From conceptualising to modelling structural determinants and interventions in HIV transmission dynamics models: a scoping review and methodological framework for evidence-based analyses.

BACKGROUND: Including structural determinants (e.g. criminalisation, stigma, inequitable gender norms) in dynamic HIV transmission models is important to help quantify their population-level impacts and guide implementation of effective interventions that reduce the burden of HIV and inequalities thereof. However, evidence-based modelling of structural determinants is challenging partly due to a limited understanding of their causal pathways and few empirical estimates of their effects on HIV acquisition and transmission. METHODS: We conducted a scoping review of dynamic HIV transmission modelling studies that evaluated the impacts of structural determinants, published up to August 28, 2023, using Ovid Embase and Medline online databases. We appraised studies on how models represented exposure to structural determinants and causal pathways. Building on this, we developed a new methodological framework and recommendations to support the incorporation of structural determinants in transmission dynamics models and their analyses. We discuss the data and analyses that could strengthen the evidence used to inform these models. RESULTS: We identified 17 HIV modelling studies that represented structural determinants and/or interventions, including incarceration of people who inject drugs (number of studies [n] = 5), violence against women (n = 3), HIV stigma (n = 1), and housing instability (n = 1), among others (n = 7). Most studies (n = 10) modelled exposures dynamically. Almost half (8/17 studies) represented multiple exposure histories (e.g. current, recent, non-recent exposure). Structural determinants were often assumed to influence HIV indirectly by influencing mediators such as contact patterns, condom use, and antiretroviral therapy use. However, causal pathways' assumptions were sometimes simple, with few mediators explicitly represented in the model, and largely based on cross-sectional associations. Although most studies calibrated models using HIV epidemiological data, less than half (7/17) also fitted or cross-validated to data on the prevalence, frequency, or effects of exposure to structural determinants. CONCLUSIONS: Mathematical models can play a crucial role in elucidating the population-level impacts of structural determinants and interventions on HIV. We recommend the next generation of models reflect exposure to structural determinants dynamically and mechanistically, and reproduce the key causal pathways, based on longitudinal evidence of links between structural determinants, mediators, and HIV. This would improve the validity and usefulness of predictions of the impacts of structural determinants and interventions.

Estimating community-wide indirect effects of influenza vaccination: triangulation using mathematical models and bias analysis.

Understanding whether influenza vaccine promotion strategies produce community-wide indirect effects is important for establishing vaccine coverage targets and optimizing vaccine delivery. Empirical epidemiologic studies and mathematical models have been used to estimate indirect effects of vaccines but rarely for the same estimand in the same dataset. Using these approaches together could be a powerful tool for triangulation in infectious disease epidemiology because each approach is subject to distinct sources of bias. We triangulated evidence about indirect effects from a school-located influenza vaccination program using two approaches: a difference-in-difference (DID) analysis, and an age-structured, deterministic, compartmental model. The estimated indirect effect was substantially lower in the mathematical model than in the DID analysis (2.1% (95% Bayesian credible intervals 0.4 - 4.4%) vs. 22.3% (95% CI 7.6% - 37.1%)). To explore reasons for differing estimates, we used sensitivity analyses and probabilistic bias analyses. When we constrained model parameters such that projections matched the DID analysis, results only aligned with the DID analysis with substantially lower pre-existing immunity among school-age children and older adults. Conversely, DID estimates corrected for potential bias only aligned with mathematical model estimates under differential outcome misclassification. We discuss how triangulation using empirical and mathematical modelling approaches could strengthen future studies.

Exploring Osmotic Dehydration for Food Preservation: Methods, Modelling, and Modern Applications.

This study summarizes the most recent findings on osmotic dehydration, a crucial step in food preservation. The many benefits of osmotic dehydration are listed, including longer shelf life and preserved nutritional value. Mass transfer dynamics, which are critical to understanding osmotic dehydration, are explored alongside mathematical models essential for comprehending this process. The effect of osmotic agents and process parameters on efficacy, such as temperature, agitation and osmotic agent concentration, is closely examined. Pre-treatment techniques are emphasized in order to improve process effectiveness and product quality. The increasing demand for sustainability is a critical factor driving research into eco-friendly osmotic agents, waste valorization, and energy-efficient methods. The review also provides practical insights into process optimization and discusses the energy consumption and viability of osmotic dehydration compared to other drying methods. Future applications and improvements are highlighted, making it an invaluable tool for the food industry.

