Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy: Depression is a major confounding factor

Objective: To assess the efficacy of Sativex, a cannabis-based medicinal extract, as adjuvant treatment in painful diabetic peripheral neuropathy (DPN). Research design and methods: In this randomized controlled trial, 30 subjects with painful DPN received daily Sativex or placebo. The primary outcome measure was change in mean daily pain scores, and secondary outcome measures included quality-of-life assessments. Results: There was significant improvement in pain scores in both groups, but mean change between groups was not significant. There were no significant differences in secondary outcome measures. Patients with depression had significantly greater baseline pain scores that improved regardless of intervention. Conclusions: This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN. Depression was a major confounder and may have important implications for future trials on painful DPN

Modeling seizures in the Human Phenotype Ontology according to contemporary ILAE concepts makes big phenotypic data tractable.

OBJECTIVE: The clinical features of epilepsy determine how it is defined, which in turn guides management. Therefore, consideration of the fundamental clinical entities that comprise an epilepsy is essential in the study of causes, trajectories, and treatment responses. The Human Phenotype Ontology (HPO) is used widely in clinical and research genetics for concise communication and modeling of clinical features, allowing extracted data to be harmonized using logical inference. We sought to redesign the HPO seizure subontology to improve its consistency with current epileptological concepts, supporting the use of large clinical data sets in high-throughput clinical and research genomics. METHODS: We created a new HPO seizure subontology based on the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types, and integrated concepts of status epilepticus, febrile, reflex, and neonatal seizures at different levels of detail. We compared the HPO seizure subontology prior to, and following, our revision, according to the information that could be inferred about the seizures of 791 individuals from three independent cohorts: 2 previously published and 150 newly recruited individuals. Each cohort\u27s data were provided in a different format and harmonized using the two versions of the HPO. RESULTS: The new seizure subontology increased the number of descriptive concepts for seizures 5-fold. The number of seizure descriptors that could be annotated to the cohort increased by 40% and the total amount of information about individuals\u27 seizures increased by 38%. The most important qualitative difference was the relationship of focal to bilateral tonic-clonic seizure to generalized-onset and focal-onset seizures. SIGNIFICANCE: We have generated a detailed contemporary conceptual map for harmonization of clinical seizure data, implemented in the official 2020-12-07 HPO release and freely available at hpo.jax.org. This will help to overcome the phenotypic bottleneck in genomics, facilitate reuse of valuable data, and ultimately improve diagnostics and precision treatment of the epilepsies

Sr-Nd-Pb-Hf isotope results from ODP Leg 187: Evidence for mantle dynamics of the Australian-Antarctic Discordance and origin of the Indian MORB source

New high precision PIMMS Hf and Pb isotope data for 14–28 Ma basalts recovered during ODP Leg 187 are compared with zero-age dredge samples from the Australian-Antarctic Discordance (AAD). These new data show that combined Nd-Hf isotope systematics can be used as an effective discriminant between Indian and Pacific MORB source mantle domains. In particular, Indian mantle is displaced to lower εNd and higher εHf ratios compared to Pacific mantle. As with Pb isotope plots, there is almost no overlap between the two mantle types in Nd-Hf isotope space. On the basis of our new Nd-Hf isotope data, we demonstrate that Pacific MORB-source mantle was present near the eastern margin of the AAD from as early as 28 Ma, its boundary with Indian MORB-source mantle coinciding with the eastern edge of a basin-wide arcuate depth anomaly that is centered on the AAD. This observation rules out models requiring rapid migration of Pacific MORB mantle into the Indian Ocean basin since separation of Australia from Antarctica. Although temporal variations in isotopic composition can be discerned relative to the fracture zone boundary of the modern AAD at 127°E, the distribution of different compositional groups appears to have remained much the same relative to the position of the residual depth anomaly for the past 30 m.y. Thus significant lateral flow of mantle along the ridge axis toward the interface appears unlikely. Instead, the dynamics that maintain both the residual depth anomaly and the isotopic boundary between Indian and Pacific mantle are due to eastward migration of the Australian and Antarctic plates over a stagnated, but slowly upwelling, slab oriented roughly orthogonal to the ridge axis. Temporal and spatial variations in the compositions of Indian MORB basalts within the AAD can be explained by progressive displacement of shallower Indian MORB-source mantle by deeper mantle having a higher εHf composition ascending ahead of the upwelling slab. Models for the origin of the distinctive composition of the Indian MORB-source based on recycling of a heterogeneous enriched component that consist of ancient altered ocean crust plus<10% pelagic sediment are inconsistent with Nd-Hf isotope systematics. Instead, the data can be explained by a model in which Indian mantle includes a significant proportion of material that was processed in the mantle wedge above a subduction zone and was subsequently mixed back into unprocessed upper mantle

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth\u27s climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth\u27s climate history

GEOTRACES IC1 (BATS) contamination-prone trace element isotopes Cd, Fe, Pb, Zn, Cu, and Mo intercalibration

International audienceWe report data on the isotopic composition of cadmium, copper, iron, lead, zinc, and molybdenum at the GEOTRACES IC1 BATS Atlantic intercalibration station. In general, the between lab and within-lab precisions are adequate to resolve global gradients and vertical gradients at this station for Cd, Fe, Pb, and Zn. Cd and Zn isotopes show clear variations in the upper water column and more subtle variations in the deep water; these variations are attributable, in part, to progressive mass fractionation of isotopes by Rayleigh distillation from biogenic uptake and/or adsorption. Fe isotope variability is attributed to heavier crustal dust and hydrothermal sources and light Fe from reducing sediments. Pb isotope variability results from temporal changes in anthropogenic source isotopic compositions and the relative contributions of U.S. and European Pb sources. Cu and Mo isotope variability is more subtle and close to analytical precision. Although the present situation is adequate for proceeding with GEOTRACES, it should be possible to improve the within-lab and between-lab precisions for some of these properties

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth\u27s climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth\u27s climate history

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix