Automated segmentation of epilepsy surgical resection cavities: Comparison of four methods to manual segmentation.

Accurate resection cavity segmentation on MRI is important for neuroimaging research involving epilepsy surgical outcomes. Manual segmentation, the gold standard, is highly labour intensive. Automated pipelines are an efficient potential solution; however, most have been developed for use following temporal epilepsy surgery. Our aim was to compare the accuracy of four automated segmentation pipelines following surgical resection in a mixed cohort of subjects following temporal or extra temporal epilepsy surgery. We identified 4 open-source automated segmentation pipelines. Epic-CHOP and ResectVol utilise SPM-12 within MATLAB, while Resseg and Deep Resection utilise 3D U-net convolutional neural networks. We manually segmented the resection cavity of 50 consecutive subjects who underwent epilepsy surgery (30 temporal, 20 extratemporal). We calculated Dice similarity coefficient (DSC) for each algorithm compared to the manual segmentation. No algorithm identified all resection cavities. ResectVol (n = 44, 88 %) and Epic-CHOP (n = 42, 84 %) were able to detect more resection cavities than Resseg (n = 22, 44 %, P < 0.001) and Deep Resection (n = 23, 46 %, P < 0.001). The SPM-based pipelines (Epic-CHOP and ResectVol) performed better than the deep learning-based pipelines in the overall and extratemporal surgery cohorts. In the temporal cohort, the SPM-based pipelines had higher detection rates, however there was no difference in the accuracy between methods. These pipelines could be applied to machine learning studies of outcome prediction to improve efficiency in pre-processing data, however human quality control is still required.

Elevated plasma neurofilament light and glial fibrillary acidic protein in epilepsy versus nonepileptic seizures and nonepileptic disorders.

OBJECTIVE: Research suggests that recurrent seizures may lead to neuronal injury. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) levels increase in cerebrospinal fluid and blood in response to neuroaxonal damage, and they have been hypothesized as potential biomarkers for epilepsy. We examined plasma NfL and GFAP levels and their diagnostic utility in differentiating patients with epilepsy from those with psychogenic nonepileptic seizures (PNES) and other nonepileptic disorders. METHODS: We recruited consecutive adults admitted for video-electroencephalographic monitoring and formal neuropsychiatric assessment. NfL and GFAP levels were quantified and compared between different patient groups and an age-matched reference cohort (n = 1926) and correlated with clinical variables in patients with epilepsy. RESULTS: A total of 138 patients were included, of whom 104 were diagnosed with epilepsy, 22 with PNES, and 12 with other conditions. Plasma NfL and GFAP levels were elevated in patients with epilepsy compared to PNES, adjusted for age and sex (NfL p = .04, GFAP p = .04). A high proportion of patients with epilepsy (20%) had NfL levels above the 95th age-matched percentile compared to the reference cohort (5%). NfL levels above the 95th percentile of the reference cohort had a 95% positive predictive value for epilepsy. Patients with epilepsy who had NfL levels above the 95th percentile were younger than those with lower levels (37.5 vs. 43.8 years, p = .03). SIGNIFICANCE: An elevated NfL or GFAP level in an individual patient may support an underlying epilepsy diagnosis, particularly in younger adults, and cautions against a diagnosis of PNES alone. Further examination of the association between NfL and GFAP levels and specific epilepsy subtypes or seizure characteristics may provide valuable insights into disease heterogeneity and contribute to the refinement of diagnosis, understanding pathophysiological mechanisms, and formulating treatment approaches.

A systematic review of the impact of brain tumours on risk of motor vehicle crashes.

