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ALKS 3831, currently under development for the treatment of schizophrenia, is composed of olanzapine (OLZ) and a fixed dose of 10mg of samidorphan. In a Phase 2 study in stable patients with schizophrenia, ALKS 3831mitigated OLZ-associated weight gain while maintaining an antipsychotic efficacy profile similar to OLZ.
To assess the efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia.
This was a Phase 3, 4-week, randomized, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomized 1:1:1 to receive ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2weeks of the study and could be treated as inpatients or outpatients for the remaining 2weeks. Patients were excluded if they received OLZ within 6months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression–Severity (CGI-S) and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs).
Of 401 randomized patients who received ALKS 3831, OLZ, or PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean±standard deviation scores were 101.7±11.9 for PANSS total score and 5.1±0.7 for CGI-S scale score. The mean OLZ dose was 18.4mg/day in both active treatment arms. Least squares (LS) mean difference±standard error (SE) vs PBO from baseline to Week 4 in PANSS total score was –6.4±1.8 (P<.001) for the ALKS 3831 group and –5.3±1.8 (P=.004) for the OLZ group. LS mean difference±SE vs PBO from baseline to Week 4 in CGI-S scale score was −0.4±0.1 (P=.002) for the ALKS3831 group and −0.4±0.1 (P<.001) for the OLZ group. The percentage of patients with improvement in PANSS response (≥30% from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I scale response (score of ≤2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (≥5% in any group) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia.
Treatment with ALKS 3831 was more effective than PBO, as measured by the PANSS and CGI-S scale, and its antipsychotic efficacy was similar to the active control OLZ. The safety profile of ALKS 3831 was similar toOLZ.
Funding Acknowledgements: This study was funded by Alkermes, Inc.
Good education requires student experiences that deliver lessons about practice as well as theory and that encourage students to work for the public good—especially in the operation of democratic institutions (Dewey 1923; Dewy 1938). We report on an evaluation of the pedagogical value of a research project involving 23 colleges and universities across the country. Faculty trained and supervised students who observed polling places in the 2016 General Election. Our findings indicate that this was a valuable learning experience in both the short and long terms. Students found their experiences to be valuable and reported learning generally and specifically related to course material. Postelection, they also felt more knowledgeable about election science topics, voting behavior, and research methods. Students reported interest in participating in similar research in the future, would recommend other students to do so, and expressed interest in more learning and research about the topics central to their experience. Our results suggest that participants appreciated the importance of elections and their study. Collectively, the participating students are engaged and efficacious—essential qualities of citizens in a democracy.
We prove that the matrix analogue of the Veronese curve is strongly extremal in the sense of Diophantine approximation, thereby resolving a question posed by Beresnevich, Kleinbock and Margulis (2015) in the affirmative.
There is no consensus as to whether magnetic resonance imaging (MRI) should be used as part of the initial clinical evaluation of patients with first-episode psychosis (FEP).
(a) To assess the logistical feasibility of routine MRI; (b) to define the clinical significance of radiological abnormalities in patients with FEP.
Radiological reports from MRI scans of two FEP samples were reviewed; one comprised 108 patients and 98 healthy controls recruited to a research study and the other comprised 241 patients scanned at initial clinical presentation plus 66 healthy controls.
In the great majority of patients, MRI was logistically feasible. Radiological abnormalities were reported in 6% of the research sample and in 15% of the clinical sample (odds ratio (OR) = 3.1, 95% CI 1.26–7.57, χ2(1) = 6.63, P = 0.01). None of the findings necessitated a change in clinical management.
Rates of neuroradiological abnormalities in FEP are likely to be underestimated in research samples that often exclude patients with organic abnormalities. However, the majority of findings do not require intervention.
