bluuebunny/crossref_metadata_2025 huggingface dataset:
Nestling Immunocompetence is Affected by Captivity but not Investigator Handling
Authors: Butler Michael W. , Dufty Alfred M.
Published: September 2019

Environmental conditions during the neonatal period can affect the growth, physiology, behavior, and immune function of birds. In many avian studies the nestling environment includes investigator handling of young, which may be stressful. While neonatal handling is known to affect the adult phenotype in rats, the effects of handling on development have rarely been examined in wild birds. We examined the effect of short, repeated periods of neonatal handling on avian growth and immune system development. We subjected American Kestrels (Falco sparverius) and European Starlings (Sturnus vulgaris) to 15 min of daily investigator handling throughout the nestling period, while controls remained undisturbed. Immediately prior to fledging we assessed cutaneous immunity, humoral immunity, mass, and degree of fluctuating asymmetry. Daily handling did not significantly affect any of these measurements. We also addressed the possibility that treatment differences would appear only when birds were challenged with a more substantial stressor by bringing birds into captivity for 24 hr. Captivity did not affect mass, but significantly lowered the cutaneous immune response, although this was independent of treatment. Therefore, brief periods of investigator handling did not appear to affect immune or morphological development in these species, whereas 24 hr of captivity resulted in suppressed cutaneous immune responses.
Power to Detect Trend in Short-Term Time Series of Bird Abundance
Authors: Thogmartin Wayne E. , Gray Brian R. , Gallagher Maureen , Young Neal , Rohweder Jason J. , Knutson Melinda G.
Published: September 2019

Avian point counts for population monitoring are often collected over a short timespan (e.g., 3–5 years). We examined whether power was adequate (power ≥0.80) in short-duration studies to warrant the calculation of trend estimates. We modeled power to detect trends in abundance indices of eight bird species occurring across three floodplain habitats (wet prairie, early successional forest, and mature forest) as a function of trend magnitude, sample size, and species-specific sampling and among-year variance components. Point counts (5 min) were collected from 365 locations distributed among 10 study sites along the lower Missouri River; counts were collected over the period 2002 to 2004. For all study species, power appeared adequate to detect trends in studies of short duration (three years) at a single site when exponential declines were relatively large in magnitude (more than −5% year−1) and the sample of point counts per year was ≥30. Efforts to monitor avian trends with point counts in small managed lands (i.e., refuges and parks) should recognize this sample size restriction by including point counts from offsite locations as a means of obtaining sufficient numbers of samples per strata. Trends of less than −5% year−1 are not likely to be consistently detected for most species over the short term, but short-term monitoring may still be useful as the basis for comparisons with future surveys.
Approximating Variance of Demographic Parameters Using the Delta Method: A Reference for Avian Biologists
Authors: Powell Larkin A.
Published: September 2019

Avian biologists routinely estimate sampling variance for parameter estimates such as daily nest survival, fecundity, annual survival, and density. However, many biologists are not certain of methods to derive sampling variance for parameters when survival rates change temporal scales. Similar methods are needed to obtain sampling variance when biologists combine parameter estimates to calculate an indirect demographic parameter, such as population growth rate. The delta method is a useful technique for approximating sampling variance when the desired demographic parameter is a function of at least one other demographic parameter. However, the delta method is rarely taught in most graduate-level biology or ecology courses, and application of this method may be discouraged by seemingly daunting formulas in reference books. Here, I provide five examples of sampling variance approximations for common situations encountered by avian ecologists, with step-by-step explanations of the equations involved.
The Family Behavior of California Quail: A Molecular Analysis
Authors: Calkins Jennifer D.
Published: September 2019

During the breeding season, California Quail (Callipepla californica) form two types of groups: those with a single associated adult female (single family groups), and those with more than one associated female (communal family groups). Although single family groups are assumed to be the result of a monogamous pairing of the associated male and female, additional males often associate with these groups. I conducted a preliminary investigation of the genetic relationship among the adults and young in California Quail families using three single-locus microsatellite markers. Both male and female adults were excluded as being the parents of some proportion of the associated young. Females had higher exclusion rates in communal than in single families, while there was no difference for males. A limited number of young were excluded from being the offspring of any of the adults associated with their family. In the first of three study years, adults were more related to one another in families than they were to the population; this relationship disappeared in subsequent years, possibly as a result of disturbance on site. These results suggest that families form, in part, as a result of factors other than direct genetic parentage. These factors might include selection for increasing group size, intermittent kin selection, and proximate factors related to the gregarious behavior of California Quail.
Hypoxia Probably Does not Explain Short Incubation Periods of Woodpeckers
Authors: Wiebe Karen L.
Published: September 2019