PURPOSE: Brain tumours are associated with neurocognitive impairments that are important for safe driving. Driving is vital to maintaining patient autonomy, despite this there is limited research on driving capacity amongst patients with brain tumours. The purpose of this review is to examine MVC risk in patients with brain tumours to inform development of clearer driving guidelines. METHODS: A systematic review was performed using Medline and EMBASE. Observational studies were included. The outcome of interest was MVC or measured risk of MVC in patients with benign or malignant brain tumours. Descriptive analysis and synthesis without meta-analysis were used to summarise findings. A narrative review of driving guidelines from Australia, United Kingdom and Canada was completed. RESULTS: Three studies were included in this review. One cohort study, one cross-sectional study and one case-control study were included (19,135 participants) across United States and Finland. One study evaluated the incidence of MVC in brain tumour patients, revealing no difference in MVC rates. Two studies measured MVC risk using driving simulation and cognitive testing. Patients found at higher risk of MVC had greater degrees of memory and visual attention impairments. However, predictive patient and tumour characteristics of MVC risk were heterogeneous across studies. Overall, driving guidelines had clear recommendations on selected conditions like seizures but were vague surrounding neurocognitive deficits. CONCLUSION: Limited data exists regarding driving behaviour and MVC incidence in brain tumour patients. Existing guidelines inadequately address neurocognitive complexities in this group. Future studies evaluating real-world data is required to inform development of more applicable driving guidelines. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO 2023 CRD42023434608.

The impact of cognitive resource constraints on goal prioritization.

Many decisions we face daily entail deliberation about how to coordinate resources shared between multiple, competing goals. When time permits, people appear to approach these goal prioritization problems by analytically considering all goal-relevant information to arrive at a prioritization decision. However, it is not yet clear if this normative strategy extends to situations characterized by resource constraints such as when deliberation time is scarce or cognitive load is high. We evaluated the questions of how limited deliberation time and cognitive load affect goal prioritization decisions across a series of experiments using a gamified experimental task, which required participants to make a series of interdependent goal prioritization decisions. We fit several candidate models to experimental data to identify decision strategy adaptations at the individual subject-level. Results indicated that participants tended to opt for a simple heuristic strategy when cognitive resources were constrained rather than making a general tradeoff between speed and accuracy (e.g., the type of tradeoff that would be predicted by evidence accumulation models). The most common heuristic strategy involved disproportionately weighing information about goal deadlines compared to other goal-relevant information such as the goal's difficulty and the goal's subjective value.

Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Impact of epilepsy surgery on quality of life: Systematic review and meta-analysis.

Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug-resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta-analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre- and post-epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta-analysis assessed the postsurgery change in QoL. Meta-regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre- and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory-31 item (QOLIE-31) meta-analysis included six studies, and QOLIE-89 meta-analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE-31 (95% confidence interval [CI] = 10.9-30.1, I2 = 95.5) and 12.1 for QOLIE-89 (95% CI = 8.0-16.1, I2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta-regression demonstrated a higher postoperative QOLIE-31 score as well as change in pre- and postoperative QOLIE-31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an individual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between individual studies and high risk of bias.

Intrinsic and secondary epileptogenicity in focal cortical dysplasia type II.

OBJECTIVE: Favorable seizure outcome is reported following resection of bottom-of-sulcus dysplasia (BOSD). We assessed the distribution of epileptogenicity and dysplasia in and around BOSD to better understand this clinical outcome and the optimal surgical approach. METHODS: We studied 27 children and adolescents with magnetic resonance imaging (MRI)-positive BOSD who underwent epilepsy surgery; 85% became seizure-free postresection (median = 5.0 years follow-up). All patients had resection of the dysplastic sulcus, and 11 had additional resection of the gyral crown (GC) or adjacent gyri (AG). Markers of epileptogenicity were relative cortical hypometabolism on preoperative 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and spiking, ripples, fast ripples, spike-high-frequency oscillation cross-rate, and phase amplitude coupling (PAC) on preresection and postresection electrocorticography (ECoG), all analyzed at the bottom-of-sulcus (BOS), top-of-sulcus (TOS), GC, and AG. Markers of dysplasia were increased cortical thickness on preoperative MRI, and dysmorphic neuron density and variant allele frequency of somatic MTOR mutations in resected tissue, analyzed at similar locations. RESULTS: Relative cortical metabolism was significantly reduced and ECoG markers were significantly increased at the BOS compared to other regions. Apart from spiking and PAC, which were greater at the TOS compared to the GC, there were no significant differences in PET and other ECoG markers between the TOS, GC, and AG, suggesting a cutoff of epileptogenicity at the TOS rather than a tapering gradient on the cortical surface. MRI and tissue markers of dysplasia were all maximal in the BOS, reduced in the TOS, and mostly absent in the GC. Spiking and PAC reduced significantly over the GC after resection of the dysplastic sulcus. SIGNIFICANCE: These findings support the concept that dysplasia and intrinsic epileptogenicity are mostly limited to the dysplastic sulcus in BOSD and support resection or ablation confined to the MRI-visible lesion as a first-line surgical approach. 18 F-FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena.

