Search

Despite the fundamental role of bacterial strain variation in gut microbiota function1, 2, 3, 4, 5–6, the number of unique strains of a species that can stably colonize the human intestine is still unknown for almost all species. Here we determine the strain richness (SR) of common gut species using thousands of sequenced bacterial isolates with paired metagenomes. We show that SR varies across species, is transferable by faecal microbiota transplantation, and is uniquely low in the gut compared with soil and lake environments. Active therapeutic administration of supraphysiologic numbers of strains per species increases recipient SR, which then converges back to the population average after dosing is ceased. Stratifying engraftment outcomes by high or low SR shows that SR predicts microbial addition or replacement in faecal transplants. Together, these results indicate that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and thereby influence strain addition and replacement in faecal microbiota transplantation and defined live biotherapeutic products.

ABSTRACTIntroductionUstekinumab use in ulcerative colitis had shown low adverse event and high persistence rates to 3 years via the UNIFI long-term extension study. Outcomes beyond 3 years have not been previously described. We describe the safety signals of the entire UNIFI Australian population beyond 3 years.MethodsThis retrospective multicenter observational cohort study recruited from all Australian UNIFI centers. The primary outcome was safety via adverse events. Secondary outcomes included the clinical relapse rate on ustekinumab, and the need to switch from ustekinumab to an alternate agent.ResultsThere were 14 patients [11 male, mean age 47 (±14) years], with a median diagnosis of 10.8 (±4.5) years prior to UNIFI enrollment. Median follow-up was 298 weeks (5.7 years) (Interquartile range (IQR): 220–311 weeks). Within the long-term extension, there were three serious adverse events and one minor event. 42.9% (6/14) patients had clinical relapses, of which clinical remission was recaptured in 83.3% (5/6). 85.7% (12/14) persisted on ustekinumab in the long-term, with 7.1% (1/14) electively ceasing ustekinumab and 7.1% (1/14) changed from ustekinumab due to clinical relapse.ConclusionFor moderate-to-severe UC in Australia, ustekinumab maintained efficacy beyond 3 years with a high persistence rate and no new safety signals.Trial RegistrationThe trial is registered at ANZCTR (identifier: ACTRN12622001332718).

In this article, we develop a modular neural network for real-time (>10 Hz) semantic mapping in uncertain environments, which explicitly updates per-voxel probabilistic distributions within a neural network layer. Our approach combines the reliability of classical probabilistic algorithms with the performance and efficiency of modern neural networks. Although robotic perception is often divided between modern differentiable methods and classical explicit methods, a union of both is necessary for real-time and trustworthy performance. We introduce a novel convolutional Bayesian kernel inference (ConvBKI) layer which incorporates semantic segmentation predictions online into a 3-D map through a depthwise convolution layer by leveraging conjugate priors. We compare ConvBKI against state-of-the-art deep learning approaches and probabilistic algorithms for mapping to evaluate reliability and performance. We also create a robot operating system package of ConvBKI and test it on real-world perceptually challenging off-road driving data.

The combat capabilities development command (DEVCOM) ground vehicle systems centre (GVSC) is supporting unmanned ground vehicle (UGV) development. Past experimentations of a military UGV demonstrated that its autonomous mode performed worse than the tele-operated mode. To address this, a systematic investigation into path planners for military vehicles in off-road environments was executed. A UGV simulator was used to evaluate vehicle and planner performance through a range of obstacle avoidance scenarios in deformable soil to capture the effects of vehicle-terrain interactions across multiple soil types. Monte Carlo methods were used to evaluate the robustness of five path planners ranging from classical to state-of-the-art planners, with normally-distributed variability in environmental and vehicle initial conditions. After running thousands of simulations, results show how each algorithm compares to one another in several key metrics including overall success rates. These results will help inform decisions in future military UGV path planner selection.

