bluuebunny/crossref_metadata_2025 huggingface dataset:
Coalescence-induced droplet spreading: Experiments aboard the International Space Station
Authors: McCraney J. , Ludwicki J. , Bostwick J. , Daniel S. , Steen P.
Published: October 2022

We report experiments of centimeter-sized sessile drop coalescence aboard the International Space Station, where microgravity conditions enable inertial-capillary spreading motions to be explored for a range of hydrophobic wetting conditions. Observations of the time traces of the coalescence event and projected areas compare favorably to numerical simulations, which employ the Davis–Hocking contact line (CL) condition with contact line mobility M parameter independently measured using the resonant-frequency scan technique of Xia and Steen [“Moving contact-line mobility measured,” J. Fluid Mech. 841, 767–783 (2018)]. This observation suggests that M is a material parameter, and that the Davis–Hocking model is an appropriate CL model for inertial-capillary spreading.
Rapid identification of a major locus qPRL-C06 affecting primary root length in Brassica napus by QTL-seq
Authors: Wang Wei , Liu Haijiang , Xie Yiwen , King Graham John , White Philip John , Zou Jun , Xu Fangsen , Shi Lei
Published: October 2022

Background and Aims

Brassica napus is one of the most important oilseed crops worldwide. Seed yield of B. napus significantly correlates with the primary root length (PRL). The aims of this study were to identify quantitative trait loci (QTLs) for PRL in B. napus.

Methods

QTL-seq and conventional QTL mapping were jointly used to detect QTLs associated with PRL in a B. napus double haploid (DH) population derived from a cross between ‘Tapidor’ and ‘Ningyou 7’. The identified major locus was confirmed and resolved by an association panel of B. napus and an advanced backcross population. RNA-seq analysis of two long-PRL lines (Tapidor and TN20) and two short-PRL lines (Ningyou 7 and TN77) was performed to identify differentially expressed genes in the primary root underlying the target QTLs.

Key Results

A total of 20 QTLs impacting PRL in B. napus grown at a low phosphorus (P) supply were found by QTL-seq. Eight out of ten QTLs affecting PRL at a low P supply discovered by conventional QTL mapping could be detected by QTL-seq. The locus qPRL-C06 identified by QTL-seq was repeatedly detected at both an optimal P supply and a low P supply by conventional QTL mapping. This major constitutive QTL was further confirmed by regional association mapping. qPRL-C06 was delimited to a 0.77 Mb genomic region on chromosome C06 using an advanced backcross population. A total of 36 candidate genes within qPRL-C06 were identified that showed variations in coding sequences and/or exhibited significant differences in mRNA abundances in primary root between the long-PRL and short-PRL lines, including five genes involved in phytohormone biosynthesis and signaling.

Conclusions

These results both demonstrate the power of the QTL-seq in rapid QTL detection for root traits and will contribute to marker-assisted selective breeding of B. napus cultivars with increased PRL.
Large-scale lesion symptom mapping of depression identifies brain regions for risk and resilience
Authors: Trapp Nicholas T , Bruss Joel E , Manzel Kenneth , Grafman Jordan , Tranel Daniel , Boes Aaron D
Published: October 2022

Understanding neural circuits that support mood is a central goal of affective neuroscience, and improved understanding of the anatomy could inform more targeted interventions in mood disorders. Lesion studies provide a method of inferring the anatomical sites causally related to specific functions, including mood. Here, we performed a large-scale study evaluating the location of acquired, focal brain lesions in relation to symptoms of depression. Five hundred and twenty-six individuals participated in the study across two sites (356 male, average age 52.4 ± 14.5 years). Each subject had a focal brain lesion identified on structural imaging and an assessment of depression using the Beck Depression Inventory-II, both obtained in the chronic period post-lesion (>3 months). Multivariate lesion–symptom mapping was performed to identify lesion sites associated with higher or lower depression symptom burden, which we refer to as ‘risk’ versus ‘resilience’ regions. The brain networks and white matter tracts associated with peak regional findings were identified using functional and structural lesion network mapping, respectively. Lesion–symptom mapping identified brain regions significantly associated with both higher and lower depression severity (r = 0.11; P = 0.01). Peak ‘risk’ regions include the bilateral anterior insula, bilateral dorsolateral prefrontal cortex and left dorsomedial prefrontal cortex. Functional lesion network mapping demonstrated that these ‘risk’ regions localized to nodes of the salience network. Peak ‘resilience’ regions include the right orbitofrontal cortex, right medial prefrontal cortex and right inferolateral temporal cortex, nodes of the default mode network. Structural lesion network mapping implicated dorsal prefrontal white matter tracts as ‘risk’ tracts and ventral prefrontal white matter tracts as ‘resilience’ tracts, although the structural lesion network mapping findings did not survive correction for multiple comparisons. Taken together, these results demonstrate that lesions to specific nodes of the salience network and default mode network are associated with greater risk versus resiliency for depression symptoms in the setting of focal brain lesions.
The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants
Authors: Williams C L , Fareed R , Mortimer G L M , Aitken R J , Wilson I V , George G , Gillespie K M , Williams A J K ,   The BOX Study Group, Ballav Chitrabhanu , Dutta Atanu , Russell-Taylor Michelle , Besser Rachel , Bursell James , Chandran Shanthi , Patel Sejal , Smith Anne , Kenchaiah Manohara , Margabanthu Gomathi , Kavvoura Foteini , Yaliwal Chandan , Long A E
Published: October 2022

