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Dasotraline is a long-acting dopamine/norepinephrine reuptake inhibitor with a PK profile characterized by slow absorption and a t½ of 47-77 hours, permitting once-daily dosing. In a previous flexible dose study, dasotraline demonstrated significant efficacy in the treatment of binge-eating disorder (BED). The aim of this confirmatory fixed-dose study was to evaluate efficacy and safety of dasotraline in the treatment of patients with BED.
Patients meeting DSM-5 criteria for BED were randomized to 12 weeks of double-blind treatment with dasotraline (4 mg/d or 6 mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating days per week at week 12. Secondary efficacy endpoints included changes at Week 12 on the Binge Eating Clinical Global Impression of Severity Scale (BE-CGI-S), the Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (Y-BOCS-BE), and the proportion of patients with 100% cessation of binge-eating episodes during the final 4 weeks of treatment. Efficacy was assessed using an MMRM analysis (and a logistic regression model for cessation) with a pre-specified sequential testing procedure used to control overall type I error rate.
A total of 486 were in the ITT population (dasotraline 6 mg/d (N=162), 4 mg/d (N=161), or placebo (N=163). At week 12, treatment with dasotraline was associated with significant reduction in number of binge-eating days per week in the 6 mg/d group vs. placebo (-3.5 vs. -2.9; P=0.0045), but non-significant improvement in the 4 mg/d group vs. placebo (-3.2; P=0.12). Greater improvement was observed vs. placebo for dasotraline 6 mg/d and 4 mg/d, respectively, on the BE-CGI-S (P<0.01 and P<0.03) and the Y-BOC-BE (P<0.001 and P<0.02; all P-values were nominal, not adjusted for multiplicity). The proportion of patients who achieved 4-week cessation of binge-eating episodes was only significant for the dasotraline 6 mg in the completer population (P<0.05; post-hoc analysis) but was not significant for either dose of dasotraline vs. placebo when drop-outs were included in the analysis. The most common adverse events on dasotraline 6 mg/d and 4 mg/d were combined insomnia (early, middle, late), dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in systolic and diastolic blood pressure were minimal. Mean baseline to endpoint changes in supine pulse rate on dasotraline 6 mg/d and 4 mg/d vs. placebo was +6.2 bpm and +4.8 vs. +0.2 bpm.
In this 12-week, placebo-controlled, fixed-dose study, treatment with dasotraline 6 mg/d was associated with a significant reduction in frequency of binge-eating days per week; efficacy was not demonstrated for the 4 mg dose. Treatment with both doses of dasotraline resulted in improvement in the Y-BOCS-BE and the BE-CGI-S. Dasotraline was safe and generally well-tolerated at both doses; most common adverse events were insomnia, dry mouth and headache.
Supported by funding from Sunovion Pharmaceuticals Inc.
The science of studying diamond inclusions for understanding Earth history has developed significantly over the past decades, with new instrumentation and techniques applied to diamond sample archives revealing the stories contained within diamond inclusions. This chapter reviews what diamonds can tell us about the deep carbon cycle over the course of Earth’s history. It reviews how the geochemistry of diamonds and their inclusions inform us about the deep carbon cycle, the origin of the diamonds in Earth’s mantle, and the evolution of diamonds through time.
Depression is a leading cause of disability, with older people particularly susceptible to poor outcomes.
To investigate whether the prevalence of depression and antidepressant use have changed across two decades in older people.
The Cognitive Function and Ageing Studies (CFAS I and CFAS II) are two English population-based cohort studies of older people aged ≥65 years, with baseline measurements for each cohort conducted two decades apart (between 1990 and 1993 and between 2008 and 2011). Depression was assessed by the Geriatric Mental State examination and diagnosed with the Automated Geriatric Examination for Computer-Assisted Taxonomy algorithm.