I tested the hypothesis that hypoxia in tree cavities causes the unusually short incubation periods characteristic of woodpeckers. I compared saturated O2 levels in ambient air to O2 levels in 13 unoccupied and 14 occupied nest cavities of the Northern Flicker (Colaptes auratus). Oxygen in unoccupied cavities did not differ from ambient levels, whereas O2 in cavities with an incubating adult was 2.2% lower than in saturated air. However, the magnitude of the decrease (20.5% oxygen in occupied cavities compared to 21.0% O2 in saturated air) is small compared to variation in the partial pressure of O2 caused by altitude. This suggests that O2 depletion is not a major selective force on embryonic development times for birds nesting in tree cavities. Alternative hypotheses for short incubation periods of woodpeckers include sexual selection on females and sibling competition.
Fruit Preference, Parasitism, and Offspring Fitness of Fopius arisanus (Hymenoptera: Braconidae) Exposed to Bactrocera dorsalis' (Diptera: Tephritidae) Infested Fruit Species
Authors: Nanga Nanga S , Hanna R , Gnanvossou D , Fotso Kuate A , Fiaboe K K M , Djieto-Lordon C
Published: September 2019

Fopius arisanus (Sonan) (Hymenoptera: Braconidae) is a koinobiont solitary parasitoid of various fruit flies, particularly those in the genus Bactrocera. Researchers introduced F. arisanus into Africa for the biological control of Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), a pest of a wide range of fruit trees and vegetables. However, the suitability of host fruit species as egg-laying substrates for parasitoid development remains poorly investigated in tropical Africa. The present study examines the preference and performance of F. arisanus on B. dorsalis reared on eleven fruit species through laboratory choice-test trials. We assessed the oviposition activity, parasitism rate, developmental time, and offspring fitness of F. arisanus on nine cultivated and two wild host fruits species. Oviposition attempts were higher on Psidium guajava (L.) (Myrtales: Myrtaceae) and Mangifera indica (L.) (Sapindales: Anacardiaceae) than on the other host fruits tested. The wasp parasitized host eggs in P. guajava in no-choice experiments. Psidium guajava, Irvingia wombulu (Vermoesen) (Malpighiales: Irvingiaceae), and Irvingia gabonensis (Aubry_Lecomte) Baill (Malpighiales: Irvingiaceae) were suitable for parasitism in choice tests. Of all host fruits tested, the body and hind tibia lengths of both parasitoid sexes emerging from M. indica were longer than on the others. The female ovipositor was long on Annona squamosa (L.) (Magnoliales: annonaceae) and short on Eribotrya japonica ([Thunb.] Lindl.; Rosales: Rosaceae). We obtained the longest preimaginal developmental time for both sexes on E. japonica and the shortest for females and males on Carica papaya (L.) (Brassicales: Caricaceae). These results demonstrate the ability of some tested fruit species to serve for the permanent establishment of F. arisanus in the field.
Ventricular response to dobutamine stress cardiac magnetic resonance imaging is associated with adverse outcome during 8-year follow-up in patients with repaired Tetralogy of Fallot
Authors: van den Bosch Eva , Cuypers Judith A A E , Luijnenburg Saskia E , Duppen Nienke , Boersma Eric , Budde Ricardo P J , Krestin Gabriel P , Blom Nico A , Breur Hans M P J , Snoeren Miranda M , Roos-Hesselink Jolien W , Kapusta Livia , Helbing Willem A
Published: September 2019

Aims

The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients.

Methods and results

In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress − parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan–Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5–34.0), age at TOF repair 0.9 years (0.6–2.1)]. After a median follow-up of 8.6 years (6.7–14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (−17 ± 15 vs. −26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5–43.7; P = 0.001) as predictor for the composite endpoint.

Conclusion

An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.
From an Unpaid Electricity Bill to the Primacy of EU Law: Gian Galeazzo Stendardi and the Making of Costa v. ENEL
Authors: Arena Amedeo
Published: September 2019

Whilst Costa v. ENEL is the starting point for most accounts of the primacy of EU law, the story of that lawsuit is still relatively unknown. What drove Flaminio Costa to sue his electricity provider over a bill of as little as £1,925 (about €22 in 2019)? Why did the small-claims court of Milan decide to involve both the Italian Constitutional Court and the European Court of Justice in such a ‘petty’ lawsuit? Why did those two courts hand down rulings going in opposite directions? How did the lawsuit end when it came back to the Milan small-claims court? Relying upon previously undisclosed court documents and interviews with some of the actors involved, this article seeks to shed some light on the less-known aspects of the Costa v. ENEL lawsuit, against the background of electricity nationalization in Italy at the height of the Cold War, and to assess the contribution of that lawsuit and of its ‘architect’, Gian Galeazzo Stendardi, to the development of the doctrine of primacy of European Union law.
Are people-centred mental health services acceptable and feasible in Timor-Leste? A qualitative study
Authors: Hall Teresa , Kakuma Ritsuko , Palmer Lisa , Martins João , Minas Harry , Kermode Michelle
Published: September 2019

