DFN-02, Sumatriptan 10 mg Nasal Spray with Permeation Enhancer, for the Acute Treatment of Migraine: A Randomized, Double-Blind, Placebo-Controlled Study Assessing Functional Disability and Subject Satisfaction with Treatment.

BackgroundThe commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent.ObjectiveThe objective of this study was to assess the efficacy of acute treatment of migraine with DFN-02, including its effect on migraine-related functional disability and patient satisfaction with treatment.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-02 in adults with episodic migraine. Functional disability and subject satisfaction with treatment were prespecified endpoints, assessed in real-time by subjects, using an electronic diary.ResultsIn total, 107 subjects were randomized. DFN-02 was significantly superior to placebo for the reduction in functional disability score from predose level at 2 h after treatment (- 1.2 vs. - 0.6, p < 0.001). Subjects treated with DFN-02 were also more likely to be satisfied or very satisfied than subjects treated with placebo at 2 h postdose (70.0% vs. 44.2%, p = 0.027). Using the Patient Perception of Migraine Questionnaire-Revised at 24 h postdose, DFN-02 mean scores were significantly superior to placebo for the subscales of efficacy (65.2 vs. 42.5, p = 0.016) and function (68.9 vs. 42.1, p = 0.001), and for total score (71.0 vs. 56.6, p = 0.016); global medication effectiveness (p = 0.027); and overall satisfaction (p = 0.019). Placebo was significantly better than DFN-02 on the tolerability subscale (94.8 vs. 88.5, p = 0.026). At 24 h postdose, subjects reported significantly higher satisfaction with DFN-02 compared with satisfaction reported pre-randomization regarding their usual migraine medication (p = 0.012).ConclusionDFN-02 was superior to placebo for the relief of migraine-related functional disability, and provided greater satisfaction than placebo or subjects' usual acute treatment.Trial registrationClinicalTrials.gov identifier: NCT02856802

Mesoscale analysis by numerical modeling coupled with satellite-based sounding

November 1988.Principal investigators: Thomas H. Vonder Haar, James F.W. Purdom.Includes bibliographical references.This dissertation deals with the development of a system for time-continuous mesoscale analysis and its use in studying the mesoscale distribution of summertime convective cloud development in the Northeastern Colorado region. There were two basic components of the system — a version of the CSU Regional Atmospheric Modeling System (RAMS) and an algorithm for retrieving temperatures and water vapor concentrations from VISSR Atmospheric Sounder (VAS) data. The system was designed to avoid some of the problems that researchers have encountered when satellite-retrieved parameters have been input to models. The primary distinguishing feature of the new method is that there is an intimate coupling of the retrieval and modeling processes. Water vapor concentrations and ground surface temperatures were the foci of the analyses. In preparation for analysis experiments we tested the sensitivity of a two-dimensional version of the model to various controls on the behavior of water vapor concentrations and surface temperatures. For water vapor mixing ratios, variations that might be caused by analysis errors had very little impact on the dynamics of circulations in the pre-convective stage. In contrast, ground surface temperature variations were shown to have a large impact on circulations, so analysis errors are very relevant to pre-convective dynamics. The first comparisons of the coupled analysis method with other, related, methods was by means of two-dimensional simulations. Analyses in which surface temperatures were derived from satellite-retrievals were compared with the alternative of relying on energy balance computations. The energy balance computations were so sensitive to soil characteristics, which were simulated as unknown, that the satellite retrieval method gave better results even with cloud contamination. In water vapor analysis comparisons no single method was superior in every respect, but the coupled method performed relatively well. Vertical gradients and horizontal gradients were well represented, and the method was relatively insensitive to a common problem in pre-convective analysis — contamination of satellite data by increasing amounts of small convective clouds. Analysis methods were further compared in a three-dimensional case study for 21 August 1983. The horizontal and time variations of satellite-retrieved surface temperatures closely corresponded to the conventional shelter temperature observations, but had much greater detail. In contrast, the energy balance-based temperatures tended to increase too quickly during the morning and lacked some of the observed gradients. According to the retrievals, there can be very large mesoscale gradients in temperatures at the ground surface even on the relatively flat plains. In the case study water vapor analyses there were substantial differences among the results of the several methods that were intercompared. The study demonstrated that, when the first set of satellite data is less reliable than the later sets, some of the contamination lingers throughout the time-continuous coupled analysis results. However, the coupled method generally appeared to be the most valuable of the methods considered in this study because it exploited the major strengths of the numerical model and the satellite data while making it relatively easy to recognize any impacts of their weaknesses. The results of this dissertation support the hypothesis that both ground surface temperatures and terrain variations can play important roles in pre-convective water vapor kinematics through their influences on vertical and horizontal winds. The development of convective clouds corresponded largely, but not exclusively, with convergence and deepening of low-level water vapor. The analysis system proved to be valuable for forecasting through the close correspondence between derived stability indices and later convective development. The new method is a step in the expanding capability of meteorologists to combine tools and sources of data for understanding and forecasting mesoscale phenomena.Research supported by National Oceanic and Atmospheric Administration Grant NA-85-RAH-05045 (53-1209) and in part by Army Research Office Center for Geosciences, Grant DALL-03-86-K-9175

