Influence of inter-observer delineation variability on radiomic features of the parotid gland.

PURPOSE: This study aimed to quantify the variability in the values of radiomic features extracted from a right parotid gland (RPG) delineated by a series of independent observers. METHODS: This was a secondary analysis of anonymous data from a delineation workshop. Inter-observer variability of the RPG from 40 participants was quantified using DICE similarity coefficient (DSC) and Hausdorff distance (HD). An additional contour was generated using Varian SmartSegmentation. Radiomic features extracted include four shape features, six histogram features, and 32 texture features. The absolute mean paired percentage difference (PPD) in feature values from the expert and participants were ranked . Feature robustness was classified using pre- determined thresholds. RESULTS: 63% of participants achieved a DSC > 0.7, the auto- segmentation DSC was 0.76. The average HD for the participants was 16.16 mm ± 0.66 mm, and 15.16 mm for the auto-segmentation. 48% (n = 20) and 33% (n = 14) of features were deemed to be robust with a mean absolute PPD < 5%, for the auto-segmentation and manual delineations respectively; the majority of which were from the grey-run length matrix family. 7% (n = 3) of features from the auto- segmentation and 10% (n = 4) from the manual contours were deemed to be unstable with a mean absolute PPD > 50%. The value of the most robust feature was not related to DSC and HD. CONCLUSION: Inter-observer delineation variability affects the value of the radiomic features extracted from the RPG. This study identifies the radiomic features least sensitive to these uncertainties. Further investigation of the clinical relevance of these features in prediction of xerostomia is warranted.

Geometric and Dosimetric Evaluation of a Commercially Available Auto-segmentation Tool for Gross Tumour Volume Delineation in Locally Advanced Non-small Cell Lung Cancer: a Feasibility Study.

AIMS: To quantify the reliability of a commercially available auto-segmentation tool in locally advanced non-small cell lung cancer using serial four-dimensional computed tomography (4DCT) scans during conventionally fractionated radiotherapy. MATERIALS AND METHODS: Eight patients with serial 4DCT scans (n = 44) acquired over the course of radiotherapy were assessed. Each 4DCT had a physician-defined primary tumour manual contour (MC). An auto-contour (AC) and a user-adjusted auto-contour (UA-AC) were created for each scan. Geometric agreement of the AC and the UA-AC to the MC was assessed using the dice similarity coefficient (DSC), the centre of mass (COM) shift from the MC and the structure volume difference from the MC. Bland Altman analysis was carried out to assess agreement between contouring methods. Dosimetric reliability was assessed by comparison of planning target volume dose coverage on the MC and UA-AC. The time trend analysis of the geometric accuracy measures from the initial planning scan through to the final scan for each patient was evaluated using a Wilcoxon signed ranks test to assess the reliability of the UA-AC over the duration of radiotherapy. RESULTS: User adjustment significantly improved all geometric comparison metrics over the AC alone. Improved agreement was observed in smaller tumours not abutting normal soft tissue and median values for geometric comparisons to the MC for DSC, tumour volume difference and COM offset were 0.80 (range 0.49-0.89), 0.8 cm3 (range 0.0-5.9 cm3) and 0.16 cm (range 0.09-0.69 cm), respectively. There were no significant differences in dose metrics measured from the MC and the UA-AC after Bonferroni correction. Variation in geometric agreement between the MC and the UA-AC were observed over the course of radiotherapy with both DSC (P = 0.035) and COM shift from the MC (ns) worsening. The median tumour volume difference from the MC improved at the later time point. CONCLUSIONS: These findings suggest that the UA-AC can produce geometrically and dosimetrically acceptable contours for appropriately selected patients with non-small cell lung cancer. Larger studies are required to confirm the findings.

Health professionals and students encounter multi-level barriers to implementing high-value osteoarthritis care: a multi-national study.

