Long-term reduction of seclusion and forced medication on a hospital-wide level: Implementation of an open-door policy over 6 years.

BACKGROUND: Psychiatric inpatient treatment is increasingly performed in settings with locked doors. However, locked wards have well-known disadvantages and are ethically problematic. In addition, recent data challenges the hypothesis that locked wards provide improved safety over open-door settings regarding suicide, absconding and aggression. Furthermore, there is evidence that the introduction of an open-door policy may lead to short-term reductions in involuntary measures. The aim of this study was to assess if the introduction of an open-door policy is associated with a long-term reduction of the frequency of seclusion and forced medication. METHOD: In this 6-year, hospital-wide, longitudinal, observational study, we examined the frequency of seclusion and forced medication in 17,359 inpatient cases admitted to the Department of Adult Psychiatry, Universitäre Psychiatrische Kliniken (UPK) Basel, University of Basel, Switzerland. In an approach to enable a less restrictive policy, six previously closed psychiatric wards were permanently opened beginning from August 2011. During this process, a systematic change towards a more patient-centered and recovery-oriented care was applied. Statistical analysis consisted of generalized estimating equations (GEE) models. RESULTS: In multivariate analyses controlling for potential confounders, the implementation of an open-door policy was associated with a continuous reduction of seclusion (from 8.2 to 3.5%; ηp2=0.82; odds ratio: 0.88) and forced medication (from 2.4 to 1.2%; ηp2=0.70; odds ratio: 0.90). CONCLUSION: This underlines the potential of the introduction of an open-door policy to attain a long-term reduction in involuntary measures.

Unbiased Quantitative Proteomics Reveals a Crucial Role of the Allergen Context for the Activation of Human Dendritic Cells.

Worldwide, more than 1 billion people suffer from allergic diseases. However, until now it is not fully understood how certain proteins can induce allergic immune responses, while others cannot. Studies suggest that allergenicity is a process not only determined by properties of the allergen itself but also by costimulatory factors, that are not classically associated with allergic reactions. To investigate the allergenicity of the major birch pollen allergen Bet v 1 and the impact of adjuvants associated with pollen, e.g. lipopolysaccharide (LPS), we performed quantitative proteome analysis to study the activation of monocyte-derived dendritic cells (moDCs). Thus, we treated cells with birch pollen extract (BPE), recombinant Bet v 1, and LPS followed by proteomic profiling via high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) using isobaric labelling. Enrichment and pathway analysis revealed the influence of regulated proteins especially in cytokine signalling and dendritic cell activation. We found highly regulated, but differentially expressed proteins after treatment with BPE and LPS, whereas the cellular response to Bet v 1 was limited. Our findings lead to the conclusion that Bet v 1 needs a specific "allergen context" involving cofactors apart from LPS to induce an immune response in human moDCs.

Impurity profiling of liothyronine sodium by means of reversed phase HPLC, high resolution mass spectrometry, on-line H/D exchange and UV/Vis absorption.

For the first time, a comprehensive investigation of the impurity profile of the synthetic thyroid API (active pharmaceutical ingredient) liothyronine sodium (LT3Na) was performed by using reversed phase HPLC and advanced structural elucidation techniques including high resolution tandem mass spectrometry (HRMS/MS) and on-line hydrogen-deuterium (H/D) exchange. Overall, 39 compounds were characterized and 25 of these related substances were previously unknown to literature. The impurity classification system recently developed for the closely related API levothyroxine sodium (LT4Na) could be applied to the newly characterized liothyronine sodium impurities resulting in a wholistic thyroid API impurity classification system. Furthermore, the mass-spectrometric CID-fragmentation of specific related substances was discussed and rationalized by detailed fragmentation pathways. Moreover, the UV/Vis absorption characteristics of the API and selected impurities were investigated to corroborate chemical structure assignments derived from MS data.

Levothyroxine sodium revisited: A wholistic structural elucidation approach of new impurities via HPLC-HRMS/MS, on-line H/D exchange, NMR spectroscopy and chemical synthesis.