The effect of epilepsy surgery on productivity: A systematic review and meta-analysis.

OBJECTIVES: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. METHODS: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews - Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes. RESULTS: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07-1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15-0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90-0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94-0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies - of Interventions and was low for most variables except "measurement of exposure." SIGNIFICANCE: There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.

Epileptic spasms are associated with increased stereo-electroencephalography derived functional connectivity in tuberous sclerosis complex.

OBJECTIVE: Epileptic spasms (ES) are common in tuberous sclerosis complex (TSC). However, the underlying network alterations and relationship with epileptogenic tubers are poorly understood. We examined interictal functional connectivity (FC) using stereo-electroencephalography (SEEG) in patients with TSC to investigate the relationship between tubers, epileptogenicity, and ES. METHODS: We analyzed 18 patients with TSC who underwent SEEG (mean age = 11.5 years). The dominant tuber (DT) was defined as the most epileptogenic tuber using the epileptogenicity index. Epileptogenic zone (EZ) organization was quantitatively separated into focal (isolated DT) and complex (all other patterns). Using a 20-min interictal recording, FC was estimated with nonlinear regression, h2 . We calculated (1) intrazone FC within all sampled tubers and normal-appearing cortical zones, respectively; and (2) interzone FC involving connections between DT, other tubers, and normal cortex. The relationship between FC and (1) presence of ES as a current seizure type at the time of SEEG, (2) EZ organization, and (3) epileptogenicity was analyzed using a mixed generalized linear model. Spike rate and distance between zones were considered in the model as covariates. RESULTS: Six patients had ES as a current seizure type at time of SEEG. ES patients had a greater number of tubers with a fluid-attenuated inversion recovery hypointense center (p < .001), and none had TSC1 mutations. The presence of ES was independently associated with increased FC within both intrazone (p = .033) and interzone (p = .011) networks. Post hoc analyses identified that increased FC was associated with ES across tuber and nontuber networks. EZ organization and epileptogenicity biomarkers were not associated with FC. SIGNIFICANCE: Increased cortical synchrony among both tuber and nontuber networks is characteristic of patients with ES and independent of both EZ organization and tuber epileptogenicity. This further supports the prospect of FC biomarkers aiding treatment paradigms in TSC.

Conventional MRI features can predict the molecular subtype of adult grade 2-3 intracranial diffuse gliomas.

