A Markov cost-effectiveness modeling framework for evaluating wound dressings: A concept for practical implementation of economic evaluations in an informed dressing selection process.

AIMS: Exemplify the potential of using health economy modeling and simulations to support and optimize wound dressing purchasing decisions. MATERIALS AND METHODS: We developed a Markov cost-effectiveness modeling framework fusing clinical and industry sources of healing and cost outcomes for evaluating dressings, focusing on polymeric membrane dressings compared to passive foam dressings without active inflammation modulation components. We calculated the wound care costs for patients with and without diabetes, as well as for infected and non-infected wounds, to illustrate the effectiveness of this model in supporting decision-making. RESULTS: The model results demonstrated that polymeric membrane dressings reduce the cumulative treatment costs compared to passive foam dressings, due to fewer dressing changes and lower associated labor costs, regardless of the initial product price differences. CONCLUSION: Cost-effectiveness calculations should be performed in healthcare facilities to support purchasing decisions based on true cost analyses. Making purchasing decisions focusing on the dressing price alone may provide wrong estimates of the real cost differences.

Smartphone-based scans of palate models of newborns with cleft lip and palate: Outlooks for three-dimensional image capturing and machine learning plate tool.

OBJECTIVES: To evaluate the performance of smartphone scanning applications (apps) in acquiring 3D meshes of cleft palate models. Secondarily, to validate a machine learning (ML) tool for computing automated presurgical plate (PSP). MATERIALS AND METHODS: We conducted a comparative analysis of two apps on 15 cleft palate models: five unilateral cleft lip and palate (UCLP), five bilateral cleft lip and palate (BCLP) and five isolated cleft palate (ICP). The scans were performed with and without a mirror to simulate intraoral acquisition. The 3D reconstructions were compared to control reconstructions acquired using a professional intraoral scanner using open-source software. RESULTS: Thirty 3D scans were acquired by each app, totalling 60 scans. The main findings were in the UCLP sample, where the KIRI scans without a mirror (0.22 ± 0.03 mm) had a good performance with a deviation from the ground truth comparable to the control group (0.14 ± 0.13 mm) (p = .653). Scaniverse scans with a mirror showed the lowest accuracy of all the samples. The ML tool was able to predict the landmarks and automatically generate the plates, except in ICP models. KIRI scans' plates showed better performance with (0.22 ± 0.06 mm) and without mirror (0.18 ± 0.05 mm), being comparable with controls (0.16 ± 0.08 mm) (p = .954 and p = .439, respectively). CONCLUSIONS: KIRI Engine performed better in scanning UCLP models without a mirror. The ML tool showed a high capability for morphology recognition and automated PSP generation.

Disentangling effects of dispersal, environment and anthropogenic barriers on functional connectivity in aquatic systems.

Disentangling the roles of structural landscape factors and animal movement behaviour can present challenges for practitioners managing landscapes to maintain functional connectivity and achieve conservation goals. We used a landscape genetics approach to combine robust demographic, behavioural and genetic datasets with spatially explicit simulations to evaluate the effects of anthropogenic barriers (dams, culverts) and natural landscape resistance (gradient, elevation) affecting dispersal behaviour, genetic connectivity and genetic structure in a resident population of Westslope Cutthroat Trout (Oncorhynchus clarkii lewisi). Analyses based on 10 years of sampling effort revealed a pattern of restricted dispersal, and population genetics identified discrete population clusters between distal tributaries and the mainstem stream and no structure within the mainstem stream. Demogenetic simulations demonstrated that, for this population, the effects of existing anthropogenic barriers on population structure are redundant with effects of restricted dispersal associated with the underlying environmental resistance. Our approach provides an example of how extensive field sampling combined with landscape genetics can be incorporated into spatially explicit simulation modelling to explore how, together, movement ecology and landscape resistance can be used to inform decisions around restoration and connectivity.

CT-derived simulations to predict outcomes in patients undergoing transcatheter aortic valve implantation with an ACURATE Neo2 valve the PRECISE-TAVI cohort B trial.