Rice is the primary energy source of more than half of the global population. Challenges persist in managing phosphorus (P) in paddy soils of tropical rice-growing countries. In Sri Lanka, one specific challenge is the inconsistent yield response observed when inorganic P fertilisers are applied to paddy soils. Previous research conducted in Sri Lanka has shown that the rice yield response to added P fertilisers cannot be adequately explained by factors such as soil available P, irrigation schemes, soil texture, pH, electrical conductivity, total carbon content and available Fe and Mg concentrations. Due to the submerged conditions in which rice is grown for a significant portion of its lifespan, a unique environment controlled by redox-driven processes is developed in paddy soils. Therefore, releasing P from submerged soils is an outcome influenced by complex hydrological and biogeochemical processes, strongly influenced by inherent soil characteristics. The present review paper aimed to critically examine existing literature on soil P behaviour in submerged paddy soils of Sri Lanka, to clarify the behaviour of P under submergence, identify the factors affecting such behaviour and highlight the research gaps that need to be addressed, in order to effectively manage P in the paddy soils of Sri Lanka.

In this study, a data-driven hydrodynamics model is proposed to enable quick prediction of vehicle mobility in shallow water, considering the effect of tire-soil interaction. To this end, a high-fidelity coupled vehicle-water interaction model using computational fluid dynamics (CFD) and multibody dynamics (MBD) solvers is developed to characterize the hydrodynamic loads exerted on a vehicle operated in shallow water, and it is used to generate training data for the data-driven hydrodynamics model. To account for the history-dependent hydrodynamic behavior, a Long Short-Term Memory (LSTM) neural network is introduced to incorporate effects of the historical variation of vehicle motion states as the input to the data-driven model, and it is used to predict hydrodynamic loads online exerted on vehicle components in the MBD mobility simulation. The impacts of hydrodynamic loads on the vehicle mobility capability in shallow water are examined for different water depths and incoming flow speeds using the high-fidelity coupled CFD-MBD model. Furthermore, it is demonstrated that the vehicle-water interaction behavior in scenarios not considered in the training data can be predicted using the proposed LSTM data-driven hydrodynamics model. However, the use of non-LSTM layers, which do not account for the sequential variation of vehicle motion states as the input, leads to an inaccurate prediction. A substantial computational speedup is achieved with the proposed LSTM-MBD vehicle-water interaction model while ensuring accuracy, compared to the computationally expensive high-fidelity coupled CFD-MBD model.

Modelling vehicle longitudinal dynamics is critical for developing speed-control strategies. In this work an empirical model of vehicle longitudinal dynamics is proposed. The purpose of the empirical model is to facilitate the tuning of proportional-integral-differential (PID) parameters for a real-world vehicle. With a short series of measurements, a predictive model of the vehicle speed was developed by fitting the model to the measured data. The empirical model presented in this work has the advantages that it is simple - it does not require any detailed measurements of the vehicle properties but is rather easily fit to real measurements. The model is also flexible, being applicable to a range of different vehicles. In this work, the development of the model is outlined and an application of the model is shown for two different vehicles, the Polaris MRZR4 and the Clearpath Warthog, which have different drive-train and suspension characteristics. The applicability of the empirical model is demonstrated by tuning and testing a real PID controller for the MRZR4.

ABSTRACTBackgroundBiosimilar adalimumabs have improved treatment access, but without any clinical advantage, distributors rely on delivery device design-enhancements, support services, and removal of painful excipients to capture market share. Prescribers, however, are often unaware of these differences. This article compares and contrasts originator versus biosimilar adalimumab agents to identify key differences that might influence adalimumab selection.Research design and methodsWe reviewed listed adalimumab biosimilars in Australia and compared them to the originator adalimumab. Similarities and differences identified were confirmed with the manufacturers via two rounds of interviews: the first to collate a list of features and benefits of their product, and the second to consolidate and confirm the data.ResultsThe originator adalimumab Humira [by AbbVie, U.S.A] and four adalimumab biosimilars (Amgevita [by Amgen, U.S.A], Hadlima [by Organon, U.S.A], Hyrimoz [by Sandoz, Switzerland], and Idacio [by Fresenius Kabi, Germany]) are included in this review. Key differences identified include product formulation, dosages available, delivery devices, physician support, patient support, and the supply of other biosimilar products by the company.ConclusionAdalimumab biosimilars are different from each other with unique advantages and disadvantages likely to influence prescriber and patients. Therefore, the choice of agent should be individualized to the needs of the patient and the healthcare service.

