Stakeholders' perception on including broader economic impact of vaccines in economic evaluations in low and middle income countries: a mixed methods study.

BACKGROUND: Current health economic evaluation guidelines mainly concentrate on immediate health gains and cost savings for the individual involved in the intervention. However, it has been argued that these guidelines are too narrow to capture the full impact of vaccination in low and middle income countries. The inclusion of broader economic impact of vaccines (BEIV) has therefore been proposed. Some examples of these are productivity-related gains, macro-economic impact, and different externalities. Despite their potency, the extent to which such benefits can and should be incorporated into economic evaluations of vaccination is still unclear. This mixed methods study aims to assess the relevance of BEIV to different stakeholders involved in the vaccine introduction decision making process. METHODS: In this mixed method study an internet based survey was sent to attendees of the New and Underutilized Vaccines Initiative meeting in Montreux, Switzerland in 2011. Additionally, semi-structured interviews of 15 minutes each were conducted during the meeting. Study participants included decision makers, experts and funders of vaccines and immunization programs in low and middle income countries. Descriptive analysis of the survey, along with identification of common themes and factors extracted from the interviews and open survey questions was undertaken. RESULTS: Evidence on macro-economic impact, burden of disease and ecological effects were perceived as being most valuable towards aiding decision making for vaccine introduction by the 26 survey respondents. The 14 interviewees highlighted the importance of burden of disease and different types of indirect effects. Furthermore, some new interpretations of BEIVs were discussed, such as the potential negative impact of wastage during immunization programs and the idea of using vaccines as a platform for delivering other types of health interventions. Interviewees also highlighted the importance of using a broader perspective in connection to measuring economic impacts, particularly when attempting to derive the value of newer, more expensive vaccines. CONCLUSION: According to participants, BEIVs were seen as being equally important as traditional outcome measures used in cost-effectiveness analyses. Such insight can be used to shape research agendas within this field and to eventually create broader, more inclusive practical guidelines for economic evaluations of vaccines

Efficient Zero Knowledge for Regular Language

A succinct zero knowledge proof for regular language mem- bership, i.e., to prove a secret string behind an encryption (hash) belongs to a regular language is useful, e.g., for asserting that an encrypted email is free of malware. The great challenge in practice is that the regular language used is often huge. We present zkreg, a distributed commit- and-prove system that handles such complexity. In zkreg, cryptographic operations are encoded using arithmetic circuits, and input acceptance is modeled as a zero knowledge subset problem using Σ-protocols. We in- troduce a Feedback Commit-and-Prove (FB-CP) scheme, which connects Σ-protocols and the Groth16 system with O(1) proof size and verifier cost. We present a close-to-optimal univariate instantiation of zk-VPD, a zero knowledge variation of the KZG polynomial commitment scheme, based on which an efficient zk-subset protocol is developed. We develop a 2-phase proof scheme to further exploit the locality of Aho-Corasick automata. To demonstrate the performance and scalability of zkreg, we prove that all ELF files (encrypted and hashed) in a Linux CentOS 7 are malware free. Applying inner pairing product argument, we obtain an aggregated proof of 1.96 MB which can be verified in 6.5 seconds

Membrane transporters in drug development

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling. © 2010 Macmillan Publishers Limited

Functional siRNA Delivery by Extracellular Vesicle-Liposome Hybrid Nanoparticles

The therapeutic use of RNA interference is limited by the inability of siRNA molecules to reach their site of action, the cytosol of target cells. Lipid nanoparticles, including liposomes, are commonly employed as siRNA carrier systems to overcome this hurdle, although their widespread use remains limited due to a lack of delivery efficiency. More recently, nature's own carriers of RNA, extracellular vesicles (EVs), are increasingly being considered as alternative siRNA delivery vehicles due to their intrinsic properties. However, they are difficult to load with exogenous cargo. Here, EV-liposome hybrid nanoparticles (hybrids) are prepared and evaluated as an alternative delivery system combining properties of both liposomes and EVs. It is shown that hybrids are spherical particles encapsulating siRNA, contain EV-surface makers, and functionally deliver siRNA to different cell types. The functional behavior of hybrids, in terms of cellular uptake, toxicity, and gene-silencing efficacy, is altered as compared to liposomes and varies among recipient cell types. Moreover, hybrids produced with cardiac progenitor cell (CPC) derived-EVs retain functional properties attributed to CPC-EVs such as activation of endothelial signaling and migration. To conclude, hybrids combine benefits of both synthetic and biological drug delivery systems and might serve as future therapeutic carriers of siRNA