In CFAS I, 7635 people aged ≥65 years were interviewed, of whom 1457 were diagnostically assessed. In CFAS II, 7762 people were interviewed and diagnostically assessed. Age-standardised depression prevalence in CFAS II was 6.8% (95% CI 6.3–7.5%), representing a non-significant decline from CFAS I (risk ratio 0.82, 95% CI 0.64–1.07, P = 0.14). At the time of CFAS II, 10.7% of the population (95% CI 10.0–11.5%) were taking antidepressant medication, more than twice that of CFAS I (risk ratio 2.79, 95% CI 1.96–3.97, P < 0.0001). Among care home residents, depression prevalence was unchanged, but the use of antidepressants increased from 7.4% (95% CI 3.8–13.8%) to 29.2% (95% CI 22.6–36.7%).
A substantial increase in the proportion of the population reporting taking antidepressant medication is seen across two decades for people aged ≥65 years. However there was no evidence for a change in age-specific prevalence of depression.
This pilot study explored the feasibility of a moderate time-restricted feeding (TRF) intervention and its effects on adiposity and metabolism. For 10 weeks, a free-living TRF group delayed breakfast and advanced dinner by 1·5 h each. Changes in dietary intake, adiposity and fasting biochemistry (glucose, insulin, lipids) were compared with controls who maintained habitual feeding patterns. Thirteen participants (29 (sem 2) kg/m2) completed the study. The average daily feeding interval was successfully reduced in the TRF group (743 (sem 32) to 517 (sem 22) min/d; P < 0·001; n 7), although questionnaire responses indicated that social eating/drinking opportunities were negatively impacted. TRF participants reduced total daily energy intake (P = 0·019) despite ad libitum food access, with accompanying reductions in adiposity (P = 0·047). There were significant between-group differences in fasting glucose (P = 0·008), albeit driven primarily by an increase among controls. Larger studies can now be designed/powered, based on these novel preliminary qualitative and quantitative data, to ascertain and maximise the long-term sustainability of TRF.
Nearby star-forming galaxies offer a unique environment to study the populations of young (<100 Myr) accreting binaries. These systems are tracers of past populations of massive stars that heavily affect their immediate environment and parent galaxies. Using a Chandra X-ray Visionary program, we investigate the young neutron-star binary population in the low metallicity of the Small Magellanic Cloud (SMC) by reaching quiescent X-ray luminosity levels (~few times 1032 erg/s). We present the first measurement of the formation efficiency of high-mass X-ray binaries (HMXBs) as a function of the age of their parent stellar populations by using 3 indicators: the number ratio of HMXBs to OB stars, to the SFR, and to the stellar mass produced during the specific star-formation burst they are associated with. In all cases, we find that the HMXB formation efficiency increases as a function of time up to ~40–60 Myr, and then gradually decreases.
Almost all confirmed optical counterparts of HMXBs in the SMC are OB stars with equatorial decretion disks (OBe). These sources emit strongly in Balmer lines and standout when imaged through narrow-band Hα imaging. The lack of secure counterparts for a significant fraction of the HMXBs motivated us to search for more. Using the catalogs for OB/OBe stars (Maravelias et al.2017) and for HMXBs (Haberl & Sturm 2016) we detect 70 optical counterparts (out of 104 covered by our survey). We provide the first identification of the optical counterpart to the source XTEJ0050-731. We verify that 17 previously uncertain optical counterparts are indeed the proper matches. Regarding 52 confirmed HMXBs (known optical counterparts with Hα emission), we detect 39 as OBe and another 13 as OB stars. This allows a direct estimation of the fraction of active OBe stars in HMXBs that show Hα emission at a given epoch to be at least ∼75% of their total HMXB population.
Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
Drought represents one of the major constraints on agricultural productivity and food security and in future is destined to spread widely as a consequence of climate change. Research efforts are focused on developing strategies to make crops more resilient and to mitigate the effects of stress on crop production. In this context, the use of root-associated microbial communities and chemical priming strategies able to improve plant tolerance to abiotic stresses, including drought, have attracted increasing attention in recent years. The current review offers an overview of recent research aimed at verifying the role of arbuscular mycorrhizal fungi and chemical agents to improve plant tolerance to drought and to highlight the mechanisms involved in this improvement. Attention will be devoted mainly to current knowledge on the mechanisms involved in water transport.
The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30·1 (sem 1·0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0·3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0·8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41–80) and 73 d (IQR 48–128), respectively, P=0·246), or in body composition (P≥0·437). For postprandial measures, neither diet significantly altered glycaemia (P=0·266), whereas insulinaemia was reduced comparatively (P=0·903). The reduction in C-peptide tended (P=0·057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol×360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol×360 min/l). The relative reduction in TAG responses was greater (P=0·045) following IER (106 (sem30) to 68 (sem 15) mmol×360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol×360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.
During the 125th European Study Group with Industry held in Limassol, Cyprus, 5–9 December 2016, one of the participating companies, Engino.net Ltd, posed a very interesting challenge to the members of the study group. Engino.net Ltd is a Cypriot company, founded in 2004, that produces a series of toy sets – the Engino® toy sets – consisting of a number of building blocks, which can be assembled by pupils to compose toy models. Depending on the contents of a particular toy set, the company has developed a number of models that can be built utilizing the blocks present in the set; however, the production of a step-by-step assembly manual for each model could only be done manually. The goal of the challenge posed by the company was to implement a procedure to automatically generate the assembly instructions for a given toy. In the present paper, we propose a graph-theoretic approach to model the problem and provide a series of results to solve it by employing modified versions of well-established algorithms in graph theory. An algorithmic procedure to obtain a hierarchical, physically feasible decomposition of a given toy model, from which a series of step-by-step assembly instructions can be recovered, is proposed.
Background: The present study examined the efficacy of virtual reality (VR) exposure therapy for treating individuals with storm fears by comparing a one-session VR exposure treatment with a one-session progressive muscle relaxation (PMR) and psychoeducation session. Aims: It was predicted that there would be a reduction in storm-related fear post-treatment for individuals in both conditions, but that this reduction would be greater for those in the VR exposure condition. It was predicted that improvements would be maintained at 30-day follow-up only for those in the VR exposure condition. Method: Thirty-six participants each received one of the two treatment conditions. Those in the PMR treatment group received approximately 30 minutes of PMR and approximately 15 minutes of psychoeducation regarding storms. Those in the VR treatment group received approximately 1 hour of VR exposure. Additionally, participants were asked to complete a pre-treatment and post-treatment 5-minute behavioural approach test to assess changes in storm fears. They were also asked to complete a measure assessing storm phobia. Results: There was a significant interaction between treatment group and self-reported fear at post-treatment, such that fear decreased for both groups, although the reduction was stronger in the VR group. Results also showed that reductions in storm fear were maintained at 30-day follow-up for both groups. Conclusions: Although this study used a small non-clinical sample, these results offer preliminary support for the use of VR exposure therapy in the treatment of storm-related fear.
A new macroscopic model describing the rheology and microstructure of dilute emulsions with droplet morphology is developed based on an internal contravariant conformation tensor variable which is physically identified with the deformed ellipsoidal geometry of the dispersed phase. The model is consistent with existing first-order capillary number,
, theory describing the microstructure as well as
theory describing the emulsion-contributed extra stress. These asymptotic solutions are also used to determine all of the model parameters, making it the only macroscopic emulsion model that is consistent with all available asymptotic theories in the limit of small
. The governing equations are obtained from the Poisson and dissipation brackets, as developed for an incompressible fluid system endowed with an internal contravariant second-order tensor, subject to the imposition of the constraint of a unit determinant. First proposed by Maffettone & Minale (J. Non-Newtonian Fluid Mech., vol. 78, 1998, pp. 227–241), this constraint physically corresponds to conservation of the volume of the dispersed phase in the emulsion. The Hamiltonian of the emulsion is expressed through the surface energy of the dispersed phase, in addition to the kinetic energy, following previous work by Grmela et al. (J. Non-Newtonian Fluid Mech., vol. 212, 2014, pp. 1–12), but employing a more accurate evaluation of the surface area in terms of the internal contravariant conformation tensor. Structural predictions of the ellipsoid droplet morphology obtained with the new model are compared with classic experiments by Torza et al. (J. Colloid Interface Sci., vol. 38, 1972, pp. 395–411), showing good agreement.