Novel mZVI-AC coupled micro-electrolysis systems were established for denitrificationChemical, autotrophic and heterotrophic denitrification pathways were observed in reactorsAC increased the activity of enzymes encoding denitrification and respiratory chainsThe acidification brought greater capacitance and lower impedance to carbon to facilitate iron oxidation

Copper (Cu) is the main co‐factor in the functioning of the ammonia monooxygenase (AMO) enzyme, which is responsible for the first step of ammonia oxidation. We report a greenhouse‐based pot experiment that examines the response of ammonia‐oxidizing bacteria and archaea (AOB and AOA) to different bioavailable Cu concentrations in three pastoral soils (Recent, Pallic, and Pumice soils) planted with ryegrass (Lolium perenneL.). Five treatments were used: control (no urine and Cu), urine only at 300 mg N kg−1soil (Cu0), urine + 1 mg Cu kg−1soil (Cu1), urine + 10 mg Cu kg−1soil (Cu10), and urine + 100 mg Cu kg−1soil (Cu100). Pots were destructively sampled at Day 0, 1, 7, 15, and 25 after urine application. The AOB/AOA amoAgene abundance was analyzed by real‐time quantitative polymerase chain reaction at Days 1 and 15. The AOB amoAgene abundance increased 10.0‐ and 22.6‐fold in the Recent soil and 2.1‐ and 2.5‐fold in the Pallic soil for the Cu10 compared with Cu0 on Days 1 and 15, respectively. In contrast, the Cu100 was associated with a reduction in AOB amoAgene abundance in the Recent and Pallic soils but not in the Pumice soil. This may be due to the influence of soil cation exchange capacity differences on the bioavailable Cu. Bioavailable Cu in the Recent and Pallic soils influenced nitrification and AOB amoAgene abundance, as evidenced by the strong positive correlation between bioavailable Cu, nitrification, and AOB amoA. However, bioavailable Cu did not influence the nitrification and AOA amoAgene abundance increase. Copper concentration 0.24‐0.33 mg kg‐1increased nitrification rate for Recent and Pallic soils but inhibited above 6 mg kg‐1.Changes in nitrification rate in Recent and Pallic soils were positively correlated with AOB amoA gene abundance.AOA amoA gene was stimulated at higher Cu concentration in Recent and Pallic soils but not in Pumice soil.

BackgroundSeveral randomised clinical trials (RCTs) performing faecal microbiota transplantation (FMT) for the management of inflammatory bowel disease (IBD), particularly for ulcerative colitis, have recently been published, but with major variations in study design. These include differences in administered dose, route and frequency of delivery, type of placebo and evaluated endpoints. Although the overall outcomes appear to be promising, they are highly dependent on both donor and recipient factors.ObjectiveTo develop concensus-based statements and recommendations for the evaluation, management and potential treatment of IBD using FMT in order to move towards standardised practices.DesignAn international panel of experts convened several times to generate evidence-based guidelines by performing a deep evaluation of currently available and/or published data. Twenty-five experts in IBD, immunology and microbiology collaborated in different working groups to provide statements on the following key issues related to FMT in IBD: (A) pathogenesis and rationale, (B) donor selection and biobanking, (C) FMT practices and (D) consideration of future studies and perspectives. Statements were evaluated and voted on by all members using an electronic Delphi process, culminating in a plenary consensus conference and generation of proposed guidelines.Results and conclusionsOur group has provided specific statements and recommendations, based on best available evidence, with the end goal of providing guidance and general criteria required to promote FMT as a recognised strategy for the treatment of IBD.

ObjectiveFaecal microbiota transplantation (FMT) has variable efficacy in treating UC. Recently, oral lyophilised FMT was found to induce remission in patients with UC, with one donor having 100% efficacy compared with a second donor (36% efficacy). We characterised differences in the gut microbiota of these two donors with the aim of improving FMT donor selection.DesignFaecal samples from the two donors were collected over a period of 44 (donor 1) or 70 (donor 2) weeks. The microbiome and metabolome were profiled using shotgun metagenomics and untargeted metabolomicsResultsGut microbiome long-term stability was highly evident in the effective donor. Donor microbiota species evenness was a robust feature associated with clinical efficacy across two clinical trials of FMT in UC, leading to increased donor species engraftment in patients. Alpha diversity and beta diversity of donor gut microbiotas significantly differed. 90 bacterial species and one archaeon were differentially abundant between donors, 44 of which were >0.1% in relative abundance. 17/44 species were enriched in the effective donor, 11 of which (64.7%) were assembled into high-quality genomes that were prevalent (≥75% samples) in that donor, and six showed evidence of engraftment in patients. Taxonomic differences between donors translated to substantial microbial functional differences that were validated using metabolomics.ConclusionDonor microbiota stability and species evenness were identified as novel metrics that were associated with therapeutic efficacy in UC, beyond individual microbial species or metabolites. These metrics may represent community resilience that translates to better engraftment in the host.Trial registration numberACTRN12619000611123.

