Untapped resource: the simulation-based healthcare environment as a means to study human stress.

The effects of 'stress' within the healthcare professions are wide-reaching, not least of all within the field of simulation-based healthcare education. Whilst this popular method of experiential learning offers a 'safe space' for participants to develop their skillset, it also has a more surreptitious action; namely, the incubation of simulation-related stress. Currently, research concerning the complex relationship between stress, learning, and performance is ambiguous, leaving fertile ground for simulationists to debate what level of stress is appropriate for an optimised educational experience. In this narrative review, we examine the human response to stress and outline the various methods that have been used by researchers to measure stress in a quantifiable and standardised way. We then provide a brief overview of simulation-based healthcare education before describing why stress responses have been of interest to healthcare educationalists for some time. Finally, we outline how simulation education environments might provide an ideal environment for studying the human response to stress generally, with ramifications extending beyond the field of medical education.

Stepping into the shoes of older people: a scoping review of simulating ageing experiences for healthcare professional students.

BACKGROUND: Ageing simulation suits and equipment give healthcare professional (HCP) students the opportunity to experience what it might feel like to be an older person with age-related disability or illness. Ageing simulation experiences, where students complete activities of daily living (ADL) tasks, aim to reproduce the challenges an older person may face. OBJECTIVES: We undertook a scoping literature review to establish, from the evidence base, what is known about simulating ageing experiences for HCP students and its impact on attitudes towards older patients. METHODS: We applied Arksey and O'Malley's scoping literature review framework to achieve relevant articles. Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched resulting in 114 citations. After screening and applying our exclusion criteria, 14 articles were selected for inclusion. RESULTS: Fifty percent of studies were mixed-methods, 35% quasi-experimental, 7% quantitative and 7% qualitative. Two types of simulation experience were identified: (i) workshop based and (ii) ageing games. Simulated impairments included vision, hearing and mobility issues. Most common ADLs simulated were managing medications, finances and functional ability. The majority of studies reported a positive impact on knowledge, attitudes and empathy towards older people. CONCLUSIONS: Teaching in Care of Older People is important in HCP undergraduate curricula and should be a positive experience promoting successful ageing while raising awareness of ageism. Ageing suits have a positive impact on students' attitudes and empathic skills towards older people. Future research should include interprofessional education with HCP students learning together throughout undergraduate training.

Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury.

Neuromodulatory therapies for spinal cord injury (SCI) such as electrical epidural stimulation (EES) are increasingly effective at improving patient outcomes. These improvements are thought to be due, at least in part, to plasticity in neuronal circuits. Precisely which circuits are influenced and which afferent classes are most effective in stimulating change remain important open questions. Genetic tools, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), support targeted and reversible neuromodulation as well as histological characterization of manipulated neurons. We therefore transduced and activated lumbar large diameter peripheral afferents with excitatory (hM3Dq) DREADDs, in a manner analogous to EES, in a rat hemisection model, to begin to trace plasticity and observe concomitant locomotor changes. Chronic DREADDs activation, coupled with thrice weekly treadmill training, was observed to increase afferent fluorescent labeling within motor pools and Clarke's column when compared to control animals. This plasticity may underlie kinematic differences that we observed across stages of recovery, including an increased and less variable hindquarters height in DREADDs animals, shorter step durations, a more flexed ankle joint early in recovery, a less variable ankle joint angle in swing phase, but a more variable hip joint angle. Withdrawal of DREADDs agonist, clozapine-N-oxide (CNO) left these kinematic differences largely unaffected; suggesting that DREADDs activation is not necessary for them later in recovery. However, we observed an intermittent "buckling" phenomenon in DREADDs animals without CNO activation, that did not occur with CNO re-administration. Future studies could use more refined genetic targeted of specific afferent classes, and utilize muscle recordings to find where afferent modulation is most influential in altering motor output.

