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ImportanceMany patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.ObjectiveTo evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).Design, setting, and participantsThis phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.InterventionsPatients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).Main outcomes and measuresThe primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.ResultsA total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P

Abstract Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase the probability of successful drug development. The frequency analysis of electroencephalographic (EEG) activity, either spontaneous or evoked by transcranial magnetic stimulation (TMS-EEG) can provide cortical readouts for AEDs. However, a systematic evaluation of the effect of AEDs on spontaneous oscillations and TMS-related spectral perturbation (TRSP) has not yet been provided. We studied the effects of Lamotrigine, Levetiracetam, and of a novel potassium channel opener (XEN1101) in two groups of healthy volunteers. Levetiracetam suppressed TRSP theta, alpha and beta power, whereas Lamotrigine decreased delta and theta but increased the alpha power. Finally, XEN1101 decreased TRSP delta, theta, alpha and beta power. Resting-state EEG showed a decrease of theta band power after Lamotrigine intake. Levetiracetam increased theta, beta and gamma power, while XEN1101 produced an increase of delta, theta, beta and gamma power. Spontaneous and TMS-related cortical oscillations represent a powerful tool to characterize the effect of AEDs on in vivo brain activity. Spectral fingerprints of specific AEDs should be further investigated to provide robust and objective biomarkers of biological effect in human clinical trials.

BackgroundRSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors.MethodsThe pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity.ResultsIn rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized.ConclusionsRSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.

Abstract Objective Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS‐evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. Methods TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2‐, 4‐, and 6‐hours post drug intake in a double‐blind, placebo‐controlled, randomized, two‐period crossover study of 20 healthy male volunteers. Results Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15–55 msec after TMS) and at late (150–250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time‐dependent increase that correlated with the XEN1101 plasma concentration. Interpretation Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early‐stage clinical trials.

Managing forests and forest products has substantial potential to help mitigate climate change but the cost has not been extensively examined in Canada. We estimated the cost of seven forest-related mitigation strategies in Canada's 230 million hectares of managed forest, divided into 32 spatial units. For each strategy and spatial unit, we determined forest sector mitigation cost per tonne (t) using estimated impacts on forest sector greenhouse gas emissions and removals and net revenue. National cost curves showed that mitigation averaged 11.0 Mt C[O.sub.2]e x [year.sup.-1] in 2015-2050 at costs below $50 x t C[O.sub.2]e x [year.sup.-1] for a strategy of increased recovery of harvested biomass, increased salvage, extraction of harvest residues for bioenergy, and increased production of longer lived products. We also examined national portfolios in which the strategy selected for each spatial unit (from among the seven examined) was chosen to maximize mitigation or minimize costs. At low levels of mitigation, portfolios chosen to minimize costs were much cheaper than those that maximized mitigation, but overall, they yielded less than half the total mitigation of the latter portfolios. Choosing strategies to maximize mitigation in 2015-2050 yielded an average of 16.5 Mt-year-1 at costs below $50 x t C[O.sub.2]e x [year.sup.-1]. Our analysis suggests that forest-related strategies may be cost-effective choices to help achieve long-term emission reductions in Canada. Key words: Canada, cost, climate change mitigation, forest management, harvested wood products. L'amenagement des forets et les produits forestiers ont un potentiel considerable pour attenuer les changements climatiques, mais au Canada peu d'etudes ont examine les couts associes a ces mesures. Nous avons estime le cout de sept strategies d'attenuation en milieu forestier dans les 230 millions d'hectares de forets amenagees du Canada divisees en 32 unites spatiales. Pour chaque strategie et chaque unite spatiale, nous avons determine le cout par tonne (t) de l'attenuation due au secteur forestier en ayant recours a l'estimation des impacts sur l'emission et l'absorption de gaz a effet de serre et sur le revenu net associes au secteur forestier. Selon les courbes de cout nationales, le niveau d'attenuation atteindrait en moyenne 11,0 Mt eq. C[O.sub.2] x [an.sup.-1] de 2015 a 2050 a un cout de moins de 50 $-t eq. [C[O.sub.2].sup.-1] pour une strategie qui inclut la recuperation accrue de la biomasse recoltee, une plus grande recuperation, la recolte des residus forestiers pour la bioenergie et une augmentation de la production de produits qui ont une plus longue duree de vie. Nous avons aussi evalue les portefeuilles nationaux dans lesquels la strategie selectionnee pour chaque unite spatiale (parmi les sept strategies etudiees) a ete choisie pour maximiser l'attenuation et minimiser les couts. Pour des niveaux d'attenuation faibles, les portefeuilles qui ont ete retenus pour minimiser les couts etaient beaucoup moins dispendieux que ceux qui maximisaient l'attenuation, mais globalement ils ont produit moins de la moitie de l'attenuation totale. Choisir des strategies qui maximisent l'attenuation de 2015 a 2050 entrainerait une reduction moyenne des emissions de 16,5 Mt x [an.sup.-1] a un cout de moins de 50 $-t eq. [C[O.sub.2].sup.-1]. Notre analyse indique que les strategies en lien avec le secteur forestier peuvent etre des choix rentables pour atteindre les objectifs a long terme de reduction des emissions au Canada. [Traduit par la Redaction] Mots-cles: Canada, cout, attenuation des changements climatiques, amenagement forestier, recolte de produits forestiers., 1. Introduction Management of forests and forest products has substantial global potential to mitigate climate change by reducing greenhouse gas (GHG) emissions or increasing carbon sequestration (Barker et al. 2007; [...]

