Sleep in people with and without intellectual disabilities: a systematic review and meta-analysis.

BACKGROUND: Sleep problems are regularly reported in people with intellectual disabilities. Recent years have seen a substantial increase in studies comparing sleep in people with intellectual disabilities to control participants, with an increase in the use of validated, objective measures. Emerging patterns of differences in sleep time and sleep quality warrant pooled investigation. METHODS: A systematic search was conducted across three databases (Ovid Embase, PsycInfo and Medline) and returned all papers comparing sleep in people with intellectual disabilities to a control group, published since the last meta-analysis on the topic. A quality framework was employed to rate the risk of bias across studies. Separate meta-analyses of sleep duration and sleep quality were conducted. Subgrouping compared findings for those studies with participants with genetic syndromes or neurodevelopmental conditions and those with heterogeneous intellectual disability. RESULTS: Thirteen new papers were identified and combined with those from the previous meta-analysis to provide 34 papers in total. Quality of studies was generally rated highly, though sampling provided risk of bias and adaptive functioning was rarely measured. People with intellectual disability associated with genetic syndromes or neurodevelopmental conditions sleep for shorter time periods (standardised mean difference = .26) and experience worse sleep quality (standardised mean difference = .68) than their peers. People with intellectual disability of heterogeneous origin show no difference in sleep time but have poorer sleep quality. There was some evidence that age moderated these effects. CONCLUSIONS: People with intellectual disability have poorer sleep than those without. Subtle patterns suggest that aetiology of intellectual disability moderates the topography of these difficulties, with further work needed to differentiate common and distinct mechanisms across groups.

Mathematical modelling of contact dermatitis from nickel and chromium.

Dermal exposure to metal allergens can lead to irritant and allergic contact dermatitis (ACD). In this paper we present a mathematical model of the absorption of metal ions, hexavalent chromium and nickel, into the viable epidermis and compare the localised irritant and T-lymphocyte (T-cell) mediated immune responses. The model accounts for the spatial-temporal variation of skin health, extra and intracellular allergen concentrations, innate immune cells, T-cells, cytokine signalling and lymph node activity up to about 6 days after contact with these metals; repair processes associated with withdrawal of exposure to both metals is not considered in the current model, being assumed secondary during the initial phases of exposure. Simulations of the resulting system of PDEs are studied in one-dimension, i.e. across skin depth, and three-dimensional scenarios with the aim of comparing the responses to the two ions in the cases of first contact (no T-cells initially present) and second contact (T-cells initially present). The results show that on continuous contact, chromium ions elicit stronger skin inflammation, but for nickel, subsequent re-exposure stimulates stronger responses due to an accumulation of cytotoxic T-cell mediated responses which characterise ACD. Furthermore, the surface area of contact to these metals has little effect on the speed of response, whilst sensitivity is predicted to increase with the thickness of skin. The modelling approach is generic and should be applicable to describe contact dermatitis from a wide range of allergens.

Multicellular Mathematical Modelling of Mesendoderm Formation in Amphibians.

The earliest cell fate decisions in a developing embryo are those associated with establishing the germ layers. The specification of the mesoderm and endoderm is of particular interest as the mesoderm is induced from the endoderm, potentially from an underlying bipotential group of cells, the mesendoderm. Mesendoderm formation has been well studied in an amphibian model frog, Xenopus laevis, and its formation is driven by a gene regulatory network (GRN) induced by maternal factors deposited in the egg. We have recently demonstrated that the axolotl, a urodele amphibian, utilises a different topology in its GRN to specify the mesendoderm. In this paper, we develop spatially structured mathematical models of the GRNs governing mesendoderm formation in a line of cells. We explore several versions of the model of mesendoderm formation in both Xenopus and the axolotl, incorporating the key differences between these two systems. Model simulations are able to reproduce known experimental data, such as Nodal expression domains in Xenopus, and also make predictions about how the positional information derived from maternal factors may be interpreted to drive cell fate decisions. We find that whilst cell-cell signalling plays a minor role in Xenopus, it is crucial for correct patterning domains in axolotl.

