bluuebunny/crossref_metadata_2025 huggingface dataset:
Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma
Authors: Oliver Millner Thomas , Ricci Barbara , Zhang Xinyu , Pomella Nicola , Marino Silvia
Published: October 2019

Introduction

The epigenetic regulator Bmi1 is essential for the self-renewal of neural stem cells (NSC), and highly expressed in glioblastoma (GBM) stem/initiating cells (GIC), where knockdown significantly reduces tumour growth in xenograft models. We have used a combined genome-wide and target gene-driven approach to identify EphrinA5 (EfnA5) as a mediator of Bmi1 function in mouse and human GIC.

Methods and results

We compared mGIC, from a PTEN/p53 deletion mouse model, to matched NSC. Combined ChIPSeq and RNASeq showed a differential redistribution of the repressive PRC mark H3K27me3 in mGIC, and that transcriptional regulation is Bmi1-dependent in a proportion of H3K27me3 marked genes. Subsequently, using shRNA knockdown, we show that Bmi1 regulates cell morphology, proliferation and migration/invasion via repression of EfnA5 in mGIC, and that the same mechanism is essential for GBM development in an allograft model. To confirm the translational potential of the BMI1/EFNA5 pathway we examined published RNA microarray, RNAseq and single-cell RNAseq datasets and found a significant inverse relationship between BMI1 and EFNA5. Finally, we show that BMI1 also regulates cell proliferation via repression of EFNA5 in primary human GIC in vitro.

Conclusions

We present evidence from a mouse model, human expression datasets and human primary cells showing that the Bmi1-EfnA5 pathway plays a prominent regulatory role in GIC. As the anti-proliferative role of BMI1 silencing is mediated by de-repression of EFNA5 in hGIC, precision targeting of Ephrin signalling, for example with agents that mimic EFNA5 action, could be an effective therapeutic tool in human GBM overexpressing BMI1.
Hippocampal sparing radiotherapy in adults with primary brain tumours: a comparative planning and dosimetric study using IMPT, IMRT and 3DCRT.
Authors: Patrice Aka Fleman , Taylor Roger , Hugtenburg Richard , Lambert Jamil , Powell James
Published: October 2019

Introduction

We assessed the feasibility of hippocampal sparing in adults with primary brain tumours using Intensity Modulated Proton Therapy (IMPT) and compared this with Intensity Modulated Radiotherapy (IMRT) and 3D-Conformal Radiotherapy (3DCRT).

Methods and Materials

20 patients were identified, and each patient underwent a radiotherapy planning CT scan and 2 MRI scans. A pre-operative diagnostic MRI scan was fused with the planning CT and used for target delineation and a dedicated 3T MRI scan at the time of planning was fused with the CT for hippocampus delineation.

3 hippocampal sparing plans were generated for each patient with specific prescriptions (54Gy/30 fractions, 60Gy/30 fractions and 59.4Gy/33 fractions) using IMPT, IMRT and 3DCRT. Hippocampal sparing was defined as median dose to contralateral hippocampus ≤25Gy without compromising target coverage and organ at risk dose constraints.

Results

Hippocampal sparing was achieved in 19 patients (95%) with IMPT, 16 patients (80%) with IMRT and 13 patients (65%) with 3DCRT. The largest median hippocampal dose reduction was seen with IMPT, with a mean median hippocampal dose of 4.8Gy (range: 0.0Gy-24.9Gy), 14.6Gy (range: 1.9Gy-21.7Gy), and 16.2Gy (range: 2.3Gy-25.0Gy) for IMPT, IMRT and 3DCRT respectively. Hippocampal sparing IMPT failed in one case with the largest tumour volume (650cc) where 2/3 of the hippocampus overlapped the target volume.

Conclusion

IMPT as compared to IMRT and 3DCRT plans showed a trend towards significant and effective hippocampal sparing in adult patients with primary brain tumours. We are currently evaluating this in a larger patient cohort and comparing IMPT with VMAT.
Survival and Seizure Control have improved for Adult Low-Grade Gliomas over the last eleven years
Authors: Solomons Matt , Weil Rimona , Jaunmuktan Zane , El-Hassan Tedani , Brandner Sebastian , Rees Jeremy
Published: October 2019

Background

There has been a trend towards earlier and more aggressive resection for adult Low-Grade Gliomas (LGG) in the last decade. This study set out to compare seizure control and survival of unselected adults with LGG seen in the same neuro-oncology clinic over 11 years and to determine if a change in surgical philosophy has led to a corresponding improvement in outcomes.

Methods

Retrospective analysis using case-note review of 153 adults with histologically verified or radiologically suspected LGG, collecting data on patient, tumour and seizure characteristics in 2006 and 2017.

Results

We studied 79 patients in 2006 and 74 patients in 2017. There were no significant differences between the two groups in age at presentation, tumour location or histological or molecular subtype. The numbers of complete or partial resections increased from 21.5 % in 2006 to 60.8% in 2017 (p<0.05). There was a highly significant improvement in 5- and 10-year survival from 81.8% and 51.7% in 2006 to 100% and 95.8% in 2017 (p<0.001); and a similar improvement was seen in progression free survival. The proportion of patients with intractable epilepsy reduced from 72.2% in 2006 to 43.2% in 2017 (p<0.05). The neurosurgical morbidity rate was identical in both groups (11.8% in 2006 vs 11.1% in 2017).

