bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of autoimmune neurology testing clinical utility and stewardship initiatives
Authors: Kroner Grace , Kunchok Amy 
Published: October 2024

Abstract
Testing for neural autoantibodies associated with autoimmune neurological diseases has an important role in clinical care. However, as they are niche tests for relatively rare diseases, they often have longer turn-around-times and more expensive costs than many other laboratory tests. In addition, due to the low yield of positive results, they often appear as attractive stewardship targets. Our objective was to review current utilization and ordering patterns and evaluate the impact of ongoing stewardship efforts to inform next steps regarding stewardship of these tests. Methods: Data on utilization and ordering patterns of autoimmune and paraneoplastic neural autoantibody panels from January 1 to December 31, 2023, was obtained from reference laboratory and electronic medical record (EMR) data. Additional data on best practice advisories from the most recent six months was obtained from the EMR. Results: Overall, we observed that providers tested 2270 patients both from our defined test menu (five total tests, ~89% of total orders) and through the miscellaneous route (12 total tests, ~11% of total orders), which allows providers to place orders for tests not currently on our menu. Just under one third of the orders were in cerebrospinal fluid (CSF) (n=725), while the remaining were for serum (n=1545). The percent positivity was generally higher in serum specimens, ranging from 0 to 50% per test (n=227 total positive specimens). The percent positivity in CSF specimens ranged from 0 to 40% per test (n=29 total positive specimens), which is generally consistent with previously published literature. Most of the orders were placed by neurology providers (56%). The best practice advisories (BPAs) currently in use are soft stops that target repeat tests in the same specimen type within thirty days of a previous order. Of note, these BPAs can only catch orders placed through the defined process. In six months, the BPA for repeat serum orders fired 104 times for 42 unique patients; the BPA for repeat CSF orders fired 96 times for 38 unique patients. The serum BPA resulted in elimination of the repeat order for 43% of patients (n=18), while the CSF BPA resulted in elimination of the repeat order for 24% of patients (n=9). We observed some situations in which the BPA appeared to be firing when previous orders were incorrectly collected and so not able to be sent out. Conclusion: Based on these data, we plan three main steps to continue to refine autoimmune neurology testing: 1) update our test menu to offer the most clinically useful orders through the defined route, 2) pilot review of tests ordered through the miscellaneous route, and 3) optimize BPAs to target situations with inappropriate utilization rather than technical issues.
Transcriptome analysis reveals selectively high expression of beige adipocyte marker genes in mouse perinephric fat
Authors: Misawa Yoshinori , Takahashi Yu , Sasaki Takashi , Sato Ryuichiro , Yamauchi Yoshio 
Published: October 2024

Abstract
To reveal the differences in the properties of visceral adipose tissue in healthy unstimulated mice, we performed transcriptome analysis using RNA sequencing. Among visceral adipose tissues, perinephric adipose tissue was found to exclusively express beige adipocyte markers while expressing white adipocyte markers. These results imply potential specific roles of perinephric adipose tissue in both physiological and pathological conditions.
Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder
Authors: Seaby Eleanor G , Godwin Annie , Meyer-Dilhet Géraldine , Clerc Valentine , Grand Xavier , Fletcher Tia , Monteiro Laloe , Kerkhofs Martijn , Carelli Valerio , Palombo Flavia , Seri Marco , Olivucci Giulia , Grippa Mina , Ciaccio Claudia , D’Arrigo Stefano , Iascone Maria , Bermudez Marion , Fischer Jan , Di Donato Nataliya , Goesswein Sophie , Leung Marco L , Koboldt Daniel C , Myers Cortlandt , Arnadottir Gudny Anna , Stefansson Kari , Sulem Patrick , Goldberg Ethan M , Bruel Ange-Line , Tran-Mau-Them Frederic , Willems Marjolaine , Bjornsson Hans Tomas , Hognason Hakon Bjorn , Thorolfsdottir Eirny Tholl , Agolini Emanuele , Novelli Antonio , Zampino Giuseppe , Onesimo Roberta , Lachlan Katherine , Baralle Diana , Rehm Heidi L , O’Donnell-Luria Anne , Courchet Julien , Guille Matt , Bourgeois Cyril F , Ennis Sarah 
Published: October 2024

