Energy Balance and Bone Health: a Nutrient Availability Perspective.

PURPOSE OF REVIEW: Obesity is highly prevalent and is associated with bone fragility and fracture. The changing nutrient availability to bone in obesity is an important facet of bone health. The goal of this article is to summarize current knowledge on the effects of carbohydrate and dietary fat availability on bone, particularly in the context of other tissues. RECENT FINDINGS: The skeleton is a primary site for fatty acid and glucose uptake. The trafficking of carbohydrates and fats into tissues changes with weight loss and periods of weight gain. Exercise acutely influences nutrient uptake into bone and may affect nutrient partitioning to bone. Bone cells secrete hormones that signal to the brain and other tissues information about its energetic state, which may alter whole-body nutrient trafficking. There is a critical need for studies to address the changes that metabolic perturbations have on nutrient availability in bone.

Leveraging metabolic modeling to identify functional metabolic alterations associated with COVID-19 disease severity.

OBJECTIVE: Since the COVID-19 pandemic began in early 2020, SARS-CoV2 has claimed more than six million lives world-wide, with over 510 million cases to date. To reduce healthcare burden, we must investigate how to prevent non-acute disease from progressing to severe infection requiring hospitalization. METHODS: To achieve this goal, we investigated metabolic signatures of both non-acute (out-patient) and severe (requiring hospitalization) COVID-19 samples by profiling the associated plasma metabolomes of 84 COVID-19 positive University of Virginia hospital patients. We utilized supervised and unsupervised machine learning and metabolic modeling approaches to identify key metabolic drivers that are predictive of COVID-19 disease severity. Using metabolic pathway enrichment analysis, we explored potential metabolic mechanisms that link these markers to disease progression. RESULTS: Enriched metabolites associated with tryptophan in non-acute COVID-19 samples suggest mitigated innate immune system inflammatory response and immunopathology related lung damage prevention. Increased prevalence of histidine- and ketone-related metabolism in severe COVID-19 samples offers potential mechanistic insight to musculoskeletal degeneration-induced muscular weakness and host metabolism that has been hijacked by SARS-CoV2 infection to increase viral replication and invasion. CONCLUSIONS: Our findings highlight the metabolic transition from an innate immune response coupled with inflammatory pathway inhibition in non-acute infection to rampant inflammation and associated metabolic systemic dysfunction in severe COVID-19.

Vibrational spectroscopy in the electron microscope.

Vibrational spectroscopies using infrared radiation, Raman scattering, neutrons, low-energy electrons and inelastic electron tunnelling are powerful techniques that can analyse bonding arrangements, identify chemical compounds and probe many other important properties of materials. The spatial resolution of these spectroscopies is typically one micrometre or more, although it can reach a few tens of nanometres or even a few ångströms when enhanced by the presence of a sharp metallic tip. If vibrational spectroscopy could be combined with the spatial resolution and flexibility of the transmission electron microscope, it would open up the study of vibrational modes in many different types of nanostructures. Unfortunately, the energy resolution of electron energy loss spectroscopy performed in the electron microscope has until now been too poor to allow such a combination. Recent developments that have improved the attainable energy resolution of electron energy loss spectroscopy in a scanning transmission electron microscope to around ten millielectronvolts now allow vibrational spectroscopy to be carried out in the electron microscope. Here we describe the innovations responsible for the progress, and present examples of applications in inorganic and organic materials, including the detection of hydrogen. We also demonstrate that the vibrational signal has both high- and low-spatial-resolution components, that the first component can be used to map vibrational features at nanometre-level resolution, and that the second component can be used for analysis carried out with the beam positioned just outside the sample--that is, for 'aloof' spectroscopy that largely avoids radiation damage.

Evaluation and Prediction of Human Lumbar Vertebrae Endplate Mechanical Properties Using Indentation and Computed Tomography.