Two different network topologies yield bistability in models of mesoderm and anterior mesendoderm specification in amphibians.

Understanding the Gene Regulatory Networks (GRNs) that underlie development is a major question for systems biology. The establishment of the germ layers is amongst the earliest events of development and has been characterised in numerous model systems. The establishment of the mesoderm is best characterised in the frog Xenopus laevis and has been well studied both experimentally and mathematically. However, the Xenopus network has significant differences from that in mouse and humans, including the presence of multiple copies of two key genes in the network, Mix and Nodal. The axolotl, a urodele amphibian, provides a model with all the benefits of amphibian embryology but crucially only a single Mix and Nodal gene required for the specification of the mesoderm. Remarkably, the number of genes within the network is not the only difference. The interaction between Mix and Brachyury, two transcription factors involved in the establishment of the endoderm and mesoderm respectively, is not conserved. While Mix represses Brachyury in Xenopus, it activates Brachyury in axolotl. Thus, whilst the topology of the networks in the two species differs, both are able to form mesoderm and endoderm in vivo. Based on current knowledge of the structure of the mesendoderm GRN we develop deterministic models that describe the time evolution of transcription factors in a single axolotl cell and compare numerical simulations with previous results from Xenopus. The models are shown to have stable steady states corresponding to mesoderm and anterior mesendoderm, with the in vitro model showing how the concentration of Activin can determine cell fate, while the in vivo model shows that ß-catenin concentration can determine cell fate. Moreover, our analysis suggests that additional components must be important in the axolotl network in the specification of the full range of tissues.

The resolution of inflammation: a mathematical model of neutrophil and macrophage interactions.

There is growing interest in inflammation due to its involvement in many diverse medical conditions, including Alzheimer's disease, cancer, arthritis and asthma. The traditional view that resolution of inflammation is a passive process is now being superceded by an alternative hypothesis whereby its resolution is an active, anti-inflammatory process that can be manipulated therapeutically. This shift in mindset has stimulated a resurgence of interest in the biological mechanisms by which inflammation resolves. The anti-inflammatory processes central to the resolution of inflammation revolve around macrophages and are closely related to pro-inflammatory processes mediated by neutrophils and their ability to damage healthy tissue. We develop a spatially averaged model of inflammation centring on its resolution, accounting for populations of neutrophils and macrophages and incorporating both pro- and anti-inflammatory processes. Our ordinary differential equation model exhibits two outcomes that we relate to healthy and unhealthy states. We use bifurcation analysis to investigate how variation in the system parameters affects its outcome. We find that therapeutic manipulation of the rate of macrophage phagocytosis can aid in resolving inflammation but success is critically dependent on the rate of neutrophil apoptosis. Indeed our model predicts that an effective treatment protocol would take a dual approach, targeting macrophage phagocytosis alongside neutrophil apoptosis.

A mathematical model of the human metabolic system and metabolic flexibility.

In healthy subjects some tissues in the human body display metabolic flexibility, by this we mean the ability for the tissue to switch its fuel source between predominantly carbohydrates in the postprandial state and predominantly fats in the fasted state. Many of the pathways involved with human metabolism are controlled by insulin and insulin-resistant states such as obesity and type-2 diabetes are characterised by a loss or impairment of metabolic flexibility. In this paper we derive a system of 12 first-order coupled differential equations that describe the transport between and storage in different tissues of the human body. We find steady state solutions to these equations and use these results to nondimensionalise the model. We then solve the model numerically to simulate a healthy balanced meal and a high fat meal and we discuss and compare these results. Our numerical results show good agreement with experimental data where we have data available to us and the results show behaviour that agrees with intuition where we currently have no data with which to compare.

Modelling the role of enzymatic pathways in the metabolism of docosahexaenoic acid by monocytes and its association with osteoarthritic pain.

