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Purpose: To establish the clinical applicability of deep‐learning organ‐at‐risk autocontouring models (DL‐AC) for brain radiotherapy. The dosimetric impact of contour editing, prior to model training, on performance was evaluated for both CT and MRI‐based models. The correlation between geometric and dosimetric measures was also investigated to establish whether dosimetric assessment is required for clinical validation. Method: CT and MRI‐based deep learning autosegmentation models were trained using edited and unedited clinical contours. Autosegmentations were dosimetrically compared to gold standard contours for a test cohort. D1%, D5%, D50%, and maximum dose were used as clinically relevant dosimetric measures. The statistical significance of dosimetric differences between the gold standard and autocontours was established using paired Student's t‐tests. Clinically significant cases were identified via dosimetric headroom to the OAR tolerance. Pearson's Correlations were used to investigate the relationship between geometric measures and absolute percentage dose changes for each autosegmentation model. Results: Except for the right orbit, when delineated using MRI models, the dosimetric statistical analysis revealed no superior model in terms of the dosimetric accuracy between the CT DL‐AC models or between the MRI DL‐AC for any investigated brain OARs. The number of patients where the clinical significance threshold was exceeded was higher for the optic chiasm D1% than other OARs, for all autosegmentation models. A weak correlation was consistently observed between the outcomes of dosimetric and geometric evaluations. Conclusions: Editing contours before training the DL‐AC model had no significant impact on dosimetry. The geometric test metrics were inadequate to estimate the impact of contour inaccuracies on dose. Accordingly, dosimetric analysis is needed to evaluate the clinical applicability of DL‐AC models in the brain. [ABSTRACT FROM AUTHOR]

Fertility‐targeted gene drives have been proposed as an ethical genetic approach for managing wild populations of vertebrate pests for public health and conservation benefit. This manuscript introduces a framework to identify and evaluate target gene suitability based on biological gene function, gene expression and results from mouse knockout models. This framework identified 16 genes essential for male fertility and 12 genes important for female fertility that may be feasible targets for mammalian gene drives and other non‐drive genetic pest control technology. Further, a comparative genomics analysis demonstrates the conservation of the identified genes across several globally significant invasive mammals. In addition to providing important considerations for identifying candidate genes, our framework and the genes identified in this study may have utility in developing additional pest control tools such as wildlife contraceptives. [ABSTRACT FROM AUTHOR]

Summary: This study aimed to examine the impact of break duration between consecutive shifts, time of break onset, and prior shift duration on total sleep time (TST) between shifts in heavy vehicle drivers (HVDs), and to assess the interaction between break duration and time of break onset. The sleep (actigraphy and sleep diaries) and work shifts (work diaries) of 27 HVDs were monitored during their usual work schedule for up to 9 weeks. Differences in TST between consecutive shifts and days off were assessed. Linear mixed models (followed by pairwise comparisons) assessed whether break duration, prior shift duration, time of break onset, and the interaction between break duration and break onset were related to TST between shifts. Investigators found TST between consecutive shifts (mean [SD] 6.38 [1.38] h) was significantly less than on days off (mean [SD] 7.63 [1.93] h; p < 0.001). Breaks starting between 12:01 and 8:00 a.m. led to shorter sleep (p < 0.05) compared to breaks starting between 4:01 and 8:00 p.m. Break durations up to 7, 9, and 11 h (Australian and European minimum break durations) resulted in a mean (SD) of 4.76 (1.06), 5.66 (0.77), and 6.41 (1.06) h of sleep, respectively. The impact of shift duration prior to the break and the interaction between break duration and time of break were not significant. HVDs' sleep between workdays is influenced independently by break duration and time of break onset. This naturalistic study provides evidence that current break regulations prevent sufficient sleep duration in this industry. Work regulations should evaluate appropriate break durations and break onset times to allow longer sleep opportunities for HVDs. [ABSTRACT FROM AUTHOR]

