The bottom-up approach of the Nationally Determined Contributions (NDCs) in the Paris Agreement has led countries to self-determine their greenhouse gas (GHG) emission reduction targets. The planned ...‘ratcheting-up’ process, which aims to ensure that the NDCs comply with the overall goal of limiting global average temperature increase to well below 2 °C or even 1.5 °C, will most likely include some evaluation of ‘fairness’ of these reduction targets. In the literature, fairness has been discussed around equity principles, for which many different effort-sharing approaches have been proposed. In this research, we analysed how country-level emission targets and carbon budgets can be derived based on such criteria. We apply novel methods directly based on the global carbon budget, and, for comparison, more commonly used methods using GHG mitigation pathways. For both, we studied the following approaches: equal cumulative per capita emissions, contraction and convergence, grandfathering, greenhouse development rights and ability to pay. As the results critically depend on parameter settings, we used the wide authorship from a range of countries included in this paper to determine default settings and sensitivity analyses. Results show that effort-sharing approaches that (i) calculate required reduction targets in carbon budgets (relative to baseline budgets) and/or (ii) take into account historical emissions when determining carbon budgets can lead to (large) negative remaining carbon budgets for developed countries. This is the case for the equal cumulative per capita approach and especially the greenhouse development rights approach. Furthermore, for developed countries, all effort-sharing approaches except grandfathering lead to more stringent budgets than cost-optimal budgets, indicating that cost-optimal approaches do not lead to outcomes that can be regarded as fair according to most effort-sharing approaches.
Cerebral cavernous malformations (CCMs) are vascular lesions affecting the central nervous system. CCM occurs either sporadically or in an inherited, autosomal dominant manner. Constitutional ...(germline) mutations in any of three genes, KRIT1, CCM2 and PDCD10, can cause the inherited form. Analysis of CCM lesions from inherited cases revealed biallelic somatic mutations, indicating that CCM follows a Knudsonian two-hit mutation mechanism. It is still unknown, however, if the sporadic cases of CCM also follow this genetic mechanism. We extracted DNA from 11 surgically excised lesions from sporadic CCM patients, and sequenced the three CCM genes in each specimen using a next-generation sequencing approach. Four sporadic CCM lesion samples (36%) were found to contain novel somatic mutations. Three of the lesions contained a single somatic mutation, and one lesion contained two biallelic somatic mutations. Herein, we also describe evidence of somatic mosaicism in a patient presenting with over 130 CCM lesions localized to one hemisphere of the brain. Finally, in a lesion regrowth sample, we found that the regrown CCM lesion contained the same somatic mutation as the original lesion. Together, these data bolster the idea that all forms of CCM have a genetic underpinning of the two-hit mutation mechanism in the known CCM genes. Recent studies have found aberrant Rho kinase activation in inherited CCM pathogenesis, and we present evidence that this pathway is activated in sporadic CCM patients. These results suggest that all CCM patients, including those with the more common sporadic form, are potentially amenable to the same therapy.
Summary
Objective
Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 ...to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions.
Methods
Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded.
Results
Eighty‐two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording.
Significance
About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video‐EEG monitoring, and can contribute to treatment decisions.
Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% ...of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.PurposeExecute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.ExperimentalTen patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.ResultsFive out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.ConclusionThe clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.
Highlights • Outcomes of epilepsy surgery are improved with detection of structural pathology. • Double Inversion Recovery on 3T MRI allowed detection of new lesions in 3 of 29 cases. • Lesions were ...clinically concordant in 1 case and non-discordant in 1 case. • More data are needed to assess the clinical utility of Double inversion recovery.
•A robust prospective pharmacokinetic study demonstrates an interaction between lamotrigine and coffee.•Coffee consumption decreases lamotrigine area under the curve and maximum ...concentration.•Cigarette use does not change lamotrigine area under the curve and maximum concentration.
The objective of this analysis was to determine possible interactions between lamotrigine (LTG) and coffee or cigarette use. As part of the statistical analysis of factors influencing LTG pharmacokinetics (PK) in the Equigen chronic dose study, we collected prospective data from enrolled patients on their use of coffee and cigarettes. Subjects were part of a crossover replication study of generic LTG products with rigorous blood sampling and were instructed to not change their typical consumption of these products for the duration of the study. A total of 35 subjects were enrolled, with 33 subjects having sufficient data for analysis. Higher consumption of coffee was associated with a significantly lower area under the curve (AUC) and maximum concentration (Cmax) of lamotrigine (LTG). Higher cigarette use did not result in a significant change in AUC or Cmax. Coffee, but not cigarette use, either induces LTG metabolism or inhibits LTG absorption.
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