Conclusion

Increasing use of surgery for LGG over the last eleven years has led to substantial improvements in survival and seizure control but not at the cost of long-term morbidity.
Minimally invasive resection of brain metastases
Authors: Phang Isaac , Leach John , Leggate James , Karabatsou Konstatina , Coope David , D’Urso Pietro
Published: October 2019

Minimally invasive resection of brain metastases aims to maximize resection while minimizing brain trauma. Patients with one or more metastases resection following neuro-oncology multidisciplinary meeting discussion from Sep 2014 to Oct 2018 with pre- and post-operative MRI were included. All patients including posterior fossa metastases or multiple metastases were positioned supine. Hair was not shaved. Volumetric post-contrast T1 MRI was used for incision planning and neuronavigation. The craniotomy site was tailored to tumor depth according to keyhole principles and ranged between 2 to 3cm. Intraoperative monitoring and awake mapping were carried out in selected cases. Out of 320 consecutive patients with brain metastases, 44 patients were identified as suitable for minimally invasive resection. 9 had no post-operative imaging and were excluded. There were 39 metastases in 35 patients. There were 18 cerebellar metastases, 9 frontal, 5 parietal, 3 occipital, 2 temporal, 1 intraventricular and 1 basal ganglia. Median length of stay was days (range: 1 – 24). Average tumor volume was 54.7cm3 (range: 10 – 240cm3). Endoscopic assistance was used in 4 patients. Median performance status improved from 2 to 1(range: pre-operative: 0 – 4; post-operative: 0 – 2). Median survival was 14.7 months. Minimally invasive resection of brain metastasis is safe and effective and in selected cases confers advantages compared to standard techniques.
DNA methylation and transcriptomic alterations define distinct groups in pediatric spinal ependymoma
Authors: Ahmad Omar , Chapman Rebecca , Storer Lisa , Luo Li , Resar Linda , Cohen Kenneth , Grundy Richard , Lourdusamy Anbarasu
Published: October 2019

In contrast, compared to adults, spinal ependymomas (SEPN) are less common in childhood and adolescents. Children with these tumours are likely to experience a more aggressive disease course, with a higher rate of local failure, and a higher rate of metastasis. Presently the molecular basis of SEPN is poorly characterized. Therefore, we have analyzed 29 SEPN tumour samples from pediatric patients (female: 11, male: 15; age range: 4 – 21 years) and performed DNA methylation (n=28) and transcriptome profiling (n=29). Unsupervised analysis of methylation data reliably separated these tumours into two distinct groups: one group covering all myxopapillary ependymomas (MPE) and a second group dominated by grade II SPENs (SP-EPN). We identified 242 differentially methylated regions between these two groups, of which 56% showed high methylation levels in MPE, including 22 regions localized on chromosome 6. Genome-wide copy number analysis using methylation data showed differences in numbers and pattern of DNA copy number alterations between these groups. Gain of chromosome 20 (39%) followed by loss of chromosomes 6 (28%), 10 (28%), and 13 (28%) were detected in the MPE group, whereas loss of chromosome 22 was frequent (60%) in the SP-EPN group. Transcriptomic analysis showed that genes associated with oxidative phosphorylation, TCA cycle components, electron transport, and Interferon-gamma production characterize the MPE group whereas potassium ion import and regulation of astrocyte differentiation characterize the SP-EPN group. Taken together, this data suggest that mitochondrial oxidative phosphorylation may drive the regulation of energy metabolism of MPE tumours.
Using nanobiopsy of single brain tumour cells to investigate transcriptional reprogramming during standard treatment.
Authors: Elpidorou Marilena , Actis Paolo , Stead Lucy
Published: October 2019

Glioblastoma (GBM) is an incurable brain cancer because, despite aggressive standard treatment (consisting of surgery, radiation and Temozolomide chemotherapy), 100% of tumours recur. GBM tumours are characterised by significant intratumour heterogeneity, with genotypically or phenotypically distinct subpopulations of cells co-existing within each tumour. However, it is not yet known whether the inevitable recurrence of GBM is owing to Darwinian selection of inherently treatment resistant cells within the primary tumour, or the ability of cells to transcriptional reprogram and acquire treatment resistance properties. Knowing this is fundamental to developing more effective treatment for GBM: should we therapeutically target existing cells or their ability to reprogram? The only way to know this is to profile individual cells longitudinally, which has not been possible until now.

Here we present a pioneering technology, known as nanobiopsy, which can longitudinally track the transcriptional profile of single GBM cells through standard treatment. The nanobiopsy allows injection or extraction of cytoplasmic material by electrowetting. We have proved that this technique is able to sample cytoplasmic fractions from cells without killing them, giving us the advantage to capture the transcriptional changes occurring through treatment using optimised scRNA sequencing protocols. We are applying this novel technology to help us identify treatment resistance modes and mechanisms to reveal novel targets for drug development.
The ketogenic diet alters the epigenetic landscape of GBM to potentiate the effects of chemotherapy and radiotherapy
Authors: Zeng Qingyu , Stylianou Tzouliana , Preston Jessica , Glover Sophie , O’Neill Kevin , Woolf Eric C , Scheck Adrienne C , Syed Nelofer
Published: October 2019

Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumour, with a median survival of 12–14 months after diagnosis. Although GBM has been extensively characterised on the molecular level during the past decades, many targeted therapies have been proved to be ineffective due to high heterogeneity of GBM. Thus, novel therapies targeting the altered metabolism which is exhibited by all cancer cells have gained more attentions. Our strategy is the therapeutic ketogenic diet (KD), a high fat, low carbohydrate and adequate protein diet, which has been recognized as a treatment for refractory paediatric epilepsy. Recent studies have shown that KD reduces tumour growth and potentiates the effects of radiotherapy in some glioma animal models. However, the underlying mechanism is still unclear. To unravel the mechanism of action, we carried out small-RNA sequencing and chromatin modifying enzyme analysis using brain tumour samples from GBM mice model, fed with either KD or standard diet (SD). Our results highlighted an overall upregulation of tumour suppressor miRNAs and key chromatin modifying enzymes that are typically downregulated in GBM in mice fed with KD compared with those fed with SD. We also observed a corresponding downregulation in target genes of these miRNAs and chromatin modifying enzymes. These genes have been reported as key regulators in tumour growth, tumour invasion and chemo/radio-resistance in previous publications. Therefore, our study indicates that targeting cancer metabolism using the KD alters the epigenetic landscape of GBM and induces changes in key genes that potentiate the effects of chemo/radiotherapy.
Characterising a SOX2+ OLIG2+ glioma stem cell using Crispr-engineered fluorescent reporters in primary patient-derived GBM and DIPG cells.
Authors: Finlay Jack , Hallou Clement , Dewari Pooran , Pollard Steven , Pathania Manav , Bulstrode Harry , Rowitch David
Published: October 2019

Malignant glioma can be understood as a cancer stem cell disease. There is strong evidence that expression of a core set of neural stem cell master regulators is necessary and sufficient for tumour initiation in both adult and childhood disease subtypes, and across a range of underlying mutation signatures and expression profiles. We hypothesise that a double positive SOX2+ OLIG2+ progenitor is the cancer stem cell in H3K27M diffuse intrinsic pontine glioma (DIPG) and adult glioblastoma (GBM) alike. We present expression data in 4 patient-derived cell lines (2 adult GBM, 2 DIPG) in vitro and in a defined mutation mouse model of the H3K27M disease, demonstrating high expression levels of SOX2 and OLIG2 in serum-free culture and especially in the invasive tumour. We then demonstrate derivation of patient-derived human dual reporter lines, using a CRISPR targeting approach to add fluorescent reporters at the endogenous SOX2 and OLIG2 loci. With these tools, we aim to characterise the tumour-initiating potential of the SOX2+ OLIG2+ fraction. We further aim to identify cell surface markers whose expression is driven by this transcription program and which might represent targets for novel molecular therapies.
Characterisation of the metabolomes of epigenetically distinct subgroups of paediatric ependymoma
Authors: Woodward Alison , Abdelrazig Salah , Ortori Catharine , Barrett David , Grundy Richard , Kim Dong-Hyun , Rahman Ruman
Published: October 2019

Paediatric ependymoma relapses in up to half of patients, with a five-year survival rate of only 25%. Comprehensive characterisation of the genetic/epigenetic mutation and transcriptome landscape has not yet translated to improved treatments. Metabolomics is a functional genomic approach, offering an opportunity to elucidate aberrant metabolic pathways and new therapeutic avenues. Metabolomics thus far has concentrated on 1H High-resolution Magic Angle Spinning, Magnetic Resonance Spectroscopy and Raman Spectroscopy, where low numbers of metabolites were identified compared to that feasible by Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS).

Here we present broader metabolome coverage using LC-MS/MS to separately analyse ependymoma polar and non-polar metabolites, comparing two subgroups from distinct neuro-anatomical compartments with different genetic and epigenetic drivers. We homogenised surgically resected ependymoma tissue from two epigenetic subgroups, posterior fossa A (n=10) and supratentorial RELA fusion (n=5), and extracted polar metabolites and lipids using methanol/water/chloroform 1:1:3. LC-MS/MS using a quadrupole-Orbitrap revealed 167 putative metabolites and 400 putative lipids significantly altered in relative abundance between the two subgroups. The metabolites predominantly mapped onto the taurine and hypotaurine pathway. Grade II and III PF-A tumours could be distinguished by the abundances of 53 metabolites, with three metabolites in the protein-lysine degradation pathway increased in abundance.

The study presents a first-in-kind description of the paediatric ependymoma metabolome revealing PF-A and ST-RELA subgroups are metabolically distinct brain tumours and therefore warrant consideration of distinct anti-metabolite therapies. Paediatric ependymoma intra-tumour regions have been collected from 6 surgical resections and ongoing intra-tumour metabolomics/lipidomics integrated with transcriptomics will be discussed.
The Prevalence of BRAF Mutations in Patients with Glioma: A Systematic Review
Authors: Samir Saincher Saanwalshah , Higgins Julian P T , McAleenan Alexandra , Kurian Kathreena M
Published: October 2019

Background

The V600mutation in the v-raf murine sarcoma oncogene homologue B1 (BRAF) enzyme, is a potential clinically actionable target in gliomas. BRAF inhibitors are in wide clinical use for other tumour types, particularly melanoma. The prevalence of this mutation across all gliomas is not fully elucidated and is needed to inform potential screening and treatment.