People-centred mental healthcare is an influential concept for health system strengthening and sustainable development that has been developed and promoted primarily in Western contexts. It characterizes service users, families and communities as active participants in health system development. However, we have limited understanding of how well people-centred mental healthcare aligns with the multiplicity of peoples, cultures, languages and contexts in low- and middle-income countries (LMICs). Timor-Leste, a lower-middle income country in South-East Asia, is in the process of strengthening its National Mental Health Strategy 2018–22 to align with people-centred mental healthcare. To support the implementation of this Strategy, this study investigated the acceptability and feasibility of people-centred mental health services in Timor-Leste. In-depth semi-structured individual (n = 57) and group interviews (n = 15 groups) were conducted with 85 adults (≥18 years). Participants were service users, families, decision-makers, service providers and members of civil society and multilateral organizations across national and sub-national sites. Government and non-government mental health and social care was also observed. Framework analysis was used to analyse interview transcripts and observation notes. The study found that the ecology of mental healthcare in Timor-Leste is family-centred and that government mental health services are largely biomedically oriented. It identified the following major challenges for people-centred mental health services in Timor-Leste: different sociocultural perceptions of (in)dividual personhood, including a diminished status of people with mental illness; challenges in negotiating individual and family needs; a reliance on and demand for biomedical interventions; and barriers to health service access and availability. Opportunities for people-centred mental healthcare are better available within the social and disability sectors, which focus on social inclusion, human rights and peer support. Accounting for local cultural knowledge and understandings will strengthen design and implementation of people-centred mental healthcare in LMIC settings.
Obesity prediction by modelling BMI distributions: application to national survey data from Mexico, Colombia and Peru, 1988–2014
Authors: Yamada Goro , Castillo-Salgado Carlos , Jones-Smith Jessica C , Moulton Lawrence H
Published: September 2019

Background

The prediction of future obesity patterns is crucial for effective strategic planning. However, disproportionally changing body mass index (BMI) distributions pose particular challenges. Flexible modelling of the shape of BMI distributions may improve prediction performance.

Methods

We used data from repeated national health surveys conducted in Mexico, Colombia and Peru at four or five time points between 1988 and 2014. Data from all surveys except the last survey were used to construct prediction models for three obesity indicators (median BMI, overweight/obesity prevalence and obesity prevalence) for the time of the last survey. We assessed their performance using predicted curves, absolute prediction errors and comparison of actual and predicted distributions. With one method, we modelled the shape of BMI distributions assuming BMI follows a Box-Cox Power Exponential (BCPE) distribution, whose parameters were modelled as a function of interval or nominal 5-year age groups, time and their interaction terms. In a second method, we modelled each of the obesity indicators directly as a function of the same covariates using quantile and logistic regression.

Results

The BCPE model with interval age groups yielded the best prediction performance in predicting obesity prevalence. Average absolute prediction errors across all age groups were 4.3 percentage points (95% percentile interval: 1.9, 7.5), 2.5 (1.2, 6.1) and 1.7 (1.0, 9.3), with data from Mexico, Colombia and Peru, respectively. This superiority was weak or none for overweight/obesity prevalence and median BMI.

Conclusion

The BCPE model performed better for prediction of the extremes of BMI distribution, possibly by incorporating its shape more precisely.
In Vitro Metabolic Profile Elucidation of Synthetic Cannabinoid APP-CHMINACA (PX-3)
Authors: Presley Brandon C , Logan Barry K , Jansen-Varnum Susan A
Published: September 2019

Indazole carboxamide synthetic cannabinoids remain the most prevalent subclass of new psychoactive substances (NPS) reported internationally. However, the metabolic and pharmacological properties of many of these compounds remain unknown. Elucidating these characteristics allows members of the clinical and forensic communities to identify causative agents in patient samples, as well as render conclusions regarding their toxic effects. This work presents a detailed report on the in vitro phase I metabolism of indazole carboxamide synthetic cannabinoid APP-CHMINACA (PX-3). Incubation of APP-CHMINACA with human liver microsomes, followed by analysis of extracts via high-resolution mass spectrometry, yielded 12 metabolites, encompassing 7 different metabolite classes. Characterization of the metabolites was achieved by evaluating the product ion spectra, accurate mass and chemical formula generated for each metabolite. The predominant biotransformations observed were hydrolysis of the distal amide group and hydroxylation of the cyclohexylmethyl (CHM) substituent. Nine metabolites were amide hydrolysis products, of which five were monohydroxylated, one dihydroxylated and two were ketone products. The metabolites in greatest abundance in the study were products of amide hydrolysis with no further biotransformation (M1), followed by amide hydrolysis with monohydroxylation (M2.1). Three APP-CHMINACA-specific metabolites were generated, all of which were hydroxylated on the CHM group; one mono-, di- and tri-hydroxylated metabolite each was produced, with dihydroxylation (M6) present in the greatest abundance. The authors propose that metabolites M1, M2.1 and M6 are the most appropriate markers to determine consumption of APP-CHMINACA. The methods used in the current study have broad applicability and have been used to determine the in vitro metabolic profiles of multiple synthetic cannabinoids and other classes of NPS. This research can be used to guide analytical scientists in method development, synthesis of reference material, pharmacological testing of proposed metabolites and prediction of metabolic processes of compounds yet to be studied.
Measure, Modulation and Metadesign: NC Fabrication in Industrial Design and Architecture
Authors: Brennan AnnMarie
Published: September 2019

