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Over the last 25 years, radiowave detection of neutrino-generated signals, using cold polar ice as the neutrino target, has emerged as perhaps the most promising technique for detection of extragalactic ultra-high energy neutrinos (corresponding to neutrino energies in excess of 0.01 Joules, or 1017 electron volts). During the summer of 2021 and in tandem with the initial deployment of the Radio Neutrino Observatory in Greenland (RNO-G), we conducted radioglaciological measurements at Summit Station, Greenland to refine our understanding of the ice target. We report the result of one such measurement, the radio-frequency electric field attenuation length $L_\alpha$. We find an approximately linear dependence of $L_\alpha$ on frequency with the best fit of the average field attenuation for the upper 1500 m of ice: $\langle L_\alpha \rangle = ( ( 1154 \pm 121) - ( 0.81 \pm 0.14) \, ( \nu /{\rm MHz}) ) \,{\rm m}$ for frequencies ν ∈ [145 − 350] MHz.
Some constitutional scholars suggest that the US Constitution stands as one of the oldest yet least changed national constitutions in part because Americans’ tendency to “revere” the Constitution has left them unwilling to consider significant changes to the document. Several recent studies support aspects of this claim, but no study establishes a direct link between individuals’ respect for the Constitution and their reluctance to amend it. To address this, we replicate and extend the research design of Zink and Dawes (2016) across two survey experiments. The key difference in our experiments is we include measures of respondents’ propensity to revere the Constitution, which in turn allows us to more directly test whether constitutional veneration translates into resistance to amendment. Our results build on Zink and Dawes’s findings and show that, in addition to institutional factors, citizens’ veneration of the Constitution can act as a psychological obstacle to constitutional amendment.
Depressive symptoms during long-term course of schizophrenia constitute an important and frequent clinical problem. They may occur either as stand-alone major depressive episodes (MDEs) or as part of the schizophrenic negative syndrome. Teatment resistant schizophrenia due to affective deficits results in high subjective burden of disease and a marked subgroup of schizophrenia patients die from suicide. International treatment guidelines strongly suggest offering cognitive behavioural therapy to all patients with schizophrenia. Within pharmacological approaches evidence in favour of second generation antipsychotics exist. The application of mood stabilizers lacks evidence from clinical trials, but is often used in clinical practice. Several antidepressive agents have been administered to depressed patients with schizophrenia and were effective in alleviating both affective and negative symptoms. Treatment outcomes, however, were often limited by side effects and pharmacokinetic interactions, which constitutes the necessity of more easily tolerable pharmacological interventions. Data regarding duloxetine, bupropion, vortioxetine and agomelatine are presented in more detail and discussed within the perspective of multimodal treatment of schizophrenia.
Disclosure
M.Z. received scientific grants from the German Research Foundation and Servier. Speaker and travel grants were provided from Otsuka, Servier, Lundbeck, Roche, Ferrer and Trommsdorff.
The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study.
Methods:
We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher’s exact test was performed to compare categorical variables. Wilcoxon’s rank-sum test was used to compare continuous variables between cohorts.
Results:
Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005–3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3–12.3] versus 15.9 [15.1–17.2], p < 0.001) and international normalised ratio (0.8 [0.73–0.90] versus 1.3 [1.2–1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls.
Conclusions:
In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.