Objective: To investigate and compare the effect of simulator training on quantitative scores for ultrasound‐related skills for trainees with novice level ultrasound experience and expert ultrasound operators. Methods: Three novice (comprising of 11, 32, 23 participants) and one expert (10 participants) subgroups undertook an ultrasound simulation training session. Pre‐ and post‐training test scores were collected for each subgroup. Outcome measures were as follows: mean accuracy score for obtaining the correct anatomical plane, percentage of correctly acquired target planes, mean number of movements, time to achieve image, distance travelled by probe and accumulated angling of the probe. Results: The novices showed improvement in image acquisition after completion of the simulation training session with an improvement in the rate of correctly acquired target planes from 28–57% to 39–83%. This was not replicated in the experts. The novice's individual ratios based on pre‐ vs. post‐training metrics improved between 1.7‐ and 4.3‐fold for number of movements, 1.9‐ and 6.7‐fold for distance, 2.0‐ and 5.2‐fold for time taken and 1.8‐ and 7.3‐fold for accumulated angling. Among the experts, there was no relationship between pre‐training simulator metrics and years of ultrasound experience. Conclusions: The individual simulation metrics suggest the sessions were delivered at an appropriate level for basic training as novice trainees were able to show demonstrable improvements in both efficiency and accuracy on the simulator. Experts did not improve after the simulation modules, and the novice scores post‐training were similar to those of experts, suggesting the exercises were valid in testing ultrasound skills at novice but not expert level. [ABSTRACT FROM AUTHOR]

This study analyzes Facebook engagement among the nation's symphonies and their stakeholder publics. Factors such as reliance on donor contributions, program revenues, government grants, investment income, and total assets are proposed as contributing factors in predicting effective stakeholder relations. Public relations scholarship emphasizes the significance of relationships between the organization and its stakeholders and argues that positive relationships are integral to organizational success. Stewardship theory suggests nonprofits rely on a number of tools, including relationship nurturing, to sustain relationships with supportive publics. Scholars have increasingly identified stewardship as an effective method by which to build and maintain relationships. This study assesses one particular aspect of stewardship - relationship nurturing - and the attributes of nonprofit organizations that are successfully cultivating relationships with their stakeholders via social media. We find that benefactors matter. As dependence on stakeholder contributions increases so does stakeholder engagement via Facebook. Findings regarding program revenues and total assets are also significant., Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Contests over Australian history captivate governments, historians and public commentators; they grab headlines and spawn endless public commentary. The 'history wars', as those debates have come to be known, play out over museum exhibits, national commemorations, public apologies and the ways we teach the past to the next generation: should the Australian War Memorial commemorate the victims of the Australian frontier wars? Should Australians be sorry for historical actions in the past? Should Australian history be compulsory in school? (And so on.) But does that 'national story' have any meaning for Australian families and communities? This paper canvasses some recent qualitative research into historical consciousness in Australia to explore the ways those historical discourses operate beyond the public domain. It asks participants to speak in their own words about what history means: how they relate to their local and family histories, and how they engage with Australian history more broadly. Importantly, the project reveals a depth and complexity to Australians' historical engagement and demonstrates that public and personal discourses about the past do indeed intersect in everyday life around the country. [ABSTRACT FROM AUTHOR]

Objective To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagen-induced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs. Methods Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin gene-related peptide (CGRP) antagonist (CGRP8-37) from day 11 to day 18 postimmunization on CIA-induced hypersensitivity. During CIA development, CGRP and p-ERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with Fluoro-Gold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached. Results CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased p-ERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP8-37 attenuated established mechanical hypersensitivity and reduced spinal microgliosis. Conclusion Sensory neuron-derived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients. [ABSTRACT FROM AUTHOR]

The article looks at the career of historian and sociologist Leonore Davidoff. Particular focus is given to her books, including "The Best Circles: Society, Etiquette and the Season," "Family Fortunes: Men and Women of the English Middle Class," written with historian Catherine Hall, and "Thicker Than Water: Siblings and Their Relations, 1780-1920". Details on her collaborations with various scholars are presented. Themes of gender, class, and family relationships in her work are discussed.