Ammonia leakage can underpin nitrogen-sharing among soil microorganisms.

Soil microbial communities host a large number of microbial species that support important ecological functions such as biogeochemical cycling and plant nutrition. The extent and stability of these functions are affected by inter-species interactions among soil microorganisms, yet the different mechanisms underpinning microbial interactions in the soil are not fully understood. Here, we study the extent of nutrient-based interactions among two model, plant-supporting soil microorganisms, the fungi Serendipita indica, and the bacteria Bacillus subtilis. We found that S. indica is unable to grow with nitrate - a common nitrogen source in the soil - but this inability could be rescued, and growth restored in the presence of B. subtilis. We demonstrate that this effect is due to B. subtilis utilising nitrate and releasing ammonia, which can be used by S. indica. We refer to this type of mechanism as ammonia mediated nitrogen sharing (N-sharing). Using a mathematical model, we demonstrated that the pH dependent equilibrium between ammonia (NH3) and ammonium (NH+4) results in an inherent cellular leakiness, and that reduced amonnium uptake or assimilation rates could result in higher levels of leaked ammonia. In line with this model, a mutant B. subtilis - devoid of ammonia uptake - showed higher S. indica growth support in nitrate media. These findings highlight that ammonia based N-sharing can be a previously under-appreciated mechanism underpinning interaction among soil microorganisms and could be influenced by microbial or abiotic alteration of pH in microenvironments.

Pathogen non-planktonic phases within the urinary tract impact early infection and resistance evolution.

Treatment of urinary tract infections and the prevention of their recurrence is a pressing global health problem. In a urinary infection, pathogenic bacteria not only reside in the bladder lumen but also attach to and invade the bladder tissue. Planktonic, attached, and intracellular bacteria face different selection pressures from physiological processes such as micturition, immune response, and antibiotic treatment. Here, we use a mathematical model of the initial phase of infection to unravel the effects of these different selective pressures on the ecological and evolutionary dynamics of urinary infections. We explicitly model planktonic bacteria in the bladder lumen, bacteria attached to the bladder wall, and bacteria that have invaded the epithelial cells of the bladder. We find that the presence of non-planktonic bacteria substantially increases the risk of infection establishment and affects evolutionary trajectories leading to resistance during antibiotic treatment. We also show that competitive inoculation with a fast-growing non-pathogenic strain can reduce the pathogen load and increase the efficacy of an antibiotic, but only if the antibiotic is used in moderation. Our study shows that including different compartments is essential to create more realistic models of urinary infections, which may help guide new treatment strategies.

Modelling antibody dynamics in humans after different Ad26.COV2.S vaccination schemes.

AIMS: To develop a semimechanistic model that describes the kinetic profile and variability of antibody (Ab) concentrations following vaccination with Ad26.COV2.S at different doses and dosing intervals. METHODS: Data were collected from participants randomized into 5 clinical trials receiving the Ad26.COV2.S vaccine. The model considered key elements of humoral immune response, dose proportionality and the evolutionary processes of the immune response. Interindividual variability and covariates were explored. RESULTS: Fast and slow kinetic phases of Ab and their evolution over time were differentiated. After first and second administrations, Ab concentrations of both phases increased less than dose proportionally, indicating a saturation of B-cell production processes. Ab concentrations produced during the fast kinetic phase increased significantly after the second administration, indicating an underlying evolutive process after antigen exposures. For the slow kinetic phase, a less pronounced increase occurred after the second and third administrations but was relatively higher in subjects who had low concentrations after the first administration. Ab concentrations of the slow phase were higher in females and decreased with age. After multiple administrations, the fast phase had Ab maximum concentrations about 5 times higher than the slow phase. The limiting kinetic factors in the fast and slow phases were the elimination rates of Ab itself and Ab producing cells, respectively. CONCLUSION: The model appears suitable to quantitatively describe the inter- and intraindividual kinetics of the immune response and the impact of covariates after multiple administrations of a vaccine.

