Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19

Background Currently, only dexamethasone, tocilizumab and sarilumab have conclusively been shown to reduce mortality of COVID-19. Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programmes. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices. Methods We searched for repurposed drugs that have been approved by at least one of the WHO, FDA or NICE, or at least given emergency use authorisation or recommended for off-label prescription. Drug prices were searched for, for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab and imdevimab, and sarilumab using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug. Results Repurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from $2.58 for IV dexamethasone (or $0.19 orally) and $4.34 for inhaled budesonide. No export price data was available for baricitinib, tocilizumab, casirivimab and imdevimab or sarilumab, but courses of these treatments are priced highly, ranging from $6.67 for baricitinib to $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries. Conclusions Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whilst monoclonal antibodies and IV treatment courses are more expensive.

Prices versus costs of production for molnupiravir as a COVID-19 treatment

Background Molnupiravir has been recently approved in the United Kingdom for the treatment of COVID-19 for showing promising survival benefits in clinical trials. This analysis will estimate and compare potential generic minimum costs of molnupiravir as well as observe countries eligible for pricing discounts as agreed by Merck and The Medicines Patent Pool (MPP). Methods Drug prices were searched for molnupiravir using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability. Trends of molnupiravir drugs prices were also evaluated for the last 6-month period. Mean daily COVID-19 diagnosis rates were calculated for the countries eligible for voluntary licensing. Results Molnupiravir can be generically manufactured at the very low per-course cost of $9.00. Over the past 6 months, prices of molnupiravir have fallen significantly, and when comparing reported international prices, we found wide variations between countries. Only 9% of diagnosed patients worldwide were in the countries eligible for voluntary licensing. Conclusions Prices of molnupiravir range from $20 to $750 per course. Only 9% of worldwide COVID-19 diagnoses are made in countries covered by voluntary licenses. Middle income countries not eligible for voluntary licensing may need to issue compulsory licenses to secure access to molnupiravir at affordable prices.

Integrated Genomic, Transcriptomic and Proteomic Analysis for Identifying Markers of Alzheimer’s Disease

There is an urgent need to identify biomarkers for Alzheimer’s disease (AD), but the identification of reliable blood-based biomarkers has proven to be much more difficult than initially expected. The current availability of high-throughput multi-omics data opens new possibilities in this titanic task. Candidate Single Nucleotide Polymorphisms (SNPs) from large, genome-wide association studies (GWAS), meta-analyses exploring AD (case-control design), and quantitative measures for cortical structure and general cognitive performance were selected. The Genotype-Tissue Expression (GTEx) database was used for identifying expression quantitative trait loci (eQTls) among candidate SNPs. Genes significantly regulated by candidate SNPs were investigated for differential expression in AD cases versus controls in the brain and plasma, both at the mRNA and protein level. This approach allowed us to identify candidate susceptibility factors and biomarkers of AD, facing experimental validation with more evidence than with genetics alone.

EVALUATION OF RTH IN REGIONAL SPATIAL PLAN WITH NDVI IN KENDARI CITY

Kendari City is the capital of Southeast Sulawesi Province with a population of 345,110 people. The number of residents can trigger a narrowing of RTH (RTH) due to meeting the need for land over time. RTH in urban areas ideally is 30% of the total area with 20% public RTH and 10% private RTH. This study aims for RTH based on the comparison of the area of the RTH Regional Spatial Plan (RTRW) and the actual RTH, the population, the ability to produce oxygen (O2) and absorption of carbon dioxide (CO2) in the actual RTH. This research uses quantitative descriptive research in evaluating RTH. The results showed that public RTH in the RTRW still lacked 6.93% so that it was still necessary to review the RTRW to meet these needs. The current RTH is also still less than the minimum standard of RTH in Kendari City of 7.01% in public RTH. If it is accumulated, the current availability of RTH still does not meet the minimum standard of RTH in Kendari City. The availability of oxygen (O2) and absorption of carbon dioxide (CO2) in Kendari City can still meet the needs of residents in Kendari City.