The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range −1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01–-0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.
Feeding mediated web-building plasticity in a cobweb spider
Authors: Zhang Haixin , Li Gang , Li Changchun , Chen Jian , Zhao Zeyu , Zhang Shichang , Liu Jie
Published: October 2022

Behavioral plasticity has been proposed as a means by which animals alter their phenotypes in response to changing conditions. Animals may display behavioral plasticity as a consequence of environmental variation. The detritus-based, bell-shaped cobweb spider Campanicola campanulata is an ideal model to study behavioral plasticity, because its web architecture is easy to be quantified, and the functions of different parts of the web are clear. Though the plasticity of cobweb architecture has been reported in a few species, retreats as important defensive structures have rarely been considered before because retreats in most cobwebs are relatively small compared with the web size. We studied the web-building behaviors of C. campanulata under different feeding regimes. We set up 3 spider treatments with different feeding conditions: marginally well fed, moderately well fed, and extremely well fed, and observed the differences in the web architecture among them. In addition, we measured the mechanical properties of anchor silk, and also calculated the foraging and defense investment of the spiders. The results showed that marginally well-fed spiders build cobwebs with significantly longer length of anchor silk, lower retreat to the ground, more number and longer gumfooted lines, and larger capture area, while extremely well-fed spiders build cobwebs with significantly bigger retreat volume and higher height of retreat to the ground. In addition, marginally well-fed spiders invest significantly less during cobweb construction. However, there was no significant difference between the breaking force and elongation at break in anchor silk among different treatments. These results demonstrated that marginally well-fed spiders invest more in foraging, and extremely well-fed spiders invest more in defense, and the spider made a balance between foraging and predator avoidance in response to changes in physiological state. Our study strengthens the current understanding of web construction in cobweb spiders, especially those facing high costs during retreat construction.
Values of spleen-preserving distal pancreatectomy in well-differentiated non-functioning pancreatic neuroendocrine tumors: a comparative study
Authors: Huang Xi-Tai , Xie Jin-Zhao , Cai Jian-Peng , Fang Peng , Huang Chen-Song , Chen Wei , Liang Li-Jian , Yin Xiao-Yu
Published: October 2022

Background

The feasibility of spleen-preserving distal pancreatectomy (SPDP) to treat well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-pNETs) located at the body and/or tail of the pancreas remains controversial. Distal pancreatectomy with splenectomy (DPS) has been widely applied in the treatment of NF-pNETs; however, it may increase the post-operative morbidities. This study aimed to evaluate whether SPDP is inferior to DPS in post-operative outcomes and survivals when being used to treat patients with NF-pNETs in our institute.

Methods

Clinicopathological features of patients with NF-pNETs who underwent curative SPDP or DPS at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2010 and January 2022 were collected. Short-term outcomes and 5-year survivals were compared between patients undergoing SPDP and those undergoing DPS.

Results

Sixty-three patients (SPDP, 27; DPS, 36) with well-differentiated NF-pNETs were enrolled. All patients had grade 1/2 tumors. After identifying patients with T1–T2 NF-pNETs (SPDP, 27; DPS, 15), there was no disparity between the SPDP and DPS groups except for tumor size (median, 1.4 vs 2.6 cm, P = 0.001). There were no differences in operation time (median, 250 vs 295 min, P = 0.478), intraoperative blood loss (median, 50 vs 100 mL, P = 0.145), post-operative major complications (3.7% vs 13.3%, P = 0.287), clinically relevant post-operative pancreatic fistula (22.2% vs 6.7%, P = 0.390), or post-operative hospital stays (median, 9 vs 9 days, P = 0.750) between the SPDP and DPS groups. Kaplan–Meier curve showed no significant differences in the 5-year overall survival rate (100% vs 100%, log-rank P > 0.999) or recurrence-free survival (100% vs 100%, log-rank P > 0.999) between patients with T1–T2 NF-pNETs undergoing SPDP and those undergoing DPS.

Conclusions

In patients with T1–T2 well-differentiated NF-pNETs, SPDP could achieve comparable post-operative outcomes and prognosis compared with DPS.
Using health policy and systems research to influence national health policies: lessons from Mexico, Cambodia and Ghana
Authors: Strachan Daniel Llywelyn , Teague Kirsty , Asefa Anteneh , Annear Peter Leslie , Ghaffar Abdul , Shroff Zubin Cyrus , McPake Barbara
Published: October 2022

