bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing multimorbidity: a qualitative study of the Australian general practitioner experience
Authors: Damarell Raechel A , Morgan Deidre D , Tieman Jennifer J , Senior Tim
Published: September 2022

Background

Multimorbidity is prevalent in general practice and general practitioners internationally report challenges in its management. Understanding the perspectives of general practitioners at the frontline of care is important for system sustainability and accessibility as populations age.

Objective

To explore Australian general practitioner perspectives on managing multimorbidity, the factors supporting their work, and those impeding their ability to meet their own standards of care provision.

Method

A qualitative study conducted with Australian general practitioners using semistructured, in-depth interviews and inductive thematic data analysis.

Results

Twelve interviews with general practitioners were conducted. Three main themes were constructed from the data: Multimorbidity as an encounter with complexity and contingency; Evidence constraints in multimorbidity care; and Concerns for patient safety. System structure and the Australian general practice model restrict general practitioners’ ability to provide care to their level of satisfaction by linking short consultation times to practice remuneration. Attitudes toward the applicability of guideline evidence were mixed despite most general practitioners questioning its generalizability. Patient safety concerns pervaded most interviews and largely centered on system fragmentation and insufficient intersectoral communication. General practitioners rely on multiple sources of information to provide patient-centered care but chiefly the accumulated knowledge of their patients.

Conclusions

Australian general practitioners share many multimorbidity concerns with international colleagues. While multimorbidity-specific evidence may be unrealistic to expect in the immediate term, system investment and adaptation is needed to support general practice sustainability and clinician ability to provide adequate multimorbidity care, suitably remunerated, into the future.
Comedy, Misrule and the Irish Revival
Authors: Hewitt Seán
Published: September 2022

By pairing roughly contemporary comedies by two of the Irish Revival’s leading playwrights, this article sets up a case study for comparison, demonstrating how various forms of comedy were received by Dublin audiences during the Revival, and illustrating the ways in which comedy produced, and unsettled, political myths in the context of the nascent Irish theatre. Attending to plays by J. M. Synge and Lady Gregory, alongside the manifestos and political manoeuvring of the directors of the Abbey Theatre and its earlier iterations, the article suggests that, through comedic misrule, the comedies of the Revival challenged the ‘misrule’ of forms of imperialism, capitalism and modernization, clearing the way for new narratives and myths to take shape. In the fraught conditions of the opening decade of the twentieth century, comedy is the genre through which we can most acutely see the parameters of Irishness being tested on stage.
Implementation of mental health policies and reform in post-conflict countries: the case of post-genocide Rwanda
Authors: Sabey Courtney S
Published: September 2022

The global burden of mental illness is rising, with populations in post-conflict countries contributing significantly to the numbers. Governments in these countries face the dual challenge of responding to increased mental health needs and implementing this response with institutions and economies weakened by war. This research studies the process, successes and challenges of implementing mental health reform in a low-resource, post-conflict country, a subject that is rarely studied. Based on fieldwork conducted in Rwanda in 2019, the study focuses on the implementation of this African country’s post-genocide mental health policy, which relies primarily on strategies of decentralization and integration into the primary health care system. The results are based on 30 interviews conducted in Kigali and Ngoma with primary stakeholders including government officials, representatives from nongovernmental organizations, service providers and academics. These stakeholders held a positive view of the main strategies of the policy as they resulted in increased accessibility and availability of care for Rwandans. However, they also noted the institutionalization and individualization of mental health care as gaps in the implementation that do not respond to the Rwandan context. Building on complexity theory, the analysis found that many of these gaps, as well as opportunities to address them, are missed by the government due to top-down implementation and a lack of collaboration with local organizations and service providers working in the domain. The research results suggest that although it is possible to prioritize mental health in low-resource, complex settings, the implementation of such reform requires collaborative, adaptive and horizontal approaches in order to adequately address and respond to citizen needs and ensure quality mental health care for all.
Low copper levels measured in the aortic wall of New Zealand patients with non-syndromic ascending thoracic aortic aneurysm
Authors: El-Gamel Adam , Mak Josephenine , Bird Steve , Grainger Megan N C , Jacobson Gregory M
Published: September 2022

OBJECTIVES

Studies in animals have shown causal relationships between copper (Cu) deficiency and the development of thoracic aortic aneurysms (TAAs) [1, 2]. Cu deficiency is widespread in New Zealand (NZ) soils; the high soil pH from the use of lime fertilizers reduces the bioavailability of Cu for grazing animals and growing plants; this, in turn, reduces Cu availability in the NZ human food chain. Our study is a pilot study to explore associations between Cu and TAA. We measured Cu levels in aneurysmal aortic tissues in patients undergoing Bentall procedures and non-aneurysmal aortic tissue from coronary artery bypass graft patients.

