Enabling product development partnerships to bring forward the next generation of health technologies.

Over the past quarter century, product development partnerships (PDPs) have importantly brought health technologies, particularly for neglected diseases, to market for low- and middle-income countries (LMICs). With public sector financing, PDPs de-risk the gulf between where the global burden of disease falls and where paying markets exist. From fighting COVID-19 to developing novel antibiotics, the work of PDPs now extends beyond these traditional bounds. As PDPs have shepherded more health technologies to market, they are also confronting new access challenges. This article lays out 5 areas to strategically leverage the PDP model for better access to new health technologies. Making the case for enhanced support of the PDP approach will require greater transparency, as well as recognition of the contributions made by both public and private sector partners. The governance and funding of PDPs must be accountable to meeting the needs and building capacity of target beneficiaries in LMICs. To take an end-to-end approach, PDPs must work in tandem with other public sector institutions as well as local manufacturers as part of a larger innovation ecosystem. PDPs will need to keep pace with both the dynamics of diseases and markets in delivering the next generation of much needed health technologies.

Product development partnerships (PDPs) play an important role in bringing new and needed health technologies to market, particularly in low- and middle-income countries. As these products emerge from the R&D pipeline, new access challenges in paying for and delivering them in the health care system have emerged. The COVID-19 pandemic has also both stretched and tapped into this work. These developments provide a window of opportunity, both to take stock of lessons learned and of strategic opportunities to leverage the PDP model beyond its traditional bounds of neglected diseases. Greater transparency and recognition of the contributions of PDPs, accountability of governance and surety of financing, and coordination with pooled procurement and local manufacturing initiatives can build a foundation for even more impactful contributions in the future.

Characterizing the Protein Isoforms of foraging (for), the PKGI Ortholog in Drosophila melanogaster.

The foraging (for) gene of Drosophila melanogaster encodes a cGMP-dependent protein kinase (PKG), which is a major effector of the cGMP signaling pathway involved in the regulation of behaviour and metabolic traits. Despite being well studied at the transcript level, little is known about the for gene at the protein level. Here, we provide a detailed characterization of the for gene protein (FOR) products and present new tools for their study, including five isoform-specific antibodies and a transgenic strain that carries an HA-labelled for allele (forBAC::HA). Our results showed that multiple FOR isoforms were expressed in the larval and adult stages of D. melanogaster and that the majority of whole-body FOR expression arises from three (P1, P1α, and P3) of eight putative protein isoforms. We found that FOR expression differed between the larval and adult stages and between the dissected larval organs we analyzed, which included the central nervous system (CNS), fat body, carcass, and intestine. Moreover, we showed that the FOR expression differed between two allelic variants of the for gene, namely, fors (sitter) and forR (rover), that are known to differ in many food-related traits. Together, our in vivo identification of FOR isoforms and the existence of temporal, spatial, and genetic differences in their expression lay the groundwork for determining their functional significance.

Ethical challenges in mass drug administration for reducing childhood mortality: a qualitative study.

BACKGROUND: Mass drug administration (MDA) of medications to entire at-risk communities or populations has shown promise in the control and elimination of global infectious diseases. MDA of the broad-spectrum antibiotic azithromycin has demonstrated the potential to reduce childhood mortality in children at risk of premature death in some global settings. However, MDA of antibiotics raises complex ethical challenges, including weighing near-term benefits against longer-term risks-particularly the development of antimicrobial resistance that could diminish antibiotic effectiveness for current or future generations. The aim of this study was to understand how key actors involved in MDA perceive the ethical challenges of MDA. METHODS: We conducted 35 semi-structured interviews from December 2020-February 2022 with investigators, funders, bioethicists, research ethics committee members, industry representatives, and others from both high-income countries (HICs) and low- and middle-income countries (LMICs). Interview participants were identified via one of seven MDA studies purposively chosen to represent diversity in terms of use of the antibiotic azithromycin; use of a primary mortality endpoint; and whether the study occurred in a high child mortality country. Data were analyzed using constructivist grounded theory methodology. RESULTS: The most frequently discussed ethical challenges related to meaningful community engagement, how to weigh risks and benefits, and the need to target MDA We developed a concept map of how participants considered ethical issues in MDA for child mortality; it emphasizes MDA's place alongside other public health interventions, empowerment, and equity. Concerns over an ethical double standard in weighing risks and benefits emerged as a unifying theme, albeit one that participants interpreted in radically different ways. Some thought MDA for reducing child mortality was ethically obligatory; others suggested it was impermissible. CONCLUSIONS: Ethical challenges raised by MDA of antibiotics for childhood mortality-which span socio-cultural issues, the environment, and effects on future generations-require consideration beyond traditional clinical trial review. The appropriate role of MDA also requires attention to concerns over ethical double standards and power dynamics in global health that affect how we view antibiotic use in HICs versus LMICs. Our findings suggest the need to develop additional, comprehensive guidance on managing ethical challenges in MDA.