It’s Time to Include Harm to Humans in Harm–Benefit Analysis — But How to Do It, That is the Question

The Three Rs ( reduction, refinement, replacement) concept put forward by Russell and Burch now appears to be widely accepted. However, their warnings concerning reliance on animals as models for humans, the insurmountable problem of species differences and the impact of human variation, have been downplayed or even ignored. Schemes for harm–benefit analysis have been introduced, but the focus has largely been on harm to the animals, rather than on the direct and indirect benefit to humans, which is much more difficult to evaluate. Greater recognition should be given to the direct or indirect harm to humans resulting from the current over-reliance of biomedical research and testing on data obtained from animal experiments. That will be hard to achieve in the current climate, given the vigorous defence of animal experimentation by those with vested interests, confusion over responsibilities for regulating animal experimentation, hierarchies of regulatory authorities which require or limit experiments on animals, and exaggerated claims about the current availability of new approach methodologies (NAMs) and relevant and reliable strategies for their use. Those who defend animal experimentation at almost any cost must bear part of the responsibility for the human harms which result. Meanwhile, much greater effort should be put into the development, validation and application of new approaches not involving animals.

The Impermanence of Obsolescence: Performance Practice Challenges in Works Written for Revival Harpsichord

<p>The revival harpsichord leads a double life today—enjoying a small fan base on the edge of obsolescence. Most regard the instrument as a twentieth-century foil to the more historically-oriented harpsichords that replaced them by around the mid-1970s. But they are also valued for the repertoire they inspired during the first seventy or so years of the twentieth century, along with their unique capabilities and signature sound. From mid-century onwards, when historical harpsichords began to gain a wider acceptance, revival harpsichords were derided as representing a false notion of teleological progress. Piano building technologies partially adapted to the construction of revival harpsichords have required compromises that ignore basic laws of the physics of sound—including the differences between plucking a string and striking it with hammer. The ontology of a harpsichord type that is piano-informed has led to a widespread conclusion that revival harpsichords are a mistaken concept and are unsuitable even for many of the compositions written for them. The common practice today is to adapt works written for revival harpsichord to historical harpsichords. Limited attention has been given to revival harpsichords in recent academic literature. While mention is made of their historical significance, a current evaluation of the instruments and treatment of revival repertoire has been lacking. This dissertation seeks to critically assess instruments and repertoire by examining perspectives of authors, builders, performers, composers and critics, addressing current issues in performance practice such as the impact of changing instrumentation from revival to historical models. A case is made for valuing revival harpsichords on their own merits as well as applying first-hand knowledge of revival harpsichords to performances of revival repertoire on historical models. This methodology is supported by interviews conducted specifically for this dissertation, playing different revival models and in presenting information neither widely available nor understood, such as a picture of the current availability of revival instruments and details of their restoration. This dissertation contributes to an understanding of revival harpsichords and their repertoire by, firstly, providing up-to-date information on the nature and history of the instrument, as well as highlighting the existence of many revival models, rather than accepting the notion of one standard type. Secondly, revival harpsichord reception is examined within a context of the changing purposes of harpsichord construction after 1889. Lastly, a selection of relevant repertoire is investigated, including Erik Bergman’s 1970 Energien for solo harpsichord (a critical edition of which also forms part of the Appendices), Darius Milhaud’s 1945 Sonata for Clavecin (or Piano) and Violin, op. 257, and Peter Child’s Concerto for Harpsichord and String Quartet (2005), which was written for an Eric Herz revival harpsichord. A tradition already exists of compromising over and discussing which historical harpsichords to use for early music repertoire that spans centuries and the building practices of different geographic regions. This dissertation explores the extent to which revival harpsichords are indeed easily replaced by historical models for revival repertoire, or whether it is sometimes best practice to consider performing these works on the instruments for which they were originally conceived. Alternatively, the performer of a revival work may choose to take certain features of revival instruments into account in developing a performance interpretation on a historical model. Factors hindering performance on historical harpsichords can include performance practice challenges and controversies that arise when transferring pieces to these instruments. Some works defy straightforward alteration and require extensive editing, whereas others are more easily accommodated. Through an examination of repertoire in performance, interviews, and changes in the reception and use of revival harpsichords, this dissertation considers the position and relevance of revival harpsichords today.</p>

The Impermanence of Obsolescence: Performance Practice Challenges in Works Written for Revival Harpsichord