Methods

A systematic review using articles on the MEDLINE and EMBASE databases (February 1, 2019) was carried out. A meta-analysis was conducted to calculate the prevalence of BRAF mutations in patients with gliomas across all populations and age groups in a clinical setting.

Preliminary Results

The review identified 75 studies including 6316 patients; the ages of participants ranged from 30 days to 90 years with a mean age of 32.75 years. Across all studies, the average prevalence of BRAF mutations was 16% (95% confidence interval (CI) from 12% to 20%) but estimates were highly variable across studies, ranging from 0% to 78%. The average prevalence of BRAF mutations in paediatric group was 15% (95% CI 10% to 20%) while the average prevalence in the adult group was 9% (95% CI 4% to 16%). Low grade gliomas had an average prevalence of 19% (95% CI 14% to 25%) compared with 7% (95% CI 4% to 11%) in high-grade gliomas.

Conclusions

BRAF mutations were found to be more prevalent in pediatric patients and in low grade gliomas. Screening these patients for BRAF mutations and treating them with BRAF inhibitors represents a promising area of future medical practice.
Factors affecting treatment strategy, completion of planned treatment and survival in older patients with glioblastoma
Authors: Goel Aimee , Shahabi Lillie , Narenthiran Ganesalingam , O’Neill Kevin , Peterson David , Nandi Dipankar , Williams Matthew , Saleem W , Falconer A , Camp Sophie
Published: October 2019

Introduction

For older patients with glioblastoma (GBM), age, extent of resection, and performance status are prognostic factors. However, an international survey conducted by our Unit found that >40% of neurosurgeons use age alone to discount surgery in older (65+) patients. The aim of this study was to review management in our Unit for 65+ GBM patients, to inform future approaches.

Methods

Patients 65+ with a new GBM diagnosis in our Unit, between 2014 and 2017, were identified. Demographic data, performance status (PS), comorbidity and frailty indices, together with details of surgical/oncological management and outcome were collected.

Results

78 patients were identified. 78% aged 65–74 underwent maximal safe resection, compared with 45% aged 75–84, and 10% aged 85+. Resection was undertaken in 68% PS1, 73% PS2 and 23% PS3 patients. No PS3 patient completed intended radiotherapy, compared with 79% PS1 and 74% PS2 patients. There was a significant difference in frailty scores of patients who completed scheduled oncological therapy compared with those who did not (median score 2 vs 4.5, p=0.0338).

Median survival was 10 months for patients 65–74, 4 months for aged 75 -84, and 40 days for 85+ (p<0.0167). Median survival was significantly lower for PS3 patients (44 days) compared with PS1 or 2 (9.5 months and 7 months respectively; p<0.0167).

Conclusion

There is considerable variability in performance status and frailty of 65+ GBM patients. PS3 patients at diagnosis are very unlikely to complete oncological treatment. These factors, rather than age alone, should be used to guide management decisions.
Glioblastoma multiforme in patients over 65 – should we operate?
Authors: Maleyko Igor , Hall Benjamin , Brodbelt Andrew , Lawson David , Jenkinson Michael , Chavredakis Emmanuel
Published: October 2019

Aim

Current standard of care for glioblastoma is maximum safe resection followed by radio chemotherapy with Temozolomide. Older patients are less likely to receive the full treatment. The aim was to determine treatment and outcomes in glioblastoma patients >65 years.

Methods

Single centre retrospective study from 2001–2016. Eligible patients had: (i) diagnosis of glioblastoma (ii) undergone biopsy or resection with radiotherapy ± adjuvant chemotherapy. Age at diagnosis, type of surgery, performance status, complications, adjuvant therapy and median survival (MS) were recorded. Patients were assigned to group A (age <65), B (age 65–69 years) or C (age >/= 70 years).

Results

637 patients met the eligibility criteria and 403 had complete records for analysis. Age distribution of the cohort was 17.9 – 91.6 years.

In the group A (n=259), those who had undergone resection had significantly longer MS compared to biopsy: 17.2 vs 13.2 months (P<0.05 CI: 444.043 – 561.957). 70 patients developed complications.

In the group B (n=79), those who had undergone resection had significantly longer MS compared to biopsy: 12.3 vs 5.1 months (P<0.05 CI: 194.354 – 335.646). 17 patients developed complications.

In the group C (n=64), analysis did not show statistically significant difference (P=0.066 CI: 220.476 – 321.524). Clinically, patients who had resection had longer MS (10.5 months vs 3.5 months). Furthermore, there was no significant difference in the rate of complications between resection and biopsy (Fisher’s exact test, P=0.755).

Conclusion

i) Patients >65 should be treated as per the Stupp protocol ii) In patients >70 surgical resection should be considered.:
Nanotherapeutics for neurosurgically-applied drug delivery
Authors: Vasey Catherine , Taresco Vincenzo , Smith Stuart , Alexander Cameron , Rahman Ruman
Published: October 2019

Despite multimodal treatment, the median survival of Glioblastoma multiforme (GBM) remains less than 15 months, in considerable part due to diffusely infiltrative disease. Better treatment methods are necessary to eradicate residual tumour burden remaining beyond the resection cavity boundary. Based on an increasing understanding of GBM intra-tumour heterogeneity, the capability to deliver multiple therapeutic moieties from single formulations is clinically-relevant. It is hypothesised that incorporating drug-loaded polymer pro-drugs, which are capable of transcytotic ‘hopping’, into a biodegradable microparticulate paste will lead to efficacious local delivery.