The structural elucidation of unknown pharmaceutical impurities plays an important role in the quality control of newly developed and well-established active pharmaceutical ingredients (APIs). The United States Pharmacopeia (USP) monograph for the API Levothyroxine Sodium, a synthetic thyroid hormone, features two high pressure liquid chromatography (HPLC) methods using UV-VIS absorption detection to determine organic impurities in the drug substance. The impurity profile of the first USP method ("Procedure 1") has already been extensively studied, however for the second method ("Procedure 2"), which exhibits a significantly different impurity profile, no wholistic structural elucidation of impurities has been performed yet. Applying minor modifications to the chromatographic parameters of USP "Procedure 2" and using various comprehensive structural elucidation methods such as high resolution tandem mass spectrometry with on-line hydrogen-deuterium (H/D) exchange or two-dimensional nuclear magnetic resonance spectroscopy (NMR) we gained new insights about the complex impurity profile of the synthetic thyroid hormone. This resulted in the characterization of 24 compounds previously unknown to literature and the introduction of two new classes of Levothyroxine Sodium impurities. Five novel compounds were unambiguously identified via isolation or synthesis of reference substances and subsequent NMR spectroscopic investigation. Additionally, Collision-Induced Dissociation (CID)-type fragmentation of identified major impurities as well as neutral loss fragmentation patterns of many characterized impurities were discussed.

Characterization of the XIAP-Inhibiting Proanthocyanidin Fraction of the Aerial Parts of Ephedra sinica.

The X-linked inhibitor of apoptosis protein is a cellular protein that inhibits the activity of mammalian caspases and promotes resistance to apoptosis. The ethanol extract of the aerial parts of Ephedra sinica has been identified to possess inhibitory activity of the X-linked inhibitor of apoptosis protein by an in vitro fluorescence polarization assay using the BIR3 domain of the X-linked inhibitor of apoptosis protein. Bioactivity-guided fractionation identified proanthocyanidin-enriched fractions as the active principles. The most active fraction showed an IC50 value of 27.3 µg/mL (CI95: 25.9-28.9 µg/mL) corresponding to 9.6 µM (CI95: 9.1-10.1 µM) calculated by the use of the determined average molecular weight of 2853.5. Samples were analyzed by a thiolytic degradation/HPLC-MS assay, UHPLC-HRMS, and 1D NMR.The thiolytic degradation/HPLC-MS assay revealed a mean degree of polymerization of 9.5 ± 0.2 units (calculated average MW 2853.5) for the active fraction and 11.4 ± 0.6 units (calculated average MW 3437.0) for the most related inactive fraction. Chemical characterization identified (epi)gallocatechin (76.6 ± 1.0 % active; 80.7 ± 2.7 % inactive sample) and (epi)catechin units as building blocks. Interestingly, the investigated proanthocyanidins turned out to be a complex mixture of double linked A-type (binding 2-O-7″, 4-6″) and single linked B-type units.This study identified oligomeric proanthocyanidins as active principles of E. sinica in vitro by a fluorescence polarization assay and via protein fragment complementation analysis.

Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution.

Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy.

[Long-term treatment of schizophrenia spectrum disorders: focus on pharmacotherapy]. / Pharmakologische Langzeitbehandlung schizophrener Erkrankungen.

Schizophrenia spectrum disorders (SSD) constitute a group of psychiatric illnesses which frequently lead to persisting mental impairment. Although some patients show a clinical course with few episodes and good long-term outcome, the course of the disease is often chronic and unfavorable. Long-term treatment (LTT) of SSD pertains to the postacute stabilization period and the remission period following pharmacological and psychosocial therapy of an acute illness episode. This article provides an overview of treatment recommendations concerning long-term pharmacotherapy, dealing with side effects, treatment of non-response and therapy resistance and the treatment of psychiatric comorbidities. Furthermore, an overview of non-pharmacological treatment options is presented. An integrated therapeutic setting combining evidence-based pharmacotherapy, psychosocial interventions, and supportive therapies is recommended for optimal LTT of SSD. Considering the limited financial resources available in the healthcare system, one of the major challenges is to provide patients with access to the evidence-based treatment options available.

Validation and application of sub-2 µm core-shell UHPLC-UV-ESI-Orbitrap MS for identification and quantification of ß-carotene and selected cleavage products with preceding solid-phase extraction.