Just as the capabilities of machine tool design influenced the aesthetic form of streamlined industrial design products during the mechanical age, the embedded curves and splines of digital software employed by architects today originated in the offices of automobile and aeroplane manufacturers from the post-war era. The use and reproduction of smooth, curvilinear forms would not appear in the field of architecture until many decades after their development within industrial design. The current relationship between architecture and industrial design is forged through the innovative use of Computer Numerical Control fabrication and the parametric procedures and software invented for its use. This article investigates the history of designing and fabricating complex, curved surfaces in industrial design and architecture in order to establish the technological and theoretical links between these two fields. It involves the transfer of technological knowledge amongst a diverse cast of designers, engineers and architects from multiple continents that took place over a period of 40 years. Moreover, this research claims that the origins of parametric architectural design can be found in this moment of developing and programming numerically controlled machines.
The Survival and Reproduction of Rhopalosiphum padi (Hemiptera: Aphididae) on Different Plants: Exploring the Possible Host Range for a Serious Wheat Pest
Authors: Peng Xiong , Liu Lang , Guo Xin , Wang Peilei , Song Chunman , Su Sha , Fang Guijie , Chen Maohua
Published: September 2019

Rhopalosiphum padi (L.) is one of the most economically important pests of wheat worldwide; however, the host ranges of R. padi remain unclear. Particularly, it is unknown which plants R. padi can survive and reproduce on after the harvest of crops. The results revealed that the survival, developmental times, longevity, and fecundity of the aphid varied among the 13 Gramineae weeds, with the life-history parameters significantly differing. The virginoparae could survive long-term and reproduce on 11 of the 13 weeds. Gramineae weeds can possibly play a significant role in the buildup of R. padi populations as reservoirs. The virginoparae could survive long term and reproduce on Iris lactea Pall. var. chinensis (Fisch.) Koidz (Liliflorae: Iridaceae), Iris tectorum Maxim. (Liliflorae: Iridaceae), Cyperus rotundus L. (Cyperales: Cyperaceae), and Brassica oleracea L. var. capitata (Rhoeadales: Cruciferae), but not on Fagopyrum esculentum Moench (Polygonales: Polygonaceae), F. tataricum (L.) Gaertn. (Polygonales: Polygonaceae), Chlorophytum comosum (Thunb.) Baker (Liliflorae: Liliaceae), and Ophiopogon japonicas (Thunb.) Ker-Gawl (Liliflorae: Liliaceae). Rhopalosiphum padi can survive and reproduce on non-Gramineae plants of different families. Detailed host range information would be helpful for more effective control of insect pests. The design and implementation of sustainable pest management strategies should consider the aphid population on weeds and other host plants.
Performance of Commercial Insecticide Formulations Against Different Developmental Stages of Insecticide-Resistant Tropical Bed Bugs (Hemiptera: Cimicidae)
Authors: Leong Xin-Yeng , Kim Dae-Yun , Dang Kai , Singham G Veera , Doggett Stephen L , Lee Chow-Yang
Published: September 2019

This study examined the presence of insecticide resistance in different developmental stages (adults, first instars, and eggs) of the tropical bed bug, Cimex hemipterus (F.) using several insecticide formulations. Adults and first instars of five strains (Queensland, Kuala Lumpur, Bukit Mertajam, Saujana, and Krystal Point) were evaluated using the surface contact method and compared with a susceptible strain (Monheim) of the common bed bug Cimex lectularius L. The insecticide formulations were used at their label rates in this study: Tandem (thiamethoxam [11.6%], lambda-cyhalothrin [3.5%]) at 183.96 mg/m2; Temprid SC (imidacloprid [21%], beta-cyfluthrin [10.5%]) at 106.13 mg/m2; Sumithion 20CS (fenitrothion [20%]) at 250 mg/m2; Pesguard FG161 (d-tetramethrin [4.4%], cyphenothrin [13.2%]) at 110 mg/m2; and Sumithrin 10SEC (d-phenothrin [10%]) at 100 mg/m2. Results showed a very high level of resistance to Pesguard FG161 (388.3 to >605.0 times) and Sumithrin (302.9 to >365.5 times) in all adults of the strains tested, whereas low to high levels of resistance were registered for Tandem (1.4–4.7 times), Temprid (7.3–16.7 times), and Sumithion (1.2–14.6 times) for adults of all bed bug strains. For first instars, resistance to the former two formulations were high to very high (31.4–118.1 times). In contrast, they showed lower resistance to Tandem, Temprid, and Sumithion (1.0–10.2 times). An immersion method used to test on bed bug eggs found high to very high resistance toward all tested formulations. Results demonstrate that the resistance level varies between bed bug developmental stages.
Glucose Utilization in the Regulation of Chitin Synthesis in Brown Planthopper
Authors: Pan Bi-Ying , Li Guo-Yong , Wu Yan , Zhou Zhong-Shi , Zhou Min , Li Can
Published: September 2019

