Optimal allocation of resources among general and species-specific tools for plant pest biosecurity surveillance.

This paper proposes a surveillance model for plant pests that can optimally allocate resources among survey tools with varying properties. While some survey tools are highly specific for the detection of a single pest species, others are more generalized. There is considerable variation in the cost and sensitivity of these tools, but there are no guidelines or frameworks for identifying which tools are most cost-effective when used in surveillance programs that target the detection of newly invaded populations. To address this gap, we applied our model to design a trapping surveillance program in New Zealand for bark- and wood-boring insects, some of the most serious forest pests worldwide. Our findings show that exclusively utilizing generalized traps (GTs) proves to be highly cost-effective across a wide range of scenarios, particularly when they are capable of capturing all pest species. Implementing surveillance programs that only employ specialized traps (ST) is cost-effective only when these traps can detect highly damaging pests. However, even in such cases, they significantly lag in cost-effectiveness compared to GT-only programs due to their restricted coverage. When both GTs and STs are used in an integrated surveillance program, the total expected cost (TEC) generally diminishes when compared to programs relying on a single type of trap. However, this relative reduction in TEC is only marginally larger than that achieved with GT-only programs, as long as highly damaging species can be detected by GTs. The proportion of STs among the optimal required traps fluctuates based on several factors, including the relative pricing of GTs and STs, pest arrival rates, potential damage, and, more prominently, the coverage capacity of GTs. Our analysis suggests that deploying GTs extensively across landscapes appears to be more cost-effective in areas with either very high or very low levels of relative risk density, potential damage, and arrival rate. Finally, STs are less likely to be required when the pests that are detected by those tools have a higher likelihood of successful eradication because delaying detection becomes less costly for these species.

Efficient border biosecurity inspection leverages superspreading to reduce biological invasion risk.

Biological invasions are a growing threat to biodiversity, food security, and economies. Rising pressure from increased global trade requires improving border inspection efficiency. Here, we depart from the conventional consignment-by-consignment approach advocated in current inspection standards. Instead, we suggest a broader perspective: evaluating border inspection regimes based on their ability to reduce propagule pressure across entire pathways. Additionally, we demonstrate that most biosecurity pathways exhibit superspreading behavior, that is, consignments from the same pathway have varying infestation rates and contain rare right-tail events (also called overdispersion). We show that greater overdispersion leads to more pronounced diminishing returns, with consequences on the optimal allocation of sampling effort. We leverage these two insights to develop a simple and efficient border inspection regime that can significantly reduce propagule pressure compared to current standards. Our analysis revealed that consignment size is a key driver of biosecurity risk and that sampling proportional to the square root of consignment size is near optimal. In testing, our framework reduced propagule pressure by 31 to 38% compared to current standards. We also identified opportunities to further improve inspection efficiency by considering additional pathway characteristics (i.e., overdispersion parameters, zero inflation, relative risk, sampling cost, detectability) and developed solutions for these more complex scenarios. We anticipate our result will mitigate biological invasion risk with significant implications for biodiversity conservation, food security, and economies worldwide.

Adaptive sampling method to monitor low-risk pathways with limited surveillance resources.

The rise of globalization has led to a sharp increase in international trade with high volumes of containers, goods, and items moving across the world. Unfortunately, these trade pathways also facilitate the movement of unwanted pests, weeds, diseases, and pathogens. Each item could contain biosecurity risk material, but it is impractical to inspect every item. Instead, inspection efforts typically focus on high-risk items. However, low risk does not imply no risk. It is crucial to monitor the low-risk pathways to ensure that they are and remain low risk. To do so, many approaches would seek to estimate the risk to some precision, but increasingly lower risks require more samples. On a low-risk pathway that can be afforded only limited inspection resources, it makes more sense to assign fewer samples to the lower risk activities. We approach the problem by introducing two thresholds. Our method focuses on letting us know whether the risk is below certain thresholds, rather than estimating the risk precisely. This method also allows us to detect a significant change in risk. Our approach typically requires less sampling than previous methods, while still providing evidence to regulators to help them efficiently and effectively allocate inspection effort.

Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+ /K+ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35-55 -induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG35-55 (PLG-MOG35-55 ) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.

Assessing the quality of offshore Binomial sampling biosecurity inspections using onshore inspections.

