Underground coal mining can cause the deformation, failure, and collapse of the overlying rock mass of a coal seam. If the mining design, monitoring, early warning, or emergency disposal are improper, in that case, it can often lead to mining disasters such as roof falls, water inrush, surface collapse, and ground fissures, seriously threatening the safety of mine engineering and the geological environment protection in mining areas. To ensure the intrinsic security of the entire coal mining process, aspace–time continuous sensing system of overburden deformation and failure was developed, which breaks through the limitations of traditional monitoring methods that characterize the evolution process of overlying rock deformation and ground subsidence. This paper summarizes the classification of typical overburden deformation and failure modes. It researches the space–time continuous sensing of rock–soil mass above the coal seam based on Distributed Fiber Optic Sensing (DFOS). A multi-range strain optical fiber sensing neural series from micron to meter was developed to achieve synchronous sensing of overburden separation, internal micro–cracks, and large rock mass deformation. The sensing cable–rock mass coupling test verified the reliability of the optical fiber monitoring data. The sensing neural network of overburden deformation was constructed using integrated optical fiber layout technology on the ground and underground. Different sensing nerves’ performance and application effects in overburden deformation and failure monitoring were compared and analyzed with field monitoring examples. A physical model was used to carry out the experimental study on the overburden subsidence prediction during coal mining. The results showed that the optical fiber monitoring data were reliable and could be used to predict overburden subsidence. The reliability of the calculation model for overlying rock subsidence based on space–time continuous optical fiber sensing data was verified in the application of mining subsidence evaluation. A systematic review of the shortcomings of current overburden deformation observation technology during coal mining was conducted, and a space–time continuous sensing system for overburden deformation and failure was proposed. This system integrated sensing, transmission, processing, early warning, decision-making, and emergency response. Based on the fusion of multi-parameter sensing, multi-method transmission, multi-algorithm processing, and multi-threshold early warning, the system realized the real-time acquisition of space–time continuous information for the overburden above coal seams. This system utilizes long-term historical monitoring data from the research area for data mining and modeling, realizing the prediction and evaluation of the evolution process of overburden deformation as well as the potential for mining subsidence. This work provides a theoretical reference for the prevention and control of mining disasters and the environmental carrying capacity evaluation of coal development. Coal resources are one type of energy mineral resource . They arIn the past thirty years, the global economy’s rapid growth has resulted in an increase sharply in demand for energy consumption; among them, coal has become an important source of energy due to its rich reserves . As showUnderground mining in coal mines often causes the deformation, separation, fracture, and collapse of overlying strata. Mine pressure is gradually created due to the movement of rock strata. In order to scientifically reveal the essence of mine pressure during mining, scholars at home and abroad have proposed a lot of hypotheses and theories of stope . In 1916However, due to the differences in the occurrence, development, and evolution of overlying rock deformation under different geological conditions, meanwhile, the deformation, movement, failure, and collapse of overlying strata is a continuous development process; the deformation both in vertical and horizontal of overlying strata and coal seams will change dynamically. Therefore, the deformation coordination and interaction between rock (soil) layers above the coal seam have a strong space–time effect. Most current studies have not considered this space–time continuous process, so they cannot fully reveal the core mechanism of overburden deformation during mining. Consequently, breaking through the technical bottleneck of coal mining monitoring is urgent. Thus, the space–time continuous cognition from overburden deformation and failure to surface-subsidence occurrence and development can be realized. The time-effect mechanism of overburden under coal mining was revealed. On this basis, a monitoring and guarantee system integrating sensing, transmission, processing, early warning, decision-making, and emergency was established based on an optical fiber neural sensing network, which is of great significance to the real-time intelligently sensing of overburden deformation, movement, failure, and collapse during coal mining.i [1]max is the maximum principal stress of rock layer i, and [σ] is the tensile strength of rock layer i. Generally, the three-hinged arch structure is formed in the roof rock layer after failure. If the effective span L of the rock layer is greater than the limit span iL of the three-hinged arch structure, the three-hinged arch will collapse. Among them:i, Global scholars have conducted many laboratory experiments and on-site tests about overburden deformation mechanism during coal mining. Systematic research has utilized similar material physical model tests, field in situ tests, numerical simulations, and theoretical calculations ,19,20. Ai ,23 are:[i is:τ] is the shear strength of rock layer i, C is the cohesive of rock layer i, σα is the normal stress on sliding surface of rock layer i, and φ is the internal friction angle of rock layer i. Then, the condition of shear failure at point  is τ = τα − [τ], if Δτ takes the maximum value [Δτ]max at point , then point  is the most susceptible to shear failure in the rock layers.Assuming ΔFiber optic sensing technology integrates the advantages of both optical sensing and data transmission. By using the change in the scattered light characteristic quantity in the optical fiber caused by external factors, the related physical amount of the measured object along the optical fiber can be continuously monitored for a long distance  Figure . In the According to the characteristics of mine engineering monitoring, glass fiber-reinforced plastic (GFRP), metal-based, and fixed-point cables are commonly used. The GFRP cable adopts high-strength polyurethane as the reinforcement, which not only ensures a high strain transfer performance, but also makes it resistant to tension, compression, and impact during the test. Therefore, it is widely used in deformation, internal force, and damage monitoring in mine engineering. The metal-based cable adopts a particular technique of steel wire twisting and packaging, which has strong wear resistance and ensures its survival rate under high-pressure grouting and pouring backfilling. It is suitable for the deformation monitoring of materials with a high elastic modulus . The fixed-point cable calculates the deformation of the measured target by using the strain value between its two fixed points, which is suitable for discontinuous and large deformation monitoring of rock–soil mass. The overburden separation and internal microcracks can be accurately identified based on the high-sensitivity cable between two contiguous fixed points. Different cables’ parameters are shown in The coupling performance between the sensing cable and the rock–soil mass affects the quality of measured data, significantly impacting the reliability of the monitoring results . TherefoIn recent years, more and more monitoring methods have been used to investigate the failure law of overlying rock and the evolution process of mining subsidence. Traditional sensing elements such as resistance strain gauges, displacement gauges, osmometers, temperature gauges, and electrodes are primarily used in the laboratory and on-site tests. Although these monitoring technologies can obtain the strain, displacement, seepage pressure, temperature, resistivity, and other physical parameters of the local position of the overlying rock–soil mass on the coal seam, it is generally found that the measurement accuracy of the sensing element is low, the layout is cumbersome, the durability is poor, and the data are discrete. It is impossible to comprehensively track the cumulative deformation of the overlying strata induced by continuous mining . ObtainiMany research results show that the layout process and quality of the monitoring system directly influence the monitoring results. Therefore, it is essential to select the corresponding layout technique according to different test environments and objects in the safety mining monitoring of mine engineering. Currently, most test systems combine ground with underground techniques in the practical application of mine engineering. The surface layout method is mainly the ground monitoring system layout. Firstly, implement a monitoring borehole on the ground. Then, according to the different monitoring conditions and geological environment, it is essential to select the appropriate sensing cable and device for the borehole layout. There are four stages: (a) making a counterweight guiding hammer; (b) implanting a sensing cable; (c) borehole backfilling coupled with steady; (d) sensing cable protection .The underground layout method mainly uses high-strength lightweight pipe fittings as the sensing cable (sensor) attachment carrier, which is buried in the rock mass above the coal seam. Firstly, the underground upwards borehole is designed according to the stope conditions. Secondly, Implement a monitoring borehole above the working face with a certain angle. Meanwhile, cable layout and grouting operations are carried out. Finally, the initial value is collected after the borehole reaches the coupling strength. Regularly collect monitoring data based on the actual mining progress of the working face. The response characteristics of overburden deformation and failure in the borehole control height under mining action are analyzed based on the initial value of the sensing cable and the regular data. Zhang Pingsong et al. carried out a dynamic monitoring test for roof overburden combining optical and electrical technology, designed a set of monitoring sections, implemented two roof boreholes at depths of 150 m and 135 m, controlled the advance distance of 96 m, controlled the vertical height of 70 m, and obtained a caving zone height of 18.5 m and water–flowing fractured zone height of 54.5 m . The resBased on the mode distribution characteristics of overlying rock deformation and failure, the space–time continuous strain data of overlying rock can be obtained using fiber optic sensing technology, which can accurately grasp the mining progress and conditions. The stress concentration and electric field (resistivity) mutation areas are captured, combined with the variation law of the geothermal gradient, pore water pressure, and overburden resistivity, which can infer the evolution stage and potential failure mode of overburden stability. At the same time, the early warning analysis of periodic anomalies, multi-parameter common anomalies, and the statistical analysis of historically accumulated data should be strengthened. The early warning model based on critical indicators such as deformation, temperature, seepage pressure, and resistivity should be researched to improve the early warning accuracy of overlying rock deformation during coal mining.To study the evolution mechanism of deformation and failure for overburden, providing a theoretical basis for disaster prevention and control of mining subsidence, Liu Yu  et al. rPiao Chunde  predicteFor a long time, global scholars have researched the occurrence, development, and failure characteristics of overburden deformation during mining through empirical formulas, mechanical analysis, numerical calculation, model tests, and field detection. Karmis M (1983) and Palchik (2002) found that there were three different moving zones  above the coal seam under the condition of longwall mining through field measurement ,43. BaseIn particular, clustering, regression analysis, Bayesian inference, genetic algorithms, and gray theory can be introduced into the integrated overburden deformation sensing system for data mining and modeling with the rapid development and broad application of machine learning, chatGPT, and other technologies. Mining out the disaster characteristic information can reflect the overlying rock deformation and instability during coal mining. The temporal information, spatial information, multi-modulus, and other attributes of monitoring data were used to construct the hypergraph structure of big data for overburden deformation. Hypergraph clustering and segmentation technology were used to complete big data mining and prediction of overburden deformation. Bayesian rules were used to optimize feature information mining and prediction results. According to the strain evolution characteristics of overburden, combined with the variation laws of geothermal gradient, pore water pressure and overburden resistivity, the stress concentration area and electric field (resistivity) mutation area were captured, and the evolution stage and potential failure mode of overburden stability were inferred accordingly. The primary processes of this method are as follows: Through a data cleaning method based on the topic model and integrating the effectiveness analysis mechanism of the IoT sensing data source, intelligent processing of massive data in the whole process of overburden deformation and failure sensing is carried out. These strengthened the machine learning research of key layer data missing from error correction, association analysis, and data mining. The hyperparameters were optimized by combining optimization algorithms such as moving average, random forest, Kalman filter, and multi-variate Bayesian. The trend term displacement of overburden was predicted based on the Kalman filter. The Bayesian optimized random forest model was used to predict the periodic term displacement of overburden, and the predictive value of accumulated displacement of overburden was formed. The model’s accuracy was verified and combined with the measured data of displacement to improve the prediction accuracy of overburden deformation .The current methods are difficult to continuously obtain the impact of overlying rock–soil mass deformation during coal mining on local deformation of underground tunnels and ground subsidence. Therefore, it is vital to overcome the technical barriers of sensing massive space–time continuous information in overburden during coal mining and carry out space–time continuous sensing research on the evolution from overlying rock deformation and failure to surface subsidence. Based on this, an integrated safety guarantee system for coal mining that covers sensing–transmission–processing–early warning–decision is established : (a) A mThis paper summarized the typical types of overburden deformation and failure modes. It compared and analyzed the parameter performance and applicable conditions of sensing cables (sensors) suitable for overburden deformation monitoring in mine engineering. Based on the achievements of the author’s research team in the coupling test for sensing cable–rock mass, a high-precision, large-capacity, and full-coverage distributed sensing network for mining was constructed, combined with the ground–underground integrated cable layout techniques. A space–time continuous sensing system for the overburden deformation and failure integrating sensing–transmission–processing–warning–decision–emergency was proposed. The main conclusions are as follows:(1) There are three typical modes of tensile failure, overall shear, and shear slip in the overburden deformation and failure induced by mining. Their occurrence, development, and evolution have a cumulative space–time effect. To clarify the evolution process and disaster mechanism of overburden deformation and failure, research on the space–time continuous state sensing for overlying strata should be strengthened, the space–time continuous sensing data of overburden deformation and failure should be integrated, and the accurate characterization of overburden deformation and failure should be realized. It is necessary to focus on the abrupt abnormal data, consider the gradual change data of overburden deformation regularity simultaneously, and realize the scientific evaluation for the stability of overlying strata during mining by combining the distribution of stratum profile and the field measured data.(2) According to the characteristics of mine engineering monitoring, combined with the performance parameters and application conditions of the sensing cables (sensors) used for overburden deformation monitoring, a multi-range strain optical fiber sensing nerve series from micrometer to meter is formed to realize the simultaneous sensing of overburden separation layer and its internal microcracks as well as large deformation of the overlying rock. The testing method, process, and criteria for the cable–rock coupling test to verify the reliability of optical fiber monitoring data were introduced. By utilizing the integrated method of laying cables on the ground and underground, the installation process of cables has been improved, and a distributed fiber optic neural sensing network has been set up to achieve space–time continuous and precise sensing for the overburden deformation during the whole cycle of coal production. In particular, for the large deformation monitoring of mines, it was proposed to reduce the diameter of the fixed-point cable’s outer sheath, and adapt the shape of the fixed point to be an olive shape, which can not only avoid scratching the sensing cable during cable layout but can also improve the coupling performance between the cable and the rock–soil mass.(3) Based on DFOS technology, a space–time continuous sensing system for the deformation of rock–soil mass above the coal seam during mining was constructed, integrating multi-parameter sensing, multi-method transmission, multi-algorithm processing, and multi-threshold warning. The real-time sensing of space–time continuous information under mining was realized. The disaster risk of coal mining and the potential of ground subsidence was accurately predicted by combining computer intelligence analysis algorithms such as clustering, regression analysis, Bayesian inference, genetic algorithm, and gray theory to realize the whole process cognition from the deformation, failure, and collapse of overburden to the occurrence, development, and evolution of ground subsidence.


Tackling antimicrobial resistance (AMR) through antimicrobial stewardship (AMS) interventions is a key objective within the World Health Organization (WHO)’s Global Action on AMR. We outline the reasons why global collaborations for AMS are needed. We provide examples of global collaborations, and we offer considerations when starting on a global health journey focused on AMS. Antimicrobial resistance (AMR) has significant impacts across geographic borders for human health as well as veterinary medicine, agriculture, and the environment. It is therefore an important One Health issue. Conserving the effectiveness of antimicrobial agents and optimizing their use through antimicrobial stewardship (AMS) is 1 of 5 objectives of the WHO Global Action Plan on AMR. Multiple-country collaborations and bidirectional learning across different income settings are essential for building and strengthening capacity for AMS interventions. Although variations in the composition of AMS teams, their functions, activities, and challenges exist, opportunities can be gleaned from the lessons of existing partnerships in AMS.Although the term global health is often associated with work linked to low- to middle-income countries (LMICs), any collaborative transnational research and actions promoting health for all constitute global health.In this article, we highlight some examples of international collaborative AMS efforts that the authors have been involved in, and we identify opportunities for stewards to learn from and apply in their own practices.The priority areas of focus for JPIAMR, a collaborative platform engaging the European Commission and 29 member countries representing 5 continents, include AMS efforts such as improving diagnostics, therapeutic regimens, and surveillance Table . Example The TTT program included bilateral site visits, development of pharmacists’ AMS skills as well as research and publication. Mentees transferred their AMS skills to train an additional 120 pharmacists with no prior AMS experience. These pharmacists made >40,000 AMS interventions in 60 hospitals and coauthored AMS publications.A partnership between OSU and South African Society of Antimicrobial Stewardship (SAASP) implemented a Train the Trainer (TTT) Antimicrobial Stewardship Program for South African pharmacists. A NICU ASP tool kit was developed for ongoing training of additional pharmacists. This effort led to a research collaboration with physician members of the South Africa National Neonatal Sepsis Task Force  for the first national neonatal intensive care unit (NICU)–ASP study across South Africa. The OSU–NCH collaboration expanded the TTT program with partnerships in Lebanon and Latin America.Another collaboration formed between the Centers for Disease Control and Prevention, OSU, Nationwide Children’s Hospital (NCH), and SAASP to implement neonatal antibiotic stewardship TTT pharmacist program. An equivalent leadership program has been developed for pharmacists based in Africa.Since 2018, through the CwPAMS program, there have been 26 partnerships involving UK institutions and institutions in 8 African countries  . In addition, ECRs were trained in AMS, infection prevention and control, as well as specific research methods to evaluate AMS interventions. Career development was encouraged through creating opportunities for research fellowship and doctoral (PhD) studentships. Initially, training and learning opportunities were mainly focused in a North–South direction, but capacity strengthening resulted in strong and equitable bidirectional collaborations. Cross-country visits provided insight into site-specific cultures and context enabling learning and knowledge exchange. This collaboration forged strong partnerships among the institutions leading to sustainable capacity for AMS-related work and research beyond the original intended course of the project.The multicentric social science Antibiotic use across Surgical Pathways - Investigating, Redesigning and Evaluating Systems (ASPIRES) study, has aimed to optimize antibiotic usage along surgical pathways through research collaboration among the United Kingdom, India, and South Africa. and they collaborated on a second publication to provide examples of ASP resilience from pharmacists and physicians with different resources and approaches to ASP.At the peak of the COVID-19 pandemic, AMS and infection pharmacists across 9 countries, 5 continents, high-income countries (HICs) and LMICs  collaborated to reinforce the ways in which pharmacists contributed to essential patient care and well-being of the public during the COVID-19 pandemic. They also codelivered a training webinar hosted by the Center for Infectious Disease Research and Policy (CIDRAP) ASP,First, consider some fundamental questions: Will the collaboration result in mutual benefit and how it will progress knowledge and skills? What are the skills, expertise and needs of the teams, organizations, and individuals I intend to work with? How do these match with my own and that of my team, organization, and context? Identifying colleagues who share a mutual interest and the capacity to have the time to work with are important. Once a need and clear gap have been established, as well as a means of how the mutual skills and expertise can address that need, then one can begin to consider the practicalities of collaboration Fig. .We encourage anyone interested in a global perspective of AMS to take the first step by reaching out to colleagues leading AMS in different settings including universities and professional organizations. AMS research teams within healthcare institutions are usually good places to start. Also, relevant authors of peer review publications or funding bodies can be contacted. One of the simplest ways to start a international AMS collaboration is to connect with people on social media. For example, infectious diseases experts from 4 countries met on Twitter and collaborated to coauthor a paper on the antibiotic topic “Shorter is better and oral is the new IV.” The paper was subsequently posted on Twitter and received 88,900 views in 23 hours.In the long run, the health of a collaboration is dependent on the strength of the relationships between the collaborators. Invest in building strong relationships, focusing on mutual trust, interest, and complementary expertise and skills. Ensure that there is adequate commitment from all sides to investing with time and intellectual input into the project. Often, this relationship may benefit from a contractual agreement or memorandum of understanding between partnering organizations. The WHO ESSENCE criteria for capacity strengthening or the Tropical Health and Education Trust (THET) principles for partnership can be used as a framework for establishing equitable partnerships. Key characteristics of successful international partnerships provided by interviewees included personal connections and understanding each other’s programs and systems. These researchers listed open mindedness, adaptability, global citizenship, and cultural and structural awareness as essential qualities for partners and learners.A recent study using semistructured interviews of global collaborators based in Africa, the Americas, the Eastern Mediterranean, Europe, Southeast Asia, and the Western Pacific highlighted important partnership components.Although available funding opportunities are highly competitive, applying for them is usually encouraged, especially in the context of international collaborations. Examples of US–UK funding opportunities include Bill and Melinda Gates Foundation, infectious diseases societies, the Centers for Disease Control and Prevention (CDC), pharmaceutical companies, the Wellcome Trust, the UK Aid Fleming Fund, and Health Education England Global Health Fellowships. These websites should be checked regularly for grant funding opportunities, as should other governmental, nongovernmental organizations (NGOs), and foundations. Travel is an important part of global health work, and some humanitarian organizations require experience of working internationally for at least 3 months. Travel is not always required to make important contributions; however, understanding contextual norms in different settings is a valuable skill. Early discussion with partner organizations is ideal to determine what costs need to be covered, how finances will be managed, and whether the involvement of the finance teams of all organizations is needed. The drivers and purposes of collaborations and the beneficiaries must be ascertained. Mutual benefits, including bidirectional learning and capacity strengthening, should be the goals of collaboration. Intentional effort is needed to assure equitable partnerships, especially because funding often flows in one direction from HICs to LMICs.A monitoring and evaluation plan is important to ensure that goals and outcomes are met. Setting up regular communication with all team members, particularly when working remotely or across different sites, is also an important element of a successful collaboration.Those interested in global collaborations should consider volunteering with global professional bodies such as the International Pharmaceutical Federation (FIP), Doctors of the World, Médecins Sans Frontières, the Red Cross, Save the Children, and many others. Examples of global health fellowship opportunities include the Harkness Fellowships in Health Care Policy and Practice of the Commonwealth Fund and The Churchill Fellowship. Several open university online short courses are available on global health  and some programs include a global health master’s degree.As stated by Margaret Mead “Never doubt that a small group of thoughtful, committed citizens can change the world; indeed, it’s the only thing that ever has.” In addition to benefits for patients and the public, there are important personal and professional development benefits for global collaborations to address the threat of AMR. Furthermore, such collaborations broaden the experiences, worldview and leadership skills of antimicrobial stewards who traditionally have not been as involved in global health activities. These efforts will lead to increased ability to implement innovations, will help us learn about health inequalities, and will provide opportunities for bidirectional learning.


A transient ischemic attack (TIA), a constellation of temporary neurological symptoms, precedes stroke in one-fifth of patients. Thus far, many clinical models have been introduced to optimize the quality, time to treatment, and cost of acute TIA care, either in an inpatient or outpatient setting. In this article, we aim to review the characteristics and outcomes of outpatient TIA clinics across the globe. In addition, we discussed the main challenges for outpatient management of TIA, including triage and diagnosis, and the system dynamics of the clinics. We further reviewed the potential developments in TIA care, such as telemedicine, predictive analytics, personalized medicine, and advanced imaging. A transient ischemic attack (TIA) is manifested by transient focal neurologic dysfunction due to loss of blood flow to the brain, spinal cord, or retina without evident acute infarction or tissue injury . Per defAlthough published years later, the FAST-TRACK TIA Clinic (1992–2004)  is amongBy setting 15 exclusion criteria, including multiple items, such as age under 40, presence of vertigo, balance difficulty without weakness, or any arrhythmia, the authors reported an 86% rate of cerebral ischemia among referred patients, significantly above the national average of 55%. A study of a larger cohort of patients referred to the daily TIA clinic of a United Kingdom general hospital (2010–2012)  was consIn Lothian, Scotland , patientIn France, the SOS-TIA (2003–2008) ,16 proviIn Australia, the Monash Transient Ischemic Attack Triaging Treatment (M3T) protocol 2004–2007) [–2007 [4]In the United States, the TWO ACES study   proposedThe Aarhus TIA study in Denmark (2007–2008)  defined In Canada, one study  used theIn Germany, Klinikum Harlaching stroke center  introducIn New Zealand, the Australian National Stroke Foundation introduced a triaging system consisting of ABCD2 and a set of high-risk indicators . This naThe primary definition of TIA emphasized the temporary nature of the symptoms to distinguish it from a minor stroke. Accordingly, the time-based definition of TIA refers to a constellation of symptoms that persist for less than 24 h, making its diagnosis challenging for patients and healthcare providers. Deploying imaging in the assessment of patients with suggestive symptoms of TIA revealed the presence of cerebral ischemia in up to half of the patients ,33, evenThere has been some debate in recent years about whether the term “TIA” should be retired or redefined, as some research suggests that the risk of subsequent stroke may be higher than previously thought or that the labeling is associated with a high misdiagnosis rate. While there are arguments for and against retiring the concept of TIA, it is generally agreed that the diagnosis and management of patients with TIA-like symptoms should be based on a comprehensive assessment of their individual risk factors, symptoms, and imaging findings. Ultimately, the decision to retire or redefine the concept of TIA should be based on a careful evaluation of the available evidence and the potential implications for patient care. While the concept of TIA may evolve over time, the need for prompt and accurate diagnosis and management of patients with TIA-like symptoms remains a critical component of neurologic care.The system dynamics of outpatient TIA clinics, also referred to as the “learning health systems” strategy, can refer to the various factors and interrelationships that affect the functioning and performance of these facilities, resources, and metrics. Some key factors that influence the dynamics of outpatient TIA clinics can include: (a) demographics and patient demand; (b) staffing and scheduling; (c) availability of medical imaging ; (d) funding and reimbursement; and (e) regulations and policies.As mentioned above, studies attempted to deploy strategies to maximize the efficiency of referral systems and minimize waiting periods and loss of follow-up. However, our prior meta-analysis  demonstrSimilar to the outcomes in patients with stroke, growing evidence suggests a decreased risk of recurrent ischemic events among patients with TIA who received antiplatelets. The addition of ticagrelor   or clopiDiffusion-weighted MRI is the preferred method for the detection of cerebral ischemia in the acute phase . HoweverRapid-access outpatient clinics are promising models to mitigate the length of hospital stays and total cost to the health system ,45,46,47Although earlier models of TIA clinics were concerning for a high rate of stroke and other major complications after the index TIA , our recLike other areas of medicine, telemedicine intends to extend access and optimize the quality of care for patients with cerebral ischemia. The COVID-19 pandemic was a turning point for many healthcare systems to implement telemedicine in a regular flow of patient care . At the A study of 18 centers with rapid TIA pathways across the globe demonstrated that the majority (63%) of these clinics offered telehealth exclusively during the pandemic . OutcomeEvaluation of the Effectiveness of a City Hospital Care Network for the Care of Patients with Transient Ischemic Accident   aimed toTIA care will likely undergo several changes in the coming years due to technological advancements and healthcare delivery models. Some potential developments include: (A) Telemedicine: As discussed above, with the rise of telemedicine, TIA patients may be able to receive care remotely, which can help improve access to care, reduce costs, and increase convenience. (B) Predictive analytics and continuous self-monitoring technologies: Predictive analytics can help identify patients at risk of stroke, allowing for early intervention and prevention as well as participatory medicine, where patients are empowered to reduce and help manage their risk factors. (C) Personalized medicine: Advances in genetic testing and precision medicine may enable more personalized treatment plans for TIA and stroke patients based on their individual risk factors and genetic profiles. (D) Improved imaging technology and finding new biomarkers: Advances in imaging technology, such as CT scans and MRIs, and other laboratory advancements can help improve the accuracy of TIA and stroke diagnosis and enable more targeted treatment. (E) Multidisciplinary care teams: Collaborative care models involving neurologists, cardiologists, and other specialists may become more prevalent, allowing for more comprehensive and coordinated care for TIA patients. (F) Integration with larger healthcare systems: As healthcare consolidation continues, especially in the US, TIA clinics may increasingly become part of larger healthcare networks, such as hospitals or accountable care organizations. This could provide TIA clinics with access to greater resources and expertise, as well as a larger patient population to serve. Overall, the future of TIA care is likely to involve a greater focus on prevention, early intervention, personalized and participatory care enabled by technology and innovative healthcare delivery models, and patient empowerment.Despite some challenges, well-established TIA clinics are safe and effective in providing prompt evaluation and treatment. The future of TIA clinics, especially in the United States, is likely to be shaped by a combination of changes in healthcare policies, technology, integration with larger healthcare systems, and patient needs. By focusing on prevention, leveraging telemedicine, and embracing new medical technologies, TIA clinics can continue to provide high-quality care to patients with TIA and mild stroke.


SUMMARY: Over the past decade, the Department of Veterans Affairs (VA) Pharmacy Benefits Management Services (PBM) has enhanced its formulary management activities and added programs to ensure that the national drug plan continues to meet the pharmacy needs of veterans and to promote safe and appropriate drug therapy in the face of rising medication expenditures. This article describes the broad range of services provided by the VA PBM that work in partnership to deliver a high-quality and sustainable pharmacy benefit for veterans.In support of formulary management, VA PBM pharmacists prepare extensive clinical guidance documents  that are used by physicians and pharmacists with operational and clinical oversight of the VA national formulary. The VA PBM has utilized various contracting techniques and continually evaluates drug utilization data to identify opportunities for potential savings. Remarkably, since before 2004, the average acquisition cost for a 1-month supply of medication has remained fairly stable at approximately $13-$15.Two new VA PBM programs are the VA Center for Medication Safety (VA MedSAFE) and the Clinical Pharmacy Practice Office (CPPO). VA MedSAFE is a comprehensive pharmacovigilance program focused on the detection, assessment, and prevention of adverse drug events, and CPPO is dedicated to improving safe and appropriate medication use by supporting and expanding clinical pharmacy practice. Moving forward, the VA PBM will consider new initiatives to stay at the forefront of providing quality care while maintaining economic viability. Over tiVA PBM formulary management involves a team of physicians and pharmacists whose functions include maintaining a national drug formulary, which ensures that veterans have access to the same drugs nationwide, and promoting, optimizing, and assisting VA practitioners with the safe and appropriate use of medications. Formulary management depends on the following programs: clinical guidance, contracting/pharmacoeconomics/pharmacy efficiency, pharmaceutical prime vendor, pharmacy data domains and reporting and analytics, and medication safety.2 Within the VA PBM, 2 groups provide operational and clinical oversight for the national formulary: (1) the Medical Advisory Panel (MAP), which is composed of practicing VA physicians representing various specialties, clinical pharmacy program managers, and a Veterans Integrated Service Network (VISN) pharmacist executive (VPE), and (2) the VPE group, which includes the VPE from each of the VA’s 21 regional networks (which will decrease to 18 over the next 2 years) and a representative from the MAP, VA National Center for Patient Safety, Department of Defense, and Indian Health Services. These groups meet individually on a monthly basis and together each quarter to consider items such as the addition of medications to the national formulary and criteria for use (CFU). These meetings also include consideration of the efficacy and safety of drugs, their relevance to the VA population, other available therapies, and cost.3In 2009, all regional formularies were abolished, and a single VA national formulary was established.Currently, the VA utilizes a 2-tier system that designates drugs as formulary or nonformulary. Within those categories, CFU are often developed that guide appropriate use. Nonformulary medications, with and without CFU, can be prescribed through the nonformulary request process. Typically, this occurs at the local level using similar procedures across facilities. Hence, the term “nonformulary” does not mean that a drug is unavailable through the VA; it simply means that additional information is required for the drug to be dispensed. A small group of medications require prior authorization at the VISN  or national level; all of these medications are included in the VA formulary.www.pbm.va.gov). When creating these documents, clinical pharmacy program managers consider the efficacy and safety of the medication based on available evidence (and in populations similar to the VA if data exist), review the prevalence of the disease state treated by the medication, evaluate VA use of related drugs, and assess possible drug-drug and drug-disease interactions. The potential effect on the pharmacy budget may be determined by identifying possible candidates for treatment using VA databases and modeling various levels of uptake and cost offsets. Documents are circulated nationally to VA providers for comment and review before they are finalized by the MAP and VPE groups.Clinical pharmacy program managers are national VA PBM pharmacists who primarily collaborate with multidisciplinary groups and subject matter experts to develop policies for medication use. The guidance documents they prepare include drug monographs for new molecular entities, CFU, drug class reviews, and clinical practice guidelines  in its formulary decisions, budget impact models and occasionally CEAs are provided as part of the deliberation process. In addition to the more traditional cost analyses, the VA PBM evaluates potential savings on an ongoing basis through the National Pharmacy Efficiency Program Savings Opportunity Workgroup. This workgroup leverages drug utilization data and benchmarking to identify opportunities for cost savings where quality of patient care is not compromised. For example, over 99% of patients requiring a proton pump inhibitor are prescribed a generic product. The work of this group has helped the VA PBM to maintain low costs for pharmaceuticals. For example, the group tracks high-use items that experience significant price increases and then identifies medications in the same class with similar efficacy and safety at a lower cost. When the primary pancreatic enzyme product significantly increased its pricing to the VA, the VA PBM developed a voluntary initiative to encourage sites to convert to a lower cost option. Monthly reports track changes in use and identify cost avoidance and lost opportunity cost.5The Pharmaceutical Prime Vendor program orchestrates the procurement and distribution of pharmaceuticals within the VA using a single wholesaler and complements the contracting process by ensuring drug accountability and compliance with prices. The system allows for comparative drug pricing to determine the most economical source; more responsive procurement and faster delivery to ensure less out-of-stock items; lower total acquisition cost based on specified product volume; and a reduction in drug storage space, decreasing inventory carrying costs.Staff from the Pharmacy Data Domains section maintains the PBM data warehouse that provides near real-time medication dispensing elements in aggregate and on provider and patient levels. Maintenance of the database occurs daily, with over 12 million records loaded per month. Prescription data are assessed and translated into a secondary (tier 2) format that includes data cubes, which are browsed using commercial software. These data are available to pharmacy managers at all levels to support formulary management, ascertain variations in prescribing practices, and identify opportunities to improve prescribing. For example, pharmacy managers may compare their use of medications for a particular disease state with other similar facilities and find potential cost savings. Also, medication safety issues are routinely assessed .VA Center for Medication Safety (VA MedSAFE) is a comprehensive pharmacovigilance program within the VA PBM, and its main goals are to track and evaluate the use of high-risk medications, new molecular entities, and older medications with newly identified safety signals, as well as to determine rates of adverse drug events (ADEs). These goals are accomplished through active and passive surveillance of ADEs, national medication use evaluations, risk reduction efforts, medication safety communications, and research.Pharmacovigilance. As part of its active surveillance program, VA MedSAFE often employs rapid cycle analyses  to assess potential medication safety signals.6 If a problem is identified, then a risk reduction project is implemented to improve the safe use of the medication. Some examples of rapid cycle analyses include varenicline and neuropsychiatric events, proton pump inhibitors and fracture, and direct oral anticoagulants and major bleeding. In addition, VA MedSAFE works closely with the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention to monitor, evaluate, and communicate medication and vaccine safety issues.VA Adverse Drug Event Reporting. VA MedSAFE uses a web-based VA Adverse Drug Event Reporting System (VA ADERS), which contains detailed information on observed ADEs, as part of its passive surveillance program.7 This unique, national database allows for rapid assessment of emerging drug safety issues.8 In addition, VA ADERS is used for benchmarking reportable ADEs, assessing preventable ADEs, and generating information such as the number of ADEs reported for new drugs. From inception in 2006 through 2015, over 500,000 ADE reports were entered in VA ADERs. Examples of the most common ADEs are lisinopril and cough, atorvastatin and myalgias, and metformin and diarrhea.National Medication Use Evaluations. VA MedSAFE conducts national medication use evaluations (MUEs) to assess the safe and appropriate use of drugs across the country. Based on the findings, processes for improving the use of the medication are developed, and targeted education is provided. For a recent MUE on the duration of antibiotic therapy for inpatient pneumonia, a “Field Guidance Package to Optimize the Duration of Antimicrobial Therapy” was developed, which provides a tool for assessing appropriate duration of therapy and a process for recommending a shorter course when indicated.Risk Reduction Projects and Medication Use Evaluation Tracker. Risk reduction projects and the Medication Use Evaluation Tracker (MUET) are methods implemented at the patient level to encourage safe prescribing and monitoring of medications. MUET is a web-based application that provides VA medical centers with secured lists of target patients that meet pre-set criteria for intervention and enables the interventions to be “reported back” into a centralized database.9 As examples, use of MUET improved prescribing of erythropoiesis-stimulating agents and enhanced compliance with the direct oral anticoagulant CFU. Risk reduction projects employ a variety of methods to improve medication use. For example, the number of patients receiving more than 10 mg of zolpidem decreased by 79% between the second quarter of FY 2007 and first quarter of FY 2009 after providers were contacted.Medication Safety Communications. VA MedSAFE publishes the National PBM Bulletin, Patient Level Recall Communications , and an electronic newsletter entitled “Medication Safety in Seconds” to provide medication safety information to clinicians in the field. Recent National PBM Bulletins addressed idelalisib safety and posaconazole dosing errors.Research. VA MedSAFE occasionally expands rapid cycle analyses into formal research projects to evaluate outcomes of VA PBM initiatives or more carefully examine potential associations between medications and adverse events. For example, VA MedSAFE evaluated the effect of a risk reduction project to decrease glyburide use in elderly outpatients with renal insufficiency.10 Glyburide was discontinued in more than 70% of these veterans without compromising glucose control (mean glycated hemoglobin 7.2%).1015Consolidated mail outpatient pharmacies (CMOPs) allow centralized filling and distribution of veterans’ prescriptions at 7 highly automated facilities across the nation. In FY 2014, the VA filled almost 144 million prescriptions, with 85% by mail order and the remaining 15% by local facility pharmacies. There is also a CMOP specialty pharmacy that provides many expensive and difficult-to-obtain medications  and certain medications with a REMS  requirement. Increased use of CMOPs allows pharmacists at local medical centers to spend more time in direct care of veterans. VA mail order pharmacies received the highest score for the past 6 years from J.D. Power and Associates for cost competitiveness, prescription delivery, ordering, and customer service.The professional pharmacy practice programs within the VA PBM work to promote and expand the role of pharmacists in the safe and appropriate use of medications outside of direct formulary management. These programs include clinical pharmacy practice, pharmacy residency training, academic detailing, and antimicrobial stewardship.The Clinical Pharmacy Practice Office (CPPO) was created in 2010 to further strengthen clinical pharmacy practice in the VA. CPPO has employed a multidimensional approach consisting of education/training, policy and guidance deployment, and data reporting and analysis to support and expand clinical pharmacy practice. As of FY 2014, approximately 40% of the over 7,700 clinical pharmacists in the VA have an advanced practice role with a scope of practice that includes prescriptive authority. These pharmacists work in over 25 different areas with the highest concentrations in primary care and anticoagulation. Focused efforts by the CPPO have resulted in tremendous growth in clinical pharmacists working in targeted gap areas of hepatitis C, mental health, and antimicrobial stewardship. For example, over 120 pharmacists with a scope of practice in hepatitis C provided direct patient care and prescribed 18% of all hepatitis C prescriptions in FY 2014.The National Pharmacy Residency Program Office (PRPO) offers national support for the growth of VA pharmacy residency programs and provides expert guidance for accreditation purposes, preceptor development, and resident education. The VA has the largest postdoctorate pharmacy training program in the country with over 600 pharmacy residents annually, and all programs are accredited by the American Society of Health-System Pharmacists.16As a result of a VA academic detailing pilot that improved prescribing of psychopharmacotherapy in mental health, academic detailing programs have been implemented, or are in progress, across the VA. Thus far, initiatives have primarily focused on psychotropic drug safety and pain management. In conjunction with other efforts to improve opioid safety, some early results of academic detailing include a 3.4% decrease in opioid use in one VISN, and an almost 2% decrease in concomitant opioid and benzodiazepine prescribing in another over the last three quarters . The National Academic Detailing Program Office provides data to support initiatives, training in academic detailing, guidance for local programs, educational materials, and methods to track progress.17 The ASTF is co-chaired by a pharmacist from the VA PBM and a physician from the National Infectious Diseases Service. VA medical centers are provided a variety of tools, including examples of policies and order sets, as well as a monthly educational teleconference series. While hard outcomes with antimicrobial stewardship are challenging , ASTF has documented decreases in antimicrobial use on a global level (manuscript in preparation).The National Antimicrobial Stewardship Task Force (ASTF) assists VA facilities in the development and expansion of antimicrobial stewardship activities .The VA PBM is a robust, comprehensive program with many unique features that fall outside of traditional formulary management. These diverse aspects have augmented the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures. With a unified formulary and extensive databases, the VA PBM can easily track medication use and contact patients and providers when there is an important safety issue. Through its national pharmacovigilance program, ADEs are identified and evaluated, and when necessary, projects are initiated to improve medication prescribing and prevent future harmful events. Finally, more pharmacists are directly involved in medication therapy management, academic detailing, and antimicrobial stewardship, all of which support appropriate drug therapy. Together, VA PBM programs create a first-class and sustainable pharmacy benefit for veterans.


Chikungunya is an arboviral disease caused by the chikungunya virus (CHIKV) afflicting tropical and sub-tropical countries worldwide. It has been identified as a priority pathogen by the Coalition for Epidemics Preparedness Innovations (CEPI) and as an emerging infectious disease (EID) necessitating further action as soon as possible by the World Health Organization (WHO). Recent studies suggest that disability-adjusted life years (DALYs) due to CHIKV infection are as high as 106,089 DALYs lost globally. Significant progress has been made in the development of several vaccines, aimed at preventing CHIKV infections. This perspective article summarizes CEPI’s efforts and strategic considerations for developing a CHIKV vaccine and ensuring equitable access for CHIKV endemic countries. There are at present no licensed vaccines, although several advanced candidates are approaching the approval process. The lack of long-term surveillance programs and corresponding data in chikungunya-affected/endemic regions such as Africa, Latin America, and Southeast Asia as well as the sporadic transmission and unpredictable outbreak patterns of CHIKV have impeded conduct of randomized controlled efficacy trials. This impediment, alongside the established disease morbidity and burden, have led authorities to explore alternative data provisions to facilitate development and licensure of medical products/vaccines for CHIKV. Mature regulatory authorities, including the Food and Drug Administration (FDA) and European Medicines Agency (EMA), recognize the substantial unmet medical need posed by Chikungunya disease and the limited feasibility of Phase 3 efficacy trials and are supportive of alternative licensure pathways , using a surrogate marker of protectionHere, we introduce the Coalition of Epidemic Preparedness Innovations (CEPI’s) funding considerations to facilitate access, supply, and outbreak response of licensed vaccines and summarize our approach to support registration of CHIKV vaccines in endemic countries. We also highlight the need for multilateral and normative institutions to begin preparing mechanisms for the acceptance, procurement, and uptake of licensed CHIKV vaccines, beyond the limited scope and mandate of CEPI funding. Given the epidemic and outbreak potential of CHIKV we also highlight applications of lessons learned to future outbreak response building on regulatory and manufacturing innovations and regional use scenarios.4. CEPI is funding the progress of Phase 2–3 candidates into advanced clinical development and eventual licensure of vaccines for use in affected regions. With support from the European Commission (EC), CEPI has invested in candidates showing promising results in Phase 1 and 2 clinical trials  Measles-Vectored CHIK program which was put on hold after completion of a Phase 2 study7.Multiple CHIKV vaccines are in development from the pre-clinical stage to Phase 1, 2, and 38, which uses a surrogate endpoint of protection. The FDA defines a surrogate endpoint as a “marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit”  infection model to establish a level of biomarker induced by a vaccine candidate that is demonstrative of protection from viral infection and/or challenge10. Non-human primate CHIKV infection models have emerged as valuable tools for investigating CHIKV infection, assessing vaccines in preclinical studies, and establishing an immune correlate of protection to support regulatory needs for licensure. Data from a sero-epidemiological study performed in the Philippines11 demonstrated that participants with even a very low-positive neutralization titer (PRNT80 ≥ 10) were protected from symptomatic CHIKV infection. Developers have extrapolated this data point to their respective assays and derive a surrogate threshold of protection using challenge studies in an NHP model of infection. This approach has been complemented by other incentives such as breakthrough therapy designation, fast track designation, and financial incentives such as priority review vouchers to incentivize product/vaccine developers to fulfill an unmet need in a neglected disease area12.Notably, FDA/Center for Biologics Evaluation and Research (CBER) has endorsed an accelerated approval process for Valneva’s live attenuated CHIKV vaccine VLA1553)5538, whi13. The latter enhances support for priority medicines that target an unmet medical need supported by a surrogate  marker of protection.Similarly, EMA has endorsed three CHIKV vaccine candidates  candidates for its PRIME scheme14.As developers proceed with clinical testing in Phase 3 , ensuring the quality, standardization, and harmonization of laboratory testing of clinical samples is crucial for accurate assessment of vaccine efficacy. A diverse array of assays are employed to measure neutralizing antibodies, incorporating distinct viruses or antigens and variable operational and reporting methods. Thus, comparison of results is difficult. The World Health Organization (WHO) has recently endorsed an international antibody standard to harmonize immune response ranges across multiple vaccine trials. The WHO-endorsed standard, developed by the Paul Ehrlich Institute (PEI) in 2022 using an East/Central/South African strain of CHIKV, can facilitate the use of a uniform biomarker for immune response measurement and is readily available for useIncorporation of a harmonized standard would ensure accuracy and consistency across different vaccines, and also distinguish between immune response characteristics for each vaccine. Product characteristics can inform vaccine use in varying scenarios such as outbreak versus routine use, geographical suitability in terms of costs, and future response scenario planning and procurement planning for Ministries of Health and multilateral agencies such as PAHO , UNICEF (United Nations Children’s Fund), and GAVI  amongst others.Incorporation of the established international standard into the testing will be crucial to measure vaccine performance and provide additional data for suitability to specific groups  if multiple candidates are assessed.Knowledge gaps in CHIKV epidemiology hamper the preparation, site selection, and implementation of CHIKV vaccine efficacy trials. CHIKV has a wide geographic distribution, and available information tends to focus on large-scale outbreaks with historically few examples describing low-level or endemic transmission. As outbreaks are generally not fully characterized, details of age-specific incidence are often limited. With the example of the recent outbreak in Paraguay, the unusual pattern of chikungunya virus outbreaks and the prevalence of immunity in affected populations highlight the challenges of evaluating candidate vaccines in a Phase 3 trial.Many CHIKV endemic areas are co-endemic for arboviruses sharing similar clinical presentations . A lack of specific case definitions to differentiate between these arboviruses, as well as a low proportion of lab-confirmed cases during outbreaks  means that co-infection and/or misclassification is likely and could contribute to under- or over-reporting of chikungunya cases.15, could be applied to CHIKV. Available data  suggest that CHIKV outbreaks are unlikely to occur in areas which have recently experienced a large-scale outbreak16 but provide insufficient information to characterize the duration of population protection.While there are gaps in understanding of long-term population immunity and duration of population protection, evidence of durable protection following infection with Ross River virus (RRV), a related virus16. While some insight can be gleaned from surveillance of other arboviruses , the fact that most surveillance activities are clinic- or hospital-based and rely primarily on clinical diagnosis (rather than laboratory confirmation) means that granularity of transmission dynamics between arboviruses with similar clinical presentation  is lacking. Available ongoing surveillance reports, such as chikungunya situation reports from the Government of India’s National Center for Vector-Borne Diseases Control17, Brazil’s weekly reporting18, and the weekly chikungunya reports released by PLISA Health Information Platform of the Americas19 often share limited information publicly . Working directly with endemic countries and key stakeholders  could provide valuable depth to publicly available data. Improved and sustained surveillance of CHIKV in endemic areas, including laboratory confirmation of cases, would greatly improve our understanding of CHIKV disease dynamics and enable the planning and implementation of CHIKV vaccine efficacy trials. While some recent examples describing inter-epidemic or endemic transmission of CHIKV in Kenya20 and Thailand21, further characterization of endemic transmission in key areas could provide valuable insight, as there is insufficient evidence to suggest that vaccine effectiveness trials would be feasible in such areas.Many CHIKV-endemic countries do not have continuous CHIKV-focused surveillance systems in place, as many systems are active for a limited time and/or in a limited geographic area22.Mathematical modeling utilizing a range of data sources  could also contribute valuable insight and more granular estimates of disease burden. The disease distribution information can be used to create CHIKV risk maps to aid in planning for vaccine efficacy trials. Additionally, models can be used to predict possible future disease burden and outbreaks, inform vaccine demand, predict vaccine impact, and determine optimal vaccination strategies (and test others) under different epidemiological scenariosGiven the recent progress in CHIKV vaccine development, the knowledge gaps described above may not be addressed ahead of the licensure of a CHIKV vaccine. Filling these epidemiological knowledge gaps remains important for post-licensure activities such as Phase 4 effectiveness studies, which will inform governments’ go/no-go decision on national inclusion of any CHIKV vaccine and in turn inform demand for and equitable access to a CHIKV vaccine.23. Under these circumstances WHO considers the possibility of deriving an immunological marker of protection from non-clinical efficacy trials or passive protection trials – that is, nonclinical or clinical trials which assess the effects of administering normal or hyperimmune human gamma globulin or convalescent sera and the establishment of a minimum protective antibody level sufficient for the prevention of clinical disease that can be used to interpret data obtained in clinical trials with the candidate vaccines. This is reflected in the choice of study design of pivotal Phase 3 clinical trials of advanced vaccine candidates . The primary outcome measure was the rate of seroprotection at 28 days following vaccination in baseline seronegative participants. Seroprotection was defined as anti-CHIKV antibody titers based on a µPRNT assay that were above the level of ‘surrogate of protection’ agreed with US FDA. Results of this study formed the basis of Biologics License Application (BLA) to the US FDA for approval of the vaccine for use in adults aged 18 years and above24. In addition, Valneva, in collaboration with Instituto Butantan is conducting a Phase 3 clinical trial among adolescents—data from which may be used for Brazilian regulatory approval in this population. The trial’s primary objective is based on immunogenicity at 28 days following immunization.Valneva’s pivotal, placebo-controlled, Phase 3 clinical trial of its live attenuated vaccine candidate (VLA1553) evaluated the safety and immunogenicity following a single dose among adults (n = 3210). Using a placebo-controlled, randomized, adaptive, seamless study design, allows for modification based on dose selection done in early parts of the trial followed by a dose confirmation in later phases. The primary outcome measure is geometric mean titers (GMTs) of neutralizing antibodies at 28 days following a second vaccine dose. This trial is sponsored by the International Vaccine Institute. A parallel Phase 2/3 trial with similar primary outcome measures and study population is underway in India, sponsored by Bharat Biotech.Bharat Biotech’s inactivated vaccine candidate (BBV87) is undergoing a pivotal Phase 2/3 clinical trial in multiple countries in Latin America  and Asia (Thailand) among 12–65-year-olds (n = 3258). It will also demonstrate the immunogenic consistency of three different manufacturing lots. The primary outcome measure is based on GMTs of neutralizing antibodies against CHIKV at 21 days following vaccination. A parallel Phase 3 trial is underway to assess immunogenicity in adults > 65years (n = 413).Emergent BioSolutions’ VLP-based vaccine candidate (CHIK VLP) is being evaluated in a placebo-controlled Phase 3 clinical trial in USA among 12–65-year-old healthy seronegative individuals  stage of clinical development. All three aforementioned developers are conducting pivotal clinical trials—that form the basis of approval for use in general population—utilizing immunogenicity endpoints. Emergent has planned for a post-licensure trial25, and will likely need to be established with each individual vaccine candidate for regulatory authorization.With multiple genotypes of CHIKV in circulation such as East/Central/South African, West African, and Asian strains, cross-neutralization across lineages has been demonstratedConsidering that novel chikungunya vaccines may be authorized soon, plans for measuring effectiveness post-approval need discussion with regulators to gain good understanding of data to be generated after licensure. In addition, developers with CHIKV vaccine programs nearing licensure should plan human clinical trials in special subgroup populations to include age de-escalation into pediatric populations, pregnant women, and immunocompromised subjects, further expanding utility of licensed vaccines including in CHIKV outbreaks.The design of effectiveness studies for CHIKV vaccine may vary depending on the objectives and endpoints set by respective vaccine developers. As a result, the diagnostic requirements will also vary depending on effectiveness study design. The tests needed may include highly sensitive, specific, and validated RT-PCR assay for case confirmation, and immunoassays  for assessing vaccine induced immunity or prior exposure to a natural infection. Rapid diagnostics tests (RDTs) will be useful for early detection of an outbreak. Specifically, high performing and validated molecular RDTs will be extremely important for participant recruitment in rural areas where RT-PCR test is often unavailable.27. However, the performance of the available molecular tests has not been clinically validated. No RT-PCR test has received full regulatory approval (FDA) for CHIKV detection to date. With multiple chikungunya virus lineages circulating globally28, confirmation that available RT-PCR tests are cross-sensitive and specific across lineages/clades is needed. The performances of available RT-PCR tests for CHIKV also needs clinical validation against other closely related arboviruses including DENV, ZIKV, Yellow fever virus (YFV), and West Nile virus (WNV), and alphaviruses (Mayaro virus [MAYV] and O’Nyong Nyong virus [ONNV]). With regards to immunoassays, there are several in-house and commercially available ELISA tests for the detection of CHIKV infection27, however, the performance of these assays have not passed through an independent clinical validation. In addition, significant cross-reactivity between anti-CHIKV and anti-ONNV antibodies, as well as between anti-CHIKV and anti-MAYV has been documented. To date, there is no reliable serology assay that can distinguish between these viruses in CHIKV endemic areas; and are needed to enable Phase 4 effectiveness studies.Landscape analyses of CHIKV diagnostics have identified commercially available conventional and real-time (RT-PCR) test, isothermal and multiplex PCR assays29, but their performance is claimed to be variable. While antigen based RDTs are in development, there are no nucleic acid based RDTs for CHIKV to date.Among other diagnostic tests useful for chikungunya effectiveness studies are RDTs, for use in participant screening and recruitment for Phase 4 effectiveness studies. In addition, RDTs have a significant contribution in early detection of cases and outbreaks, especially in rural areas with limited infrastructure to properly diagnose and manage patients. Peripheral health facilities (low level) without advanced laboratory equipment and skilled personnel to perform RT-PCR tests would benefit from the availability of a high-performing and validated RDT to allow early detection and management of chikungunya cases. It will also contribute to the recruitment of Phase 4 chikungunya vaccine effectiveness study participants from rural areas where RT-PCR is not available. A recent landscaping on chikungunya RDTs showed the commercially available antibody and antigen based RDTs30. In addition, the presence of polyarthralgia may be considered as an important clinical diagnostic marker since most chikungunya cases experience arthralgia ranging from weeks to months. Specifically, it is important to combine an anti-chikungunya IgM test and clinical symptoms  for accurate diagnosis.For clinical confirmation of chikungunya, it is preferable to use RT-PCR during the first week of illness. However, as viremia declines after the first week of symptoms, an anti-chikungunya virus IgM test is the best alternative for diagnosis. IgM is detectable between 2–3 months after infectionA highly sensitive, specific, and validated RDT could be used for Phase 4 effectiveness studies. Specifically, the development and validation of a high performing, automated, self-contained chikungunya nucleic acid-based test for use at peripheral health facilities is of high importance. This work could potentially be addressed by FIND, the diagnostic alliance.31. Listing of products evaluated by these mechanisms assist UN agencies and Member States in procurement of these essential goods. The WHO EUL facilitates the availability of products for serious or immediately life threatening for pathogens with potential of causing an outbreak, epidemic or pandemic, while WHO PQ ensures that vaccines used in immunization programs are safe and effective.WHO has two procedures to determine the acceptability of vaccines and other products based on evaluation of quality, safety, efficacy, and performance, namely, the WHO Emergency Use Listing (EUL) and WHO Prequalification (PQ)Vaccines deemed eligible for WHO PQ are listed in the Vaccines PQ Priority List after discussions with UNICEF, the PAHO Revolving Fund, and other international procurement agencies and is based on the demand of UN supplied markets , suitability for WHO programmatic needs, supply security and recommendations from WHO’s Strategic Advisory Group of Experts on Immunization (SAGE). The current list does not include CHIKV vaccines. It is reviewed every two years and inclusion in following updates are subject to SAGE review, recommendation, and a Director General’s endorsement. To date, CHIKV disease and vaccines are not included in SAGE’s agenda for discussion and recommendations thus not setting the stage for establishing PQ eligibility and consequent procurement of these vaccines by multilateral procurement bodies such UNICEF, GAVI and the PAHO Revolving fund for supply and use in developing/affected countries – all of which require WHO PQ as a criterion for purchase of medicinal products.Thus, endemic countries or those where manufacturing developments are ongoing may need to anticipate appropriate regulatory pathways for vaccine licensure until a WHO PQ pathway for CHIKV vaccines is available. It is now a priority to present CHIKV vaccines as a control or prevention tool for CHIKV disease to organizations such as GAVI, UNICEF, PAHO and the Revolving fund.32, limited similar advice from WHO & SAGE are needed to establish guidelines for the regulatory processes by national regulatory authorities from LMICs.Whilst guidelines on production, quality, safety, and efficacy evaluation from EMA and US FDA for regulation of some CHIKV vaccines serve as an example33. Despite these limitations, both regulatory agencies indicate that the establishment of the SoP is specific to each vaccine and populations in which it has been established.In the meantime, promoting the understanding of the difficulties for the evaluation of CHIKV vaccines efficacy with National Regulatory Authorities and the acceptance of using surrogate markers of protection (SoP) can accelerate the availability of chikungunya vaccines in endemic countries and/or have them ready for use in case of outbreaks. It is encouraging that USFDA and EMA have accepted developers’ approach to establish a protective neutralizing antibody threshold through passive transfer in NHP’s with data from sero-epidemiological studies despite the limitations of a SoP. These limitations largely center on an appropriate animal model, in the case of CHIKV a non-human primate model, and its ability to translate to human protection. To date, only one study has demonstrated protective CHIKV neutralizing antibody levels in a prospective cohort study34.In December 2021, PAHO, ANVISA, and CEPI convened a meeting of the NRAs  of reference for PAHO to discuss the developments of chikungunya vaccines and share the regulatory experiences of the USFDA and EMA in their approaches to licensing these vaccines. Participant regulators were in agreement on the concept of approval based on SoP but indicated that they would require review of current regulations. They reiterated the importance of plans for completion of post-marketing effectiveness and safety data, and highlighted the need for more sero-epidemiological studies to support NHP studies and for a better basis for post-licensure effectiveness studiesRegulators also agreed to undertake joint and collaborative reviews using new or already existing mechanisms. This approach in the Americas could be reproduced in other regions to support chikungunya vaccines becoming available in endemic countries and generate useful information on safety and efficacy/effectiveness that will complement inclusion on the WHO PQ priority list of vaccines.35.WHO prequalification (PQ) is a critical route used to provide qualified, safe, and efficacious vaccines for United Nations’ (UN) procurement agencies and to countries for bulk purchasing and distributing medicines in resource-limited settings. The process for establishing eligibility for WHO PQ for procurement is therefore a crucial mechanism to facilitate development and access to medical products worldwide, and especially to countries with nascent regulatory capacity36. This status quo leaves countries to rely on approvals by external NRAs for local procurement and supply, until a vaccine is licensed locally or pre-qualified by WHO—significantly delaying access.The PQ prioritization process requires multiple rounds of consultation, advocacy, and final approval by the WHO Director General’s office to enable WHO prequalification eligibility of CHIKV vaccines for procurement and supply, especially in developing regions. Figure CHIKV vaccine candidates are uniquely positioned to address unmet medical need, whilst simultaneously constrained by lack of an established route to pre-qualification and licensure in LMICs. Given the financial incentives set in place by NRAs such as Accelerated Approval, Breakthrough designations (FDA), PRIME (EMA), etc., this leaves the onus of facilitating access in CHIKV endemic regions on the developer and is a gap requiring address. Given the large volume procurement that PQ facilitates, the WHO PQ pathway represents a significant financial incentive for developers and can be leveraged to expand access.Furthermore, the low case fatality rate of chikungunya infections has also influenced the prioritization of the disease, with CHIKV missing a place on the influential WHO R&D Blueprint priority pathogen list despite having a significant and well document disease burden in multiple regions. Both, WHO R&D Blueprint Prioritization process and the PQ prioritization procedures are independent processes with varying advisory bodies and accountability structures within WHO.37. WHO has also commissioned a vaccine value profile that will likely be published in 202338. More recently WHO has included CHIK as a neglected tropical disease that will be addressed as part of its 2030 disease strategy39.WHO has recently launched its Global Arboviral initiative to address gaps in arthropod borne viral disease including those with a larger disease burden including DENV (Dengue virus), YFV (Yellow fever virus), ZIKV (Zika virus) and CHIKV, which brings together key partners and setting the stage for a broad strategy to address gaps in surveillance, preparedness and response and envisions engaging a wide variety of stakeholders to address identified gaps40.In the near term, this status quo leaves the world exposed to an obvious vaccine inequity dilemma where only travelers and people in HIC (High Income Country) countries are able to access licensed vaccines. There is a clear need for interim measures to facilitate regional licensure in affected countries prior to availability of a PQ pathway for CHIKV vaccines. One example would be the EMA’s M4all Procedure (previously Article 58), which combines EMA’s scientific review capabilities with WHO expertise on local epidemiology and disease alongside involvement of national regulators in target countries. The process facilitates prequalification by WHO and can also support licensure in countries where expertise is nascentVaccine developers with CHIKV candidates in Phase 3 studies, near national regulatory licensure or licensed by a national regulatory agency will likely need to execute an extended (5 years or more) Phase 3 human clinical trial and/or Phase 4 studies to facilitate access to products. Phase 3/4 studies will be crucial to establish long-term safety of the vaccine, durability of a surrogate marker of protection based on neutralizing antibody titers, and vaccine effectiveness through surveillance for virologically confirmed disease (using RT-PCR). Ideally, these studies will be performed in CHIKV endemic countries and linked to country-specific NRA requirements for approval and use in the local population.41. Complementarily, key stakeholders such as WHO, GAVI, UNICEF will need to inform and prepare pathways to successfully facilitate acceptance, procurement, and uptake of licensed CHIKV vaccines.Given limited guidance on CHIKV vaccines, there is minimal understanding of how endemic countries aim to use CHIKV vaccines within their local jurisdictions, i.e., whether incorporation into routine EPI (Expanded Programme on Immunization) programs or as an outbreak response vaccine, volumes of vaccines needed for either use scenario, and the willingness-to-pay and procurement interest. These are key gaps that need to be explored and addressed as developers bring their products to market. CEPI recently commissioned a Request for Proposals to identify these needs and is in the process of gathering this information34. In addition, CEPI also convened a Joint Coordination Group in February 2022 to engage key stakeholders on facilitating access to CHIK vaccines, such as WHO, UNICEF, GAVI, AVAREF (Africa Vaccine Regulatory Forum), and FDA among others42.To support transition to licensure and commercial supply, CEPI and regional authorities have begun engaging on local needs and acceptability of regulatory pathways for CHIKV vaccines and needs for post licensure data such as effectiveness dataDevelopers’ strategies to facilitate access to their respective products, could potentially incorporate technology transfer for manufacturing to endemic partners. If technically and commercially feasible, availability of vaccines in a local regulatory ecosystem would enable faster and more quality controlled supply of vaccines in an endemic setting. This approach has been adopted by Valneva through a technology transfer to Instituto Butantan in order to manufacture and supply vaccines to Brazil and the surrounding regions affected by CHIKV. Such technology transfers will require supportive evidence generation in endemic populations, immunocompromised and pediatric populations while expanding the overall product indication.As countries begin to prepare and develop programs targeting the next pandemic, a number of lessons from CHIKV vaccine development can be applied to preparing for the next Disease-X response. The vector-based transmission model and CHIKV’s ability to adapt to new mosquito vectors alongside emerging climate change patterns and migration of mosquito populations highlight the potential of a next large-scale epidemic or pandemic if conditions allow.Lessons learned from CHIKV for the next Disease-X outbreak include its explosive nature of outbreaks with subsequent rapid decline of cases and the impact this has on trying to establish the clinical efficacy of future vaccines through formal RCTs. In the CHIKV case, the alternative pathway was to develop and promote the regulatory acceptance of a surrogate marker of protection based on animal studies as reasonably likely to predict clinical efficacy, followed by post-licensure commitments to provide safety and effectiveness data at the time of the next outbreak. Although these pathways are available through the US FDA, EMA, and other mature regulatory authorities, they must also be advocated as part of emergency preparedness plans of NRAs from LMICs. Regional regulatory engagements to reach consensus on emergency use and/or licensure of a vaccine for LMICs should be encouraged. Investments in the technology transfer of LMIC manufacturing and vaccine distribution, supported by enhancement of surveillance programs and diagnostics for regional disease threats will also be critical to a successful response.Lastly, the ability to utilize a SoP as a measurement of efficacy for CHIKV vaccines can be applied to develop and deploy a vaccine for the next Disease-X outbreak. As the focus currently lies on preparation and development of vaccines for the next Disease-X emergence, developing SoPs during preclinical and clinical development with appropriate animal models in conjunction with antibody transfer studies from human vaccine recipients will be key to fielding vaccines amidst a Disease-X outbreak and receiving the regulatory approval to utilize them.Having invested significantly in advancing CHIKV vaccines towards licensure, CEPI, with support from the European Commission, will continue to facilitate and drive access to licensed CHIKV vaccines in the future. By supporting Phase 4 effectiveness studies and further research to expand indications for licensed vaccines to pediatric, immunocompromised, and pregnant populations, CEPI will encourage developers to address gaps identified in this document as part of future grant proposals. This includes supporting technology transfers for manufacturing of CHIKV vaccines to endemic areas to ensure regional access and availability.Facilitate dialogue and visibility of advanced CHIKV vaccines at existing institutional fora and advisory bodies, such as SAGE, WHO PQ and others to facilitate uptake and use of these vaccines in advance of licensure.Highlight the need to streamline existing processes to facilitate access to vaccines through WHO PQ, GAVI, UNICEF and Revolving Fund procurement mechanisms, considering the significant operational burden on all key stakeholders.Encourage mechanisms such as joint regulatory review with affected country NRAs to ensure timely licensure of vaccines as an interim step to WHO PQ.Lay out and propose end-to-end interim mechanisms for regional emergency use of licensed (ML3-4 NRA) vaccines before completion of WHO PQ process.Propose use-principles for advanced and licensed vaccines by affected countries before a PQ pathway is available, such as, for outbreak and emergency use.Proactively engage with decision makers in affected countries to increase visibility and understanding of CHIKV vaccines and applications for use of licensed vaccines.Consider how learnings from CHIKV vaccine development can be applied to vaccine development for other WHO Priority pathogens such as MERS-CoV, Nipah, Lassa and Disease-X viruses.While these data become available over the coming years, we recognize CEPI’s limited mandate in market shaping and supply within the Global Health ecosystem. In this light we call on key partners such as WHO, PAHO, GAVI, UNICEF, National Regulatory Authorities, vaccine developers, and others to:Supplementary abbreviation list