Background:
Bedside nurses have been recognized as potential antibiotic stewards; however, data on effective ways that nurses can contribute to stewardship activities in acute-care hospitals are scarce. Methods: A nurse-driven urine culture intervention to improve urine culture ordering practices was implemented in a medicine and a neurocritical care unit (NCCU) at The Johns Hopkins Hospital. Bedside nurses implemented an algorithm (Fig. 1) developed by the antibiotic stewardship program (ASP) to review the appropriateness of urine culture and to guide discussions with ordering providers regarding unnecessary urine cultures. Nurses received in-person training by an ASP physician champion on how to use the algorithm and education on the definition and indications for evaluation for asymptomatic bacteriuria and urinary tract infections. The ASP physician periodically visited the units to address concerns and questions. In both units, a nurse champion was identified to serve as liaison between the ASP and bedside nurses, and physician support was obtained before the intervention. The pre- and postintervention periods for the medicine unit were September 2017–August 2018 and September 2018–August 2019, respectively. For the NCCU, these periods were September 2018–February 2019 and March 2019–September 2019, respectively. Trends in urine cultures per 100 patient days (PD) were examined with statistical process charts and compared before and after the intervention using a standard incident ratio (IRR) and Poisson regression. Results: In total, 327 urine cultures were collected in the medicine unit and 293 in the NCCU over the study period. Although the intervention led to a significant 34% reduction in the rate of urine cultures on the medicine unit (from 2.3 to 1.5 cultures/100 PD; IRR, 0.66; 95% CI, 0.50–0.87; P < .01), the number of urine cultures remained without a significant change in the NCCU (from 4.5 to 3.7 cultures/100 PD; IRR, 0.89; 95% CI, 0.65–1.22; P = .48) (Fig. 2). Conclusions: Algorithm-based, nurse-driven review of urine culture indications reduced urine cultures on a medicine unit but not in a neurosciences ICU. Success on the medicine unit may have been driven by highly engaged nurse and physician champions and by patients being able to respond questions about symptoms. The following factors might have impacted results on NCCU: presence of conflicting protocols (eg, panculturing patients every 48 hours per a hypothermia protocol), unit tradition (eg, obtaining cultures to assess treatment response), perception of greater risk benefit in NCCU patients, and unit dynamics (open unit with other primary services placing orders for patients). Unit and team dynamics can affect effective implementation of antimicrobial stewardship interventions by nurses.
Perinatal exposure to alcohol (PEA) induces general developmental and specific neuropsychiatric disturbances in association with disturbed synaptic plasticity and functions of the amino acid neurotransmitter glutamate.
Objective
We were interested in effects of ethanol during the terminal neurodevelopmental differentiation on glutamatergic neurotransmission.
Aims
To establish an animal model based on vapor chamber exposure and to assess the expression of vGluT1, EAAT1 to 4, NMDA receptor (NR) subunits 1, 2A to D and NR binding with 3H-labeled MK 801.
Methods
After delivery, female Wistar Han outbred rats (N = 4) and their pups were exposed until postnatal day 8 (P8). At the age of 5 months, the animals were behaviorally characterized. Both, at P8 and after the testing we performed in situ-hybridizations receptor binding assays.
Results
PEA-pubs showed a pronounced and highly significant retardation of body weight and length. Behavioral testing revealed no differences in locomotion and anxiety (open field and elevated plus maze) as well as T-maze-learning, but significantly impaired hippocampus-dependent spatial learning (MWM). We observed significant inductions of vGluT1, EAAT1, EAAT3, NR2A, 2B, 2C and 2D, as well as trends of increased NR1 mRNA. NR binding was found increased in hippocampus (P8) and parietal cortex (P8 and 5M).
Conclusions
The observed inductions of glial glutamate transporters validate previous in vitro data. Altered glutamatergic neurotransmission in general might be considered a molecular correlate of the learning deficit in our PEA model. This further supports the glutamatergic theory of PEA and suggests new targets for therapeutic interventions.
Anxiety is a core symptom of schizophrenia which elicits significant subjective burden of disease and contributes to treatment resistance in schizophrenia. Anxious syndromes might be attributed to incompletely remitted delusions, the negative syndrome, depressive episodes, panic attacks, social phobia, avoidance after hospitalization and down-tapering of benzodiazepine medication. Previous treatment attempts involved several strategies of combination and augmentation.
Objective
Pregabalin, an antagonist at the α2δ-subunit of voltage-gated Ca2+-channels, modulates several neurotransmitter systems and was found able to alleviate anxiety in depression and other mental disorders.
Aim
In schizophrenia, this treatment option has not been evaluated before.
Method
Here, we report a case series of 11 schizophrenic patients who suffered from treatment-resistant anxiety and received augmentation with pregabalin.
Results
This observational investigation reveals that augmentation with pregabalin was able to significantly reduce scores on the Hamilton anxiety scale; furthermore, we observed improvements of psychotic positive and negative symptoms and mood as assessed by PANSS, SANS and CDSS. After augmentation, both a complete discontinuation of concomitant benzodiazepine (BZD) treatment as well as a dose reduction of antipsychotics could be achieved. We did not observe pharmacokinetic interactions or adverse events.