Abstract
DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.
We performed in utero cortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertook ex vivo cortical electroporation on neuronal progenitors to quantitatively assess axonal development at a single cell resolution. Mosaic ddx17 crispants and heterozygous knockouts in Xenopus tropicalis were generated for assessment of morphology, behavioural assays and neuronal outgrowth measurements. We further undertook transcriptomic analysis of neuroblastoma SH-SY5Y cells, to identify differentially expressed genes in DDX17-KD cells compared to controls.
Knockdown of Ddx17 in electroporated mouse neurons in vivo showed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown of Ddx17 in vitro. The axon outgrowth phenotype was replicated in crispant ddx17 tadpoles and in heterozygotes. Heterozygous tadpoles had clear neurodevelopmental defects and showed an impaired neurobehavioral phenotype. Transcriptomic analysis identified a statistically significant number of differentially expressed genes involved in neurodevelopmental processes in DDX17-KD cells compared to control cells.
We have identified potential neurodevelopment disease-causing variants in a gene not previously associated with genetic disease, DDX17. We provide evidence for the role of the gene in neurodevelopment in both mammalian and non-mammalian species and in controlling the expression of key neurodevelopment genes.
Nontuberculous Mycobacterial Pulmonary Disease: Patients, Principles, and Prospects
Authors: Nguyen Minh-Vu H , Haas Michelle K , Kasperbauer Shannon H , Calado Nogueira de Moura Vinicius , Eddy Jared J , Mitchell John D , Khare Reeti , Griffith David E , Chan Edward D , Daley Charles L 
Published: October 2024

AbstractNontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in incidence globally and challenging to manage. The 2020 multisociety treatment guideline and the 2022 consensus recommendations provide comprehensive evidence-based guides to manage pulmonary diseases caused by the most common NTM. However, with &gt;190 different NTM species that may require different multidrug regimens for treatment, the breadth and complexity of NTM-PD remain daunting for both patients and clinicians. In this narrative review, we aim to distill this broad, complex field into principles applicable to most NTM species and highlight important nuances, specifically elaborating on the presentation, diagnosis, principles of patient-centered care, principles of pathogen-directed therapy, and prospects of NTM-PD.
MULTIMODAL (5-ALA, TRACTOGRAPHY AND ULTRASOUND GUIDED) AWAKE CRANIOTOMY FOR GLIOBLASTOMA: MAXIMISING SAFE SURGICAL RESECTION
Authors: Honeyman Dr Susan , Martin Mr Sean , Stacey Mr Richard , Apostolopoulos Mr Vasileios , Plaha Prof Puneet 
Published: October 2024

Abstract

AIMS
Maximising the extent of surgical resection of glioblastoma is a key prognostic factor for survival. This must be balanced against avoiding neurological deﬁcit, which may delay or preclude adjuvant treatments. This is a particular challenge in eloquent tumours. Optimal surgical adjuncts to enable maximal resection of glioblastomas in eloquent brain regions, remain unclear. We present the ﬁrst series assessing the safety and eﬃcacy of multimodality image-guided, awake resection of IDH-wildtype glioblastoma, combining 5-aminolevulinic acid (5-ALA), diffusion tractography (DTI) and intraoperative ultrasound (USS).

METHOD
We present a single centre retrospective series of 175 patients undergoing awake craniotomy for primary resection of glioblastomas, between January 2014 and January 2023. Awake craniotomy was considered if tumours were in or adjacent to eloquent areas. Key outcomes assessed included post-operative neurological complications (classiﬁed into transient, if persisting &lt;3 months and completely resolved, or permanent if persisting &gt;3 months), extent of resection (EOR) and overall survival (OS).

RESULTS
175 patients (103M:72F) were included, with a mean age of 58.2 years. All cases used neuronavigation, whilst 5- ALA and DTI were used in 98.9% and 97.1% of patients respectively. Intraoperative USS was used 88/175 (50.3%). Gross total resection (&gt;98%) was achieved in 101/175 patients (64.7%). 83/175 patients (47.4%) experienced a post-operative neurological deﬁcit, which was temporary in 84.3% (70/83) of cases. When transient deﬁcits occurred, these were most often speech related (49/70). Subgroup analysis found left temporal tumours were highest risk for transient dysphasia (59.2%), followed by left frontal (21.7%) and left parietal (16.0%). The median percentage EOR with USS was 100%, whilst without USS was 97.8% (Wilcox, p=0.0004).