METHODS

Aortic samples were collected from 2 groups of patients during elective open-heart surgery over 4 months between November 2017 and February 2018. The groups were a TAA group, patients with non-syndromic aortic aneurysm and without the bicuspid aortic valve or known infectious or inflammatory condition (ANEURYSM; n = 13), and a control coronary artery bypass graft group (CONTROL; n = 44). Standardized digested dry tissue weighed samples were analysed from both groups. Tissue extraction of trace elements was carried out using HCl-H2O2 digestion and a highly sensitive analytical technique, inductively coupled plasma mass spectrometry—used to measure elemental concentrations.

RESULTS

Cu concentration (mean ± SD) was significantly lower in ANEURYSM (3.34 ± 0.16 µg/g) when compared to the CONTROL group tissues (4.33 ± 0.20 µg/g) (dry weight; mean ± SD; Student's t-test, P < 0.05). Over 46% of the Aneurysm patients were Maori and live in a geographically Cu-deficient NZ territory.

CONCLUSIONS

Cu deficiency may play a role in the development or progression of non-syndromic ascending aortic aneurysms in NZ. Maori patients are more at risk as they commonly live in rural NZ, dependent on locally grown nutritional sources. Further studies are required to confirm this exciting finding and to establish cause and effect relationship.
Pharmacokinetics of levonorgestrel and etonogestrel contraceptive implants over 48 weeks with rilpivirine- or darunavir-based antiretroviral therapy
Authors: Nakalema Shadia , Chappell Catherine A , Pham Michelle , Byakika-Kibwika Pauline , Kaboggoza Julian , Walimbwa Stephen I , Musaazi Joseph , Nakijoba Ritah , Mbabazi Leah , Kyohairwe Isabella , Nassiwa Sylvia , Jeppson Jeffrey , Winchester Lee , Siccardi Marco , Fletcher Courtney V , Scarsi Kimberly K , Lamorde Mohammed
Published: September 2022

Background

Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART.

Objectives

To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks.

Patients and methods

Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI.

Results

At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99–1.37); levonorgestrel: 1.16 (0.97–1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69–3.28); levonorgestrel: 1.89 (1.38–2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel.

Conclusions

Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART.
Heterogeneity and viral replication fitness of HSV-1 clinical isolates with mutations in the thymidine kinase and DNA polymerase
Authors: Schalkwijk Hanna Helena , Gillemot Sarah , Reynders Marijke , Selleslag Dominik , Andrei Graciela , Snoeck Robert
Published: September 2022

Background

Prolonged antiviral therapy in immunocompromised individuals can result in the emergence of (multi)drug-resistant herpes simplex virus 1 (HSV-1) infections, forming a therapeutic challenge.

Objectives

To evaluate spatial and temporal differences in drug resistance of HSV-1 samples from a HSCT recipient and to determine the effect of resistance mutations on viral replication fitness.

Patients and methods

Five HSV-1 isolates were recovered from a HSCT recipient who suffered from persistent HSV-1 lesions, consecutively treated with aciclovir, foscarnet, cidofovir and a combination of ganciclovir and cidofovir. Spatial and temporal differences in HSV-1 drug resistance were evaluated genotypically [Sanger sequencing and next-generation sequencing (NGS) of the viral thymidine kinase (TK) and DNA polymerase (DP)] and phenotypically (plaque reduction assay). Viral replication fitness was determined by dual infection competition assays.

Results

Rapid evolution to aciclovir and foscarnet resistance was observed due to acquisition of TK (A189V and R222H) and DP (L778M and L802F) mutations. Virus isolates showed heterogeneous populations, spatial virus compartmentalization and minor viral variants in three out of five isolates (detectable by NGS but not by Sanger sequencing). Mutations in the TK and DP genes did not alter replication fitness without drug pressure. TK and/or DP mutants influenced replication fitness under antiviral pressure and showed increased fitness under pressure of the drug they showed resistance to.

Conclusions

The use of NGS and dual infection competition assays revealed rapid evolution of HSV-1 drug resistance in a HSCT recipient with spatial and temporal compartmentalization of viral variants that had altered replication fitness under antiviral pressure.
Quandaries of deciding when to change first-line therapy in invasive pulmonary aspergillosis
Authors: Colombo Arnaldo L , De Almeida João N , Lewis Russell E , Kontoyiannis Dimitrios P
Published: September 2022

We read the excellent viewpoint by Slavin et al. (J Antimicrob Chemother 2022; 77: 16–23) that draws upon the experience of an advisory board of notable experts to comprehensively address many of the clinical factors that drive the need for changes in antifungal therapy for invasive aspergillosis (IA). As noted by the authors, there remains a paucity of quality data to support many of the decisions faced by clinicians managing patients with IA. However, we would like to highlight several other important issues, not fully addressed in that viewpoint, that play an important role in deciding when to change antifungal therapy for IA.
Patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients at primary and secondary healthcare facilities in Bugisu, Eastern Uganda
Authors: Allwell-Brown Gbemisola , Namugambe Juliet Sanyu , Ssanyu Jacquellyn Nambi , Johansson Emily White , Hussain-Alkhateeb Laith , Strömdahl Susanne , Mårtensson Andreas , Kitutu Freddy Eric
Published: September 2022

Objectives

To describe patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients at primary and secondary healthcare facilities across Bugisu, Eastern Uganda.

