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Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

To explore the cortical morphological associations of the psychoses of epilepsy.Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC; n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10).POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network; (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall.The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.

Introduction The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab is a fully humanised VEGFR2 monoclonal antibody that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of olinvacimab in recurrent GBM (rGBM). Methods Adult patients with a measurable lesion, histopathological diagnosis of primary GBM with tumour progression after chemoradiotherapy were included. No prior biologic treatment was allowed. Three dose levels of intravenous olinvacimab were assessed: 8 mg/kg (dose level 1) and 12mg/kg (dose level 2) weekly for 3 out of 4 weeks, and 12 mg/kg weekly (dose level 3). Efficacy was assessed by MRI using RANO criteria. Dynamic Contrast-Enhanced MRIs (DCE-MRIs) were analysed for changes in perfusion parameters during treatment. Results Twelve patients were enrolled in this study: three each in dose levels 1 and 2, and six in dose level 3. The main toxicity was development of grade 1 (67%) and 2 (8%) cutaneous haemangiomas. Common toxicities noted with other VEGF directed therapies- including hypertension, impaired wound healing, and proteinuria- were not seen. The 6-month progression free survival rate was 17%, disease control rate 25%, and the longest response 15 months. No significant difference in perfusion parameters was found between baseline and 1st follow-up DCE-MRI comparing those with stable and progressive disease. ConclusionOlinvacimab was well tolerated across three dose levels and had a distinct toxicity profile. Disease control was seen in 25% of patients and warrants further follow up in further clinical trials.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted ‘gold-standard’ subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

IntroductionOne outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualise on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide.MethodsThe Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonised a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance.ResultsOur pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. Overall, after including a border-zone around lesions, the developed MELD FCD surface-based algorithm had a sensitivity of 67% and a specificity of 54% on the withheld test cohort, and a sensitivity of 85% on a restricted subcohort of seizure free patients with FCD type IIB who had T1 and FLAIR MRI data.ConclusionsThis multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions.HighlightsThis large, multi-centre, multi-scanner neuroimaging cohort captures the heterogeneity of histopathological subtypes and imaging features of patients with FCD.We developed a robust and interpretable surface-based algorithm which detects FCDs with a sensitivity of 67% and a specificity of 54%.The algorithm generates individual patient reports that “open the AI black-box” highlighting predicted lesion locations, alongside the imaging features and their relative saliency to the classifier.

The ability to mentally travel forward through time allows humans to envisage a diverse array of possible events taking place in the future, helping us to choose which pathway to take in life. In epilepsy, we assume that patients use this cognitive ability when deciding between various treatment options, but this assumption has not been robustly tested. The temporal lobes are key contributors to this ‘future thinking’ and its building blocks include cognitive functions commonly impaired in temporal lobe epilepsy such as memory and language, giving rise to a hypothesis that ‘future thinking’ is impaired in this patient cohort. Participants were 68 adults: 37 with neurosurgically-naïve, unilateral temporal lobe epilepsy (51% right lateralized) and 31 healthy controls of similar age, sex and intellectual ability to the participants with epilepsy. Future thinking was measured using an imagined experiences task validated in other neurological populations. Tools well-established in temporal lobe epilepsy were used to measure potential cognitive correlates of future thinking. Analysis of variance revealed significantly impoverished future thinking in both left and right temporal lobe epilepsy relative to controls (P = 0.001, ηp2=0.206), with no difference between temporal lobe epilepsy groups (P > 0.05). Future thinking deficits in left temporal lobe epilepsy were paralleled by deficits in scene construction, whereas impoverished future thinking in right temporal lobe epilepsy occurred in the setting of intact scene construction. Deficits in future thinking were associated with reductions in lexical access and episodic autobiographic memory in both epilepsy groups. In sum, future thinking is compromised in both left and right temporal lobe epilepsy. The deficit in left temporal lobe epilepsy is largely explainable by dysfunction in verbal cognitive processes including scene construction. While the basis of the deficits observed with right temporal foci shares features with that of left temporal lobe epilepsy, their intact scene construction raises questions about the role of the left and right temporal lobes in future thinking and scene construction and the relationship between these two constructs, including whether right temporal lobe might play a specific role in future thinking in terms of creative processing. Clinicians should take impaired future thinking into account when counselling temporal lobe epilepsy patients about various treatment options, as they may struggle to vividly imagine what different outcomes might mean for their future selves.