PURPOSE: Molecular biomarkers are important for classifying intracranial gliomas, prompting research into correlating imaging with genotype ("radiogenomics"). A limitation of the existing radiogenomics literature is the paucity of studies specifically characterizing grade 2-3 gliomas into the three key molecular subtypes. Our study investigated the accuracy of multiple different conventional MRI features for genotype prediction. METHODS: Grade 2-3 gliomas diagnosed between 2007 and 2013 were identified. Two neuroradiologists independently assessed nine conventional MRI features. Features with better inter-observer agreement (κ ≥ 0.6) proceeded to consensus assessment. MRI features were correlated with genotype, classified as IDH-mutant and 1p/19q-codeleted (IDHmut/1p19qcodel), IDH-mutant and 1p/19q-intact (IDHmut/1p19qint), or IDH-wildtype (IDHwt). For IDHwt tumors, additional molecular markers of glioblastoma were noted. RESULTS: One hundred nineteen patients were included. T2-FLAIR mismatch (stratified as > 50%, 25-50%, or < 25%) was the most predictive feature across genotypes (p < 0.001). All 30 tumors with > 50% mismatch were IDHmut/1p19qint, and all seven with 25-50% mismatch. Well-defined margins correlated with IDHmut/1p19qint status on univariate analysis (p < 0.001), but this related to correlation with T2-FLAIR mismatch; there was no longer an association when considering only tumors with < 25% mismatch (p = 0.386). Enhancement (p = 0.001), necrosis (p = 0.002), and hemorrhage (p = 0.027) correlated with IDHwt status (especially "molecular glioblastoma"). Calcification correlated with IDHmut/1p19qcodel status (p = 0.003). A simple, step-wise algorithm incorporating these features, when present, correctly predicted genotype with a positive predictive value 91.8%. CONCLUSION: T2-FLAIR mismatch strongly predicts IDHmut/1p19qint even with a lower threshold of ≥ 25% mismatch and outweighs other features. Secondary features include enhancement, necrosis and hemorrhage (predicting IDHwt, especially "molecular glioblastoma"), and calcification (predicting IDHmut/1p19qcodel).

Reduction effect of individual N, P, K fertilization on antibiotic resistance genes in reclaimed water irrigated soil.

The transfer of antibiotic resistance genes (ARGs) in soil under reclaimed water irrigation poses a potential environmental risk. Regulation of NPK fertilizer could influence the behavior of bacterial communities, mobile genetic elements (MGEs), and soil properties, which determine the fate of ARGs. To identify the key element in NPK fertilizer and realize efficient regulation, we explored the effect of individual N, P, K fertilization on ARG variation in tomato rhizosphere and bulk soils. Compared with an unfertilized treatment, N fertilization resulted in greater decreases in the abundance of ARGs (decreases of 24.06%-73.09%) than did either P fertilization (increases of up to 35.84%, decreases of up to 58.80%) or K fertilization (decreases of 13.47%-72.47%). The influence of different forms of N (CO(NH2)2, NaNO3, and NH4HCO3), P (Ca(H2PO4)2 and CaMgO4P+), and K (KCl and K2(SO4)) fertilizers was also investigated in this study, and showed the influence of NaNO3, CaMgO4P+, and K2(SO4) on reducing ARGs abundance was greater in different types of N, P, K fertilizers. Bacterial communities showed the strongest response to N fertilization. The reduced bacterial diversity and abundance of ARG-host and non-host organisms explained the decline of total ARG abundance in soil. In soils fertilized with either P or K, the effect of soil properties, especially total nitrogen and pH, on ARG variation was greater than that of bacterial community and MGEs. These results suggest that N regulation of in NPK fertilizer may be an effective way to reduce the risks of ARGs in soil associated with reclaimed water irrigation.

The effects of long-term fertilizations on soil hydraulic properties vary with scales.

