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Effective treatments for patients with high levels of negative symptoms of schizophrenia are lacking. Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with subnanomolar potency. Long-term treatment with brexpiprazole demonstrated broad efficacy across all five Marder factor groupings, including positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. This post-hoc analysis of long-term effects of brexpiprazole in patients with clinically relevant levels of negative symptoms of schizophrenia is based on data from two similarly designed short-term, placebo-controlled studies (Vector; NCT01396421 or Beacon; NCT01393613) for the brexpiprazole-treated patients who continued into an open-label extension study (Zenith; NCT01397786).
In the short-term studies, patients with acute schizophrenia were randomly assigned to fixed once-daily doses of brexpiprazole 0.25mg (Vector), 1mg (Beacon), 2mg , 4mg or placebo for 6weeks. The long-term study was an open-label, 52-week (amended to 26weeks), safety extension study with flexible-dose (1–4mg/day) brexpiprazole. The post-hoc analyses were performed on brexpiprazole-treated patients from the short-term studies who continued into the long-term study, and who had clinically relevant negative symptoms, defined as PANSS Factor Score for Negative Symptoms (PANSS-FSNS; N1, N2, N3, N4, G7, G16) of ≥24, and score of ≥4 on at least two of three core negative symptom PANSS items at randomization in the parent study. The outcome of the analysis included change from baseline to up to 58weeks in PANSS-FSNS, PANSS Total, and PSP. Safety was also assessed.
A total of 187 patients with clinically relevant levels of negative symptoms in the parent study rolled-over into the open-label extension study and were available for analysis. Eighty-three of these patients remained in the studies for 58weeks. Due to the study amendment, not all patients had the opportunity of complete 52weeks of open-label treatment. Baseline PANSS Total score was 104.4, while baseline PANSS-FSNS was 27.6 and baseline PSP Total score was 41.3. Mean change (SD) from baseline in PANSS-FSNS was –10.9 (5.0), and –44.2 (17.5) for PANSS Total score at Week 58. Change from baseline (SD) to Week 58 for PSP Total score was 24.8 (12.9) with improvement in all domains (socially useful activities, personal and social relationship, self-care, and disturbing and aggressive behaviors). The TEAEs reported ≥5% were schizophrenia (18.9%), insomnia (8.6%), weight increased (5.9%) and akathisia (5.9%).
This post-hoc analysis suggests that brexpiprazole has long-term effectiveness on negative symptoms and functioning in patients with schizophrenia and clinically relevant levels of negative symptoms.
Funding Acknowledgements: The study was funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S
This contribution presents a comprehensive analysis of the low temperature deformation behavior of CoCrFeMnNi on the basis of quasistatic tensile tests at temperatures ranging from room temperature down to 4.2 K. Different deformation phenomena occur in the high-entropy alloy in this temperature range. These include (i) serrated plastic flow at certain cryogenic temperatures (4.2 K/8 K), (ii) deformation twinning (4.2 K/8 and 77 K), and (iii) dislocation slip (active from 4.2 K up to room temperature). The importance of deformation twinning for a stable work-hardening rate over an extended stress range as well as strain range has been addressed through the use of comprehensive orientation imaging microscopy studies. The proposed appearance of ε-martensite as well as a previously uninvestigated route of analysis, essentially a quantitative time-dependent, strain-dependent, and stress-dependent evaluation of the serrated plastic flow in CoCrFeMnNi is provided.
Symptoms of anxiety are prevalent in Major Depressive Disorder (MDD) and are associated with greater illness severity, suicidality, impaired functioning and poor response to antidepressant treatment (ADT). In MDD, anxiety symptoms can be assessed as ‘anxious distress’ (new DSM-5 specifier) or ‘anxious depression’ (score ≥7 on the HAM-D anxiety/somatization factor). Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors – all at similar potency. Brexpiprazole is approved in the US for treatment ofschizophrenia, and as adjunctive treatment in MDD. The objective of this post-hoc analysis was to assess the efficacy of brexpiprazole as adjunct to ADT in patients with MDDand anxiety symptoms, using these two definitions of anxiety.
Data were pooled from three randomized, double-blind, placebo-controlled studies with similar designs (Pyxis – NCT01360645; Polaris – NCT01360632; Sirius – NCT02196506). In each study, patients with MDD and an inadequate response to 1–3 ADTs received single-blind ADT for 8 weeks. Patients with inadequate response throughout this prospective phase were randomized to receive either ADT+brexpiprazole (2mg in Pyxis and Sirius; 1mg or 3 mg in Polaris) or ADT+placebo for 6 weeks. Proxies used to categorize patients as having ‘anxious distress’ included a score of ≥2 on the following symptoms at randomization: tension (MADRS item 3 score ≥3); restlessness (IDS item 24 score ≥2); concentration (MADRS item 6 score ≥3); or apprehension (HAM-D item 10 score ≥3). Scores on the items of the HAM-D anxiety/somatization factor at randomization (baseline) were used to identify patients with ‘anxious depression’. Efficacy was assessed as the change in MADRS total score from baseline to Week 6. Statistical analysis used a Mixed Model Repeated Measure approach using pooled brexpiprazole doses.