In this qualitative study, over the period of one year, we assessed the appropriateness of a mainstream early childhood education intervention, the Home Instruction for Parents of Preschool Youngsters (HIPPY) programme, in five on-reserve First Nations communities, by focusing on the experiences of the Aboriginal women who delivered the programme. Findings revealed a process of "taking ownership" of HIPPY. "Taking ownership" included three subprocesses: changes in the women's views regarding (1) the strengths of the programme; (2) self-identity; and (3) the identification of the programme as Aboriginal. Through taking ownership, the women were no longer content to deliver HIPPY strictly as it was described in the programme manuals. Although the women continued to maintain that HIPPY was valuable for their communities, their actions and words clearly demonstrated that sharing cultural knowledge in the context of the programme was important to them and, they believed, important for the children and families they worked with. The process documented here points to the importance of Aboriginal culture reflected in educational provisions for Aboriginal children--whether this can be appropriately achieved through supplementing and/or adapting mainstream programmes remains a point of debate. (Contains 2 tables.)

Quantitative assessment of Canada's boreal forest mitigation potential is not yet possible, though the range of mitigation activities is known, requirements for sound analyses of options are increasingly understood, and there is emerging recognition that biogeophysical effects need greater attention. Use of a systems perspective highlights trade-offs between activities aimed at increasing carbon storage in the ecosystem, increasing carbon storage in harvested wood products (HWPs), or increasing the substitution benefits of using wood in place of fossil fuels or more emissions-intensive products. A systems perspective also suggests that erroneous conclusions about mitigation potential could result if analyses assume that HWP carbon is emitted at harvest, or bioenergy is carbon neutral. The greatest short-run boreal mitigation benefit generally would be achieved by avoiding greenhouse gas emissions; but over the longer run, there could be significant potential in activities that increase carbon removals. Mitigation activities could maximize landscape carbon uptake or maximize landscape carbon density, but not both simultaneously. The difference between the two is the rate at which HWPs are produced to meet society's demands, and mitigation activities could seek to delay or reduce HWP emissions and increase substitution benefits. Use of forest biomass for bioenergy could also contribute though the point in time at which this produces a net mitigation benefit relative to a fossil fuel alternative will be situation-specific. Key knowledge gaps exist in understanding boreal mitigation strategies that are robust to climate change and how mitigation could be integrated with adaptation to climate change. Key words: boreal forest, Canada, carbon, climate change, mitigation. L'evaluation quantitative du potentiel de mitigation des forets boreales canadiennes n'est pas encore possible bien que l'on connaisse l'amplitude des activites de mitigation, que les besoins en analyses solides des options soient de mieux en mieux compris et qu'on observe une reconnaissance emergente que les effets biogeographiques necessitent une plus grande attention. Une approche par systeme souligne les balances entre les activites cherchant a augmenter l'immobilisation du carbone dans l'ecosysteme, a augmenter l'accumulation du carbone dans les produits ligneux recoltes (PLRs), ou a augmenter les benefices de substitution consistant a utiliser le bois plutot que les combustibles fossiles ou des produits a plus fortes emissions. Une approche par systeme suggere egalement que les conclusions erronees quant au potentiel de mitigation pourraient apparaitre si les analyses assument que le carbone PLR est emis a la recolte, ou que la bioenergie est carbone neutre. Le meilleur benefice a court terme de la mitigation boreale serait generalement atteint en evitant les emissions a effet serre, mais sur le long terme il pourrait y avoir un potentiel significatif dans les activites augmentant la suppression du carbone. Les activites de mitigation pourraient maximiser l'absorption du carbone du paysage ou maximiser la densite en carbone du paysage, mais non pas les deux simultanement. La difference entre les deux se trouve dans le taux avec lequel les PLRs sont produits pour rencontrer les besoins de la societe et les activites de mitigation pourraient chercher a retarder ou reduire les emissions des PRL et a augmenter les benefices de la substitution. L'utilisation de la biomasse pour l'energie pourrait aussi contribuer bien que le moment auquel ceci produit un benefice net de mitigation par rapport a l'alternative du combustible fossile sera specifique a une situation. Il existe un manque de connaissances pour comprendre les strategies de mitigation boreales qui soient robustes par rapport au changement climatique et savoir comment on pourrait integrer la mitigation avec l'adaptation au changement climatique. [Traduit par la Redaction] Mots-cles: foret boreale, Canada, carbone, changement climatique, mitigation., 1. Introduction Global emissions of carbon dioxide (C[O.sub.2]) averaged 32.3 [+ or -] 3.2 Gt C[O.sub.2]/year in 2000-2009 as a result of fossil fuel combustion, cement production, and land-use change [...]

Abstract In this qualitative study, over the period of one year, we assessed the appropriateness of a mainstream early childhood education intervention, the Home Instruction for Parents of Preschool Youngsters (HIPPY) programme, in five on-reserve First Nations communities, by focusing on the experiences of the Aboriginal women who delivered the programme. Findings revealed a process of “taking ownership” of HIPPY. “Taking ownership” included three subprocesses: changes in the women’s views regarding (1) the strengths of the programme; (2) self-identity; and (3) the identification of the programme as Aboriginal. Through taking ownership, the women were no longer content to deliver HIPPY strictly as it was described in the programme manuals. Although the women continued to maintain that HIPPY was valuable for their communities, their actions and words clearly demonstrated that sharing cultural knowledge in the context of the programme was important to them and, they believed, important for the children and families they worked with. The process documented here points to the importance of Aboriginal culture reflected in educational provisions for Aboriginal children - whether this can be appropriately achieved through supplementing and/or adapting mainstream programmes remains a point of debate.

Whole cell patch-clamp techniques were utilized to determine the sensitivity of delayed rectifier potassium currents (IK) in guinea pig ventricular myocytes to intracellular Mg2+ concentrations ([Mg2+]i). The delayed rectifier IK current in guinea pig ventricular myocytes was reduced by elevated concentrations of [Mg2+]i during low levels of free intracelllur Mg2+. Furthermore, the reductions in IK by [Mg2+]i were caused by a voltage-dependent shift in activation to more depolarized potentials.