Interpersonal communication plays a significant role in the maintenance of culturally shared stereotypes. This paper reports on two experiments in which two different stories were transmitted conversationally through communication chains. In both experiments, people tended to emphasize more stereotype consistent than stereotype inconsistent ( SI) information, thus rendering the stories more confirming, rather than challenging, of the stereotypes. Although SI information sometimes attracted more attention in conversation, this did not translate into a greater likelihood of passing on SI information, thus keeping the story character's impression largely stereotypical even after a second retelling of the story. [ABSTRACT FROM AUTHOR]

Objective The induction of rheumatoid arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as the swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. The purpose of this study was to examine the development of pain in the rat model of collagen-induced arthritis (CIA) and to evaluate the contribution of neuroimmune interactions to established arthritis pain. Methods Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a cathepsin S (CatS) inhibitor and a fractalkine (FKN) neutralizing antibody, from day 11 to day 18 following immunization. Results Rats with CIA developed significant mechanical hypersensitivity, which started on day 9, before the onset of clinical signs of arthritis. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic responses, alongside T cell infiltration, were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor, or an FKN neutralizing antibody attenuated mechanical hypersensitivity and spinal microglial response in rats with CIA. Conclusion The inhibition of microglial targets by centrally penetrant CatS inhibitors and CX3CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA. [ABSTRACT FROM AUTHOR]

Background: The cell-cycle regulator Cyclin D1 is expressed in embryonic retinal progenitor cells (RPCs) and regulates their cell-cycle rate and neurogenic output. We report here that Cyclin D1 also has important functions in postnatal retinal histogenesis. Results: The initial production of Müller glia and bipolar cells was enhanced in Cyclin D1 knockout ( Ccnd1−/−) retinas. Despite a steeper than normal rate of depletion of the RPC population at embryonic ages, postnatal Ccnd1−/− retinas exhibited an extended window of proliferation, neurogenesis, and gliogenesis. Cyclin D3, normally confined to Müller glia, was prematurely expressed in Ccnd1−/− RPCs. However, Cyclin D3 did not compensate for Cyclin D1 in regulating cell-cycle kinetics or neurogenic output. Conclusions: The data presented in this study along with our previous finding that Cyclin D2 was unable to completely compensate for the absence of Cyclin D1 indicate that Cyclin D1 regulates retinal histogenesis in ways not shared by the other D-cyclins. Developmental Dynamics 241:941-952, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Tumor-induced immune suppression involves the accumulation of suppressive infiltrates in the tumor microenvironment such as regulatory T-cells (Tregs). Previous studies demonstrated that NK-dependant increases in CCL22 secretion selectively recruit Tregs toward murine lungs bearing Lewis Lung Carcinoma (LLC). To extend the in vitro studies, the present studies utilized in vivo depletion of NK cells to ascertain the contribution of NK-derived CCL22 toward total CCL22 and subsequent Treg levels in both normal and LLC-bearing lungs. However, NK depletion had the unexpected effect of increasing both CCL22 secretion and Treg levels in the lungs of NK-depleted LLC-bearing mice. This was concurrent with an increase in tumor burden. Flow cytometry and a series of both immunomagnetic and FACS isolations were used to identify the CCL22-producing cellular fractions in LLC-bearing lungs. A novel CD11b [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 114, 1143–1157. The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. Naive CX3CR1 KO mice had normal responses to acute noxious stimuli. However, KO mice showed deficits in inflammatory and neuropathic nociceptive responses. After intraplantar zymosan, KO mice did not display thermal hyperalgesia, whereas mechanical allodynia developed fully. In the partial sciatic nerve ligation model of neuropathic pain, both mechanical allodynia and thermal hyperalgesia were less severe in KO mice than in wild-types (WT). Dorsal horn Iba1 immunostaining and phosphorylation of p38 MAPK increased after injury in WT controls but not in KO animals. In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models. [ABSTRACT FROM AUTHOR]

The political potency of national history has been understood for generations. Yet there has been an unquestionable surge in history's political influence over the last twenty or thirty years, as the various history wars that have broken out around the world attest. Australia has been no exception: disputes over its national story continue to generate considerable controversy in the media, in politics and in public debate. But how has this politicisation of the past affected Australian political history in the present? This paper examines how history is practised in contemporary Australian politics — and notices an increasingly strategic use of the past by politicians in recent years. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes mellitus is the leading cause of peripheral neuropathy worldwide. Despite this high level of incidence, underlying mechanisms of the development and maintenance of neuropathic pain are still poorly understood. Evidence supports a prominent role of glial cells in neuropathic pain states. Gabapentin is used clinically and shows some efficacy in the treatment of neuropathic pain. Here we investigate the distribution and activation of spinal microglia and astrocytes in streptozotocin (STZ)-diabetic rats and the effect of the gold standard analgesic, Gabapentin, on these cells. Mechanical allodynia was observed in four week-diabetic rats. Oral administration of Gabapentin significantly attenuated mechanical allodynia. Quantification of cell markers Iba-1 for microglia and GFAP for astrocytes revealed extensive activation of microglia in the dorsal horn of diabetic rats, whereas a reduction in the number of astrocytes could be observed. In addition, an attenuation of microglial activation correlated with reduced allodynia following Gabapentin treatment, while Gabapentin had no effect on the number of astrocytes. Here we show a role of microglia in STZ-induced mechanical allodynia and furthermore, that the anti-allodynic effect of Gabapentin may be linked to a reduction of spinal microglial activation. Astrocytic activation in this model appears to be limited and is unaffected by Gabapentin treatment. Consequently, spinal microglial activation is a key mechanism underlying diabetic neuropathy. Furthermore, we suggest that Gabapentin may exert its anti-allodynic actions partially through alterations of microglial cell function. [Copyright &y& Elsevier]

Abstract: Loss of function is usually considered the major consequence of spinal cord injury (SCI). However, pain severely compromises the quality of life in nearly 70% of SCI patients. The principal aim of this study was to assess the contribution of Tumor necrosis factor α (TNF-α) to SCI pain. TNF-α blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain, especially following SCI. Following T13 spinal cord hemisection, we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept, a fusion protein blocker of TNF-α. Immediate treatment (starting at the time of injury) with etanercept resulted in markedly reduced mechanical allodynia 1, 2, 3 and 4 weeks after SCI. Delayed treatment had no effect. Immediate etanercept treatment also reduced spinal microglial activation assessed by OX-42 immunostaining, a putative marker of activated microglia. To assess whether the effects of etanercept were mediated via decreased microglial activation, we examined the effects of the microglial inhibitor, minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment. Minocycline also significantly reduced microglial OX-42 expression. Furthermore, minocycline decreased the expression of noxious-stimulation-induced c-Fos, suggesting an effect on evoked neuronal activity. This study demonstrates that TNF-α plays an important role in the establishment of neuropathic pain following SCI, seemingly dependent on microglial activation. Pharmacological targeting of TNF-α may offer therapeutic opportunities for treating SCI pain. [Copyright &y& Elsevier]

Abstract: While neuroimmune interactions are increasingly recognized as important in nociceptive processing, the nature and functional significance of these interactions is not well defined. There are multiple reports that the activation of spinal microglia is a critical event in the generation of neuropathic pain behaviors but the mediators of this activation remain disputed. Here we show that the chemokine CCL2, produced by both damaged and undamaged primary sensory neurons in neuropathic pain states in rats, is released in an activity dependent manner from the central terminals of these fibres. We also demonstrate that intraspinal CCL2 in naïve rats leads to activation of spinal microglia and neuropathic pain-like behavior. An essential role for spinal CCL2 is demonstrated by the inhibition of neuropathic pain behavior and microglial activation by a specific neutralising antibody to CCL2 administered intrathecally. Thus, the neuronal expression of CCL2 provides a mechanism for immune activation, which in turn regulates the sensitivity of pain signaling systems in neuropathic pain states. [Copyright &y& Elsevier]

There is evidence that we may be more likely to share stories about other people to the extent that they arouse emotion. If so, this emotional social talk may have important social consequences, providing the basis for many of our social beliefs and mobilising people to engage or disengage with the targets of the talk. Across three studies, we tested the situated communicability of emotional social information by examining if the ability of emotionality to increase communicability would depend on the emotion that was aroused and the identity of the audience. Study 1 showed that participants were more willing to share social anecdotes that aroused interest, surprise, disgust and happiness with an unspecified audience. Study 2 provided a behavioural replication of these findings. Study 3 showed that the communicability of emotional social talk did vary with audience identity (friend or stranger). Together, these findings suggest that emotional social events (particularly those that arouse disgust and happiness) are likely to become part of a society's social beliefs, with important consequences for the structure of social relationships. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Mounting evidence supports the hypothesis that spinal microglia modulate the development and maintenance of some chronic pain states. Here we examined the role of spinal microglia following both peripheral inflammatory insult and peripheral nerve injury. We observed significant ipsilateral dorsal horn microglia activation 2 weeks after injury and bilateral activation 50 days following nerve injury as well as 24 h following intraplantar zymosan but not intraplantar complete Freund’s adjuvant (CFA). Ipsilateral but not contralateral microglia activation was associated with hind paw mechanical hyperalgesia. Spinal injection of the glial metabolic inactivator fluorocitrate attenuated ipsilateral hyperalgesia and bilateral spinal microglia activation after peripheral nerve injury. Intrathecal fluorocitrate reversed hyperalgesia after intraplantar zymosan and produced no reversal of CFA-induced hyperalgesia. These data suggest a role for spinal glia in the persistence of mechanical hyperalgesia following peripheral nerve injury. However, activation of spinal microglia contralaterally did not correlate to nociception. Furthermore, it would appear that the time course of microglia activation and their contribution to inflammatory pain is dependent on the inflammatory stimulus administered. [Copyright &y& Elsevier]

Mounting evidence supports the hypothesis that pro-inflammatory cytokines secreted by astrocytes and microglia modulate nociceptive function in the injured CNS and following peripheral nerve damage. Here we examine the involvement of interleukin-1β (IL-1β) and microglia activation in nociceptive processing in rat models of spinal cord inflammation. Following application of lipopolysaccharide (LPS) to an ex vivo dorsal horn slice preparation, we observed rapid secretion of IL-1β which was prevented by inhibition of glial cell metabolism and by inhibitors of either p38 mitogen-activated protein kinase (MAPK) or caspase 1. LPS superfusion also induced rapid secretion of active caspase 1 and apoptosis-associated speck-like protein containing a caspase recruitment domain from the isolated dorsal horn. Extensive microglial cell activation in the dorsal horn, as determined by immunoreactivity for phosphorylated p38 MAPK, was found to correlate with the occurrence of IL-1β secretion. In behavioural studies, intrathecal injection of LPS in the lumbar spinal cord produced mechanical hyperalgesia in the rat hind-paws which was attenuated by concomitant injections of a p38 MAPK inhibitor, a caspase 1 inhibitor or the rat recombinant interleukin 1 receptor antagonist. These data suggest a critical role for the cytokine IL-1β and caspase 1 rapidly released by activated microglia in enhancing nociceptive transmission in spinal cord inflammation. [ABSTRACT FROM AUTHOR]

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