After 8 weeks of prospective ADT monotherapy, 57.6% (n=797/1,383) of patients met the criteria for anxious distress, and 48.5% (n=671/1,383) for anxious depression. The mean MADRS total score was 29.0 for patients with anxious distress in the adjunctive brexpiprazole (n=462) group and 29.1 in the placebo (n=327) group; while those with anxious depression were 28.9 (brexpiprazole; n=384) and 28.6 (placebo; n=282). Compared to those receiving placebo, patients with both anxious distress and anxious depression who received adjunctive brexpiprazole showed a greater improvement in MADRS total score (LS mean difference -2.38, p=0.0001 and -1.68, p=0.012, respectively). These improvements, compared to placebo, were similar to those in patients who had not met the criteria for anxious distress (-1.40, p=0.023) or anxious depression (-2.17, p<0.001).
Adjunctive brexpiprazole may be efficacious in reducing depressive symptoms both in patients with or without symptoms of anxiety.
The studies were funded by H. Lundbeck A/S and Otsuka Pharmaceutical Development & Commercialization, Inc.
There is a need for clinical tools to identify cultural issues in diagnostic assessment.
To assess the feasibility, acceptability and clinical utility of the DSM-5 Cultural Formulation Interview (CFI) in routine clinical practice.
Mixed-methods evaluation of field trial data from six countries. The CFI was administered to diagnostically diverse psychiatric out-patients during a diagnostic interview. In post-evaluation sessions, patients and clinicians completed debriefing qualitative interviews and Likert-scale questionnaires. The duration of CFI administration and the full diagnostic session were monitored.
Mixed-methods data from 318 patients and 75 clinicians found the CFI feasible, acceptable and useful. Clinician feasibility ratings were significantly lower than patient ratings and other clinician-assessed outcomes. After administering one CFI, however, clinician feasibility ratings improved significantly and subsequent interviews required less time.
The CFI was included in DSM-5 as a feasible, acceptable and useful cultural assessment tool.
On 16 September 1976, in the neighbourhood of Cite du Havre in Montréal, Québec, a 24-year-old singer and songwriter named Christina ‘Tia’ Blake recorded a demo tape in Studio A of the Canadian Broadcasting Corporation (CBC). Tia had responded to a general request from CBC Radio looking for original songs written by local artists. She recorded three original songs that Thursday, including one song about her father and another written for an old boyfriend. She and the CBC producer listened to the playback together. The producer shook his head. There was nothing there he could use. He gave Tia the tape to keep.
Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies.
Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2–4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1–4 mg), 52-week, placebo-controlled maintenance study.
The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of −20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs.
Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.
EXPOSE-R flew as the second of the European Space Agency (ESA) EXPOSE multi-user facilities on the International Space Station. During the mission on the external URM-D platform of the Zvezda service module, samples of eight international astrobiology experiments selected by ESA and one Russian guest experiment were exposed to low Earth orbit space parameters from March 10th, 2009 to January 21st, 2011. EXPOSE-R accommodated a total of 1220 samples for exposure to selected space conditions and combinations, including space vacuum, temperature cycles through 273 K, cosmic radiation, solar electromagnetic radiation at >110, >170 or >200 nm at various fluences up to GJ m−2. Samples ranged from chemical compounds via unicellular organisms and multicellular mosquito larvae and seeds to passive radiation dosimeters. Additionally, one active radiation measurement instrument was accommodated on EXPOSE-R and commanded from ground in accordance with the facility itself. Data on ultraviolet radiation, cosmic radiation and temperature were measured every 10 s and downlinked by telemetry and data carrier every few months. The EXPOSE-R trays and samples returned to Earth on March 9th, 2011 with Shuttle flight, Space Transportation System (STS)-133/ULF 5, Discovery, after successful total mission duration of 27 months in space. The samples were analysed in the individual investigators laboratories. A parallel Mission Ground Reference experiment was performed on ground with a parallel set of hardware and samples under simulated space conditions following to the data transmitted from the flight mission.
A model-based fitting algorithm for electron energy-loss spectroscopy spectra is introduced, along with an intuitive user-interface. As with Verbeeck & Van Aert, the measured spectrum, rather than the single scattering distribution, is fit over a wide range. An approximation is developed that allows for accurate modeling while maintaining linearity in the parameters that represent elemental composition. Also, a method is given for generating a model for the low-loss background that incorporates plural scattering. Operation of the user-interface is described to demonstrate the ease of use that allows even nonexpert users to quickly obtain elemental analysis results.
Recommendations for fruit and vegetable consumption are largely unmet. Lower socio-economic status (SES), neighbourhood poverty and poor access to retail outlets selling healthy foods are thought to predict lower consumption. The objective of the present study was to assess the interrelationships between these risk factors as predictors of fruit and vegetable consumption.
Cross-sectional multilevel analyses of data on fruit and vegetable consumption, socio-demographic characteristics, neighbourhood poverty and access to healthy retail food outlets.
Survey data from the 2002 and 2004 New York City Community Health Survey, linked by residential zip code to neighbourhood data.
Adult survey respondents (n 15 634).
Overall 9·9 % of respondents reported eating ≥5 servings of fruits or vegetables in the day prior to the survey. The odds of eating ≥5 servings increased with higher income among women and with higher educational attainment among men and women. Compared with women having less than a high-school education, the OR was 1·12 (95 % CI 0·82, 1·55) for high-school graduates, 1·95 (95 % CI 1·43, 2·66) for those with some college education and 2·13 (95 % CI 1·56, 2·91) for college graduates. The association between education and fruit and vegetable consumption was significantly stronger for women living in lower- v. higher-poverty zip codes (P for interaction < 0·05). The density of healthy food outlets did not predict consumption of fruits or vegetables.
Higher SES is associated with higher consumption of produce, an association that, in women, is stronger for those residing in lower-poverty neighbourhoods.
Highly efficient polytype 4H silicon carbide (4H-SiC) p–n diodes for ultraviolet (UV) light detection have been fabricated, characterized, and exposed to high-intensity mercury lamp irradiation (up to 17 mW/cm2). The behavior of the photocurrent response under UV light irradiation using a low-pressure mercury UV-C lamp (4 mW/cm²) and a medium-pressure mercury discharge lamp (17 mW/cm²) has been studied. We report on long-term UV photoaging tests performed for up to 22 mo. Results demonstrate the robustness of SiC photodiodes against UV radiation. The devices under test showed an initial burn-in effect, i.e., the photocurrent response dropped by less than 5% within the first 40 h of artificial UV aging. Such burn-in effect under UV stress was also observed for previously available polytype 6H silicon carbide (6H–SiC) p–n photodetectors. After burn-in, no measurable degradation has been detected, which makes the devices excellent candidates for high irradiance UV detector applications.
Articular cartilage is a low-friction, load-bearing tissue located at joint
surfaces. It experiences static and dynamic forces including shear,
compression and tension. We investigate the relationship between structure
and function by measuring the osmotic and mechanical properties in cartilage
layers as a function of the distance from the articular surface. Atomic
force microscopy is used to probe the mechanical properties at high spatial
resolution. The mechanical measurements are complemented by osmotic swelling
pressure observations made on the same samples using a novel tissue
osmometer. The results show that the osmotic modulus significantly depends
on the distance from the articular surface. Its value is highest in the deep
zone and lowest in the middle zone.
Modulus mapping using nanoDMA (Dynamic Mechanical Analysis) is a recently developed technique based on a nanoindentation instrument equipped with an AFM-like piezoscanner and dynamic force modulation system. The surface properties, storage and loss moduli are quantified based on the Hertz model for the contact mechanics of the sample-tip configuration. In this approach, the applied load, topography features, and their size may have a pronounced effect on the obtained results. In order to demonstrate that, internal interfaces of deep sea sponge (Monorhaphis chuni), which comprises alternating layers of relatively thick (4 μm in average) biosilica and thin (60 nm) organic material, were characterized using the nanoDMA modulus mapping technique. Experimental data were analyzed in tight interrelation with finite element simulations. This combination allowed us to evaluate elastic modulus of a 60 nm wide organic layers in M. chuni.
The objectives of the study were to compare the ovarian activity of Holstein-Friesian (CH HF), Fleckvieh (CH FV) and Brown Swiss (CH BS) dairy cows of Swiss origin with that of Holstein-Friesian (NZ HF) dairy cows of New Zealand origin, the latter being used as a reference for reproductive performance in pasture-based seasonal calving systems. Fifty, second-lactation NZ HF cows were each paired with a second-lactation Swiss cow (17, 15 and 18 CH HF, CH FV and CH BS respectively) in 13 pasture-based, seasonal-calving commercial dairy farms in Switzerland. Ovarian activity was monitored by progesterone profiling from calving to first breeding service. CH BS cows produced less energy-corrected milk (mean 22·8 kg/d) than the other breeds (26·0–26·5 kg/d) during the first 100 d of lactation. CH HF cows had the lowest body condition score (BCS) at calving and the greatest BCS loss from calving to 30 d post partum. Commencement of luteal activity (CLA) was later for NZ HF than for CH FV (51·5 v. 29·2 d; P <0·01), with CH HF and CH BS intermediate (43 d). On average, NZ HF and CH HF cows had one oestrous cycle before the onset of the seasonal breeding period; this was less (P<0·01) than either CH FV (1·7) or CH BS (1·6). There was a low prevalence of luteal persistency (3%) among the studied cows. First and second oestrous cycle inter-ovulatory intervals did not differ between breeds (20·5–22·6 d). The luteal phase length of CH BS during the second cycle was shorter (10·6 d) than that of the other breeds (13·8–16·0 d), but the inter-luteal interval was longer (9·8 d v. 7·0–8·0 d). The results suggest that the Swiss breeds investigated have a shorter interval from calving to CLA than NZ HF cows.