Objective: To evaluate women’s experiences after hysterectomy and predictors of their contentment and regret with the surgical approaches. Methods: Cross-sectional, Patient-Reported Experience Measures survey in 2319 Australian women aged 21 to 90 years (median age of 52 years) who had received hysterectomy in the preceding 2 years. Results: Overall, the vast majority of women (>96%) did not regret having had the hysterectomy. Women who received an open abdominal hysterectomy reported slower recovery with about 7% of women still not fully recovered after 12 months compared to those whose surgery was through a less invasive approach. Women who reported no adverse events, having been given a choice of type of hysterectomy, women who received an alternative to open abdominal hysterectomy, and women who felt prepared for discharge from hospital were significantly more likely to be content with their hysterectomy and report positive patient experiences. Conclusions: Compared with those who received a less invasive approach to hysterectomy, women who received open surgery were more likely to express negative experiences relating to their hospital stay and recovery from surgery. The results inform future improvements of care for women planning a hysterectomy.

The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed by MRI using RANO criteria. 6 month PFS was 17%, with disease control in 25%, with steroid dose reduction. The longest response was 15 months. On DCE MRI, there was no significant difference in perfusion parameters between baseline and 1st follow-up MRI comparing those with SD and PD. However, 6 of 12 patients showed decreased Ktrans > 20 % of baseline, consistent with an anti-angiogenic effect of Olinvacimab. Pharmacokinetics showed a decreased clearance rate and increased half-life of Olinvacimab compared to the prior Phase I study. Pharmacodynamic studies showed significantly higher levels of angiogenic markers, particularly VEGF-A in those treated at 12mg/kg vs arm 1. VEGF-A, C and D levels were elevated in patients with SD compared to those with PD. Conclusion: Olinvacimab was well tolerated with a different toxicity profile to other VEGFR directed therapies. There were promising responses in 25% of patients.

Minimally invasive approaches to hysterectomy have been shown to be safe, effective and have recovery advantages over open hysterectomy, yet in Australia 36% of hysterectomies are still conducted by open surgery. In 2006, a survey of Australian gynaecological specialists found the main impediment to increasing laparoscopic hysterectomy to be a lack of surgical skills training opportunities. We resurveyed specialists to explore contemporary factors influencing surgeons’ approaches to hysterectomy; 258 (estimated ~19%) provided analysable responses. Despite >50% of surveyed specialists wishing to practise laparoscopic hysterectomy in the future, lack of surgical skills, arising from the lack of training opportunities, remains the main impediment.

Physical education (PE) is often perceived as a learning area of lesser importance than others, for instance literacy and numeracy. Arguments for raising its status and gaining a greater share in the school day founder on uncertainty as to just what is educational about it, and on the view that really it is no more than skill acquisition and improving fitness with a few games thrown in. The majority of teachers tasked with teaching it in New Zealand primary schools may have had very little or no specialist preparation in PE theory and pedagogy. It is increasingly being left to outside providers to step into the breech. This paper outlines a way of reframing PE that widens its scope and potential for learning, makes PE teaching much more accessible to teachers who do not see themselves as experts in this area, and may enable teachers of all levels and expertise to explore and enrich the PE experience of their students. This approach is summarised as going beyond skills and fitness. It is unpacked and located in relation to existing pedagogical approaches before recounting how it was enacted with several cohorts of initial teacher education students in a New Zealand university. Readers may find useful the table of PE activities and how they can be invigorated within creative and diverse contexts. This is a practice paper, and is designed to appeal to the demand of busy teachers for examples of the theory in action. But it is also a call for teachers to reflect on those practices, and in particular the implications of large scale abdication of teaching to non-professionals.

Objective To explore factors influencing how well-informed women felt about hysterectomy, influences on their decision making, and on them receiving a less-invasive alternative to open surgery. Methods Online questionnaire, conducted in 2015–2016, of women who had received a hysterectomy in Australia, in the preceding two years. Results Questionnaires were completed by 2319/6000 women (39% response). Most women (n = 2225; 96%) felt well-informed about hysterectomy. Women were more aware of the open abdominal approach (n = 1798; 77%), than of less-invasive vaginal (n = 1552; 67%), laparoscopic (n = 1540; 66%), laparoscopic-assisted (n = 1303; 56%), and robotic approaches (n = 289; 12%). Most women (n = 1435; 62%) reported their gynaecologist was the most influential information source. Women who received information about hysterectomy from a GP (OR = 1.47; 95% CI 1.15-1.90), or from a gynaecologist (OR = 1.3; 95% CI 1.06-1.58), were more likely to feel better informed (p