Methods

We surveyed 37 public and private-not-for-profit healthcare facilities and conducted a retrospective review of antimicrobial prescribing patterns among febrile under-five outpatients (with a focus on antibiotics) in 2019–20, based on outpatient registers. Multilevel logistic regression analysis was used to identify determinants of antibiotic prescribing at patient- and healthcare facility-levels.

Results

Antibiotics were prescribed for 62.2% of 3471 febrile under-five outpatients. There were a total of 2478 antibiotic prescriptions of 22 antibiotic types: amoxicillin (52.2%), co-trimoxazole (14.7%), metronidazole (6.9%), gentamicin (5.7%), ceftriaxone (5.3%), ampicillin/cloxacillin (3.6%), penicillin (3.1%), and others (8.6%). Acute upper respiratory tract infection (AURTI) was the commonest single indication for antibiotic prescribing, with 76.3% of children having AURTI as their only documented diagnosis receiving antibiotic prescriptions. Only 9.2% of children aged 2–59 months with non-severe pneumonia received antibiotic prescriptions in line with national guidelines. Higher health centre levels, and private-not-for-profit ownership (adjusted OR, 4.30; 95% CI, 1.91–9.72) were significant contextual determinants of antibiotic prescribing.

Conclusions

We demonstrated a high antibiotic prescribing prevalence among febrile under-five outpatients in Bugisu, Eastern Uganda, including prescriptions for co-trimoxazole and ampicillin/cloxacillin (which are not indicated in the management of the common causes of under-five febrile illness in Uganda). Study findings may be linked to limited diagnostic capacity and inadequate antibiotic availability, which require prioritization in interventions aimed at improving rational antibiotic prescribing among febrile under-five outpatients.
Antibiotic utilization study in a teaching hospital in Nigeria
Authors: Sekoni Kehinde F , Oreagba Ibrahim A , Oladoja Farouk A
Published: September 2022

Background

Antibiotics have been the bedrock of modern medical care, particularly bacterial infections. However, globally, antimicrobial resistance has become a well-recognized public health threat in recent years, and interventions to reduce its burden have been launched worldwide.

Objectives

The present study evaluated antibiotic utilization in both hospitalized patients and outpatients in a University Hospital in Nigeria.

Methods

In a 3 year retrospective study between January 2017 and December 2019, 246 case files of patients were selected for the study based on inclusion and exclusion criteria. In addition, the antibiotic consumption rate for hospitalized and outpatients was determined.

Results

The total antibiotic consumption for hospitalized patients in this study was 260.9 DDD/100 bed-days, while the outpatient department’s patients were 72.3 DDD/1000 inhabitants per day. Peptic ulcer disease was the most frequent indication for antibiotic use for outpatients, with the fluoroquinolones and macrolides being the most prescribed antibiotic class and antibiotic class with the highest DDD, respectively. The most frequent indication for antibiotic use for hospitalized patients was chronic kidney diseases, with the fluoroquinolones and second-generation cephalosporins being the most prescribed antibiotic class and antibiotic class with the highest DDD, respectively. DDD per 100 bed-days and DDD per 1000 patient-days were highest in 2018. The P values for the years were 0.019, 0.195 and 0.001 for 2017, 2018 and 2019, respectively.

Conclusions

Our findings revealed irrationality in antibiotic use. Therefore, antimicrobial stewardship programmes should be implemented.
Association between tumor response to systemic therapy and patient-reported disease symptoms
Authors: Ito Yu , Awano Nobuyasu , Takahashi Naoko , Izumo Takehiro , Kunitoh Hideo
Published: September 2022

Background

The association of treatment-induced tumor shrinkage with symptom palliation for patients with lung cancer remains unknown. We investigated this correlation using the Edmonton Symptom Assessment System–Revised.

Methods

Using the in-hospital cancer registry, we identified patients receiving chemotherapy and/or immunotherapy for newly diagnosed advanced or metastatic lung cancer. Tumor response and post-treatment Edmonton Symptom Assessment System–Revised were obtained after 2–3 treatment cycles. Patients were divided into groups with or without >30% unidirectional tumor shrinkage (objective response [OR] or non-OR [N-OR] groups, respectively). They were further classified as good-objective response (>50% unidirectional tumor shrinkage), moderate-objective response (30–50% shrinkage), progressive disease (>20% tumor growth or new lesion) or stable disease (SD; N-objective response and non-progressive disease). The primary endpoint was change in the total Edmonton Symptom Assessment System–Revised score from baseline. The Mann–Whitney U test was used for analysis.

