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Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours. This phase 3 study evaluated the efficacy and safety of dasotraline in children with attention deficithyperactivity disorder (ADHD) throughout the day, in a laboratory classroom setting (NCT02734693).
Children (6–12 years) meeting DSM-5 criteria for ADHD were randomized to 2 weeks of dasotraline or placebo (dosed daily at home at approximately 8 PM). Following an abbreviated practice day, laboratory classroom evaluations took place at baseline and on Day 15. The primary endpoint was mean change from baseline at Day 15 in ADHD symptoms, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Combined Score (SKAMP-CS), obtained from the average of 7 assessments collected across the 12-hour laboratory classroom day (12–24 hours post-dose). Secondary endpoints included SKAMP scores obtained throughout the day at individual timepoints from 8 AM through 8 PM (12–24 hours post-dose), and measures of safety and tolerability.
The ITT population comprised 112 patients. Mean age was 9.5 years, 68.8% were male; 92% completed the study. Dasotraline 4 mg/day significantly improved mean SKAMP-CS versus placebo (p<0.0001, effect size 0.85) with significant effects persisting throughout the day. Mean SKAMP subscores improved significantly versus placebo (Attention p<0.0001, effect size 0.81; Deportment p<0.001, effect size 0.70). Treatment-emergent adverse events were generally mild or moderate in severity; most frequent (with dasotraline 4 mg/day; placebo) included: insomnia (19.6%; 3.6%, all terms combined), decreased appetite (10.7%; 3.6%), headache (10.7%; 8.9%), affect lability (8.9%; 7.1%), irritability (5.4%; 3.6%), postural orthostatic tachycardia syndrome (5.4%; 0%), and perceptual disturbances (5.4%; 0%).
In this 2-week, randomized, double-blind, laboratory classroom study in children with ADHD, once-daily dasotraline significantly improved ADHD symptoms (including deportment and attention), compared with placebo, and demonstrated sustained efficacyup to 24 hours post-dose. The most common adverse events were insomnia, decreased appetite, and headache.
Binge eating disorder (BED) is the most common eating disorder in the US, with a lifetime prevalence of 2.8%. Disturbances in reward circuitry have been implicated in its pathogenesis. Dasotraline is a novel and potent dopamine and norepinephrine reuptake inhibitor with slow absorption and a long half-life resulting in stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated the efficacy and safety of flexibly-dosed dasotraline (4, 6, and 8 mg/day) vs placebo in adults with moderate to severe BED over a 12-week period (NCT02564588).
Key inclusion criteria included moderate to severe BED based on a history of ≥2 binge eating days/week for ≥6 months prior to screening, and ≥3 binge eating days for each of2 weeks prior to randomization, as documented in participant’s binge eating diary. Patients were randomized 1:1 to flexibly-dosed dasotraline (4, 6, 8 mg/day) or placebo. Theprimary endpoint was change from baseline (CFB) in the number of binge eating days per week at Week 12. Key secondary endpoints were: CFB in Clinical Global Impression–Severity (CGI-S) Scale at Week 12; CFB in Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (YBOCS-BE) at Week 12; and the percentage ofsubjects with a 4-week cessation from binge eating prior to Week 12 or end of treatment (EOT). Except for 4-week cessation, the other three variables were analyzed using amixed model for repeated measures (MMRM).
317 subjects (84% female) received ≥1 dose of study medication (mean age was 38.2 years; mean number of binge eating days per week, 4.25; mean CGI-S score, 4.5; mean BMI, 34.7). The MMRM analysis of CFB at Week 12 in the number of binge days/week yielded a significant mean difference of –0.99 (95% CI: –0.65 to –1.33; p<0.001) infavour of dasotraline (–3.74 in the dasotraline group vs –2.75 in the placebo group). All three key secondary endpoints were met at Week 12 or EOT: 46.5% of subjects in thedasotraline group achieved at least 4 consecutive weeks’ cessation from binge eating vs 20.6% in the placebo group (p<0.001); CFB in CGI-S and YBOCS-BE scores were also statistically significant in favour of dasotraline (p<0.001). The treatment-emergent adverse events (TEAEs) that occurred more frequently with dasotraline vs placebo at >2% incidence included: insomnia (44.6% vs 8.1%), dry mouth (27.4% vs 5.0%), decreased appetite (19.7% vs 6.9%), anxiety (17.8% vs 2.5%), nausea (12.7% vs 6.9%) and decreased body weight (12.1% vs 0%). Discontinuation due to AEs occurred in 11.5% of patients taking dasotraline vs 2.5% taking placebo.
In adults with moderate to severe BED, there were highly significant and clinically meaningful reductions with dasotraline vs placebo in the frequency of binge eating, global severity of illness, and obsessive-compulsive symptoms related to binge eating. These results suggest dasotraline may offer a novel, well-tolerated and efficacious treatmentfor BED.
Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).
Patients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.
The mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, p<0.001; effect size [ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day vs placebo at Week 6 (p=0.001, p=0.003, respectively). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day vs placebo(LS mean [SE] CFB at Week 6: –1.39 [±0.12] vs –1.04 [±0.12], respectively, p=0.040; ES: 0.29). No significant improvement was observed on the ADHD RS-IV HV total score and the CGI-S score for dasotraline 2 mg/day vs placebo. The most frequent treatment-emergent AEs (≥5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%).
Compared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.