Graphical abstract:

Youth with Duchenne and Becker muscular dystrophy (DBMD) experience challenges in attaining adult roles, which may impact quality of life. New interventions and treatments may facilitate adult role attainment through improved function. Historical data on adult role attainment is important to assess the impact of new interventions on teens and young adults with DBMD. This study assesses medical knowledge, independence and employment, and relationships among adolescents and young adults with DBMD. This study uses data from a 2013 Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) survey on adult transition. Males with DBMD aged 16–30 years were included. Sixty-five of 258 eligible males participated; we report results on 60 participants with an MD STARnetcase definition of DMD or BMD. Individuals with BMD reported higher rates than those with DMD of frequently staying home without supervision (50% BMD; 14% DMD), independently performing daily physical needs (93% BMD; 7% DMD) and being employed full or part time (33% BMD; 4% DMD). Most participants understood medication and physical therapy goals; less than half indicated being often or always responsible for scheduling DMBD-related management and refilling medications. Most had not been in a romantic relationship but reported desiring such relationships. Our data reinforce the impact of DMD (and to a lesser extent, BMD) on transition to adult roles. These results provide an important historical comparator for teen and adult patients who are trying new interventions and therapies. Such data are important for assessing the quality-of-life impact of new treatments and to inform support and training programs for people with DBMD as they transition to new adult roles and responsibilities.

Faecal microbiota transplantation (FMT) delivered via colonoscopic infusion or enemas have been shown to induce remission in a proportion of patients with active ulcerative colitis. Whether orally administered FMT is effective in ulcerative colitis is unknown. We aimed to assess the efficacy of oral lyophilised FMT for the treatment of active ulcerative colitis.

Context Cadmium (Cd) accumulation is a concern in permanent pasture soils, as it can lead to increased Cd uptake by plants. Aims This study aimed to quantify the effect of full inversion tillage (FIT or ploughing deeper than 30cm), used during pasture renewal, on the redistribution of Cd within the soil profile and on plant Cd concentration. Methods Two field trials (Trial 1, Alfisol; Trial 2, Andisol) were established in New Zealand using contrasting tillage practices (FIT; SIT, shallow tillage; and NT, no tillage) to sow turnips as summer forage crops, followed by autumn re-sowing of perennial ryegrass/white clover pasture. Key results In the Alfisol, no measurable differences (P >0.05) in soil and plant Cd were detected among the tillage treatments. In the Andisol, FIT decreased (P P =0.034) extractable soil Cd concentration than the ST treatment. In addition, the subsequent new pasture had lower (P =0.007) average Cd concentration following FIT compared to ST (0.03 vs 0.05mg/kg). Conclusions We demonstrated that the use of FIT during pasture renewal is a potential solution to reduce topsoil Cd concentration. Implications The FIT is more effective in soil where total soil Cd concentration or its degree of vertical stratification with depth is relatively high.