Current implant materials and designs used in spinal fusion show high rates of subsidence. There is currently a need for a method to predict the mechanical properties of the endplate using clinically available tools. The purpose of this study was to develop a predictive model of the mechanical properties of the vertebral endplate at a scale relevant to the evaluation of current medical implant designs and materials. Twenty vertebrae (10 L1 and 10 L2) from 10 cadavers were studied using dual-energy X-ray absorptiometry to define bone status (normal, osteopenic, or osteoporotic) and computed tomography (CT) to study endplate thickness (µm), density (mg/mm3), and mineral density of underlying trabecular bone (mg/mm3) at discrete sites. Apparent Oliver-Pharr modulus, stiffness, maximum tolerable pressure (MTP), and Brinell hardness were measured at each site using a 3 mm spherical indenter. Predictive models were built for each measured property using various measures obtained from CT and demographic data. Stiffness showed a strong correlation between the predictive model and experimental values (r = 0.85), a polynomial model for Brinell hardness had a stronger predictive ability compared to the linear model (r = 0.82), and the modulus model showed weak predictive ability (r = 0.44), likely due the low indentation depth and the inability to image the endplate at that depth (≈0.15 mm). Osteoporosis and osteopenia were found to be the largest confounders of the measured properties, decreasing them by approximately 50%. It was confirmed that vertebral endplate mechanical properties could be predicted using CT and demographic indices.

Coral calcifying fluid pH is modulated by seawater carbonate chemistry not solely seawater pH.

Reef coral calcification depends on regulation of pH in the internal calcifying fluid (CF) in which the coral skeleton forms. However, little is known about calcifying fluid pH (pHCF) regulation, despite its importance in determining the response of corals to ocean acidification. Here, we investigate pHCF in the coral Stylophora pistillata in seawater maintained at constant pH with manipulated carbonate chemistry to alter dissolved inorganic carbon (DIC) concentration, and therefore total alkalinity (AT). We also investigate the intracellular pH of calcifying cells, photosynthesis, respiration and calcification rates under the same conditions. Our results show that despite constant pH in the surrounding seawater, pHCF is sensitive to shifts in carbonate chemistry associated with changes in [DIC] and [AT], revealing that seawater pH is not the sole driver of pHCF Notably, when we synthesize our results with published data, we identify linear relationships of pHCF with the seawater [DIC]/[H+] ratio, [AT]/ [H+] ratio and [[Formula: see text]]. Our findings contribute new insights into the mechanisms determining the sensitivity of coral calcification to changes in seawater carbonate chemistry, which are needed for predicting effects of environmental change on coral reefs and for robust interpretations of isotopic palaeoenvironmental records in coral skeletons.

Interbody Spacer Material Properties and Design Conformity for Reducing Subsidence During Lumbar Interbody Fusion.

There is a need to better understand the effects of intervertebral spacer material and design on the stress distribution in vertebral bodies and endplates to help reduce complications such as subsidence and improve outcomes following lumbar interbody fusion. The main objective of this study was to investigate the effects of spacer material on the stress and strain in the lumbar spine after interbody fusion with posterior instrumentation. A standard spacer was also compared with a custom-fit spacer, which conformed to the vertebral endplates, to determine if a custom fit would reduce stress on the endplates. A finite element (FE) model of the L4-L5 motion segment was developed from computed tomography (CT) images of a cadaveric lumbar spine. An interbody spacer, pedicle screws, and posterior rods were incorporated into the image-based model. The model was loaded in axial compression, and strain and stress were determined in the vertebra, spacer, and rods. Polyetheretherketone (PEEK), titanium, poly(para-phenylene) (PPP), and porous PPP (70% by volume) were used as the spacer material to quantify the effects on stress and strain in the system. Experimental testing of a cadaveric specimen was used to validate the model's results. There were no large differences in stress levels (<3%) at the bone-spacer interfaces and the rods when PEEK was used instead of titanium. Use of the porous PPP spacer produced an 8-15% decrease of stress at the bone-spacer interfaces and posterior rods. The custom-shaped spacer significantly decreased (>37%) the stress at the bone-spacer interfaces for all materials tested. A 28% decrease in stress was found in the posterior rods with the custom spacer. Of all the spacer materials tested with the custom spacer design, 70% porous PPP resulted in the lowest stress at the bone-spacer interfaces. The results show the potential for more compliant materials to reduce stress on the vertebral endplates postsurgery. The custom spacer provided a greater contact area between the spacer and bone, which distributed the stress more evenly, highlighting a possible strategy to decrease the risk of subsidence.

Recruitment of pregnant women to an exercise-intervention study.

We share here our experience of recruiting pregnant women into an exercise intervention study. Recruitment challenges were anticipated owing to the study design, which required four hospital visits for cardiovascular assessment, a long-term (nine-month) commitment, and adherence to a 20-week exercise programme. Fifty-three women were assigned to one of three groups (no-exercise, land exercise or water exercise) using a 2 × 2 × 2 flexible randomisation design. Seven hundred forty-four women were screened at an antenatal clinic, of whom 501 were eligible to participate in the study. One hundred forty-five women were subsequently approached: 46 (32%) of whom agreed to participate, 42 (29%) were interested but then declined and 57 (39%) declined outright. Our study design helped recruit pregnant women as it allowed them some choice of group membership. We also noted that the participant-researcher relationship is important in reducing attrition. Our experience provides indications of likely recruitment and attrition rates for future randomised controlled trials of this type.

Ultrafast initiation of a neural race by impending errors.

KEY POINTS: The brain makes decisions by means of races between neural units representing alternative choices. In the present study, we record the eyemovements made in the Wheeless task, when a visual stimulus is followed after a short delay by another stimulus demanding a different response. The behaviour can be very precisely described as a race between three independent decision processes: one Go process for each of the responses, and a Stop process that tries to cancel the first, now erroneous, response. To explain the high success rate for cancellation that we observe, the onset time for the Stop process must be some 10-20 ms shorter than for Go. As well as extending our understanding of the dynamics of complex decision-making, this task provides a rapid, non-invasive method for quantifying disorders of higher neural function. ABSTRACT: The brain makes decisions by means of races between neural units representing alternative choices, and such models can predict behaviour in decision tasks in a precisely quantitative way. But what is less clear is how soon after the stimulus the race actually starts. In the present study, we re-visit a complex decision experiment: the Wheeless task, in which a saccadic stimulus is followed after a short delay by a second stimulus, with the subject sometimes making a saccade to the first, now inappropriate, stimulus, and sometimes going straight to the correct one. We demonstrate that a simple model with three accumulator units, two 'Go' and one 'Stop', can then account in detail for the individual responses made, as well as their timing. This complex decision-making behaviour is predicted directly for each individual subject by their performance in a simple step saccadic task, which identifies the two free parameters that are specific for each subject. By contrast to previous assumptions, we find that it is necessary for the onset time of the Stop unit to be shorter than for Go by 10-20 ms. This suggests a specifically fast mechanism for altering responses in situations where urgent action is needed to prevent an impending error.

Saccadic foraging: reduced reaction time to informative targets.

The study of saccadic reaction times has revealed a great deal about the neural mechanisms underlying neural decision, in terms of Bayesian factors such as prior probability and information supply. In addition, recent work has shown that saccades are faster to visual targets associated with conventional monetary or food rewards. However, because the purpose of saccades is to acquire information, it could be argued that this is an unnatural situation: the most natural and fundamental reward is the amount of information supplied by a target. Here, we report the results of a study investigating the hypothesis that a saccade to a target whose colour provides information about the location of a subsequent target is faster than to one that does not. We show that the latencies of saccades to a location that provides reliable information about the location of a future target are indeed shorter, their distributions being shifted in a way that implies that the rate of rise of the underlying decision signal is increased. In a race between alternative targets, this means that expected information will be an important factor in deciding where to look, so that 'foraging' saccades are more likely to be made to useful targets.

Using saccades to diagnose covert hepatic encephalopathy.

Covert Hepatic Encephalopathy (CHE), previously known as Minimal Hepatic Encephalopathy, is a subtle cognitive defect found in 30-70 % of cirrhosis patients. It has been linked to poor quality of life, impaired fitness to drive, and increased mortality: treatment is possible. Despite its clinical significance, diagnosis relies on psychometric tests that have proved unsuitable for use in a clinical setting. We investigated whether measurement of saccadic latency distributions might be a viable alternative. We collected data on 35 cirrhosis patients at Addenbrooke's Hospital, Cambridge, with no evidence of clinically overt encephalopathy, and 36 age-matched healthy controls. Performance on standard psychometric tests was evaluated to determine those patients with CHE as defined by the World Congress of Gastroenterology. We then compared visually-evoked saccades between those with CHE and those without, as well as reviewing blood test results and correlating saccadic latencies with biochemical parameters and prognostic scores. Cirrhosis patients have significantly longer median saccadic latencies than healthy controls. Those with CHE had significantly prolonged saccadic latencies when compared with those without CHE. Analysis of a cirrhosis patient's saccades can diagnose CHE with a sensitivity of 75 % and a specificity of 75 %. We concluded that analysis of a cirrhosis patient's saccadic latency distributions is a fast and objective measure that can be used as a diagnostic tool for CHE. This improved early diagnosis could direct avoidance of high-risk activities such as driving, and better inform treatment strategies.

Re-starting a neural race: anti-saccade correction.

In the anti-saccade task, a subject must make a saccadic eye movement in the opposite direction from a suddenly-presented visual target. This sets up a conflict between the natural tendency to make a pro-saccade towards the target and the required anti-saccade. Consequently there is a tendency to make errors, usually corrected by a second movement in the correct anti-saccade direction. In a previous paper, we showed that a very simple model, with racing LATER (Linear Approach to Threshold at Ergodic Rate) units for the pro- and anti-directions, and a stop unit that inhibits the impending error response, could account precisely for the detailed distributions of reaction times both for correct and error responses. However, the occurrence and timing of these final corrections have not been studied. We propose a novel mechanism: the decision race re-starts after an error. Here we describe measurements of all the responses in an anti-saccade task, including corrections, in a group of human volunteers, and show that the timing of the corrections themselves can be predicted by the same model with one additional assumption, that initiation of an incorrect pro-saccade also resets and initiates a corrective anti-saccade. No extra parameters are needed to predict this complex aspect of behaviour, adding weight to our proposal that we correct our mistakes by re-starting a neural decision race. The concept of re-starting a decision race is potentially exciting because it implies that neural processing of one decision can influence the next, and may be a fruitful way of understanding the complex behaviour underlying sequential decisions.

Pacific-wide contrast highlights resistance of reef calcifiers to ocean acidification.

Ocean acidification (OA) and its associated decline in calcium carbonate saturation states is one of the major threats that tropical coral reefs face this century. Previous studies of the effect of OA on coral reef calcifiers have described a wide variety of outcomes for studies using comparable partial pressure of CO2 (pCO2) ranges, suggesting that key questions remain unresolved. One unresolved hypothesis posits that heterogeneity in the response of reef calcifiers to high pCO2 is a result of regional-scale variation in the responses to OA. To test this hypothesis, we incubated two coral taxa (Pocillopora damicornis and massive Porites) and two calcified algae (Porolithon onkodes and Halimeda macroloba) under 400, 700 and 1000 µatm pCO2 levels in experiments in Moorea (French Polynesia), Hawaii (USA) and Okinawa (Japan), where environmental conditions differ. Both corals and H. macroloba were insensitive to OA at all three locations, while the effects of OA on P. onkodes were location-specific. In Moorea and Hawaii, calcification of P. onkodes was depressed by high pCO2, but for specimens in Okinawa, there was no effect of OA. Using a study of large geographical scale, we show that resistance to OA of some reef species is a constitutive character expressed across the Pacific.

Target direction rather than position determines oculomotor expectation in repeating sequences.

Saccadic latencies to targets appearing to the left and right of fixation in a repeating sequence are significantly increased when a target is presented out of sequence. Is this because the target is in the wrong position, the wrong direction, or both? To find out, we arranged for targets in a horizontal plane occasionally to appear with an unexpected eccentricity, though in the correct direction. This had no significant effect on latency, unlike what is observed when targets appeared in the unexpected direction. That subjects learnt sequences of directions rather than simply positions was further confirmed in an experiment where saccade direction was a repeating sequence, but eccentricity was randomised. Latency was elevated when a target was episodically presented in an unexpected direction. Latencies were also elevated when targets appeared in the correct hemifield but at an unexpected direction (35° polar angular displacement from the horizontal, a displacement roughly equivalent in collicular spacing to our unexpected eccentricity), although this elevation was of a smaller magnitude than when targets appeared in an unexpected direction along the horizontal. Finally, we confirmed that not all changes in the stimulus cause disruption: an unexpected change in the orientation or colour of the target did not alter latency. Our results show that in a repeating sequence, the oculomotor system is primarily concerned with predicting the direction of an upcoming eye movement rather than its position. This is consistent with models of oculomotor control developed for randomly appearing targets in which the direction and amplitude of saccades are programmed separately.

Finite element modeling of the free boundary effect on gyroid additively manufactured samples.

There is a significant need for models that can capture the mechanical behavior of complex porous lattice architectures produced by 3D printing. The free boundary effect is an experimentally observed behavior of lattice architectures including the gyroid triply periodic minimal surface where the number of unit cell repeats has been shown to influence the mechanical performance of the lattice. The purpose of this study is to use finite element modeling to investigate how architecture porosity, unit cell size, and sample size dictate mechanical behavior. Samples with varying porosity and increasing number of unit cells (relative to sample size) were modeled under an axial compressive load to determine the effective modulus. The finite element model captured the free boundary effect and captured experimental trends in the structure's modulus. The findings of this study show that samples with higher porosity are more susceptible to the impact of the free boundary effect and in some samples, the modulus can be 20% smaller in samples with smaller numbers of unit cell repeats within a given sample boundary. The outcomes from this study provide a deeper understanding of the gyroid structure and the implications of design choices including porosity, unit cell size, and overall sample size.

Antisaccades as decisions: LATER model predicts latency distributions and error responses.

Antisaccades are widely used in the study of voluntary behavioural control: a subject told to look in the opposite direction to a stimulus must suppress the automatic response of looking towards it, leading to delays and errors that are commonly believed to be generated by competing decision processes. However, currently we lack a precise model of the details of antisaccade behaviour, or indeed detailed quantitative data in the form of full reaction time distributions by which any such model could be evaluated. We measured subjects' antisaccade latency distributions and error rates, and found that we could account precisely for both distributions and errors with a model having three competing LATER processes racing to threshold. In an even more stringent test, we manipulated subjects' expectation of the stimulus, leading to large changes in behaviour that were nevertheless still accurately predicted. The antisaccade task is widely used in the laboratory and clinic because of the relative complexity and vulnerability of the underlying decision mechanisms: our model, grounded in detailed quantitative data, is a robust way of conceptualizing these processes.

Coral reef calcifiers buffer their response to ocean acidification using both bicarbonate and carbonate.

Central to evaluating the effects of ocean acidification (OA) on coral reefs is understanding how calcification is affected by the dissolution of CO(2) in sea water, which causes declines in carbonate ion concentration [CO(3)(2-)] and increases in bicarbonate ion concentration [HCO(3)(-)]. To address this topic, we manipulated [CO(3)(2-)] and [HCO(3)(-)] to test the effects on calcification of the coral Porites rus and the alga Hydrolithon onkodes, measured from the start to the end of a 15-day incubation, as well as in the day and night. [CO(3)(2-)] played a significant role in light and dark calcification of P. rus, whereas [HCO(3)(-)] mainly affected calcification in the light. Both [CO(3)(2-)] and [HCO(3)(-)] had a significant effect on the calcification of H. onkodes, but the strongest relationship was found with [CO(3)(2-)]. Our results show that the negative effect of declining [CO(3)(2-)] on the calcification of corals and algae can be partly mitigated by the use of HCO(3)(-) for calcification and perhaps photosynthesis. These results add empirical support to two conceptual models that can form a template for further research to account for the calcification response of corals and crustose coralline algae to OA.

Finite element analysis of the hip and spine based on quantitative computed tomography.

Quantitative computed tomography (QCT) provides three-dimensional information about bone geometry and the spatial distribution of bone mineral. Images obtained with QCT can be used to create finite element models, which offer the ability to analyze bone strength and the distribution of mechanical stress and physical deformation. This approach can be used to investigate different mechanical loading scenarios (stance and fall configurations at the hip, for example) and to estimate whole bone strength and the relative mechanical contributions of the cortical and trabecular bone compartments. Finite element analyses based on QCT images of the hip and spine have been used to provide important insights into the biomechanical effects of factors such as age, sex, bone loss, pharmaceuticals, and mechanical loading at sites of high clinical importance. Thus, this analysis approach has become an important tool in the study of the etiology and treatment of osteoporosis at the hip and spine.

Altered interictal saccadic reaction time in migraine: a cross-sectional study.

AIMS: The underlying mechanisms of migraine remain poorly understood, partly because we lack objective methods for quantitative analysis of neurological function. To address this issue, we measured interictal saccadic latency in migraineurs and controls. METHODS: In a cross-sectional study, we compared interictal saccadic latency distributions of 12,800 saccades in 32 migraineurs with 32 age- and sex-matched controls. RESULTS: The variability of migraineurs' reaction time distributions was significantly smaller (σ = 1.01 vs. 1.13; p < 0.05) compared with controls. In addition, a smaller proportion of migraineurs generated 'early' saccades (31% vs. 56%: p < 0.05). Sensitivity/specificity analysis demonstrated the potential benefit of this technique to diagnostic discrimination. CONCLUSIONS: The migraineur's brain behaves significantly differently from that of a control during the interictal period. By analysing whole distributions, rather than just means, data can be related directly to current neurophysiological models: specifically, the observed decrease in variability suggests a functional deficit in the noradrenergic systems influencing the cerebral cortex. From a clinical perspective, this novel method of characterising neurological function in migraine is more rapid, practicable, inexpensive, objective and quantitative than previous methods such as evoked potentials and transcranial magnetic stimulation, and has the potential both to improve current diagnostic discrimination and to help guide future research into the underlying neural mechanisms.