Cost-effectiveness and impact on infections and associated antimicrobial resistance of 20-valent pneumococcal conjugate vaccine in US children previously immunized with PCV13.

AIM: The US Food and Drug Administration approved the 20-valent pneumococcal conjugate vaccine (PCV20) to prevent pneumococcal disease. In the context of routine PCV20 vaccination, we evaluated the cost-effectiveness and public health and economic impact of a PCV20 catch-up program and estimated the number of antibiotic prescriptions and antibiotic-resistant infections averted. MATERIALS AND METHODS: A population-based, multi-cohort, decision-analytic Markov model was developed using parameters consistent with previous PCV20 cost-effectiveness analyses. In the intervention arm, children aged 14-59 months who previously completed PCV13 vaccination received a supplemental dose of PCV20. In the comparator arm, no catch-up PCV20 dose was given. The direct and indirect benefits of vaccination were captured over a 10-year time horizon. RESULTS: A PCV20 catch-up program would prevent 5,469 invasive pneumococcal disease cases, 50,286 hospitalized pneumonia cases, 218,240 outpatient pneumonia cases, 582,302 otitis media cases, and 1,800 deaths, representing a net gain of 30,014 life years and 55,583 quality-adjusted life years. Furthermore, 720,938 antibiotic prescriptions and 256,889 antibiotic-resistant infections would be averted. A catch-up program would result in cost savings of $800 million. These results were robust to sensitivity and scenario analyses. CONCLUSIONS: A PCV20 catch-up program could prevent pneumococcal infections, antibiotic prescriptions, and antimicrobial-resistant infections and would be cost-saving in the US.

Cost-effectiveness of 20-valent pneumococcal conjugate vaccine in US infants.

BACKGROUND: As of June 2023, two pneumococcal conjugate vaccines, 20- (PCV20) and 15- (PCV15) valent formulations, are recommended for US infants under a 3 + 1 schedule. This study evaluated the health and economic impact of vaccinating US infants with a new expanded valency PCV20 formulation. METHODS: A population-based, multi cohort, decision-analytic Markov model was developed to estimate the public health impact and cost-effectiveness of PCV20 from both societal and healthcare system perspectives over 10 years. Epidemiological data were based on published studies and unpublished Active Bacterial Core Surveillance System (ABCs) data. Vaccine effectiveness was based on PCV13 effectiveness and PCV7 efficacy studies. Indirect impact was based on observational studies. Costs and disutilities were based on published data. PCV20 was compared to both PCV13 and PCV15 in separate scenarios. RESULTS: Replacing PCV13 with PCV20 in infants has the potential to avert over 55,000 invasive pneumococcal disease (IPD) cases, 2.5 million pneumonia cases, 5.4 million otitis media (OM) cases, and 19,000 deaths across all ages over a 10-year time horizon, corresponding to net gains of 515,000 life years and 271,000 QALYs. Acquisition costs of PCV20 were offset by monetary savings from averted cases resulting in net savings of $20.6 billion. The same trend was observed when comparing PCV20 versus PCV15, with a net gain of 146,000 QALYs and $9.9 billion in net savings. A large proportion of the avoided costs and cases were attributable to indirect effects in unvaccinated adults and elderly. From a health-care perspective, PCV20 was also the dominant strategy compared to both PCV13 and PCV15. CONCLUSIONS: Infant vaccination with PCV20 is estimated to further reduce pneumococcal disease and associated healthcare system and societal costs compared to both PCV13 and PCV15.

CRIMSON: An open-source software framework for cardiovascular integrated modelling and simulation.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization.

Twenty-Year Public Health Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines in US Children.

Pneumococcal conjugate vaccines (PCVs) have been used in the United States since 2000. To assess the cumulative 20-year effect of PCVs on invasive pneumococcal disease (IPD) incidence among children <5 years of age, we analyzed Active Bacterial Core Surveillance data, conducted a literature review, and modeled expected and observed disease. We found that PCVs have averted >282,000 cases of IPD, including ≈16,000 meningitis, ≈172,000 bacteremia, and ≈55,000 bacteremic pneumonia cases. In addition, vaccination has prevented 97 million healthcare visits for otitis media, 438,914-706,345 hospitalizations for pneumonia, and 2,780 total deaths. IPD cases declined 91%, from 15,707 in 1997 to 1,382 in 2019. Average annual visits for otitis media declined 41%, from 78 visits/100 children before PCV introduction to 46 visits/100 children after PCV13 introduction. Annual pneumonia hospitalizations declined 66%-79%, from 110,000-175,000 in 1997 to 37,000 in 2019. These findings confirm the substantial benefits of PCVs for preventing IPD in children.

Ten year public health impact of 13-valent pneumococcal conjugate vaccination in infants: A modelling analysis.

Pneumococcal disease is a substantial contributor to illness and death in young children globally. The introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 had a significant impact in preventing pneumococcal disease in both vaccinated children and unvaccinated individuals (through herd effect). A higher valent PCV13 replaced PCV7 in late 2009. This analysis was undertaken to assess how many cases and deaths have been averted over the last decade since PCV13 introduction. A model estimated the number of infants vaccinated annually with PCV13, as well as the number of cases and deaths of invasive pneumococcal disease, pneumococcal pneumonia, and acute otitis media cases averted. PCV13 vaccination was estimated to have prevented 175.2 million cases of all pneumococcal diseases and 624,904 deaths globally between 2010 and 2019. These results demonstrate the substantial public health impact of PCV13 and highlight the importance of increasing the global reach of PCV programs.

Non-invasive estimation of relative pressure in turbulent flow using virtual work-energy.

Vascular pressure differences are established risk markers for a number of cardiovascular diseases. Relative pressures are, however, often driven by turbulence-induced flow fluctuations, where conventional non-invasive methods may yield inaccurate results. Recently, we proposed a novel method for non-turbulent flows, νWERP, utilizing the concept of virtual work-energy to accurately probe relative pressure through complex branching vasculature. Here, we present an extension of this approach for turbulent flows: νWERP-t. We present a theoretical method derivation based on flow covariance, quantifying the impact of flow fluctuations on relative pressure. νWERP-t is tested on a set of in-vitro stenotic flow phantoms with data acquired by 4D flow MRI with six-directional flow encoding, as well as on a patient-specific in-silico model of an acute aortic dissection. Over all tests νWERP-t shows improved accuracy over alternative energy-based approaches, with excellent recovery of estimated relative pressures. In particular, the use of a guaranteed divergence-free virtual field improves accuracy in cases where turbulent flows skew the apparent divergence of the acquired field. With the original νWERP allowing for assessment of relative pressure into previously inaccessible vasculatures, the extended νWERP-t further enlarges the method's clinical scope, underlining its potential as a novel tool for assessing relative pressure in-vivo.

Estimation of Cardiovascular Relative Pressure Using Virtual Work-Energy.

Many cardiovascular diseases lead to local increases in relative pressure, reflecting the higher costs of driving blood flow. The utility of this biomarker for stratifying the severity of disease has thus driven the development of methods to measure these relative pressures. While intravascular catheterisation remains the most direct measure, its invasiveness limits clinical application in many instances. Non-invasive Doppler ultrasound estimates have partially addressed this gap; however only provide relative pressure estimates for a range of constricted cardiovascular conditions. Here we introduce a non-invasive method that enables arbitrary interrogation of relative pressures throughout an imaged vascular structure, leveraging modern phase contrast magnetic resonance imaging, the virtual work-energy equations, and a virtual field to provide robust and accurate estimates. The versatility and accuracy of the method is verified in a set of complex patient-specific cardiovascular models, where relative pressures into previously inaccessible flow regions are assessed. The method is further validated within a cohort of congenital heart disease patients, providing a novel tool for probing relative pressures in-vivo.

Modeling Left Atrial Flow, Energy, Blood Heating Distribution in Response to Catheter Ablation Therapy.

Introduction: Atrial fibrillation (AF) is a widespread cardiac arrhythmia that commonly affects the left atrium (LA), causing it to quiver instead of contracting effectively. This behavior is triggered by abnormal electrical impulses at a specific site in the atrial wall. Catheter ablation (CA) treatment consists of isolating this driver site by burning the surrounding tissue to restore sinus rhythm (SR). However, evidence suggests that CA can concur to the formation of blood clots by promoting coagulation near the heat source and in regions with low flow velocity and blood stagnation. Methods: A patient-specific modeling workflow was created and applied to simulate thermal-fluid dynamics in two patients pre- and post-CA. Each model was personalized based on pre- and post-CA imaging datasets. The wall motion and anatomy were derived from SSFP Cine MRI data, while the trans-valvular flow was based on Doppler ultrasound data. The temperature distribution in the blood was modeled using a modified Pennes bioheat equation implemented in a finite-element based Navier-Stokes solver. Blood particles were also classified based on their residence time in the LA using a particle-tracking algorithm. Results: SR simulations showed multiple short-lived vortices with an average blood velocity of 0.2-0.22 m/s. In contrast, AF patients presented a slower vortex and stagnant flow in the LA appendage, with the average blood velocity reduced to 0.08-0.14 m/s. Restoration of SR also increased the blood kinetic energy and the viscous dissipation due to the presence of multiple vortices. Particle tracking showed a dramatic decrease in the percentage of blood remaining in the LA for longer than one cycle after CA (65.9 vs. 43.3% in patient A and 62.2 vs. 54.8% in patient B). Maximum temperatures of 76° and 58°C were observed when CA was performed near the appendage and in a pulmonary vein, respectively. Conclusion: This computational study presents novel models to elucidate relations between catheter temperature, patient-specific atrial anatomy and blood velocity, and predict how they change from SR to AF. The models can quantify blood flow in critical regions, including residence times and temperature distribution for different catheter positions, providing a basis for quantifying stroke risks.

Novel MRI Technique Enables Non-Invasive Measurement of Atrial Wall Thickness.

Knowledge of atrial wall thickness (AWT) has the potential to provide important information for patient stratification and the planning of interventions in atrial arrhythmias. To date, information about AWT has only been acquired in post-mortem or poor-contrast computed tomography (CT) studies, providing limited coverage and highly variable estimates of AWT. We present a novel contrast agent-free MRI sequence for imaging AWT and use it to create personalized AWT maps and a biatrial atlas. A novel black-blood phase-sensitive inversion recovery protocol was used to image ten volunteers and, as proof of concept, two atrial fibrillation patients. Both atria were manually segmented to create subject-specific AWT maps using an average of nearest neighbors approach. These were then registered non-linearly to generate an AWT atlas. AWT was 2.4 ± 0.7 and 2.7 ± 0.7 mm in the left and right atria, respectively, in good agreement with post-mortem and CT data, where available. AWT was 2.6 ± 0.7 mm in the left atrium of a patient without structural heart disease, similar to that of volunteers. In a patient with structural heart disease, the AWT was increased to 3.1 ± 1.3 mm. We successfully designed an MRI protocol to non-invasively measure AWT and create the first whole-atria AWT atlas. The atlas can be used as a reference to study alterations in thickness caused by atrial pathology. The protocol can be used to acquire personalized AWT maps in a clinical setting and assist in the treatment of atrial arrhythmias.

Effects of age-associated regional changes in aortic stiffness on human hemodynamics revealed by computational modeling.

Although considered by many as the gold standard clinical measure of arterial stiffness, carotid-to-femoral pulse wave velocity (cf-PWV) averages material and geometric properties over a large portion of the central arterial tree. Given that such properties may evolve differentially as a function of region in cases of hypertension and aging, among other conditions, there is a need to evaluate the potential utility of cf-PWV as an early diagnostic of progressive vascular stiffening. In this paper, we introduce a data-driven fluid-solid-interaction computational model of the human aorta to simulate effects of aging-related changes in regional wall properties (e.g., biaxial material stiffness and wall thickness) and conduit geometry (e.g., vessel caliber, length, and tortuosity) on several metrics of arterial stiffness, including distensibility, augmented pulse pressure, and cyclic changes in stored elastic energy. Using the best available biomechanical data, our results for PWV compare well to findings reported for large population studies while rendering a higher resolution description of evolving local and global metrics of aortic stiffening. Our results reveal similar spatio-temporal trends between stiffness and its surrogate metrics, except PWV, thus indicating a complex dependency of the latter on geometry. Lastly, our analysis highlights the importance of the tethering exerted by external tissues, which was iteratively estimated until hemodynamic simulations recovered typical values of tissue properties, pulse pressure, and PWV for each age group.

Multi-modality image-based computational analysis of haemodynamics in aortic dissection.

Aortic dissection is a disease whereby an injury in the wall of the aorta leads to the creation of a true lumen and a false lumen separated by an intimal flap which may contain multiple communicating tears between the lumina. It has a high associated morbidity and mortality, but at present, the timing of surgical intervention for stable type B dissections remains an area of debate. Detailed knowledge of haemodynamics may yield greater insight into the long-term outcomes for dissection patients by providing a greater understanding of pressures, wall shear stress and velocities in and around the dissection. In this paper, we aim to gather further insight into the complex haemodynamics in aortic dissection using medical imaging and computational fluid dynamics modelling. Towards this end, several computer models of the aorta of a patient presenting with an acute Stanford type B dissection were created whereby morphometric parameters related to the dissection septum were altered, such as removal of the septum, and the variation of the number of connecting tears between the lumina. Patient-specific flow data acquired using 2D PC-MRI in the ascending aorta were used to set the inflow boundary condition. Coupled zero-dimensional (Windkessel) models representing the distal vasculature were used to define the outlet boundary conditions and tuned to match 2D PC-MRI flow data acquired in the descending aorta. Haemodynamics in the dissected aorta were compared to those in an equivalent 'healthy aorta', created by virtually removing the intimal flap (septum). Local regions of increased velocity, pressure, wall shear stress and alterations in flow distribution were noted, particularly in the narrow true lumen and around the primary entry tear. The computed flow patterns compared favourably with those obtained using 4D PC-MRI. A lumped-parameter heart model was subsequently used to show that in this case there was an estimated 14 % increase in left ventricular stroke work with the onset of dissection. Finally, the effect of secondary connecting tears (i.e. those excluding the primary entry and exit tears) was also studied, revealing significant haemodynamic changes when no secondary tears are included in the model, particularly in the true lumen where increases in flow over [Formula: see text] and drops in peak pressure of 18 % were observed.