Voxel-based analysis of diffusion MRI data is increasingly popular. However, most white matter voxels contain contributions from multiple fibre populations (often referred to as crossing fibres), and therefore voxel-averaged quantitative measures (e.g. fractional anisotropy) are not fibre-specific and have poor interpretability. Using higher-order diffusion models, parameters related to fibre density can be extracted for individual fibre populations within each voxel (‘fixels’), and recent advances in statistics enable the multi-subject analysis of such data. However, investigating within-voxel microscopic fibre density alone does not account for macroscopic differences in the white matter morphology (e.g. the calibre of a fibre bundle). In this work, we introduce a novel method to investigate the latter, which we call fixel-based morphometry (FBM). To obtain a more complete measure related to the total number of white matter axons, information from both within-voxel microscopic fibre density and macroscopic morphology must be combined. We therefore present the FBM method as an integral piece within a comprehensive fixel-based analysis framework to investigate measures of fibre density, fibre-bundle morphology (cross-section), and a combined measure of fibre density and cross-section. We performed simulations to demonstrate the proposed measures using various transformations of a numerical fibre bundle phantom. Finally, we provide an example of such an analysis by comparing a clinical patient group to a healthy control group, which demonstrates that all three measures provide distinct and complementary information. By capturing information from both sources, the combined fibre density and cross-section measure is likely to be more sensitive to certain pathologies and more directly interpretable., Graphical abstract fx1, Highlights • A fixel is defined as a specific fibre population within a voxel. • We describe a comprehensive approach to fixel-based analysis (FBA) of white matter. • A novel method to investigate fibre bundle morphology (cross-section) is presented. • We compare fibre density, cross-section and a combined measure in a clinical cohort. • The three different analyses give unique yet complementary information.

Changes in hardware or image processing settings are a common issue for large multi-center studies. In order to pool MRI data acquired under these changed conditions, it is necessary to demonstrate that the changes do not affect MRI-based measurements. In these circumstances classical inference testing is inappropriate because it is designed to detect differences, not prove similarity. We used a method known as statistical equivalence testing to address this limitation. Equivalence testing was carried out on three datasets: (i) cortical thickness and automated hippocampal volume estimates obtained from healthy individuals imaged using different multi-channel head coils; (ii) manual hippocampal volumetry obtained using two readers; and (iii) corpus callosum area estimates obtained using an automated method with manual cleanup carried out by two readers. Equivalence testing was carried out using the “two one-sided tests” (TOST) approach. Power analyses of the two one-sided tests were used to estimate sample sizes required for well-powered equivalence testing analyses. Mean and standard deviation estimates from the automated hippocampal volume dataset were used to carry out an example power analysis. Cortical thickness values were found to be equivalent over 61% of the cortex when different head coils were used (q < 0.05, FDR correction). Automated hippocampal volume estimates obtained using the same two coils were statistically equivalent (TOST p = 4.28 × 10-15). Manual hippocampal volume estimates obtained using two readers were not statistically equivalent (TOST p = 0.97). The use of different readers to carry out limited correction of automated corpus callosum segmentations yielded equivalent area estimates (TOST p = 1.28 × 10-14). Power analysis of simulated and automated hippocampal volume data demonstrated that the equivalence margin affects the number of subjects required for well-powered equivalence tests. We have presented a statistical method for determining if morphometric measures obtained under variable conditions can be pooled. The equivalence testing technique is applicable for analyses in which experimental conditions vary over the course of the study.

Simultaneous measurement of renal blood flow, renal ATP, renal pH and mean arterial pressure (MAP) might help investigators understand the mechanisms responsible for acute renal failure (ARF) in sepsis.(1) To develop a technique to simultaneously measure MAP, renal blood flow, renal ATP and renal pH in a large mammal during severe sepsis and after circulatory arrest; and (2) To describe preliminary observations during such measurements.We implanted a custom-made phosphorus coil around the left kidney and a magnetic resonance-compatible blood flow probe around the renal artery of an adult Merino ewe. We induced severe sepsis by intravenous administration of Escherichia coli and obtained 31P magnetic resonance spectroscopic data at 3tesla, and continuous blood flow and MAP data before and during severe sepsis over several hours. We induced circulatory arrest with potassium chloride and measured the same 31P signal immediately and again 30 minutes later.We successfully and simultaneously measured MAP, renal blood flow, renal ATP and renal pH in a large mammal during severe sepsis and induced circulatory arrest. With these techniques, we observed that, despite marked hypotension, there were limited changes in renal ATP and renal pH, and that renal blood flow increased. A rapid and dramatic decrease in ATP and pH occurred with circulatory arrest.We have developed a technique to simultaneously monitor MAP, renal blood flow, ATP and pH in a large mammal during severe sepsis. Our initial observations indicate preservation of renal ATP in septic shock.