BACKGROUND: Paravalvular leakage (PVL) and conduction disorders that require permanent pacemaker implantation (PPI) remain clinically relevant challenges after transcatheter aortic valve implantation (TAVI). Computed tomography-based simulations may predict the risk of significant PVL and PPI. AIMS: To evaluate the feasibility and accuracy of preprocedural computer simulation with FEops HEARTguide™ to predict >trace PVL and PPI after TAVI with the self-expanding supra-annular ACURATE Neo2 transcatheter heart valve. METHODS: Prospective multicenter observational study that included consecutive patients undergoing TAVI with an ACURATE Neo2 valve. Computer simulations were performed before the TAVI procedure as part of the preprocedural planning. Follow-up period for PPI and PVL was 30 days. RESULTS: Sixty-five patients were included (median age 81 years (25th-75th percentile 77-84.5)). New left bundle branch block occurred in five patients (7.7%) and PPI in two patients (3%). Contact pressure index (CPI) was similar for patients with vs without new conduction disorders. Patients with PPI had numerically higher CPI than those without PPI (median CPI 20.0% (25th-75th percentile 15.0-25.0) vs. 13.0% (25th-75th percentile 5.5-18), p = 0.27). More than trace PVL occurred in 30%. Median PVL was significantly lower in patients with none-trace PVL (3.2 mL/s [25th-75th percentile 2.2-5.0]), compared to mild PVL (5.2 mL/s [25th-75th percentile 3.2-10.3]) and moderate PVL (12.6 mL/s [25th-75th percentile 3.9-21.3])(p = 0.036). A simulated PVL-cutoff of 9.65 mL/s identified patients with >trace PVL (AUC 0.70 (95% CI 0.55-0.85), sensitivity 42%, specificity 95%). CONCLUSION: In our study FEops HEARTguide™ simulations identified patients at risk for >trace PVL with ACURATE Neo2 TAVI but not for PPI.

Dynamical modelling of lipid droplet formation suggests a key function of membrane phospholipids.

Cells store triacylglycerol (TAG) within lipid droplets (LDs). A dynamic model describing complete LD formation at the endoplasmic reticulum (ER) membrane does not yet exist. A biochemical-biophysical model of LD synthesis is proposed. It describes the time-dependent accumulation of TAG in the ER membrane as the formation of a potential LD (pLD) bounded by spherical caps of the inner and outer monolayers of the membrane. The expansion rate of the pLD depends on the TAG supply, the elastic properties of the ER membrane, and the recruitment of phospholipids (PLs) to the cap-covering monolayers. Model simulations provided the following insights: (a) Marginal differences in the surface tension of the cap monolayers are sufficient to fully drive the expansion of the pLD towards the cytosol or lumen. (b) Selective reduction of PL supply to the luminal monolayer ensures stable formation of cytosolic LDs, irrespective of variations in the elasto-mechanical properties of the ER membrane. (c) The rate of TAG supply to the cytosolic monolayer has a major effect on the size and maturation time of LDs but has no significant effect on the TAG export per individual LD. The recruitment of additional PLs to the cap monolayers of pLDs critically controls the budding direction, size, and maturation time of LDs. The ability of cells to acquire additional LD initiation sites appears to be key to coping with acutely high levels of potentially toxic free fatty acids.

When the Poisson Ratio of Polymer Networks and Gels Is Larger Than 0.5?

We use coarse-grained molecular dynamics simulations to study deformation of networks and gels of linear and brush strands in both linear and nonlinear deformation regimes under constant pressure conditions. The simulations show that the Poisson ratio of networks and gels could exceed 0.5 in the nonlinear deformation regime. This behavior is due to the ability of the network and gel strands to sustain large reversible deformation, which, in combination with the finite strand extensibility results in strand alignment and monomer density, increases with increasing strand elongation. We developed a nonlinear network and gel deformation model which defines conditions for the Poisson ratio to exceed 0.5. The model predictions are in good agreement with the simulation results.

Completeness and readability of GPT-4-generated multilingual discharge instructions in the pediatric emergency department.

Objectives: The aim of this study was to assess the completeness and readability of generative pre-trained transformer-4 (GPT-4)-generated discharge instructions at prespecified reading levels for common pediatric emergency room complaints. Materials and Methods: The outputs for 6 discharge scenarios stratified by reading level (fifth or eighth grade) and language (English, Spanish) were generated fivefold using GPT-4. Specifically, 120 discharge instructions were produced and analyzed (6 scenarios: 60 in English, 60 in Spanish; 60 at a fifth-grade reading level, 60 at an eighth-grade reading level) and compared for completeness and readability (between language, between reading level, and stratified by group and reading level). Completeness was defined as the proportion of literature-derived key points included in discharge instructions. Readability was quantified using Flesch-Kincaid (English) and Fernandez-Huerta (Spanish) readability scores. Results: English-language GPT-generated discharge instructions contained a significantly higher proportion of must-include discharge instructions than those in Spanish (English: mean (standard error of the mean) = 62% (3%), Spanish: 53% (3%), P = .02). In the fifth-grade and eighth-grade level conditions, there was no significant difference between English and Spanish outputs in completeness. Readability did not differ across languages. Discussion: GPT-4 produced readable discharge instructions in English and Spanish while modulating document reading level. Discharge instructions in English tended to have higher completeness than those in Spanish. Conclusion: Future research in prompt engineering and GPT-4 performance, both generally and in multiple languages, is needed to reduce potential for health disparities by language and reading level.