Health system reforms across Africa, Asia and Latin America in recent decades demonstrate the value of health policy and systems research (HPSR) in moving towards the goals of universal health coverage in different circumstances and by various means. The role of evidence in policy making is widely accepted; less well understood is the influence of the concrete conditions under which HPSR is carried out within the national context and which often determine policy outcomes. We investigated the varied experiences of HPSR in Mexico, Cambodia and Ghana (each selected purposively as a strong example reflecting important lessons under varying conditions) to illustrate the ways in which HPSR is used to influence health policy. We reviewed the academic and grey literature and policy documents, constructed three country case studies and interviewed two leading experts from each of Mexico and Cambodia and three from Ghana (using semi-structured interviews, anonymized to ensure objectivity). For the design of the study, design of the semi-structured topic guide and the analysis of results, we used a modified version of the context-based analytical framework developed by Dobrow et al. (Evidence-based health policy: context and utilisation. Social Science & Medicine 2004;58:207–17). The results demonstrate that HPSR plays a varied but essential role in effective health policy making and that the use, implementation and outcomes of research and research-based evidence occurs inevitably within a national context that is characterized by political circumstances, the infrastructure and capacity for research and the longer-term experience with HPSR processes. This analysis of national experiences demonstrates that embedding HPSR in the policy process is both possible and productive under varying economic and political circumstances. Supporting research structures with social development legislation, establishing relationships based on trust between researchers and policy makers and building a strong domestic capacity for health systems research all demonstrate means by which the value of HPSR can be materialized in strengthening health systems.
Taking global administrative law one step ahead: Online giants and the digital democratic sphere
Authors: Fischman-Afori Orit
Published: October 2022

Societal speech activities are increasingly conducted online, and therefore free speech concerns focus on the digital sphere. Major online service platforms operate speech-moderation practices that constrain digital speech. These platforms are run by a few multinational corporations—the so-called online giants. Online giants, in fact, control the backbone of democracies on a global scale. This article stresses a potential legal path to appropriately regulating digital speech, while preserving the free and thriving global digital culture. The argument introduced here is that the online giants should, to a certain extent, emulate global organizations, and since they control an essential public utility, they should operate under basic administrative legal norms that include accountability, transparency, giving reason, and objective review. To this end, the article inspects the global administrative law movement and proposes to extend its overarching conceptualization of global public procedural principles facilitating “good governance” to the online giants’ procedures, despite their private ownership.
Virtual Reality as an Adjunctive Non-pharmacological Therapy to Reduce Pain in School-Aged Children With Burn Wounds
Authors: Wang Qiongfang , Xu Shun , Guo Bing , Xu Yan , Lu Weixin
Published: October 2022

This paper explores the effectiveness of virtual reality in reducing pain in school-aged children undergoing burn wound care. From June 2020 to September 2021, 34 cases of burned children treated in the burn clinic of a hospital were selected. A before- and after-study design was utilized to observe the first and second wound dressing changes of the same patients. The two dressing changes were randomly selected for the VR plan and the Non-VR plan. In VR Plan, patients played virtual reality games using a headset and gamepad to distract from their pain. To determine the effectiveness of VR, the children’s pain score, heart rate, blood oxygen saturation, and adverse reactions such as dizziness and nausea were recorded ten minutes before wound dressing change, during wound dressing change and ten minutes after the bandages was on. The Wong-Baker and FLACC scores of the patients in the VR group were (5.79 ± 1.84) and (4.91 ± 2.08), respectively, whereas the scores of the patients in the non-VR group were (5.47 ± 1.99) and (4.91 ± 2.25), respectively, 10 minutes before wound dressing changes. During wound dressing changes, the Wong-Baker and FLACC scores of patients in the VR group were (3.78 ± 1.49) and (2.73 ± 1.38), respectively, whereas the scores of patients in the non-VR group were (5.58 ± 2.48) and (4.97 ± 2.39), respectively. After wound dressing changes, the Wong-Baker and FLACC scores of patients in the VR group were (2.44 ± 1.65) and (2.12 ± 1.34), respectively, and the scores of patients in the non-VR group were (4.21 ± 2.42) and (3.75 ± 2.05), respectively. The study concludes that virtual reality is effective in reducing pain in school-aged children with burn wounds. The study also concludes that virtual reality does not cause adverse reactions.
Seasonal Dynamics of Flight Phenology of the Euwallacea fornicatus Species Complex and an Associated Parasitoid Wasp in Avocado Groves in Taiwan
Authors: Liu Fang-Ling , Rugman-Jones Paul , Liao Yi-Chang , Husein Deena , Liang Hui-Hung , Tuan Shu-Jen , Stouthamer Richard
Published: October 2022

The Euwallacea fornicatus species complex (Coleoptera: Curculionidae: Scolytinae: Xyleborini) is a group of four cryptic ambrosia beetle species. Native to Asia, several members of the complex have invaded other continents, where they cause significant economic losses to agricultural crops (e.g., avocado) and natural ecosystems. We were primarily interested in developing management strategies by focusing on the flight behavior of the beetles. Thus, seasonal differences in flight activity were assessed using panel traps baited with a commercial quercivorol lure, placed in infested avocado orchards in Danei, Tainan, Taiwan. Same traps were used to investigate the flight activity of a natural enemy, an undescribed species of the Braconid genus Eucosmophorus sp. Shothole borer species were identified using a DNA-based, high resolution melting assay. Trap data were compared to the predictions of a simple degree-day model, incorporating developmental data and several environmental parameters known to influence flight. Such as the time period representing most of flight activity in a day and temperature-dependent flight propensity. In stark contrast to the degree-day model which predicted the highest emergence, and by extension flight, of shothole borers during spring and summer (May to November), flight activity was actually lowest during these months, and instead, peaked during the winter (October to March). Abundance of the parasitoid wasp closely mirrored flight activity of the shothole borers. The mismatch of trapping and modeling data can have many causes, heavy precipitation and possibly cooperative brood care may suppress the dispersal behavior of the shothole borers during the summer.
Presentation and evaluation of an atypical, supraclavicular mass in a pediatric patient
Authors: Schafer Austin D , Allen David Z , Niermeyer Weston L , Elmaraghy Charles A , Conces Miriam
Published: October 2022