To determine the age‐standardised prevalence of inflammatory bowel disease (IBD) in a metropolitan area of Sydney, with a focus on its prevalence among older people. Population‐based epidemiological study of people with IBD in the City of Canada Bay, a local government area in the inner west of Sydney, during 1 March 2016 – 10 November 2016. Patients diagnosed with confirmed IBD according to the Copenhagen or revised Porto criteria. Crude prevalence of IBD, including Crohn disease and ulcerative colitis; age‐standardised prevalence of IBD, based on the World Health Organization standard population; prevalence rates among people aged 65 years or more. The median age of 364 people with IBD was 47 years (IQR, 34–62 years); 185 were women (50.8%). The crude IBD prevalence rate was 414 cases (95% CI, 371–456 cases) per 100 000 population; the age‐standardised rate was 348 cases (95% CI, 312–385 cases) per 100 000 population. The age‐standardised rate for Crohn disease was 166 cases (95% CI, 141–192 cases) per 100 000 population; for ulcerative colitis, 148 cases (95% CI, 124–171 cases) per 100 000 population. The IBD prevalence rate in people aged 65 years or more was 612 cases (95% CI, 564‒660 cases) per 100 000, and for those aged 85 years or more, 891 cases (95% CI, 833–949 cases) per 100 000; for people under 65, the rate was 380 cases (95% CI, 342–418 cases) per 100 000. We found that the prevalence of confirmed IBD in a metropolitan sample was highest among older people. Challenges for managing older patients with IBD include higher rates of comorbid conditions, polypharmacy, and cognitive decline, and the immunosuppressive nature of standard therapies for IBD.

ABSTRACTIntroduction: The peak age of diagnosis of inflammatory bowel disease (IBD) occurs during childbearing years, therefore management of IBD during pregnancy is a frequent occurrence. Maintenance of disease remission is crucial to optimize pregnancy outcomes, and potential maternal or fetal toxicity from medications must be balanced against the risks of untreated IBD.Areas covered: This review summarizes the literature on safety and use of medications for IBD during pregnancy and lactation.Expert opinion: 5-aminosalicylates, corticosteroids and thiopurines are safe for use during pregnancy, while methotrexate and tofacitinib should only be used with extreme caution. Anti-TNF agents (except certolizumab), vedolizumab, ustekinumab and tofacitinib readily traverse the placenta via active transport, therefore theoretically may affect fetal development. Certolizumab only undergoes passive transfer across the placenta, thus has markedly lower cord blood levels making it likely the safest biologic agent for infants. There is reasonable evidence to support the safety of anti-TNF monotherapy and combination therapy during pregnancy and lactation. Vedolizumab and ustekinumab are also thought to be safe in pregnancy and lactation, while tofacitinib is generally avoided due to teratogenic effects in animal studies.

Mobility of teleoperated unmanned ground vehicles can be significantly compromised under large communication delays, if the delays are not compensated. This article considers a recently developed delay compensation theory and presents its first empirical evaluation in improving mobility and drivability of a high-speed teleoperated vehicle under large delays. The said delay compensation theory is a predictor-based framework. Two realizations of this framework are considered: a model-free realization that relies only on model-free predictors, and a blended realization, where the heading predictions from the model-free predictor are blended with those from a steering-model-based feedforward predictor for a more accurate prediction of the vehicle heading. A teleoperated track-following task is designed in a human-in-the-loop simulation platform. This platform is used to compare the teleoperation performance with and without the predictor-based framework under both constant and varying delays. Through repeated measurement analysis of variance, it is concluded that the predictor-based framework is effective in achieving a higher vehicle speed, more accurate lateral control, and better drivability as indicated by the three performance metrics of track completion time, track keeping error, and steering control effort, respectively. In addition, it is shown that the blended architecture can lead to further improvements in these metrics compared to using the model-free predictors alone. The analysis also shows that there is no statistically significant difference between constant and varying delay cases in the designed experiment, nor there is any direct relation between drivers' skill level and level of improvement in metrics.

Supplemental Digital Content is available in the text.

The soil fluorine (F) concentration in New Zealand agricultural soils has increased with time as a direct result of the widespread application of phosphate fertilizer to land. Elevated soil F concentrations may potentially harm soil microorganisms, which are important for nutrient cycling and soil formation. Rhizobium leguminosarumis a N2–fixing soil bacterium that is a fundamental component in New Zealand legume‐based pastoral farming. Any impact of F on Rhizobium leguminosarumwould have an adverse effect on New Zealand pasture production. In this study, F toxicity to Rhizobium leguminosarumwas examined as a first step to develop F guideline values for New Zealand agricultural soils. Bottle‐based experiments were conducted to examine the effect of the F−ion on Rhizobium–white clover (Trifolium repensL.) symbiosis by observing nodule morphology and growth. Results indicate that the F−concentration that causes 10% inhibition of Rhizobiumrespiration (IC10) for F−toxicity to Rhizobium leguminosarumwas >100 mg F−L−1. Significant morphological changes occurred when Rhizobiumwas exposed to F concentrations of 500 and 1000 mg L−1. Both light and transmission electron micrographs confirmed that the Rhizobium leguminosarum–white clover interaction was not influenced by F−concentrations >100 mg L−1. The toxic F−concentration for Rhizobium leguminosarumdetermined in this study is orders of magnitude higher than the F−concentration in New Zealand agriculture soils under “normal conditions.” There appears to be no indication of imminent risk of soil F to Rhizobium leguminosarum.

