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Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR 5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR 5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy.

Australian geography has been implicated in the White settler colonial project, including in the dispossession of Aboriginal peoples from their lands and the denigration of Aboriginal knowledges. Recognising the harm caused by this racist past is crucial if geography education is to play a stronger role in decolonisation. Much work is already underway. This article reports on a process to Indigenise the curriculum, building a partnership between Aboriginal people and Australian geography educators at the University of Tasmania. Tasmanian geographers and spatial scientists have begun working with Aboriginal people to come to terms with the discipline’s history of genocide, dispossession and cultural politics of extinction. A workshop that was the foundation for this process generated valuable insights into how to include the knowledge and practices of Aboriginal peoples in geography and planning curricula; build communities of practice; and learn to live lawfully and lore-fully on Country. Lessons learned have informed curriculum renewal and are helping to build new relationships.

1.Grasslands occur around the globe and, in temperate regions, their natural management by fire, drought and wild herbivores has largely been replaced by grazing with domestic livestock. Successful management for agriculture is not always suitable for conservation and can have a detrimental effect on biodiversity. Conservation grazing of saltmarshes, delivered through agri‐environment schemes, may provide a solution to counteract biodiversity loss by providing farmers with financial incentives to graze these internationally important coastal wetlands more sensitively. 2.To assess whether conservation grazing is being achieved, and whether agri‐environment schemes are effective in delivering this management, we conducted a national survey on English saltmarshes, scoring the management on each site as optimal, suboptimal or detrimental in terms of suitability for achieving conservation aims for five aspects of grazing: presence, stock type, intensity, timing and habitat impact. 3.Although most saltmarshes suitable for grazing in England were grazed, conservation grazing was not being achieved. Sites under agri‐environment management for longer did score higher and approached optimal levels in terms of grazing intensity in one region, but sites with agri‐environment agreements were no more likely to be grazed at optimal conservation levels than sites without them overall, indicating that agri‐environment schemes, in their current form, are an ineffective delivery mechanism for conservation grazing on saltmarsh. 4.The low specificity of agri‐environment prescription wording may contribute to this failure, with prescriptions either being vague or specifying suboptimal or detrimental management objectives, particularly for grazing intensity, timing and stock type. These objectives are often set too high or too low, during unsuitable periods, or using stock types inappropriate for achieving conservation aims. 5.Synthesis and applications. Our national survey indicates that agri‐environment schemes are not currently delivering conservation grazing on English saltmarshes. Agri‐environment schemes are the only mechanism through which such grazing can be implemented on a national scale, so improving their effectiveness is a priority. Policymakers, researchers and managers need to work together to ensure better translation of conservation guidelines into schemes, increasing the specificity of management prescriptions and improving understanding of the need for management measures. A more detailed and reliable system of auditing to ensure that management activities are taking place would be beneficial, or alternatively moving to a results‐based scheme where payments are made on desirable outcomes rather than on evidence of management.

We have recently identified a novel plasticity protein, doublecortin-like (DCL), that is specifically expressed in the shell of the mouse suprachiasmatic nucleus (SCN). DCL is implicated in neuroplastic events, such as neurogenesis, that require structural rearrangements of the microtubule cytoskeleton, enabling dynamic movements of cell bodies and dendrites. We have inspected DCL expression in the SCN by confocal microscopy and found that DCL is expressed in GABA transporter-3 (GAT3)-positive astrocytes that envelope arginine vasopressin (AVP)-expressing cells. To investigate the role of these DCL-positive astrocytes in circadian rhythmicity, we have used transgenic mice expressing doxycycline-induced short-hairpin (sh) RNA's targeting DCL mRNA (DCL knockdown mice). Compared with littermate wild type (WT) controls, DCL-knockdown mice exhibit significant shorter circadian rest-activity periods in constant darkness and adjusted significantly faster to a jet-lag protocol. As DCL-positive astrocytes are closely associated with AVP-positive cells, we analyzed AVP expression in DCL-knockdown mice and in their WT littermates by 3D reconstructions and transmission electron microscopy (TEM). We found significantly higher numbers of AVP-positive cells with increased volume and more intensity in DCL-knockdown mice. We found alterations in the numbers of dense core vesicle-containing neurons at ZT8 and ZT20 suggesting that the peak and trough of neuropeptide biosynthesis is dampened in DCL-knockdown mice compared to WT littermates. Together, our data suggest an important role for the astrocytic plasticity in the regulation of circadian rhythms and point to the existence of a specific DCL+ astrocyte-AVP(+) neuronal network located in the dorsal SCN implicated in AVP biosynthesis.