Although the vast majority of pediatric neck masses are benign, pediatric malignancies commonly present in the supraclavicular region. We present the case of a 4-year-old male who presented with a mass in the trapezius muscle with accompanying lymphadenopathy. An extensive work-up was performed to exclude malignancy, and the patient was ultimately diagnosed with a benign monocytic mass, which surgically excised. He has been doing well since surgery with no evidence of recurrence. A review of the literature revealed this case to be the first of its kind to be reported.
Laparoscopic treatment of entero-neobladder fistula after radical cystectomy
Authors: Araújo Ana Sofia , Anacleto Sara , Laranjo-Tinoco Catarina , Cardoso Andreia , Morais Nuno , Torres João Nuno , Mendes Miguel , Leão Ricardo , Carvalho-Dias Emanuel
Published: October 2022

Entero-neovesical fistula is a rare complication of orthotopic ileal neobladder after radical cystectomy occurring in <2% of cases. Surgical treatment is usually required and includes open resection of the affected bowel tract and reconstitution of bowel transit. Here we present a case of a laparoscopic treatment of entero-to-neobladder fistula 8 years after laparoscopic radical cystectomy to demonstrate the feasibility and safety of minimally invasive treatment (Supplementary Video). To the best of our knowledge, this is the first report of minimally invasive treatment of entero-neobladder fistula.
Case of laparoscopic parastomal hernia repair using modified Sugarbaker mesh method
Authors: Tsuchiya Yuki , Takahashi Hiromitsu , Ishibiki Yosiro , Iwanuma Yoshimi , Sakamoto Kazuhiro , Fukunaga Masaki
Published: October 2022

A 75-year-old woman underwent sigmoid colon resection and transverse colostomy for perforation of the diverticulum of the sigmoid colon at 70 years of age at another hospital. She was referred to our hospital with complaints of abdominal discomfort 3 months prior to presentation. Abdominal computed tomography revealed a parastomal hernia (PSH). We performed laparoscopic repair using the Sugarbaker approach with a Symbotex Composite Mesh™ and laparoscopic adhesive intestinal repair. The patient’s post-operative course was unremarkable, and she was transferred to the Department of Internal Medicine after 10 days. There was no recurrence 6 months after surgery. Tension-free surgery using a mesh has been reported to be effective in preventing the recurrence of PSH. We performed a laparoscopic modified Sugarbaker mesh method using the Symbotex Composite Mesh™ with collagen film to repair an abdominal hernia.
Concordance between practice and published evidence in the management of ANCA-associated vasculitis in Japan: A cross-sectional web-questionnaire survey
Authors: Miyawaki Yoshia , Fujii Takao , Anan Keisuke , Kodera Masanari , Kikuchi Masao , Sada Ken-Ei , Nagasaka Kenji , Bando Masashi , Sugiyama Hitoshi , Kaname Shinya , Harigai Masayoshi , Tamura Naoto
Published: October 2022

Objectives

We conducted a descriptive study of the physicians’ evidence–practice gap for adults covered by the 2017 clinical practice guidelines for the management of antineutrophil cytoplasmic antibody-associated vasculitis in Japan.

Methods

This web-based survey, conducted between January and February 2021, involved physicians who had treated at least five patients in the preceding year at a regional core hospital. The outcome was the physicians’ experience in treating patients with microscopic polyangiitis or granulomatosis with polyangiitis [prevalence with 95% confidence intervals (CIs)], defined as treating at least 60% of their patients with the recommended therapy during the year. A modified Poisson regression analysis was performed to explore the factors associated with concordance.

Results

The 202 participants included 49 pulmonologists, 65 nephrologists, 61 rheumatologists, and other physicians. The concordance was 31.5% (95% CI, 25.1–38.5) of physicians who used cyclophosphamide or rituximab for the induction of remission. Rheumatology showed the highest concordance with published evidence (risk ratio = 2.4; 95% CI, 1.10–5.22, p = .03).

Conclusions

These results suggest an evidence–practice gap, which varies substantially among subspecialties. Further studies and a new promotional initiative are necessary to close this gap in clinical practice.
Where Do People With Primary Malignant Brain Tumours Die? A National Cohort Study in England, Using GlioCova Data
Authors: Caldano Micah , Droney Joanne , Mauricaite Radvile , Le Calvez Kerlann , Williams Matt
Published: October 2022

AIMS

The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Despite poor outcomes, there is little work on end of life care in primary brain tumour patients. The majority of patients with cancer prefer to die at home, but most do not.