Effects of Acute Hypernatremia on the Electrophysiology of Single Human Ventricular Cardiomyocytes: An In Silico Study.

Background: Clinical and experimental data on the cardiac effects of acute hypernatremia are scarce and inconsistent. We aimed to determine and understand the effects of different levels of acute hypernatremia on the human ventricular action potential. Methods: We performed computer simulations using two different, very comprehensive models of the electrical activity of a single human ventricular cardiomyocyte, i.e., the Tomek-Rodriguez model following the O'Hara-Rudy dynamic (ORd) model and the Bartolucci-Passini-Severi model as published in 2020 (known as the ToR-ORd and BPS2020 models, respectively). Mild to extreme levels of hypernatremia were introduced into each model based on experimental data on the effects of hypernatremia on cell volume and individual ion currents. Results: In both models, we observed an increase in the intracellular sodium and potassium concentrations, an increase in the peak amplitude of the intracellular calcium concentration, a hyperpolarization of the resting membrane potential, a prolongation of the action potential, an increase in the maximum upstroke velocity, and an increase in the threshold stimulus current at all levels of hypernatremia and all stimulus rates tested. The magnitude of all of these effects was relatively small in the case of mild to severe hypernatremia but substantial in the case of extreme hypernatremia. The effects on the action potential were related to an increase in the sodium-potassium pump current, an increase in the sodium-calcium exchange current, a decrease in the rapid and slow delayed rectifier potassium currents, and an increase in the fast and late sodium currents. Conclusions: The effects of mild to severe hypernatremia on the electrical activity of human ventricular cardiomyocytes are relatively small. In the case of extreme hypernatremia, the effects are more pronounced, especially regarding the increase in threshold stimulus current.

Polyampholytes with Various Charge Distributions: Conformation States via Computer Simulation.

By means of molecular dynamics computer simulation, the conformational space of polyampholyte macromolecules with various distributions of the charged groups along the chain is studied. A coarse-grained model where each monomer unit of the chain is presented as a non-charged group in the backbone of the macromolecule connected with a charged side pendant is considered. A limiting case of fully charged chains in the isoelectric point is investigated. The oppositely charged monomer units are distributed in various patterns: regular alternating, multiblock, or random sequences. It is found that the chains with random unit distribution adopt much more compacted conformations than the chains with regular distributions with comparable block lengths. Calculating the chain size and its fluctuation along with the spatial density distribution, coil, and globular conformations are distinguished and arranged on the diagrams in terms of chain length, block length, and Bjerrum length.

Experimental and simulation-based characterization of surfactant adsorption layers at fluid interfaces.

Adsorption of surfactants to fluid interfaces occurs in numerous technological and daily-life contexts. The coverage at the interface and other properties of the formed adsorption layers determine the performance of a surfactant with regard to the desired application. Given the importance of these applications, there is a great demand for the comprehensive characterization and understanding of surfactant adsorption layers. In this review, we provide an overview of suitable experimental and simulation-based techniques and review the literature in which they were used for the investigation of surfactant adsorption layers. We come to the conclusion that, while these techniques have been successfully applied to investigate Langmuir monolayers of water-insoluble surfactants, their application to the study of Gibbs adsorption layers of water-soluble surfactants has not been fully exploited. Finally, we emphasize the great potential of these methods in providing a deeper understanding of the behavior of soluble surfactants at interfaces, which is crucial for optimizing their performance in various applications.

Mechanical Behaviour of Photopolymer Cell-Size Graded Triply Periodic Minimal Surface Structures at Different Deformation Rates.

This study investigates how varying cell size affects the mechanical behaviour of photopolymer Triply Periodic Minimal Surfaces (TPMS) under different deformation rates. Diamond, Gyroid, and Primitive TPMS structures with spatially graded cell sizes were tested. Quasi-static experiments measured boundary forces, representing material behaviour, inertia, and deformation mechanisms. Separate studies explored the base material's behaviour and its response to strain rate, revealing a strength increase with rising strain rate. Ten compression tests identified a critical strain rate of 0.7 s-1 for "Grey Pro" material, indicating a shift in failure susceptibility. X-ray tomography, camera recording, and image correlation techniques observed cell connectivity and non-uniform deformation in TPMS structures. Regions exceeding the critical rate fractured earlier. In Primitive structures, stiffness differences caused collapse after densification of smaller cells at lower rates. The study found increasing collapse initiation stress, plateau stress, densification strain, and specific energy absorption with higher deformation rates below the critical rate for all TPMS structures. However, cell-size graded Primitive structures showed a significant reduction in plateau and specific energy absorption at a 500 mm/min rate.

X-Ray Calc 3: improved software for simulation and inverse problem solving for X-ray reflectivity.

This work introduces X-Ray Calc (XRC), an open-source software package designed to simulate X-ray reflectivity (XRR) and address the inverse problem of reconstructing film structures on the basis of measured XRR curves. XRC features a user-friendly graphical interface that facilitates interactive simulation and reconstruction. The software employs a recursive approach based on the Fresnel equations to calculate XRR and incorporates specialized tools for modeling periodic multilayer structures. This article presents the latest version of the X-Ray Calc software (XRC3), with notable improvements. These enhancements encompass an automatic fitting capability for XRR curves utilizing a modified flight particle swarm optimization algorithm. A novel cost function was also developed specifically for fitting XRR curves of periodic structures. Furthermore, the overall user experience has been enhanced by developing a new single-window interface.

Exploration of the Binding Mechanism of Cyclic Dinucleotide Analogs to Stimulating Factor Proteins and the Implications for Subsequent Analog Drug Design.

Cyclic dinucleotides (CDNs) are cyclic molecules consisting of two nucleoside monophosphates linked by two phosphodiester bonds, which act as a second messenger and bind to the interferon gene stimulating factor (STING) to activate the downstream signaling pathway and ultimately induce interferon secretion, initiating an anti-infective immune response. Cyclic dinucleotides and their analogs are lead compounds in the immunotherapy of infectious diseases and tumors, as well as immune adjuvants with promising applications. Many agonists of pathogen recognition receptors have been developed as effective adjuvants to optimize vaccine immunogenicity and efficacy. In this work, the binding mechanism of human-derived interferon gene-stimulating protein and its isoforms with cyclic dinucleotides and their analogs was theoretically investigated using computer simulations and combined with experimental results in the hope of providing guidance for the subsequent synthesis of cyclic dinucleotide analogs.

Natural and Synthetic Coumarins as Potential Drug Candidates Against SARS-CoV-2/CoViD-19.

COVID-19, an airborne disease caused by a betacoronavirus named SARS-- CoV-2, was officially declared a pandemic in early 2020, resulting in more than 770 million confirmed cases and over 6.9 million deaths by September 2023. Although the introduction of vaccines in late 2020 helped reduce the number of deaths, the global effort to fight COVID-19 is far from over. While significant progress has been made in a short period, the fight against SARS-CoV-2/COVID-19 and other potential pandemic threats continues. Like AIDS and hepatitis C epidemics, controlling the spread of COVID-19 will require the development of multiple drugs to weaken the virus's resistance to different drug treatments. Therefore, it is essential to continue developing new drug candidates derived from natural or synthetic small molecules. Coumarins are a promising drug design and development scaffold due to their synthetic versatility and unique physicochemical properties. Numerous examples reported in scientific literature, mainly by in silico prospection, demonstrate their potential contribution to the rapid development of drugs against SARS-CoV-2/COVID-19 and other emergent and reemergent viruses.

Impact of super-resolution and image acquisition on the detection of calcifications in digital breast tomosynthesis.