<p>The revival harpsichord leads a double life today—enjoying a small fan base on the edge of obsolescence. Most regard the instrument as a twentieth-century foil to the more historically-oriented harpsichords that replaced them by around the mid-1970s. But they are also valued for the repertoire they inspired during the first seventy or so years of the twentieth century, along with their unique capabilities and signature sound. From mid-century onwards, when historical harpsichords began to gain a wider acceptance, revival harpsichords were derided as representing a false notion of teleological progress. Piano building technologies partially adapted to the construction of revival harpsichords have required compromises that ignore basic laws of the physics of sound—including the differences between plucking a string and striking it with hammer. The ontology of a harpsichord type that is piano-informed has led to a widespread conclusion that revival harpsichords are a mistaken concept and are unsuitable even for many of the compositions written for them. The common practice today is to adapt works written for revival harpsichord to historical harpsichords. Limited attention has been given to revival harpsichords in recent academic literature. While mention is made of their historical significance, a current evaluation of the instruments and treatment of revival repertoire has been lacking. This dissertation seeks to critically assess instruments and repertoire by examining perspectives of authors, builders, performers, composers and critics, addressing current issues in performance practice such as the impact of changing instrumentation from revival to historical models. A case is made for valuing revival harpsichords on their own merits as well as applying first-hand knowledge of revival harpsichords to performances of revival repertoire on historical models. This methodology is supported by interviews conducted specifically for this dissertation, playing different revival models and in presenting information neither widely available nor understood, such as a picture of the current availability of revival instruments and details of their restoration. This dissertation contributes to an understanding of revival harpsichords and their repertoire by, firstly, providing up-to-date information on the nature and history of the instrument, as well as highlighting the existence of many revival models, rather than accepting the notion of one standard type. Secondly, revival harpsichord reception is examined within a context of the changing purposes of harpsichord construction after 1889. Lastly, a selection of relevant repertoire is investigated, including Erik Bergman’s 1970 Energien for solo harpsichord (a critical edition of which also forms part of the Appendices), Darius Milhaud’s 1945 Sonata for Clavecin (or Piano) and Violin, op. 257, and Peter Child’s Concerto for Harpsichord and String Quartet (2005), which was written for an Eric Herz revival harpsichord. A tradition already exists of compromising over and discussing which historical harpsichords to use for early music repertoire that spans centuries and the building practices of different geographic regions. This dissertation explores the extent to which revival harpsichords are indeed easily replaced by historical models for revival repertoire, or whether it is sometimes best practice to consider performing these works on the instruments for which they were originally conceived. Alternatively, the performer of a revival work may choose to take certain features of revival instruments into account in developing a performance interpretation on a historical model. Factors hindering performance on historical harpsichords can include performance practice challenges and controversies that arise when transferring pieces to these instruments. Some works defy straightforward alteration and require extensive editing, whereas others are more easily accommodated. Through an examination of repertoire in performance, interviews, and changes in the reception and use of revival harpsichords, this dissertation considers the position and relevance of revival harpsichords today.</p>

407. Minimum Manufacturing Costs, National Prices and Estimated Global Availability of New Repurposed Therapies for COVID-19

Background Currently, only dexamethasone, tocilizumab and sarilumab have conclusively been shown to reduce mortality of COVID-19. No drug for prevention or treatment in earlier stages of COVID-19 are yet found, with previously promising drugs such as hydroxychloroquine and remdesivir have been shown to be ineffective. Several new candidates are now being studied in clinical trials. Safe and effective treatments will need to be both affordable and widely available. We therefore revised our original 2020 analysis to reflect recent developments. In this update we analysed the cost of production, current national list prices, and API availability for oral and IV dexamethasone, ivermectin, colchicine, dutasteride, budesonide, baricitinib and monoclonal antibodies tocilizumab and sarilumab. Methods Costs of production for new and potential COVID-19 drugs (dexamethasone, ivermectin, dutasteride, budesonide, baricitinib, tocilizumab, sarilumab and colchicine) were estimated using an established and published methodology based on costs of active pharmaceutical ingredients (API), extracted from the global shipping records database Panjiva. This was compared with national pricing data from low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug. Results Repurposed therapies can be generically manufactured at very low per-course costs: ranging from &2.58 for IV dexamethasone (or &0.19 orally) to &0.12 for ivermectin. No export price data was available for baricitinib, tocilizumab or sarilumab. When compared against international list prices, we found wide variations between countries. Drug API availability was generally good, with colchicine being the most available with sufficient annual API exported for 59.8 million treatment courses. A summary is shown in Table 1. Table 1. Summary of list prices, estimated production costs, and current availability of potential COVID-19 drugs selected for analysis. OD = Once daily, BD = twice per day, EUA = Emergency Use Authorisation (only to be given with remdesivir) *In most recent 12-month period. Conclusion Successful management of COVID-19 will require equitable access to treatment for all, not just those able to pay. Repurposed drugs can be manufactured at very low costs if shown to be clinically effective, and offers an affordable, widely available option for patients at all stages of the disease from pre-exposure prophylaxis to asymptotic and mild infections, through to critical care until vaccination coverage is expanded. Disclosures All Authors: No reported disclosures