Equitable Access to Antibiotics: A Core Element and Shared Global Responsibility for Pandemic Preparedness and Response.

Securing equitable antibiotic access as an essential component for health system resilience and pandemic preparedness requires a systems perspective. This article discusses key components that need to be coordinated and paired with adequate financing and resources to ensure antibiotic effectiveness as a global public good, which should be central while discussing a new global agreement.

Resetting the agenda for antibiotic resistance through a health systems perspective.

Although the individual and societal consequences of antibiotic resistance spiral upwards, coordinated action has not kept pace on a global scale. The COVID-19 pandemic has highlighted the need for resilient health systems and has resulted in an unprecedented rate of collaboration in scientific, medical, social, and political dimensions. The pandemic has also created a renewed awareness of the importance of infectious diseases and is a substantial entry point for reigniting the momentum towards containing the silent pandemic of antibiotic resistance. In this Viewpoint, we discuss the limitations in the current narrative on antibiotic resistance and how it could be improved, including concerted efforts to close essential data gaps. We discuss the need for capacity building and coordination at the national and global levels to strengthen the understanding of the importance of sustainable access to effective antibiotics for all health systems that could generate tangible links to current processes for global health and development.

Achieving path-dependent equity for global COVID-19 vaccine allocation.

Committing to global access for COVID-19 vaccines is key to avoiding a resurgence of the pandemic. However, agreements between countries and vaccine manufacturers have undermined a globally coordinated approach, and the ongoing vaccine rollout highlights long-standing inequities in health. Yet, the surest path out of this pandemic is one toward greater equity.

Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis.

OBJECTIVE: To analyze the premarket purchase commitments for coronavirus disease 2019 (covid-19) vaccines from leading manufacturers to recipient countries. DESIGN: Cross sectional analysis. DATA SOURCES: World Health Organization's draft landscape of covid-19 candidate vaccines, along with company disclosures to the US Securities and Exchange Commission, company and foundation press releases, government press releases, and media reports. ELIGIBILITY CRITERIA AND DATA ANALYSIS: Premarket purchase commitments for covid-19 vaccines, publicly announced by 15 November 2020. MAIN OUTCOME MEASURES: Premarket purchase commitments for covid-19 vaccine candidates and price per course, vaccine platform, and stage of research and development, as well as procurement agent and recipient country. RESULTS: As of 15 November 2020, several countries have made premarket purchase commitments totaling 7.48 billion doses, or 3.76 billion courses, of covid-19 vaccines from 13 vaccine manufacturers. Just over half (51%) of these doses will go to high income countries, which represent 14% of the world's population. The US has reserved 800 million doses but accounts for a fifth of all covid-19 cases globally (11.02 million cases), whereas Japan, Australia, and Canada have collectively reserved more than one billion doses but do not account for even 1% of current global covid-19 cases globally (0.45 million cases). If these vaccine candidates were all successfully scaled, the total projected manufacturing capacity would be 5.96 billion courses by the end of 2021. Up to 40% (or 2.34 billion) of vaccine courses from these manufacturers might potentially remain for low and middle income countries-less if high income countries exercise scale-up options and more if high income countries share what they have procured. Prices for these vaccines vary by more than 10-fold, from $6.00 (£4.50; €4.90) per course to as high as $74 per course. With broad country participation apart from the US and Russia, the COVAX Facility-the vaccines pillar of the World Health Organization's Access to COVID-19 Tools (ACT) Accelerator-has secured at least 500 million doses, or 250 million courses, and financing for half of the targeted two billion doses by the end of 2021 in efforts to support globally coordinated access to covid-19 vaccines. CONCLUSIONS: This study provides an overview of how high income countries have secured future supplies of covid-19 vaccines but that access for the rest of the world is uncertain. Governments and manufacturers might provide much needed assurances for equitable allocation of covid-19 vaccines through greater transparency and accountability over these arrangements.