Reactive extraction of muconic acid by hydrophobic phosphonium ionic liquids - Experimental, modelling and optimisation with Artificial Neural Networks.

Muconic acid is a six-carbon dicarboxylic acid with conjugated double bonds that finds extensive use in the food (additive), chemical (production of adipic acid, monomer for functional resins and bio-plastics), and pharmaceutical sectors. The biosynthesis of muconic acid has been the subject of recent industrial and scientific attention. However, because of its low concentration in aqueous solutions and high purity requirement, downstream separation presents a significant problem. Artificial Neural Networks and Differential Evolution were used to optimize process parameters for the recovery of muconic acid from aqueous streams in a system with n-heptane as an organic diluent and ionic liquids as extractants. The system using 120 g/L tri-hexyl-tetra-decyl-phosphonium decanoate dissolved in n-heptane, pH of the aqueous phase 3, 20 min contact time, and 45 °C temperature assured a muconic acid extraction efficiency of 99,24 %. Low stripping efficiency compared to extraction efficiency was observed for the optimum conditions on the extraction step (120 g/L ionic liquids dissolved in heptane). However, re-extraction efficiencies obtained for the recycled organic phase in three consecutive stages were close to the first extraction stage. The mechanism analysis proved that the analysed phosphonium ionic liquids (PILSs) extracts only undissociated molecules of muconic acid through H-bonding.

Early mathematical models of COVID-19 vaccination in high-income countries: a systematic review.

OBJECTIVES: Since COVID-19 first emerged in 2019, mathematical models have been developed to predict transmission and provide insight into disease control strategies. A key research need now is for models to inform long-term vaccination policy. We aimed to review the early modelling methods utilised during the pandemic period (2019-2023) in order to identify gaps in the literature and highlight areas for future model development. STUDY DESIGN: This study was a systematic review. METHODS: We searched PubMed, Embase and Scopus from 1 January 2019 to 6 February 2023 for peer-reviewed, English-language articles describing age-structured, dynamic, mathematical models of COVID-19 transmission and vaccination in high-income countries that include waning immunity or reinfection. We extracted details of the structure, features and approach of each model and combined them in a narrative synthesis. RESULTS: Of the 1109 articles screened, 47 were included. Most studies used deterministic, compartmental models set in Europe or North America that simulated a time horizon of 3.5 years or less. Common outcomes included cases, hospital utilisation and deaths. Only nine models included long COVID, costs, life years or quality of life-related measures. Two studies explored the potential impact of new variants beyond Omicron. CONCLUSIONS: This review demonstrates a need for long-term models that focus on outcome measures such as quality-adjusted life years, the population-level effects of long COVID and the cost effectiveness of future policies - all of which are essential considerations in the planning of long-term vaccination strategies.

Effect of the flow-force relationships used in two parameter modelling of freezing and vitrification protocols for bovine embryos.

Cells may become damaged by strong volume changes and related intracellular changes during slow freezing or vitrification. These osmotic events can be modelled mathematically, using descriptions of transmembrane flow of solute and water. We compared different variants of an often used 2-parameter (2P) formalism in fitting of an empirical shrink-swell curve of a bovine embryo in 5 vol% glycerol, and in simulations of CPA loading and removal in a vitrification protocol. In its original form, the 2P model uses a flow-force relationship for the flux of CPA that is not analogous to that for water (asymmetrical), but in the other variants used, the flow-force relationships for water and CPA are analogous to each other (symmetrical). The effect of used model on estimated values for Lp and Ps in 5 vol% glycerol was small. Also the effect on shrinking and swelling in vitrification media was small, but the original 2P model predicted stronger swelling of embryos during one-step CPA removal. One variant that we compared simply assumes Raoult's law, i.e. M = m, even in very concentrated solutions We conclude that this simple model is easy and appropriate for simulating osmotic events of embryo's. But if a method for correcting for the deviation from Raoult's law is used, a symmetrical model seems more appropriate than the original (asymmetrical) 2P model.