Here we report the formulation of numerous self-assembling cytocompatible nanoparticles, based on different linear and branched polymeric architectures. The polymers were synthesised by ring opening polymerisation with organic catalysts, leading to controlled reaction kinetics and greater potential biomedical applicability. We demonstrated that copolymerisation of a monomer with functional capability enabled the successful conjugation of doxorubicin to the polymer chain. We hypothesised that polymers with a greater degree of branching over traditional linear structures would lead to greater drug loading, and successfully tested this hypothesis through the encapsulation of olaparib.

We will discuss strategies to incorporate: i) pH-sensitive linkers to the polymeric backbone, which would allow controlled drug release in acidic microenvironments; ii) multiple combined chemotherapeutics, including doxorubicin and olaparib. Future work will assess the efficacy of the polymer pro-drugs against primary GBM lines derived from the invasive margin and safety/efficacy using orthotopic syngeneic allografts.

This is the first study incorporating polymer pro-drugs of this type into an existing localised micro-scale delivery system for GBM therapies.
Spontaneous glioma-induced seizures recorded in a living human brain tissue preparation
Authors: Kirby Alastair , Pedro Lavrador Jose , Brogna Christian , Vergani Francesco , Zebian Bassel , Chandler Christopher , Bodi Istvan , Bhangoo Ranjeev , Keyoumars Ashkan , Finnerty Gerald
Published: October 2019

Gliomas often present clinically with seizures. Tumour-associated seizures can be difficult to control with medication. A deeper understanding of the cellular mechanisms underlying tumour-associated seizures would provide a basis for developing new treatments. Here, we investigate epileptic discharges in peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II – III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the seizure-like discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.
Relationship between travel time to primary and tertiary care centres and survival in glioblastoma: the NHS Grampian experience.
Authors: Veljanoski Damjan , Barlas Raphae , Jamjoom Aimun , Myint Phyo
Published: October 2019

Background

Studies have demonstrated a distance-decay effect, whereby patients who live further away from their healthcare facility have poorer health outcomes. The geographical catchment area served by the neurosurgical unit in Aberdeen, Grampian region, Scotland is one of the largest in the UK. We aimed to examine the relationship between travel time as a proxy of distance travelled, and survival outcome for glioblastoma.

Methods

We conducted a retrospective, cohort analysis of patients with glioblastoma referred for treatment from January 2009 to December 2018. Travel time was calculated from the patients’ home to their general practitioner (GP) and to the neurosurgical unit. Logistic regression models were constructed to estimate survival at three, six and 12 months, as well as treatment within 62 days of GP referral, and within 31 days of diagnosis controlling for age, sex and treatment type.

Results

There were 195 patients (mean age (SD) 64.4 ± 12.9 years)57.9% were men, 65.1% were treated surgically, and 48.2% were alive after one year. Longer time travelled to GP, but not to tertiary care centre, was associated with reduced odds of mortality at three months (OR 0.88 95%CI 0.79–0.98; p=0.005) and six months (OR 0.92 95%CI 0.85–0.99; p=0.01), for each incremental increase in one minute.

Conclusions

Patients with glioblastoma with longer travel times to their GP were more likely to be alive at three months and six months. Further work is required to identify other factors, including degrees of socio-economic deprivation and rurality, which may influence this finding.
A tale of two water markets in Australia: lessons for understanding participation in formal water markets
Authors: Ann Wheeler Sarah , Garrick Dustin E
Published: October 2019

Water markets are promoted as a demand-management strategy for addressing water scarcity. Although there is an increasing literature on the institutional preconditions required for successful formal water markets, there has been less focus on understanding what drives participation after establishment of the basic enabling conditions. Participation can be measured in terms of either trading activity (conducting either a permanent or temporary water trade) and/or trade volumes across time and market products. Australia’s water markets in the Southern and Northern Basins of the Murray-Darling Basin provide a notable example of a ‘tale of two water markets’, offering insights about the economic policy levers that can drive participation across different hydrological, irrigation, and socioeconomic contexts. Key lessons include: distribution of initial property rights in resource allocation; the need to prepare for and seize opportunities to strengthen property rights; and robust monitoring and compliance requirements—all of which will reduce transaction costs and increase participation.
Potassium disturbance associated with an inpatient childhood asthma pathway
Authors: Hung Jonathan , Kraft Timothy , Seefried Brent , Johnson David W , Bailey Michelle , Dersch-Mills Deonne
Published: October 2019

Background

Paediatric asthma exacerbations in Alberta are treated via standardized order sets known as the Alberta Acute Childhood Asthma Pathway (ACAP). This pathway is utilized in paediatric tertiary hospitals and in remote and rural locations. Incidence, magnitude, and risk factors for hypokalemia in inpatients receiving salbutamol for asthma exacerbations via this pathway are presently unknown.

Objective

Establish incidence, magnitude, and risk factors for hypokalemia associated with salbutamol therapy as directed by a paediatric asthma pathway.

Methods

Retrospective cohort study using visit-level electronic medical data. Inpatients aged <18 years old receiving salbutamol via the ACAP with at least one potassium level were included. Hypokalemia was defined as mild (3.0 ≤ [K+] < 3.5 mEq/L), moderate (2.5 ≤ [K+] < 3.0 mEq/L), or severe ([K+] < 2.5 mEq/L), as measured in serum or blood gas. Binomial logistic regression was utilized to examine risk factors for hypokalemia, route of administration, location of lowest [K+], nil per os (NPO) status during admission, potassium supplementation, gender, and age.