Conclusions
These observations suggest that treating anxious syndromes in schizophrenia with pregabalin can be effective and tolerable. Further investigations should differentiate schizophrenic sub-syndromes of anxiety and evaluate benefits and risks of pregabalin in comparison to placebo and active competitors.
Treatment of schizophrenia with antipsychotic drugs is frequently sub-optimal. One reason for this may be heterogeneity between patients with schizophrenia. The objectives of this study were to identify patient, disease and treatment attributes that are important for physicians in choosing an antipsychotic drug, and to identify empirically subgroups of patients who may respond differentially to antipsychotic drugs. The survey was conducted by structured interview of 744 randomly-selected psychiatrists in four European countries who recruited 3996 patients with schizophrenia. Information on 39 variables was collected. Multiple component analysis was used to identify dimensions that explained the variance between patients. Three axes, accounting for 99% of the variance, were associated with disease severity (64%), socioeconomic status (27%) and patient autonomy (8%). These dimensions discriminated between six discrete patient subgroups, identified using ascending hierarchical classification analysis. The six subgroups differed regarding educational level, illness severity, autonomy, symptom presentation, addictive behaviors, comorbidities and cardiometabolic risk factors. Subgroup 1 patients had moderately severe physician-rated disease and addictive behaviours (23.2%); Subgroup 2 patients were well-integrated and autonomous with mild to moderate disease (6.7%); Subgroup 3 patients were less well-integrated with mild to moderate disease, living alone (11.2%); Subgroup 4 patients were women with low education levels (5.4%), Subgroup 5 patients were young men with severe disease (36.8%); and Subgroup 6 patients were poorly-integrated with moderately severe disease, needing caregiver support (16.7%). The presence of these subgroups, which require confirmation and extension regarding potentially identifiable biological markers, may help individualizing treatment in patients with schizophrenia.
The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-Methyl-D-aspartate (NMDA)-receptors (NR). Several therapeutic strategies address NR function and effects of antipsychotic agents on NR expression have been described.
Objectives
The partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract behavioural effects of NR antagonists, but effects of APZ on NR expression have not been investigated.
Aims
To evaluate effects of APZ on NR mRNA and protein expression
Methods
We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kg body weight. Expression of the NR subunits NR1, NR2A, NR2B, NR2C and NR2D was assessed by semiquantitative radioactive in situ-hybridization, and in parallel receptor binding using 3H-MK-801 receptor autoradiography.
Results
Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months) and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses and time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40 mg-group and after 4 months in the 10 mg-group.
Conclusions
The effects of APZ converge in enhanced NMDA-receptor expression and a shift of subunit-composition towards adult-type receptors. Our results confirm regulatory connections between dopaminergic, serotonergic and glutamatergic neurotransmission with relevance for cognitive and negative symptoms of schizophrenia.
Cognitive deficits impair social and vocational rehabilitation in schizophrenic patients but little is known to which extend these symptoms are perceived by psychiatrists and how they influence antipsychotic treatment. Therefore, an online survey was performed in four European countries (Germany, Greece, Italy and Spain).
Methods
The survey involving 744 psychiatrists and assessed demographic characteristics including vocational status, presenting symptomatology, cognitive dysfunction severity, and current antipsychotic treatement. Methodology is described in full detail by Gorwood (2010).
Results
Out of 3,996 patients, 29% were clinically assessed as having mild, 54% moderate and 17% severe cognitive dysfunction. In the mild dysfunction group, mean time since diagnosis was 9.7 years, 12.0 years in the moderate dysfunction group, and 17.0 years in the severe dysfunction group, and majority were outpatients (74.7%, 57.9% and 56.7%, respectively). The respective mean number of previous episodes was 5.1, 6.2 and 7.2 (6.0 for the total sample). Full or part time employment was reported in 32,2%, 19.1% and 11.8% of the patients, respectively. Olanzapine was the most frequently used antipsychotic in the mild group (21.0%) and severe group (24.9%), and risperidone in the moderate group (23.0%). Ziprasidone was used in 10.2%, 0.8% and 7.1% of subjects.
Conclusion
Cognitive dysfunction is frequently perceived by psychiatrist in every day clinical practice and severely interferes with the vocational status. Major associations between specific antipsychotics and the levels of cognitive impairment were not observed. Irrespective of the level of cognitive dysfunction, > 50% of subjects were outpatients.