Space is one of the primary limiting resources for organisms on the intertidal rocky shore. This paper examined the effect of reduced density on key traits (mortality and growth) on the intertidal barnacles, Chthamalus montagui and Semibalanus balanoides, on the mid-shore in Plymouth, UK. Intra- and interspecific treatments comprising of C. montagui and S. balanoides were manipulated to reduce densities at two similar sites. Changes in mortality and operculum growth were assessed over an 8-week period using digital photography. Covariates of growth included nearest neighbour distance, competition between closest pairs and initial size. Conflicting patterns were observed when comparing growth rates between treatments and sites. At Site 1, interspecific treatments had a lower growth rate than intraspecific treatments, whereas at Site 2, interspecific growth rates were higher. ANCOVA showed that nearest neighbour distance had no significant effect on growth, but when comparing differences in growth of closest neighbouring pairs, C. montagui treatment showed evidence of competition whereas S. balanoides did not. ANCOVA analysis indicated no difference in growth between each outcome of pair competition, suggesting winners are initially bigger than losers. Comparisons of mortality between treatments indicated mortality over time with no significant differences observed between treatments, but response surface methodology (RSM) revealed no effects of competition on mortality of S. balanoides, but negative effects of both intra- and interspecific competition on C. montagui survivorship. Examination of natural populations of barnacles in the mid-shore indicated there was strong spatial variation in growth rates, perhaps driven by small-scale differences within sites.
Two intermittent fasting variants, intermittent energy restriction (IER) and time-restricted feeding (TRF), have received considerable interest as strategies for weight-management and/or improving metabolic health. With these strategies, the pattern of energy restriction and/or timing of food intake are altered so that individuals undergo frequently repeated periods of fasting. This review provides a commentary on the rodent and human literature, specifically focusing on the effects of IER and TRF on glucose and lipid metabolism. For IER, there is a growing evidence demonstrating its benefits on glucose and lipid homeostasis in the short-to-medium term; however, more long-term safety studies are required. Whilst the metabolic benefits of TRF appear quite profound in rodents, findings from the few human studies have been mixed. There is some suggestion that the metabolic changes elicited by these approaches can occur in the absence of energy restriction, and in the context of IER, may be distinct from those observed following similar weight-loss achieved via modest continuous energy restriction. Mechanistically, the frequently repeated prolonged fasting intervals may favour preferential reduction of ectopic fat, beneficially modulate aspects of adipose tissue physiology/morphology, and may also impinge on circadian clock regulation. However, mechanistic evidence is largely limited to findings from rodent studies, thus necessitating focused human studies, which also incorporate more dynamic assessments of glucose and lipid metabolism. Ultimately, much remains to be learned about intermittent fasting (in its various forms); however, the findings to date serve to highlight promising avenues for future research.
Objectives: The aim of this study was to adapt and assess the value of a Multi-Criteria Decision Analysis (MCDA) framework (EVIDEM) for the evaluation of Orphan drugs in Catalonia (Catalan Health Service).
Methods: The standard evaluation and decision-making procedures of CatSalut were compared with the EVIDEM methodology and contents. The EVIDEM framework was adapted to the Catalan context, focusing on the evaluation of Orphan drugs (PASFTAC program), during a Workshop with sixteen PASFTAC members. The criteria weighting was done using two different techniques (nonhierarchical and hierarchical). Reliability was assessed by re-test.
Results: The EVIDEM framework and methodology was found useful and feasible for Orphan drugs evaluation and decision making in Catalonia. All the criteria considered for the development of the CatSalut Technical Reports and decision making were considered in the framework. Nevertheless, the framework could improve the reporting of some of these criteria (i.e., “unmet needs” or “nonmedical costs”). Some Contextual criteria were removed (i.e., “Mandate and scope of healthcare system”, “Environmental impact”) or adapted (“population priorities and access”) for CatSalut purposes. Independently of the weighting technique considered, the most important evaluation criteria identified for orphan drugs were: “disease severity”, “unmet needs” and “comparative effectiveness”, while the “size of the population” had the lowest relevance for decision making. Test–retest analysis showed weight consistency among techniques, supporting reliability overtime.
Conclusions: MCDA (EVIDEM framework) could be a useful tool to complement the current evaluation methods of CatSalut, contributing to standardization and pragmatism, providing a method to tackle ethical dilemmas and facilitating discussions related to decision making.