The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis.

Autonomous systems are the future of the Army and Ground Vehicle Systems Center has aligned itself accordingly to support unmanned ground vehicle (UGV) development. Physically testing autonomous algorithms and vehicle systems can be expensive and time consuming, a problem addressed by the use of modelling and simulation (M&S) tools. A multitude of both Government owned and commercial off-the-shelf tools (COTS) are widely available, all claim to virtually evaluate autonomous ground vehicles operating on various environments and scenarios. Most of the COTS tools primarily focus on the commercial automotive industry where vehicles are driven in a structured environment. In this paper two M&S tools, viz., Autonomous Navigation Virtual Environment Laboratory (ANVEL) and rover analysis modelling and simulation (ROAMS) are evaluated for military applications, where the demands for navigation include both on-road and off-road, as well as both structured and unstructured environments as a preliminary benchmark.

Workload management is of critical concern in teleoperation of unmanned vehicles, because high workload can lead to sub-optimal task performance and can harm human operators’ long-term well-being. In the present study, we conducted a human-in-the-loop experiment, where the human operator teleoperated a simulated High Mobility Multipurpose Wheeled Vehicle (HMMWV) and performed a secondary visual search task. We measured participants’ gaze trajectory and pupil size, based on which their workload level was estimated. We proposed and tested a Bayesian inference (BI) model for assessing workload in real time. Results show that the BI model can achieve an encouraging 0.69 F1score, 0.70 precision, and 0.69 recall.

ABSTRACTIntroduction: Medications in treating Crohn’s disease (CD) have evolved over the last two decades, particularly with the use of biologic agents. There are, however, concerns about the safety and adverse events associated with these medications. The authors review the safety profile of immunosuppressive medications used in Crohn’s disease in adult patients.Areas covered: The authors performed a literature search until October 2018 to examine safety data on thiopurines, methotrexate, anti-TNFα agents, vedolizumab and ustekinumab. The authors focused on ‘trial’ and ‘real-world’ data for the biologic agents. Safety in pregnancy and the elderly are also presented.Expert opinion: Available data in CD suggest that immunosuppressive medications are relatively safe, although there are concerns about an elevated risk of serious infections, skin cancer and lymphoma particularly with thiopurines and anti-TNFα agents. Data on vedolizumab and ustekinumab suggest these newer biologic agents are well tolerated; however, longer term data in CD are required to identify risks with extended use. Apart from methotrexate, there appear to be no adverse congenital outcomes with exposure of drugs during pregnancy.

In the United States and some other NATO (North Atlantic Treaty Organization) countries, the NATO Reference Mobility Model is currently used to evaluate military ground vehicle mobility. The module of the NATO Reference Mobility Model for predicting the cross-country performance of military vehicles is empirically based and was developed using test data collected decades ago. The NATO Reference Mobility Model has inherent limitations, such as the uncertainty whether its empirical relations can be extrapolated beyond the test conditions upon which they were derived or whether it can be used for evaluating new-generation military vehicles. This suggests that there is a need for the development of a physics-based model that takes into account the advancements in terramechanics and modelling/simulation techniques. This paper describes the results of a detailed evaluation of a physics-based model – the Nepean Tracked Vehicle Performance Model – for assessing military tracked vehicle cross-country performance. The performance of a notional tracked vehicle (an armoured personnel carrier) predicted by the latest version of the Nepean Tracked Vehicle Performance Model is compared with test data obtained on sandy terrain, muskeg and snow-covered terrain. The correlations between the predicted and measured performance are evaluated using the coefficient of correlation, coefficient of determination, root mean square deviation and coefficient of variation. The applications of the Nepean Tracked Vehicle Performance Model to predicting the maximum possible vehicle speed (speed-made-good) on a given terrain, the sensitivity of vehicle performance to variations in the values of terrain parameters and the mean maximum pressure are demonstrated. The results of this study indicate that the Nepean Tracked Vehicle Performance Model has potential to form the basis for the development of the next-generation cross-country performance assessment methodology for military tracked vehicles.

This paper describes a model for deformable soil based on triangular meshes with vertical deformation. Such soil model can be used in a multi-body simulation environment to study the performance of wheeled or tracked vehicles. The formulation is inspired by the soil contact model (SCM), but unlike the original idea, our implementation uses triangular meshes with arbitrary topology. We leverage on this representation of the soil in order to provide a system that automatically refines the level of detail (LOD) of the mesh when tyres or track shoes sink into the soil; this allows the use of coarse meshes as initial approximations of large areas, for the sake of faster performance and lowoverhead on computer memory. A general-purpose collision detection algorithm is used to detect the shape of contacting objects, hence allowing the use of generic geometries to represent lugs, tyre threads, or even track shoes or robotic legs. The method has also been tested with deformable tyres.

Assessing the mobility of off-road vehicles is a complex task that most often falls back on semi-empirical approaches to quantify the tire-terrain interaction. We introduce a high-fidelity ground vehicle mobility simulation framework that uses physics-based models of the vehicle, tyres, and terrain to factor in both tyre flexibility and soil deformation. The tyres are modelled using a nonlinear finite element approach that involves layers of orthotropic shell elements. The soil is represented as a large collection of rigid elements that interact through contact, friction, and cohesive forces. The high-fidelity vehicle models incorporate suspension, steering, driveline, and powertrain models. To alleviate the prohibitive computational costs associated with a coupled simulation of the overall problem, we propose a decoupled approach implemented as an explicit, force-displacement co-simulation framework which is demonstrated on several full-vehicle on soft soil simulations. UNCLASSIFIED: Distribution Statement A. Approved for public release; distribution is unlimited. #28937.

The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

Background: Earlier goals of care (GOC) discussions in patients with advanced cancer are associated with less aggressive end-of-life care including decreased use of medical technologies. Unfortunately, conversations often occur late in the disease trajectory when patients are acutely unwell. Here, we evaluate practitioner perspectives of patient, family, physician, and external barriers to early GOC discussions in the ambulatory oncology setting.Methods: A previously published survey to assess barriers to GOC discussions among clinicians on inpatient medical wards was modified for the ambulatory oncology setting and distributed to oncologists from 12 centers in Ontario, Canada. Physicians were asked to rank the importance of various barriers to having GOC discussions (1 = extremely unimportant to 7 = extremely important).Results: Questionnaires were completed by 30 (24%) of 127 physicians. Respondents perceived patient- and family-related factors as the most important barriers to GOC discussions. Of these, patient difficulty accepting prognosis or desire for aggressive treatment were perceived as most important. Patients’ inflated expectation of treatment benefit was also considered an important barrier to discontinuing active cancer-directed therapy. While physician barriers were ranked lower than patient-related factors, clinicians’ self-identified difficulty estimating prognosis and uncertainty regarding treatment benefits were also considered important. Patient’s refusal for referral was the most highly rated barrier to early palliative care referral. Most respondents were nonetheless very or extremely willing to initiate (90%) or lead (87%) GOC discussions.Conclusion: Oncologists ranked patient- and family-related factors as the most important barriers to GOC discussions, while clinicians’ self-identified difficulty estimating prognosis and uncertainty regarding treatment benefits were also considered important. Further work is required to assess patient preferences and perceptions and develop targeted interventions.

A high-fidelity physics-based approach for predicting vehicle mobility over large soft-soil terrain maps is presented. The approach is based on an HPC design-of-experiments (DOE) procedure, and the integration of multibody dynamics for modelling the vehicle and the discrete element method (DEM) for modelling the soil into one solver. A general cohesive soil DEM material model is used which includes the effects of cohesion, elasticity, plasticity/compressibility, damping, friction, and viscosity. To manage problem size, a novel moving soil patch technique is developed in which DEM particles which are behind the vehicle are continuously eliminated and then reemitted in front of the vehicle, levelled and compacted. The DEM inter-particle cohesion and friction are calibrated to the cone index using a simulation of a cone penetrometer. The DOE approach is demonstrated by predicting the speed-made-good distribution on 22 × 22 km terrain map for a 4 × 4 military vehicle. Two terrain parameters are considered in the DOE: terrain positive slope and soil strength.