OBJECTIVES: A virtual clinical trial (VCT) method is proposed to determine the limit of calcification detection in tomosynthesis. METHODS: Breast anatomy, focal findings, image acquisition, and interpretation (n = 14 readers) were simulated using screening data (n = 660 patients). Calcifications (0.2-0.4 mm3) were inserted into virtual breast phantoms. Digital breast tomosynthesis (DBT) acquisitions were simulated assuming various acquisition geometries: source motion (continuous and step-and-shoot), detector element size (140 and 70 µm), and reconstructed voxel size (35-140 µm). VCT results were estimated using multiple-reader multiple-case analyses and d' statistics. Signal-to-noise (SNR) analyses were also performed using BR3D phantoms. RESULTS: Source motion and reconstructed voxel size demonstrated significant changes in the performance of imaging systems. Acquisition geometries that use 70 µm reconstruction voxel size and step-and-shoot motion significantly improved calcification detection. Comparing 70 with 100 µm reconstructed voxel size for step-and-shoot, the ΔAUC was 0.0558 (0.0647) and d' ratio was 1.27 (1.29) for 140 µm (70 µm) detector element size. Comparing step-and-shoot with a continuous motion for a 70 µm reconstructed voxel size, the ΔAUC was 0.0863 (0.0434) and the d' ratio was 1.40 (1.19) for 140 µm (70 µm) detector element. Small detector element sizes (e.g., 70 µm) did not significantly improve detection. The SNR results with the BR3D phantom show that calcification detection is dependent upon reconstructed voxel size and detector element size, supporting VCT results with comparable agreement (ratios: d' = 1.16 ± 0.11, SNR = 1.34 ± 0.13). CONCLUSION: DBT acquisition geometries that use super-resolution (smaller reconstructed voxels than the detector element size) combined with step-and-shoot motion have the potential to improve the detection of calcifications. CLINICAL RELEVANCE: Calcifications may not always be discernable in tomosynthesis because of differences in acquisition and reconstruction methods. VCTs can identify strategies to optimize acquisition and reconstruction parameters for calcification detection in tomosynthesis, most notably through super-resolution in the reconstruction. KEY POINTS: • Super-resolution improves calcification detection and SNR in tomosynthesis; specifically, with the use of smaller reconstruction voxels. • Calcification detection using step-and-shoot motion is superior to that using continuous tube motion. • A detector element size of 70 µm does not provide better detection than 140 µm for small calcifications at the threshold of detectability.

Development, validation, and simplification of a scanner-specific CT simulator.

BACKGROUND: Simulated computed tomography (CT) images allow for knowledge of the underlying ground truth and for easy variation of imaging conditions, making them ideal for testing and optimization of new applications or algorithms. However, simulating all processes that affect CT images can result in simulations that are demanding in terms of processing time and computer memory. Therefore, it is of interest to determine how much the simulation can be simplified while still achieving realistic results. PURPOSE: To develop a scanner-specific CT simulation using physics-based simulations for the position-dependent effects and shift-invariant image corruption methods for the detector effects. And to investigate the impact on image realism of introducing simplifications in the simulation process that lead to faster and less memory-demanding simulations. METHODS: To make the simulator realistic and scanner-specific, the spatial resolution and noise characteristics, and the exposure-to-detector output relationship of a clinical CT system were determined. The simulator includes a finite focal spot size, raytracing of the digital phantom, gantry rotation during projection acquisition, and finite detector element size. Previously published spectral models were used to model the spectrum for the given tube voltage. The integrated energy at each element of the detector was calculated using the Beer-Lambert law. The resulting angular projections were subsequently corrupted by the detector modulation transfer function (MTF), and by addition of noise according to the noise power spectrum (NPS) and signal mean-variance relationship, which were measured for different scanner settings. The simulated sinograms were reconstructed on the clinical CT system and compared to real CT images in terms of CT numbers, noise magnitude using the standard deviation, noise frequency content using the NPS, and spatial resolution using the MTF throughout the field of view (FOV). The CT numbers were validated using a multi-energy CT phantom, the noise magnitude and frequency were validated with a water phantom, and the spatial resolution was validated with a tungsten wire. These metrics were compared at multiple scanner settings, and locations in the FOV. Once validated, the simulation was simplified by reducing the level of subsampling of the focal spot area, rotation and of detector pixel size, and the changes in MTFs were analyzed. RESULTS: The average relative errors for spatial resolution within and across image slices, noise magnitude, and noise frequency content within and across slices were 3.4%, 3.3%, 4.9%, 3.9%, and 6.2%, respectively. The average absolute difference in CT numbers was 10.2 HU and the maximum was 22.5 HU. The simulation simplification showed that all subsampling can be avoided, except for angular, while the error in frequency at 10% MTF would be maximum 16.3%. CONCLUSION: The simulation of a scanner-specific CT allows for the generation of realistic CT images by combining physics-based simulations for the position-dependent effects and image-corruption methods for the shift-invariant ones. Together with the available ground truth of the digital phantom, it results in a useful tool to perform quantitative analysis of reconstruction or post-processing algorithms. Some simulation simplifications allow for reduced time and computer power requirements with minimal loss of realism.