Chronic pain is a major cause of disability and suffering in osteoarthritis (OA) patients. Endogenous specialised pro-resolving molecules (SPMs) curtail pro-inflammatory responses. One of the SPM intermediate oxylipins, 17-hydroxydocasahexaenoic acid (17-HDHA, a metabolite of docosahexaenoic acid (DHA)), is significantly associated with OA pain. The aim of this multidisciplinary work is to develop a mathematical model to describe the contributions of enzymatic pathways (and the genes that encode them) to the metabolism of DHA by monocytes and to the levels of the down-stream metabolites, 17-HDHA and 14-hydroxydocasahexaenoic acid (14-HDHA), motivated by novel clinical data from a study involving 30 participants with OA. The data include measurements of oxylipin levels, mRNA levels, measures of OA severity and self-reported pain scores. We propose a system of ordinary differential equations to characterise associations between the different datasets, in order to determine the homeostatic concentrations of DHA, 17-HDHA and 14-HDHA, dependent upon the gene expression of the associated metabolic enzymes. Using parameter-fitting methods, local sensitivity and uncertainty analysis, the model is shown to fit well qualitatively to experimental data. The model suggests that up-regulation of some ALOX genes may lead to the down-regulation of 17-HDHA and that dosing with 17-HDHA increases the production of resolvins, which helps to down-regulate the inflammatory response. More generally, we explore the challenges and limitations of modelling real data, in particular individual variability, and also discuss the value of gathering additional experimental data motivated by the modelling insights.

Multimodal assessment improves neuroprognosis performance in clinically unresponsive critical-care patients with brain injury.

Accurately predicting functional outcomes for unresponsive patients with acute brain injury is a medical, scientific and ethical challenge. This prospective study assesses how a multimodal approach combining various numbers of behavioral, neuroimaging and electrophysiological markers affects the performance of outcome predictions. We analyzed data from 349 patients admitted to a tertiary neurointensive care unit between 2009 and 2021, categorizing prognoses as good, uncertain or poor, and compared these predictions with observed outcomes using the Glasgow Outcome Scale-Extended (GOS-E, levels ranging from 1 to 8, with higher levels indicating better outcomes). After excluding cases with life-sustaining therapy withdrawal to mitigate the self-fulfilling prophecy bias, our findings reveal that a good prognosis, compared with a poor or uncertain one, is associated with better one-year functional outcomes (common odds ratio (95% CI) for higher GOS-E: OR = 14.57 (5.70-40.32), P < 0.001; and 2.9 (1.56-5.45), P < 0.001, respectively). Moreover, increasing the number of assessment modalities decreased uncertainty (OR = 0.35 (0.21-0.59), P < 0.001) and improved prognostic accuracy (OR = 2.72 (1.18-6.47), P = 0.011). Our results underscore the value of multimodal assessment in refining neuroprognostic precision, thereby offering a robust foundation for clinical decision-making processes for acutely brain-injured patients. ClinicalTrials.gov registration: NCT04534777 .

Single-trial decoding of auditory novelty responses facilitates the detection of residual consciousness.

Detecting residual consciousness in unresponsive patients is a major clinical concern and a challenge for theoretical neuroscience. To tackle this issue, we recently designed a paradigm that dissociates two electro-encephalographic (EEG) responses to auditory novelty. Whereas a local change in pitch automatically elicits a mismatch negativity (MMN), a change in global sound sequence leads to a late P300b response. The latter component is thought to be present only when subjects consciously perceive the global novelty. Unfortunately, it can be difficult to detect because individual variability is high, especially in clinical recordings. Here, we show that multivariate pattern classifiers can extract subject-specific EEG patterns and predict single-trial local or global novelty responses. We first validate our method with 38 high-density EEG, MEG and intracranial EEG recordings. We empirically demonstrate that our approach circumvents the issues associated with multiple comparisons and individual variability while improving the statistics. Moreover, we confirm in control subjects that local responses are robust to distraction whereas global responses depend on attention. We then investigate 104 vegetative state (VS), minimally conscious state (MCS) and conscious state (CS) patients recorded with high-density EEG. For the local response, the proportion of significant decoding scores (M=60%) does not vary with the state of consciousness. By contrast, for the global response, only 14% of the VS patients' EEG recordings presented a significant effect, compared to 31% in MCS patients' and 52% in CS patients'. In conclusion, single-trial multivariate decoding of novelty responses provides valuable information in non-communicating patients and paves the way towards real-time monitoring of the state of consciousness.