IMPORTANCE: The Second Universal Definition of Myocardial Infarction (MI) divides MIs into different types. Type 1 MIs result spontaneously from instability of atherosclerotic plaque, whereas type 2 MIs occur in the setting of a mismatch between oxygen demand and supply, as with severe hypotension. Type 2 MIs are uncommon in the general population, but their frequency in human immunodeficiency virus (HIV)–infected individuals is unknown. OBJECTIVES: To characterize MIs, including type; identify causes of type 2 MIs; and compare demographic and clinical characteristics among HIV-infected individuals with type 1 vs type 2 MIs. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal study identified potential MIs among patients with HIV receiving clinical care at 6 US sites from January 1, 1996, to March 1, 2014, using diagnoses and cardiac biomarkers recorded in the centralized data repository. Sites assembled deidentified packets, including physician notes and electrocardiograms, procedures, and clinical laboratory tests. Two physician experts adjudicated each event, categorizing each definite or probable MI as type 1 or type 2 and identifying the causes of type 2 MI. MAIN OUTCOMES AND MEASURES: The number and proportion of type 1 vs type 2 MIs, demographic and clinical characteristics among those with type 1 vs type 2 MIs, and the causes of type 2 MIs. RESULTS: Among 571 patients (median age, 49 years [interquartile range, 43-55 years]; 430 men and 141 women) with definite or probable MIs, 288 MIs (50.4%) were type 2 and 283 (49.6%) were type 1. In analyses of type 1 MIs, 79 patients who underwent cardiac interventions, such as coronary artery bypass graft surgery, were also included, totaling 362 patients. Sepsis or bacteremia (100 [34.7%]) and recent use of cocaine or other illicit drugs (39 [13.5%]) were the most common causes of type 2 MIs. A higher proportion of patients with type 2 MIs were younger than 40 years (47 of 288 [16.3%] vs 32 of 362 [8.8%]) and had lower current CD4 cell counts (median, 230 vs 383 cells/µL), lipid levels (mean [SD] total cholesterol level, 167 [63] vs 190 [54] mg/dL, and mean (SD) Framingham risk scores (8% [7%] vs 10% [8%]) than those with type 1 MIs or who underwent cardiac interventions. CONCLUSIONS AND RELEVANCE: Approximately half of all MIs among HIV-infected individuals were type 2 MIs caused by heterogeneous clinical conditions, including sepsis or bacteremia and recent use of cocaine or other illicit drugs. Demographic characteristics and cardiovascular risk factors among those with type 1 and type 2 MIs differed, suggesting the need to specifically consider type among HIV-infected individuals to further understand MI outcomes and to guide prevention and treatment.

A new hierarchical multiscale terrain model is developed using the material point method (MPM) to enable effective modeling of large terrain deformation for high-fidelity off-road mobility simulations. Unlike the Lagrangian finite element (FE) model, MPM allows for modeling large deformation of a continuum without mesh distortion using material points as moving quadrature points for the background grid. This unique feature is extended to account for complex granular soil material behavior with the hierarchical multiscale modeling approach in the context of off-road mobility simulations. The grain-scale discrete-element (DE) representative volume element (RVE) and its neural network surrogate model (artificial neural network (ANN) RVE) are developed and introduced to the upper-scale MPM model through the scale-bridging algorithm. The DE RVE is used to generate training data for the ANN RVE, allowing for predicting the history-dependent grain-scale soil material behavior efficiently at every material point that moves through the upper-scale MPM background grid. A numerical procedure for modeling the interaction of the nonlinear FE tire model with the MPM-ANN multiscale terrain model is developed considering moving soil patches generalized for the upper-scale MPM terrain model. It is fully integrated into the general off-road mobility simulation framework by leveraging scalable high-performance computing techniques. The predictive ability of the proposed MPM-ANN multiscale off-road mobility model is examined and validated against the full-scale vehicle test data, involving large deformation of soft terrain. The computational benefit from the neural network surrogate model is also demonstrated.