Influence of silicon nanocone on cell membrane self-sealing capabilities for targeted drug delivery-Computer simulation study.

Efficient and non-invasive techniques of cargo delivery to biological cells are the focus of biomedical research because of their great potential importance for targeted drug therapy. Therefore, much effort is being made to study the characteristics of using nano-based biocompatible materials as systems that can facilitate this task while ensuring appropriate self-sealing of the cell membrane. Here, we study the effects of indentation and withdrawal of nanocone on phospholipid membrane by applying steered molecular dynamics (SMD) technique. Our results show that the withdrawal process directly depends on the initial position of the nanocone. The average force and work are considerably more significant in case of the withdrawal starting from a larger depth. This result is attributed to stronger hydrophobic interactions between the nanocone and lipid tails of the membrane molecules. Furthermore, when the indenter was started from the lower initial depth, the number of lipids removed from the membrane was several times smaller than the deeper indentation. The choice of the least invasive method for nanostructure-assisted drug delivery is crucial for possible applications in medicine. Therefore, the results presented in this work might be helpful in efficient and safe drug delivery with nanomaterials.

Membrane-Mediated Cooperative Interactions of CD47 and SIRPα.

The specific binding of the ubiquitous 'marker of self' protein CD47 to the SIRPα protein anchored in the macrophage plasma membrane results in the inhibition of the engulfment of 'self' cells by macrophages and thus constitutes a key checkpoint of our innate immune system. Consequently, the CD47-SIRPα protein complex has been recognized as a potential therapeutic target in cancer and inflammation. Here, we introduce a lattice-based mesoscale model for the biomimetic system studied recently in fluorescence microscopy experiments where GFP-tagged CD47 proteins on giant plasma membrane vesicles bind to SIRPα proteins immobilized on a surface. Computer simulations of the lattice-based mesoscale model allow us to study the biomimetic system on multiple length scales, ranging from single nanometers to several micrometers and simultaneously keep track of single CD47-SIRPα binding and unbinding events. Our simulations not only reproduce data from the fluorescence microscopy experiments but also are consistent with results of several other experiments, which validates our numerical approach. In addition, our simulations yield quantitative predictions on the magnitude and range of effective, membrane-mediated attraction between CD47-SIRPα complexes. Such detailed information on CD47-SIRPα interactions cannot be obtained currently from experiments alone. Our simulation results thus extend the present understanding of cooperative effects in CD47-SIRPα interactions and may have an influence on the advancement of new cancer treatments.

Partitioning variance in reproductive success, within years and across lifetimes.

Variance in reproductive success (sk2, with k = number of offspring) plays a large role in determining the rate of genetic drift and the scope within which selection acts. Various frameworks have been proposed to parse factors that contribute to sk2, but none has focused on age-specific values of ϕ=sk2/k¯, which indicate the degree to which reproductive skew is overdispersed (compared to the random Poisson expectation) among individuals of the same age and sex. Instead, within-age effects are generally lumped with residual variance and treated as "noise." Here, an ANOVA sums-of-squares framework is used to partition variance in annual and lifetime reproductive success into between-group and within-group components. For annual reproduction, the between-age effect depends on age-specific fecundity (b x), but relatively few empirical data are available on the within-age effect, which depends on ϕ x. By defining groups by age-at-death rather than age, the same ANOVA framework can be used to partition variance in lifetime reproductive success (LRS) into between-group and within-group components. Analytical methods are used to develop null-model expectations for random contributions to within-group and between-group components. For analysis of LRS, random variation in longevity appears as part of the between-group variance, and effects (if any) of skip breeding and persistent individual differences contribute to the within-group variance. Simulations are used to show that the methods for variance partitioning are asymptotically unbiased. Practical application is illustrated with empirical data for annual reproduction in American black bears and lifetime reproduction in Dutch great tits. Results show that overdispersed within-age variance (1) dominates annual sk2 in both male and female black bears, (2) is the primary factor that reduces annual effective size to a fraction of the number of adults, and (3) represents most of the opportunity for selection. In contrast, about a quarter of the variance in LRS in great tits can be attributed to random variation in longevity, and most of the rest is due to modest differences in fecundity with age estimated for a single cohort of females. R code is provided that reads generic input files for annual and lifetime reproductive success and allows users to conduct variance partitioning with their own data.