Results

In total, 113 patients were enrolled. The total Edmonton Symptom Assessment System–Revised score was significantly more improved in the OR group versus the N-OR group (median: 5 vs. 2, respectively; P = 0.013). This association was more prominent in patients with small-cell lung cancer and large-cell neuroendocrine tumor than those with other histology. Sensitivity analyses showed that the total Edmonton Symptom Assessment System–Revised score was more improved in the OR group versus the SD group (median: 5 vs. 3, respectively; P = 0.029) and in the ‘good-OR’ group versus the ‘moderate-OR and SD’ group (median: 7.5 vs. 2, respectively; P = 0.003), suggesting that greater tumor shrinkage led to more symptom amelioration.

Conclusions

Tumor shrinkage was associated with Edmonton Symptom Assessment System–Revised score improvement in patients with lung cancer receiving systemic therapy.
Chronological Changes in the Expression Pattern of Hippocampal Prion Proteins During Disease Progression in Sporadic Creutzfeldt-Jakob Disease MM1 Subtype
Authors: Yagita Kaoru , Noguchi Hideko , Koyama Sachiko , Hamasaki Hideomi , Komori Takashi , Aishima Shinichi , Kosaka Takayuki , Ueda Mitsuharu , Komohara Yoshihiro , Watanabe Akihiro , Sasagasako Naokazu , Ninomiya Toshiharu , Oda Yoshinao , Honda Hiroyuki
Published: September 2022

The differential effects of sporadic Creutzfeldt-Jakob disease (sCJD) on the hippocampus and other neocortical areas are poorly understood. We aimed to reveal the histological patterns of cellular prion protein (PrPC) and abnormal prion protein (PrPSc) in hippocampi of sCJD patients and normal controls (NCs). Our study examined 18 postmortem sCJD patients (MM1, 14 cases; MM1 + 2c, 3 cases; MM1 + 2t, 1 case) and 12 NCs. Immunohistochemistry was conducted using 4 primary antibodies, of which 3 targeted the N-terminus of the prion protein (PrP), and 1 (EP1802Y) targeted the C-terminal domain. PrPC expression was abundant in the hippocampus of NCs, and the distribution of PrPC at CA3/4 was reminiscent of synaptic complexes. In sCJD cases with a disease history of <2 years, antibodies against the N-terminus could not detect synapse-like PrP expression at CA4; however, EP1802Y could characterize the synapse-like expression. PrPSc accumulation and spongiform changes became evident after 2 years of illness, when PrPSc deposits were more noticeably detected by N-terminal-specific antibodies. Our findings highlighted the chronology of histopathological alterations in the CA4 region in sCJD patients.
Local voluntary reports: the implementation of sustainable development goals in northern and southern cities
Authors: Ruiz-Campillo Xira , Rosas Nieva Samanta
Published: September 2022

Given the increasing relevance of cities in the global agenda, we examine the voluntary local reports from six northern and southern cities around the world to understand their approach to the 2030 Agenda for sustainable development. We examine not only the framework but also the content of the reports to identify the differences in reporting on sustainable development goals (SDGs) and the factors that may explain why these cities have voluntarily submitted their reports. The research has revealed a wide diversity in the structure and content of the voluntary local reports, demonstrating that there was little to no institutional framework used to submit and compile the reports. Although the reports of northern cities tend to align with previous strategies for the SDGs, the implementation of the 2030 Agenda in southern cities has had a more significant impact on the adoption of monitoring and evaluation mechanisms at the local level. We have found that both international bodies and national policies have an influence on the development of sustainable practices at the local level. Our analysis also indicates that all cities have some sort of international exposure either through their participation in transnational municipal networks or through their collaboration with international organizations, especially in southern cities, which can explain why these cities (and not others) are more active in the adoption of SDGs at the local level and in the submission of voluntary reports.
A Synagogue Center Grows in Tel Aviv: On Glocalization, Consumerism and Religion
Authors: Libel-Hass Einat , Ferziger Adam S
Published: September 2022