Number of Months of Baseball in the Previous Year and Preseason Olecranon Tenderness: Risk Factors for Shoulder and Elbow Injuries in High-School Baseball Players.

OBJECTIVE: To identify risk factors for shoulder and elbow injuries in high-school baseball position players and pitchers in the preseason history and physical examination. DESIGN: Retrospective cohort study. SETTING: Community high-school baseball. PARTICIPANTS: Three hundred seventy-one male baseball players' mean age 15.0 ± 1.8 years. OUTCOME MEASURES: A preseason history and physical examination was performed on all athletes. Injury information was collected by weekly self-report and athletic trainer injury logs throughout the season. Comparisons between injured and noninjured players were performed using t tests and χ 2 analyses. Binary logistic regression models were developed to identify risk factors for injury. RESULTS: Seventy-six injuries were recorded over the season. In univariate analysis, the injured group had greater months of baseball participation ( P = 0.007) and shoulder visual analog scale for the past year ( P = 0.003). The injured group also had more olecranon tenderness ( P < 0.0001, odds ratio [OR] 2.9) and decreased elbow arc of motion. All other factors were not significantly different ( P > 0.05). In multivariable logistic regression, months per year of baseball participation was the only factor significantly associated with injuries ( P = 0.010, OR = 1.21). CONCLUSIONS: Baseball players who developed arm injuries during a season were more likely to play more months of baseball and report shoulder pain in the previous year. The presence of preseason olecranon tenderness was associated with nearly triple the risk of injury during the season. Every additional month of baseball participation in the previous year was associated with a 1.2× increased odds of injury. The presence of glenohumeral internal rotation deficit was not a predictor of injury.

The economy of terrestrial locomotion.

All else being equal, evolution is going to drive animals to require the least food to move a unit distance. What is the best way to do that? Some efficiencies can be 'hard-wired' into the body - the relatively unchanging morphology of the animal. But flexibility is also needed - given the task at hand, state of the body, or state of the external environment, it may be best to dynamically choose an appropriate mode of locomotion. For example, slow walking may be great for searching and foraging, but it won't catch fast moving prey. Similarly, maximum speed gallops may be great for escaping danger, but they preclude eating along the way. This primer summarizes what we know about the determinants of locomotor costs and the strategies animals use to minimize cost. It summarizes key findings across levels of organization, from individual muscles to interactions with other organisms and the environment. At the mid-level of organization we highlight gaits, a particularly interesting topic of inquiry with a rich history. We are in an exciting time for the science of movement because we have more, better tools than ever before for observing and manipulating systems, from the molecular level to herds of animals on the Savannah. Even more importantly, there are so many open, exciting questions to ask.

Correction: Addition of angled rungs to the horizontal ladder walking task for more sensitive probing of sensorimotor changes.

[This corrects the article DOI: 10.1371/journal.pone.0246298.].

Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production.

Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.

A versatile system for neuromuscular stimulation and recording in the mouse model using a lightweight magnetically coupled headmount.

Neural stimulation and recording in rodents are common methods to better understand the nervous system and improve the quality of life of individuals who are suffering from neurological disorders (e.g., epilepsy), as well as for permanent reduction of chronic pain in patients with neuropathic pain and spinal-cord injury. This method requires a neural interface (e.g., a headmount) to couple the implanted neural device with instrumentation system. The size and the total weight of such headmounts should be designed in a way to minimize its effect on the movement of the animal. This is a crucial factor in gait, kinematic, and behavioral neuroscience studies of freely moving mice. Here we introduce a lightweight 'snap-in' electro-magnetic headmount that is extremely small, and uses strong neodymium magnetics to enable a reliable connection without sacrificing the lightweight of the device. Additionally, the headmount requires minimal surgical intervention during the implantation, resulting in minimal tissue damage. The device has demonstrated itself to be robust, and successfully provided direct electrical stimulation of nerve and electrical muscle stimulation and recording, as well as powering implanted LEDs for optogenetic use scenarios.