A Field Test of Bandit Algorithms for Recommendations: Understanding the Validity of Assumptions on Human Preferences in Multi-armed Bandits

Personalized recommender systems suffuse modern life, shaping what media we read and what products we consume. Algorithms powering such systems tend to consist of supervised learning-based heuristics, such as latent factor models with a variety of heuristically chosen prediction targets. Meanwhile, theoretical treatments of recommendation frequently address the decision-theoretic nature of the problem, including the need to balance exploration and exploitation, via the multi-armed bandits (MABs) framework. However, MAB-based approaches rely heavily on assumptions about human preferences. These preference assumptions are seldom tested using human subject studies, partly due to the lack of publicly available toolkits to conduct such studies. In this work, we conduct a study with crowdworkers in a comics recommendation MABs setting. Each arm represents a comic category, and users provide feedback after each recommendation. We check the validity of core MABs assumptions-that human preferences (reward distributions) are fixed over time-and find that they do not hold. This finding suggests that any MAB algorithm used for recommender systems should account for human preference dynamics. While answering these questions, we provide a flexible experimental framework for understanding human preference dynamics and testing MABs algorithms with human users. The code for our experimental framework and the collected data can be found at https://github.com/HumainLab/human-bandit-evaluation.Comment: Accepted to CHI. 16 pages, 6 figure

Approximate Query Service on Autonomous IoT Cameras

Elf is a runtime for an energy-constrained camera to continuously summarize video scenes as approximate object counts. Elf's novelty centers on planning the camera's count actions under energy constraint. (1) Elf explores the rich action space spanned by the number of sample image frames and the choice of per-frame object counters; it unifies errors from both sources into one single bounded error. (2) To decide count actions at run time, Elf employs a learning-based planner, jointly optimizing for past and future videos without delaying result materialization. Tested with more than 1,000 hours of videos and under realistic energy constraints, Elf continuously generates object counts within only 11% of the true counts on average. Alongside the counts, Elf presents narrow errors shown to be bounded and up to 3.4x smaller than competitive baselines. At a higher level, Elf makes a case for advancing the geographic frontier of video analytics

Guidelines of the International Headache Society for controlled trials of pharmacological preventive treatment for persistent post-traumatic headache attributed to mild traumatic brain injury

Background: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. Methods: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. Objective: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease

Estimating the clinical effectiveness and value-based price range of erenumab for the prevention of migraine in patients with prior treatment failures: a US societal perspective

BACKGROUND: Frequent migraine with four or more headache days per month is a common, disabling neurovascular disease. From a US societal perspective, this analysis models the clinical efficacy and estimates the value-based price (VBP) for erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor. METHODS: A Markov health state transition model was developed to estimate the incremental costs, quality-adjusted life-years (QALYs), and value-based price range for erenumab in migraine prevention. The model comprises "on preventive treatment", "off preventive treatment", and "death" health states across a 10-year time horizon. The evaluation compared erenumab to no preventive treatment in episodic and chronic migraine patients that have failed at least one preventive therapy. Therapeutic benefits are based on estimated changes in monthly migraine days (MMD) from erenumab pivotal clinical trials and a network meta-analysis of migraine studies. Utilities were estimated using previously published mapping algorithms. A VBP analysis was performed to identify maximum erenumab annual prices at willingness-to-pay (WTP) thresholds of $100,000-$200,000 per QALY. Estimates of VBP under different scenarios such as choice of different comparators, assumptions around inclusion of placebo effect, and exclusion of work productivity losses were also generated. RESULTS: Erenumab resulted in incremental QALYs of 0.185 vs supportive care (SC) and estimated cost offsets due to reduced MMD of $8,482 over 10 years, with an average duration of treatment of 2.01 years. The estimated VBP at WTP thresholds of$100,000-$200,000 for erenumab compared to SC ranged from$14,238-$23,998. VBP estimates including the placebo effect and excluding work productivity ranged from$7,445-$13,809; increasing to$12,151-$18,589 with onabotulinumtoxinA as a comparator in chronic migraine. CONCLUSION: Erenumab is predicted to reduce migraine-related direct and indirect costs, and increase QALYs compared to SC