OBJECTIVE: Consistent evidence-practice gaps in osteoarthritis (OA) care are observed in primary care settings globally. Building workforce capacity to deliver high-value care requires a contemporary understanding of barriers to care delivery. We aimed to explore barriers to OA care delivery among clinicians and students. DESIGN: A cross-sectional, multinational study sampling clinicians (physiotherapists, primary care nurses, general practitioners (GPs), GP registrars; total possible denominator: n = 119,735) and final-year physiotherapy and medical students (denominator: n = 2,215) across Australia, New Zealand and Canada. Respondents answered a survey, aligned to contemporary implementation science domains, which measured barriers to OA care using categorical and free-text responses. RESULTS: 1886 clinicians and 1611 students responded. Items within the domains 'health system' and 'patient-related factors' represented the most applicable barriers experienced by clinicians (25-42% and 20-36%, respectively), whereas for students, 'knowledge and skills' and 'patient-related factors' (16-24% and 19-28%, respectively) were the most applicable domains. Meta-synthesis of qualitative data highlighted skills gaps in specific components of OA care (tailoring exercise, nutritional/overweight management and supporting positive behaviour change); assessment, measurement and monitoring; tailoring care; managing case complexity; and translating knowledge to practice (especially among students). Other barriers included general infrastructure limitations (particularly related to community facilities); patient-related factors (e.g., beliefs and compliance); workforce-related factors such as inconsistent care and a general knowledge gap in high-value care; and system and service-level factors relating to financing and time pressures, respectively. CONCLUSIONS: Clinicians and students encounter barriers to delivery of high-value OA care in clinical practice/training (micro-level); within service environments (meso-level); and within the health system (macro-level).

Introduction to the ESTRO European Qualifications Framework (EQF) 7 and 8: Benchmarking Radiation Therapist (RTT) advanced education.

Innovations in radiotherapy practice continue to develop and expand. With this comes a requirement for suitably educated Radiation TherapisTs (RTTs) to expand their scope of practice and work at advanced levels within radiotherapy departments. This paper introduces the ESTRO European Qualifications Framework (EQF) 7 and 8 benchmarking document, where the distinction between levels 7 and 8 is discussed. It details the evolution of the profession of RTT from graduate to extended and advanced roles. As professionals within the radiation oncology team, this advancement brings with it the necessity for appropriate education at EQF levels 7 and 8 in order to ensure the knowledge base, critical analysis skills and safe practice of RTTs in such roles and to drive the profession forward for the future.

Prevalence of arthritis according to age, sex and socioeconomic status in six low and middle income countries: analysis of data from the World Health Organization study on global AGEing and adult health (SAGE) Wave 1.

BACKGROUND: In higher income countries, social disadvantage is associated with higher arthritis prevalence; however, less is known about arthritis prevalence or determinants in low to middle income countries (LMICs). We assessed arthritis prevalence by age and sex, and marital status and occupation, as two key parameters of socioeconomic position (SEP), using data from the World Health Organization Study on global AGEing and adult health (SAGE). METHODS: SAGE Wave 1 (2007-10) includes nationally-representative samples of older adults (≥50 yrs), plus smaller samples of adults aged 18-49 yrs., from China, Ghana, India, Mexico, Russia and South Africa (n = 44,747). Arthritis was defined by self-reported healthcare professional diagnosis, and a symptom-based algorithm. Marital status and education were self-reported. Arthritis prevalence data were extracted for each country by 10-year age strata, sex and SEP. Country-specific survey weightings were applied and weighted prevalences calculated. RESULTS: Self-reported (lifetime) diagnosed arthritis was reported by 5003 women and 2664 men (19.9% and 14.1%, respectively), whilst 1220 women and 594 men had current symptom-based arthritis (4.8% and 3.1%, respectively). For men, standardised arthritis rates were approximately two- to three-fold greater than for women. The highest rates were observed in Russia: 38% (95% CI 36%-39%) for men, and 17% (95% CI 14%-20%) for women. For both sexes and in all LMICs, arthritis was more prevalent among those with least education, and in separated/divorced/widowed women. CONCLUSIONS: High arthritis prevalence in LMICs is concerning and may worsen poverty by impacting the ability to work and fulfil community roles. These findings have implications for national efforts to prioritise arthritis prevention and management, and improve healthcare access in LMICs.