Setting the standard: multidisciplinary hallmarks for structural, equitable and tracked antibiotic policy.

There is increasing concern globally about the enormity of the threats posed by antimicrobial resistance (AMR) to human, animal, plant and environmental health. A proliferation of international, national and institutional reports on the problems posed by AMR and the need for antibiotic stewardship have galvanised attention on the global stage. However, the AMR community increasingly laments a lack of action, often identified as an 'implementation gap'. At a policy level, the design of internationally salient solutions that are able to address AMR's interconnected biological and social (historical, political, economic and cultural) dimensions is not straightforward. This multidisciplinary paper responds by asking two basic questions: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise 'good' antibiotic policy? Our multistage analysis revealed four central challenges facing current international antibiotic policy: metrics, prioritisation, implementation and inequality. In response to this diagnosis, we propose three hallmarks that can support robust international antibiotic policy. Emerging hallmarks for good antibiotic policies are: Structural, Equitable and Tracked. We describe these hallmarks and propose their consideration should aid the design and evaluation of international antibiotic policies with maximal benefit at both local and international scales.

An Integrated Approach of Machine Learning and Systems Thinking for Waiting Time Prediction in an Emergency Department.

OBJECTIVE: The objective of this study is to apply machine learning algorithms for real-time and personalized waiting time prediction in emergency departments. We also aim to introduce the concept of systems thinking to enhance the performance of the prediction models. METHODS: Four popular algorithms were applied: (i) stepwise multiple linear regression; (ii) artificial neural networks; (iii) support vector machines; and (iv) gradient boosting machines. A linear regression model served as a baseline model for comparison. We conducted computational experiments based on a dataset collected from an emergency department in Hong Kong. Model diagnostics were performed, and the results were cross-validated. RESULTS: All the four machine learning algorithms with the use of systems knowledge outperformed the baseline model. The stepwise multiple linear regression reduced the mean-square error by almost 15%. The other three algorithms had similar performances, reducing the mean-square error by approximately 20%. Reductions of 17 - 22% in mean-square error due to the utilization of systems knowledge were observed. DISCUSSION: The multi-dimensional stochasticity arising from the ED environment imposes a great challenge on waiting time prediction. The introduction of the concept of systems thinking led to significant enhancements of the models, suggesting that interdisciplinary efforts could potentially improve prediction performance. CONCLUSION: Machine learning algorithms with the utilization of the systems knowledge could significantly improve the performance of waiting time prediction. Waiting time prediction for less urgent patients is more challenging.

External Societal Costs of Antimicrobial Resistance in Humans Attributable to Antimicrobial Use in Livestock.

Antimicrobial use (AMU) in animal agriculture contributes to antimicrobial resistance (AMR) in humans, which imposes significant health and economic costs on society. Economists call these costs negative externalities, societal costs that are not properly reflected in market prices. We review the relevant literature and develop a model to quantify the external costs of AMU in animal agriculture on AMR in humans. Parameters required for this estimate include (a) the health and economic burden of AMR in humans,(b) the impact of AMU in animal agriculture on AMR in animals, (c) the fraction of AMR in humans attributable to animal agriculture, and (d) AMU in animals. We use a well-documented historic case to estimate an externality cost of about US$1,500 per kilogram of fluoroquinolones administered in US broiler chicken production. Enhanced data collection, particularly on the third and fourth parameters, is urgently needed to quantify more fully the externalities of AMU in animal agriculture.

Illicit Cigarette Consumption and Government Revenue Loss in Vietnam: Evidence from a Primary Data Approach.

This article provides the first comprehensive picture and independent estimates of both illicit cigarette consumption and the resulting government tax revenue loss in Vietnam using data from a representative survey of cigarette smokers in 12 Vietnamese provinces. The survey consisted of face-to-face interviews and on-site cigarette pack examinations. We find that more than 720 million illicit cigarette packs, or 20.7% of total cigarette consumption, circulated in Vietnam in 2012. Consequently, government tax revenue loss due to illicit trade ranged from US $223 to 295 million. Our estimates also indicate that 1) the most popular illicit brands were Jet and Hero, both were sold at higher prices than the average legal brand; 2) the average price of illicit cigarettes was 51% higher than the average price of legal cigarettes; and 3) majority of illicit cigarettes were sold at convenience stores, which were registered and licensed businesses. Our findings suggest that prices are not a driver of illicit cigarette consumption in Vietnam, and this illicit trade is at least partially a consequence of weak market control enforcement.