METHOD

We identified all patients with a malignant primary brain tumour diagnosed in England between 2013-2018 and who died up until 1st of August 2020.

RESULTS

20,684 patients were selected. The median age at diagnosis was 68 years (IQR=19), 42% were female. 55% died within 6 months of diagnosis. 36% of people died at home (compared to 24% of the entire population in England), 25% died in hospital, 15% died in a hospice, 9% died in a nursing home. 15% had an unrecorded or other place of death.

47% (n=9,682) patients had radiotherapy, of which 8.7% (n=1,806) had radiotherapy in the 3 months before death; 29% (n=5,947) patients received chemotherapy (6%(n=1,292) during the last 3 months). 87%(n=18,013) patients had surgery (36%(n=7,370) during the last three months). For all treatments the chance of patients dying at home decreases if the patient has treatment in the last three months of life.

CONCLUSION

To our knowledge, this is the first work exploring the relationship between anti-cancer treatment near the end of life and the location of death. Further work will focus on building a comprehensive model to predict rates of death in hospital, and examine variation on a national level.
ChemoSeed®: A Novel Implantable Device for the Treatment of High Grade Gliomas
Authors: Abdelnabi Dina , Watts Colin , Hingtgen Shawn , Valdivia Alain , McConville Christopher
Published: October 2022

AIMS

The treatment of high grade gliomas (HGGs) is extremely toxic, while offering a dismal prognosis of 15 months survival. Irinotecan (IRN) is a second-line therapy due to its dose-limiting toxicities when delivered systemically. The aim of this research is to formulate IRN into ChemoSeed for local administration to the resection margin of HGGs and evaluate it for toxicity and efficacy in a Patient-Derived Xenograft mouse resection model.

METHOD

30 and 40% w/w IRN-loaded ChemoSeeds were manufactured using hot melt extrusion and were subsequently implanted into the resection cavity of HGG tumour bearing mice.

RESULTS

The 30% w/w IRN-loaded ChemoSeeds showed moderate local toxicity two days after implantation, which diminished by day 4. The 40% w/w IRN-loaded ChemoSeeds showed signs of moderate local toxicity up to six days post implantation, diminishing by day 8 with mild toxicity returning at day 14. Histopathology of the implantation site showed signs of the onset of necrosis at day 45 and 14 for the 30% and 40% w/w IRN-loaded ChemoSeeds. Hematological analysis and clinical chemistry showed no signs of serious systemic toxicity for either the 30 or 40% w/w IRN-loaded ChemoSeeds. The 30% w/w IRN-loaded ChemoSeeds had an 80% survival at day 148, with no sign of tumour recurrence, while the 40% w/w group showed signs of tumour recurrence at day 21, with all mice dead by day 70.

CONCLUSION

This study demonstrates that the 30% w/w IRN-loaded ChemoSeeds are a promising novel treatment for HGGs that could be quickly translated into the clinic.
The Cost of Treating Adult Glioblastoma Patients in England
Authors: Kanso Nour , Mauricaite Radvile , Calvez Kerlann Le , Williams Matt
Published: October 2022

AIMS

The GlioCova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018, of which 15,277 patients were diagnosed with a cranial glioblastoma. Here we present data on the direct care costs of treatment, based on secondary care data.

METHOD

We examined data on inpatient and outpatient care for all cranial glioblastoma patients in the dataset. We used the NHS HRG4+ Reference Costs Grouper 2017-2018 to assign costs standardised to 2017-2018.

RESULTS

A total of 14,999 patients were admitted to hospital between the last three months of 2012 and up to the end of 2019, of which we were able to assign costs to 14,691 patients. Total inpatient cost was over £321 million (34% of which was attributed to direct costs of spells of neurosurgery, chemotherapy, and radiotherapy). 14,528 patients had outpatient care, of which we were able to assign costs to 14,419 patients. Total outpatient cost was over £92 million (41% of which was attributed to chemotherapy and radiotherapy).

CONCLUSION

The estimated secondary care costs for adult glioblastoma patients in England were over £414 million for patients diagnosed between 2013-2018, but do not include patient out-of-pocket costs, primary care, social care, or end of life care costs. Future work will examine variation in care and costs and extend it to the wider brain tumour cohort. We also hope these data will help make the economic argument for improvements in care for brain tumour patients. More information on GlioCova: https://blogs.imperial.ac.uk/gliocova/about-gliocova/
The Experiences of People With Glioma and Their Caregivers: Living With Uncertainty and Long Term Consequences (COBra Study)
Authors: Baddeley Elin , Retzer Ameeta , Sivell Stephanie , Seddon Kathy , Bulbeck Helen , Nelson Annmarie , Calvert Melanie , Grant Robin , Adams Richard , Watts Colin , Aiyegbusi Olalekan Lee , Rivera Samantha Cruz , Kearns Pamela , Dirven Linda , Byrne Anthony
Published: October 2022

AIMS

Glioma, the most common primary brain tumour, has variable survival rates. Existing evidence describes detriment to quality of life from persistent symptoms/side effects, functional loss and feelings of disconnection, particularly in glioblastoma; however, there remains limited focus on the experience of longer-term survivors.

