Understanding cell migration is a key step in unraveling many physiological phenomena and predicting several pathologies, such as cancer metastasis. In particular, confinement has been proven to be a key factor in the cellular migration strategy choice. As our insight in the field improves, new tools are needed in order to empower biologists’ analysis capabilities. In this framework, microfluidic devices have been used to engineer the mechanical and spatial stimuli and to investigate cellular migration response in a more controlled way. In this work, we will review the existing technologies employed in the realization of microfluidic cellular migration assays, namely the soft lithography of PDMS and hydrogels and femtosecond laser micromachining. We will give an overview of the state of the art of these devices, focusing on the different geometrical configurations that have been exploited to study specific aspects of cellular migration. Our scope is to highlight the advantages and possibilities given by each approach and to envisage the future developments in in vitro migration studies under spatial confinement in microfluidic devices. Cell migration is a complex phenomenon that plays a key role in a variety of biological processes in multicellular organisms, including embryological development, wound healing and immune response. Pathological processes, such as tumor invasion and metastatic spread, also rely on cell migration . For insConfinement is an important mechanical cue for motile cells, as it can trigger a variety of cellular responses . For insDissemination can occur through single cell invasion or collective invasion, depending on whether the cells have transitioned to a fully mesenchymal phenotype or whether they still retain epithelial characteristics ,18. In 3When escaping the primary tumor and moving through the ECM, tumor cells squeeze through 1–30 de pores ,28 and 1diameter ,18. Suchdiameter ,30 and fdiameter ,34,35,36Because of its clinical relevance particularly in the context of cancer research, understanding the effects that confinement and related mechanical cues such as stiffness and shear stress can have on cellular behaviors may prove to be a valuable contribution to the development of strategies and therapies tackling metastatic spread at its early stages. Given its importance, many in vitro systems have been developed in order to study and characterize cellular motility and migration patterns as well as to replicate the physiology of human tissues and in particular ECM mechanical, structural and chemical characteristics.The four main standard techniques used to study cell migration, whether in 2D or in 3D environments, are the scratch assay, the cell exclusion zone assay, the Boyden chamber and patterned lines . In a scA similar assay that aims to avoid the variability in the scratch process is the cell exclusion zone assay . In thisThe Boyden chamber  is a sysThe last technique standardly used to study cell migration is the so-called “patterned lines”. In this case, a planar substrate is patterned with proteins that can drive cell adhesion, so that the seeded cells naturally stretch along the defined geometry . These long lines allow the study of cell migration, imposing a lateral constrain induced by the limited contact area. This technique allows the engineering of the spatial stimuli by changing the shape of the patterned lines, but it does not give hints of the behaviors of cells under mechanical confinement, as in the case of migration through pores.The previously described assays constitute the pillar of cell migration studies, but they have some limits, i.e., they are intrinsically two-dimensional (2D) techniques, they do not allow a perfect control of the biological conditions, and they have a poor reproducibility. In this framework, a technological improvement to overcome these critical points is needed. Microfluidics has proved to be a new enabling technology for biological assays and in particular in the case of cell migration. One first strong advantage of microfluidics is the precise and reproducible control on the biological environment, i.e., the possibility to induce precise flow rate, control the temperature and the composition of the buffer and even the ability to induce chemical gradients with different shapes thanks to engineered micromixer geometries . SecondlIn recent years, many different microfluidic platforms have been proposed to study migration, under spatial confinement, of adherent cells. Their characteristics depend mainly on the material and fabrication method that set important aspects as the minimum constrain dimensions or the 3D level. In the present work, we present a review of different approaches of microfluidic cell migration assays (MCMAs) under spatial confinement. We discuss their technological aspects such as fabrication technique, material or design.As we will show, despite their designs or dimensions, or the biological problem they aim to study, it is possible to classify them depending on the material and/or the fabrication technique. In this framework, we identify three main categories for the existing MCMAs platforms: namely, those made in polydimethylsiloxane (PDMS), in hydrogels, and those made by ultrafast laser writing in glass and/or photopolymers see . The posPDMS is a broadly used material in microfluidics ,76,77. Iapproach ,79. It iExploiting standard soft lithography, it is possible to easily reproduce arbitrary 2D geometries with a minimum feature size of few micrometers. To further reduce the channel dimensions down to the nanometer scale, more advanced techniques can be used, such as controlled collapsing of microchannel structures  or inducIn addition to being very easy to manipulate, PDMS has some known characteristics that must be taken into account during microfluidic device design . PDMS isIn the field of the study of confined cell migration, it is possible to exploit different geometries, with increasing complexity. In the following, we will present the main strategies in order to give an overview of the implementation of microfluidic channels for migration assays, with a focus on the possibility to tailor the geometries addressing specific biological aspects.The most simple geometry of a PDMS biochip used to study cell migration and chemotaxis consists of an array of straight channels connecting two reservoirs. As in Boyden chambers, the first reservoir is used for cell seeding, while the second contains the solution that is used to create a chemical gradient along the microchannels. Differently from Boyden chambers, using these MCMAs, it is easy to observe the cells migrating in the channel and study their motion by putting the PDMS biochip on a standard microscope. A simple configuration of this type is presented by Rolli et al. , where tg et al.  designedg et al.  realizedAnother important feature that can be added to PDMS-based MCMAs is the possibility to easily coat the capillaries with specific proteins or chemical agents. Straight arrays of capillaries in PDMS have been used as comparative assays in order to explore the effect of the coating on the cells migration, using for instance fibronectin  or collaThe shape of these straight PDMS channels can be engineered in order to induce controlled spatial stimuli on the cells during their migration and study their response. Mak et al.  designedUp to now, we presented some simple geometries consisting of a series of straight channels with a bi-dimensional geometry, and we introduced possible variations on this scheme. In this section, we will present advanced geometries that exploit the possibility of exploring three-dimensional complexity or integrating several microfluidic components in the same device. Some of these examples are reported in The first example is a 3D version of the periodic modulation of the straight channel cross-section introduced above. Ma et al.  presenteented in : upon peRaman et al.  fabricatAn additional strategy is to use micropillars to mimic the ECM. In this case, a 2D array of pillar structures with different dimensions and spacing is used to study the migration of cells either atop of it or, in case of migration under constriction, within the array. Doolin and Stroka  presenteigration . A partiBoneschansker et al.  proposedOne last example of high-complexity MCMA is the so-called “fluidic mazes”. A series of microfluidic channels are realized in between the seeding and the collection chamber, including bifurcation, parallel channels with different fluidic resistance and dead-end channels. These complex networks are used to study the “decisions” taken by the cells during the motion and to investigate the mechanism underneath these choices. For instance, it is possible to study the response of the cells to different degrees of fluidic resistance, to different mechanical stimuli  or the fHydrogels are a class of three-dimensional structures of hydrophilic polymers, which are able to imbibe large amounts of water. Typically, hydrogels do not dissolve in water solution thanks to different mechanisms such as crosslinking and chain entanglement. They are characterized by a number of physiochemical properties that make them suitable for a variety of biomedical applications. They can have natural origin, such as collagen, fibrin, gelatin or agarose, or they can be synthetic, such as polyacrylic acid and polyethylene oxide. Hydrogels present a series of properties that make them interesting for the fabrication of microfluidic devices mimicking an in vivo environment  such as:An example of the use of hydrogel (agarose)-based MCMA for the study of chemotaxis, even if without mechanical confinement, is presented by Cheng et al. . The devA different approach is to embed the cells directly in the hydrogel, exactly as they would be in a biological tissue in a real case scenario, such as in the devices reported in The permeability of the hydrogel matrix can be used to study the effect of liquid media flux and pressure on the migrating cells. Huang et al.  embeddedTruong et al.  developeAyuso et al.  used a cHydrogel matrices were used in microfluidic platforms to study biological phenomena other than single cell migration, such as for instance angiogenesis. Trappmann et al.  developeIn general, hydrogels are an interesting platform for the realization of microfluidic devices, thanks to their specific aforementioned chemical and mechanical properties. The use of hydrogel matrices to simulate biological ECM in migration assays is a promising application, as they can faithfully replicate interesting characteristics such as stiffness or perfusion of the tissues. At the same time, being transparent at visible wavelengths and with a low light scattering, they allow for direct optical inspection and cell morphology study. On the other hand, as the internal structure of these hydrogel matrixes is random, it is not possible to directly engineer the mechanical stimulus applied to the migrating cell. This aspect limits the analysis to a statistical observation of population characteristics, rather than probing the specific response of the cell to a given stimulus, as was performed instead in the case of hydrogel-based microchannels.Femtosecond laser micromachining (FLM) of microfluidic devices for cell assays allows fabricating biochips with complex 3D geometries in several materials, as glass or polymer, with micrometer (and even nanometer) accuracy, and with a robustness that is difficult to obtain with PDMS and hydrogels strategies.FLM is implemented by focusing a femtosecond laser beam inside a material that is transparent to the laser wavelength. Due to the high intensities reached at the focal spot, non-linear absorption phenomena take place, leading to a permanent modification of the material properties. In the case of glasses, under specific irradiation conditions, it will lead to a local increase in the etching rate that will allow obtaining embedded microfluidic channels after a chemical etching process. This regime is exploited to fabricate 3D microfluidic devices, inside glasses such as fused silica or Foturan ,90 with In the case of photopolymers, it will induce a local photo-crosslinking of the material and consequent polymerization of sub-micrometer features , which iThere are a few examples in the literature that exploit FLM for the development of microfluidic devices to study cell motility under a constrained environment. The first applications were dedicated to the fabrication of free-standing scaffold-like structures fabricated by TPP in order to study human fibrosarcoma (cell line HT1080) migration . TayaliaIn order to have a more controllable chemical environment for the cell growth, Olsen et al.  fabricatme group . They faA possibility is to take advantage of FLM versatility to fabricate both the microfluidic chip and the migrating assay constrains. Indeed, Sima and co-workers developed a fully FLM-fabricated device to study the migration potential in sub-micrometer constrictions of PC3 cancer cells under a chemical gradient . The micμm see b. These Additional exploitation of the FLM 3D capabilities was demonstrated by Ficorella and co-workers ,74 in thAlthough FLM fabrication is more expensive and time consuming than PDMS and hydrogels soft lithography, the possibility of reusing the devices makes FLM an attractive alternative. In fact, the non-porosity of the materials and the robustness of the fabricated devices allows cleaning them with solvents such as ethanol or detergents such as Mucasol . MoreoveMicrofluidic platforms are emerging as a valuable tool for the study of cell migration under spatial confinement. Although their fabrication requires specific competencies and a careful design and their use can be less intuitive and straightforward than the more traditional methods, such as Boyden chambers or scratch assays, these microfluidic devices offer several advantages, such as a precise control of the biological and chemical environment, an easy interface, and the possibility of being tailored to the requirements of the specific biological experiment. Indeed, MCMA platforms constitute a powerful tool to perform more focused cell migration experiments and improve the quantity and the quality of information that can be extracted from these biological studies if compared to traditional approaches.Thanks to the precise control on the geometry and on the characteristics of the MCMA, it is possible to perform several different experiments, choosing the type of ECM and the mechanical stimulus or the environmental conditions. Microfluidics enables the realization of more complicated assays, opening the possibility to inquire into aspects of cell migration that would not be detectable with standard techniques. Furthermore, we envisage that in the near future, the possibility to integrate them with embedded sensors, or new microscopy techniques, will improve the interpretation of cell behavior.The choice of the fabrication technology employed in the MCMA realization has some consequences on the possible characteristics of the final device. PDMS and hydrogels are inexpensive and easy to handle materials that can be used to straightforwardly realize microfluidic prototypes. The process of soft lithography allows the realization of minimum feature sizes comparable to the one of the single cells (few micrometers); thus, they can be used for the realization of MCMA to study spatial confinement. At the same time, complex geometries can be realized to investigate specific aspects, such as the memory effect of a series of constrictions or the traction force that the cells exert on bendable pillars.Still, this type of technology remains intrinsically planar, and the shape of the single channel or constriction is dependent on the characteristics of the mold; thus, it cannot be easily changed. Additionally, it is hard to push the geometrical limit toward or below the micrometer level. Furthermore, these materials tend to adsorb proteins with time, and this strongly limits their use in the field of pharmacology and drug-related studies .Laser-writing techniques such as FLICE and TPP offer the possibility to realize custom-made geometries with micrometer or even sub-micrometer precision and the capacity of shaping the microchannels in a three-dimensional way. This allows the realization of structures for the analysis of cell migration under mechanical confinement with features hardly reproducible with other techniques. The materials that have been used for the laser fabrication of MCMA platforms are glass and polymers, which are known to be rigid and non-porous, thus avoiding the absorption of proteins of other biological materials. Moreover, they are proved to be biocompatible and mostly inert, thus allowing chemical and biochemical analysis.Although the realization of these devices by laser-writing techniques requires dedicated equipment, which limits the fabrication of MCMA with this approach to specialized laboratories, the devices fabricated by FLM offer the advantage of being reusable several times. This technology expresses its advantages in the prototyping and in the realization of customized devices, with strict requirements from the point of view of the design complexity. Furthermore, it allows the integration of other possible technological elements, such as micromechanical or optical components, in the same platform and fabricated with the same setup, pushing the devices from simple, single-task systems toward multi-analysis lab-on-a-chip platforms .


Mitigating climate change is a global challenge demanding effort from all sectors, and sports are no exception. While transportation is one of the key issues regarding sustainable sports, the methods by which children and adolescents get to practice have not received much attention. The objectives of this study were, therefore, to present how adolescents in Southern Norway travel to soccer practice and assess how the mode of transportation is related to sex, socioeconomic status, age, ethnicity, and distance from home to practice. Cross-sectional data were collected from 558 adolescent soccer players (398 boys and 190 girls) representing 30 different clubs from settlements of varying rurality. While most of the participants lived within cycling distance from the field of practice, the majority opted for passive modes of transportation (55% passive vs. 45% active). A logistic regression analysis found that traveling distance and age were associated with active transportation habits, while sex, ethnicity, and socioeconomic status were not. Further research is needed to examine the main barriers to active travel for this already active population, as active transport represents an opportunity for sports to become more sustainable. Climate change is a global challenge that demands effort from all sectors ,2,3. SpoThe health of the planet is essential if we are to continue to consume and participate in sports ,10,11. WFor sports to become more sustainable, we as a society have to acknowledge that sports as an industry is often in conflict with the environment . CreatinEven though the concept of sustainable sports has been in the spotlight for some time , the metWith organized sports being as popular as they are in Norway, with 93% of all kids participating at some point during their childhood , gettingAlthough most research on active transport focuses on health improvement and increasing daily physical activity ,24, kidsThe objectives of this study were, therefore, (1) to present how adolescents in Southern Norway travel to soccer practice and (2) to assess how the mode of transportation is related to sex, age, ethnicity, distance from home to practice and socioeconomic status.Data were gathered from 558 soccer players between the age of 13 and 19  from 30 soccer clubs in Southern Norway . The minimum sample size of 526 was determined based on the studied population . The goal was to sample at least 20% of the population with a confidence level of 95% and a less than 3% margin of error. Participants were recruited in clusters, with individual teams serving as the clusters. In an effort to recruit a representative study population, teams from various types of municipalities, ranging from urban to rural, were recruited. The data collection was performed using an electronic questionnaire during the fall of 2021. The players answered the questionnaire on their personal mobile devices at the beginning or the end of a practice session after receiving a link or QR code that had been provided to the coach by a member of the research group.The project was approved by the Norwegian Center for Research Data and the ethics committee of the Faculty of Health and Sport Sciences at the University of Agder prior to the data collection. After receiving consent from the general managers of the respective soccer clubs, the coaches of the various teams were contacted. The coaches then relayed the relevant information to the players and their legal guardians so that they could make an informed decision regarding participation in the project. Information given included background on the project, what participation would involve, and that consent could be withdrawn at any point. Players that had reached the age of 16 were allowed to consent on their own, while legal guardians consented on behalf of players under the age of 16.Mode of transport to soccer practice was measured using a multiple-choice question asking, “which mode of transportation do you usually take to practice?”. Response options were by foot, by bike, by e-bike, by e-scooter, on a bus, in a car, and by motorbike. An open-ended question asking, “how far from the practice field do you live?” assessed the distance from the player’s home to the practice field.Socioeconomic status was measured using the Family Affluence Scale (FAS III ), which Other variables of interest were age, sex, and ethnicity, where ethnicity was grouped into native and immigrant backgrounds depending on the birthplace of the player, their parents, and their grandparents.A logistic regression analysis was used to assess the relationship between the independent variables  and active transport. The non-linear analysis produced an odds ratio and 95% confidence intervals for all independent variables. All statistical analyses were performed in SPSS , with significance accepted as long as the 95% confidence interval of the odds ratio did not include 1.As can be seen in 2 was 0.419.A logistic regression analysis found the odds of opting for passive transport to practice to increase with traveling distance and age see . Sex, etDespite most of the participants living within cycling distance from the field of practice, our study found that the majority of adolescent soccer players from Southern Norway opted for passive modes of transport to practice. These results are in line with the findings of previous studies, which revealed a culture of chauffeuring children to organized leisure activities in Norway ,16. The These results run somewhat counter to findings from Spain, where walking to leisure activities appears to be much more common . WhetherThese findings prompt two questions: “how far do we expect the players to travel actively?” and “why does the distance to the field of practice increase so drastically as the players age?” While the answers to these questions are beyond the scope of this paper, some preliminary reflections will be offered. As several previous studies have pointed out, organized leisure activities are often outside of the adolescents’ immediate environment ,12,15; hWhile the reasons why the traveling distance to practice increases can be many, they may be related to changes in the sport-specific needs of the players. Some might change clubs in search of the best available sporting environment, and others may opt for more suitable social environments . Some miContrary to findings from the school context ,24,31, sIn line with previous recommendations for environmentally friendly mobility in sport ,8,12,18,Implementing these recommendations would likely reduce traffic and lead to more active transportation behavior among current and former soccer players. Policymakers and sporting authorities cannot continue to ignore the negative environmental outcomes of sports participation, which offsets, in many ways, the positive impact of physical activity . A conceSome limitations to this study should be noted. The study design does not allow seasonal variation to be taken into account. Some participants may alter their travel behavior depending on weather conditions and the time of year, and the timing of the data collection could therefore affect the results. However, collecting the data in the fall, when weather conditions for active transport are optimal, reduces the likelihood of underestimating active modes of transport substantially. The sampling procedure yielded multiple small clusters of participants that were not adequately large to perform multilevel analyses . NeverthWhile the number of participants with an immigrant background was relatively modest  and not representative of the Norwegian population as a whole (18.9% of inhabitants have an immigrant background ), it is Future research should examine why travel distance increases so drastically with age and whether the increase is mostly due to club changes or whether other mechanisms are at play. Future research should also address whether and how distance and sustainability factor in when young athletes change clubs or whether their choices are purely based on sporting- or social reasons. Whether sustainability and transport behavior factor in during the planning phase and when municipalities and sports clubs distribute practice slots would also be of interest.A minority of adolescent soccer players in Southern Norway reported active modes of transportation to soccer practice. Furthermore, traveling distance and age were found to be associated with active transportation habits, while sex, ethnicity, and socioeconomic status were not. While the reasons this already active population opts for passive modes of transportation to such an extent are unclear, these results should act as a wake-up call for the stakeholders in Norwegian youth sports. As recognized by the United Nations Framework Convention on Climate Change , sports


Antimicrobial resistance (AMR) is a growing threat to global health. With pathogenic bacteria inevitably becoming more resistant to existing antimicrobials, mortality and costs due to AMR will significantly increase over the next few decades if adequate action is not taken. A major challenge in addressing AMR is the lack of financial incentives for manufacturers to invest in developing new antimicrobials. This is partly because current approaches in health technology assessment (HTA) and standard modeling methods fail to capture the full value of antimicrobials.We explore recent reimbursement and payment frameworks, particularly pull incentives, aimed to address the market failures in antimicrobials. We focus on the “subscription-style” payment model recently used in the UK and discuss the learnings for other European countries.A pragmatic literature review was conducted to identify recent initiatives and frameworks between 2012 and 2021, across seven European markets. The National Institute for Health and Care Excellence (NICE) technology appraisals for cefiderocol and for ceftazidime with avibactam were reviewed to evaluate how the new UK model has been applied in practice and identify the key challenges.The UK and Sweden are the first European countries to pilot the feasibility of implementing pull incentives through fully and partially delinked payment models, respectively. The NICE appraisals highlighted the complexity and large areas of uncertainty of modeling antimicrobials. If HTA and value-based pricing are part of the future in tackling the market failure in AMR, European-level efforts may be needed to overcome some of the key challenges. WhilIn 2015, the World Health Organization (WHO) adopted a global action plan for AMR using the One Health approach, which involves a collaborative effort between the human health, animal health, and agricultural sectors. This global action plan provides a framework for countries to address AMR, focusing on five key areas: (i) increasing awareness and understanding of AMR; (ii) increasing knowledge through surveillance and research; (iii) reducing the incidence of infection; (iv) optimizing the use of antimicrobial agents; and (v) ensuring sustainable investment in combating AMR through investing in new medicines, diagnostics, vaccines, and other interventions  and 2021Currently, member states are addressing AMR primarily by monitoring, limiting, and safeguarding the use of antimicrobials until strictly necessary, through surveillance and stewardship programs. Moreover, “push” incentives  have been suggested and implemented to promote the development of new products—for example, by making research and development (R&D) funds available. Some initiatives include the Innovative Medicines Initiative's “New Drugs for Bad Bugs” , the AMRWhile these initiatives partially address the high R&D costs, they do not fully tackle the market failures post regulatory approval. A key challenge lies in the fact that the expected return on investment through current reimbursement methods is low. When a new antimicrobial becomes available, its use should be delayed for as long as possible to limit the development of AMR. Once resistance to existing drugs arises and the new antimicrobial is used, it will likely be joined by low-cost generics with the same mechanism of action, due to its patent expiring. Furthermore, there is uncertainty around how resistance—and thus the eligible population—will change over time, making it difficult for manufacturers to predict the long-term returns on a product , 15. As Recent studies have emphasized the need for “pull” incentives  alongside push incentives to bridge the gap between high R&D costs and expected low returns on investment , 17–19—fHealth technology assessment (HTA) can play an important role in evaluating the value of new antimicrobial products and informing reimbursement and pricing decisions. However, this requires a shift in the commonly used concept of “value” in HTA in terms of cost per quality-adjusted life year (QALY) for the individual, to consider a broader definition of value and costs of novel antimicrobials , 20. TheIn this review, we aimed to explore new initiatives and frameworks that have been used to tackle the market failures in AMR in Europe, with a focus on pull incentives and innovative payment models. We also reviewed the recent NICE appraisals of ceftazidime with avibactam and cefiderocol to (i) understand how a subscription-style payment model has been used in practice; (ii) identify the challenges posed by these analyses and how they had been addressed; and (iii) consider the learnings for other countries.2.A pragmatic literature review was conducted using PubMed® to identify innovative reimbursement and payment models, focusing on pull incentives that have either been implemented or are in the process of being implemented in Europe   reported3.1.1.PHAS started a pilot scheme in 2018 to explore whether introducing a new, partially delinked, supply-based procurement model would be feasible to ensure access to existing and new antimicrobials. Manufacturers who participate in this agreement are rewarded with a minimum annual revenue on top of volume-based sales. In return, they are expected to guarantee supply of the product within pre-determined time frames. To meet this requirement, manufacturers must ensure that a certain volume of stock is available in Sweden. The availability-based annual revenue is set at SEK 4 million minus the annual sales. If the annual sales exceed SEK 4 million, manufacturers are still entitled to 10% of the minimum (SEK 4 million) annual revenue.Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae); and that can be used in at least two high-priority indications. Agreements lasted from 15 July 2020 to 15 July 2022, with a potential 2-year extension. The pilot will formally run until the end of 2022, after which it will be evaluated based on the availability of the selected products, the economic consequences of the pilot, and PHAS'experiences with the procurement process (Five products are included in the pilot: Merck Sharp & Dohme's ceftolozane/tazobactam (Zerbaxa®) and imipenem/cilastatin/relebactam (Recarbrio®); Shionogi's cefiderocol (Fetcroja®); Menarini's meropenem/vaborbactam (Vaborem®); and InfectoPharm's fosfomycin. The products were selected for the pilot based on their risk of insufficient availability in Sweden and their special medical value. This includes products that have a good safety profile; that demonstrate good activity against critical pathogens included in the WHO's priority list from 2017 , such as process , 26.3.1.2.NICE, in collaboration with NHS England and NHS Improvement, is testing a new HTA process and innovative payment model for antimicrobial products. Unlike the Swedish model, the UK model is demand based and fully delinks payment from sales volume. It does this by paying manufacturers a yearly fee to have on-demand access to their product, known as a subscription-based payment. The value of this fee is based on the product's value to the NHS, as assessed through an adapted HTA process.•Spectrum value: the value of replacing broad-spectrum antimicrobials with narrow-spectrum antimicrobials•Transmission value: the ability to avoid onward spread of the pathogen in the population•Enablement value: the value of enabling other treatments and procedures to take place, such as chemotherapy, organ transplant, and surgical procedures•Diversity value: the value in having a range of treatment options available•Insurance value: the value in having effective antimicrobials available in the event of a sudden increase of infections with pathogens resistant to existing antimicrobialsAs well as including a broader definition of value, the adapted HTA process for antimicrobials differs from NICE's standard process with respect to its purpose and key outcomes of interest. The standard process considers whether a product should be reimbursed or not based on whether it offers value for money, whereas the proposed new evaluation process for antimicrobials provides guidance on the value of the product and informs commercial discussions . Rather than the incremental cost per QALY  per patient, the new process seeks to express the overall value of antimicrobials in QALYs for the population as a whole, or a range of QALYs, depending on the uncertainty  framework for the evaluation of new antimicrobials , 28. Theertainty , 23.NICE piloted this new evaluation and payment model between January and February 2022 during the assessment of ceftazidime with avibactam and cefiderocol. Both assessments aimed to estimate the incremental population-level net health benefits of the products against the current standard of care, as measured in QALYs gained for the expected eligible population in England. The overarching objective of these appraisals was to inform the value-based payment of both products. The economic analysis was led by an academic group; in this case, it was led by the EEPRU. The key challenges and learnings from this pilot are summarized below.3.2.3.2.1.In both HTAs, the marketing authorization of the products was broader than the population included in the EEPRU's analysis, which focused on high-value clinical scenarios (HVCSs). These scenarios referred to treating only those patients who would benefit most from the drug, in terms of mortality and health-related quality of life (HRQL). While it was acknowledged that the products might be used in a wider population than those defined in the HVCSs, restrictions and pragmatic decisions were required due to time, resource and evidential constraints , 30.3.2.1.1•The microbiology-directed setting, where the pathogen has been formally identified and its susceptibility tested and confirmed before treatment. This is applicable to non-critical infections only•The empiric setting, in which treatment is urgently needed and initiated based on clinician suspicion of the pathogen and its mechanism of resistanceTo inform the patient-level QALY gains, both HTAs considered infections with hospital-acquired and ventilator-associated pneumonia in the empiric setting  resulted in a simplified approach to modeling the comparators.Another issue in defining the decision problem was defining the appropriate comparators. This is particularly important, as the development of resistance over time is largely dependent on the treatments used. In both appraisals, a range of different comparators were considered potentially relevant, depending on the infection site, pathogen, mechanism of resistance and whether the treatment is used in the microbiology-directed or empiric setting . The finin vitro susceptibility predicts in vivo clinical outcomes), the different comparators were not modeled individually. Instead, they compared outcomes  of patients under existing care to those of patients with the new products available. In the model, one of the key benefits of cefiderocol and ceftazidime with avibactam becoming available was a reduced risk of developing acute kidney injury and chronic kidney disease, plus the long-term outcomes associated with these. Combination therapies were not included due to a lack of available evidence.In the microbiology-directed setting, patients were expected to be treated with the intervention either (1) if susceptibility testing showed the pathogen exhibits resistance to multiple existing therapies (multi-drug resistance); or (2) if the pathogen is susceptible only to treatments that are associated with an increased risk of nephrotoxicity, specifically colistin or aminoglycoside-based therapies. Because the EEPRU assumed that susceptibility is the only predictor of effectiveness  pathogen mechanism causing the infection, patients' treatment pathways can differ—and, ultimately, patients may either be correctly or incorrectly treated based on the clinician's suspicion of the pathogen. This means that some patients will stay on their treatment initiated in the empiric setting once susceptibility test results become available, while others will switch treatments. Again, the EEPRU assumed that all treatments in the empiric setting had the same effectiveness, while safety profiles might differ. Therefore, in the model, comparators were grouped as either colistin-/aminoglycoside-based or not colistin-/aminoglycoside-based.Key learnings: Modeling wide-spectrum antibiotics is complex, in part due to the many potential indications and comparators to consider. Within the context of HTA decision-making, groups responsible for reviewing the clinical and economic evidence have limited time and budget available. In addition, evidence on the populations relevant to these appraisals was limited. This forces any evaluation to consider a narrower scope than may be relevant to the products, inherently leading to pragmatic decision-making and, therefore, uncertainty in the true value of evaluated products.A more holistic view on the potential uses of antimicrobials, with less emphasis on capturing the intricacies of specific use cases, may help to reduce uncertainty on the population level, while accepting a greater degree of uncertainty at the micro level. Whether this trade-off would reduce the overall uncertainty in the decision problem is subject to further research.3.2.2.Traditional HTAs typically quantify patient outcomes using QALYs, which represent a standardized approach to measuring both length of life and quality of life. Quality of life is usually derived from utility values: numerical values representing the preference of a particular individual or society for a certain health state, with 0 and 1 typically equivalent to death and perfect health, respectively . As the Within the draft guidance of both ceftazidime with avibactam and cefiderocol, this approach to estimating patient utilities was neither discussed nor critiqued. However, it does have several limitations, a clear one being the lack of direct utility data. The approach also requires a number of inherent assumptions that may not necessarily be reflected in practice. In particular, it assumes that the cohort of patients receiving treatment will remain similar, in terms of the incidence and prevalence of comorbidities over time. This assumption may not reflect reality—for example, resistance patterns could result in a change in the treated cohort.Key learnings: Within the antimicrobial space, using QALYs as a primary outcome measure in economic modeling is challenging for a number of reasons. First, obtaining quality-of-life data (such as patient-reported EQ-5D responses) is difficult. Trial designs for antimicrobials do not lend themselves for the collection of these data, as patients are typically acutely unwell and experiencing other conditions at the time of infection; therefore, direct quality-of-life data are often scarce or absent entirely. Second, rather than looking at the QALYs of individual patients , subscription-based reimbursement models of AMR scenarios require the consideration of QALYs at the population level. This requires an accurate reflection of the number and distribution of patients who are eligible for treatment . Finally, the population of individuals likely to require antimicrobial treatment is a heterogeneous one—not only in terms of patient characteristics such as age and extent of co-morbidities, but also in terms of expression of disease and benefits of treatment.Incorporating health outcomes is a key pillar of HTA processes and an essential requirement for any reimbursement methodology seeking to determine the value of a product relative to the rest of the healthcare system. Given the lack of available data and wider population-level considerations, determining health outcomes in antimicrobials is uniquely challenging. While many of these challenges remain intractable, further study may lead to more reliable estimates. For example, it is unlikely that reliable quality-of-life data will ever be available from antimicrobial clinical trials. However, these data could be obtained from patients retrospectively following discharge, or vignette studies involving (recovered) patients and treating clinicians could be undertaken.3.2.3.One of the key challenges in assessing antimicrobials is understanding the size of the treatment-eligible population. This depends on both i) the growing number of people with infections that are eligible for treatment with the new product; and ii) the emergence of resistance to the new intervention and comparators over time, which itself is a product of how both existing and new products are used in practice. In other words, a level of forecasting about the expected size of the population is required, and this is accompanied by substantial levels of uncertainty.3.2.3.1.The current size of the eligible population in both HTAs was based on microbiology test results from the UK Health Security Agency Second-Generation Surveillance System (UKHSA SGSS), which covers 98% of English hospital laboratories and provides information on the mechanism of resistance and susceptibility to antimicrobials. Key limitations to using these data include: the lack of information about the site of infection; the fact that the database does not cover all hospitals; the fact that information regarding whether a product has been used in clinical practice is omitted; and the fact that the data are retrospective, and therefore may not reflect the current reality.3.2.3.2.The expected growth of the treatment-eligible population was predicted in both appraisals based on historical data from Public Health England's Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) national reference laboratory. The growth data were subsequently extrapolated over the modeled 20-year time horizon using two different approaches: one that assumed persistent growth over time, and one that assumed initial growth followed by stabilization. In both HTAs, the Committee concluded that persistent growth is more plausible than stabilization.3.2.3.3.As usage of an antimicrobial product increases, so does the development of resistance to the product. Resistance to ceftazidime with avibactam and cefiderocol, and how this resistance might progress over time, was initially based on historic data from the European Antimicrobial Resistance Surveillance Network linking usage with resistance for other antimicrobials. However, as the EEPRU deemed the outcome of this prediction unrealistic , alternative assumptions were explored in the base case analysis, ranging from 1% to 30%. Assuming good stewardship, and in discussions with the EEPRU alongside the company and clinical experts, the Committee concluded that a 5% increase in resistance to both products over 20 years was a reasonable assumption.Resistance to existing antimicrobials affects the usage of new products and thus also plays a role in the emergence of resistance to the new product. It is therefore important to consider the expected growth in resistance to all comparators over time. Despite the likely increase of resistance to comparators , the EEPRU assumed that resistance to comparators would remain constant over time, as historic evidence for England did not provide sufficient evidence of any growth in resistance. The Committee noted that “it was important to account for the benefits of being prepared for a catastrophic emergence of widespread multi-drug-resistant infections” , 23. To The Committee considered that resistance to comparators was likely to increase, but that the EEPRU's scenario analysis was highly uncertain. Important limitations include the lack of population-level incremental net health benefits covering all infection sites, and the fact that the pathogens included in the base case analysis were not modeled in the scenario analysis. The Committee concluded that the model underestimated the benefits of both therapies by not accounting for increased resistance to comparators.Key learnings: Given the random and spontaneous nature of pathogen mutation, there is a substantial level of uncertainty around how resistance to antimicrobial agents evolves over time. While it is possible to estimate an “average” course of resistance emergence (the approach taken by the EEPRU), it is impossible to predict all potential patterns of resistance emergence, which may result in very different outcomes. It is important to recognize that the impact of this uncertainty is not linear and that potential errors in these estimates can have an extensive impact on the costs and benefits to society. In the most extreme scenarios, if a new antimicrobial is not used to treat anyone, governments using subscription-style payment models might pay millions per year for a treatment that remains on the shelf. On the other end of the spectrum, if there is an outbreak in resistance to existing treatments and the new antimicrobial becomes the only available effective treatment, it could, theoretically, save humanity. While these are extreme scenarios, they do emphasize the importance of understanding and quantifying the level of uncertainty and range of potential scenarios. This raises the question whether future HTAs for antimicrobials should consider a wider range of different scenarios, rather than searching for the average treatment-eligible population.3.2.4.Another key challenge in assessing antimicrobials is the difficulty in obtaining clinical trial data that can be used for economic evaluation. The randomized controlled trials (RCTs) that were available were associated with the following issues: (1) they were typically not in the same population as the one of interest ; (2) clinical outcomes were not in the form required for modeling ; (3) evidence was typically only available for the empiric setting; and (4) there was uncertainty about the representativeness of the “usual care” arm.in vitro data. It did this by using laboratory tests of patient samples of the pathogen to assess its susceptibility to the antimicrobial treatment being reviewed. The results of two published studies were used to link mortality and length of hospital stay with pathogen susceptibility to treatment, which allowed clinical outcomes to be modeled empirically. To model outcomes in the microbiology-directed treatment setting, between five and seven experts were consulted to predict the relationship between susceptibility data and clinical outcomes . However, this method was criticized by the Committee as it did not consider other factors affecting treatment efficacy and outcomes, such as the resistance mechanism causing the infection and the site of tissue penetration. Nonetheless, clinical experts accepted these data in the absence of better estimates, and the Committee concluded that susceptibility was a reasonable proxy for clinical outcomes even though it introduced uncertainty into the model.In both appraisals, rather than using direct evidence from patient outcomes, the EEPRU assessed relative clinical effectiveness using Key learnings: Identification of reliable clinical effectiveness data remains a fundamental challenge. To sufficiently report outcomes by site, susceptibility, and antimicrobial used, a very large RCT would be required. Despite this, there are potential avenues to generating more appropriate evidence. For example, products with demonstrated in vitro effectiveness could be piloted in test case hospitals, and outcomes could be compared with those from analogous hospitals without access to these products to generate evidence for wider reimbursement. While less reliable than clinical trial data, this form of prospective real-world evidence could provide an improved data source, albeit one that would require substantial planning and investment.3.2.5.One of the aims of the HTAs was to consider the broader, more dynamic population benefits of antimicrobials, using the STEDI values. The ways in which each value was included (or not) in the appraisals are described below.Spectrum value was not included in either appraisal. Clinical advisors and other stakeholders did not consider spectrum value to be significant for either cefiderocol or ceftazidime with avibactam, as both were considered to have a broad spectrum of activity. Modeling of transmission value was also absent in the appraisals. Clinical advisors indicated that the direction of effect of the therapies on transmission was uncertain, but that the overall magnitude of effect was expected to be small. This is because introducing a new effective drug for the treatment of multi-drug-resistant infections has several opposing effects. The NICE appraisal documents explain that if a drug reduces time in hospital, then this is expected to reduce transmission. However, more effective treatments could also increase time spent in hospital, and therefore transmission, by reducing mortality. The true effect is ultimately unknown.Enablement value was captured in some aspects of the evaluations. Improved treatment of pre- and post-operative infections was included in the EEPRU's HVCSs and expected usage projections, despite some uncertainty around whether the analyses captured the full benefits of treating pre-operative infections. For example, the evaluation captured the value of enabling care to other patients . However, other aspects of enablement value were not captured. Both products under review are associated with reduced renal toxicity when compared with existing antimicrobials, yet the analyses did not consider the extent to which cefiderocol and ceftazidime with avibactam would free up resources by reducing the need for dialysis. Similarly, the value created by reducing lost time and resources caused by procedures being cancelled because of infection was not captured. There was also no consideration of how the availability of effective treatments for resistant infections could allow hospital wards to stay open in the face of outbreaks, as this was deemed to be an unlikely scenario. The Committee acknowledged the challenges in modeling enablement value, but felt that some important aspects were neglected; it therefore concluded that the EEPRU's model had not fully captured this value.Diverse prescribing strategies—such as randomly allocating patients with similar clinical indications to different treatments—were not included in the EEPRU's quantitative assessments of population-level incremental net health effects. This is because clinical advisors indicated that in the HVCSs, diverse prescribing strategies were unlikely to be appropriate due to the lack of safe and effective alternative treatments. For diversity value, clinical experts suggested that the EEPRU's model underestimated the benefit of providing an alternative treatment option when there are supply issues with other antimicrobials. The experts explained that this would be particularly important when treating severe infections in intensive care units, because patients are also likely to have organ failure and few treatment options available.Neither appraisal fully accounted for the insurance value of the therapies. The EEPRU did not model a scenario where the use of cefiderocol or ceftazidime with avibactam is completely held back to preserve its effectiveness. In this case, the EEPRU believed that the scenarios modeled in the HVCSs reflected this form of insurance value, as they involve heavily restricting usage to preserve long-term effectiveness. While the EEPRU did consider a scenario in which the products under review are the only effective treatments against a newly emerging drug-resistant pathogen, the Committee noted that the analyses were based on adopting a risk-neutral perspective. However, when estimating the insurance value of an antimicrobial, taking a risk-averse perspective  is likely to be more appropriate.Taken together, the NICE Committee identified that the model had not fully captured the STEDI values and, therefore, the potential benefits of ceftazidime with avibactam and cefiderocol.Key learnings: Accurate incorporation of the STEDI values is a highly complex task, requiring a great deal of modeling effort and expertise as well as data that are unlikely to exist in full. Efforts could be made to quantify certain elements outside of individual assessments; for example, aspects of enablement and insurance value are likely to be applicable and similar across other antimicrobials. Research could be undertaken at a higher level, and in advance of future assessments, to allow for more realistic and consistent incorporation of these values. Nonetheless, incorporation of the STEDI values remains a daunting task, and it is questionable whether the effort required to model and quantify them accurately is worth it when a more pragmatic (and less resource-heavy) approach, such as the one used in Sweden, could suffice.3.2.6.Using the Committee's preferred assumptions, the outcomes of the economic analysis from the EEPRU resulted in an incremental net health benefit of 5,400 QALYs for cefiderocol and 3,700 QALYs for ceftazidime with avibactam, over a 20-year time horizon in England. However, as the models likely underestimated the size of the eligible population for treatment, omitted consideration of the development of resistance to comparators, and insufficiently captured all aspects of value, the Committee applied several multipliers. In the case of cefiderocol, the incremental QALYs were doubled to reflect the expected larger population size, and another 50% increase was applied to cover the wider value of the product, resulting in a total of 16,200 QALYs . Similarly, for ceftazidime with avibactam, the QALY gains were doubled and increased by a further 20%, to account for the larger population size and value, respectively, resulting in a total of 8,800 QALYs .Key learnings: The NICE appraisals of ceftazidime with avibactam and cefiderocol demonstrated the challenges in capturing the full value of antimicrobials. Despite a collaboration between two leading academic institutions' best efforts to model the STEDI values, the outcomes of the economic model were deemed insufficient to inform decision-making because they were expected to substantially underestimate the incremental benefits of both products. Experts were consulted throughout the appraisals to address areas of uncertainty, although this was carried out in an unstructured way, and the final estimated total benefits relied heavily on Committee deliberation and assumptions. The Committee ultimately resorted to applying arbitrary multipliers, and pragmatic decision-making, rather than considering the outcomes of the modeling exercise. This raises the question of whether it is worthwhile to attempt to formally model the incremental health benefits of antimicrobials within the current framework.4.The new approach to HTA and the innovative payment model applied by NICE and NHS England show the ambition to address the issues associated with HTA processes when evaluating antimicrobials, which typically result in a low expected return on investment for manufacturers. By capturing the overall value to society of the antimicrobials, and by basing the fees paid to the manufacturer for the subscription to use the product on this overall value, manufacturers are guaranteed reimbursement for their product at an appropriate level—even if it is completely held back from use to preserve its effectiveness.in vitro data to estimate effectiveness, the economic model necessarily relies heavily on assumptions and is thus susceptible to a high level of uncertainty and bias.The recent NICE pilot demonstrated that economic modeling in AMR is extremely challenging. Despite the efforts of two highly regarded academic institutions, the modeling approach did not sufficiently capture the full product value that would be required for informed decision-making. There are numerous reasons for this, including the sheer technical effort and time required for such a complex modeling task, as well as fundamental limitations in the data available. A recurring theme throughout the appraisals of ceftazidime with avibactam and cefiderocol was uncertainty. Given (1) the lack of reliable data on the current use of the antimicrobials being reviewed and the eligible populations for these; (2) the complexity of prediction needed to estimate future eligible populations and expected resistance over time; and (3) the reliance on While economic models are always a simplification of reality and include a degree of uncertainty, the complexity and challenges associated with modeling antimicrobials result in uncertainty vastly greater than that typically seen in health economic modeling exercises. The potential consequences of this uncertainty are much greater in antimicrobial products and could have a considerable impact on the wider society. During the NICE Committee meeting of both HTAs, it became apparent that, due to the limitations of the economic model, the cost-effectiveness outcomes played a smaller part in the decision-making process than they normally would in other appraisals. A large part of the Committee's decision was based on consultation with clinical experts and deliberation, rather than evidence from health economic analyses. In addition, Committee members with expertise in infectious diseases were involved in informing several estimates of scenario analyses in the economic model, as well as the decision-making process, which can be seen as a limitation.Future HTAs in antimicrobials should consider the role of structured expert elicitation, as is now suggested by NICE for all their technology appraisals , to obtaThe draft guidance published by NICE for the two respective antibiotic regimens suggest QALY gains of 970 and 530 QALYs per year for cefiderocol and ceftazidime with avibactam, respectively. In both cases, this includes the application of a seemingly arbitrary multiplier, substantially increasing the estimates from the economic model. If NHS England were to pay £20,000 per QALY gained—the lower bound of the range of willingness-to-pay thresholds considered by NICE—this would result in annual payments of £19.4 million for cefiderocol and £10.6 million for ceftazidime with avibactam. Interestingly, this comes close to the annual subscription fee determined by Rex and Outterson in 2020 . Based oThe key benefit of NICE's subscription-style payment model is that it allows for reimbursement on the basis of a product's value to the healthcare system rather than volume of sales. However, NICE's pilot highlighted the challenges in determining this value and thus the appropriate level of reimbursement to provide. As the final decision relied largely on Committee deliberation and clinical input rather than quantitative outcomes from the economic model, it should be considered whether a simpler and more pragmatic approach, such as the supply-based model in Sweden, is a more viable solution. The approach taken in Sweden appears to be simpler than NICE's approach. It does not apply conventional HTA methods, and neither comparative effectiveness nor cost-effectiveness are considered. Instead, a sum of money is provided for antimicrobial products that offer a high medical value for which the manufacturer can guarantee sufficient stock and supply of the product within pre-determined time frames. The Swedish pilot is still ongoing; once it is completed, it would be of interest to reflect on the outcomes and the type of challenges that were faced with this approach, and whether ultimately the more complex approach attempted by NICE was advantageous.de novo modeling to be undertaken for every antimicrobial product in every market. A more centralized approach to economic modeling could be more appropriate. For example, an international network such as EUnetHTA could create a single approved modeling framework that can be adapted for products  , giving access across numerous jurisdictions iatives) . This ce


Background: Human papillomavirus (HPV) is a sexually transmitted infection, and HPV types 16 and 18 are responsible for approximately 66% of all U.S. cervical cancer cases in women. The quadrivalent HPV vaccine was licensed in mid-2006, and it was designed to target and protect against HPV types 6, 11, 16, and 18. The aim of this study is to examine the utilization rate of the HPV vaccine, and the trends and incidence rate of malignant cervical cancer across the United States. Methods: This study utilized data from Surveillance, Epidemiology, and End Results (SEER) and the National Immunization Survey’s (NIS) teenage datasets across select years. For the SEER survey, the modification for confidence intervals by Tiwari et al., 2006, was utilized to obtain the incidence rate per 100,000, so that it could be age-adjusted for the 2000 U.S. standard population, as noted in the data provided by the U.S. Census. The dates examined started in the year 2000 and ended in 2017. For the NIS-Teen survey, the public-use data file was used, and a point estimate (%), with a 95% confidence interval, was performed to examine the trends in HPV vaccine utilization across the U.S. adolescent female population from the years 2007 to 2019. Results: This study found that the rate of diagnosis had been falling over the nearly two decades examined in this study. Implications: This study would support current efforts to encourage the utilization of HPV vaccines that are currently in the vaccination schedule rotation, and to illustrate the importance of completing all doses of the three-step series. The second most common tumor found in women worldwide is cervical cancer, and the sexually transmitted infection, human papillomavirus (HPV) is the cause of more than 80% of all cervical cancers. It is estimated that currently 79 million Americans are infected with a type of HPV . HPV is It has been revealed that in the U.S., cervical cancer disproportionally affects some racial/ethnic groups at higher rates than White women. Hispanic women were found to have a 9.2 rate of new cases per 100,000, compared with a rate of 7.2 in White women. Black women were also detected as having higher rates of new cases, with a score of 8.7, and Native American/Alaskan Native women had the next highest score with a rate of 7.9. The most frequent age of cervical cancer diagnosis is 35–44, but the median age of diagnosis is 50 based on national cancer registry data [HPV is the most common sexually transmitted infection, and it is estimated that in the United States, those who have had just one sexual partner have at least an 84% lifetime probability of becoming infected .The detection of HPV in the tissue of cervical cancer biopsies was discovered by German virologist, Harald zur Hausen, and his team in late 1979. With continued examination, they were able to isolate HPV-16 in 1983, and HPV-18 in 1984, from within the DNA of cervical cancer cells .Since this discovery, other variations of the vaccine have been licensed, targeting even more HPV types, though types 16 and 18 continue to be considered the most threatening. The utilization of these vaccines has been promoted and introduced into the recommended vaccine routine for females, beginning at age 11–12, with catch-up dose vaccinations approved to age 26 to enable the completion of the three-dose series.Since 2006, over 100 countries have licensed HPV vaccines, and the United States was one of the first countries to introduce the vaccines into its population . The objThe utilization of the human papillomavirus vaccine, since it first gained its license, has steadily increased, according to studies performed by other researchers. Despite this, we still have not yet been able to meet the HPV Cancer Free vaccination rate goals set by the American Cancer Society. Indeed, the target currently aims for an 80% vaccination initiation rate across the 13-year-old female population in the United States by the year 2026   data pertaining to teenagers from 2008 to 2010, and in their sample pool of the population they found that Black adolescents were 22% less likely to initiate the HPV vaccination series compared with White adolescents (2013). The authors have further argued that populations that are more privileged in terms of wealth, knowledge, education, money, and status, are able to benefit from health promoting resources compared with people who do not have these advantages. Dr. Madina Agénor and their colleagues examined the 2015 National Health Interview Survey (NHIS) in search of racial/ethnic disparities in the initiation and completion of the HPV vaccination series across the female population. In their results, they found that initiating vaccination did not have statistically significant differentiations across race/ethnicity, but they did find a differentiation across race/ethnicity when focusing upon the completion of the vaccination series   examine the trends and incidence rate of malignant cervical cancer across the United States population and (2) to examine the utilization rates of the human papillomavirus vaccine in the adolescent female population of the United States.The data collected and included in the Surveillance, Epidemiology, and End Results (SEER) dataset are collected through state registries, and the consent practices are different according to each state’s individual regulations. All data included in the SEER dataset are non-identifiable, thus protecting participant identities. The National Immunization Survey (NIS) keeps all respondents’ personal information concealed, as per federal law through the Public Health Service Act. All CDC staff and contractor staff signed NIS-Teen confidentiality agreements prior to handling data. All participants of the NIS must give informed consent prior to their phone questionnaire, and any health records shared are only acquired if the participant orally consents. Next, each provider was mailed an immunization history questionnaire (IHQ). The University of Nevada, Las Vegas Internal Review Board, stated that since the data used in this study was shared for public-use, and was performed without the 18 HIPAA identifiers, it does not qualify as having used a “human subject”, and therefore, it did not need to be submitted for approval.This study consists of two parts. Part one is an incidence rate analysis of malignant cervical cancer cases in the United States during the years 2000 to 2017. The second part is a trend analysis of HPV vaccine utilization estimates from the year 2007 to 2019 in the adolescent female population of the United States. This study utilized dates from the Surveillance, Epidemiology, and End Results (SEER) and the National Immunization Survey’s (NIS) public-use datasets that concern teenagers.The SEER data was analyzed using the required SEERStat system, which is controlled through the National Cancer Institute, a part of the National Institute of Health. Within the SEERStat system, the SEER Research Data 18 Registries dataset was used, and incidence trend analysis was carried out within the system. For the SEER survey, the modification of confidence intervals by Tiwari et al., 2006, was utilized to obtain the incidence rate per 100,000, which was age-adjusted for the 2000 U.S. standard population, as described in the data provided by the U.S. Census. The dates examined start in the year 2000 and end in 2017.For the NIS-Teen survey, the data was analyzed using SAS, and the results describe the HPV vaccination female coverage estimates measured by the sample. The estimates are presented as a point estimate (%), with a 95% confidence interval to examine the trends in HPV vaccine utilization across the adolescent female population during the years 2007 to 2019. The data is adjusted for those whose parents did not participate, those living in households without telephones, and those whose vaccination records were not shared by their provider.Inclusion criteria of this study were limited to those who were assigned female at birth in both datasets; this is because both datasets have their own extensive exclusion criteria which did not illustrate the need for further additions to be made. Excluded from this study will be those who did not meet the inclusion criteria set out by the datasets being analyzed. SEER exclusion includes those who are/have: male genitalia, non-malignant tumors, any tumor site outside of the “Cervix Uteri” classification, and those under the age of 19 at time of diagnosis. NIS-Teen exclusion includes those who are/have: outside the ages of 13–17, incomplete screening of the household, and those with incomplete household surveys.SEER: Data provided is routinely collected on an annual basis, and the data includes patient demographics, the primary tumor site, tumor morphology and stage at diagnosis, the first course of treatment, and follow-ups for vital status. All mortality information published by SEER is provided by the National Center for Health Statistics. The staff of the National Cancer Institute, the organization that runs the SEER data collection, work closely with the North American Association of Central Cancer Registries (NAACCR) to guide state registries with their archiving systems to improve compatibility for the pooling of data. The data represents approximately 34.6% of the U.S. population, all collected from population-based cancer registries. The race/ethnicity of the participants are 31.4% White, 30% of African American, 44% Hispanic, 49.3% Native American, 57.5% Asian, and 68.5% Hawaiian/Pacific Islander.NIS-Teen: Surveys are conducted of those who are deemed eligible based on the age of the adolescent members in a household. One member of the household must be at least 19–35 months of age for the NIS-Child survey, and the NIS-Teen survey is an extension of the NIS-Child survey. All eligible household adolescents must be rostered, then, one eligible member will be selected randomly, and the questionnaire will only be administered to that one selected eligible member per household. It collects data from 56 geographic areas across the country, states, select cities, and territories. It is a national survey that targets adolescents aged 13 to 17, and to achieve a coefficient of variation (CV), they need to have adequate provider data, which equates to 230 eligible adolescents per estimation area. The questionnaire is designed around the vaccination schedule dictated in the ‘Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger’, which is updated annually as new vaccines are added by the Advisory Committee on Immunization Practices. After being vetted to ensure the eligibility criteria were met, in 2017, the landline sample resulted in 6678 household interviews, and the cell phone sample resulted in 37,007 eligible household interviews. The surveys collected data on vaccination history, the teenager’s health and household health, demographic and socioeconomic information, and the Health Insurance Module (HIM). The sample of data released in the public-use file contains over 20,000 participants from the nationwide survey.Due to the fact that we do not have longitudinal data, a correlation analysis could not be performed with the data that are currently available. Given that the median age of cervical cancer diagnosis is 50, it is not yet possible to determine if those vaccinated in the first year that the vaccine was licensed are connected to any reduction in the malignant cervical cancer diagnoses that are currently being seen across the population. In addition, both datasets have extensive inclusion and exclusion criteria which might have caused limitations in some of the data presented.In order to obtain a better understanding of the racial/ethnic coverage gaps that are present, with regard to the initiation and completion of the HPV vaccination series, in some cases, further research is needed. A qualitative study designed to examine cultural views and beliefs might shed light on some of the factors contributing to the unequal distribution of coverage. This proposed study should examine the various ethnic/racial groups found in the United States across different regions of the country to examine the varying beliefs that might present barriers to the initiation and completion of the vaccination series.The incidence rate trend analysis performed on the SEER data for malignant cervical cancer found that the rate of diagnosis has been falling over the nearly two decades examined in this study. In 2000, the incidence rate for malignant cervical cancer diagnoses was 9.6, and by 2007, the rate reduced to 8.2. Since around 2015, the incidence rate for malignant cervical cancer diagnoses leveled out to 7.5, and this rate has remained consistent for the most recently released data, which pertains to the year 2017. There are years of fluctuation, with slight increases and decreases across the seventeen years evaluated, but overall, the rate of incidence is steadily decreasing across the U.S. population, which is illustrated below in The National Immunization Survey’s (NIS) teenage results indicate that since 2007, female vaccination coverage has gradually increased, as illustrated below in The incidence rate of malignant cervical cancer has fallen significantly; however, it is still a present danger to the health of females not only in the United States, but globally. The fact that we have an available method that can prevent significant levels of disease and deaths associated with dangerous strains of the human papillomavirus but are failing to protect our population more effectively through its utilization, is concerning. We know that the HPV vaccine can effectively protect against the most common causal factors associated with cervical cancer, but we still have not even been able to meet the desired initiation rates. Greater levels of focus and energy dedicated to increasing our initiation and completion rates of the HPV vaccination series need to be further established. Those engaged in planning this need to be conscious of the unequal distribution of knowledge that has already been detected across race/ethnicity and socioeconomic status, in the hope of reducing the present gaps that have been detected in the population.In Raising the awareness of the dangers associated with HPV needs to be a focus of public health officials at federal, state, and local levels. The language used when communicating these known and scientifically proven dangers needs to be carefully chosen and should be written at a sixth grade reading level to improve the odds of overall comprehension. The messaging needs to be culturally conscious and inclusive to better register with the overall U.S. population which is very diverse. Specialized marketing  paraphernalia should be designed to target specific audiences found in the subgroups of our country, based on age, language, and religious and cultural views. Each of these subgroups is more likely to engage with messaging if the message is delivered in a way that is understandable and relatable. Communication is a tremendously important factor in the decision to initiate and complete a vaccination series, and with that in mind, we need to produce content that, at the very least, encourages the audience to begin a conversation with their healthcare provider.There are specific initiatives that are needed to expand HPV vaccine coverage, reduce the risk of cervical cancer, and reduce cervical cancer rates. According to the recommendation by the World Health Organization, the HPV vaccine should be a part of the national immunization program  . The level of HPV vaccination recommendations that are provided by physicians, and other clinical staff, to eligible candidates should be tracked and benchmarked. Along with organization-wide vaccination initiation and completion goals, expectations should be clearly set and internally displayed. With clearly set goals, members of the organization are more likely to feel that efforts are being invested in universally, and therefore, this will hopefully enhance motivation.Due to the COVID-19 pandemic, that broadly took hold in early 2020, it is highly likely that we will see disruption in the initiation and completion of HPV vaccinations that were planned or continued into the year 2020. In an attempt to contain the spread of the virus, states across the United States entered mandatory lockdowns and business closures to varying degrees, but these policies resulted in the halt of all non-essential medical practice as well. Once many of these policies were reduced or withdrawn, and when businesses began to reopen, it was found that anxieties and fears of infection were still affecting people’s behaviors. Many continue to avoid unnecessary trips outside of the home, and some may even be avoiding medical facilities due to fear of possible infection. This change in behavior is likely to be represented in the rate of HPV vaccine utilization (initiation and completion) for the year 2020, but we will have to wait for the results to be shared to truly see the impact. This is concerning because those who had previously initiated vaccination prior to, or going into early 2020, will likely experience disruption to their vaccination schedule. Disruption of the vaccination schedule is concerning in terms of whether it will cause weakened effectiveness, which could mean these individuals’ will not receive the same protective benefits as those who were able to complete their series in accordance with the designated schedule. It will likely take years for us to see the ramifications of this disruption, and a push for ‘catch-up dosing’ will need to be encouraged in the hope of providing the best protection possible given the circumstances.The incidence rate of cervical cancer has been falling across the United States, but at a rate that now appears to have plateaued. The HPV vaccine, when administered according to the manufacturer’s guidelines, appears to offer effective protection against the most hazardous types of HPV, which are known to be causal factors in the majority of malignant cervical cancer cases. Further support, and a push from physicians and public health officials, will likely be necessary for the rate of HPV vaccine utilization to increase over the coming years. A collaborative effort between public health officials, medical professionals, and healthcare administrators is needed if we hope to reach the 2026 HPV Cancer Free goals set out by the American Cancer Society.In the United States, further research is needed to better understand the disproportionate rate at which HPV vaccination series are not being completed among racial/ethnic minorities, compared with the completion rates of White people. Research has determined that these are statistically significant rates, with Black, Latina, and Asian women completing the series at lower rates than those seen in White women. Socioeconomic status has already been determined as a factor when measuring for HPV and HPV vaccine knowledge, but research into how cultural factors can contribute to these results would prove to be useful. With a better understanding, the professionals involved can adjust their approach accordingly, with the hope of increasing the rate of vaccination series completion as a result.