Soil structure is an indicator of soil quality and its alterations following cropping system conversion or fertilization change evolve slowly. How such alterations vary with scale remains elusive. We investigated this based on the Rothamsted long-term wheat experiment (since 1843) in the UK. Triplicate cores 7 cm high and 10 cm in diameter were taken from plots that have been under different fertilizations or returned to natural woodland for more than one century for imaging using X-ray computed tomography with the voxel size being 40 µm. We then broke each core and sampled three aggregates from it to scan with the voxel size being 1.5 µm. For each core and aggregate sample, we calculated its pore size distribution, permeability and tortuosity. The results showed that the fertilization change >170 years ago reshaped the soil structure differently between the core scale and the aggregate scale. Macro-porosity of the pores (>40 µm) in the cores unfertilized or fertilized with inorganic fertilizers was low and the pores were poorly connected in the top 10 cm of soil, compared to those given farmyard manure or in the woodland. In all treatments, the pores in the core images were hydraulically anisotropic with their permeability in the horizontal direction being higher than that in the vertical direction, whereas the aggregates were comparatively isotropic. The fertilization affected image porosity and permeability at core scale more significantly than at aggregate scale, and the aggregates fertilized with farmyard manure and in the woodland were more permeable than the aggregates in other treatments. It was also found that compared to no-fertilization or fertilization with complete fertilizers, fertilizing without phosphorus over the past 20 years increased the porosity and permeability of the aggregates but not of the cores. Fertilization with inorganic fertilizers increased the tortuosity of the macropores in the cores but not of the intra-aggregate pores, compared to no-fertilization. Porosity-permeability relationship for aggregates unfertilized or fertilized with inorganic fertilisers followed a power law with R 2 > 0.8. In contrast, the permeability of the aggregates in farmyard manure and in the woodland trended differently as their porosity increased. The results also revealed that the transport ability of the aggregates and cores responded differently to carbon in that with soil carbon increasing, the permeability of the aggregates increased asymptotically while the permeability of the cores, especially its horizontal component, increased exponentially.

Epileptogenicity in tuberous sclerosis complex: A stereoelectroencephalographic study.

OBJECTIVE: In tuberous sclerosis complex (TSC)-associated drug-resistant epilepsy, the optimal invasive electroencephalographic (EEG) and operative approach remains unclear. We examined the role of stereo-EEG in TSC and used stereo-EEG data to investigate tuber and surrounding cortex epileptogenicity. METHODS: We analyzed 18 patients with TSC who underwent stereo-EEG (seven adults). One hundred ten seizures were analyzed with the epileptogenicity index (EI). In 13 patients with adequate tuber sampling, five anatomical regions of interest (ROIs) were defined: dominant tuber (tuber with highest median EI), perituber cortex, secondary tuber (tuber with second highest median EI), nearby cortex (normal-appearing cortex in the same lobe as dominant tuber), and distant cortex (in other lobes). At the seizure level, epileptogenicity of ROIs was examined by comparing the highest EI recorded within each anatomical region. At the patient level, epileptogenic zone (EZ) organization was separated into focal tuber (EZ confined to dominant tuber) and complex (all other patterns). RESULTS: The most epileptogenic ROI was the dominant tuber, with higher EI than perituber cortex, secondary tuber, nearby cortex, and distant cortex (P < .001). A focal tuber EZ organization was identified in seven patients. This group had 80% Engel IA postsurgical outcome and distinct dominant tuber characteristics: continuous interictal discharges (IEDs; 100%), fluid-attenuated inversion recovery (FLAIR) hypointense center (86%), center-to-rim EI gradient, and stimulation-induced seizures (71%). In contrast, six patients had a complex EZ organization, characterized by nearby cortex as the most epileptogenic region and 40% Engel IA outcome. At the intratuber level, the combination of FLAIR hypointense center, continuous IEDs, and stimulation-induced seizures offered 98% specificity for a focal tuber EZ organization. SIGNIFICANCE: Tubers with focal EZ organization have a striking similarity to type II focal cortical dysplasia. The presence of distinct EZ organizations has significant implications for EZ hypothesis generation, invasive EEG approach, and resection strategy.

Information Processing Under Reward Versus Under Punishment.