Objective Morbid obesity is the fastest growing subcategory of childhood obesity, associated with an increased health risk that persists into adulthood. There is an urgent need to develop multifaceted interventions that target initial and long-term lifestyle changes. This review investigates the effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with morbid obesity. The influence of age, gender and family participation on health outcomes and intensive treatment alternatives are explored. Methods The review includes 16 studies conducted between 1995 and 2017. Studies examined youth with morbid obesity, 4-18 years old, undergoing multidisciplinary treatment. Results All studies found a reduction in body mass index (BMI or z-score) and if measured, cardiovascular risk factors. Physical activity, nutrition education, behavioural modification and family involvement are commonly included treatment components and have improved weight loss and health-related outcomes. However, initial weight loss was often not sustainable, despite the favourable interventional effect on cardiometabolic risk markers. Weight loss was prolonged in younger children and among the male sex. Conclusions There is not a 'one-size-fits-all' treatment approach, and matched care to personal needs is preferable. The integration of a chronic care approach is critical for the successful adaption of sustainable health behaviours.

Objective: To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability and fatigue in patients with established rheumatoid arthritis (RA). Methods: In the pragmatic 12-month POET trial, 817 RA patients with ≥6 months of remission or stable low disease activity were randomized 2:1 to stopping or continuing TNFi. In case of flare, TNFi was restarted at the discretion of the rheumatologist. PROs were assessed every 3 months. Results: TNFi was restarted within 12 months in 252/531 patients (47.5%) in the stop group. At 3 months, mean PRO scores were significantly worse in the stop group and a larger proportion of patients experienced a minimal clinically important difference (MCID) on all PROs. Effect sizes (ES) were strongest for health utility (ES = -0.24) and pain (ES = -0.30). Mean scores improved again after this point but disability scores remained significantly different at 12 months. After 12 months, the relative risk of experiencing a MCID ranged from 1.16 for mental health status to 1.58 for fatigue. Mean PRO scores for patients restarting TNFi within 6 months were no longer significantly different from those that did not restart TNFi at 12 months. Conclusion: Stopping TNFi had a significant negative short-term impact on a broad range of PROs. Long-term negative consequences appeared to be limited and outcomes in patients needing to restart TNFi within the first 6 months tended to be restored at 12 months. This article is protected by copyright. All rights reserved.

Studies on natural variation are an important tool to unravel the genetic basis of quantitative traits in plants. Despite the significant roles of phytohormones in plant development, including root architecture, hardly any studies have been done to investigate natural variation in endogenous hormone levels in plants. Therefore, in the present study a range of hormones were quantified in root extracts of thirteen Arabidopsis thaliana accessions using a ultra performance liquid chromatography triple quadrupole mass spectrometer. Root system architecture of the set of accessions was quantified, using a new parameter (mature root unit) for complex root systems, and correlated with the phytohormone data. Significant variations in phytohormone levels among the accessions were detected, but were remarkably small, namely less than three-fold difference between extremes. For cytokinins, relatively larger variations were found for ribosides and glucosides, as compared to the free bases. For root phenotyping, length-related traits-lateral root length and total root length-showed larger variations than lateral root number-related ones. For root architecture, antagonistic interactions between hormones, for example, indole-3-acetic acid to trans-zeatin were detected in correlation analysis. These findings provide conclusive evidence for the presence of natural variation in phytohormone levels in Arabidopsis roots, suggesting that quantitative genetic analyses are feasible.