Potential of coupled array harvester in enhanced energy harvesting.

Harvesting energy from nonlinear systems has been at the centre of research in the energy harvesting community. Many such proposed systems are single nonlinear harvester. While these systems show an increase in bandwidth of harvesting frequency, overall, they are not effective enough in power generation. This article studies power harvesting and frequency bandwidth characteristics of an array of harvesters. Multiple harvesters are considered with linear and nonlinear coupling between the harvesters. The phenomena of internal resonance (IR) and stochastic resonance (SR) are reported. The IR in multiple coupled nonlinear harvesters is explored using multiple-scale analysis. A parametric study is conducted to demonstrate the effect of coupling strength, frequency mistuning, innate nonlinearity and other parameters. The parametric study helped establish effective ways to increase bandwidth. Moreover, a stochastically loaded linearly coupled bistable harvester array is numerically analysed to find the effect of coupling strength and array size on the phenomenon of SR and on the system's harvesting performance. Through these studies, the potential of multiple coupled nonlinear harvesters in enhanced energy harvesting is demonstrated under both harmonic and stochastic excitation.This article is part of the theme issue 'Celebrating the 15th anniversary of the Royal Society Newton International Fellowship'.

Effects of mobility, immunity and vaccination on SARS-CoV-2 transmission in the Dominican Republic: a modelling study.

Background: COVID-19 dynamics are driven by a complex interplay of factors including population behaviour, new variants, vaccination and immunity from prior infections. We quantify drivers of SARS-CoV-2 transmission in the Dominican Republic, an upper-middle income country of 10.8 million people. We then assess the impact of the vaccination campaign implemented in February 2021, primarily using CoronaVac, in saving lives and averting hospitalisations. Methods: We fit an age-structured, multi-variant transmission dynamic model to reported deaths, hospital bed occupancy, and seroprevalence data until December 2021, and simulate epidemic trajectories under different counterfactual scenarios. Findings: We estimate that vaccination averted 7210 hospital admissions (95% credible interval, CrI: 6830-7600), 2180 intensive care unit admissions (95% CrI: 2080-2280) and 766 deaths (95% CrI: 694-859) in the first 6 months of the campaign. If no vaccination had occurred, we estimate that an additional decrease of 10-20% in population mobility would have been required to maintain equivalent death and hospitalisation outcomes. We also found that early vaccination with CoronaVac was preferable to delayed vaccination using a product with higher efficacy. Interpretation: SARS-CoV-2 transmission dynamics in the Dominican Republic were driven by a substantial accumulation of immunity during the first two years of the pandemic but, despite this, vaccination was essential in enabling a return to pre-pandemic mobility levels without considerable additional morbidity and mortality. Funding: Medical Research Council, Wellcome Trust, Royal Society, US CDC and Australian National Health and Medical Research Council.

Sensory feedback and central neuronal interactions in mouse locomotion.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyse a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behaviour to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Challenges in the case-based surveillance of infectious diseases.

To effectively inform infectious disease control strategies, accurate knowledge of the pathogen's transmission dynamics is required. Since the timings of infections are rarely known, estimates of the infection incidence, which is crucial for understanding the transmission dynamics, often rely on measurements of other quantities amenable to surveillance. Case-based surveillance, in which infected individuals are identified by a positive test, is the predominant form of surveillance for many pathogens, and was used extensively during the COVID-19 pandemic. However, there can be many biases present in case-based surveillance indicators due to, for example test sensitivity, changing testing behaviours and the co-circulation of pathogens with similar symptom profiles. Here, we develop a mathematical description of case-based surveillance of infectious diseases. By considering realistic epidemiological parameters and situations, we demonstrate many of the potential biases in common surveillance indicators based on case-based surveillance data. Crucially, we find that many of these common surveillance indicators (e.g. case numbers, test-positive proportion) are heavily biased by circulating pathogens with similar symptom profiles. Future surveillance strategies could be designed to minimize these sources of bias and uncertainty, providing more accurate estimates of a pathogen's transmission dynamics and, ultimately, more targeted application of public health measures.