A validated ultrahigh-performance liquid chromatography method using 1.7 µm core-shell particles is presented for the identification and quantification of ß-carotene (BC) and related cleavage products (CPs) in primary cell culture media. Besides BC, apo-4'-, apo-8'-, apo-10'-, and apo-12'-carotenals, as well as 5,6-epoxy-ß-carotene, were selected as target analytes. Detection was performed via an 80-Hz diode array detector and an electrospray ionization-linear quadrupole ion trap-Orbitrap XL mass spectrometer, both hyphenated in series. Total analysis time was below 6 min with peak widths <12 s. Addition of trifluoroacetic acid and tetrahydrofuran to the mobile phase allowed for the mass spectrometric detection of BC and related CPs and reduced peak tailing due to improved solubility of hydrophobic analytes. Intra-day and inter-day precision for UV and mass spectrometric detection were ≤1.5 % for retention times and ≤5.1 % for peak areas. Instrumental linearity was confirmed by Mandel's fitting test between 0.25 (or 1.00 µg/mL) and 5.00 µg/mL for UV detection. The higher sensitivity of mass spectrometric detection allowed for the coverage of three concentration domains between 0.025 and 5.00 µg/mL in linearity testing. Homoscedasticity was confirmed between 0.10 and 5.00 µg/mL for Orbitrap XL MS. The limits of quantification were between 52.6 and 889.4 ng/mL for UV detection and between 19.3 and 102.4 ng/L for mass spectrometric detection. Offline solid-phase extraction from culture media fortified with BC and CPs provided intra- and inter-day recoveries between 65.8 and 102.4 % with coefficients of variation ≤6.2 %. Primary rat hepatocyte cultures treated with BC and subjected to different oxidative stress conditions contained 5,6-epoxy-BC and apo-4'-carotenal besides residual BC. Apparently, 5,6-epoxy-BC was formed in the medium via autoxidation of BC by ambient oxygen.

Are ratings on the positive and negative syndrome scale for schizophrenia biased by personality traits?

OBJECTIVE: The aim of this study was to estimate the potential bias by personality traits for ratings on the Positive and Negative Syndrome Scale (PANSS). METHODS: Personality dimensions (five factor model), personality traits (SCID-II) and PANSS scores were assessed prospectively in 45 patients with schizophrenia spectrum disorders (SSD). RESULTS: Borderline (r=0.34; p=0.021), avoidant (r=0.66; p<0.001) and depressive (r=0.51; p<0.001) personality traits were significantly correlated with the PANSS total score. There were significant correlations for all PANSS subscores with the exemption of PANSS positive. In multivariate analyses, the final models for PANSS total score and PANSS depressive explained a total of 45.3% and 54.3% of the variance. Avoidant traits could lead to a difference of 13.1 (95% CI: 5.6-20.7) points regarding PANSS total score, depressive traits could cause differences of 4.8 points (95% CI: 2.2-7.3) for PANSS depressive subscore. CONCLUSION: Although PANSS positive subscore and PANSS excited component are relatively robust against bias by personality traits, PANSS total score and the remaining subscores are affected to a clinically relevant degree. Outcome studies in SSD patients should control for personality traits.

Applicability of the Clinical Global Impressions-Aggression (CGI-A) scale for use in file audit trials.

The aim of this study was to evaluate the applicability and validity of a clinical global impressions-aggression (CGI-A) scale in retrospective trials. CGI-A scores were derived from clinical records, BPRS scores were assessed prospectively in 101 patients with first-episode psychosis. CGI-A showed highly significant correlations to the brief psychiatric rating scale (BPRS) excited component (BPRS-EC; r=0.32; p=0.001) and BPRS resistance (r=0.25; p=0.011), to aggression at admission (r=0.70; p<0.001) and to involuntary treatment (r=0.55; p<0.001). The CGI-A retains high construct and face validity in retrospective trials.

[Patient centeredness and decision-making in localised prostate cancer: possible fields of health services research in urology]. / Patientenorientierung und Entscheidungsfindung bei lokal begrenztem Prostatakarzinom : Mögliche Felder urologischer Versorgungsforschung.