Modelling auxin efflux carrier phosphorylation and localization.

Regulation of the activity and localization of PIN-FORMED (PIN) membrane proteins, which facilitate efflux of the plant hormone auxin from cells, is important for plants to respond to environmental stimuli and to develop new organs. The protein kinase PINOID (PID) is involved in regulating PIN phosphorylation, and this is thought to affect PIN localization by biasing recycling towards shootwards (apical) (rather than rootwards (basal)) membrane domains. PID has been observed to undergo transient internalization following auxin treatment, and it has been suggested that this may be a result of calcium-dependent sequestration of PID by the calcium-binding protein TOUCH3 (TCH3). We present a mathematical formulation of these processes and examine the resulting steady-state and time-dependent behaviours in response to transient increases in cytosolic calcium. We further combine this model with one for the recycling of PINs in polarized cells and also examine its behaviour. The results provide insight into the behaviour observed experimentally and provide the basis for subsequent studies of the tissue-level implications of these subcellular processes for phenomena such as gravitropism.

Mathematical modelling of toxicity associated with intracellular chromium reduction.

Chromium is a known allergen and carcinogen, but the mechanisms by which damage is caused are not clearly understood. Based on experimental literature, we devise a conceptual model examining the intracellular reduction of chromium through reductants such as glutathione and ascorbic acid. From this, we build a mathematical model describing these events in detail and we use this to clarify the key steps in the process of chromium reduction within cells.In particular, we consider the free radicals which are generated as a result of chromium reduction and that are likely to cause most harm to the cell. To explore the practical implications of the model predication, we investigate what the effects of a single eight hours of exposure and multiple eight hour exposures over the course of 3 days with increasing extracellular chromium concentration are. The dependence on initial chromium concentration is of particular significance with the proportions of the various chromium states changing as well as free radical generation increasing with greater chromium exposure.

Wave pinning and spatial patterning in a mathematical model of Antivin/Lefty-Nodal signalling.

Nodal signals are key regulators of mesoderm and endoderm development in vertebrate embryos. It has been observed experimentally that in Xenopus embryos the spatial range of Nodal signals is restricted by the signal Antivin (also known as Lefty). Nodal signals can activate both Nodal and Antivin, whereas Antivin is thought to antagonise Nodal by binding either directly to it or to its receptor. In this paper we develop a mathematical model of this signalling network in a line of cells. We consider the heterodimer and receptor-mediated inhibition mechanisms separately and find that, in both cases, the restriction by Antivin to the range of Nodal signals corresponds to wave pinning in the model. Our analysis indicates that, provided Antivin diffuses faster than Nodal, either mechanism can robustly account for the experimental data. We argue that, in the case of Xenopus development, it is wave pinning, rather than Turing-type patterning, that is underlying Nodal-Antivin dynamics. This leads to several experimentally testable predictions, which are discussed. Furthermore, for heterodimer-mediated inhibition to prevent waves of Nodal expression from propagating, the Nodal-Antivin complex must be turned over, and diffusivity of the complex must be negligible. In the absence of molecular mechanisms regulating these, we suggest that Antivin restricts Nodal signals via receptor-mediated, and not heterodimer-mediated, inhibition.

Fiber reinforced hydrated networks recapitulate the poroelastic mechanics of articular cartilage.

The role of poroelasticity on the functional performance of articular cartilage has been established in the scientific literature since the 1960s. Despite the extensive knowledge on this topic there remain few attempts to design for poroelasticity and to our knowledge no demonstration of an engineered poroelastic material that approaches the physiological performance. In this paper, we report on the development of an engineered material that begins to approach physiological poroelasticity. We quantify poroelasticity using the fluid load fraction, apply mixture theory to model the material system, and determine cytocompatibility using primary human mesenchymal stem cells. The design approach is based on a fiber reinforced hydrated network and uses routine fabrication methods (electrohydrodynamic deposition) and materials (poly[ɛ-caprolactone] and gelatin) to develop the engineered poroelastic material. This composite material achieved a mean peak fluid load fraction of 68%, displayed consistency with mixture theory, and demonstrated cytocompatibility. This work creates a foundation for designing poroelastic cartilage implants and developing scaffold systems to study chondrocyte mechanobiology and tissue engineering. STATEMENT OF SIGNIFICANCE: Poroelasticity drives the functional mechanics of articular cartilage (load bearing and lubrication). In this work we develop the design rationale and approach to produce a poroelastic material, known as a fiber reinforced hydrated network (FiHy™), that begins to approach the native performance of articular cartilage. This is the first engineered material system capable of exceeding isotropic linear poroelastic theory. The framework developed here enables fundamental studies of poroelasticity and the development of translational materials for cartilage repair.

Continuum limits of pattern formation in hexagonal-cell monolayers.

Intercellular signalling is key in determining cell fate. In closely packed tissues such as epithelia, juxtacrine signalling is thought to be a mechanism for the generation of fine-grained spatial patterns in cell differentiation commonly observed in early development. Theoretical studies of such signalling processes have shown that negative feedback between receptor activation and ligand production is a robust mechanism for fine-grained pattern generation and that cell shape is an important factor in the resulting pattern type. It has previously been assumed that such patterns can be analysed only with discrete models since significant variation occurs over a lengthscale concomitant with an individual cell; however, considering a generic juxtacrine signalling model in square cells, in O'Dea and King (Math Biosci 231(2):172-185 2011), a systematic method for the derivation of a continuum model capturing such phenomena due to variations in a model parameter associated with signalling feedback strength was presented. Here, we extend this work to derive continuum models of the more complex fine-grained patterning in hexagonal cells, constructing individual models for the generation of patterns from the homogeneous state and for the transition between patterning modes. In addition, by considering patterning behaviour under the influence of simultaneous variation of feedback parameters, we construct a more general continuum representation, capturing the emergence of the patterning bifurcation structure. Comparison with the steady-state and dynamic behaviour of the underlying discrete system is made; in particular, we consider pattern-generating travelling waves and the competition between various stable patterning modes, through which we highlight an important deficiency in the ability of continuum representations to accommodate certain dynamics associated with discrete systems.

Multiscale modelling of auxin transport in the plant-root elongation zone.

In the root elongation zone of a plant, the hormone auxin moves in a polar manner due to active transport facilitated by spatially distributed influx and efflux carriers present on the cell membranes. To understand how the cell-scale active transport and passive diffusion combine to produce the effective tissue-scale flux, we apply asymptotic methods to a cell-based model of auxin transport to derive systematically a continuum description from the spatially discrete one. Using biologically relevant parameter values, we show how the carriers drive the dominant tissue-scale auxin flux and we predict how the overall auxin dynamics are affected by perturbations to these carriers, for example, in knockout mutants. The analysis shows how the dominant behaviour depends on the cells' lengths, and enables us to assess the relative importance of the diffusive auxin flux through the cell wall. Other distinguished limits are also identified and their potential roles discussed. As well as providing insight into auxin transport, the study illustrates the use of multiscale (cell to tissue) methods in deriving simplified models that retain the essential biology and provide understanding of the underlying dynamics.

Axisymmetric indentation of curved elastic membranes by a convex rigid indenter.

Motivated by applications to seed germination, we consider the transverse deflection that results from the axisymmetric indentation of an elastic membrane by a rigid body. The elastic membrane is fixed around its boundary, with or without an initial pre-stretch, and may be initially curved prior to indentation. General indenter shapes are considered, and the load-indentation curves that result for a range of spheroidal tips are obtained for both flat and curved membranes. Wrinkling may occur when the membrane is initially curved, and a relaxed strain-energy function is used to calculate the deformed profile in this case. Applications to experiments designed to measure the mechanical properties of seed endosperms are discussed.

Mathematical modelling of the Aux/IAA negative feedback loop.