Glucose-6-phosphatase (G6Pase) and hexokinase (HK) are two key enzymes in the glycolysis and gluconeogenesis pathways, which catalyze the synthesis and degradation of glucose in insects, respectively. G6Pase and HK play an important role in insect growth by regulating the metabolism of glucose, leading to the efficient metabolism of other macromolecules. However, it is unclear whether these genes could be investigated for pest control through their actions on chitin metabolism. We studied the potential functions of G6Pase and HK genes in the regulation of chitin metabolism pathways by RNAi technology. Interference with G6Pase expression did not affect trehalose and chitin metabolism pathways in brown planthopper, Nilaparvata lugens (Stål). However, knockdown of the HK gene resulted in a significant decrease of expression of genes associated with the trehalose metabolic pathway but had no significant effect on trehalase activity, trehalose content, or glucogen content. Additionally, HK knockdown resulting in downregulation of the genes involved in chitin metabolism in the brown planthopper. These insects also showed wing deformities and difficulty in molting to varying degrees. We suggest that the silencing of HK expression directly inhibited the decomposition of glucose, leading to impaired chitin synthesis.
Comprehensive analysis of variation of cadmium accumulation in rice and detection of a new weak allele of OsHMA3
Authors: Sun Cuiju , Yang Meng , Li Yuan , Tian Jingjing , Zhang Yuanyuan , Liang Limin , Liu Zonghao , Chen Kai , Li Yutong , Lv Kai , Lian Xingming
Published: September 2019

Excessive cadmium (Cd) accumulation in rice poses a potential threat to human health. Rice varieties vary in their Cd content, which depends mainly on root-to-shoot translocation of Cd. However, cultivars accumulating high Cd in the natural population have not been completely investigated. In this study, we analyzed the variation in Cd accumulation in a diverse panel of 529 rice cultivars. Only a small proportion (11 of 529) showed extremely high root-to-shoot Cd transfer rates, and in seven of these cultivars this was caused by two known OsHMA3 alleles. Using quantitative trait loci mapping, we identified a new OsHMA3 allele that was associated with high Cd accumulation in three of the remaining cultivars. Using heterologous expression in yeast and comparative analysis among different rice cultivars, we observed that this new allele was weak at both the transcriptional and protein levels compared with the functional OsHMA3 genotypes. The weak Cd transport activity was further demonstrated to be caused by a Gly to Arg substitution at position 512. Our study comprehensively analyzed the variation in root-to-shoot Cd translocation rates in cultivated rice and identified a new OsHMA3 allele that caused high Cd accumulation in a few rice cultivars.
The MiMeS survey of magnetism in massive stars: magnetic properties of the O-type star population
Authors: Petit V , Wade G A , Schneider F R N , Fossati L , Kamp K , Neiner C , David-Uraz A , Alecian E ,   the MiMeS Collaboration
Published: September 2019

In this paper, we describe an analysis of the MiMeS (Magnetism in Massive Stars) survey of O-type stars to explore the range of dipolar field strengths permitted by the polarization spectra that do not yield a magnetic detection. We directly model the Stokes V profiles with a dipolar topology model using Bayesian inference. The noise statistics of the Stokes V profiles are in excellent agreement with those of the null profiles. Using a Monte Carlo approach, we conclude that a model in which all the stars in our sample were to host 100 G, dipolar magnetic field can be ruled out by the MiMeS data. Furthermore, if all the stars with no detection were to host a magnetic field just below their detection limit, the inferred distribution in strength of these undetected fields would be distinct from the known distribution in strength of the known magnetic O-type stars. This indicates that the 'initial magnetic field function' (IBF) is likely bimodal – young O-type stars are expected to have either weak/absent magnetic fields or strong magnetic fields. We also find that better upper limits, by at least a factor of 10, would have been necessary to rule out a detection bias as an explanation for the apparent lack of evolved main-sequence magnetic O-type stars reported in the literature, and we conclude that the MiMeS survey cannot confirm or refute a magnetic flux decay in O-type stars.
Global dynamics of the interstellar medium in magnetized disc galaxies
Authors: Körtgen Bastian , Banerjee Robi , Pudritz Ralph E , Schmidt Wolfram
Published: September 2019

Magnetic fields are an elemental part of the interstellar medium in galaxies. However, their impact on gas dynamics and star formation in galaxies remains controversial. We use a suite of global magnetohydrodynamic simulations of isolated disc galaxies to study the influence of magnetic fields on the diffuse and dense gas in the discs. We find that the magnetic field acts in multiple ways. Stronger magnetized discs fragment earlier due to the shorter growth time of the Parker instability. Due to the Parker instability in the magnetized discs, we also find cold ($T \lt 50\, \mathrm{K}$) and dense ($n\sim 10^3 {--}10^4\, \mathrm{cm}^{-3}$) gas several hundred pc above/below the mid-plane without any form of stellar feedback. In addition, magnetic fields change the fragmentation pattern. While in the hydrodynamic case, the disc breaks up into ring-like structures, magnetized discs show the formation of filamentary entities that extent both in the azimuthal and radial direction. These kpc scale filaments become magnetically (super-)critical very quickly and allow for the rapid formation of massive giant molecular clouds. Our simulations suggest that major differences in the behaviour of star formation – due to a varying magnetization – in galaxies could arise.
Cosmic-ray-driven outflow from the Galactic Centre and the origin of magnetized radio filaments
Authors: Yusef-Zadeh F , Wardle M
Published: September 2019