Alongside the ongoing dominance of Orthodox Judaism in Israel, novel liberal religious frameworks have emerged that seek to address the needs of various constituencies through innovative approaches to synagogue life. One of the most active and successful is the Reform “Beit-Daniel” in Tel- Aviv, Israel's urban epicenter. In this article, the institutional structure that emerged in Beit-Daniel is compared with another neighboring synagogue, the Conservative/Masorti, Tiferet Shalom. Both adapted two well-established elements of the American Jewish experience—the synagogue-center and the “Rabbi as CEO”—and applied them to the Tel-Aviv environment. Yet Beit-Daniel has been more impactful. We examine its unique formula in the context of broader trends relating to religion in Israeli society since the late twentieth century, along with the particular features of Tel Aviv's urban environment. Tel-Aviv is a predominantly secular milieu with a strong consumerist orientation. By homing in on these features, Beit-Daniel's leadership facilitated a novel Israeli framework that operates as a religious, educational, and cultural service provider for a heterogeneous spectrum of target populations, a “community of communities” grounded on its diverse network. The data provided in this article was collected during four years of ethnographic fieldwork at Tel-Aviv's liberal congregations.
A 3′ UTR-derived small RNA connecting nitrogen and carbon metabolism in enteric bacteria
Authors: Walling Lauren R , Kouse Andrew B , Shabalina Svetlana A , Zhang Hongen , Storz Gisela
Published: September 2022

Increasing numbers of small, regulatory RNAs (sRNAs) corresponding to 3′ untranslated regions (UTR) are being discovered in bacteria. One such sRNA, denoted GlnZ, corresponds to the 3′ UTR of the Escherichia coli glnA mRNA encoding glutamine synthetase. Several forms of GlnZ, processed from the glnA mRNA, are detected in cells growing with limiting ammonium. GlnZ levels are regulated transcriptionally by the NtrC transcription factor and post-transcriptionally by RNase III. Consistent with the expression, E. coli cells lacking glnZ show delayed outgrowth from nitrogen starvation compared to wild type cells. Transcriptome-wide RNA–RNA interactome datasets indicated that GlnZ binds to multiple target RNAs. Immunoblots and assays of fusions confirmed GlnZ-mediated repression of glnP and sucA, encoding proteins that contribute to glutamine transport and the citric acid cycle, respectively. Although the overall sequences of GlnZ from E. coli K-12, Enterohemorrhagic E. coli and Salmonella enterica have significant differences due to various sequence insertions, all forms of the sRNA were able to regulate the two targets characterized. Together our data show that GlnZ impacts growth of E. coli under low nitrogen conditions by modulating genes that affect carbon and nitrogen flux.
RMDisease V2.0: an updated database of genetic variants that affect RNA modifications with disease and trait implication
Authors: Song Bowen , Wang Xuan , Liang Zhanmin , Ma Jiongming , Huang Daiyun , Wang Yue , de Magalhães João Pedro , Rigden Daniel J , Meng Jia , Liu Gang , Chen Kunqi , Wei Zhen
Published: September 2022

Recent advances in epitranscriptomics have unveiled functional associations between RNA modifications (RMs) and multiple human diseases, but distinguishing the functional or disease-related single nucleotide variants (SNVs) from the majority of ‘silent’ variants remains a major challenge. We previously developed the RMDisease database for unveiling the association between genetic variants and RMs concerning human disease pathogenesis. In this work, we present RMDisease v2.0, an updated database with expanded coverage. Using deep learning models and from 873 819 experimentally validated RM sites, we identified a total of 1 366 252 RM-associated variants that may affect (add or remove an RM site) 16 different types of RNA modifications (m6A, m5C, m1A, m5U, Ψ, m6Am, m7G, A-to-I, ac4C, Am, Cm, Um, Gm, hm5C, D and f5C) in 20 organisms (human, mouse, rat, zebrafish, maize, fruit fly, yeast, fission yeast, Arabidopsis, rice, chicken, goat, sheep, pig, cow, rhesus monkey, tomato, chimpanzee, green monkey and SARS-CoV-2). Among them, 14 749 disease- and 2441 trait-associated genetic variants may function via the perturbation of epitranscriptomic markers. RMDisease v2.0 should serve as a useful resource for studying the genetic drivers of phenotypes that lie within the epitranscriptome layer circuitry, and is freely accessible at: www.rnamd.org/rmdisease2.
KS01.4.A Transcriptional evolution of glioblastoma point towards changes in bulk composition, mesenchymal sub-type as end-state, and a prognostic association with increased extracellular matrix gene expression
Authors: Hoogstrate Y , Draaisma K , van Hijfte L , Ghisai S A , de Heer I , de Heer I , van den Bent M J , Robe P A , French P J
Published: September 2022

Background

Glioblastoma is the most prevalent and severe type of malignant brain tumor in adults. Although the genetic make-up initiating glioblastoma is increasingly better understood, a better understanding in the mechanisms that drive its evolution, heterogeneity and therapy resistance may reveal new directions for therapy development. To get better insights into glioblastoma evolution, we analyzed and deconvoluted transcriptomes of primary and recurrent glioblastoma resections.

Material and Methods

Matching primary and secondary resections from n=185 uniformly treated glioblastoma patients were collected as part of EORTC Study 1542 and RNA-sequenced. Data was extended with pairs from n=51 patients from the GLASS study. The datasets were subjected to differential and deconvolution analysis using in-house algorithms.