The hormone auxin is implicated in regulating a diverse range of developmental processes in plants. Auxin acts in part by inducing the Aux/IAA genes. The associated pathway comprises multiple negative feedback loops (whereby Aux/IAA proteins can repress Aux/IAA genes) that are disrupted by auxin mediating the turnover of Aux/IAA protein. In this paper, we develop a mathematical model of a single Aux/IAA negative feedback loop in a population of identical cells. The model has a single steady-state. We explore parameter space to uncover a number of dynamical regimes. In particular, we identify the ratio between the Aux/IAA protein and mRNA turnover rates as a key parameter in the model. When this ratio is sufficiently small, the system can evolve to a stable limit cycle, corresponding to an oscillation in Aux/IAA expression levels. Otherwise, the steady-state is either a stable-node or a stable-spiral. These observations may shed light on recent experimental results.

Modelling of the activation of G-protein coupled receptors: drug free constitutive receptor activity.

G-protein coupled receptors (GPCRs) form a crucial component of approximately 80% of hormone pathways. In this paper, the most popular mechanism for activation of GPCRs-the shuttling mechanism-is modelled mathematically. An asymptotic analysis of this model clarifies the dynamics of the system in the absence of drug, in particular which reactions dominate during the different timescales. Equilibrium analysis of the model demonstrates the model's ability to predict constitutive receptor activity.

Distribution of the Red Imported Fire Ant Solenopsis invicta (Hymenoptera: Formicidae) in Central Florida Pastures.

Habitat disturbance has been found to facilitate the introduction of a wide range of species, including the red imported fire ant Solenopsis invicta Buren (Hymenoptera: Formicidae: Myrmicinae). Despite the link between S. invicta colonization and disturbance, little is known about how different intensities or types of disturbance might impact S. invicta populations. In this study, we used S. invicta populations in cattle pastures to understand how variation in disturbance type and frequency correlates with the density of S. invicta mounds. In total, 56 plots were surveyed for mound abundance during both the wet and dry seasons on a subtropical south Florida ranch. Explanatory variables were grouped into five categories based on disturbance type: 1) historic pasture conversion; 2) modern pasture management (mowing, dragging, chopping, or aerating); 3) grazing intensity (a measure vegetation height and dung pat abundance); 4) distance to human-made and natural localized disturbance (roads, ditches, and wetlands); and 5) abiotic conditions (soil temperature, soil moisture). Overall, the average number of mounds per plot was not significantly different between seasons, but was significantly higher in intensive pastures, which are converted to nonnative forage grasses than in seminative pastures during the dry season. Time since soil disturbance (aeration and chopping of pasture) was a significant predictor of S. invicta densities in both dry and wet seasons, with an increase in time since disturbance being associated with higher mound densities. Other forms of pasture management that did not disturb the soil, such as dragging and mowing, as well as distance to localized disturbances (wetlands, roads, and ditches) were not found to have a significant correlation in either season.

Bistability in a model of mesoderm and anterior mesendoderm specification in Xenopus laevis.

In this paper we develop a model of mesendoderm specification in Xenopus laevis based on an existing gene regulation network. The mesendoderm is a population of cells that may contribute to either the mesoderm or endoderm. The model that we develop encompasses the time evolution of transcription factor concentrations in a single cell and is shown to have stable steady states that correspond to mesoderm and anterior mesendodermal cell types, but not endoderm (except in cells where Goosecoid expression is inhibited). Both in vitro and in vivo versions of the model are developed and analysed, the former indicating how cell fate is determined in large part by the concentration of Activin administered to a cell, with the model results comparing favourably with current quantitative experimental data. A numerical investigation of the in vivo model suggests that cell fate is determined largely by a VegT and beta-Catenin pre-pattern, subsequently being reinforced by Nodal. We argue that this sensitivity of the model to a VegT and beta-Catenin pre-pattern indicates that a key VegT self-limiting mechanism (for which there is experimental evidence) is absent from the model. Furthermore, we find that the lack of a steady state corresponding to endoderm is entirely consistent with current in vivo data, and that the in vivo model corresponds to mesendoderm specification on the dorsal, but not the ventral, side of the embryo.