BACKGROUND: Quality of care is essential for health services research. Therefore, our patients' preferences are of major importance and this can be illustrated by decision-making in localised prostate cancer. MATERIAL AND METHODS: A total of 349 patients reported on their preferred mode of decision-making, on their habits of information procurement, and on their feeling of being well informed. Moreover, we tried to objectify their actual knowledge. Their mean age was 63.0 years and mean PSA level 9.4 ng/ml. As 40% had a higher level of education we investigated possible influences of this feature by applying the chi-square test. RESULTS: Half of the patients preferred to share the treatment decision and 39% wanted to choose for themselves considering their physician's recommendation. The most important sources of information were treating physicians (88%) and the Internet (77%). All patients felt well informed and 94% knew their latest PSA count. Patients with a higher level of education had better knowledge of their clinical data and used the Internet more (84 vs 71%; p=0.007). CONCLUSIONS: Our patients actively take part in medical decision-making and thereby contribute significantly to everyday health care. Based on this aspect, the whole scope of urology is developed as a promising field of health services research.

[Online support groups for localized prostate cancer: qualitative analysis of decision making]. / Selbsthilfe im Onlineforum bei lokal begrenztem Prostatakarzinom : Qualitative Analyse der Entscheidungsfindung.

BACKGROUND: In localized prostate cancer individual treatment decisions cannot be reached relying exclusively on medical data. Therefore, social interaction is of considerable importance and online support groups allow us to get to know a facet of this communication. MATERIAL AND METHODS: We investigated 82 thematically relevant threads representing 5% of the largest German online support group on prostate cancer (http://forum.prostatakrebs-bps.de). Two independent investigators used methods derived from grounded theory and linguistic conversation analysis to characterize the sample. RESULTS: Users report on personal experience and provide subjective recommendations. At the same time those seeking advice are encouraged to weigh the information and to decide for themselves. Some urologists contribute to the discussion and seem to have a corrective influence, but their involvement is judged diversely. As mainly lay people with different levels of knowledge are involved in the discussion, a tentative language style is frequently used. The disease itself appears to be a linguistic taboo. Besides treatment recommendations, emotional support is of major concern. Being personally affected establishes a sense of unity, which adds to the subjective value of the communication. CONCLUSIONS: Patients readily receive information, advice and emotional support in online support groups. Knowledge of such online services is useful in ensuring good counselling for our patients.

Hippocampal-neocortical networks differ during encoding and retrieval of relational memory: functional and effective connectivity analyses.

Encoding and retrieval of relational information requires interaction between the hippocampus and various neocortical regions, but it is unknown whether the connectivity of hippocampal-neocortical networks is different at input and output stages. To examine this, we conducted a network analysis of event-related fMRI data collected during a face-recognition, remember/know paradigm. Directed analyses in the medial temporal lobe identified a small region in the left hippocampus that showed differential activation for encoding and retrieval of recollected versus familiar items. Multivariate seed partial least squares (PLS) analysis was used to identify brain regions that were functionally connected to this hippocampal region at encoding and retrieval of 'remembered' items. Anatomically based structural equation modeling (SEM) was then used to test for differences in effective connectivity of network nodes between these two memory stages. The SEM analysis revealed a reversal of directionality between the left hippocampus (LHC) and left inferior parietal cortex (LIPC) at encoding and retrieval. During encoding, activation of the LHC had a positive influence on the LIPC, whereas during retrieval the reverse pattern was found, i.e., the LIPC activation positively influenced LHC activation. These findings emphasize the importance of hippocampal-parietal connections and underscore the complexity of their interactions in initial binding and retrieval/reintegration of relational memory. We also found that, during encoding, the right hippocampus had a positive influence on the right retrospenial cortex, whereas during retrieval this influence was significantly weaker. We submit that examining patterns of connectivity can be important both to elaborate and constrain models of memory involving hippocampal-neocortical interactions.

Early- and delayed antipsychotic response and prediction of outcome in 528 severely impaired patients with schizophrenia treated with amisulpride.

