Trends in the Concentration and Distribution of Health Care Expenditures in the US, 2001-2018.

Importance: The concentration of health care expenditures has important implications for managing risk pools, drug benefit design, and care management. Objective: To examine trends in the concentration of health care spending in different population groups and expenditure categories in the US between 2001 and 2018. Design, Setting, and Participants: This study is a cross-sectional analysis of Medical Expenditure Panel Surveys (MEPS) collected between 2001 and 2018. The MEPS is a household survey of medical expenditures weighted to represent national estimates in the US. Respondents were a nationally representative sample of the US civilian noninstitutionalized population. Data analysis was performed from December 2020 to February 2021. Main Outcomes and Measures: The main outcome is the concentration of health care expenditures as measured by the cumulative percentage of health expenditure vs percentage of ranked population. This study reports trends in the distribution of populations across 4 concentration curve parameters: top 50% expenditure (high spenders), next 49% expenditure (medium spenders), next 1% expenditure (low spenders), and nonspenders. Results: The mean sample size of the MEPS surveys used in the analysis was 34 539 individuals, and the sample size varied between 30 461 and 39 165 individuals over the years studied. On the basis of data from 30 461 MEPS respondents (15 867 women [52.1%]; mean [SD] age, 38.9 [24.0] years) in 2018, the top 4.6% (95% CI, 4.3%-4.9%) of the US population by spending accounted for 50% of health care expenditures. Although this fraction varied across population groups or expenditure categories, it remained remarkably stable over time with one exception: the concentration of spending on prescription drugs. In 2001, one-half of all expenditures on prescription drugs were concentrated in 6.0% (95% CI, 5.6%-6.4%) of the US population, but by 2018, this proportion had decreased to 2.3% (95% CI, 2.1%-2.5%). This change does not appear to be associated with a change in the overall share of prescription drug expenses, which increased by only a small amount, from 20.4% in 2001 to 24.8% in 2018. Conclusions and Relevance: The overall concentration of health care expenditures remained stable between 2001 and 2018, but these findings suggest that there has been a sharp increase in the concentration of spending on prescription drugs in the US. This coincides with the genericization of many primary care drugs, along with a shift in focus of the biopharmaceutical industry toward high-cost specialty drugs targeted at smaller populations. If this trend continues, it will have implications for the minimum scale of risk-bearing and drug management needed to operate efficiently, as well as the optimal cost-sharing features of insurance products.

An integrative toy model of cell flattening, spreading, and ruffling.

BACKGROUND: The processes of cell spreading and crawling are frequently associated with mysterious waves and ruffling cycles of the leading edge. OBJECTIVE: To develop a physical model that can account for these phenomena based on a few simple and plausible rules governing adhesion, contractility, polymerization of cytoskeleton, and membrane tension. METHODS: Extension of a continuum mechanical model of phagocytosis [J Cell Sci. (2006);119(Pt 9):1903-13] adding a simple coupling between membrane curvature and cytoskeletal polymerization. RESULTS: We show that our generalized model has just the right nonlinearity needed for triggering of stochastic/chaotic cycles of ruffling similar to those that are observed in real cells. CONCLUSIONS: The cycles are caused by a branching instability at the leading edge that leads to bifurcations of protrusion into forward moving lamellipodium and upward and rearward folding ruffles. The amplitude of the instability is modulated by the surface tension, with higher tension stabilizing against ruffling (but inhibiting protrusion) and lower tension promoting ruffling and protrusion.

Target-specific mechanics of phagocytosis: protrusive neutrophil response to zymosan differs from the uptake of antibody-tagged pathogens.

The physical mechanisms that control target-specific responses of human neutrophils to distinct immune threats are poorly understood. Using dual-micropipette manipulation, we have quantified and compared the time courses of neutrophil phagocytosis of two different targets: zymosan (a prominent model of fungal infection), and antibody-coated (Fc) particles. Our single-live-cell/single-target approach exposes surprising differences between these two forms of phagocytosis. Unlike the efficient uptake of 3-µm Fc targets (within ~66 seconds), the engulfment of similarly sized zymosan is slow (~167 seconds), mainly due to the formation of a characteristic pedestal that initially pushes the particle outwards by ~1 µm. Despite a roughly twofold difference in maximum cortical tensions, the top 'pull-in' speeds of zymosan and Fc targets are indistinguishable at ~33 nm/second. Drug inhibition shows that both actin as well as myosin II partake in the regulation of neutrophil cortical tension and cytoplasmic viscosity; other than that, myosin II appears to play a minor role in both forms of phagocytosis. Remarkably, an intact actin cytoskeleton is required to suppress, in antibody-mediated phagocytosis, the initially protrusive deformation that distinguishes the neutrophil response to zymosan.

Protrusive push versus enveloping embrace: computational model of phagocytosis predicts key regulatory role of cytoskeletal membrane anchors.

Encounters between human neutrophils and zymosan elicit an initially protrusive cell response that is distinct from the thin lamella embracing antibody-coated targets. Recent experiments have led us to hypothesize that this behavior has its mechanistic roots in the modulation of interactions between membrane and cytoskeleton. To test and refine this hypothesis, we confront our experimental results with predictions of a computer model of leukocyte mechanical behavior, and establish the minimum set of mechanistic variations of this computational framework that reproduces the differences between zymosan and antibody phagocytosis. We confirm that the structural linkages between the cytoskeleton and the membrane patch adherent to a target form the "switchboard" that controls the target specificity of a neutrophil's mechanical response. These linkages are presumably actin-binding protein complexes associating with the cytoplasmic domains of cell-surface receptors that are engaged in adhesion to zymosan and Fc-domains.

Cytopede: a three-dimensional tool for modeling cell motility on a flat surface.

When cultured on flat surfaces, fibroblasts and many other cells spread to form thin lamellar sheets. Motion then occurs by extension of the sheet at the leading edge and retraction at the trailing edge. Comprehensive quantitative models of these phenomena have so far been lacking and to address this need, we have designed a three-dimensional code called Cytopede specialized for the simulation of the mechanical and signaling behavior of plated cells. Under assumptions by which the cytosol and the cytoskeleton are treated from a continuum mechanical perspective, Cytopede uses the finite element method to solve mass and momentum equations for each phase, and thus determine the time evolution of cellular models. We present the physical concepts that underlie Cytopede together with the algorithms used for their implementation. We then validate the approach by a computation of the spread of a viscous sessile droplet. Finally, to exemplify how Cytopede enables the testing of ideas about cell mechanics, we simulate a simple fibroblast model. We show how Cytopede allows computation, not only of basic characteristics of shape and velocity, but also of maps of cell thickness, cytoskeletal density, cytoskeletal flow, and substratum tractions that are readily compared with experimental data.

Analysis of actin FLAP dynamics in the leading lamella.

BACKGROUND: The transport of labeled G-actin from the mid-lamella region to the leading edge in a highly motile malignant rat fibroblast line has been studied using fluorescence localization after photobleaching or FLAP, and the transit times recorded in these experiments were so fast that simple diffusion was deemed an insufficient explanation (see Zicha et al., Science, v. 300, pp. 142-145 [1]). METHODOLOGY/PRINCIPAL FINDINGS: We re-examine the Zicha FLAP experiments using a two-phase reactive interpenetrating flow formalism to model the cytoplasm and the transport dynamics of bleached and unbleached actin. By allowing an improved treatment of effects related to the retrograde flow of the cytoskeleton and of the geometry and finite thickness of the lamella, this new analysis reveals a mechanism that can realistically explain the timing and the amplitude of all the FLAP signals observed in [1] without invoking special transport modalities. CONCLUSIONS/SIGNIFICANCE: We conclude that simple diffusion is sufficient to explain the observed transport rates, and that variations in the transport of labeled actin through the lamella are minor and not likely to be the cause of the observed physiological variations among different segments of the leading edge. We find that such variations in labeling can easily arise from differences and changes in the microscopic actin dynamics inside the edge compartment, and that the key dynamical parameter in this regard is the so-called "dilatation rate" (the velocity of cytoskeletal retrograde flow divided by a characteristic dimension of the edge compartment where rapid polymerization occurs). If our dilatation hypothesis is correct, the transient kinetics of bleached actin relocalization constitute a novel and very sensitive method for probing the cytoskeletal dynamics in leading edge micro-environments which are otherwise very difficult to directly interrogate.

Form and function in cell motility: from fibroblasts to keratocytes.

It is plain enough that a horse is made for running, but similar statements about motile cells are not so obvious. Here the basis for structure-function relations in cell motility is explored by application of a new computational technique that allows realistic three-dimensional simulations of cells migrating on flat substrata. With this approach, some cyber cells spontaneously display the classic irregular protrusion cycles and handmirror morphology of a crawling fibroblast, and others the steady gliding motility and crescent morphology of a fish keratocyte. The keratocyte motif is caused by optimal recycling of the cytoskeleton from the back to the front so that more of the periphery can be devoted to protrusion. These calculations are a step toward bridging the gap between the integrated mechanics and biophysics of whole cells and the microscopic molecular biology of cytoskeletal components.

Baseline mechanical characterization of J774 macrophages.

Macrophage cell lines like J774 cells are ideal model systems for establishing the biophysical foundations of autonomous deformation and motility of immune cells. To aid comparative studies on these and other types of motile cells, we report measurements of the cortical tension and cytoplasmic viscosity of J774 macrophages using micropipette aspiration. Passive J774 cells cultured in suspension exhibited a cortical resting tension of approximately 0.14 mN/m and a viscosity (at room temperature) of 0.93 kPa.s. Both values are about one order of magnitude higher than the respective values obtained for human neutrophils, lending support to the hypothesis that a tight balance between cortical tension and cytoplasmic viscosity is a physical prerequisite for eukaryotic cell motility. The relatively large stiffness of passive J774 cells contrasts with their capacity for a more than fivefold increase in apparent surface area during active deformation in phagocytosis. Scanning electron micrographs show how microscopic membrane wrinkles are smoothed out and recruited into the apparent surface area during phagocytosis of large targets.

Mechanics of neutrophil phagocytosis: experiments and quantitative models.

To quantitatively characterize the mechanical processes that drive phagocytosis, we observed the FcgammaR-driven engulfment of antibody-coated beads of diameters 3 mum to 11 mum by initially spherical neutrophils. In particular, the time course of cell morphology, of bead motion and of cortical tension were determined. Here, we introduce a number of mechanistic models for phagocytosis and test their validity by comparing the experimental data with finite element computations for multiple bead sizes. We find that the optimal models involve two key mechanical interactions: a repulsion or pressure between cytoskeleton and free membrane that drives protrusion, and an attraction between cytoskeleton and membrane newly adherent to the bead that flattens the cell into a thin lamella. Other models such as cytoskeletal expansion or swelling appear to be ruled out as main drivers of phagocytosis because of the characteristics of bead motion during engulfment. We finally show that the protrusive force necessary for the engulfment of large beads points towards storage of strain energy in the cytoskeleton over a large distance from the leading edge ( approximately 0.5 microm), and that the flattening force can plausibly be generated by the known concentrations of unconventional myosins at the leading edge.

Mechanics of neutrophil phagocytosis: behavior of the cortical tension.

The mechanical implementation of phagocytosis requires a well-coordinated deployment of cytoplasm and membrane during the creation of a phagosome. We follow the time course of this process in initially round passive neutrophils presented with antibody-coated beads of radii 1.1 to 5.5 microm. In particular, we monitor the cortical tension as the apparent cellular surface area increases due to cell-driven deformations induced by phagocytosis. The behavior of the tension is then compared with conditions of similar area expansion caused by externally imposed deformations during cell aspiration into a micropipette. Whereas the resting tension remains low for an area expansion of up to only 30% during aspiration, it remains low even after an area expansion of up to 80% in phagocytosis. This is probably the result of membrane insertion from inner stores by exocytosis. We further find that the onset of viscous tension, proportional to the rate of area expansion and caused by the unfurling of plasma membrane wrinkles, is significantly delayed in phagocytosis compared with aspiration. We propose that this is the result of phagocytosis-triggered enzymatic activity that releases spare plasma membrane normally sequestered by velcro-like bonds in a reservoir of surface folds and villi.

The mechanics of neutrophils: synthetic modeling of three experiments.

Much experimental data exist on the mechanical properties of neutrophils, but so far, they have mostly been approached within the framework of liquid droplet models. This has two main drawbacks: 1), It treats the cytoplasm as a single phase when in reality, it is a composite of cytosol and cytoskeleton; and 2), It does not address the problem of active neutrophil deformation and force generation. To fill these lacunae, we develop here a comprehensive continuum-mechanical paradigm of the neutrophil that includes proper treatment of the membrane, cytosol, and cytoskeleton components. We further introduce two models of active force production: a cytoskeletal swelling force and a polymerization force. Armed with these tools, we present computer simulations of three classic experiments: the passive aspiration of a neutrophil into a micropipette, the active extension of a pseudopod by a neutrophil exposed to a local stimulus, and the crawling of a neutrophil inside a micropipette toward a chemoattractant against a varying counterpressure. Principal results include: 1), Membrane cortical tension is a global property of the neutrophil that is affected by local area-increasing shape changes. We argue that there exists an area dilation viscosity caused by the work of unfurling membrane-storing wrinkles and that this viscosity is responsible for much of the regulation of neutrophil deformation. 2), If there is no swelling force of the cytoskeleton, then it must be endowed with a strong cohesive elasticity to prevent phase separation from the cytosol during vigorous suction into a capillary tube. 3), We find that both swelling and polymerization force models are able to provide a unifying fit to the experimental data for the three experiments. However, force production required in the polymerization model is beyond what is expected from a simple short-range Brownian ratchet model. 4), It appears that, in the crawling of neutrophils or other amoeboid cells inside a micropipette, measurement of velocity versus counterpressure curves could provide a determination of whether cytoskeleton-to-cytoskeleton interactions (such as swelling) or cytoskeleton-to-membrane interactions (such as polymerization force) are predominantly responsible for active protrusion.