Pengenalan Anatomi Tubuh Menggunakan Teknologi Augmented Reality Berbasis Android

Media aplikasi pembelajaran dapat mempermudah sarana dalam pembelajaran di berbagai bidang pendidikan khususnya tentang pengenalan anatomi tubuh, namun saat ini masih minim tersedianya suatu aplikasi mobile terkait hal tersebut yang dapat meningkatkan minat belajar bagi siswa dan masyarakat terutama pendidikan pada anak usia dini. Penelitian ini ditujukan untuk mengembangkan sistem pengenalan anatomi tubuh manusia menggunakan teknologi Augmented Reality berbasis Android. Metode penelitian ini adalah metode MDLC (Multimedia Development Life Cycle) dengan tahapannya meliputi: Concept, Design, Material Collecting, Assembly, Testing, dan Distribution. Data penelitian diperoleh melalui observasi, wawancara, studi literatur. Hasil penelitian diperoleh berupa aplikasi pengenalan anatomi tubuh manusia menggunakan teknologi augmented reality yang dapat membantu siswa maupun masyarakat dalam mencari informasi serta menjadi sarana media pembelajaran mengenai organ tubuh manusia. Adapun media pembelajaran augmented reality dapat memvisualisasikan konsep abstrak untuk pemahaman dan struktur suatu model objek dan memungkinkan augmented reality sebagai media yang lebih efektif sesuai dengan tujuan dari media pembelajaran. It is widely known that a mobile learning application can facilitate learning in various fields of education, including the introduction to human anatomy topic. However, the current availability of a mobile application associated with the topic remains insufficient despite its use to improve the student’s and community’s interest to learn, particularly in early childhood education is effective. The research aims to develop a system of introduction to human anatomy by using android-based augmented reality. The method employed in this research is Multimedia Development Life Cycle (MDLC), where its stages comprise concept, design, material collecting, assembly, testing, and distribution. The research data are collected through observation, interview, and literature study. The research result is in the form of application to introduce human anatomy by using augmented reality technology that can assist students or community in seeking information and be a learning media to introduce the human anatomy. In addition, the augmented reality media can visualize an abstract concept for comprehension and structure of object model where it enables the augmented reality to be a more effective media to meet learning media goals.

Dual-energy computed tomography: Survey results on current uses and barriers to further implementation

Objective: To gauge the current availability of dual-energy computed tomography (DECT) scanners in the UK, establish available technologies, look broadly at current clinical uses in adults and paediatrics, and identify barriers to implementation and potential ways to increase use. Methods: A survey was distributed amongst 10 radiology departments and shared on two national professional co-operation mail bases; the survey ran from 20th July to 9th December 2020. It explored current DECT utilisation in adults and paediatrics as well as barriers to use and suggestions to overcome those barriers. Results: The survey demonstrated DECT availability on 39 (40%) of the 98 CT scanners, but there was limited clinical use in adults and paediatrics. Eighteen (72%) of the 25 respondents had access to at least one DECT scanner, with 14 (56%) having adult DECT protocols in clinical use; <10% head examinations and <50% for other anatomical areas. Only two (8%) respondents had DECT paediatric protocols in clinical use; <10% examinations for all anatomical areas. The main barriers to implementation identified were lack of experience with DECT (8 (44%) users (adult) and 10 (56%) users (paediatric)) and no clinical protocols available (6 (33%) users (adult and paediatric)). Understanding DECT benefits and establishing suitable protocols were the most popular suggestions for increased implementation (10 (40%) of 25 respondents). Conclusion: DECT scanners are available, but clinical use is limited for both adults and paediatrics. The main barriers identified were lack of experience with DECT and the availability of suitable protocols. Further work identified to help implementation included better education on the benefits of DECT, provision of clinical protocols and ensuring a multidisciplinary approach. Advances in knowledge: Barriers to implementation of clinical DECT protocols were identified, together with potential solutions to overcome these and enable further implementation.