CONCLUSION
Patients should be counselled about the high risk of transient neurological complications following awake surgery, particularly speech deﬁcit. Multimodal image-guided surgery can maximise the extent of safe resection for glioblastoma.
EVALUATION OF AN ALLIED HEALTH PROFESSIONAL PREHABILITATION SERVICE IN NEURO-ONCOLOGY
Authors: Humphreys Ms Rosie , Farrow Ms Madeleine , Moran Ms Charlotte 
Published: October 2024

Abstract

AIMS
The evidence base for the beneﬁts of prehabilitation in the cancer population is increasing. So far, the focus has been on colorectal, breast and lung cancer sites with no current research into the effects in patients with primary or secondary brain tumours. It is hypothesised that patients with brain cancer would beneﬁt from prehabilitation as current evidence demonstrates the positive effects of exercise, cognitive and language rehabilitation in this patient group. The aim of this project is to demonstrate the feasibility and impact of a two-year prehabilitation pilot service. The service comprises physiotherapy, occupational therapy and speech and language therapy for patients with brain cancer in the pre-operative phase.

METHOD
A pilot study was carried out at a tertiary UK neurosurgery centre. Patients over the age of 17 with a diagnosis of primary or secondary brain tumour awaiting surgery were eligible for the prehabilitation service. The impact was measured through Length of Stay, Quality of Life (EQ-5D-5L), emergency department attendances and admission rates 90 days post-surgery.

RESULTS
128 patients were seen in prehabilitation from 01/11/2022 to 31/01/2024. Length of hospital stay post-surgery was lower for the prehabilitation group (0.9 days with 95% conﬁdence interval) compared to control group. A mean improvement in the EQ-5D-5L Index from pre-operative assessment to post-surgery follow up was demonstrated

CONCLUSION
This study reveals data demonstrating the beneﬁts of prehabilitaiton for patients with brain tumours. Prehabilitation for this patient group appears to improve clinical outcomes alongside patients’ quality of life. Future directions for the service will focus on expanding the provision to patients with spinal and benign tumours, where this is also a possibility of therapeutic need in the pre and post-operative phase.
INTEGRATING ALLIED HEALTH PROFESSIONALS DURING THE ONCOLOGICAL TREATMENT PHASE FOR GLIOBLASTOMA PATIENTS: A CASE STUDY AT A UK CANCER CENTRE
Authors: Wyatt Mrs Toni , Peat Mrs Nicola 
Published: October 2024

Abstract

AIMS
Primary brain tumour patients should be offered neurological rehabilitation assessment at diagnosis and every stage of follow With only 5% of glioblastoma patients surviving more than 5 years, specialist management that spans across all phases of the Dietz rehabilitation model is required to optimise function, treatment tolerance and Quality-of-life. At Guy’s cancer centre an Allied health multi-disciplinary team (Physiotherapy, Occupational therapy and Speech and language therapy) work alongside the oncologist-led clinic to support this patient group.

METHOD
Case history A 54-year-old, male, was diagnosed with right parietal Glioblastoma, WHO grade 4, IDH wildtype, MGMT 5.47% methylated (August 2023) on biopsy only. He underwent chemo/radiotherapy - 60gy/90 fractions with Temozolmide (TMZ) on 3/11/2023 Currently C4 of adjuvant TMZ. Dexamethazone 2mg was discontinued on 29/11/2023, he continues with Keppra 500mg twice daily.

RESULTS
Dietz Intervention approach in phases:

PREVENTATIVE
Fatigue management was introduced prior to radiotherapy including a physical activity review, advice on pacing, sleep hygiene and relaxation techniques. Given the patient’s history of shift work and altered sleep patterns, managing risks of treatment-related fatigue was of particular importance. Restorative & Supportive: A targeted and periodised exercise programme was initiated, comprising 1:1 gym based physiotherapy sessions. The aims included enhancing exercise conﬁdence, improve balance, endurance, maintain strength, pain management and weight maintenance during chemo/radiotherapy and adjuvant TMZ. Education was deployed on adjusting activity levels based on chemotherapy cycle and day to day side effects, alongside ongoing fatigue management advice around pacing and sleep hygiene.

CONCLUSION
Learning and Recommendations Implementing tailored rehabilitation interventions early in the patient’s treatment pathway, enables proactive management to mitigate the impact of treatment-related side effects on their QOL. Based on our experience, early engagement with a dedicated therapy team is recommended to foster strong rapport with both the patient and their caregivers. This facilitates timely rehabilitation planning for optimal outcomes.
ROR1 MRNA EXPRESSION IN GLIOMA - A NOVEL PROGNOSTIC BIOMARKER
Authors: Madani Dr Daniel , Satgunaseelan Dr Laveniya , El-Hayek Ms Jessica , Shivalingam Prof Brindha , Ford Prof Caroline 
Published: October 2024

Abstract

AIMS
Glioblastoma is the most common and aggressive primary brain tumour in adults. Despite maximal surgical resection followed by concomitant chemo-/radiotherapy, the three-year survival remains less than 5%. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) overexpression is associated with poor prognosis in several cancers. ROR1 therapeutics are in Phase I/II clinical trials making it an exciting novel target with translational potential to explore for glioblastoma treatment. The aim of this study was to examine the association between ROR1 mRNA expression and overall survival (OS), by applying the WHO 2021 classiﬁcation of transcriptomic glioma datasets.

METHOD
Clinical, histological, and molecular data were extracted from four independent glioma datasets (TCGA, CGGA, Rembrandt, and Gravendeel) via the GlioVis portal and analysed using the WHO 2021 classiﬁcation. Only conﬁrmed cases of astrocytoma, oligodendroglioma, or glioblastoma, and ROR1 mRNA expression data were included (2,216 cases). Kaplan-Meier survival curves were produced for OS with low/high grade glioma versus ROR1 mRNA expression. Log-rank (Mantel-Cox) multivariate regression was applied to analyse the effect of selected covariates on OS and ROR1 mRNA expression.

RESULTS
We observed a signiﬁcant decrease in median OS in patients with high-ROR1 mRNA expression when compared to the low-ROR1 mRNA expression cohort (20 and 70 months, respectively). High-grade gliomas represented the highest ROR1 mRNA expression across the consortium, resulting in a poor median OS of 16 months.

CONCLUSION
This study represents the ﬁrst report of an association between OS and the oncogenic role of ROR1 in glioma, a targetable cell surface marker for novel putative treatment in glioblastoma.
KINOME-WIDE SYNTHETIC LETHAL SCREEN IDENTIﬁES PANK4 AS A MODULATOR OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA
Authors: Vella Dr Viviana , Ditsiou Dr Angeliki , Chalari Dr Anna , Eravci Dr Murat , Wooller Dr Sarah K , Gagliano Prof Teresa , Bani Ms Cecilia , Kerschbamer Dr Emanuela , Karakostas Mr Christos , Xu Dr Bin , Zhang Dr Yongchang , Pearl Dr Frances M G , Lopez Dr Gianluca , Peng Dr Ling , Stebbing Prof Justin , Klinakis Prof Apostolos , Giamas Prof Georgios 
Published: October 2024

Abstract

AIMS
Temozolomide (TMZ) represents the cornerstone of glioblastoma (GBM) therapy. However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains conﬁned to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterised. We aimed to uncover synthetic lethal partners of TMZ in GBM that could enhance the effect of TMZ, thus improving TMZ therapy response.

METHOD
A kinome-wide RNAi screen was performed in a TMZ-resistant GBM cell model. A panel of several TMZ-resistant and patient-derived GBM cell lines was implemented for in vitro validation of our ﬁndings through several phenotypic assays. In vivo TMZ-resistant GBM xenografts and immunohistochemical (IHC) analysis of IDH- wildtype GBM specimens were employed to assess the clinical relevance of our ﬁndings. Tandem Mass Tag (TMT)-based quantitative proteomic studies were undertaken to elucidate the underlying mechanisms.

RESULTS
Following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) was uncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborated the potential translational signiﬁcance of these ﬁndings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. A Tandem Mass Tag (TMT)-based quantitative proteomic approach revealed that PANK4 abrogation leads to a signiﬁcant downregulation of numerous proteins with central roles in cellular detoxiﬁcation and cellular response to oxidative stress. Mechanistically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death.