Online Nonlinear AUC Maximization for Imbalanced Data Sets.

Classifying binary imbalanced streaming data is a significant task in both machine learning and data mining. Previously, online area under the receiver operating characteristic (ROC) curve (AUC) maximization has been proposed to seek a linear classifier. However, it is not well suited for handling nonlinearity and heterogeneity of the data. In this paper, we propose the kernelized online imbalanced learning (KOIL) algorithm, which produces a nonlinear classifier for the data by maximizing the AUC score while minimizing a functional regularizer. We address four major challenges that arise from our approach. First, to control the number of support vectors without sacrificing the model performance, we introduce two buffers with fixed budgets to capture the global information on the decision boundary by storing the corresponding learned support vectors. Second, to restrict the fluctuation of the learned decision function and achieve smooth updating, we confine the influence on a new support vector to its -nearest opposite support vectors. Third, to avoid information loss, we propose an effective compensation scheme after the replacement is conducted when either buffer is full. With such a compensation scheme, the performance of the learned model is comparable to the one learned with infinite budgets. Fourth, to determine good kernels for data similarity representation, we exploit the multiple kernel learning framework to automatically learn a set of kernels. Extensive experiments on both synthetic and real-world benchmark data sets demonstrate the efficacy of our proposed approach.

An overview of biologic disease-modifying antirheumatic drugs in axial spondyloarthritis and psoriatic arthritis.

Biologic disease-modifying antirheumatic drugs (bDMARDs) are engineered proteins with high affinity for various proinflammatory immune mediators to reduce inflammation and its sequelae in various rheumatic diseases. These medications, introduced at the advent of the 21st century, have revolutionized the treatment of axial spondyloarthritis (including ankylosing spondylitis) and psoriatic arthritis. Currently approved bDMARDs for axial spondyloarthritis are etanercept, infliximab, adalimumab, golimumab, certolizumab pegol, and secukinumab. For psoriatic arthritis, all of these drugs are approved in addition to ixekizumab, ustekinumab, abatacept, and tofacitinib. Selection of the optimal bDMARD should consider patient comorbidity including uveitis, psoriasis, and inflammatory bowel disease.

Delinking Investment in Antibiotic Research and Development from Sales Revenues: The Challenges of Transforming a Promising Idea into Reality.

Kevin Outterson and colleagues outline a model to address access, conservation, and innovation of antibiotics.

Exploring the evidence base for national and regional policy interventions to combat resistance.

The effectiveness of existing policies to control antimicrobial resistance is not yet fully understood. A strengthened evidence base is needed to inform effective policy interventions across countries with different income levels and the human health and animal sectors. We examine three policy domains-responsible use, surveillance, and infection prevention and control-and consider which will be the most effective at national and regional levels. Many complexities exist in the implementation of such policies across sectors and in varying political and regulatory environments. Therefore, we make recommendations for policy action, calling for comprehensive policy assessments, using standardised frameworks, of cost-effectiveness and generalisability. Such assessments are especially important in low-income and middle-income countries, and in the animal and environmental sectors. We also advocate a One Health approach that will enable the development of sensitive policies, accommodating the needs of each sector involved, and addressing concerns of specific countries and regions.

An Integrated Systems Approach is Needed to Ensure the Sustainability of Antibiotic Effectiveness for Both Humans and Animals.

The growing demand for animal products and the widespread use of antibiotics in bringing food animals to market have heightened concerns over cross-species transmission of drug resistance. Both the biology and emerging epidemiology strongly support the need for global coordination in stemming the generation and propagation of resistance, and the patchwork of global and country-level regulations still leaves significant gaps. More importantly, discussing such a framework opens the door to taking modular steps towards solving these challenges - for example, beginning among targeted parties rather than all countries, tying accountability to financial and technical support, or taxing antibiotic use in animals to deter low-value usage of these drugs. An international agreement would allow integrating surveillance data collection, monitoring and enforcement, research into antibiotic alternatives and more sustainable approaches to agriculture, technical assistance and capacity building, and financing under the umbrella of a One Health approach.

Illicit cigarette consumption and government revenue loss in Indonesia.