This study aimed to ascertain the lived experience of people with glioma and their caregivers, part of a larger study identifying outcomes for a core outcome set for use in glioma trials (COBra study).

METHOD

Semi-structured interviews with UK glioma patients, or patient-caregiver dyads, analysed using Thematic Analysis.

RESULTS

Nineteen interviews were undertaken. Patients and caregivers described living with uncertainty long after diagnosis and treatment, including prognostic uncertainty and anxiety surrounding recurrence and worsening symptoms. Patients described an inability to plan long-term, struggling to return to normal activities, either due to progressive tumour symptoms, and/or treatment side effects. Long-term physical and psychological side effects were highly impactful; patients felt left alone to cope, with support following treatment dropping off rapidly. Patients/caregivers sought self-directed ways to cope, focusing on routine and achieving some normality. However, the physical and neurological effects of glioma and its treatment affected all aspects of daily life and social interactions, impacting on sense of wellbeing and quality of life.

CONCLUSION

People with glioma, and their caregivers, struggle with loss of normality and living with uncertainty long after diagnosis. They proactively engage in self-directed approaches towards mitigating these effects, but experience gaps in support after treatment finishes. Clinical follow up should target these aspects of assessment and intervention.
SYNGN: A Novel Patient-Specific Drug-Matching Strategy in Glioblastoma
Authors: Marino Silvia
Published: October 2022

AIMS

The alteration of the glioblastoma genome by epigenetic mechanisms that share functions with normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC), is a key piece of evidence that links brain cancer pathogenesis with dysregulated stem cell functions. A patient-specific comparison of glioblastoma cells with NSC, a putative cell of origin of at least a proportion of these tumours, is not feasible as patient-matched endogenous NSC are not surgically accessible and all epigenetic studies in glioblastoma have so far compared epigenetic changes of different tumours with each other or to comparators obtained from foetal brains or an unrelated donor. We reasoned that availability of matched GIC and NSC pairs would allow to identify crucial epigenetic differences on a patient-specific basis and would provide essential therapeutic contrast to define disease-and patient-intrinsic biomarkers of drug response that are less confounded by germline variation.

METHOD

We have harnessed state-of-the-art stem cell technologies and next-generation sequencing methods to compare the epigenetic and transcriptional profile of IDH-wildtype glioblastoma with that of patient-matched normal expanded potential stem cell-derived NSC (iNSC).

RESULTS

We demonstrate that integrated analysis of the transcriptome and DNA methylome of GIC/iNSC pairs identifies druggable target genes (PTGER4, ALDH3B1, NTRK2 and others) in a proportion of patients and we validate this patient-specific prediction of drug response at pre-clinical level in 3D synGLICO and in in vivo models.

CONCLUSION

We provide proof of principle that the SYNGN platform can identify patient-specific druggable targets in glioblastoma.
Identifying Enhancing Tumour Without Contrast-Enhanced Imaging
Authors: Ruﬄe James , Mohinta Samia , Gray Robert , Hyare Harpreet , Nachev Parashkev
Published: October 2022

AIMS

Brain tumours are heterogenous entities comprising multiple broad tissue sub-types when imaged with MRI. Delineating the enhancing tumour component is vital for neuro-oncological therapeutic planning, to-date only demonstrable with contrast-enhanced imaging. But not all patients can undergo this necessary contrast-enhanced acquisition, whether due to allergy, renal impairment, or scanning acquisition parameters. We therefore evaluated how well fully convolutional deep learning models identify a patient’s enhancing tumour when contrast-enhanced imaging was not available.

METHOD

We constructed a suite of deep-learning models to segment brain tumours when contrast-enhanced imaging was missing. Specifically, we developed all possible combinations of other structural sequences being provided, including T1-weighted, T2-weighted and FLAIR. Models were trained and tested with five-fold cross-validation on the 2021 BraTS-RSNA glioma population of 1251 patients, with additional out-of-sample validation with neuroradiologist hand-labelled lesions from our own centre.

RESULTS

Models missing post-contrast imaging still achieved a Dice coefficient for the whole tumour of 0.942. Model performances for identifying enhancing-tumour – despite no contrast-enhanced imaging being provided to the model – ranged from Dice coefficients of 0.759 (single sequence model) to 0.790 (three sequence T1 + T2 + FLAIR model). Moreover, models lacking contrast-enhanced imaging still robustly quantified the volume of enhancing tumour (R2 range 0.953-0.976).

CONCLUSION

Models missing contrast-enhanced imaging still identify both whole lesions and enhancing tumour components, and accurately quantifying the enhancing volumetric burden. These models provide opportunity for lesion detection in patients or clinical situations in which contrast-enhanced imaging cannot be acquired, and challenge the current nosology of defining ‘enhancing tumour’.
Modulation of GABA Neurotransmitter Signalling Impacts Glioblastoma Spheroid Growth and Response to Standard Treatment
Authors: Barrow Rhiannon , Poulter James A , Finetti Martina A , Wilson Erica , Johnson Colin A , Stead Lucy
Published: October 2022

AIMS

We have identified two subtypes within glioblastoma (GBM), defined by whether a specific subset of genes is upregulated (Up responders) or downregulated (Down responders) in response the standard treatment. The biology of therapy-driven transcriptional reprogramming in the two subtypes suggests the differential involvement of GABA neurotransmitter signalling in the underlying treatment resistance mechanisms. Our aim was to address our hypothesis that modulating GABA signalling will impact treatment response in GBM, in different ways for different responder subtypes.