Is SARS-CoV-2 elimination or mitigation best? Regional and disease characteristics determine the recommended strategy.

Public health responses to the COVID-19 pandemic varied across the world. Some countries (e.g. mainland China, New Zealand and Taiwan) implemented elimination strategies involving strict travel measures and periods of rigorous non-pharmaceutical interventions (NPIs) in the community, aiming to achieve periods with no disease spread; while others (e.g. many European countries and the USA) implemented mitigation strategies involving less strict NPIs for prolonged periods, aiming to limit community spread. Travel measures and community NPIs have high economic and social costs, and there is a need for guidelines that evaluate the appropriateness of an elimination or mitigation strategy in regional contexts. To guide decisions, we identify key criteria and provide indicators and visualizations to help answer each question. Considerations include determining whether disease elimination is: (1) necessary to ensure healthcare provision; (2) feasible from an epidemiological point of view and (3) cost-effective when considering, in particular, the economic costs of travel measures and treating infections. We discuss our recommendations by considering the regional and economic variability of Canadian provinces and territories, and the epidemiological characteristics of different SARS-CoV-2 variants. While elimination may be a preferable strategy for regions with limited healthcare capacity, low travel volumes, and few ports of entry, mitigation may be more feasible in large urban areas with dense infrastructure, strong economies, and with high connectivity to other regions.

Degree-based topological indices and entropies of diamond crystals.

High hardness, low friction coefficient and chemical resistance are only a few of the exceptional mechanical qualities of diamond. Diamonds can be artificially created to have different levels of conductivity, or they can be single, micro or nanocrystalline and highly electrically insulating. It also has high biocompatibility and is famous for being mechanically robust. Due to its high hardness, lack of ductility and difficulty in welding, diamond is a challenging material to construct devices with. Diamonds have experienced a rise in attention as a biological material in recent decades due to new synthesis and fabrication techniques that have eliminated some of these disadvantages. In general, entropic measurements are used for investigating the chemical or biological properties of molecular structures. This study calculates several important K-Banhatti entropies, redefined Zagreb entropies and atom-bond sum connectivity entropy for diamond crystals. We also present a numeric and graphical explanations of obtain indices.

Sensitivity analysis of models of gas exchange for lung hyperpolarised 129Xe MR.

Sensitivity analysis enables the identification of influential parameters and the optimisation of model composition. Such methods have not previously been applied systematically to models describing hyperpolarised 129Xe gas exchange in the lung. Here, we evaluate the current 129Xe gas exchange models to assess their precision for identifying alterations in pulmonary vascular function and lung microstructure. We assess sensitivity using established univariate methods and scatter plots for parameter interactions. We apply them to the model described by Patz et al and the Model of Xenon Exchange (MOXE), examining their ability to measure: i) importance (rank), ii) temporal dependence and iii) interaction effects of each parameter across healthy and diseased ranges. The univariate methods and scatter plot analyses demonstrate consistently similar results for the importance of parameters common to both models evaluated. Alveolar surface area to volume ratio is identified as the parameter to which model signals are most sensitive. The alveolar-capillary barrier thickness is identified as a low-sensitivity parameter for the MOXE model. An acquisition window of at least 200 ms effectively demonstrates model sensitivity to most parameters. Scatter plots reveal interaction effects in both models, impacting output variability and sensitivity. Our sensitivity analysis ranks the parameters within the model described by Patz et al and within the MOXE model. The MOXE model shows low sensitivity to alveolar-capillary barrier thickness, highlighting the need for designing acquisition protocols optimised for the measurement of this parameter. The presence of parameter interaction effects highlights the requirement for care in interpreting model outputs.

Modelling glioblastoma resistance to temozolomide. A mathematical model to simulate cellular adaptation in vitro.