BACKGROUND: Illicit cigarettes comprise more than 11% of tobacco consumption and 17% of consumption in low- and middle-income countries. Illicit cigarettes, defined as those that evade taxes, lower consumer prices, threaten national tobacco control efforts, and reduce excise tax collection. METHODS: This paper measures the magnitude of illicit cigarette consumption within Indonesia using two methods: the discrepancies between legal cigarette sales and domestic consumption estimated from surveys, and discrepancies between imports recorded by Indonesia and exports recorded by trade partners. Smuggling plays a minor role in the availability of illicit cigarettes because Indonesians predominantly consume kreteks, which are primarily manufactured in Indonesia. RESULTS: Looking at the period from 1995 to 2013, illicit cigarettes first emerged in 2004. When no respondent under-reporting is assumed, illicit consumption makes up 17% of the domestic market in 2004, 9% in 2007, 11% in 2011, and 8% in 2013. Discrepancies in the trade data indicate that Indonesia was a recipient of smuggled cigarettes for each year between 1995 and 2012. The value of this illicit trade ranges from less than $1 million to nearly $50 million annually. Singapore, China, and Vietnam together accounted for nearly two-thirds of trade discrepancies over the period. Tax losses due to illicit consumption amount to between Rp 4.1 and 9.3 trillion rupiah, 4% to 13% of tobacco excise revenue, in 2011 and 2013. CONCLUSIONS: Due to the predominance of kretek consumption in Indonesia and Indonesia's status as the predominant producer of kreteks, illicit domestic production is likely the most important source for illicit cigarettes, and initiatives targeted to combat this illicit production carry the promise of the greatest potential impact.

New business models for antibiotic innovation.

The increase in antibiotic resistance and the dearth of novel antibiotics have become a growing concern among policy-makers. A combination of financial, scientific, and regulatory challenges poses barriers to antibiotic innovation. However, each of these three challenges provides an opportunity to develop pathways for new business models to bring novel antibiotics to market. Pull-incentives that pay for the outputs of research and development (R&D) and push-incentives that pay for the inputs of R&D can be used to increase innovation for antibiotics. Financial incentives might be structured to promote delinkage of a company's return on investment from revenues of antibiotics. This delinkage strategy might not only increase innovation, but also reinforce rational use of antibiotics. Regulatory approval, however, should not and need not compromise safety and efficacy standards to bring antibiotics with novel mechanisms of action to market. Instead regulatory agencies could encourage development of companion diagnostics, test antibiotic combinations in parallel, and pool and make transparent clinical trial data to lower R&D costs. A tax on non-human use of antibiotics might also create a disincentive for non-therapeutic use of these drugs. Finally, the new business model for antibiotic innovation should apply the 3Rs strategy for encouraging collaborative approaches to R&D in innovating novel antibiotics: sharing resources, risks, and rewards.

The empirical analysis of cigarette tax avoidance and illicit trade in Vietnam, 1998-2010.

Illicit trade carries the potential to magnify existing tobacco-related health care costs through increased availability of untaxed and inexpensive cigarettes. What is known with respect to the magnitude of illicit trade for Vietnam is produced primarily by the industry, and methodologies are typically opaque. Independent assessment of the illicit cigarette trade in Vietnam is vital to tobacco control policy. This paper measures the magnitude of illicit cigarette trade for Vietnam between 1998 and 2010 using two methods, discrepancies between legitimate domestic cigarette sales and domestic tobacco consumption estimated from surveys, and trade discrepancies as recorded by Vietnam and trade partners. The results indicate that Vietnam likely experienced net smuggling in during the period studied. With the inclusion of adjustments for survey respondent under-reporting, inward illicit trade likely occurred in three of the four years for which surveys were available. Discrepancies in trade records indicate that the value of smuggled cigarettes into Vietnam ranges from $100 million to $300 million between 2000 and 2010 and that these cigarettes primarily originate in Singapore, Hong Kong, Macao, Malaysia, and Australia. Notable differences in trends over time exist between the two methods, but by comparison, the industry estimates consistently place the magnitude of illicit trade at the upper bounds of what this study shows. The unavailability of annual, survey-based estimates of consumption may obscure the true, annual trend over time. Second, as surveys changed over time, estimates relying on them may be inconsistent with one another. Finally, these two methods measure different components of illicit trade, specifically consumption of illicit cigarettes regardless of origin and smuggling of cigarettes into a particular market. However, absent a gold standard, comparisons of different approaches to illicit trade measurement serve efforts to refine and improve measurement approaches and estimates.