METHOD

We identified two cell lines representing the different responder subtypes: established GBM cell line A172 is an Up responder; GBM63 is a patient derived Down responder. We have grown these cells as spheroids and inspected the response to standard treatment (2 Gy radiation and 30 mM temozolomide), via growth and cell viability assays, versus untreated controls in the presence and absence of a GABAA receptor (GABAAR) modulators. We have performed RNAseq to investigate the pathways affected by inhibition and treatment.

RESULTS

In all cases, modulation of GABAAR activity significantly alters both growth and response to standard treatment. However, this is most commonly in different directions in the Up vs Down responders. Furthermore, the majority of genes that are differentially expressed through treatment and inhibition are dysregulated in different directions.

CONCLUSION

Modulation of GABA neurotransmitter signalling impacts GBM spheroid growth and response to standard treatment. Identifying the key pathways affected in different responder subtypes may indicate how this can be used in the development of more effective combination treatments for GBM.
Intravoxel Incoherent Motion (IVIM) Diffusion-Weighted Imaging to Assess Treatment Response of Choline Kinase Inhibition on GL261 Mouse Glioblastoma
Authors: Ahmed Nooradean , Alrashidi Tareq , Bhaduri Sourav , Mukherjee Soham , Poptani Harish
Published: October 2022

AIMS

To monitor changes in IVIM parameters in response to JAS239 treatment in preclinical glioblastoma models.

METHOD

C57BL/6 mice were injected intracranially with 5x105 GL261 glioblastoma cells and tumours were observed on T2 weighted MRI. Mice were imaged on day 0 (T0, baseline), day 3 (T3), 6 (T6) of treatment and post-treatment day 10 (T10). IVIM DWI was performed using a single-shot spin-echo echo planar sequence and processed using Matlab to acquire IVIM parameters of f, D, and D*.

RESULTS

Percentage changes in values with respect to baseline from saline treated control mice were compared to JAS239 treated animals with respect to baseline. Treated mice showed a slight increase in ADC and pseudo-diffusion on day 3 and day 6, with an increase in the perfusion fraction on day 6. However, no statistically significant difference between the two groups with respect to all 3 parameters (P>0.05). Analysis of the change in parameters post treatment (T10) also showed no statistically (P>0.05) significant difference between the mice treated with JAS239 and the control group treated with saline.

CONCLUSION

In this study of the IVIM based parameters, we observed no significant differences in these parameters which indicates that JAS329 may be ineffective in the treatment of GL261 tumours. There was no significant change in the diffusion and perfusion related parameters in the tumour region. IVIM parameters may be useful in studying the tumour microenvironment, however, these may not be sensitive in detecting tumour resistance to ChoK inhibitor therapies.
Development of Novel LAT1 Targeting Small Molecules for Boron Neutron Capture Therapy (BNCT) and Potential Application for Treating Glioblastoma
Authors: Morrison Kendall
Published: October 2022

AIMS

to make molecules that deliver more Boron than BPA for boron neutron capture therapy BNCT

METHOD

Boronated compounds were designed based on known LAT-1 substrates, synthesized using boronation techniques and purified using preparative HPLC. The compounds were formulated to achieve high concentrations when compared to BPA-fructose (BPA-F). Boronated compounds were tested for boron uptake and retention in multiple cell lines expressing either LAT1 and/or PEPT1. Compounds were further tested in multiple human xenograft models representing the cancer indication currently treatable by BNCT as well as in one syngeneic colon tumor model that may have high PEPT1 expression. Intracellular and intra tumor boron concentration were measured by ICP OES. We also synthesized 2 dipeptides and tested them in BNCT experiments with our collaborators at Kyoto University in Japan. They were tested in a CT26 mouse syngeneic model using neutrons from KURR1.

RESULTS

We synthesized multiple boronated compounds with better solubility than BPA (100 mg/ml v 30mg/ml in fructose). They were readily taken up in multiple cell lines and one of these compounds had longer retention than others. In competition experiments we were able to show that this compound was a superior substrate for LAT1. We also showed better BNCT results with our molecules compared to BPA.

CONCLUSION

BPA works for BNCT but it has limitations such as poor solubility. We made several new boronated compounds with better solubility than BPA and showed that we could deliver 2-3 x more boron in vitro and in vivo and better BNCT outcomes at KURR1.
The Value of Diffusion Tractography for Awake Surgery
Authors: Roach Joy , Voets Natalie , Pretorius Pieter , Birch Martin , Apostolopoulos Vasileios , Stacey Richard , Plaha Puneet
Published: October 2022

AIMS

Despite evidence of correspondence with intraoperative stimulation, there remains limited data on MRI diffusion tractography (DT)’s sensitivity to predict morbidity after brain tumour resection. Our aims were: (1) evaluate DT against subcortical stimulation mapping and performance changes during and following awake surgery; (2) evaluate the use of early post-operative DT to predict recovery from post-surgical deficits.