We highlight a connection between Diophantine approximation and the lower Assouad dimension by using information about the latter to show that the Hausdorff dimension of the set of badly approximable points that lie in certain non-conformal fractals, known as self-affine sponges, is bounded below by the dynamical dimension of these fractals. For self-affine sponges with equal Hausdorff and dynamical dimensions, the set of badly approximable points has full Hausdorff dimension in the sponge. Our results, which are the first to advance beyond the conformal setting, encompass both the case of Sierpiński sponges/carpets (also known as Bedford–McMullen sponges/carpets) and the case of Barański carpets. We use the fact that the lower Assouad dimension of a hyperplane diffuse set constitutes a lower bound for the Hausdorff dimension of the set of badly approximable points in that set.
We solve the problem of giving sharp asymptotic bounds on the Hausdorff dimensions of certain sets of badly approximable matrices, thus improving results of Broderick and Kleinbock (preprint 2013) as well as Weil (preprint 2013), and generalising to higher dimensions those of Kurzweil ('51) and Hensley ('92). In addition we use our technique to compute the Hausdorff f-measure of the set of matrices which are not ψ-approximable, given a dimension function f and a function ψ : (0, ∞) → (0, ∞). This complements earlier work by Dickinson and Velani ('97) who found the Hausdorff f-measure of the set of matrices which are ψ-approximable.
Processing and measurement of 200 biomedical samples has provided an opportunity to better understand the characteristics of accelerator mass spectrometry (AMS) analysis of such samples. We have utilized established procedures (Vogel 1992) and developed new methods for handling various biological samples. We have included secondary standards of known isotope ratio for all assays. A method of determining maximum precision for each unknown sample value is also reported. The presented data are an update of the ongoing radiocarbon AMS biomedical program at Purdue University.
The use of cannabis with higher Δ9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users.
The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment.
Across the whole sample, users of high-potency cannabis had higher total CC MD and higher total CC AD than both low-potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis.
Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.
We provide a new proof of a theorem whose proof was sketched by Sullivan [Disjoint spheres, approximation by imaginary quadratic numbers, and the logarithm law for geodesics. Acta Math.149(3–4) (1982), 215–237], namely that if the Poincaré exponent of a geometrically finite Kleinian group
is strictly between its minimal and maximal cusp ranks, then the Patterson–Sullivan measure of
is not proportional to the Hausdorff or packing measure of any gauge function. This disproves a conjecture of Stratmann [Multiple fractal aspects of conformal measures; a survey. Workshop on Fractals and Dynamics (Mathematica Gottingensis, 5). Eds. M. Denker, S.-M. Heinemann and B. Stratmann. Springer, Berlin, 1997, pp. 65–71; Fractal geometry on hyperbolic manifolds. Non-Euclidean Geometries (Mathematical Applications (N.Y.), 581). Springer, New York, 2006, pp. 227–247].
We provide a closed formula of Bowen type for the Hausdorff dimension of a very general shrinking target scheme generated by the nonautonomous dynamical system on the interval
, viewed as
, corresponding to a given method of Cantor series expansion. We also examine a wide class of examples utilising our theorem. In particular, we give a Diophantine approximation interpretation of our scheme.
Schmidt’s game is a powerful tool for studying properties of certain sets which arise in Diophantine approximation theory, number theory and dynamics. Recently, many new results have been proven using this game. In this paper we address determinacy and indeterminacy questions regarding Schmidt’s game and its variations, as well as more general games played on complete metric spaces (for example, fractals). We show that, except for certain exceptional cases, these games are undetermined on certain sets. Judging by the vast numbers of papers utilising these games, we believe that the results in this paper will be of interest to a large audience of number theorists as well as set theorists and logicians.
This chapter traces the history of human settlement in Kaikoura, focusing in particular on its origins as an important centre of Māori settlement (c. 950–1130 ad) and livelihood, subsequent European settlement (from the 1830s ad) to a world-class tourism destination based on whale-watching. Historical patterns of settlement, (indigenous) Māori–Pakeha (settler) relations, the early use of whales for commercial trade, subsequent periods of resource extraction and agricultural cycles of growth and decline establish the historical context of tourism development. Contemporary tourism development is, however, primarily based on desperate local economic conditions brought about by restructuring of the New Zealand economy in the mid-1980s.
The history of Kaikoura as a whale-watching destination must first be explored by examining its evolution within a larger set of Māori values. For Kaikoura these are centred around key concepts of:
mother earth (papatuanuku);
Mauri (the physical life force that imbues all living things) and
kaitiakitanga (guardianship of natural resources).
Although these are argued to be particularly poignant in Kaikoura where the (Ngai Tahu) Māori owned-and-operated Whalewatch Kaikoura has become the cornerstone tourist experience, elsewhere in New Zealand they have provided a unique context for resource management. Thus Māori values, alongside more recent resource exploitations, subsequent ‘boom and bust’ economic cycles and finally significant ‘restructuring’ of the late 1980s have paved the way for a cautious approach to contemporary tourism management based on scientific research and destination benchmarking and certification. The early adoption of the GreenGlobe21/earthcheck™ certification system, and Kaikoura's claim as the world's first independently certified tourism destination, have engendered sufficient momentum to see this approach to sustainability permeate all the District's activities and many of its productive sectors. This pathway, in turn, is argued to have arisen out of the unique concurrence of Māori values, tourism focused on marine mega-fauna, and a set of scientific partnerships that have been able to integrate and support a strong focus on governance and management for sustainability.
Project Energize, a region-wide whole-school nutrition and physical activity programme, commenced as a randomised controlled trial (RCT) in the period 2004–6 in 124 schools in Waikato, New Zealand. In 2007, sixty-two control schools were engaged in the programme, and by 2011, all but two of the 235 schools in the region were engaged. Energizers (trained nutrition and physical activity specialists) work with eight to twelve schools each to achieve the goals of the programme, which are based on healthier eating and enhanced physical activity. In 2011, indices of obesity and physical fitness of 2474 younger (7·58 (sd 0·57) years) and 2330 older (10·30 (sd 0·51) years) children attending 193 of the 235 primary schools were compared with historical measurements. After adjusting for age, sex, ethnicity, socio-economic status (SES) and school cluster effects, the combined prevalence of obesity and overweight among younger and older children in 2011 was lower by 31 and 15 %, respectively, than that among ‘unEnergized’ children in the 2004 to 2006 RCT. Similarly, BMI was lower by 3·0 % (95 % CI − 5·8, − 1·3) and 2·4 % (95 % CI − 4·3, − 0·5). Physical fitness (time taken to complete a 550 m run) was significantly higher in the Energized children (13·7 and 11·3 %, respectively) than in a group of similarly aged children from another region. These effects were observed for boys and girls, both indigenous Māori and non-Māori children, and across SES. The long-term regional commitment to the Energize programme in schools may potentially lead to a secular reduction in the prevalence of overweight and obesity and gains in physical fitness, which may reduce the risk of developing obesity and type 2 diabetes.
Through-school nutrition and physical activity interventions are designed to help reduce excess weight gain and risk of chronic disease. From 2004 to 2006, Project Energize was delivered in the Waikato Region of New Zealand as a longitudinal randomised controlled study of 124 schools (year 1–6), stratified by rurality and social deprivation, and randomly assigned to intervention or control. Children (686 boys and 662 girls) aged 5 (1926) and 10 (1426) years (692 interventions and 660 controls) had height, weight, body fat (by bioimpedance) and resting blood pressure (BP) measured at baseline and 2 years later. Each intervention school was assigned an ‘Energizer’; a trained physical activity and nutrition change agent, who worked with the school to achieve goals based on healthier eating and quality physical activity. After adjustment for baseline measures, rurality and social deprivation, the intervention was associated with a reduced accumulation of body fat in younger children and a reduced rate of rise in systolic BP in older children. There was some evidence that the pattern of change within an age group varied with rurality, ethnicity and sex. We conclude that the introduction of an ‘Energizer led’ through-school programme may be associated with health benefits over 2 years, but the trajectory of this change needs to be measured over a longer period. Attention should also be paid to the differing response by ethnicity, sex, age group and the effect of rurality and social deprivation.