Patients with psychotic disorders often suffer from intercurrent major depressive episodes (MDEs). Case reports suggested successful antidepressive treatment with duloxetine, a selective dual reuptake inhibitor of serotonin and norepinephrine (SSNRI). We initiated this open prospective clinical trial in order to evaluate efficacy, safety and tolerability of this approach.
Methods:
Patients with a psychotic lifetime diagnosis suffering from mildly severe MDEs were treated with duloxetine over a period of 6 weeks. We evaluated effects on mood, monitored the psychotic psychopathology and assessed side effects, basal clinical and pharmacological parameters.
Results:
Twenty patients were included and experienced a significant improvement of their MDE during the observation period (CDSS: Calgary Depression Scale for Schizophrenia, HAMD: Hamilton Depression scale). Psychotic positive symptoms remained stably absent while negative syndrome and global psychopathology considerably improved (PANSS: Positive and Negative Syndrome Scale). In general, the treatment was well tolerated, serum prolactin levels stayed unchanged, but pharmacokinetic interactions with a number of antipsychotic agents were observed.
Conclusions:
This open prospective evaluation revealed antidepressive efficacy of duloxetine in patients with co-morbid psychotic disorders. With regard to the psychotic disorder, the treatment appears to be safe and well tolerable. Further investigations should involve a randomized control group.
Treatment-resistant schizophrenia often leads to combined application of antipsychotic drugs. We report first experience with the combination of olanzapine and amisulpride. Improvement of psychopathological state and side effects could be achieved, and drug doses were lower than under monotherapy. We thus conclude that this approach represents a useful therapeutic option.
Schizophrenia is a frequent psychiatric disorder whose prevalence appears to be relatively stable across different patient groups. However, attitudes to care and resources devoted to mental health care may differ between countries. The objective of this analysis was to compare sociodemographic and psychopathological features of patients, antipsychotic treatment and frequency of hospitalisation between four European countries (Germany, Greece, Italy and Spain) collected as part of a large survey of the characteristics of patients with schizophrenia. The survey was conducted by structured interview of 744 randomly-selected psychiatrists in four European countries who recruited 3996 patients. Information on 39 variables was collected. A number of between-country differences were observed which tended to distinguish Germany on the one hand, from the Mediterranean countries, and Greece in particular, on the other. While demographic features and clinical features were essentially similar, more patients in Germany were considered to have severe disease by their psychiatrist (59.0% versus 35.9% in Greece) and to be hospitalised (49.3% versus 15.0%). 46.7% of German patients were living alone compared to less than 20% in the Mediterranean countries and 50.2% were living with their family (versus over70% elsewhere). Smoking and addictive behaviours were more frequently reported for patients in Spain. With regard to empirically derived patient subgroups, Subgroup 2, corresponding to well-integrated and autonomous patients with mild to moderate disease severity was most highly represented in Greece (23.6% of patients compared to less than 10% elsewhere) elsewhere, Subgroup 6 (poorly-integrated patients with moderately severe disease who require caregiver support) was under-represented in Germany (4.5% versus over 17% elsewhere). Patterns of treatment were essentially similar, although quetiapine was more frequently prescribed and paliperidone less frequently prescribed in Germany than elsewhere. Reasons for treatment choice were comparable between countries, primarily related to good tolerability and control of positive symptoms. The differences observed may be attributed to differences in mental health care resource provision, socio-cultural or educational differences or to resource issues.
To explore safety, tolerability, treatment response and hospitalizations in adult patients with schizophrenia treated with long-acting injectable risperidone (RLAI) or oral antipsychotic standard of care (oAP) in routine clinical practice.
Methods
Prospective one-year open-label non-interventional study exploring flexible doses of RLAI and oAPs. Primary outcome was the number of hospitalizations from baseline to endpoint. Additional outcomes were changes in the Clinical Global Impression of Schizophrenia (CGI-SCH), patient functioning (Global Assessment of Functioning) and treatmentemergent adverse events (TEAEs).