Results

When projecting the tumor samples into a reduced Glioblastoma Intrinsic Transcriptional Subtype space, visualization of transitions indicated that the CL subtype switches most often. As we found no more transitions from MES to other subtypes than to be expected by chance, we concluded that MES is an end-state. On average, tumor purity percentages decreased from ~67% to ~50%, mostly due to an increase in macrophages/microglia. Differential expression analysis was performed with correction for the fraction of non-malignant cells. While expression of glioblastoma associated oncogenes did not change significantly over time, marker genes for macrophages/microglia, neurons and oligodendrocytes were up-regulated whereas endothelial cell markers were down-regulated. A cluster of ~30 extracellular matrix associated (ECM) genes increased significantly over time. Single cell RNA-seq, IF-staining and RNA-ish indicated the signature is most strongly expressed near intra-tumoral vessels. Since endothelial marker genes were down-regulated over time, this suggests a form of prognostic vessel progression with a representative transcriptome signature.

Conclusion

Using a large cohort and validation set of uniformly treated patients, we demonstrate how the glioblastoma transcriptome changes over time with in particular changes the composition of the tumor and its environment. The tumor purity decrease over times suggests a more invasive phenotype or recruitment of non-malignant cells or a combination of both. A post-progression increase in expression of ECM-associated genes expressed near blood vessels was associated with poor survival. Concluding, while no consistent path for transcriptional evolution of tumor cells was observed other than transitions to the MES subtype, glioblastoma becomes more aggressive in time by (re-)organizing its environment.
KS02.6.A Application of positive psychology intervention in continuous quality improvement of nursing care for patients with intracranial tumor
Authors: Bai L , Zhou Z
Published: September 2022

Background

To investigate the effect of positive psychology intervention on continuous quality improvement of nursing care for patients with intracranial tumor

Material and Methods

A total of 124 patients with intracranial tumor who received surgical treatment in our hospital from October 2020 to December 2021 were selected by convenience sampling method, and the patients were randomly divided into control group and intervention group.Patients in the control group received continuous quality improvement of postoperative routine care, and patients in the intervention group received positive psychological intervention based on postoperative routine care. Postoperative treatment compliance, subjective well-being and daily living ability were compared between the two groups

Results

The excellent compliance rate of intervention group was 95.15%, significantly higher than that of control group 83.87% (P < 0.05). The subjective well-being in intervention group (56.73±3.42) was significantly higher than that in control group (53.81±2.76) (P < 0.05). There was no significant difference in daily living ability score between 2 groups before intervention (P > 0.05). After intervention, the daily living ability score of the intervention group was (57.49±9.16), which was significantly higher than that of the control group and before intervention (P < 0.05).

Conclusion

Positive psychology intervention for patients with intracranial tumor can effectively improve the quality of nursing, increase the patient's treatment compliance, and improve the subjective well-being of patients and the ability of daily life is of great significance.
KS02.7.A Impact of FET PET on multidisciplinary neurooncological tumor board decisions in patients with brain tumors
Authors: Ceccon G S , Werner J , Ruge M I , Goldbrunner R , Celik E , Baues C , Deckert M , Brunn A , Büttner R , Golla H , Nogova L , Schlamann M , Kabbasch C , Rueß D , Hampl J , Wollring M , Bauer E K , Tscherpel C , Fink G R , Langen K , Galldiks N
Published: September 2022

Background

Following neurooncological treatment of brain tumors, neurooncologists are often confronted with equivocal MRI findings (e.g., treatment-related changes such as pseudoprogression, non-measurable contrast-enhancing lesions, T2/FLAIR signal alterations, pseudoresponse). Especially in Europe, amino-acid PET is increasingly integrated into multidisciplinary neurooncological tumor boards (MNTB) to overcome these diagnostic uncertainties. We evaluated the correctness of MNTB decisions, in which amino acid PET findings were taken into account.

Material and Methods

In a single-university center study, we retrospectively evaluated 182 MNTB decisions of 154 patients with histomolecularly defined WHO grade 3 or 4 gliomas (n=123), including glioblastoma (n=80), anaplastic glioma (n=42), and gliosarcoma (n=1), or brain metastases (n=31) secondary to lung cancer, melanoma, breast cancer, or colorectal cancer presenting equivocal MRI findings following anticancer treatment. All patients underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET imaging as an adjunct for decision-making. Additionally, the patients’ clinical status, pretreatment, and conventional MRI findings were considered for decision-making. The presence of neoplastic tissue was considered if the mean FET uptake as assessed by tumor-to-brain ratios was > 2.0. MNTB decisions were validated using the neuropathological result in 42% (n=77) or clinicoradiologically in 58% (n=105). The diagnostic performance of MTNB decisions was evaluated using 2x2 contingency tables.