Much is known about the effects of reward and punishment on behavior, yet little research has considered how these incentives influence the information-processing dynamics that underlie decision making. We fitted the linear ballistic accumulator to data from a perceptual-judgment task to examine the impacts of reward- and punishment-based incentives on three distinct components of information processing: the quality of the information processed, the quantity of that information, and the decision threshold. The threat of punishment lowered the average quality and quantity of information processed, compared with the prospect of reward or no performance incentive at all. The threat of punishment also induced less cautious decision making by lowering people's decision thresholds relative to the prospect of reward. These findings suggest that information-processing dynamics are determined not only by objective properties of the decision environment but also by the higher order goals of the system.

Calcium exerts a strong influence upon phosphohydrolase gene abundance and phylogenetic diversity in soil.

The mechanisms by which microbial communities maintain functions within the context of changing environments are key to a wide variety of environmental processes. In soil, these mechanisms support fertility. Genes associated with hydrolysis of organic phosphoesters represent an interesting set of genes with which to study maintenance of function in microbiomes. Here, we shown that the richness of ecotypes for each gene varies considerably in response to application of manure and various inorganic fertilizer combinations. We show, at unprecedented phylogenetic resolution, that phylogenetic diversity of phosphohydrolase genes are more responsive to soil management and edaphic factors than the taxonomic biomarker 16S rRNA gene. Available phosphorus - assessed by measuring Olsen-P - exerted some influence on alkaline phosphatase distribution: however, consistent and significant differences were observed in gene abundance between treatments that were inconsistent with bioavailable orthophosphate being the dominant factor determining gene abundance. Instead, we observed gene niche separation which was most strongly associated with soil exchangeable calcium. Our study suggests that the bioavailability of enzyme cofactors (exchangeable calcium in the case of phoD, phoX and ßPPhy studied here) influence the abundance of genes in soil microbial communities; in the absence of cofactors, genes coding for alternative enzyme families that do not require the limiting cofactor (for example, non-specific acid phosphatases which require vanadate) become more abundant.

Synthesis of the natural product descurainolide and cyclic peptides from lignin-derived aromatics.

Alternative sources of potential feedstock chemicals are of increasing importance as the availability of oil decreases. The biopolymer lignin is viewed as a source of useful mono-aromatic compounds as exemplified by the industrial scale production of vanillin from this biomass. Alternative lignin-derived aromatics are available in pure form but to date examples of the use of these types of compounds are rare. Here we address this issue by reporting the conversion of an aromatic keto-alcohol to the anti- and syn-isomers of Descurainolide A. The key step involves a rhodium-catalyzed allylic substitution reaction. Enantio-enriched allylic alcohols were generated via an isothiourea-catalyzed kinetic resolution enabling access to both the (2R,3R) and (2S,3S) enantiomers of anti-Descurainolide A. In addition we show that the lignin-derived keto-alcohols can be converted into unnatural amino acid derivatives of tyrosine. Finally, these amino acids were incorporated into cyclic peptide scaffolds through the use of both chemical and an enzyme-mediated macrocylisation.

Efficacy and tolerability of adjuvant lacosamide: The role of clinical characteristics and mechanisms of action of concomitant AEDs.

OBJECTIVE: The objective of this study was to analyze the effectiveness and long-term tolerability of adjuvant lacosamide (LCM) in a multicenter cohort. We aim to assess outcomes of LCM-containing antiepileptic drug (AED) combinations based upon 'mechanism of action' (MoA) and patient's clinical features. METHODS: Consecutive patients commenced on LCM, with focal epilepsy were identified from three Australian hospitals. The 12-month efficacy endpoints were greater than 50% reduction in seizure frequency (responders) and seizure freedom. Tolerability endpoints were cessation of LCM for any reason, cessation due to side-effects and censoring due to inefficacy. Outcomes were assessed according to concomitant AEDs according to their MoA and the clinical risk factor profile. RESULTS: Three hundred ten patients were analyzed and followed for median 17.3months. Two hundred ninety-nine (97%) had drug-resistant epilepsy, and 155 (50%) had tried more than 7 AEDs at LCM commencement. Adjuvant LCM was associated with responder and seizure freedom rate of 29% and 9% respectively at 12months. Lower baseline seizure frequency, a prior 6-month period of seizure freedom at any time since epilepsy diagnosis and being on fewer concomitant AEDs were predictive of 12-month seizure freedom. Previous focal to bilateral tonic-clonic seizures (FBTCS), lower baseline seizure frequency, and concomitant AED reduction after LCM commencement were associated with improved LCM tolerability. No specific MoA AED combinations offered any efficacy or tolerability advantage. SIGNIFICANCE: Adjuvant LCM is associated with seizure freedom rates of 9% at 12months after commencement and is predicted by lower prior seizure frequency, a period of 6months or longer of seizure freedom since diagnosis and fewer concomitant AEDs. While the broad MoA of concomitant AEDs did not influence efficacy or tolerability outcomes, we have provided a framework that may be utilized in future studies to help identify optimal synergistic AED combinations.

IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy.

OBJECTIVE: Isocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II-IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency. METHODS: This was a retrospective study. Patients with grades II-IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A - postoperative seizure freedom; Group B - 1-11 seizures over 12months (less than one seizure per month); and Group C - greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data. RESULTS: One hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p=0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p=0.032) and Group B (RR 9.70, p=0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p=0.004). SIGNIFICANCE: In patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy.

Effects of cropping systems upon the three-dimensional architecture of soil systems are modulated by texture.

Soil delivers fundamental ecosystem functions via interactions between physical and biological processes mediated by soil structure. The structure of soil is also dynamic and modified by natural factors and management intervention. The aim of this study was to investigate the effects of different cropping systems on soil structure at contrasting spatial scales. Three systems were studied in replicated plot field experiments involving varying degrees of plant-derived inputs to the soil, viz. perennial (grassland), annual (arable), and no-plant control (bare fallow), associated with two contrasting soil textures (clayey and sandy). We hypothesized the presence of plants results in a greater range (diversity) of pore sizes and that perennial cropping systems invoke greater structural heterogeneity. Accordingly, the nature of the pore systems was visualised and quantified in 3D by X-ray Computed Tomography at the mm and µm scale. Plants did not affect the porosity of clay soil at the mm scale, but at the µm scale, annual and perennial plant cover resulted in significantly increased porosity, a wider range of pore sizes and greater connectivity compared to bare fallow soil. However, the opposite occurred in the sandy soil, where plants decreased the porosity and pore connectivity at the mm scale but had no significant structural effect at the µm scale. These data reveal profound effects of different agricultural management systems upon soil structural modification, which are strongly modulated by the extent of plant presence and also contingent on the inherent texture of the soil.

Land-use influences phosphatase gene microdiversity in soils.

Phosphorus cycling exerts significant influence upon soil fertility and productivity - processes largely controlled by microbial activity. We adopted phenotypic and metagenomic approaches to investigate phosphatase genes within soils. Microbial communities in bare fallowed soil showed a marked capacity to utilise phytate for growth compared with arable or grassland soil communities. Bare fallowed soil contained lowest concentrations of orthophosphate. Analysis of metagenomes indicated phoA, phoD and phoX, and histidine acid and cysteine phytase genes were most abundant in grassland soil which contained the greatest amount of NaOH-EDTA extractable orthophosphate. Beta-propeller phytase genes were most abundant in bare fallowed soil. Phylogenetic analysis of metagenome sequences indicated the phenotypic shift observed in the capacity to mineralise phytate in bare fallow soil was accompanied by an increase in phoD, phoX and beta-propeller phytase genes coding for exoenzymes. However, there was a remarkable degree of genetic similarity across the soils despite the differences in land-use. Predicted extracellular ecotypes were distributed across a greater range of soil structure than predicted intracellular ecotypes, suggesting that microbial communities subject to the dual stresses of low nutrient availability and reduced access to organic material in bare fallowed soils rely upon the action of exoenzymes.