METHOD

We performed a retrospective review our first 100 awake neurosurgery procedures using DTneuronavigation. Intra-operative stimulation and performance outcomes were assessed to classify DT predictions for sensitivity and specificity calculations.

RESULTS

Between 2014 and 2019 a total of 91 adult brain tumour patients (mean age 49.2 years) underwent 100 awake surgeries with subcortical stimulation. The sensitivity and specificity of pre-operative DT predictions were 92.2% and 69.2%, varying among tracts. Post-operative deficits occurred after 41 procedures (39%), but were prolonged (>3 months) in only 4 patients (4%). Post-operative DT was available in 51 patients and confirmed surgical preservation of tracts. Post-operative DT anticipated complete recovery in a patient with supplementary motor area syndrome, and indicated infarct-related damage to corticospinal fibers associated with delayed, partial recovery in a second patient.

CONCLUSION

Pre-operative DT provided very accurate predictions of the spatial location of tracts in relation to a tumour. As expected, however, the presence of a tract did not provide information on its functional status, resulting in variable DT specificity among individual tracts. While prolonged deficits were rare in our series, DT in the immediate post-operative period offered additional information to monitor neurological deficits and anticipate recovery potential.
Identification of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients
Authors: Cilibrasi Chiara , Simon Thomas , Vintu Marian , Tolias Christos , Samuels Mark , Mazarakis Nektarios , Eravci Murat , Stewart Nicholas , Critchley Giles , Giamas Giorgios
Published: October 2022

AIMS

Description of effective biomarkers present in biofluids could prove invaluable in GBM diagnosis. Extracellular vesicles (EVs) are essential to intercellular crosstalk in the tumour bulk and circulating EVs have been described as a potential reservoir of GBM biomarkers. Therefore, EV-based liquid biopsies have been suggested as a promising tool for GBM

METHOD

Ethical approval was obtained for a prospective study of healthy donors and consenting GBM patients at the University Hospitals Sussex (Brighton). To identify GBM specific proteins, small EVs (sEVs) were isolated from plasma samples using differential ultracentrifugation and validated through Nanoparticles tracking analysis, transmission electron microscopy and detection of known sEVs markers such as CD9, CD63, CD81 and HSP70. sEVs content was characterised through mass spectrometry and bioinformatic tools.

RESULTS

Our data indicate the presence of a GBM inflammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation including VWF, FCGBP, C3, PROS1, and SERPINA1. Bioinformatic analysis highlighted that all potential markers exclusively identified in patient samples had already been linked with either GBM diagnosis, prognosis or associated signalling, suggesting that sEVs protein cargo could mirror the landscape of the original tumour and that selective circulating sEV-derived proteins might be used as hallmarks for GBM patients.

CONCLUSION

this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GBM diagnosis and, consequently, patients’ prognosis and quality of life.
Long Term Quality of Life Outcomes Following Surgical Resection Alone for Benign Paediatric Intracranial Tumours
Authors: Kumar Siddhant , Islim Abdurrahman , Moon Richard , Millward Christopher , Hennigan Dawn , Bakhsh Ali , Thorpe Antonia , Foster Mitchell , Pizer Barry , Mallucci Conor , Jenkinson Michael
Published: October 2022

AIMS

Survivors of paediatric intracranial malignancies are at increased risk of psychosocial, neuro-developmental and functional impairment, important measures of patients’ well-being. This study aimed to evaluate long-term quality of life outcomes (QOL) in patients with benign paediatric brain tumours treated curatively with surgical resection alone.

METHOD

Cross-sectional cohort study of benign paediatric intracranial tumours managed with surgery alone between 2000-2015. Validated QOL questionnaires were administered: SF-36, QLQ-BN20, QLQ-C30 and PedsQLTM.

RESULTS

Twenty-three patients participated (median age at surgery 13 years; range 1-18), twelve were male. The most common diagnosis was pilocytic astrocytoma (n=15). Median time from surgery to participation was 11 years (range 6-19). Fourteen patients achieved A-level qualifications and two obtained an undergraduate degree. Twelve patients were employed, eight were studying and three were unemployed or volunteering. Twelve patients were currently driving. QOL outcomes demonstrated significant limitation from social functioning (p=0.03) and cognitive functioning (p=0.023) compared to the general population norms. Patients also experienced increased loss of appetite (p=0.009) and symptoms of nausea and vomiting (p=0.031). Ten patients were under transitional teenager and young-adult (TYA) clinic follow-up. TYA patients achieved higher levels of education (p=0.014), were more likely to hold a driver’s license (p=0.041) and had improved physical functioning (p=0.005) compared to patients not transitioned through these services.

CONCLUSION

Childhood brain-tumour survivors are particularly vulnerable and at greater risk of developing psychological, neuro-cognitive, socialisation and physical development challenges. Early identification, comprehensive assessment and specialist TYA cancer healthcare input are vital to support these patients and improve their quality of life.