Antibody Architecture: Responding to Bioterrorism

Bioterrorism, the use of biological and chemical agents for terrorist purposes, is one of the most potentially significant health and security threats currently facing the United States. Healthcare facilities as isolated entities are alone unable to provide sufficient, adaptable emergency response options during a bioterrorist attack--an unpredictable, low probability, high consequence event. Bioterrorism response must be systemic, distributed, flexible, and responsive for a wide range of event incidents, scenarios and contexts. A significant problem yet to be adequately addressed is the mitigation of the walking well--those who are not sick or injured but have the potential to inundate any designated response setting. Architectural interventions alone are limited in their ability to provide an appropriate response to an act of bioterrorism. An analogy to the human immune system and how it operates in the body to overcome pathogens will be used to articulate a systematic bioterrorism response and a series of architectural interventions for dealing with the walking well. Similar to our immune system, a response network (or system) should be created that operates throughout high risk urban contexts and takes advantage of existing architectural settings in order to deploy as needed and where needed in response to a bioterrorist attack. An antibody response to bioterrorism must be able to adapt to meeting the needs of various scenarios and contexts in which an incident might occur. Drawing on this biological metaphor, any proposed architectural interventions must include latent capabilities while having the ability to be activated in place and scalable in order to accommodate the multiple potential threats and the many variables inherent with bioterrorism. The proposal for an architectural response to bioterrorism is situated in Washington, D.C., identified as the highest potential target city in the United States for acts of bioterrorism. Appropriate latent resources capable of acting as a part of the response network throughout the D.C. urban context will be identified and their potential activation will be explored through two example scenarios, which will be used to illustrate the proposed model for systematic response. The most architecturally significant locations for (activated) small scale interjections will be designed to meet the first response needs of the general population who would be moving about in the city during the detection of an event. These sites and features will allow for differing degrees of self-diagnosis during and following an event as well as provide general day to day and event related public health information. The proposed architectural interjections will be designed to respond to the predicted fear and panic exhibited by the walking well during a bioterrorist attack, and minimize their potential for overwhelming hospitals and other healthcare settings in the target region

One-pot synthesis of charged amphiphilic diblock and triblock copolymers via high-throughput Cu(0)-mediated polymerization

Block copolymers containing functionalized monomers, for example those containing charged groups, can be used for many purposes, one of which is the design of polymeric supramolecular materials based on electrostatic interactions. In this paper the synthesis of diblock copolymers and ABA-triblock copolymers containing poly(n-butyl acrylate) as a first or middle block and poly(2-(dimethylamino) ethyl acrylate), poly(1-ethoxyethyl acrylate) and poly(1-ethoxyethyl-2-carboxyethyl acrylate) as second or outer blocks, resulting in block copolymers that can contain positive or negative charges, is reported. The polymerizations were performed and optimized via one-pot sequential monomer addition reactions via Cu(0)-mediated polymerization using an automated parallel synthesizer. Different initiators, monomer concentrations and polymerization times were tested. While a bromide-containing initiator led to the best results for most monomers, when polymerizing 2-(dimethylamino) ethyl acrylate the use of a chloride-containing initiator was necessary. Due to the slower polymerization using this initiator, a longer polymerization time was needed before addition of the second monomer. Using the optimized conditions, the diblock and triblock copolymers could be synthesized with good control over molecular weight and dispersities around 1.1 were obtained

Streaming Tensor Train Approximation

Tensor trains are a versatile tool to compress and work with high-dimensional data and functions. In this work we introduce the Streaming Tensor Train Approximation (STTA), a new class of algorithms for approximating a given tensor $\mathcal T$ in the tensor train format. STTA accesses $\mathcal T$ exclusively via two-sided random sketches of the original data, making it streamable and easy to implement in parallel -- unlike existing deterministic and randomized tensor train approximations. This property also allows STTA to conveniently leverage structure in $\mathcal T$, such as sparsity and various low-rank tensor formats, as well as linear combinations thereof. When Gaussian random matrices are used for sketching, STTA is admissible to an analysis that builds and extends upon existing results on the generalized Nystr\"om approximation for matrices. Our results show that STTA can be expected to attain a nearly optimal approximation error if the sizes of the sketches are suitably chosen. A range of numerical experiments illustrates the performance of STTA compared to existing deterministic and randomized approaches.Comment: 21 pages, code available at https://github.com/RikVoorhaar/tt-sketc