Introduction of pests and diseases through trade is one of the main socio-ecological challenges worldwide. Although Binomial sampling inspection at the border can reduce pest entry risk, it is common for consignments to fail inspection, wasting resources for both exporter and importer. Outsourcing the inspection to the exporting country could reduce the cost of inspection for both parties. However, there is then a need to assess the quality of the offshore inspection. In this paper, we develop an inverse method combining past inspection data on the pathway, an onshore inspection sample, and the Beta-Binomial model to infer the sample size of the offshore inspection. We illustrate the method on two case studies: the importation of live plants through germplasm into Australia and the importation of pelleted seeds in New Zealand. In these case studies, we found that detecting four to five infested units in a single onshore inspection was typically sufficient to significantly doubt the presence of a compliant offshore inspection. We also ran a simulation experiment to quantify the statistical power to reject or accept the presence of compliant offshore inspection in practice: In highly infested pathways, we could detect the absence of offshore inspections after inspecting five consignments onshore. Less infested pathways required inspecting 20 to 60 consignments onshore. Our study demonstrates that Binomial sampling onshore can be used to assess the quality of offshore inspections.

Arthropods on imported plant products: Volumes predict general trends while contextual details enhance predictive power.

Agricultural biosecurity interventions are aimed at minimizing introductions of harmful non-native organisms to new areas via agricultural trade. To prioritize such interventions, historical data on interceptions have been used to elucidate which factors determine the likelihood that a particular import is carrying a harmful organism. Here we use an interception data set of arthropod contaminants recorded on plant imports arriving in South Africa from 2005 to 2019, comprising 13,566 samples inspected for arthropod contaminants, of which 4902 were positive for the presence of at least one arthropod. We tested 29 predictor variables that have previously been used to explain variation in rates of detection and three variables describing possible sources of additional variation and grouped these into six mutually exclusive "factor classes." We used boosted regression trees as a non-parametric stochastic machine-learning method to build models for each factor class and interactions between them. We explored the influence of these variables with data split either randomly or chronologically. While we identified some specific patterns that could be explained post-hoc by historical events, only inspected volumes were reliably correlated with detection of arthropod contaminants across the whole data set. However, inspected volumes could not predict future interceptions of arthropods, which instead relied on contextual factors such as country, crop or year of import. This suggests that, although certain factors may be important in certain circumstances or for particular crops or commodities, there is little general predictive power in the current data. Instead, an idiographic approach would be most beneficial in biosecurity to ascertain the details of why a particular pest arrived on a particular pathway and how it might move (and be stopped) in future.

A field experiment characterizing variable detection rates during plant surveys.

Surveys aimed at finding threatened and invasive species can be challenging due to individual rarity and low and variable individual detection rates. Detection rate in plant surveys typically varies due to differences among observers, among the individual plants being surveyed (targets), and across background environments. Interactions among these 3 components may occur but are rarely estimated due to limited replication and control during data collection. We conducted an experiment to investigate sources of variation in detection of 2 Pilosella species that are invasive and sparsely distributed in the Alpine National Park, Australia. These species are superficially similar in appearance to other yellow-flowered plants occurring in this landscape. We controlled the presence and color of flowers on target Pilosella plants and controlled their placement in plots, which were selected for their variation in cover of non-target yellow flowers and dominant vegetation type. Observers mimicked Pilosella surveys in the plots and reported 1 categorical and 4 quantitative indicators of their survey experience level. We applied survival analysis to detection data to model the influence of both controlled and uncontrolled variables on detection rate. Orange- and yellow-flowering Pilosella in grass- and heath-dominated vegetation were detected at a higher rate than nonflowering Pilosella. However, this detection gain diminished as the cover of other co-occurring yellow-flowering species increased. Recent experience with Pilosella surveys improved detection rate. Detection experiments are a direct and accessible means of understanding detection processes and interpreting survey data for threatened and invasive species. Our detection findings have been used for survey planning and can inform progress toward eradication. Interaction of target and background characteristics determined detection rate, which enhanced predictions in the Pilosella eradication program and demonstrated the difficulty of transferring detection findings into untested environments.