Results

There were 821 patients screened for analysis and 433 patients were analyzed after exclusions. There was an incidence of hypokalemia of 38.8%. Of patients experiencing hypokalemia, 71.4% were mild, 25.6% moderate, and 3.0% severe. Risk factors included nebulized salbutamol, patient location (emergency department or paediatric intensive care unit), and age (>5 years) although these risk factors may actually represent patients receiving higher doses of salbutamol.

Conclusions

The majority of the 38.8% of children experiencing hypokalemia associated with the ACAP were mild. Routine monitoring of potassium status in children receiving salbutamol per standardized pathway is recommended for children with described risk factors, and ideally within the first 12 hours of presentation.
Optimal Dynamic Carbon Taxes in a Climate–Economy Model with Distortionary Fiscal Policy
Authors: Barrage Lint
Published: October 2019

How should carbon be taxed as a part of fiscal policy? The literature on optimal carbon pricing often abstracts from other taxes. However, when governments raise revenues with distortionary taxes, carbon levies have fiscal impacts. While they raise revenues directly, they may shrink the bases of other taxes (e.g. by decreasing employment). This article theoretically characterizes and then quantifies optimal carbon taxes in a dynamic general equilibrium climate–economy model with distortionary fiscal policy. First, this article establishes a novel theoretical relationship between the optimal taxation of carbon and of capital income. This link arises because carbon emissions destroy natural capital: they accumulate in the atmosphere and decrease future output. Consequently, this article shows how the standard logic against capital income taxes extends to distortions on environmental capital investments. Second, this article characterizes optimal climate policy in sub-optimal fiscal settings where income taxes are constrained to remain at their observed levels. Third, this article presents a detailed calibration that builds on the seminal DICE approach but adds features essential for a setting with distortionary taxes, such as a differentiation between climate change production impacts (e.g. on agriculture) and direct utility impacts (e.g. on biodiversity existence value). The central quantitative finding is that optimal carbon tax schedules are 8–24% lower when there are distortionary taxes, compared to the setting with lump-sum taxes considered in the literature.
LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation
Authors: Christ Annabel , Willnow Thomas E.
Published: October 2019

Conotruncal malformations are a major cause of congenital heart defects in newborn infants. Recently, genetic screens in humans and mouse models have identified mutations inLRP2as a novel cause of a common arterial trunk, a severe form of outflow tract (OFT) defect. Yet, the underlying mechanism why the morphogen receptor LRP2 is essential for OFT development remained unexplained. Studying LRP2-deficient mouse models, we now show that LRP2 is expressed in the cardiac progenitor niche of the anterior second heart field (SHF) that contributes to elongation of the OFT during separation into aorta and pulmonary trunk. Loss of LRP2 in mutant mice results in depletion of a pool of sonic hedgehog-dependent progenitor cells in the SHF due to premature differentiation into cardiomyocytes as they migrate into the OFT myocardium. Depletion of this cardiac progenitor cell pool results in aberrant shortening of the OFT, the cause of CAT formation in affected mice. Our findings identified the molecular mechanism whereby LRP2 controls maintenance of progenitor cell fate in the anterior SHF essential for OFT separation, and why receptor dysfunction is a novel cause of conotruncal malformation.
Single-cell RNA sequencing of adultDrosophilaovary identifies transcriptional programs governing oogenesis
Authors: Jevitt Allison , Chatterjee Deeptiman , Xie Gengqiang , Wang Xian-Feng , Otwell Taylor , Huang Yi-Chun , Deng Wu-Min
Published: October 2019

Oogenesis is a complex developmental process that involves spatiotemporally regulated coordination between the germline and supporting, somatic cell populations. This process has been modelled extensively using theDrosophilaovary. While different ovarian cell types have been identified through traditional means, the large-scale expression profiles underlying each cell type remain unknown. Using single-cell RNA sequencing technology, we have built a transcriptomic dataset for the adultDrosophilaovary and connected tissues. This dataset captures the entire transcriptional trajectory of the developing follicle cell population over time. Our findings provide detailed insight into processes such as cell-cycle switching, migration, symmetry breaking, nurse cell engulfment, egg-shell formation, and signaling during corpus luteum formation, marking a newly identified oogenesis-to-ovulation transition. Altogether, these findings provide a broad perspective on oogenesis at a single-cell resolution while revealing new genetic markers and fate-specific transcriptional signatures to facilitate future studies.
Insulator proteins contribute to expression of gene loci repositioned into heterochromatin in the course ofDrosophilaevolution
Authors: Funikov Sergei Yu. , Rezvykh Alexander P. , Kulikova Dina A. , Zelentsova Elena S. , Chuvakova Lyubov N. , Tyukmaeva Venera I. , Arkhipova Irina R. , Evgen’ev Michael B.
Published: October 2019