Radio, X-ray, and infrared observations of the inner few hundred parsecs of the Galactic Centre have highlighted two characteristics of the interstellar medium. The cosmic-ray ionization rate derived from molecular ions such as H$^+_3$ is at least two to three orders of magnitude higher than in the Galactic disc. The other is bipolar X-ray and radio emission away from the Galactic plane. These features are consistent with a scenario in which high cosmic-ray pressure drives large-scale winds away from the Galactic plane. The interaction of such a wind with stellar wind bubbles may explain the energetic non-thermal radio filaments found throughout the Galactic Centre. Some of the implications of this scenario is the removal of gas driven by outflowing winds, acting as a feedback to reduce the star formation rate in the central molecular zone (CMZ), and the distortion of azimuthal magnetic field lines in the CMZ to vertical direction away from the plane. The combined effects of the wind and the vertical magnetic field can explain why most magnetized filaments run perpendicular to the galactic plane. This proposed picture suggests our Milky Way nucleus has recently experienced starburst or black hole activity, as recent radio and X-ray observations indicate.
PL3.3 Second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion
Authors: van den Bent M J , Erridge S , Vogelbaum M A , Nowak A K , Sanson M , Brandes A A , Wick W , Clement P M , Baurain J F , Mason W , Wheeler H , Weller M , Aldape K , Wesseling P , Kros J M , Tesileanu C M S , Golfinopoulos V , Gorlia T , Baumert B G , French P J
Published: September 2019

BACKGROUND

The 1st interim analysis of the CATNON trial showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) but remained inconclusive about concurrent (conc) TMZ. A 2nd interim analysis was planned after 356 events.

MATERIAL AND METHODS

The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ (doi: 10.1016/S0140-6736(17)31442-3). MGMT promoter methylation (MGMTmeth) status was re-assessed with the Infinium Methylation EPIC Beadchip using the MGMT_STP27 model. Isocitrate dehydrogenase 1 and 2 (IDH) mutation (mt) status was assessed with glioma targeted Agilent SureSelect baits sequence using an Illumina HiSeq2500 Rapid PE100.

RESULTS

With a median follow-up of 56 months and 356 events, the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.968 (99.1% CI 0.73, 1.28). 5-year OS was 50.2% with and 52.7% without concTMZ (95% CI [44.4, 55.7] and [46.9, 58.1]). An IDHmt was found in 335 of 480 assessed cases (70%). Median OS was 19 mo (95% CI 16.3, 22.3) in IDHwt tumors and 116 mo (95% CI 82.0, 116.6) in IDHmt tumors. The interaction test based on IDH status was significant (p=0.016) in the univariate HR analysis for OS after concTMZ (IDHwt, n=145, events=120, HR = 1.27, 95% CI 0.89, 1.82, p=0.19; IDHmt, n=335, events=92, HR= 0.67, 95% CI 0.44, 1.03, p=0.06). IDHmt was predictive of benefit from adjTMZ (IDHmt HR: 0.41, 95% CI 0.27, 0.64; IDHwt: HR 1.05, 95% CI 0.73, 1.52; interaction test p = 0.001). In IDHmt patients that received adjTMZ, the HR for OS after concTMZ was 0.71 (95% CI 0.35, 1.42, p=0.32). MGMTmeth was found in 288 of 410 assessed cases (70%), interaction test for concTMZ (p = 0.092) and adjTMZ (p = 0.166) did not reach statistical significance.

CONCLUSION

In the entire study cohort, concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present. AdjTMZ increased OS in IDHmt but not in IDHwt tumors. Further analyses and follow-up will allow full assessment of efficacy in the molecular subgroups.
OS1.1 Plasma PD-L1 levels over time differ between glioblastoma and lower-grade glioma patients
Authors: Mair M , Ilhan-Mutlu A , Pajenda S , Widhalm G , Dieckmann K , Hainfellner J A , Marosi C , Wagner L , Preusser M , Berghoff A S
Published: September 2019

BACKGROUND

Immune modulating therapies are a promising treatment approach in patients with primary brain tumors, however their clinical efficacy is still under investigation as the systemic inflammatory responses are potentially challenged by the brain’s tight immune regulatory mechanisms. Here, we aimed to investigate soluble PD-L1 (sPD-L1) in the plasma of recurrent glioblastoma (GBM) and recurrent WHO grade II - III glioma (LGG) patients over their course of disease.

MATERIAL AND METHODS

30 patients with recurrent GBM and 10 patients with recurrent LGG were treated with bevacizumab (400mg, q14 days) as a salvage therapy at the Medical University of Vienna. EDTA plasma samples were drawn prior to each treatment cycle. sPD-L1 was analyzed using a sandwich ELISA (Millipore ABF133 and clone 5H1). The lower limit of detection was 0.050 ng/ml as determined by serial dilutions of recombinant human PD-L1.

RESULTS

sPD-L1 values could be retrieved in a median of 6 timepoints per patient (range: 2 - 24). No significant difference in sPD-L1 concentrations between GBM and LGG patients was present at baseline (p > 0.05). After 2 weeks of bevacizumab treatment, LGG patients presented with statistically significant lower sPD-L1 concentrations as compared to baseline (p = 0.036, Wilcoxon signed rank test), while no difference in sPD-L1 concentration was observed in GBM patients. Significantly higher sPD-L1 intra-patient variability was evident in LGG patients compared to GBM patients (p = 0.012, Mann-Whitney-U). In LGG patients, sPD-L1 correlated with leukocyte count (Spearman’s r = 0.397, p = 0.001) as well as with C-reactive protein level (Spearman’s r = -0.424, p = 0.001), while in GBM patients no correlation of sPD-L1 and systemic markers of inflammation was evident (-0.3 < Spearman’s r < 0.3).

CONCLUSION

sPD-L1 as a systemic marker of inflammation was lower in recurrent LGG patients compared to recurrent GBM patients after bevacizumab-based treatment, arguing that the glioma-immune system interactions differ between LGG and GBM.

SUPPORT/DISCLOSURE

This project was funded by the research budget of the Medical University of Vienna.
OS1.2 Development and Validation of a RNA-Seq Based Prognostic Signature in Neuroblastoma
Authors: Zhou J , Ma H
Published: September 2019

BACKGROUND

Credible prognostic stratification remains a challenge for neuroblastoma (NBL) with variable clinical manifestations. RNA expression signatures might predict the outcomes; notwithstanding, independent cross-platform validation is still rare.

MATERIAL AND METHODS

expression data were obtained from NBL patients and then analyzed. In TARGET-NBL data, an RNA-based prognostic signature was developed and validated. Survival prediction was assessed using a time-dependent receiver operating characteristic (ROC) curve. Functional enrichment analysis of the RNAs was conducted using bioinformatics methods.

RESULTS

A total of 1,119 differentially expressed RNAs and 149 prognosis-related RNAs were identified sequentially. Then, in the training cohort, 12 RNAs were identiﬁed as signiﬁcantly associated with overall survival (OS) and were combined to develop a model that stratified NBL patients into low- and high-risk groups. Twelve RNA signature high-risk patients had poorer OS in the training cohort (n = 105, Hazard Ratios (HR)= 0.10 (0.05–0.20), P < 0.001) and in the validation cohort (n = 44, HR = 0.25 (0.09–0.69), P = 0.008). ROC curve analysis also showed that both the training and validation cohorts performed well in predicting OS (12-month AUC values of 0.852 and 0.438, 36-month AUC values of 0.824 and 0.737, and 60-month AUC values of 0.802 and 0.702, respectively). Moreover, these 12 RNAs may be involved in certain events that are known to be associated with NBL through functional enrichment analysis.

CONCLUSION

This study identiﬁed and validated a novel 12-RNA prognostic signature to reliably distinguish NBL patients at low and high risk of death. Further larger, multicenter prospective studies are desired to validate this model.
OS1.7 Plasmatic differential scanning fluorimetry profiles discriminate glioma patients from healthy controls
Authors: Tabouret E , Tsvetkov P , Eyraud R , Peel T , Malesinski S , Figarella-Branger D , Chinot O , Devred F
Published: September 2019

BACKGROUND

differential scanning fluorimetry (DSF) has been recently proposed to be used to perform high throughput biofluids profiling by following protein denaturation. Our objective was to discriminate patients with glioma from healthy controls using plasmatic DSF profiles.

MATERIAL AND METHODS

We included 78 glioma patients and 44 healthy controls. Plasmas were collected using EDTA tubes and analyzed in duplicate using nanoDSF Prometheus NT.Plex instrument (Nanotemper). The following DSF data were analyzed: protein fluorescence at 330 and 350 nm, first derivation of the ratio of fluorescence at 330 and 350 and the absorbance at 350 nm. Then we ran several machine learning algorithms to differentiate gliomas from healthy controls: Logistic Regression (LR), Support Vector Machine (SVM), Neural Networks (NN), Random Forest (RF) and Adaptive Boosting (AdaBoost). All these methods have been tested using a leave-one-out approach where each datum is used once as test while the other are used to train the automatic classifiers.

RESULTS

We included 78 patients with a median age of 57.8 years (range, 21.8 - 89.9). Thirteen patients (17%) presented with a 1p/19q codeleted IDH mutated oligodendroglioma, 12 patients (15%) with an IDH mutated astrocytoma and 53 patients (68%) with an IDH wild-type astrocytoma, including 26 patients with a recurrent grade IV IDH wild-type astrocytoma. DSF data were independent from classical prognostic factors or patient characteristics: age, Karnofsky Performans Status, IDH mutation status, 1p19q codeletion, grade, initial or recurrent setting, steroid doses, patient size and weight, tumor size and location. The different datasets of the DFS output were tested independently and in combination as input of the machine learning algorithms. Results were obtained using the tuned best parameters on 157 data. The best obtained accuracy was 95.54% with 2% of fake positives and 5% of fake negatives (algorithm: SVM). Others achieved ≥ 90% of correct classification: LR accuracy was 89.17%, NN accuracy was 92.99%, RF accuracy was 91.72% and Adaboost accuracy was 92.36%.

CONCLUSION

DSF profiles analyzed by machine learning algorithms could allow us to identify glioma patients from healthy controls with an accuracy of more than 95%. These results suggest that DSF of biofluid could be a useful and non-invasive tool to monitor glioma patients. Further investigations, including longitudinal profile analyses are ongoing.
OS3.2 Relevant topics for brain tumor patients in the Distress Thermometer, first results of the HEAT study
Authors: Renovanz M , Coburger J , Tabatabai G , Ringel F , Wirtz C , Mehdorn M , Goebel S
Published: September 2019

BACKGROUND

Patient-centered assessments and disease-adjusted patient-reported outcome measures (PROMs) are crucial in neuro-oncology. The Distress Thermometer (DT) is a well-accepted screening tool for cancer patients including a numerical rating scale (1–10, cut-offs indicating relevant distress ≥4–6) and 40 items describing possible problem categories (emotional, social, physical, practical and spiritual). The aims of the first part of the “Adaption of the Distress Thermometer in patients with intracranial tumors” (HEAT) study were to evaluate the importance and relevance of items for brain tumor patients (BTP).

MATERIAL AND METHODS

The multicenter study included three University hospitals. After given informed consent patients were prospectively evaluated either during their hospital stay or in the outpatient setting using DT as well as the 40 item problem list. Clinical and demographic data were recorded. We performed an analysis regarding frequency of indicated topics and evaluated their relevance for patients’ psychosocial well-beings via Pearson correlations with the DT score.

RESULTS

Data of n = 670 patients were analyzed. Mean age was 52 years (SD = 14, range 18–81), most of the patients harbored WHO°I tumors (37%) and WHO°IV tumors (28%). Male to female ratio was 1:1, 17% were assessed preoperatively, 40% postoperatively and 43% during adjuvant therapy or follow-up. 14% of the patients faced a tumor recurrence at assessment. Mean score of DT was 5.23 (SD = 2.9, range 0–10). Applying a cut-off score ≥ 4, 61% reported distress (≥ 5: 46% and ≥ 6: 37%). Regarding the relevance of the problem list for BTP, emotional problems (e. g., anxiety, depression) were most frequently reported. A total of 14/40 (35 %) of items were endorsed by less than 10% of patients. With exception of emotional problems all areas were reflected: practical problems (e. g., problems with child care or insurance), social problems (e. g., problems with children), spiritual concerns (e. g., loss of faith), and physical problems (e. g., breathing, fever). However, some of these rarely reported problems were of relevance for patients’ psychosocial well-being as indicated by significant correlations between the respective item and the DT score. This was, for example, the case for problems with childcare (r = .106; p < .01) or breathing (r = .125; p = .001).

CONCLUSION

Tools developed for cancer patients do not yet perfectly reflect all needs of BTP. Based on our data, we suggest further adjustments of available tools. Yet, it should be taken into account that subgroups of BTP may require different problem lists in the DT, as we observed some topics (e.g. breathing) probably be related to BTP under chemotherapy or steroids only. Moreover, our data require cross-cultural validation as especially results regarding practical problems and insurance might differ in cultures with different social security systems.
OS4.1 MEVITEM: A European, randomized, open-label, Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog (SHH) pathway
Authors: Frappaz D , Barritault M , Montané L , Laigle-Donadey F , Chinot O , Le Rhun E , Bonneville-Levard A , Meyronnet D , Garin G , Pérol D
Published: September 2019

BACKGROUND

Vismodegib (V) suppresses sonic hedgehog (SHH) signaling. We postulated that vismodegib together with chemotherapy may be more efficient than chemotherapy alone in patients (pts) relapsing of a SHH-activated medulloblastoma (MB).

MATERIAL AND METHODS

Adult pts with recurrent SHH-MB not previously exposed to temozolomide (T) were randomly assigned (2:1 ratio) to Arm A (V daily 150mg/d, po) + T (D1-5: 150 mg/m2 for cycle 1 and 200 mg/m2 thereafter; n=up to 25pts) or Am B (T alone; n=up to 13pts). Identification of SHH activation was performed centrally by IHC (GAB1, β-catenin, filamin A, and YAP1). NGS analyses were performed to identify the mutations responsible for SHH activation. Primary objectives were to assess the incidence of severe toxicities (safety run-in based on a 3 + 3 design) and the 6-month non-progression rate (NPR-6m) according to WHO criteria and based on central read tumor assessment (Phase II). A Minimax Simon’s two-stage design was used to detect NPR-6m of 55% (p0: 30%, type I error rate of 5%, power of 80%). At first stage, ≥ 3/9 pts without progression at 6m were required for the accrual of 16 additional pts in Arm A. A 3rd independent and parallel arm with V as single agent (Arm C, n= up to15pts) was added for pts previously treated by T.

RESULTS

24 SHH-MB pts were enrolled (Arm A: 10, Arm B: 5 and Arm C: 9; median age: 37 y [21–55]). At the end of the safety run-in; no major safety concerns were reported. At the end of Stage I: no objective response were reported and 2 pts among 10 were free of progression at 6m among in Arm A. According to statistical rules, the study was definitively closed to enrolment. NGS analyses showed a PTCH1 inactivating mutation in 6 pts (n=4 in arm A; n= 2 in arm B); a SMO activating mutation in 4 pts (n= 3 in Arm A; n=1 in Arm B). For 1 pt in each arm, no tumor sample was available for analysis, for 1 pt in Arm A DNA quality was insufficient, and for 1 patient in each arm no mutations of SMO, PTCH1, SUFU or SHH were found. Out of the 4 pts in Arm A with an inactivating PTCH1 mutation, only 1 was progression free at 6m. PFS and OS data will be presented at the meeting.

CONCLUSION

The combination of vismodegib with monthly T failed to demonstrate superior activity as compared with T alone. Further studies are warranted to refine therapeutic indication for vismodegib