 6–18 months. Data were collected using cross-sectional surveys at baseline and endline by selecting households from intervention (baseline, n 2184; endline, n 2170) and control (baseline, n 2176; endline, n 2122) communities using a two-stage cluster-randomised sampling strategy. Children in the intervention group had a significantly larger improvement from baseline to endline compared with those in the control group on scores for motor and mental development (Cohen’s d, motor=0·12; 95 % CI 0·03, 0·22; mental=0·15; 95 % CI 0·06, 0·25). Greater impacts of MNP on motor and mental development were observed in children from households with higher stimulation scores at baseline compared with those with lower stimulation (Cohen’s d, motor=0·20 v. 0·09; mental=0·22 v. 0·14; Pinteraction<0·05). No significant treatment differences were seen for executive function or memory. Home fortification with MNP through the existing health infrastructure in Bihar was effective in improving motor and mental development and should be considered in combination with other child development interventions such as stimulation.
Exercise during pregnancy has beneficial effects on maternal and offspring’s health in humans and mice. The underlying mechanisms remain unclear. This comparative study aimed to determine the long-term effects of an exercise program on metabolism, weight gain, body composition and changes in hormones [insulin, leptin, brain-derived neurotrophic factor (BDNF)]. Pregnant women (n=34) and mouse dams (n=44) were subjected to an exercise program compared with matched controls (period I). Follow-up in the offspring was performed over 6 months in humans, corresponding to postnatal day (P) 21 in mice (period II). Half of the mouse offspring was challenged with a high-fat diet (HFD) for 6 weeks between P70 and P112 (period III). In period I, exercise during pregnancy led to 6% lower fat content, 40% lower leptin levels and an increase of 50% BDNF levels in humans compared with controls, which was not observed in mice. After period II in humans and mice, offspring body weight did not differ from that of the controls. Further differences were observed in period III. Offspring of exercising mouse dams had significantly lower fat mass and leptin levels compared with controls. In addition, at P112, BDNF levels in offspring were significantly higher from exercising mothers while this effect was completely blunted by HFD feeding. In this study, we found comparable effects on maternal and offspring’s weight gain in humans and mice but different effects in insulin, leptin and BDNF. The long-term potential protective effects of exercise on biomarkers should be examined in human studies.
Most patients born with CHD nowadays reach adulthood, and thus quality of life, life situation, and state of medical care aspects are gaining importance in the current era. The present study aimed to investigate whether patients’ assessment depends on their means of occupation. The findings are expected to be helpful in optimising care and for developing individual treatment plans.
The present study was based on an online survey conducted in cooperation with patient organisations. Participants were recruited from the database of the German National Register for Congenital Heart Defects. In total, 1828 individuals (777 males, 1051 females) took part. Participants were asked to rate aspects such their state of health on a six-tier scale (1=worst specification). Response behaviour was measured against the background of occupational details.
Training for or pursuing a profession was found to be significantly associated with participants’ rating of five of the six examined aspects (p<0.05). Sex seemed to play an important part in four of the six aspects.
An optimal treatment plan for adults with CHD should always consider aspects such as sex and employment status. To work out such an optimal and individual treatment plan for each adult CHD patient, an objective tool to measure patients’ actual CHD-specific knowledge precluding socially accepted response bias would be very useful.
The Dark Energy Survey is undertaking an observational programme imaging 1/4 of the southern hemisphere sky with unprecedented photometric accuracy. In the process of observing millions of faint stars and galaxies to constrain the parameters of the dark energy equation of state, the Dark Energy Survey will obtain pre-discovery images of the regions surrounding an estimated 100 gamma-ray bursts over 5 yr. Once gamma-ray bursts are detected by, e.g., the Swift satellite, the DES data will be extremely useful for follow-up observations by the transient astronomy community. We describe a recently-commissioned suite of software that listens continuously for automated notices of gamma-ray burst activity, collates information from archival DES data, and disseminates relevant data products back to the community in near-real-time. Of particular importance are the opportunities that non-public DES data provide for relative photometry of the optical counterparts of gamma-ray bursts, as well as for identifying key characteristics (e.g., photometric redshifts) of potential gamma-ray burst host galaxies. We provide the functional details of the DESAlert software, and its data products, and we show sample results from the application of DESAlert to numerous previously detected gamma-ray bursts, including the possible identification of several heretofore unknown gamma-ray burst hosts.