Results
The intent-to-treat analysis included 561 patients on RLAI and 522 patients on oAPs (44% female gender, mean age (±SD) 42.2±13.1 years). Demographics and baseline characteristics were comparable, yet RLAI-treated patients had higher disease severity, lower baseline functioning and more substance abuse. The number of hospitalizations did not differ between the two groups while median duration of hospitalization was significantly shorter with RLAI (12.3 vs 20.6 days). Positive, negative, cognitive symptoms, disease severity, patient functioning and medication satisfaction improved significantly better with RLAI than oAPs. The most frequently reported TEAEs (=2% in any group) for RLAI and oral APs were increase of body weight (5.0%; 5.6%), psychotic disorder (2.7%; 4.0%), schizophrenia (2.5%; 3.1%), anxiety (2.3%; 2.7%), insomnia (0.9%; 3.1%) and somnolence (0.4%; 2.5%), respectively.
Conclusion
This one-year non-interventional study supports results of recent randomized controlled trials that treatment with RLAI is associated with less days spent in hospital, better symptomatic and functional outcomes and higher patient satisfaction with medication compared to oral APs.
Recent metaanalyses have reported conflicting results on the efficacy of long-acting compared to oral antipsychotics in the prevention of relapse in patients with schizophrenia.
Methods
2-year international randomized active controlled, open-label, rater-blinded study evaluating time to relapse, relapse rates, psychotic symptoms (PANSS) and treatment-emergent adverse events (TEAEs) in recently diagnosed patients with schizophrenia (≥1-5 years) treated with a monotherapy of paliperidone palmitate (PP) compared to investigators’ choice of oral antipsychotics (oAPs), i.e. aripiprazole, olanzapine, quetiapine, paliperidone ER, risperidone or haloperidol.
Results
715 patients (58.4% male, mean age 32.5±10.4 years, 86.2% paranoid schizophrenia, no significant differences in baseline characteristics) entered the 2-year study period (352 PP, 363 oAPs). Time to relapse was significantly longer with PP compared to oAPs (mean±SE: 616±10.9 vs 603±13.1 days, p=0.019). Relapse rates were significantly lower with PP vs oAPs (14.8% vs 20.9%; p=0.032), reflecting a relative risk reduction of 29.2%. Reduction of psychotic symptoms in PANSS was significantly superior with PP at treatment day 8 (p=0.021) and showed a trend in favor of PP at endpoint (p=0.074). TEAEs reported in ≥5% in any group (PP vs oAPs) were weight increase (15.9% vs 17.4%), headache (11.1% vs 8.5%), insomnia (9.7% vs 8.0%), schizophrenia (8.2% vs 9.6%), nasopharyngitis (7.1% vs 5.0%), injection site pain (6.8% vs 0%), anxiety (5.7% vs 4.4%), tremor (5.1% vs 2.2%) and suicidal ideation (4.5% vs 5.5%).
Conclusion
In this randomized active controlled 2-year study PP was significantly delaying time to relapse and reducing relapse rates compared to investigators’ choice of oral APs.
Epidemiological studies estimated that amongst patients with schizophrenia a large subgroup of up to 25% also suffers from comorbid obsessive compulsive symptoms (OCS). The association between these comorbid OCS and neuropsychological impairment remains unclear and somewhat contradictory. Longitudinal approaches which investigate the stability of OCS related cognitive deficits are missing.
Methods
37 patients with schizophrenia and comorbid OCS and 43 schizophrenia patients without OCS were assessed with a comprehensive cognitive test-battery and compared at baseline and again 12 months later.
Results
Schizophrenia patients with comorbid OCS showed significant pronounced deficits with increasing effect sizes over the 12 month assessment period in specific cognitive areas such as visuo-spatial perception and visual memory (WAIS-R block design, Rey-Osterrieth Complex Figure Test), executive functioning (perseveration in the Wisconsin card sorting test) and cognitive flexibility (Trail making test B). These cognitive domains correlated with OCS severity and are known to be candidate domains in obsessive compulsive disorder (OCD).
Conclusions
OCS in schizophrenia is associated longitudinally stable specific cognitive deficits. Prospective studies involving patients with at risk mental states for psychosis are necessary to decipher the interaction of cognitive impairment and the clinical manifestation of schizophrenia and OCS. This might facilitate the definition of patients at high risk for OCS, an early detection of subclinical levels, therapeutic interventions and clinical monitoring.