Pericentric heterochromatin inDrosophilais generally composed of repetitive DNA forming a transcriptionally repressive environment. Nevertheless, dozens of genes were embedded into pericentric genome regions during evolution ofDrosophilidaelineage and retained functional activity. However, factors that contribute to “immunity” of these gene loci to transcriptional silencing remain unknown. Here, we investigated molecular evolution of the essentialMybandRanbp16genes. These protein-coding genes reside in euchromatic loci of chromosome X inD. melanogasterand related species, while in other studiedDrosophilaspecies, including evolutionary distant ones, they are located in genomic regions highly enriched with the remnants of transposable elements (TEs), suggesting their heterochromatic nature and location. The promoter region ofMybexhibits a conserved structure throughout theDrosophilaphylogeny and carries motifs for binding of chromatin remodeling factors, including insulator BEAF-32, regardless of eu- or heterochromatic surroundings. Importantly, BEAF-32 occupies not only the promoter region ofMybbut is also found in the vicinity of transcriptional start sites (TSS) ofRanbp16gene as well as in a wide range of genes located in the contrasting chromatin types inD. melanogasterandD. virilis,denoting the boundary of the nucleosome-free region available for RNA polymerase II recruitment and the surrounding heterochromatin. We also find that along with BEAF-32, insulators dCTCF and GAF are enriched at the TSS of heterochromatic genes inD. melanogaster. Thus, we propose that insulator proteins contribute to gene expression in the heterochromatic environment and, hence, facilitate the evolutionary repositioning of gene loci into heterochromatin.

Author summary

Heterochromatin inDrosophilais generally associated with transcriptional silencing. Nevertheless, hundreds of essential genes have been identified in the pericentric heterochromatin ofDrosophila melanogaster. Interestingly, genes embedded in pericentric heterochromatin ofD. melanogastermay occupy different genomic loci, euchromatic or heterochromatic, due to repositioning in the course of evolution ofDrosophilaspecies. By surveying factors that contribute to the normal functioning of the relocated genes in distantDrosophilaspecies, i.e.D. melanogasterandD. virilis, we identify certain insulator proteins (e.g.BEAF-32) that facilitate the expression of heterochromatic genes in spite of the repressive environment.
Removal of calcifications from distal canals of mandibular molars by a non‐instrumentational cleaning system: A micro‐CT study
Authors: Chen Binwen , Szabo Deb , Shen Ya , Zhang Duo , Li Xianyu , Ma Jingzhi , Haapasalo Markus
Published: October 2019

Pulpal calcifications can present problems in endodontic treatment. This micro‐CT study examined the removal of calcifications by a multisonic cleaning system in uninstrumented mandibular molar distal canals. The teeth were accessed and distal canals located and their patency ensured. Micro‐CT images were obtained, and 15 teeth with distal canal calcifications were selected. The volume of distal canals and calcifications were calculated from the micro‐CT images before and after cleaning with the GentleWave system. Calcifications were observed in all thirds of the canals. Attached and free calcification were detected. Root canal volumes were slightly increased after GentleWave treatment, whereas the calcifications were completely or partially removed in all canals. Mean reduction percentage of calcification was 86.4 ± 3.9%, in individual canals from 60% to 100%. Calcifications in the distal canals of mandibular molars could be partially or completely removed by the multisonic cleaning system without instrumentation.
Economywide effects of climate‐smart agriculture in Ethiopia
Authors: Komarek Adam M. , Thurlow James , Koo Jawoo , De Pinto Alessandro
Published: October 2019

Climate‐smart agriculture (CSA) is an approach for transforming and reorienting agricultural systems to support food security under climate change. Few studies, however, quantify at the national scale CSA's economic effects or compare CSA to input‐intensive technologies, like fertilizer or irrigation. Such quantification may help with priority setting among competing agricultural investment options. Our study uses an integrated biophysical and economic modeling approach to quantify and contrast the economywide effects of CSA (integrated soil fertility management in our study) and input‐intensive technologies in Ethiopia's cereal systems. We simulate impacts for 20‐year sequences of variable weather, with and without climate change. Results indicate that adopting CSA on 25% of Ethiopia's maize and wheat land increases annual gross domestic product (GDP) by an average 0.18% (US$49.8 million) and reduces the national poverty rate by 0.15 percentage points (112,100 people). CSA is more effective than doubling fertilizer use on the same area, which increases GDP by US$33.0 million and assists 75,300 people out of poverty. CSA and fertilizer have some substitutability, but CSA and irrigation appear complementary. Although not a panacea for food security concerns, greater adoption of CSA in Ethiopia could deliver economic gains but would need substantial tailoring to farmer‐specific contexts.
New insights into the sensitization to nonspecific lipid transfer proteins from pollen and food: New role of allergen Ole e 7
Authors: Oeo‐Santos Carmen , Navas Ana , Benedé Sara , Ruíz‐León Berta , Díaz‐Perales Araceli , Vogel Lothar , Moreno‐Aguilar Carmen , Jurado Aurora , Villalba Mayte , Barderas Rodrigo
Published: October 2019

Background

Ole e 7 is a nonspecific lipid transfer protein (nsLTP) from olive pollen, one of the main allergenic pollens worldwide. This allergenic nsLTP is responsible for severe symptoms in regions with high olive pollen exposure, where many Ole e 7‐sensitized patients exhibit a co‐sensitization to the peach nsLTP, Pru p 3. However, there is no evidence of cross‐reactivity, which explains this observed co‐sensitization. Therefore, the purpose of this study was to explore the relationship between Ole e 7 and Pru p 3.