A MATLAB application for automated H-Reflex measurements and analyses.

OBJECTIVE: H-Reflex is a test that is carried out to measure the relative excitability of reflex pathways. Although reliable, conventional methods consist of performing many small steps, which requires a high level of attentiveness, and thus can carry an elevated risk of human error, despite proper training. Equipment that is available to perform those tests with different levels of automation are typically proprietary, inextensible by the user, and expensive. Here we present a novel MATLAB application that can accurately and reliably perform automated H-Reflex measurements, test the stimulating electrodes, and carry out typical subsequent analyses. METHODS: This application is a Graphical User Interface that works with inexpensive equipment and offers many important features such as measuring electrode impedance in-situ, automating lengthy measurements like recruitment curves and frequency response trials, standardizing electric stimulation properties, automatic exporting of digital data and metadata, and immediately analyzing acquired data with single-click events. RESULTS: Our new method was validated against conventional H-Reflex measurement methods with 2 anesthetized rats. The difference between acquired data using both methods was negligible (mean difference=0.0038; std=0.0121). Our app also detected electrode impedance with high accuracy (94%). CONCLUSION: The method presented here allows reliable and efficient automated H-reflex measurements and can accurately analyze the collected data. SIGNIFICANCE: The features provided by our app can speed up data collection and reduce human error, and unlike conventional methods, allow the user to analyze data immediately after the record. This can result in higher research quality and give broader access to the technique.

Dog galloping on rough terrain exhibits similar limb co-ordination patterns and gait variability to that on flat terrain.

Understanding how animals regulate their gait during locomotion can give biological insight and inspire controllers for robots. Why animals use the gallop at the highest speeds remains incompletely explained. Hypothesized reasons for galloping include that it enables recruitment of spinal musculoskeletal structures, that it minimizes energy losses as predicted by collisional theory, or that it provides extended flight phases with more time for leg placement and hence enhances or provides necessary maneuverability [Alexander 1988 Am. Zool. 28 237-45; Ruina, Bertram and Srinivasan 2005 J. Theor. Biol. 237 170-92; Usherwood 2019 J. Exp. Zool. Part A 333 9-19; Hildebrand1989 Bioscience 39 766-75]. The latter-most hypothesis has implications in robotics, where controllers based on the concept of multistability have gained some traction. Here we examine this hypothesis by studying the dynamics of dog gait on flat and rough terrain. This hypothesis predicts that injection of noise into timing and location of ground contacts during the galloping gait by rough terrain will result in an isotropically more noisy gallop gait, centered around the gallop used on flat terrain. We find that dog gait in terms of leg swing timing on rough terrain is not consistently more variable about the mean gait, and constrain the upper limits of this variability to values that are unlikely to be biologically relevant. However the location of the mean gait indeed only shifts by a small amount. Therefore, we find limited support for this hypothesis. This suggests that achieving a target gallop gait with tight regulation is still the desired behavior, and that large amounts of variability in gait are not a desired feature of the gallop. For robotics, our results suggest that the emergent animal-environment dynamics on rough terrain do not exhibit uniformly wider basins of attraction. Future robotics work could test whether controllers that do or do not allow shifts in mean gait and gait variability produce more economical and/or stable gallops.

Addition of angled rungs to the horizontal ladder walking task for more sensitive probing of sensorimotor changes.