Un Experimento de Campo que Caracteriza las Tasas Variables de Detección en los Censos de Plantas Resumen Los censos enfocados en encontrar especies amenazadas e invasoras pueden ser un reto debido a la rareza individual y las tasas bajas y variables de detección individual. Las tasas de detección en los censos botánicos varían comúnmente por las diferencias entre los observadores, entre las plantas individuales que se están censando (objetivo de búsqueda) y en el entorno ambiental. La interacción entre estos tres componentes puede ocurrir, pero rara vez se calcula debido a la replicación y control limitados durante la recolección de datos. Realizamos un experimento para investigar el origen de las variaciones en la detección de dos especies de Pilosella que son invasoras y están distribuidas escasamente en el Parque Nacional Alpino en Australia. Estas especies son superficialmente similares en apariencia a otras plantas de flores amarillas que habitan este paisaje. Controlamos la presencia y el color de las flores en las plantas de Pilosella, así como su colocación en lotes, los cuales fueron seleccionados por su variación en la cobertura de flores amarillas y tipos de vegetación circundantes. Los observadores imitaron los censos de Pilosella en los lotes y reportaron un indicador categórico y cuatro cuantitativos de su nivel de experiencia en censos. Aplicamos el análisis de supervivencia a los datos de detección para modelar la influencia de las variables controladas y no controladas sobre la tasa de detección. Las plantas de Pilosella con flores amarillas y anaranjadas en la vegetación dominada por pastos y brezales fueron detectadas con una tasa mayor que las plantas de Pilosella sin flores. Sin embargo, esta ganancia en la detección disminuyó conforme incrementó la cobertura de otras plantas con flores amarillas. La experiencia reciente de los observadores con censos de Pilosella aumentó la tasa de detección. Los experimentos de detección son un medio directo y accesible para entender los procesos de detección e interpretar los datos de los censos de especies amenazadas e invasoras. Nuestros resultados en la detección han sido utilizados para la planeación de censos y pueden guiar el progreso hacia la erradicación. La interacción de las características diana y del entorno determinaron la tasa de detección, la cual mejoró las predicciones en el programa de erradicación de Pilosella y demostró la dificultad de transferir los resultados de detección hacia ambientes sin ensayos.

Approaches for estimating benefits and costs of interventions in plant biosecurity across invasion phases.

Nonnative plant pests cause billions of dollars in damages. It is critical to prevent or reduce these losses by intervening at various stages of the invasion process, including pathway risk management (to prevent pest arrival), surveillance and eradication (to counter establishment), and management of established pests (to limit damages). Quantifying benefits and costs of these interventions is important to justify and prioritize investments and to inform biosecurity policy. However, approaches for these estimations differ in (1) the assumed relationship between supply, demand, and prices, and (2) the ability to assess different types of direct and indirect costs at invasion stages, for a given arrival or establishment probability. Here we review economic approaches available to estimate benefits and costs of biosecurity interventions to inform the appropriate selection of approaches. In doing so, we complement previous studies and reviews on estimates of damages from invasive species by considering the influence of economic and methodological assumptions. Cost accounting is suitable for rapid decisions, specific impacts, and simple methodological assumptions but fails to account for feedbacks, such as market adjustments, and may overestimate long-term economic impacts. Partial equilibrium models consider changes in consumer and producer surplus due to pest impacts or interventions and can account for feedbacks in affected sectors but require specialized economic models, comprehensive data sets, and estimates of commodity supply and demand curves. More intensive computable general equilibrium models can account for feedbacks across entire economies, including capital and labor, and linkages among these. The two major considerations in choosing an approach are (1) the goals of the analysis (e.g., consideration of a single pest or intervention with a limited range of impacts vs. multiple interventions, pests or sectors), and (2) the resources available for analysis such as knowledge, budget and time.

Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

Estimating Consignment-Level Infestation Rates from the Proportion of Consignment that Failed Border Inspection: Possibilities and Limitations in the Presence of Overdispersed Data.

Introduction of pests and diseases through trade is one of the main socioecological challenges worldwide. Targeted sampling at border security can efficiently provide information about biosecurity threats and also reduce pest entry risk. Prioritizing sampling effort requires knowing which pathways are most infested. However, border security inspection data are often right-censored, as inspection agencies often only report that a consignment has failed inspection (i.e., there was at least one unit infested), not how many infested units were found. A method has been proposed to estimate the mean infestation rate of a pathway from such right-censored data (Chen et al.). Using simulations and case study data from imported germplasm consignments inspected at the border, we show that the proposed method results in negatively biased estimates of the pathway infestation rate when the inspection data exhibit overdispersion (i.e., varying infestation rates among different consignments of the same pathway). The case study data also show that overdispersion is prevalent in real data sets. We demonstrate that the method proposed by Chen et al. recovers the median infestation rate of the pathway, rather than its mean. Therefore, it underpredicts the infestation rate when the data are overdispersed (in right-skewed distributions, the mean is above the median). To allow better monitoring and optimizing sampling effort at the border, we recommend that border protection agencies report all the data (the number of infested units found together with the sample size of the inspection) instead of only that the consignment failed inspection.

Risk factors for fouling biomass: evidence from small vessels in Australia.

Invasive non-indigenous species (NIS) are a threat to marine biodiversity and marine reliant industries. Recreational vessels are recognised as an important vector of NIS translocation, particularly domestically. This paper reports on a novel application of multilevel modelling and multiple imputation in order to quantify the relationship between biofouling biomass (wet weight) and the vessel-level characteristics of recreational and fishing vessels. It was found that the number of days since the vessel was last cleaned strongly related to the biofouling biomass, yet differed dependent on vessel type. Similarly, the median number of trips undertaken was related to the biofouling biomass, and varied according to the type of antifouling paint (AF) used. No relationship was found between vessel size and biofouling biomass per sample unit. To reduce the spread of NIS, vessel owners should use an AF paint suitable to their vessel's operational profile, and follow a maintenance schedule according to the paint manufacturer's specifications.

When Does Poor Governance Presage Biosecurity Risk?

Border inspection, and the challenge of deciding which of the tens of millions of consignments that arrive should be inspected, is a perennial problem for regulatory authorities. The objective of these inspections is to minimize the risk of contraband entering the country. As an example, for regulatory authorities in charge of biosecurity material, consignments of goods are classified before arrival according to their economic tariff number. This classification, perhaps along with other information, is used as a screening step to determine whether further biosecurity intervention, such as inspection, is necessary. Other information associated with consignments includes details such as the country of origin, supplier, and importer, for example. The choice of which consignments to inspect has typically been informed by historical records of intercepted material. Fortunately for regulators, interception is a rare event; however, this sparsity undermines the utility of historical records for deciding which containers to inspect. In this article, we report on an analysis that uses more detailed information to inform inspection. Using quarantine biosecurity as a case study, we create statistical profiles using generalized linear mixed models and compare different model specifications with historical information alone, demonstrating the utility of a statistical modeling approach. We also demonstrate some graphical model summaries that provide managers with insight into pathway governance.

ER Chaperone BiP/GRP78 Is Required for Myelinating Cell Survival and Provides Protection during Experimental Autoimmune Encephalomyelitis.

Myelinating cells synthesize large amounts of membrane protein through the secretory pathway, which makes these cells particularly sensitive to perturbations of the endoplasmic reticulum (ER). Ig binding protein (BiP), also known as glucose-regulated protein 78 (GRP78), is a critical ER chaperone that also plays a pivotal role in controlling the cellular response to ER stress. To examine the potential importance of BiP to myelinating cells, we used a conditional knock-out approach to BiP gene inactivation in oligodendrocytes during development, in adulthood, and in response to experimental autoimmune encephalomyelitis (EAE), an animal model of the inflammatory demyelinating disorder multiple sclerosis (MS). During development, mice lacking functional BiP gene expression in oligodendrocytes developed tremors and ataxia and died before reaching maturity. When BiP gene inactivation in oligodendrocytes was initiated in adulthood, the mice displayed severe neurological symptoms including tremors and hind-limb paralysis. The inactivation of BiP in oligodendrocytes during development or in adulthood resulted in oligodendrocyte loss and corresponding severe myelin abnormalities. Mice heterozygous for the oligodendrocyte-specific inactivation of BiP, which were phenotypically normal without evidence of neuropathology, displayed an exacerbated response to EAE that correlated with an increased loss of oligodendrocytes. Furthermore, mice in which the BiP gene was specifically inactivated in developing Schwann cells displayed tremor that progressed to hindlimb paralysis, which correlated with diminished numbers of myelinating Schwann cells and severe PNS hypomyelination. These studies demonstrate that BiP is critical for myelinating cell survival and contributes to the protective response of oligodendrocyte against inflammatory demyelination.

IL-17A activates ERK1/2 and enhances differentiation of oligodendrocyte progenitor cells.

Inflammatory signals present in demyelinated multiple sclerosis lesions affect the reparative remyelination process conducted by oligodendrocyte progenitor cells (OPCs). Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 have differing effects on the viability and growth of OPCs, however the effects of IL-17A are largely unknown. Primary murine OPCs were stimulated with IL-17A and their viability, proliferation, and maturation were assessed in culture. IL-17A-stimulated OPCs exited the cell cycle and differentiated with no loss in viability. Expression of the myelin-specific protein, proteolipid protein, increased in a cerebellar slice culture assay in the presence of IL-17A. Downstream, IL-17A activated ERK1/2 within 15 min and induced chemokine expression in 2 days. These results demonstrate that IL-17A exposure stimulates OPCs to mature and participate in the inflammatory response.

Advanced Preoperative Planning Techniques in the Management of Complex Proximal Humerus Fractures.

This review evaluates the current literature on the recent advances of preoperative planning in the management of complex proximal humerus fractures (PHF). PHFs can pose a considerable challenge for orthopaedic surgeons due to their diversity in presentation and complexity. Poor preoperative planning can lead to prolonged operations, increased blood loss, higher risk of complications, and increased stress on the surgical team. Recent advances have seen the evolution of preoperative planning from conventional methods to computer-assisted virtual surgical technology (CAVST) and three-dimensional (3D) printing, which have been highlighted as transformative tools for improving preoperative planning and postoperative outcomes. CAVST allows the creation of 3D renderings of patient-specific anatomy, clearly demonstrating fracture patterns and facilitating detailed planning for arthroplasty or surgical fixation. The early studies show promising outcomes however the literature calls for more high-quality randomised controlled trials. Using 3D printing for high-fidelity simulation involving patient-specific physical models offers an immersive experience for surgical planning. Preoperative planning with 3D printing reduces operative time, blood loss and use of fluoroscopy. The technology's potential to produce customisable surgical implants further improves its versatility. There is a need for a cost analysis for the use of these technologies within the orthopaedic field, particularly considering the high expense of 3D printing materials and extended hospital stays until the printed models are available. CAVST and 3D printing also show promising applications within high-fidelity simulation surgical training, with CAVST offering possibilities in virtual reality and haptic-enhanced simulations and 3D printing providing physical models for trainee surgeons to hone their skills. Moving forward, a reduction in the cost of 3D printing and the advancement of CAVST using artificial intelligence would lead to future improvement. In conclusion, preoperative planning supported by these innovative technologies will play a pivotal role in improving surgical outcomes and training for complex PHF cases.

Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.

High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. Here we demonstrate that HMGB1 drives neuroinflammatory responses in experimental autoimmune encephalomyelitis (EAE), a murine model for MS, and that inhibition of HMGB1 signaling ameliorates disease. Specifically i.v. injection of an HMGB1 neutralizing antibody in the C57BL/6 model of chronic EAE or SJL/J model of relapsing-remitting EAE ameliorated clinical disease prophylactically or during ongoing disease, blocked T cell infiltration of the central nervous system, and inhibited systemic CD4(+) T cell responses to myelin epitopes. Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro, and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity.

Robotic-Assisted Knee Arthroplasty: Insights and Implications From Current Literature.

Robotic-assisted knee arthroplasty has emerged as a promising development, aiming to enhance surgical precision and patient outcomes. This literature review examines the clinical efficacy, cost implications, environmental impact, and potential of telesurgery in robotic-assisted total knee arthroplasty (RATKA) and robotic-assisted unicompartmental knee arthroplasty (RAUKA) relative to conventional techniques. A thorough literature search was conducted across medical databases. Clinical and radiological outcomes of RATKA and RAUKA were extracted and analyzed. Direct costs, operating time, surgeon learning curve, environmental implications, and the futuristic concept of telesurgery were also considered. Subjective patient assessments such as WOMAC, Oxford Knee Score, and SF-36, alongside objective measures like HSS score and KSS, were commonly used. Radiological parameters like hip-knee-ankle (HKA) and femorotibial angle provided insights into post-operative alignment. Evidence indicated sporadic high-level design studies, often with limited samples. Cost remains a major constraint with robotic systems, though high-volume cases might offset expenses. Environmental assessments revealed robotic surgeries generate a higher carbon footprint. Telesurgery, an evolving field, could transcend geographical boundaries but is not without challenges, including high costs, latency issues, and cyber threats. While robotic-assisted surgeries may hold promise in the future, substantial barriers, including acquisition costs, potential surgeon deskilling, and environmental concerns, need addressing. Greater robot utilization may drive costs down with more competitors entering the market. Continued research, especially multi-center RCTs, is pivotal to solidifying the role of robotic systems in knee arthroplasty.

Development of a validation imaging dataset for Molecular Radiotherapy dosimetry multicenter intercomparison exercises based on anthropomorphic phantoms.

Validation of a Molecular Radiotherapy (MRT) dosimetry system requires imaging data for which an accompanying "ground truth" pharmacokinetic model and absorbed dose calculation are known. METHODS: We present a methodology for production of a validation dataset for image based 177Lu dotatate dosimetry calculations. A pharmacokinetic model is presented with activity concentrations corresponding to common imaging timepoints. Anthropomorphic 3D printed phantoms, corresponding to the organs at risk, have been developed to provide SPECT/CT and Whole Body imaging with known organ activities corresponding to common clinical timepoints. RESULTS: Results for the accuracy of phantom filling reproduce the activity concentrations from the pharmacokinetic model for all timepoints and organs within measurement uncertainties, with a mean deviation of 0.6(8)%. The imaging dataset, ancillary data and phantoms designs are provided as a source of well characterized input data for the validation of clinical MRT dosimetry systems. CONCLUSIONS: The combination of pharmacokinetic modelling with the use of anthropomorphic 3D printed phantoms are a promising procedure to provide data for the validation of Molecular Radiotherapy Dosimetry systems, allowing multicentre comparisons.

Optimisation of the air fraction correction for lung PET/CT: addressing resolution mismatch.

BACKGROUND: Increased pulmonary [Formula: see text]F-FDG metabolism in patients with idiopathic pulmonary fibrosis, and other forms of diffuse parenchymal lung disease, can predict measurements of health and lung physiology. To improve PET quantification, voxel-wise air fractions (AF) determined from CT can be used to correct for variable air content in lung PET/CT. However, resolution mismatches between PET and CT can cause artefacts in the AF-corrected image. METHODS: Three methodologies for determining the optimal kernel to smooth the CT are compared with noiseless simulations and non-TOF MLEM reconstructions of a patient-realistic digital phantom: (i) the point source insertion-and-subtraction method, [Formula: see text]; (ii) AF-correcting with varyingly smoothed CT to achieve the lowest RMSE with respect to the ground truth (GT) AF-corrected volume of interest (VOI), [Formula: see text]; iii) smoothing the GT image to match the reconstruction within the VOI, [Formula: see text]. The methods were evaluated both using VOI-specific kernels, and a single global kernel optimised for the six VOIs combined. Furthermore, [Formula: see text] was implemented on thorax phantom data measured on two clinical PET/CT scanners with various reconstruction protocols. RESULTS: The simulations demonstrated that at [Formula: see text] iterations (200 i), the kernel width was dependent on iteration number and VOI position in the lung. The [Formula: see text] method estimated a lower, more uniform, kernel width in all parts of the lung investigated. However, all three methods resulted in approximately equivalent AF-corrected VOI RMSEs (<10%) at [Formula: see text]200i. The insensitivity of AF-corrected quantification to kernel width suggests that a single global kernel could be used. For all three methodologies, the computed global kernel resulted in an AF-corrected lung RMSE <10%  at [Formula: see text]200i, while larger lung RMSEs were observed for the VOI-specific kernels. The global kernel approach was then employed with the [Formula: see text] method on measured data. The optimally smoothed GT emission matched the reconstructed image well, both within the VOI and the lung background. VOI RMSE was <10%, pre-AFC, for all reconstructions investigated. CONCLUSIONS: Simulations for non-TOF PET indicated that around 200i were needed to approach image resolution stability in the lung. In addition, at this iteration number, a single global kernel, determined from several VOIs, for AFC, performed well over the whole lung. The [Formula: see text] method has the potential to be used to determine the kernel for AFC from scans of phantoms on clinical scanners.