Habits of Mind: Designing Courses for Student Success

Although content knowledge remains at the heart of college teaching and learning, forward-thinking instructors recognize that we must also provide 21st-century college students with transferable skills (sometimes called portable intellectual abilities) to prepare them for their futures (Vazquez, 2020; Ritchhart, 2015; Venezia & Jaeger, 2013; Hazard, 2012). To “grow their capacity as efficacious thinkers to navigate and thrive in the face of unprecedented change” (Costa et al., 2023), students must learn and improve important study skills and academic dispositions throughout their educational careers. If we do not focus on skills-building in college courses, students will not be prepared for the challenges that await them after they leave institutions of higher education. If students are not prepared for these postsecondary education challenges, then it is fair to say that college faculty have failed them

Satellite remote sensing of surface winds, waves, and currents: Where are we now?

This review paper reports on the state-of-the-art concerning observations of surface winds, waves, and currents from space and their use for scientific research and subsequent applications. The development of observations of sea state parameters from space dates back to the 1970s, with a significant increase in the number and diversity of space missions since the 1990s. Sensors used to monitor the sea-state parameters from space are mainly based on microwave techniques. They are either specifically designed to monitor surface parameters or are used for their abilities to provide opportunistic measurements complementary to their primary purpose. The principles on which is based on the estimation of the sea surface parameters are first described, including the performance and limitations of each method. Numerous examples and references on the use of these observations for scientific and operational applications are then given. The richness and diversity of these applications are linked to the importance of knowledge of the sea state in many fields. Firstly, surface wind, waves, and currents are significant factors influencing exchanges at the air/sea interface, impacting oceanic and atmospheric boundary layers, contributing to sea level rise at the coasts, and interacting with the sea-ice formation or destruction in the polar zones. Secondly, ocean surface currents combined with wind- and wave- induced drift contribute to the transport of heat, salt, and pollutants. Waves and surface currents also impact sediment transport and erosion in coastal areas. For operational applications, observations of surface parameters are necessary on the one hand to constrain the numerical solutions of predictive models (numerical wave, oceanic, or atmospheric models), and on the other hand to validate their results. In turn, these predictive models are used to guarantee safe, efficient, and successful offshore operations, including the commercial shipping and energy sector, as well as tourism and coastal activities. Long-time series of global sea-state observations are also becoming increasingly important to analyze the impact of climate change on our environment. All these aspects are recalled in the article, relating to both historical and contemporary activities in these fields

Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles

Lipid Nanoparticles (LNPs) are a promising drug delivery vehicle for clinical siRNA delivery. Modified mRNA (modRNA) has recently gained great attention as a therapeutic molecule in cardiac regeneration. However, for mRNA to be functional, it must first reach the diseased myocardium, enter the target cell, escape from the endosomal compartment into the cytosol and be translated into a functional protein. However, it is unknown if LNPs can effectively deliver mRNA, which is much larger than siRNA, to the ischemic myocardium. Here, we evaluated the ability of LNPs to deliver mRNA to the myocardium upon ischemia-reperfusion injury functionally. By exploring the bio-distribution of fluorescently labeled LNPs, we observed that, upon reperfusion, LNPs accumulated in the infarct area of the heart. Subsequently, the functional delivery of modRNA was evaluated by the administration of firefly luciferase encoding modRNA. Concomitantly, a significant increase in firefly luciferase expression was observed in the heart upon myocardial reperfusion when compared to sham-operated animals. To characterize the targeted cells within the myocardium, we injected LNPs loaded with Cre modRNA into Cre-reporter mice. Upon LNP infusion, Tdtomato+ cells, derived from Cre mediated recombination, were observed in the infarct region as well as the epicardial layer upon LNP infusion. Within the infarct area, most targeted cells were cardiac fibroblasts but also some cardiomyocytes and macrophages were found. Although the expression levels were low compared to LNP-modRNA delivery into the liver, our data show the ability of LNPs to functionally deliver modRNA therapeutics to the damaged myocardium, which holds great promise for modRNA-based cardiac therapies

AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs)