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To report response to first treatment in infants with infantile spasms (IS), including incremental benefit of prednisolone 60 mg/day and vigabatrin following prednisolone 40 mg/day failure in infants commenced on the United Kingdom Infantile Spasms Study (UKISS) treatment sequence.In this retrospective analysis, we compared effectiveness of prednisolone, vigabatrin and nonstandard treatments as first treatment for IS. In infants who commenced the UKISS treatment sequence, we evaluated response to each step. Primary outcome was spasm cessation after 42 days. Secondary outcomes were severe side effects and spasm relapse after 42 days.Treatment response data were available for 151 infants. First treatment was prednisolone in 99 infants, vigabatrin in 18 and nonstandard treatment in 34. The rate of spasm cessation with first treatment was significantly higher with prednisolone (62/99, 63%) than vigabatrin (5/18, 28%, P = 0.01) or nonstandard treatment (2/34, 5.9%, P 0.01). Of 112 infants who commenced the UKISS treatment sequence, 71/112 (63%) responded to prednisolone 40 mg/day. Among non-responders, 12/29 (41%) subsequently responded to prednisolone 60 mg/day, and 10/22 (45%) to vigabatrin. Severe side effects and spasm relapse were not significantly different between each treatment.We confirm higher rates of spasm cessation with initial treatment with prednisolone than vigabatrin and nonstandard therapy. Non-use of prednisolone as first treatment in over one third of infants highlights a concerning treatment gap. The UKISS treatment sequence has high overall treatment response (total 93/112; 83%), with similar benefit of subsequent prednisolone 60 mg/day and vigabatrin in prednisolone 40 mg/day non-responders.

Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes—DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.

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.We studied 27 children and adolescents with MRI-positive BOSD who underwent epilepsy surgery, 85% became seizure-free post resection (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 preoperativeRelative 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 cut-off 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.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.

Purpose Most approaches for energy use assessment in life cycle assessment do not consider the scarcity of energy resources. A few approaches consider the scarcity of fossil energy resources only. No approach considers the scarcity of both renewable and non-renewable energy resources. In this paper, considerations for including physical energy scarcity of both renewable and non-renewable energy resources in life cycle impact assessment (LCIA) are discussed. Methods We begin by discussing a number of considerations for LCIA methods for energy scarcity, such as which impacts of scarcity to consider, which energy resource types to include, which spatial resolutions to choose, and how to match with inventory data. We then suggest three LCIA methods for physical energy scarcity. As proof of concept, the use of the third LCIA method is demonstrated in a well-to-wheel assessment of eight vehicle propulsion fuels. Results and discussion We suggest that global potential physical scarcity can be operationalized using characterization factors based on the reciprocal physical availability for a set of nine commonly inventoried energy resource types. The three suggested LCIA methods for physical energy scarcity consider the following respective energy resource types: (i) only stock-type energy resources (natural gas, coal, crude oil and uranium), (ii) only flow-type energy resources (solar, wind, hydro, geothermal and the flow generated from biomass funds), and (iii) both stock- and flow-type resources by introducing a time horizon over which the stock-type resources are distributed. Characterization factors for these three methods are provided. Conclusions LCIA methods for physical energy scarcity that provide meaningful information and complement other methods are feasible and practically applicable. The characterization factors of the three suggested LCIA methods depend heavily on the aggregation level of energy resource types. Future studies may investigate how physical energy scarcity changes over time and geographical locations.

This systematic review investigated the added value of intraoperative magnetic resonance imaging (iMRI)-guidance in epilepsy surgery, compared to conventional non-iMRI surgery, with respect to the rate of gross total resection (GTR), postoperative seizure freedom, neurological deficits, non-neurological complications and reoperations. A comprehensive literature search was conducted using Medline, Embase, PubMed, and Cochrane Reviews databases. Randomized control trials, case control or cohort studies, and surgical case series published from January 1993 to February 2021 that reported on iMRI-guided epilepsy surgery outcomes for either adults or children were eligible for inclusion. Studies comparing iMRI-guided epilepsy surgery to non-iMRI surgery controls were selected for meta-analysis using random-effects models. Forty-two studies matched the selection criteria and were used for qualitative synthesis and ten of these were suitable for meta-analysis. Overall, studies included various 0.2-3.0 Tesla iMRI systems, contained small numbers with heterogenous clinical characteristics, utilized subjective GTR reporting, and had variable follow-up durations. Meta-analysis demonstrated that the use of iMRI-guidance led to statistically significant higher rates of GTR (RR = 1.31 [95% CI = 1.10-1.57]) and seizure freedom (RR = 1.44 [95% CI = 1.12-1.84]), but this was undermined by moderate to significant statistical heterogeneity between studies (I2 = 55% and I2 = 71% respectively). Currently, there is only level III-2 evidence supporting the use of iMRI-guidance over conventional non-iMRI epilepsy surgery, with respect to the studied outcomes.

ObjectiveTo determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).MethodsWe reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.ResultsThirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0–14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8–9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication.ConclusionBOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping.Classification of EvidenceThis study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.

Pathogenic somatic MTOR variants in the cerebral cortex are a frequent cause of focal cortical dysplasia (FCD). We describe a child with drug and surgery-resistant focal epilepsy due to FCD type II who developed progressive enlargement and T2 signal hyperintensity in the ipsilateral caudate and lentiform nuclei. Histopathology of caudate nucleus biopsies showed dysmorphic neurons, similar to those in resected cortex. Genetic analysis of frontal and temporal cortex and caudate nucleus identified a pathogenic somatic MTOR variant [NM_004958.4:c.4375G C (p.Ala1459Pro)] that was not present in blood-derived gDNA. The mean variant allele frequency ranged from 0.4% to 3.2% in cerebral cortex and up to 5.4% in the caudate nucleus. The basal ganglia abnormalities suggest more widespread, potentially hemispheric dysplasia in this patient, consistent with the pathogenic variant occurring in early cerebral development. This finding provides a potential explanation for persistent seizures in some patients with seemingly complete resection of FCD or disconnection of a dysplastic hemisphere.

As fossil-reliant industries turn to sustainable biomass for energy and material supply, the competition for biogenic carbon is expected to intensify. Using process level carbon and energy balance models, this paper shows how the capture of residual CO2 in conjunction with either permanent storage (CCS) or biofuel production (CCU) benefits fourteen largely residue-based biofuel production pathways. With a few noteworthy exceptions, most pathways have low carbon utilization efficiencies (30–40%) without CCS/U. CCS can double these numbers and deliver negative emission biofuels with GHG footprints below −50 g CO2 eq./MJ for several pathways. Compared to CCS with no revenue from CO2 sequestration, CCU can offer the same efficiency gains at roughly two-third the biofuel production cost (e.g., 99 EUR/MWh vs. 162 EUR/MWh) but the GHG reduction relative to fossil fuels is significantly smaller (18 g CO2 eq./MJ vs. −99 g CO2 eq./MJ). From a combined carbon, cost and climate perspective, although commercial pathways deliver the cheapest biofuels, it is the emerging pathways that provide large-scale carbon-efficient GHG reductions. There is thus some tension between alternatives that are societally best and those that are economically most interesting for investors. Biofuel pathways vent CO2 in both concentrated and dilute streams Capturing both provides the best environomic outcomes. Existing pathways that can deliver low-cost GHG reductions but generate relatively small quantities of CO2 are unlikely to be able to finance the transport infrastructure required for transformative bio-CCS deployment. CCS and CCU are accordingly important tools for simultaneously reducing biogenic carbon wastage and GHG emissions, but to unlock their full benefits in a cost-effective manner, emerging biofuel technology based on the gasification and hydrotreatment of forest residues need to be commercially deployed imminently.

The genus Cephalorhynchus contains four dolphin species, of which three are classified as Near Threatened or Endangered and one subspecies is close to extinction. Understanding the species’ abundan...

ObjectiveTo determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.MethodsTargeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.ResultsBrain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in MTOR and germline variants were identified in DEPDC5 and NPRL3. Two patients with somatic MTOR variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri.ConclusionsBOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.

Biofuel production from algae feedstock has become a topic of interest in the recent decades since algae biomass cultivation is feasible in aquaculture and does therefore not compete with use of arable land. In the present work, hydrothermal liquefaction of both microalgae and macroalgae is evaluated for biofuel production and compared with transesterifying lipids extracted from microalgae as a benchmark process. The focus of the evaluation is on both the energy and carbon footprint performance of the processes. In addition, integration of the processes with an oil refinery has been assessed with regard to heat and material integration. It is shown that there are several potential benefits of co-locating an algae-based biorefinery at an oil refinery site and that the use of macroalgae as feedstock is more beneficial than the use of microalgae from a system energy performance perspective. Macroalgae-based hydrothermal liquefaction achieves the highest system energy efficiency of 38.6%, but has the lowest yield of liquid fuel (22.5 MJ per 100 MJalgae) with a substantial amount of solid biochar produced (28.0 MJ per 100 MJalgae). Microalgae-based hydrothermal liquefaction achieves the highest liquid biofuel yield (54.1 MJ per 100 MJalgae), achieving a system efficiency of 30.6%. Macro-algae-based hydrothermal liquefaction achieves the highest CO2 reduction potential, leading to savings of 24.5 resp 92 kt CO2eq/year for the two future energy market scenarios considered, assuming a constant feedstock supply rate of 100 MW algae, generating 184.5, 177.1 and 229.6 GWhbiochar/year, respectively. Heat integration with the oil refinery is only possible to a limited extent for the hydrothermal liquefaction process routes, whereas the lipid extraction process can benefit to a larger extent from heat integration due to the lower temperature level of the process heat demand.