INTRODUCTION: 'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various antipsychotics. METHODS: Response and remission rates were assessed in 528 severely ill patients with schizophrenia at baseline, week 2, 4 and 12 using PANSS, SWN-K, CGI-S, and SOFAS. The clinical measures were combined to one outcome criterion (CombOut). Predicitive validity was analyzed for CombOut using linear regression models. RESULTS: Rate and time to response differed markedly between outcome measures. 32% reached positive symptom response at week 2, 58% at week 4 and 85% at week 12. Non-response at week 4, but not at week 2 was predictive for later non-response. The combined outcome criterion was best predicted by early response in subjective wellbeing (T=-7.88, p<0.001) and social functioning (T=-7.43, p<0.001). DISCUSSION: Rate and time to response might depend on sample characteristics and outcome measure. In severely ill patients early antipsychotic response is possibly delayed from the first 2 to the first 4 weeks. Early response in subjective wellbeing and social functioning are strong predictors for overall outcome, which make them a useful supplementation to the assessment of symptomatic response.

Treatment of severe agitation with olanzapine in 166 patients with schizophrenia, schizoaffective, or bipolar I disorder.

INTRODUCTION: Agitation is a common phenomenon in schizophrenia or acute mania. Because of the inability of patients to give informed consent in such situations, data from consenting studies are limited. METHODS: This observational prospective 5-day study evaluated the effectiveness of olanzapine in a sample of highly agitated patients with aggression. Primary endpoint was mean change of the PANSS-Excited Component (PANSS-EC) score. RESULTS: Mean PANSS-EC score at baseline was 25.5 points, 60.2% were severely agitated and 41.6% severely aggressive. A significant decrease in PANSS-EC total score (-13.3 points) was observed with rapid dose escalation and an average daily dose of 21.2 mg/day of olanzapine. 40 patients (24.1%) required treatment with another antipsychotic and 21 patients (12.7%) were not treated with olanzapine at day 5. At endpoint, 64.2% of patients were in remission of agitation. PANSS-EC reduction was not significantly different in patients with or without concurrent benzodiazepine use. DISCUSSION: Severe agitation with aggression may be well controlled with olanzapine in many cases, possibly by higher initial and overall doses of olanzapine. Controlled studies are needed to confirm these findings.

Rates and predictors of remission and recovery during 3 years in 392 never-treated patients with schizophrenia.

OBJECTIVE: Few studies have prospectively examined remission and recovery as well as their predictors in schizophrenia simultaneously. Aims of the study were to identify remission and recovery rates as well as their predictors in schizophrenia. METHOD: 392 never-treated patients with schizophrenia were assessed over 3 years. Combined remission and recovery required concurrent achievement of symptomatic and functional remission as well as adequate quality of life for at least 6 and 24 months respectively. Predictors were analysed using stepwise logistic regression models. RESULTS: At 3 years, remission rates for symptoms, functioning and subjective wellbeing were 60.3%, 45.4% and 57.0%; recovery rates were 51.7%, 35.0% and 44.3%. Of those, 28.1% were in combined remission and 17.1% in combined recovery. Predictors mainly included the baseline functional status and early remission within the first 3 months. CONCLUSION: The proportion of patients who met combined remission or recovery criteria is low. Early treatment adaptations in case of early non-remission are mandatory.

Miniaturized monolithic disks for immunoadsorption of cardiac biomarkers from serum.

Immunoadsorbers based on 2.0 x 6.0 mm i.d., epoxy-bearing, methacrylate-based monolithic disks were developed in order to target myoglobin and N-terminal pro-natriuretic peptide (NT-proBNP), two biomarkers involved in cardiovascular disease. In both cases, antibodies were successfully coupled to the polymeric disk material. The developed immunoadsorbers permitted the selective isolation of myoglobin and NT-proBNP from human serum. Myoglobin was successfully isolated and detected from serum samples at concentrations down to 250 fmol microL(-1). However, the affinity of the antibodies was not sufficient for the analysis of low-concentration clinical samples. Frontal analysis of anti-NT-proBNP disks revealed the ability of the immunoadsorber to bind up to 250 pmol NT-proBNP, which is more than sufficient for the analysis of clinical samples. Anti-NT-proBNP disks showed good stability over more than 18 months and excellent batch-to-batch reproducibility. Moreover, anti-NT-proBNP disks permitted the isolation of NT-proBNP at concentrations down to 750 amol microL(-1) in serum, corresponding to concentrations of strongly diseased patients. Using reversed-phase trapping columns, the detection of NT-proBNP eluted from immunoadsorbers by mass spectrometry was achieved for concentrations down to 7.8 fmol microL(-1).