Drug resistance is one of the biggest challenges in the fight against cancer. In particular, in the case of glioblastoma, the most lethal brain tumour, resistance to temozolomide (the standard of care drug for chemotherapy in this tumour) is one of the main reasons behind treatment failure and hence responsible for the poor prognosis of patients diagnosed with this disease. In this work, we combine the power of three-dimensional in vitro experiments of treated glioblastoma spheroids with mathematical models of tumour evolution and adaptation. We use a novel approach based on internal variables for modelling the acquisition of resistance to temozolomide that was observed in experiments for a group of treated spheroids. These internal variables describe the cell's phenotypic state, which depends on the history of drug exposure and affects cell behaviour. We use model selection to determine the most parsimonious model and calibrate it to reproduce the experimental data, obtaining a high level of agreement between the in vitro and in silico outcomes. A sensitivity analysis is carried out to investigate the impact of each model parameter in the predictions. More importantly, we show how the model is useful for answering biological questions, such as what is the intrinsic adaptation mechanism, or for separating the sensitive and resistant populations. We conclude that the proposed in silico framework, in combination with experiments, can be useful to improve our understanding of the mechanisms behind drug resistance in glioblastoma and to eventually set some guidelines for the design of new treatment schemes.

Coupling cation and anion exchange chromatography for fast separation of monoclonal antibody charge variants.

A design procedure for the separation of charge variants of a monoclonal antibody (mAb) was developed, which was based on the coupling of cation-exchange chromatography (CEX) and anion-exchange chromatography (AEX) under high loading conditions. The design of the coupled process was supported by a dynamic model. The model was calibrated on the basis of band profiles of variants determined experimentally for the mAb materials of different variant compositions. The numerical simulations were used to select the coupling configuration and the loading conditions that allowed for efficient separation of the mAb materials into three products enriched with each individual variant: the acidic (av), main (mv) and basic (bv) one. In the CEX section, a two-step pH gradient was used to split the loaded mass of mAb into a weakly bound fraction enriched with av and mv, and a strongly bound fraction containing the bv-rich product. The weakly bound fraction was further processed in the AEX section, where the mv-rich product was eluted in flowthrough, while the av-rich product was collected by a step change in pH. The choice of flow distribution and the number of columns in the CEX and AEX sections depended on the variant composition of the mAb material. For the selected configurations, the optimized mAb loading density in the CEX columns ranged from 10 to 26 mg mL-1, while in the AEX columns it was as high as 300 or 600 mg mL-1, depending on the variant composition of the mAb material. By proper selection of the loading condition, a trade-off between yield and purity of the products could be reached.

Modelling white matter microstructure using diffusion OGSE MRI: Model and analysis choices.

Alterations in white matter (WM) microstructure of the central nervous system have been shown to be pathophysiological presentations of various neurodegenerative disorders. Current methods for measuring such WM features require ex vivo tissue samples analyzed using electron microscopy. Magnetic Resonance Imaging (MRI) diffusion-weighted pulse sequences provide a non-invasive tool for estimating such microstructural features in vivo. The current project investigated the use of two methods of analysis, including the ROI-based (Region of Interest, RBA) and voxel-based analysis (VBA), as well as four mathematical models of WM microstructure, including the ActiveAx Frequency-Independent Extra-Axonal Diffusion (AAI), ActiveAx Frequency-Dependent Extra-Axonal Diffusion (AAD), AxCaliber Frequency-Independent Extra-Axonal Diffusion (ACI), and AxCaliber Frequency-Dependent Extra-Axonal Diffusion (ACD) models. Two mice samples imaged at 7 T and 15.2 T were analyzed. Both the AAI and AAD models provide a single value for each of the fit parameters, including mean effective axon diameter AxD¯, packing fraction fin, intra-cellular and Din and extra-cellular Dex diffusion coefficients, as well as the frequency dependence of Dex, ßex for the AAD model. The ACI and ACD models provide this, in addition to a distribution of axon diameters for a chosen ROI. VBA extends this, providing a parameter value for each voxel within the selected ROI, at the cost of increased computational load and analysis time. Overall, RBA-ACD and VBA-AAD were found to be optimal for parameter fitting to physically relevant values in a reasonable time frame. A full comparison of each combination of RBA and VBA with AAI, AAD, ACI, and ACD is provided to give the reader sufficient information to make an informed decision of which model is best for their own experiments.