Results

The validation of all 182 MNTB recommendations, which integrated FET PET in the decision-making process, were correct in 95% (sensitivity, 97%; specificity, 75%; positive predictive value, 96%). Due to tumor progression, MNTB recommendations prompted a treatment change in 88% (n=160 of 182 decisions). When FET PET findings suggested progressive disease (n=157), MNTB decisions were correct in 96% (positive predictive value, 97%). In 22 MNTB decisions with the recommendation to continue the current treatment regimen, 82% were correctly identified as treatment-related changes.

Conclusion

FET PET seems to have a significant impact on MNTB decisions. A prospective evaluation of MNTB decisions with and without the integration of FET PET is warranted to define the added value of FET PET.
KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients
Authors: Friedrich M , Farrher E , Caspers S , Lohmann P , Stoffels G , Filss C , Weiss Lucas C , Ruge M I , Langen K J , Shah N J , Fink G R , Galldiks N , Kocher M
Published: September 2022

Background

In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types’ impact on the local white matter fiber architecture and clinical outcome.

Patients and Methods

This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber density was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group.

Results

The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p<0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a comparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score).

Conclusions

Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients’ performance due to the larger volume affected.

Funding

Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation.
JS03.5.A Pediatric Neurofibromatosis type 1- associated Malignant Peripheral Nerve Sheath Tumors: a national experience
Authors: Silva E M , Nunes S , Luz I , Mohanlal U , Passos J
Published: September 2022

Background

Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas and although less that 10% occur in the pediatric age, they are the most feared complication in the follow-up of Neurofibromatosis Type 1 (NF1) patients. NF1-children tend to have larger tumors and worse prognosis than non-NF1 patients. There is a lack of data regarding MPNST in pediatric populations with NF1, and the present work aims to characterize a Portuguese population of pediatric NF1 patients who developed a MPNST.

Material and Methods

Retrospective analysis of all NF1-pediatric patients diagnosed with MPNST between 2000 to 2021, from three centers in Portugal. Patient characteristics, treatment modalities and clinical outcomes were reviewed.

Results

12 patients (6 males and 6 females) met the inclusion criteria. 7 had no family history of NF1. Median age at diagnosis was 14.1 years (range 10-18). 5 had been diagnosed previously with Plexiform Neurofibroma and were treated with selumetinib (2) and partial surgery (2). MPNSTs were mostly located in the retroperitoneum (7) and in the proximal lower limbs (2). Only 1 patient had a resectable tumor at diagnosis and 3 patients had metastatic disease. In the FDG-PET scan of evaluated patients (7), the mean maximum standardized uptake value of the main lesion was 6 (range 3.6-9.7).Neoadjuvant ifosfamide plus doxorubicin chemotherapy was used in 4 patients. The median overall survival in this population was 10.3 months (95% CI 0.1-20.6) 2 patients remain alive.

Conclusion

The prognosis of MPNSTs in NF1 pediatric patients is very poor. In a subset of patients, MPNSTs develop from known Plexiform Neurofibromas. Current surveillance ant treatment protocols need to be improved.
JS04.6.A The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location
Authors: Liu I , Jiang L , Samuelsson E , Marco Salas S , Hack O , Jeong D , Shaw M , Englinger B , LaBelle J , Ernst K , Palova H , Pokorna P , Sterba J , Slaby O , Geyeregger R , Jones D , Koschmann C , Svedlund J , Resnick A , Diaz A , Haberler C , Czech T , Slavc I , Cotter J , Ligon K , Alexandrescu S , Yung W , Arrillaga-Romany I , Suva M , Beck A , Gojo J , Monje M , Nilsson M , Filbin M
Published: September 2022

Background

Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus and spinal cord, presumed to be driven by the specific spatiotemporal context of these midline locations during postnatal development. While most common in the pons and at mid-childhood ages, the same oncohistone mutation is recurrently detected in adult DMGs and throughout different midline regions. The potential heterogeneity of tumors at different ages and in different anatomical locations of the midline are vastly understudied.

Material and Methods

Through dissecting the transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs - spanning the age range from 2-68 years and locations from spinal cord to thalamus - at single cell resolution, we delineate how age- and location-dependent contexts shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation.

Results

We identify that oligodendrocyte precursor (OPC)-like cells constitute the stem-like compartment in H3-K27M DMGs across all clinico-anatomical groups, however, depending on location, display varying levels of maturity resembling less differentiated pre-OPCs or more mature OPCs further differentiated along the oligodendroglial lineage. We further demonstrate increased mesenchymal cell states in adult tumors, which we link to age-related differences in glioma-associated immune cell compartments. We for the first time resolve the spatial organization of H3-K27M DMG cell types in intact patient tissues, identifying a local niche of the oligodendroglial lineage.

Conclusion

Our study provides a powerful resource for rational modeling and therapeutic frameworks taking into account determinants of age and location in this lethal glioma group.
OS02.7.A The role of epilepsy in elderly patients with Glioblastoma: An Austrian multicenter analysis
Authors: Demetz M , Hecker C , Krigers A , Kerschbaumer J , Pöppe J , Geiger P , Spinello A , Griessenauer C J , Thomé C , Schwartz C , Freyschlag C F
Published: September 2022

Background

Higher age is a significant predictor of poor outcome in glioblastoma multiforme (GBM) patients. Thus, acquisition of a better understanding of additional prognostic factors in these often-frail patients is of utmost importance. Epileptic seizures correlate with improved overall survival (OS) in low-grade gliomas; however, the impact of epilepsy in GBM patients on outcome parameters is poorly defined. Furthermore, persisting epilepsy significantly influences the patients’ quality of life (QoL). This study aims at specifically evaluating the impact of epilepsy in elderly GBM patients.

Material and Methods

Two Austrian academic neurosurgical centers retrospectively analyzed all elderly (≥65 years) GBM patients with de-novo tumors, who underwent tumor resections between 09/2006 and 07/2021. Epidemiological, histopathological and survival data were gained from patients’ electronic charts and screened for presence of epilepsy preoperatively or during follow-up.

Results

391 patients (55% males, 45% females) with a median age at surgery of 73 years (Interquartile Range (IqR) 68.5-77.5) were analyzed. The mean predicted OS was recorded to be 12.4 months (CI95% 10.9-14.0). Median preoperative Modified Rankin Scale (mRS) was 2 (IqR 1-3), and median preoperative Karnofsky performance score was 80 (IqR 60-90). Mean follow-up was 10.4 months (CI95% 9.1-11.6) in our cohort. 95/391 patients (24%) suffered from preoperative epilepsy. 17 (18%) patients still suffered from epilepsy after tumor resection with eight patients who developed new postoperative seizures, and four patients (1.0%) showed a worsening of already preoperatively diagnosed seizures. Major surgery-associated neurological complications included new motor deficits in 29 (7%) and new aphasia in 16 (4%) patients. Logistic regression showed, patients with seizures had significantly lower mRS (OR=0.735 [CI95% 0.563 0.961], p=0.032) and less frequently occipital tumor location (OR=0.347 [CI95% 0.152-0.791], p=0.018). Postoperative epilepsy resulted in significantly prolonged hospitalization after the surgery (OR=2.622[CI95% 1.496-3.979], p=0.009). Survival did not correlate with preoperative epilepsy (p>0.05). However, Cox regression revealed that multifocal tumor location (HR=1.777 [CI95% 1.197-2.639], p=0.025) as well as thalamic involvement (HR=11.121 [CI95% 3.431-36,046], p=0.030) negatively influenced OS. Furthermore, surgery-associated complications shortened OS significantly (HR=1.945 [CI95% 1,296-2,916], p=0.025).

Conclusion

Even though epilepsy was not found to directly impact survival in elderly GBM patients, we found that surgery led to epilepsy freedom in a significant proportion of our patient cohort, thereby potentially leading to improved QoL. Greatest focus should be set on avoiding any surgery-associated deficits, since these severely influence the OS.
OS05.4.A Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation
Authors: Schmassmann P , Roux J , Dettling S , Hogan S , Herter S , Bacac M , Shekarian T , Martins T A , Ritz M , Hutter G
Published: September 2022

Background

Clinical trials of systemic T cell checkpoint blockade in GBM patients showed only disappointing results. This may be attributed in part to the immunosuppressive components of the GBM immune tumor microenvironment (iTME). Therefore, major efforts have been undertaken to describe the GBM iTME on a single cell level. However, human data on the composition of the iTME in different tumor regions (contrast enhancing tumor center versus peripheral infiltration zone) remain scarce.

Material and Methods

Here, we performed high-depth single-cell RNA sequencing (scRNA-seq) on patient-matched biopsies from tumor center and the peripheral infiltration zone of five primary GBM patients. Additionally, peripheral blood mononuclear cells (PBMC) of the same patients were included in the analysis to explore the transcriptional changes occurring during tumor infiltration of circulating immune cells. Main findings of the transcriptional analysis were confirmed by flow cytometry.

Results

Through analysis of > 45’000 cells, we revealed a distinct regional transcriptional profile of microglia (MG) and monocyte-derived macrophages (MdM), a non-reactive/exhausted MG subcluster in the GBM iTME and an impaired interferon-response signature in the tumor-peripheral cytotoxic cell compartment. Comparing CD8+ T cells from the tumor periphery to PBMC-derived CD8+ T cells of the same patient revealed CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in the PBMC but lacking in the tumor periphery. Tumor peripheral CD8+ T cells shared features with tissue-resident memory CD8+ T cells with exhausted effector functions.

Conclusion

Our analysis provides a large-scale dissection of GBM-associated cell types complemented by patient-matched PBMCs, serving as a high dimensional reference map of the human GBM iTME.