Background and aim Human leukocyte antigen (HLA) typing is an important step in the diagnostic algorithm for celiac disease (CD) and is also used for screening purposes. Collection of blood is invasive and accompanied with emotional impact especially in children. Genetic technological progress now enables HLA typing from buccal cell samples. This study evaluated the reliability and feasibility of HLA typing for CD-associated HLA polymorphisms using buccal swabs as routine test in high-risk individuals. Methods Blood and buccal swabs of 77 children and adolescents with high risk for CD were prospectively collected in this cohort study. Buccal swab collection was performed either by the investigator at the outpatient clinic or by the patient or its parents at home. To evaluate the possibility of self-administration, three families performed the test at home. DNA was extracted using an adapted QIAamp method. Quantity, quality, and purity of DNA were recorded. HLA-DRB1, HLA-DQA1, and HLA-DQB1 typing was examined on buccal cell-derived and blood-derived DNA at low and, if necessary, high resolution level, using sequence-specific oligonucleotide and sequence-based typing, respectively. Results DNA isolation using buccal swabs yielded a good quality and sufficient quantity of DNA to perform HLA-DQ typing in all individuals. HLA typing results on buccal cell-derived DNA were identical to typing on blood-derived DNA, also for the self-administered samples. Conclusion Introduction of the buccal swab test for HLA typing of CD risk in routine diagnostics can omit the current venipuncture and enables self-administration at home. Therefore, the buccal swab test is beneficial for individuals with a clinical suspicion for CD, as well as for screening purposes in high-risk populations.

Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20-80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate-induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole-cell current-clamp and voltage-clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration-dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post-synaptic currents, but did not affect the frequency of spontaneous excitatory post-synaptic currents. The atorvastatin-induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D-AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate-induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol-lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.

A new sociological agenda is emerging that interrogates how morality can be established in the absence of the moral certainties of the past but there is a shortage of empirical work on this topic. This article establishes a theoretical framework for the empirical analysis of everyday morality drawing on the work of theorists including Ahmed, Bauman and Taylor. It uses the Australian Survey of Social Attitudes to assess the state and shape of contemporary moralities by asking how kind are Australians, how is its expression socially distributed, and what are the motivations for kindness. The findings demonstrate that Australians exhibit a strong attachment and commitment to kindness as a moral value that is primarily motivated by interiorized sources of moral authority. We argue these findings support the work of theorists such as Ahmed and Taylor who argue authenticity and embodied emotion are legitimate sources of morality in today's secular societies. The research also provides new evidence that generational changes are shaping understandings and practices of kindness in unexpected ways.

Large areas of arable land are often confronted with irregular rainfall resulting in limited water availability for part(s) of the growing seasons, which demands research for drought tolerance of plants. Natural variation was observed for biomass accumulation upon controlled moderate drought stress in 324 natural accessions of Arabidopsis. Improved performance under drought stress was correlated with early flowering and lack of vernalization requirement, indicating overlap in the regulatory networks of flowering time and drought response or correlated responses of these traits to natural selection. In addition, plant size was negatively correlated with relative water content (RWC) independent of the absolute water content (WC), indicating a prominent role for soluble compounds. Growth in control and drought conditions was determined over time and was modelled by an exponential function. Genome-wide association (GWA) mapping of temporal plant size data and of model parameters resulted in the detection of six time-dependent quantitative trait loci (QTLs) strongly associated with drought. Most QTLs would not have been identified if plant size was determined at a single time point. Analysis of earlier reported gene expression changes upon drought enabled us to identify for each QTL the most likely candidates.

Insulin resistance (IR) occurs in a transient manner during puberty. Obese adolescents may be at risk for persistent IR during puberty. The objective of the study is to review the literature on the association of the anthropometry and lifestyle characteristics with insulin sensitivity in overweight and obese adolescents, and include data from a new study. Relevant papers were selected and reviewed. In addition, 137 overweight and obese adolescents (42 male/95 female, age 14.4 +/- 2.3 years, BMI z-score +3.3 +/- 0.7, HOMA-IR 3.4 +/- 1.8) from the Centre for Overweight Adolescent and Children's Healthcare (MUMC+) were included in this study. Anthropometrics, Tanner stages, sleep characteristics, food intake behaviour and physical activity were determined, and possible associations with homeostasis model assessment of insulin resistance (HOMA-IR) were tested. RESULTS: Overweight and obese adolescents with unfavourable fat partitioning and family history of NIDDM are at risk for persistent IR. Overweight and obese adolescents from the new cohort showed a higher HOMA-IR postpubertally. BMI z-score, age, pubertal stage and prepubertally total sleeping time (TST) and sleep efficiency (SE) were identified as significant contributors. Overweight and obese adolescents showed a persistently higher instead of transiently higher HOMA-IR during puberty, associated with BMI z-score, age, pubertal stage and prepubertally less TST and SE.

Phytohormones, auxins in particular, play an important role in plant development and productivity. Earlier data showed positive impact of exogenous auxin on potato (Solanum tuberosum L.) tuberization. The aim of this study was to generate potato plants with increased auxin level predominantly in tubers. To this end, a pBinB33-tms1 vector was constructed harboring the Agrobacterium auxin biosynthesis gene tms1 fused to tuber-specific promoter of the class I patatin gene (B33-promoter) of potato. Among numerous independently generated B33:tms1 lines, those without visible differences from control were selected for detailed studies. In the majority of transgenic lines, tms1 gene transcription was detected, mostly in tubers rather than in shoots. Indoleacetic acid (IAA) content in tubers and the auxin tuber-to-shoot ratio were increased in tms1-expressing transformants. The organ-specific increase in auxin synthesis in B33:tms1-transformants accelerated and intensified the process of tuber formation, reduced the dose of carbohydrate supply required for in vitro tuberization, and decreased the photoperiodic dependence of tuber initiation. Overall, a positive correlation was observed between tms1 expression, IAA content in tubers, and stimulation of tuber formation. The revealed properties of B33:tms1 transformants imply an important role for auxin in potato tuberization and offer prospects to magnify potato productivity by a moderate organ-specific enhancement of auxin content.

Fluidized bed gasification processes are generally considered a good choice for biomass and waste because of its fuel flexibility. Furthermore, it is a relatively low-temperature highly efficient process operating at 700–900°C compared with, for example, coal-based entrained flow processes that mostly operate at 1400–1600°C. Indirect fluidized bed gasification is becoming increasingly popular for some applications due to the possibility of producing a N2-free gas without the need for an air separation unit, as well as complete conversion of the fuel. ECN has developed MILENA indirect gasification, in which gasification and combustion are physically separated, but both reactors are placed in the same vessel. This article aims to compare the performance of olivine as bed material in direct- and indirect (MILENA) gasification. With this purpose, oxidation/reduction cycles have been simulated in a direct gasifier to determine the effect of olivine preoxidation in terms of tar destruction and oxygen transport. Results show that olivine preoxidation mainly enhances the capacity of oxygen transport of the bed material, which adds up to the catalytic effect of iron in olivine towards tar destruction. Oxygen transport capacity of olivine has been quantified as ER = 0.25 at the maximum initial CO2 peak, and it has been estimated that 20–25% wt of iron in olivine is able to transfer oxygen during the first 10 min operation. On the other hand, it has been found that MILENA operating conditions are equivalent to the point of initial maximum peak of CO2 in the devolatilization stage. This means that oxygen transport capacity of olivine is kept at its maximum due to the continuous combustion/gasification cycles, and olivine is kept activated by cyclical migration of iron into the surface and subsequent fast reduction. The effect of oxygen transport on the overall heat balance of the MILENA gasifier is equivalent to oxidation of additional fuel in the combustor. © 2014 American Institute of Chemical Engineers Environ Prog, 33: 711–720, 2014

Hippocampal gamma oscillations have been associated with cognitive functions including navigation and memory encoding/retrieval. Gamma oscillations in area CA1 are thought to depend on the oscillatory drive from CA3 (slow gamma) or the entorhinal cortex (fast gamma). Here we show that the local CA1 network can generate its own fast gamma that can be suppressed by slow gamma-paced inputs from CA3. Moderate acetylcholine receptor activation induces fast (45 ± 1 Hz) gamma in rat CA1 minislices and slow (33 ± 1 Hz) gamma in CA3 minislices in vitro. Using pharmacological tools, current-source density analysis and intracellular recordings from pyramidal cells and fast-spiking stratum pyramidale interneurons, we demonstrate that fast gamma in CA1 is of the pyramidal-interneuron network gamma (PING) type, with the firing of principal cells paced by recurrent perisomal IPSCs. The oscillation frequency was only weakly dependent on IPSC amplitude, and decreased to that of CA3 slow gamma by reducing IPSC decay rate or reducing interneuron activation through tonic inhibition of interneurons. Fast gamma in CA1 was replaced by slow CA3-driven gamma in unlesioned slices, which could be mimicked in CA1 minislices by sub-threshold 35 Hz Schaffer collateral stimulation that activated fast-spiking interneurons but hyperpolarised pyramidal cells, suggesting that slow gamma frequency CA3 outputs can suppress the CA1 fast gamma-generating network by feed-forward inhibition and replaces it with a slower gamma oscillation driven by feed-forward inhibition. The transition between the two gamma oscillation modes in CA1 might allow it to alternate between effective communication with the medial entorhinal cortex and CA3, which have different roles in encoding and recall of memory.

Cystic fibrosis (CF) is classically attributed to the dysfunction of the single CF transmembrane conductance regulator gene. The incidence of human leukocyte antigen (HLA) polymorphisms in different CF-associated diseases raises the question of an unequal distribution of HLA genotypes in CF. This study aimed to evaluate HLA gene frequencies and possible associations in CF patients compared with a control population. Frequencies of HLA-DRB1, HLA-DQA1 and HLA-DQB1, performed by intermediate resolution typing using Luminex sequence-specific oligonucleotide, and epitope counts were similar in 340 CF patients when compared with 400 control subjects. In conclusion, HLA-DRB1, -DQA1 and -DQB1 do not seem to influence susceptibility to CF. Whether HLA plays a role in the severity of CF disease needs to be investigated.

In this paper we discuss the introduction of the Launceston Bike Network, a local government project progressed in Tasmania, Australia. The project’s implementation became subject to intense community conflict, or what we refer to here as white line fever because it arose in relation to the white traffic lines used to mark the on-road bike lanes. Our analysis of textual data gathered from relevant documents and interviews with key stakeholders relies on the development of a sociotechnical perspective.Adopting this perspective allows us to recognise the various agencies emerging collectively from the technical and social aspects and interactions analysed. The findings add to how cycling and infrastructure might be reconceptualised as an urban sociotechnical system, and assist in its transition towards the transport mainstream through policy and planning.

Aim: To explore the experiences of frontline health and welfare practitioners in working with older people experiencing abuse. Methods: In-depth interviews with 16 Tasmanian community-based health and welfare practitioners regarding their experiences of working in 49 recent cases of elder abuse. Interview transcripts were analysed using thematic analysis. Results: All participants found working in cases of elder abuse challenging and the work itself was perceived as difficult, complex and at times dangerous. The cumulative effect of intimidating work contexts, practice dilemmas and a lack of support resulted in frustration and stress for many practitioners. Nevertheless, participants were committed to providing ongoing services and support for older people experiencing abuse. Conclusion: Frontline practitioners working in cases of elder abuse face significant challenges and could be better supported through strengthening organisational elder abuse policies, increased management support and more age-inclusive family violence support services. © 2013 ACOTA.

Summary Background Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I-FABP) is a sensitive marker to study enterocyte damage. Aims To evaluate the severity of enterocyte damage in adult-onset CD and its course upon a gluten-free diet (GFD). Furthermore, the correlation among enterocyte damage, CD autoantibodies and histological abnormalities during the course of disease is studied. Methods Serum I-FABP levels were determined in 96 biopsy-proven adult CD patients and in 69 patients repeatedly upon a GFD. A total of 141 individuals with normal antitissue transglutaminase antibody (IgA-tTG) levels served as controls. I-FABP levels were related to the degree of villous atrophy (Marsh grade) and IgA-tTG. Results I-FABP levels were elevated in untreated CD (median 691 pg/mL) compared with controls (median 178 pg/mL, P