Methods

A total of 48 patients sensitized to Ole e 7 and/or Pru p 3 were included in the study. Specific IgE serum levels were measured by ImmunoCAP 250 and ELISA. Inhibition assays were performed to determine the existence of cross‐reactivity between both nsLTPs. Allergic response was analyzed ex vivo (basophil activation test) and in vitro (RBL‐2H3 mast cell model).

Results

Common IgG and IgE epitopes were identified between both allergens. IgE‐binding inhibition was detected in Ole e 7–monosensitized patients using rPru p 3 as inhibitor, reaching inhibition values of 25 and 100%. Ex vivo and in vitro assays revealed a response against rPru p 3 in four (31%) Ole e 7–monosensitized patients.

Conclusions

Our results suggest that Ole e 7 could play a new role as primary sensitizer in regions with high olive pollen exposure, leading to the peach nsLTP sensitization. This co‐sensitization process would occur because of the cross‐reactivity between Ole e 7 and Pru p 3 observed in some allergic patients.
Temporal changes of noninvasive electrocardiographic risk factors for sudden cardiac death in post‐myocardial infarction patients with preserved ejection fraction: Insights from the PRESERVE‐EF study
Authors: Xenogiannis Iosif , Gatzoulis Konstantinos A. , Flevari Panagiota , Ikonomidis Ignatios , Iliodromitis Efstathios , Trachanas Konstantinos , Vlachos Konstantinos , Arsenos Petros , Tsiachris Dimitrios , Tousoulis Dimitrios , Brilakis Emmanouil S. , Alexopoulos Dimitrios
Published: October 2019

Background

Several noninvasive risk factors (NIRFs) have been proposed for sudden cardiac death risk stratification in post‐myocardial infarction (post‐MI) patients with preserved ejection fraction (EF). However, it remains unclear if these factors change over time.

Methods

We evaluated seven electrocardiographic NIRFs as they were described in the PRESERVE‐EF trial in 80 post‐MI patients with EF ≥ 40%, at least 40 days after revascularization and 1 year later.

Results

Mean patient age was 56 ± 10 years, and 88% were men. Mean EF was 50 ± 5%. The prevalence of (a) positive late potentials (27.5% vs. 28.8%, p = .860), (b) >30 premature ventricular complexes/hour (8.8% vs. 11.3%, p = .598), (c) nonsustained ventricular tachycardia (8.8% vs. 5%, p = .349), (d) standard deviation of normal RR intervals <75 ms (3.8% vs. 3.8%, p = 1.000), (e) QTc derived from 24‐hr electrocardiography >440 ms (men) or >450 ms (women) (17.5% vs. 17.5%, p = 1.000), (f) deceleration capacity ≤4.5 ms and heart rate turbulence onset ≥0% and slope ≤2.5 ms (2.5% vs. 3.8%. p = 1.000), and (g) ambulatory T‐wave alternans ≥65 μV in two Holter channels (6.3% vs. 6.3%, p = 1.000) were similar between the two measurements. However, five patients (6.3%) without any NIRFs during the first assessment had at least one positive NIRF at the second assessment and six patients (7.5%) with at least one NIRF at baseline had no positive NIRFs at 1 year.

Conclusions

While the prevalence of the examined electrocardiographic NIRFs between the two examinations was similar on a population basis, some patients without NIRFs at baseline developed NIRFs at 1 year and vice versa, highlighting the need for risk factor reassessment during follow‐up.
ADHD and Brain Anatomy: What Do Academic Textbooks Used in the Netherlands Tell Students?
Authors: te Meerman Sanne , Batstra Laura , Freedman Justin E. , Hoekstra Rink , Grietens Hans
Published: October 2019

Studies of brain size of children classified with ADHD appear to reveal smaller brains when compared to ‘normal’ children. Yet, what does this mean? Even with the use of rigorously screened case and control groups, these studies show only small, average group differences between children with and without an ADHD classification. However, academic textbooks used in the Netherlands often portray individual children with an ADHD classification as having a different, malfunctioning brain that necessitates medical intervention. This conceptualisation of ADHD might serve professional interests, but not necessarily the interests of children.
Inter‐sonographer reproducibility of carotid ultrasound plaque detection using Mannheim consensus in subclinical atherosclerosis
Authors: Nyman Emma , Vanoli Davide , Näslund Ulf , Grönlund Christer
Published: October 2019

Aims

To determine the inter‐sonographer reproducibility of carotid ultrasound plaque detection using Mannheim consensus in a subclinical population and evaluate associations related to the reproducibility.

Methods and results

Bilateral ultrasound screening for carotid plaques defined by Mannheim consensus was performed on 106 subclinical participants. Two different sonographers scanned the same participant, and reproducibility of plaque detection was measured by Cohens kappa. Associations with reproducibility were evaluated by comparing wall, and plaque characteristics between subjects with plaques identified in one and both scans. In general, the inter‐sonographer reproducibility of plaque detection was substantial with a kappa value of 0·70 (95% CI 0·60–0·80). Plaques detected in only one scan had significantly lower plaque area and plaque thickness (6·82 mm2 and 1·45 mm) as compared to plaques detected in both scans (11·65 mm2 and 1·96 mm, P<0·001).

Conclusion

Minor carotid plaques contribute to decreased reproducibility as compared to large plaques when screening for subclinical atherosclerosis using Mannheim consensus. Using an alternative plaque definition based on plaque thickness >1.5 mm and plaque area >10 mm2 could increase the reproducibility of plaque detection in subclinical atherosclerosis.