CONCLUSION
Our study provides novel insights into chemoresistance in GBM and unveils a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM.
OPTIC PATHWAY GLIOMAS AFTER TRANSITIONING INTO ADULTHOOD – AN INSTITUTIONAL EXPERIENCE
Authors: Loebel Dr Franziska , Aquilina Dr Kristian 
Published: October 2024

Abstract

AIMS
Optic pathway gliomas (OPG) are rare tumors affecting the optic nerve and the chiasm that occur predominantly during childhood and are generally managed by pediatric neurosurgeons/ pediatric oncologists. Prognosis is quite good for these benign tumors, and many patients survive into adulthood. While clinical care for these patients in childhood is well-standardized, the clinical course of patients with OPG after transitioning into adulthood is not well studied.We herein aimed to characterize patients with OPG diagnosed in childhood after transitioning into adult neurosurgical care in order in order to ellucidate the clinical course of OPG in adulthood and to identify potential problems with clinical care of these special patients in adult neurosurgery or neuro-oncology services.

METHOD
Clinical and radiographical data from adult patients (&gt; 16 years of age) with OPG diagnosed in childhood and treated in our institution were collected from patient charts. Descriptive statistics and outcome analysis were performed using commercial statistical software.

RESULTS
Of 124 patients with OPG diagnosed in childhood, 35 patients transitioned into adulthood. The population included equal distribution of male (18, 51.4%) vs female (17, 48.6%) patients. Median age at diagnosis was 8.0 years (range 0.5 – 15.0) and median age at last follow up was 20.8 years (range 17.1 – 38.6). 12 patients were positive for NF (34.3%). 9 patients had undergone surgery for the OPG (25.7%), 11 had chemotherapy (31.4%) and 15 (42.8%) had received radiotherapy. 8 patients showed an endocrine deﬁciency (22.9%), 4 hypothalamic dysfunction (11.4%) and 8 cognitive/behavioral diﬃculties (22.9%). Visual acuity impairment was detected in 12 patients (34.3%). 9 patients experienced recurrence (25.7%).

CONCLUSION
Patients with OPG transition into adulthood frequently and experience a wide range of clinical problems. Close neurosurgical/neuro-oncology specialist follow-up is recommendable.
POSTOPERATIVE VISUAL ﬁELD DEﬁCITS ARE NOT ASSOCIATED WITH REDUCTION IN QUALITY OF LIFE IN GLIOBLASTOMA PATIENTS
Authors: Wan Mr Yizhou , Li Mr Yonghao , Sinha Mr Rohit , Jain Ms Swati , Mair Prof Richard , Morris Mr Robert , Joannides Mr Alexis , Santarius Mr Tom , Price Prof Stephen 
Published: October 2024

Abstract

AIMS
Preservation of functional integrity is a core goal of glioblastoma surgery. Visual ﬁeld deﬁcits can signiﬁcantly impact quality of life and patient function. Both tumour and surgical effects may affect visual function in these patients. The objective of this Study was to evaluate the effect of visual ﬁeld deﬁcits on HRQoL in the preoperative and early postoperative period (prior to chemoradiotherapy).

METHOD
48 patients with glioblastoma received preoperative, early postoperative (withon 1 week) and delayed postoperative testing (6 weeks) for visual function usinga combination of the OCS-Bridge neurocognitive screening tool and formal visual ﬁeld testing. Patients also completed the EORTC QLQ C30 with BN-20 and VFQ-25 visual function questionaires at the same timepoints. Statistical tests were performed using R Statistical Software (v4.1.2; R Core Team 2021).

RESULTS
The proportion of patients with visual ﬁeld deﬁcits at preoperative, early postoperative and late early postoperative timepoints were 20 (41.7%), 28 (58.3%) and 24 (50%) respectively. Most patients without a preoperative deﬁcit did not have an early 17/20 85% or late postoperative deﬁcit 19/24 79.1%. The proportion of patients with deﬁcits at early and late postoperative timepoints was signiﬁcantly higher in patients with preoperative deﬁcits compared to patients without preoperative deﬁcits, (Chi square p = 0.004) and (p = 0.008) respectively. There was no signiﬁcant differences between HRQoL measures between timepoints or between patients with deﬁcits at any timepoint compared to patients without deﬁcits.

CONCLUSION
Postoperative visual ﬁeld deﬁcits are related to preoperative tumour-effects rather than surgery. Patients can be counselled that while they do not recover following surgery, it is not associated with signiﬁcant reductions in HRQoL. Patients with preoperative visual ﬁeld deﬁcits may be considered for resection without signiﬁcant worry about the preservation of visual ﬁeld function since these deﬁcits do not recover postoperatively.