One method for the evaluation of sensorimotor therapeutic interventions, the horizontal ladder walking task, analyzes locomotor changes that may occur after disease, injury, or by external manipulation. Although this task is well suited for detection of large effects, it may overlook smaller changes. The inability to detect small effect sizes may be due to a neural compensatory mechanism known as "cross limb transfer", or the contribution of the contralateral limb to estimate an injured or perturbed limb's position. The robust transfer of compensation from the contralateral limb may obscure subtle locomotor outcomes that are evoked by clinically relevant therapies, in the early onset of disease, or between higher levels of recovery. Here, we propose angled rungs as a novel modification to the horizontal ladder walking task. Easily-adjustable angled rungs force rats to locomote across a different locomotion path for each hindlimb and may therefore make information from the contralateral limb less useful. Using hM3Dq (excitatory) Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in large diameter peripheral afferents of the hindlimb in the intact animal, we characterized the sensitivity of our design to detect stepping differences by comparing locomotor changes observed on angled rungs to those observed on a standard horizontal ladder. On our novel asymmetrical ladder, activation of DREADDs resulted in significant differences in rung misses (p = 0.000011) and weight-supporting events (p = 0.049). By comparison, on a standard ladder, we did not observe differences in these parameters (p = 0.86 and p = 0.98, respectively). Additionally, no locomotor differences were detected in baseline and inactivated DREADDs trials when we compared ladder types, suggesting that the angled rungs do not change animal gait behavior unless intervention or injury is introduced. Significant changes observed with angled rungs may demonstrate more sensitive probing of locomotor changes due to the decoupling of cross limb transfer.

Epidural Electrical Stimulation: A Review of Plasticity Mechanisms That Are Hypothesized to Underlie Enhanced Recovery From Spinal Cord Injury With Stimulation.

Spinal cord injury (SCI) often results in life-long sensorimotor impairment. Spontaneous recovery from SCI is limited, as supraspinal fibers cannot spontaneously regenerate to form functional networks below the level of injury. Despite this, animal models and humans exhibit many motor behaviors indicative of recovery when electrical stimulation is applied epidurally to the dorsal aspect of the lumbar spinal cord. In 1976, epidural stimulation was introduced to alleviate spasticity in Multiple Sclerosis. Since then, epidural electrical stimulation (EES) has been demonstrated to improve voluntary mobility across the knee and/or ankle in several SCI patients, highlighting its utility in enhancing motor activation. The mechanisms that EES induces to drive these improvements in sensorimotor function remain largely unknown. In this review, we discuss several sensorimotor plasticity mechanisms that we hypothesize may enable epidural stimulation to promote recovery, including changes in local lumbar circuitry, propriospinal interneurons, and the internal model. Finally, we discuss genetic tools for afferent modulation as an emerging method to facilitate the search for the mechanisms of action.

ACUTE KIDNEY INJURY FOLLOWING SURGERY FOR HIP FRACTURE.

OBJECTIVE: An observational study was carried out to determine the rate of acute kidney injury (AKI) following surgery for hip fracture at our institution and to look for factors associated with AKI. METHODS: Preoperative creatinine values were compared to post-operative results for all patients who underwent surgery for hip fracture at our institution between 1st January 2015 and 30th September 2016. AKI was defined as an increase in postoperative creatinine, greater than or equal to 1.5 times the preoperative value within 7 days. Chi-squared test and Student's t-test were used to look for factors associated with AKI. RESULTS: Out of 500 patients, 96 developed an AKI (19.2%). Patients with chronic kidney disease (CKD) were more likely to develop AKI (30.8%) that those without it (17.2%, p = 0.018). Similarly, patients with 2 or more comorbidities were more likely to develop AKI (22.0%) than those without it (12.4%, p = 0.009). No statistically significant association was observed between type of surgery and AKI. CONCLUSION: A large proportion of patients following surgery for hip fracture developed AKI. Patients with CKD and the presence of 2 or more comorbidities had significantly higher rates of AKI. Level III evidence, Retrospective comparative study.

OBJETIVO: Estudo observacional realizado no Altnagelvin Hospital para determinar a taxa de lesão renal aguda (LRA) após a cirurgia de fratura de quadril e procurar fatores associados à LRA. MÉTODOS: Os valores de creatinina pré-operatória foram comparados aos resultados pós-operatórios em todos os pacientes submetidos à cirurgia de fratura de quadril entre 1º de janeiro de 2015 e 30 de setembro de 2016. A LRA foi definida como aumento da creatinina pós-operatória maior ou igual a 1,5 vezes ao valor pré-operatório dentro de 7 dias. Os testes qui-quadrado e t-Student foram usados para procurar fatores associados à LRA. RESULTADOS: Dos 500 pacientes, 96 desenvolveram LRA (19,2%). Pacientes com doença renal crônica (DRC) foram mais propensos a desenvolver LRA (30,8%) do que os pacientes sem a doença (17,2%, p = 0,018). Da mesma forma, pacientes com duas ou mais comorbidades foram mais propensos a desenvolver LRA (22,0%) do que os pacientes sem comorbidades (12,4%, p = 0,009). Não houve associação estatisticamente significativa entre tipo de cirurgia e LRA. CONCLUSÃO: Após a cirurgia de fratura de quadril uma grande proporção de pacientes desenvolveu LRA. Pacientes com DRC e duas ou mais comorbidades tiveram taxas significativamente maiores de LRA. Nível de evidência III, Estudo comparativo retrospectivo .

Leveraging elastic instabilities for amplified performance: Spine-inspired high-speed and high-force soft robots.

Soft machines typically exhibit slow locomotion speed and low manipulation strength because of intrinsic limitations of soft materials. Here, we present a generic design principle that harnesses mechanical instability for a variety of spine-inspired fast and strong soft machines. Unlike most current soft robots that are designed as inherently and unimodally stable, our design leverages tunable snap-through bistability to fully explore the ability of soft robots to rapidly store and release energy within tens of milliseconds. We demonstrate this generic design principle with three high-performance soft machines: High-speed cheetah-like galloping crawlers with locomotion speeds of 2.68 body length/s, high-speed underwater swimmers (0.78 body length/s), and tunable low-to-high-force soft grippers with over 1 to 103 stiffness modulation (maximum load capacity is 11.4 kg). Our study establishes a new generic design paradigm of next-generation high-performance soft robots that are applicable for multifunctionality, different actuation methods, and materials at multiscales.

Acute kidney injury following surgery for hip fracture / Lesão renal aguda após cirurgia de fratura de quadril

ABSTRACT Objective: An observational study was carried out to determine the rate of acute kidney injury (AKI) following surgery for hip fracture at our institution and to look for factors associated with AKI. Methods: Preoperative creatinine values were compared to post-operative results for all patients who underwent surgery for hip fracture at our institution between 1st January 2015 and 30th September 2016. AKI was defined as an increase in postoperative creatinine, greater than or equal to 1.5 times the preoperative value within 7 days. Chi-squared test and Student's t-test were used to look for factors associated with AKI. Results: Out of 500 patients, 96 developed an AKI (19.2%). Patients with chronic kidney disease (CKD) were more likely to develop AKI (30.8%) that those without it (17.2%, p = 0.018). Similarly, patients with 2 or more comorbidities were more likely to develop AKI (22.0%) than those without it (12.4%, p = 0.009). No statistically significant association was observed between type of surgery and AKI. Conclusion: A large proportion of patients following surgery for hip fracture developed AKI. Patients with CKD and the presence of 2 or more comorbidities had significantly higher rates of AKI. Level III evidence, Retrospective comparative study.

RESUMO Objetivo: Estudo observacional realizado no Altnagelvin Hospital para determinar a taxa de lesão renal aguda (LRA) após a cirurgia de fratura de quadril e procurar fatores associados à LRA. Métodos: Os valores de creatinina pré-operatória foram comparados aos resultados pós-operatórios em todos os pacientes submetidos à cirurgia de fratura de quadril entre 1º de janeiro de 2015 e 30 de setembro de 2016. A LRA foi definida como aumento da creatinina pós-operatória maior ou igual a 1,5 vezes ao valor pré-operatório dentro de 7 dias. Os testes qui-quadrado e t-Student foram usados para procurar fatores associados à LRA. Resultados: Dos 500 pacientes, 96 desenvolveram LRA (19,2%). Pacientes com doença renal crônica (DRC) foram mais propensos a desenvolver LRA (30,8%) do que os pacientes sem a doença (17,2%, p = 0,018). Da mesma forma, pacientes com duas ou mais comorbidades foram mais propensos a desenvolver LRA (22,0%) do que os pacientes sem comorbidades (12,4%, p = 0,009). Não houve associação estatisticamente significativa entre tipo de cirurgia e LRA. Conclusão: Após a cirurgia de fratura de quadril uma grande proporção de pacientes desenvolveu LRA. Pacientes com DRC e duas ou mais comorbidades tiveram taxas significativamente maiores de LRA. Nível de evidência III, Estudo comparativo retrospectivo .

The role of 5α-reductase inhibitors in gastro-oesophageal cancer risk: A nested case-control study.

PURPOSE: The strong male predominance of gastro-oesophageal cancer suggests that sex hormones play an important role. 5α-Reductase (5AR) inhibitors have antiandrogen effects and have been shown to decrease cancer cell proliferation and metastasis. We conducted the first epidemiologic investigation into the association between 5AR inhibitor use and gastro-oesophageal cancer risk. METHODS: We conducted a nested case-control study within the Scottish Primary Care Clinical Information Unit Research database. Male cases diagnosed with oesophageal or gastric cancer between 1999 and 2011 were matched to up to five male controls based on birth year, diagnosis year, and general practice. We used electronic prescribing records to ascertain medication use. We used conditional logistic regression to calculate odds ratios (ORs) for the association between 5AR inhibitor use and cancer risk, after adjusting for comorbidities and aspirin, statin, or proton pump inhibitor use. RESULTS: The study included 2003 gastro-oesophageal cancer cases and 9650 controls. There was some evidence of reduced gastro-oesophageal cancer risk among 5AR inhibitor users (adjusted OR = 0.75; 95% CI, 0.56-1.02), particularly for finasteride (adjusted OR = 0.68; 95% CI, 0.50-0.94). These decreases were more marked among those who received at least 3 years of 5AR inhibitors (adjusted OR = 0.54; 95% CI, 0.27-1.05; P value = .071) or finasteride (adjusted OR = 0.49; 95% CI, 0.24-0.99; P value = .046). CONCLUSIONS: We found evidence of reduced gastro-oesophageal cancer risk among users of 5AR inhibitors, particularly finasteride. However, larger epidemiological studies are required before randomised controlled trials are considered.

Furosemide use and survival in patients with esophageal or gastric cancer: a population-based cohort study.

BACKGROUND: Pre-clinical studies have shown that furosemide slows cancer cell growth by acting on the Na-K-2Cl transporter, particularly for gastric cancer cells. However, epidemiological studies have not investigated furosemide use and mortality in gastroesophageal cancer patients. Consequently, we conducted a population-based study to investigate whether furosemide use is associated with reduced cancer-specific mortality in esophageal/gastric cancer patients. METHODS: A cohort of patients newly diagnosed with esophageal or gastric cancer between 1998 and 2013 were identified from English cancer registries and linked to the Clinical Practice Research Datalink to provide prescription records and the Office of National Statistics to provide death data up to September 2015. Time-dependant Cox-regression models were used to calculate hazard ratios (HRs) comparing cancer-specific mortality in furosemide users with non-users. Analyses were repeated restricting to patients with common furosemide indications (heart failure, myocardial infarction, edema or hypertension) to reduce potential confounding. RESULTS: The cohort contained 2708 esophageal cancer patients and 2377 gastric cancer patients, amongst whom 1844 and 1467 cancer-specific deaths occurred, respectively. Furosemide use was not associated with reduced cancer-specific mortality overall (adjusted HR in esophageal cancer = 1.28, 95% CI 1.10, 1.50 and in gastric cancer = 1.27, 95% CI 1.08, 1.50) or when restricted to patients with furosemide indications before cancer diagnosis (adjusted HR in esophageal cancer = 1.07, 95% CI 0.88, 1.30 and in gastric cancer = 1.18, 95% CI 0.96, 1.46). CONCLUSIONS: In this large population-based cohort study, furosemide was not associated with reduced cancer-specific mortality in patients with esophageal or gastric cancer.