During the three days from 11 March to 13 March 2010, a rich and remarkable scholarly event was held on the campus of Jawaharlal Nehru University (JNU), New Delhi. It was a major international conference devoted to a critical examination and discussion on a wide variety of the forms of religious devotion and sectarian practice and, more provocatively, to the various types of dissent that these forms have engendered over the longue durée of Indian history. The event, conceived and organized by Professor Vijaya Ramaswamy of the Centre for Historical Studies at JNU and hosted by the Centre, brought together scholars – both Indian and foreign – who were experts in many different religious and linguistic traditions as these traditions have evolved in different regions of the subcontinent from antiquity through the medieval period and down to modernity.
The conference – the papers presented at which appear in the present volume– represented an original and productive turn in the study of the history of religious movements over time in South Asia. It focused scholarly attention specifically on the frequently overlooked currents of dissent within and against several major, mainstream religious movements and organizations that are often represented as the uncontested, if not the exclusive, representatives of their respective faiths in India and throughout the Indian diaspora. In highlighting the phenomenon of dissent, the conference thus productively focused the attention of the scholars in attendance, and one would hope, of those who have the opportunity to read the present collection of the proceedings, on some less fully examined aspects of Indian religions.
In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.
The objective of this paper is to propose a method to estimate the average values of the dynamic modulus of elasticity and the dynamic shear modulus of cement paste-aggregate interfacial zones in mortar by applying the Logarithmic Mixture Rule (LMR). Both portland cement mortars (PC mortars) and portland cement mortars with silica fume (SF mortars) are investigated and compared, The influence of silica fume on the dynamic moduli of interfacial zone is also examined. Results indicate that for the specific ingredients and mix design used, the dynamic modulus of elasticity of interfacial zone falls between 0.4 and 2.0 (×10 6 psi) for PC mortar and 1.2 to 2.2 (× 106 psi) for SF mortar. These values are lower than the values obtained for PC mortar (4.2 ×106 psi), PC paste (2.7 ×106 psi), SF mortar (4.4 ×106 psi), and SF paste (2.5 × 106 psi).
Text of a public lecture by Robert Kogod Goldman in Kolkata on 16 August 2005.
I would like to thank the Mahanirban Calcutta Research Group (CRG) for inviting me to give a series of lectures touching on issues related to Forced Displacement, the Guiding Principles on Internal Displacement and International Law. […] As I worked very closely with Francis Deng and Walter Kalin in developing the normative framework applicable to Internally Displaced Persons (IDPs), I hope that these lectures will provide some useful insights into the origins, substantive content and normative character, as well as the impact to date, of the Guiding Principles on Internal Displacement.
ORIGIN OF THE UN MANDATE ON IDPs
It was not until the early 1990s that international concern began to increasingly focus on the plight of IDPs, i.e., people forced from their homes as a result of armed conflict, communal violence, serious human rights and humanitarian law abuses and/or natural or man-made disasters and who remain uprooted and at risk within their own countries. Unlike persons who flee across international borders and thereby may be entitled to the status and protective international legal regime applicable to refugees, IDPs remain within their country and, as such, are subject to the jurisdiction of their own government, whose very actions or policies may have caused their displacement and which all too frequently may be unwilling or unable to protect or assist them.
As the old adage goes, beauty is in the eye of the beholder. Ultimately, in the world of jewelry, the unwitting buyer uses his or her naked eye to decide which baubles are the most beautiful and worthy of wear. The expert jeweler and gemologist, however, know that each gem is subjected to rigorous scientific examinations and standards to determine its value and authenticity.
As the number of methods for altering gems grows with technology, methods to counteract counterfeiters, who can take a worthless stone and alter it to make it appear like a more expensive gem, are essential to gem buyers and traders. They must be able to detect artificial stones.
Gemologists assess gemstones based on several standards such as chemical composition and purity. Chemical composition plays a significant role in evaluating gems, as two of the same gemstone can differ chemically. One of the most well known methods of non-destructive testing for detecting gem quality is X-ray fluorescence (XRF) spectroscopy. Increasingly in demand, XRF spectroscopy is an ideal technique for fighting the battle against fraud.
This past April the Representative of the United Nations Secretary-General on Internally Displaced Persons, Francis M. Deng, presented to the UN Commission on Human Rights, at its 54th session, a report with an addendum entitled Guiding Principles on Internal Displacement (hereinafter “Guiding Principles”). The Commission adopted by consensus a resolution co-sponsored by more than 50 States which, inter alia, took note of the decision of the Inter-Agency Standing Committee welcoming the Guiding Principles and encouraging its members to share them with their Executive Boards, and also of Mr. Deng's stated intention to make use of these principles in his dialogue with governments and intergovernmental and non-governmental organizations. These principles are an important milestone in the process of establishing a generally accepted normative framework for the protection of the estimated 20 to 25 million internally displaced persons worldwide.
El mes de abril pasado, el representante del secretario general de las Naciones Unidas sobre la cuestión de los desplazados internos, señor Francis Deng, presentó a la Comisión de Derechos Humanos, en su 54° período de sesiones, un informe con una adición titulada Principios Rectores de los desplazamientos internos (en adelante, Principios Rectores). La Comisión aprobó por consenso una resolución, apoyada por más de 50 Estados, en la que, inter alia, toma nota de la decisión del Comité Permanente entre Organismos de acoger con satisfacción los Principios Rectores y alentar a sus miembros a que compartan dichos Principios con sus juntas ejecutivas, así como de la intención manifestada por el señor Deng de utilizar los Principios Rectores en su diálogo con los Gobiernos y las organizaciones intergubernamentales y no gubernamentales. Estos Principios son un hito importante en el proceso de elaboración de un marco normativo de aceptación general para la proteción de unos 20 a 25 millones de personas desplazadas internamente en todo el mundo.