Concentrations of calcium and 25-hydroxycholecalciferol (vitamin D3) in plasma of wild kakapo (Strigops habroptilus) living on two islands in New Zealand.

AIMS This preliminary study had the objectives of describing the concentrations of ionised calcium and 25-hydroxycholecalciferol (25(OH)D3) in the blood of wild kakapo (Strigops habroptilus) living on two islands in New Zealand, and to determine the effects of supplementary feeding on these blood parameters. METHODS Blood samples were obtained from 33 kakapo living on two offshore islands during routine health checks in 2015. Birds on Hauturu were sampled in May (n=5) and birds on Whenua Hou were sampled in July (n=15) and November (n=26). Of the birds sampled on Whenua Hou in November, 15 received supplementary food prior to sampling. Samples were analysed for pH, and concentrations of ionised calcium, total calcium, phosphorous, total protein, albumin, globulin, uric acid and 25(OH)D3. RESULTS Concentrations of ionised calcium did not differ between unsupplemented birds on the two islands, nor between supplemented (median 1.17 (95% CI=1.12-1.20) mmol/L) and unsupplemented (median 1.09 (95% CI=1.08-1.14) mmol/L) birds sampled in November on Whenua Hou (p>0.05), and were comparable with published normal ranges for other psittacines. Concentrations of 25(OH)D3 did not differ between unsupplemented birds on the two islands (p>0.05), but were higher in supplemented (median 8.00 (95% CI=4.76-8.45) nmol/L) than unsupplemented (median 0.00 (95% CI=-0.16-0.48) nmol/L) birds on Whenua Hou (p<0.001). All values were much lower than published ranges for healthy psittacines. There was no difference between male and female birds on Whenua Hou for any parameter measured (p>0.05). CONCLUSIONS AND CLINICAL RELEVANCE The calcium status of the kakapo in this study was comparable to other wild psittacines, however concentrations of 25(OH)D3 were much lower. The concentrations of 25(OH)D3 may be within the normal range for the species, however further data are required to confirm this. The significant increase in concentrations of 25(OH)D3 in supplementary fed birds suggests that this food was providing more of the nutrient than the wild diet at that time of year, although the effects of this are unknown. Further investigation is required into the calcium and vitamin D3 status of kakapo, across a wider range of locations, seasons and ages. This would help define normal ranges for these parameters, allow interpretation in clinically abnormal individuals, and guide the refinement of supplementary foods. This information would, therefore, assist the future conservation management of this critically endangered species.

Setting-based interventions to promote mental health at the university: a systematic review.

OBJECTIVES: Universities are dynamic environments. But university life presents challenges that may affect the mental health of its community. Higher education institutions provide opportunities to promote public health. Our objective is to summarise the current evidence on strategies to promote mental health at the university, following a setting-based model. METHODS: We conducted a systematic literature review following standard methods. Published literature that evaluated structural and organizations strategies to promote mental health at the university was selected. RESULTS: 19 papers were included. The majority of the studies were targeting the students, with only four aiming to promote employees' mental health. The most promising strategies to promote mental wellbeing included changes in the way students are taught and assessed. On the other hand, social marketing strategies had not impact on mental health. There is inconclusive evidence related to the effectiveness of policies to promote mental health. CONCLUSIONS: Universities should invest in creating supportive physical, social and academic environments that promote student and staff mental wellbeing. However, the current body of evidence is scarce and more research is needed to recommend what are the best strategies.

Expert consensus panel guidelines on geriatric assessment in oncology.

Despite consensus guidelines on best practice in the care of older patients with cancer, geriatric assessment (GA) has yet to be optimally integrated into the field of oncology in most countries. There is a relative lack of consensus in the published literature as to the best approach to take, and there is a degree of uncertainty as to how integration of geriatric medicine principles might optimally predict patient outcomes. The aim of the current study was to obtain consensus on GA in oncology to inform the implementation of a geriatric oncology programme. A four-round Delphi process was employed. The Delphi method is a structured group facilitation process, using multiple iterations to gain consensus on a given topic. Consensus was reached on the optimal assessment method and interventions required for the commonly employed domains of GA. Other aspects of GA, such as screening methods and age cut-off for assessment, represented a higher degree of disagreement. The expert panel employed in this study clearly identified the criteria that should be included in a clinical geriatric oncology programme. In the absence of evidence-based guidelines, this may prove useful in the care of older cancer patients.

Antigen-based therapies targeting the expansion of regulatory T cells in autoimmune and allergic disease.

Between 5 and 10% of the European population suffer from autoimmune disease, whilst allergic disorders affect an even higher frequency, and both these forms of immunopathology have increased markedly in recent decades. The need for more precise and effective therapeutic strategies drives the investigation of antigen-based tolerance in rodent models and in patients. The identification of the key role T-regulatory cells (Tregs) play in avoidance of immunopathology focused on either self or environmental antigens has led to a need to determine whether established and novel tolerance-inducing strategies are in fact expanding antigenreactive Treg populations. Here we review recent data from mouse and man. A consistent thread is that, both in T-helper (Th)1/Th17-driven autoimmune disease and in Th2-driven allergic disease, antigen-based tolerance induction often promotes an antigen-reactive IL-10 T-cell population whilst reducing the pathogenic response. Whether these IL-10- producing cells are from the 'natural' Treg population that expresses the forkhead box p3 (Foxp3) transcription factor is less clear, and often they are not. We discuss some recent studies that might provide insight into how best to expand these protective T cells and highlight some outstanding issues requiring further investigation.

The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response.

p53 is a transcription factor with a well-described role in the induction of apoptosis and cell cycle arrest as part of a protective response to a variety of stressful stimuli. Expansion of inflamed tissue in rheumatoid arthritis has been related to the loss of functioning p53, and the severity of collagen-induced arthritis is increased in p53-/- mice. Our objective was to assess the role of p53 in a model of adaptive immunity, antigen-induced arthritis (AIA). AIA was induced in p53-/- and wild-type mice by priming with methylated bovine serum albumin followed by intra-articular challenge. Severity of arthritis was assessed using a standardized scoring system and synovial apoptosis was detected by TdT-mediated biotin-dUTP nick-end labelling. Splenocyte proliferation was measured by [H(3)] incorporation and interferon (IFN)-gamma release. Splenocyte viability was assessed using Titreglow. Splenic T cell activation status was assessed by flow cytometry. Serum cytokines were measured using enzyme-linked immunosorbent assay. Increased severity of AIA in p53-/- mice was associated with decreased synovial apoptosis and with increased delayed-type hypersensitivity response, increased mitogen and antigen-induced splenocyte proliferation and increased IFN-gamma release in p53-/- mice compared with wild-type mice. Antigen-specific immunoglobulin responses were equivalent in both groups. Splenocyte viability was increased in p53-/- mice but T cell apoptosis was equivalent. T cell activation markers were increased in p53-/- mice compared with wild-type mice. Lipopolysaccharide-induced tumour necrosis factor release was increased in p53-/- mice with a trend to increased interleukin-6 in p53-/- mice compared with littermates. p53 is involved in the modulation of adaptive and innate immune responses relevant to arthritis models and is also involved in the modulation of severity of AIA by both cell-cycle dependent and cell-cycle-independent mechanisms.

Macrophage migration inhibitory factor and glucocorticoid sensitivity.

Glucocorticoids (GCs) are widely used in the treatment of inflammatory diseases including rheumatoid arthritis (RA). Treatment with GC is associated with significant dose-dependent side-effects. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has emerged in recent years as a candidate factor which could regulate GC sensitivity. MIF is induced by GC, and is able to override anti-inflammatory actions of GCs. In this review, we summarize the pro-inflammatory actions of MIF with respect to RA, describe the interactions between MIF and GC and examine new evidence, which identifies MIF as a specific target for steroid sparing.

Expression and function of cell cycle proteins in rheumatoid arthritis synovial tissue.

Rheumatoid Arthritis (RA) is a chronic disease characterised by synovial lining hyperplasia and progressive destruction of joint tissues. Experimental data suggests that abnormal alterations in the expression of proteins involved in maintaining homeostatic control of the cell cycle is involved in disease progression in RA. By contributing to the overgrowth of synovial tissue, factors such as dysregulated proliferation or reduced apoptosis of cells can directly influence the pathological outcome of RA.

Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations.

OBJECTIVE: Cytokines play an important role in the pathology of rheumatoid arthritis (RA). Macrophage migration inhibitory factor (MIF) is a cytokine with a broad spectrum of actions, including induction of monocyte tumour necrosis factor alpha (TNF-alpha). Evidence of the expression and proinflammatory activity of MIF has recently been demonstrated in RA synovium and in animal models of RA. We wished to assess the relationship between MIF expression in synovium and clinical disease. METHODS: Computer-assisted analysis of the cytokine content of arthroscopically obtained biopsies of RA synovium, using paired samples from eight patients with active and inactive/treated disease, was compared with documented clinical parameters. RESULTS: Synovial MIF immunostaining correlated strongly with disease activity as measured by CRP concentration. Reductions in clinical disease parameters, including CRP, tender and swollen joint counts, were accompanied by significant reductions in synovial MIF. Synovial TNF-alpha, transforming growth factor beta (TGF-beta) and interleukin (IL) 10 also showed a significant reduction in association with reduced disease activity, while IL-1 beta and IL-1 receptor agonist did not. CONCLUSION: The correlation of synovial MIF with disease activity corroborates existing evidence of the role of this cytokine in RA. The demonstration that only MIF and TNF-alpha show significant variation in synovial cytokine content with clinical remission suggests that MIF is an important member of the cytokine hierarchy in RA.

Hexahydroxybenzene-2,2'-bipyridine (1/2).

2,2'-Bipyridine (2BPY) and hexahydroxybenzene (HHB) crystallize in a 2:1 ratio as a neutral molecular adduct, C(6)H(6)O(6).2C(10)H(8)N(2), in space group P1 with Z = 1 and with the HHB molecule lying on an inversion centre. HHB, of which this is the first single-crystal X-ray structure determination, forms O-H...O hydrogen-bonded chains parallel to the a axis, with O...O distances of 2.761 (1) and 2.782 (1) A. O-H...N hydrogen bonds to the 2BPY molecules crosslink these chains, with O...N distances of 2.707 (1) and 2.735 (1) A.

Interpenetrating supramolecular lattices in 4,4'-bipyridine-2,3,5,6-tetrahydroxy-1,4-benzoquinone (3/2).

4,4'-Bipyridine (BPY) and 2,3,5,6-tetrahydroxy-1,4-benzoquinone (THBQ) crystallize in a 3:2 ratio as a neutral molecular adduct, 3C(10)H(8)N(2).2C(6)H(4)O(6), in space group P1. There are two independent and centrosymmetric THBQ molecules and two different BPY molecules in the asymmetric unit, one of which lies about an inversion centre. The molecules link together through O-H...O and O-H...N hydrogen bonds to form three interpenetrating networks which create a 'superlattice' of three times the volume of the primitive cell.

Hypothalamic-pituitary-adrenal axis regulation of inflammation in rheumatoid arthritis.

The profound anti-inflammatory effects of glucocorticoids in drug therapy are reflected in the effects in vivo of endogenous glucocorticoids produced by the adrenals. The production of adrenal glucocorticoids is driven by the hypothalamus and pituitary, which in turn are responsive to circulating products of the inflammatory response, especially cytokines. That inflammation can drive the production of anti-inflammatory glucocorticoids denotes the hypothalamic-pituitary-adrenal (HPA)-immune axis as a classic negative feedback control loop. Defects in HPA axis function are implicated in susceptibility to, and severity of, animal models of rheumatoid arthritis (RA), and are hypothesized to contribute to the human disease. In this paper, data supporting the concept of the HPA axis as a regulator of the inflammatory response in animal models of arthritis are reviewed, along with data from studies in humans. Taken together, these data support the hypothesis that the HPA axis provides one of the key mechanisms for inhibitory regulation of the inflammatory response. Manipulation of HPA axis-driven endogenous anti-inflammatory responses may provide new methods for the therapeutic control of inflammatory diseases.

A model of viral wheeze in nonasthmatic adults: symptoms and physiology.

Episodic wheezing associated with viral infections of the upper respiratory tract (URT) is a common problem in young children but also occurs in adults. It is hypothesized that an experimental infection with human coronavirus (HCoV), the second most prevalent common cold virus, would cause lower respiratory tract (LRT) changes in adults with a history of viral wheeze. Twenty-four viral wheezers (15 atopic) and 19 controls (seven atopic) were inoculated with HCoV 229E and monitored for the development of symptoms, changes in airway physiology and provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20). At baseline, viral wheezers were similar to controls in PC20 (mean+/-SD log2PC20: 5.1+/-1.9 and 5.8+/-1.4 g x L(-1), respectively) but had a lower FEV1 than controls (mean+/-SD 85.8+/-11.4 and 95.6+/-13.2% predicted, respectively p < 0.05). Nineteen viral wheezers and 11 controls developed colds. Viral wheezers with colds reported significantly more URT symptoms than controls (median scores (interquartile range): 24 (10-37) and 6 (4-15), respectively p = 0.014). Sixteen viral wheezers and no controls reported LRT symptoms (wheeze, chest tightness and shortness of breath). The viral wheezers with colds had small (3-4%) reductions in FEV1 and peak expiratory flow on days with LRT symptoms (days 3-6), but a progressive reduction in PC20 from baseline on days 2, 4 and 17 after inoculation (by 0.82, 1.35 and 1.82 doubling concentrations, respectively). The fall in PC20 affected both atopic and nonatopic subjects equally. There were no changes in FEV1 or PC20 in controls. An adult model of viral wheeze that is independent of atopy and therefore, of classical atopic asthma was established.

The 1:1 adduct of 2,5-dihydroxy-1,4-benzoquinone with 4,4'-bipyridine.

2,5-Dihydroxy-1,4-benzoquinone (DHBQ) and 4,4'-bipyridine (BPY) crystallize in a 1:1 ratio as a neutral molecular adduct, C(6)H(4)O(4).C(10)H(8)N(2), in space group C2/c, with half of each molecule in the asymmetric unit. The molecules are linked by a strong O--H...N hydrogen bond [O...N 2.6323 (15) A] and a weak C--H...O hydrogen bond [C...O 3.2082 (17) A] to form infinite stacks of parallel one-dimensional hydrogen-bonded ribbons. The two rings of the bipyridine are twisted at 28.3 degrees with respect to each other, and the benzoquinone ring is inclined at an angle of 18.3 degrees with respect to the plane of the neighbouring pyridine ring. The 4,4'-bipyridine molecule lies on a twofold axis and the benzoquinone molecule lies across an inversion centre.

Transformation of the tropane alkaloid-producing medicinal plant Hyoscyamus muticus by particle bombardment.

We report an efficient whole plant transformation system for Hyoscyamus muticus, an important medicinal plant of the Solanaceous family. We developed a system using a plasmid carrying the nptII and gusA genes, which was delivered into leaf explants by particle bombardment. Ten percent of bombarded leaf explants formed kanamycin-resistant callus, from which putative transgenic plants were recovered. The nptII gene conferring kanamycin resistance was found to be incorporated into the genome of all transgenic plants screened. Over 50% of the kanamycin resistant plants showed strong expression of the non-selected gusA gene. The majority of transgenic plants reached maturity, could be self pollinated, and produced fertile seed. A simple and efficient whole plant transformation system for this medicinal plant is an important step in furthering our understanding of tropane alkaloid production in plants.