Ground reaction forces of overground galloping in ridden Thoroughbred racehorses.

The horse has evolved to gallop economically at high speed. Limb force increases with speed but direct measures of limb ground reaction forces (GRFs) at gallop are sparse. This study reports GRFs for multiple limbs, using force plates, across seven Thoroughbred racehorses during ridden galloping. The results show peak vertical GRF values of 13.6 N kg-1 (non-lead hindlimb), 12.3 N kg-1 (lead hindlimb), 14.0 N kg-1 (non-lead forelimb) and 13.6 N kg-1 (lead forelimb) at 11.4 m s-1 and recorded values are consistent with those predicted from duty factor. The distribution of body weight between the forelimbs and hindlimbs is approximated to 50:50, and is variable with speed, unlike the 60:40 commonly stated for cursorial quadrupeds in the literature. An even distribution of load on all limbs may help minimise accumulation of fatigue and assist in injury avoidance. Cranio-caudal force data concur with the observation that horses apply a net accelerative impulse with the hindlimbs and a net decelerative impulse with the forelimbs. Capturing GRFs enhances our knowledge on the mechanics of galloping in fast-moving species and provides insight into injury risk and factors limiting athletic performance.

Lactic acid suppresses IgE-mediated mast cell function in vitro and in vivo.

Mast cells have functional plasticity affected by their tissue microenvironment, which greatly impacts their inflammatory responses. Because lactic acid (LA) is abundant in inflamed tissues and tumors, we investigated how it affects mast cell function. Using IgE-mediated activation as a model system, we found that LA suppressed inflammatory cytokine production and degranulation in mouse peritoneal mast cells, data that were confirmed with human skin mast cells. In mouse peritoneal mast cells, LA-mediated cytokine suppression was dependent on pH- and monocarboxylic transporter-1 expression. Additionally, LA reduced IgE-induced Syk, Btk, and ERK phosphorylation, key signals eliciting inflammation. In vivo, LA injection reduced IgE-mediated hypothermia in mice undergoing passive systemic anaphylaxis. Our data suggest that LA may serve as a feedback inhibitor that limits mast cell-mediated inflammation.

Polymer scaffold architecture is a key determinant in mast cell inflammatory and angiogenic responses.

Implanted polymer scaffolds can induce inflammation leading to the foreign body response (FBR), fibrosis, and implant failure. Thus, it is important to understand how immune cells interact with scaffolds to mitigate inflammation and promote a regenerative response. We previously demonstrated that macrophage phenotype is modulated by fiber and pore diameters of an electrospun scaffold. However, it is unclear if this effect is consistent among other innate immune cells. Mast cells are inflammatory sentinels that play a vital role in the FBR of implanted biomaterials, as well as angiogenesis. We determined if altering electrospun scaffold architecture modulates mast cell responses, with the goal of promoting regenerative cell-scaffold interactions. Polydioxanone (PDO) scaffolds were made from 60 mg/mL or 140 mg/mL PDO solutions, yielding structures with divergent fiber and pore diameters. Mouse mast cells plated on these scaffolds were activated with IL-33 or lipopolysaccharide (LPS). Relative to the 60 mg/mL scaffold, 140 mg/mL scaffolds yielded less IL-6 and TNF, and greater VEGF secretion. Pores >4-6 µm elicited less IL-6 and TNF secretion. IL-33-induced VEGF regulation was more complex, showing effects of both pore size and fiber diameter. These data indicate parameters that can predict mast cell responses to scaffolds, informing biomaterial design to increase wound healing and diminish implant rejection. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 884-892, 2019.