Humpback whales are known for their complex and well-structured song that is typically produced on low-latitude breeding grounds. However, there is increasing evidence of song production on migrati...

Energy Science & Engineering published by the Society of Chemical Industry and John Wiley & Sons Ltd. Renewable drop-in fuels provide a short- to medium-term solution to decreasing carbon dioxide emissions from the transport sector. Polyoxymethylene ethers (OME) are among interesting candidates with production pathways both from biomass (bio-OME) as well as electricity and CO2 (e-OME) proposed. In the present study, both bio- and e-OME production via methanol are assessed for energy performance and carbon footprint. Process integration methods are applied to evaluate synergies from colocating methanol production with further conversion to OME. Even a hybrid process, combing bio- and e-OME production is evaluated. The energy efficiency of bio-OME is considerably higher than for the e-OME pathway, and colocation synergies are more evident for bio-OME. Carbon footprint is evaluated according to EUs recast Renewable Energy Directive (RED II). If renewable electricity and natural gas are used for power and heat supply, respectively, results indicate that all pathways may be counted toward the renewable fuel targets under RED II. The largest emissions reduction is 92.8% for colocated hybrid-OME production. Carbon footprints of e- and hybrid-OME are highly sensitive to the carbon intensity of electricity, and the carbon intensity of the heat supply has a major impact on results for all pathways except colocated bio- and hybrid-OME.

Variants in the gene SCN1A are a common genetic cause for a wide range of epilepsy phenotypes ranging from febrile seizures to Dravet syndrome. Focal onset seizures and structural lesions can be present in these patients and the question arises whether epilepsy surgery should be considered. We report eight patients (mean age 13y 11mo [SD 8y 1mo], range 3-26y; four females, four males) with SCN1A variants, who underwent epilepsy surgery. Outcomes were variable and seemed to be directly related to the patient's anatomo-electroclinical epilepsy phenotype. Patients with Dravet syndrome had unfavourable outcomes, whilst patients with focal epilepsy, proven to arise from a single structural lesion, had good results. We conclude that the value of epilepsy surgery in patients with an SCN1A variant rests on two issues: understanding whether the variant is pathogenic and the patient's anatomo-electroclinical phenotype. Careful evaluation of epilepsy phenotype integrated with understanding the significance of genetic variants is essential in determining a patient's suitability for epilepsy surgery. Patients with focal onset epilepsy may benefit from epilepsy surgery, whereas those with Dravet syndrome do not. WHAT THIS PAPER ADDS: Patients should not automatically be excluded from epilepsy surgery evaluation if they carry an SCN1A variant. Patients with focal epilepsy may benefit from epilepsy surgery; those with Dravet syndrome do not.

The pulp and paper industry has a high potential to contribute to negative emissions through carbon capture and storage (CCS) applied to existing processes. However, there is a need to investigate how CCS solutions also can be combined with implementation of other emerging technologies in pulp and paper mills. This paper investigates the integration of a novel calcination process in two kraft mills and evaluates its potential combination with capture and storage of CO2 from the calcination plant. The alternative calcination process uses electric gas-plasma technology combined with steam slaking and allows replacing the conventional fuel-driven lime kilns with a process driven by electricity. The novel calcination process generates a pure, biogenic, CO2 stream, which provides an opportunity to achieve negative emissions at relatively lower costs. The potential reduction of greenhouse gas emissions when replacing the lime kiln with the plasma calcination concept depends strongly on the emissions intensity of grid electricity, and on whether fossil fuel or biomass was used as a fuel in the lime kiln. If fossil fuel is replaced and electricity is associated with very low emissions, avoided CO2 emissions reach ~50 kt/a for the smaller mill investigated in the paper (ca 400 kt pulp per year) and almost 100 kt/a for the larger mill (ca 700 kt pulp per year). Further emission reductions could then be achieved through CCS from the electrified calcination process, with capture potentials for the two mills of 95 and 164 kt/a, respectively, and capture and storage costs estimated to 36–60 EUR/tCO2.

Humpback whales (Megaptera novaeangliae) are highly vocal, producing a wide repertoire of sounds often organised into song. Song is prolific at breeding sites but also documented along migration ro...