Dabigatran for the Treatment and Secondary Prevention of Venous Thromboembolism; A Cost-Effectiveness Analysis for the Netherlands

Background Dabigatran was proven to have similar effect on the prevention of recurrence of venous thromboembolism (VTE) and a lower risk of bleeding compared to vitamin K antagonists (VKA). The aim of this study is to assess the cost-effectiveness (CE) of dabigatran for the treatment and secondary prevention in patients with VTE compared to VKAs in the Dutch setting. Methods Previously published Markov model was modified and updated to assess the CE of dabigatran and VKAs for the treatment and secondary prevention in patients with VTE from a societal perspective in the base-case analysis. The model was populated with efficacy and safety data from major dabigatran trials (i.e. RE-COVER, RECOVER II, RE-MEDY and RESONATE), Dutch specific costs, and utilities derived from dabigatran trials or other published literature. Univariate, probabilistic sensitivity and a number of scenario analyses evaluating various decision-analytic settings (e.g. the perspective of analysis, use of anticoagulants only for treatment or only for secondary prevention, or comparison to no treatment) were tested on the incremental cost-effectiveness ratio (ICER). Results In the base-case scenario, patients on dabigatran gained an additional 0.034 quality adjusted life year (QALY) while saving epsilon 1,598. Results of univariate sensitivity analysis were quite robust. The probability that dabigatran is cost-effective at a willingness-to-pay threshold of epsilon 20,000/ QALY was 98.1%. From the perspective of healthcare provider, extended anticoagulation with dabigatran compared to VKAs was estimated at epsilon 2,158 per QALY gained. The ICER for anticoagulation versus no treatment in patients with equipoise risk of recurrent VTE was estimated at epsilon 33,379 per QALY gained. Other scenarios showed dabigatran was cost-saving. Conclusion From a societal perspective, dabigatran is likely to be a cost-effective or even cost-saving strategy for treatment and secondary prevention of VTE compared to VKAs in the Netherlands

Patient listening on social media for patient-focused drug development: a synthesis of considerations from patients, industry and regulators

Patients, life science industry and regulatory authorities are united in their goal to reduce the disease burden of patients by closing remaining unmet needs. Patients have, however, not always been systematically and consistently involved in the drug development process. Recognizing this gap, regulatory bodies worldwide have initiated patient-focused drug development (PFDD) initiatives to foster a more systematic involvement of patients in the drug development process and to ensure that outcomes measured in clinical trials are truly relevant to patients and represent significant improvements to their quality of life. As a source of real-world evidence (RWE), social media has been consistently shown to capture the first-hand, spontaneous and unfiltered disease and treatment experience of patients and is acknowledged as a valid method for generating patient experience data by the Food and Drug Administration (FDA). While social media listening (SML) methods are increasingly applied to many diseases and use cases, a significant piece of uncertainty remains on how evidence derived from social media can be used in the drug development process and how it can impact regulatory decision making, including legal and ethical aspects. In this policy paper, we review the perspectives of three key stakeholder groups on the role of SML in drug development, namely patients, life science companies and regulators. We also carry out a systematic review of current practices and use cases for SML and, in particular, highlight benefits and drawbacks for the use of SML as a way to identify unmet needs of patients. While we find that the stakeholders are strongly aligned regarding the potential of social media for PFDD, we identify key areas in which regulatory guidance is needed to reduce uncertainty regarding the impact of SML as a source of patient experience data that has impact on regulatory decision making