Long-term individual retention with cenobamate in adults with focal seizures: Pooled data from the clinical development program

Objective: We determined retention on open-label cenobamate therapy in the clinical development program to assess the long-term efficacy and tolerability of adjunctive cenobamate in individuals with uncontrolled focal seizures. // Methods: Data from two randomized, controlled cenobamate studies and one open-label safety and pharmacokinetic study were pooled. Based on the percentage of participants remaining on treatment, retention rates were estimated using Kaplan-Meier survival analyses. We performed two additional analyses to assess factors contributing to retention, stratifying a robust data set (through 2 years) by cenobamate modal dose and frequently used concomitant anti-seizure medications. Cenobamate discontinuations and treatment-emergent adverse events were summarized. // Results: Data from 1844 participants were pooled: 149 from a single-dose randomized trial, 355 from a multi-dose randomized trial, and 1340 from an open-label safety and pharmacokinetic study. Most participants from randomized trials continued in open-label extensions, and pooled data represent >95% of participants exposed to cenobamate. Baseline characteristics and disease and treatment histories were similar across studies. Median duration of cenobamate exposure was 34 months, with a median modal dose of 200 mg/day. Kaplan-Meier estimates of cumulative cenobamate retention rates were 80% at 1 year and 72% at 2 years. Once participants reached the maintenance phase, retention rates were consistently high in participants receiving ≥100 mg/day cenobamate, and concomitant anti-seizure medications did not affect long-term retention. By 2 years, 535 (29%) had actually discontinued cenobamate; the most common reasons for discontinuation were adverse events (37.6%), withdrawal of consent (21.1%), and other (16.8%). // Significance: Treatment retention rates provide a proxy measure for long-term efficacy, safety, tolerability, and adherence. The consistently high retention rates we found suggest that cenobamate may be an effective and well-tolerated new treatment option for people with drug-resistant focal seizures

Soil-induced impacts on forest structure drive coarse woody debris stocks across central Amazonia

PublishedJournal Article© 2014, © 2014 Botanical Society of Scotland and Taylor & Francis. Background: Coarse woody debris (CWD) is an essential component in tropical forest ecosystems and its quantity varies widely with forest types. Aims: Relationships among CWD, soil, forest structure and other environmental factors were analysed to understand the drivers of variation in CWD in forests on different soil types across central Amazonia. Methods: To estimate CWD stocks and density of dead wood debris, 75 permanent forest plots of 0.5 ha in size were assessed along a transect that spanned ca. 700 km in undisturbed forests from north of the Rio Negro to south of the Rio Amazonas. Soil physical properties were evaluated by digging 2-m-deep pits and by taking auger samples. Results: Soil physical properties were the best predictors of CWD stocks; 37% of its variation was explained by effective soil depth. CWD stocks had a two-fold variation across a gradient of physical soil constraints (i.e. effective soil depth, anoxia and soil structure). Average biomass per tree was related to physical soil constraints, which, in turn, had a strong relationship with local CWD stocks. Conclusions: Soil physical properties appear to control average biomass per tree (and through this affect forest structure and dynamics), which, in turn, is correlated with CWD production and stocks

Noncoding RNA, antigenic variation, and the virulence genes of Plasmodium falciparum

Long non-coding RNAs (lncRNA) are being increasingly recognized as important regulators of gene expression. A recent paper in Genome Biology reports the identification of a lncRNA family in Plasmodium falciparum, the cause of the most deadly form of malaria, that may help to explain the mechanism of antigenic variation in virulence genes of this important pathogen

Late-onset erythromelalgia in a previously healthy young woman: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Erythromelalgia is a rare disorder characterized by episodic erythema and burning pain, which commonly involves the extremities. We present a case of late onset erythromelalgia in a previously healthy young woman and briefly review the literature. Our patient's case also has additional uncommon features not reported previously.</p> <p>Case presentation</p> <p>A 33-year-old previously healthy Caucasian woman presented with complaints of episodic burning pain and flushing occurring in a central distribution involving her face, ears, upper chest and, occasionally, her upper extremities. Her symptoms were triggered by lying down or warm temperature exposure and were relieved by cooling measures. Extensive diagnostic work-up looking for secondary causes for the symptoms was negative and the diagnosis of erythromelalgia was made based on details provided in her clinical history supported by raised temperature in the affected area measured by thermography during a symptomatic episode. The patient did not respond to pharmacological therapy or surgical sympathectomy. She was advised on lifestyle modification to avoid activities which triggered her symptoms. She was hypothermic with a core temperature between 92 and 95°F. She also had premature ovarian failure, which had not previously been reported.</p> <p>Conclusion</p> <p>Erythromelalgia is a rare disorder of unknown cause. There is no confirmatory diagnostic test; diagnosis is based on details provided in the patient's medical history and physical examination during the episodes. For those affected, this disorder leads to significant long-term morbidity and unfortunately, to date, no definitive therapy is available except for lifestyle modification.</p

Consequences of replacing native savannahs with acacia plantations for the taxonomic, functional and phylogenetic α- and β-diversity of bats in the northern Brazilian Amazon

Across the globe, millions of hectares of native vegetation have been replaced by commercial plantations, with negative consequences for biodiversity. The effects of the replacement of native vegetation with commercial plantations on the functional and phylogenetic diversity of bat assemblages remain understudied, and most studies have focused exclusively on the taxonomic component of diversity. Here, we investigate how the replacement of natural savannahs by acacia plantations affects the α- and β-diversity of bat assemblages. We sampled bats, using mist-nets at ground level, in natural forest, savannah areas and acacia plantations, in the Lavrados de Roraima in the northern Brazilian Amazon. Our results show that, in general, acacia is less diverse than native forests in terms of taxonomic and functional diversity, and is also less taxonomically diverse than the savannah matrix which it substitutes. The observed patterns of α- and β-diversity found in the present study are in large part driven by the superabundance of one generalist and opportunistic species, Carollia perspicillata, in the acacia plantations. Taken together, our results show that the replacement of areas of natural savannah by acacia plantations causes a regional loss in diversity across all diversity dimensions: taxonomic, functional and phylogenetic. However, further studies are required to fully understand the ecological and conservation implications of this landscape change

Ambient-aware continuous care through semantic context dissemination

Background: The ultimate ambient-intelligent care room contains numerous sensors and devices to monitor the patient, sense and adjust the environment and support the staff. This sensor-based approach results in a large amount of data, which can be processed by current and future applications, e. g., task management and alerting systems. Today, nurses are responsible for coordinating all these applications and supplied information, which reduces the added value and slows down the adoption rate. The aim of the presented research is the design of a pervasive and scalable framework that is able to optimize continuous care processes by intelligently reasoning on the large amount of heterogeneous care data. Methods: The developed Ontology-based Care Platform (OCarePlatform) consists of modular components that perform a specific reasoning task. Consequently, they can easily be replicated and distributed. Complex reasoning is achieved by combining the results of different components. To ensure that the components only receive information, which is of interest to them at that time, they are able to dynamically generate and register filter rules with a Semantic Communication Bus (SCB). This SCB semantically filters all the heterogeneous care data according to the registered rules by using a continuous care ontology. The SCB can be distributed and a cache can be employed to ensure scalability. Results: A prototype implementation is presented consisting of a new-generation nurse call system supported by a localization and a home automation component. The amount of data that is filtered and the performance of the SCB are evaluated by testing the prototype in a living lab. The delay introduced by processing the filter rules is negligible when 10 or fewer rules are registered. Conclusions: The OCarePlatform allows disseminating relevant care data for the different applications and additionally supports composing complex applications from a set of smaller independent components. This way, the platform significantly reduces the amount of information that needs to be processed by the nurses. The delay resulting from processing the filter rules is linear in the amount of rules. Distributed deployment of the SCB and using a cache allows further improvement of these performance results

Demonstration of the event identification capabilities of the NEXT-White detector

In experiments searching for neutrinoless double-beta decay, the possibility of identifying the two emitted electrons is a powerful tool in rejecting background events and therefore improving the overall sensitivity of the experiment. In this paper we present the first measurement of the efficiency of a cut based on the different event signatures of double and single electron tracks, using the data of the NEXT-White detector, the first detector of the NEXT experiment operating underground. Using a 228Th calibration source to produce signal-like and background-like events with energies near 1.6 MeV, a signal efficiency of 71.6 ± 1.5 stat± 0.3 sys% for a background acceptance of 20.6 ± 0.4 stat± 0.3 sys% is found, in good agreement with Monte Carlo simulations. An extrapolation to the energy region of the neutrinoless double beta decay by means of Monte Carlo simulations is also carried out, and the results obtained show an improvement in background rejection over those obtained at lower energies. [Figure not available: see fulltext.

Radiogenic backgrounds in the NEXT double beta decay experiment

Natural radioactivity represents one of the main backgrounds in the search for neutrinoless double beta decay. Within the NEXT physics program, the radioactivity- induced backgrounds are measured with the NEXT-White detector. Data from 37.9 days of low-background operations at the Laboratorio Subterráneo de Canfranc with xenon depleted in 136Xe are analyzed to derive a total background rate of (0.84±0.02) mHz above 1000 keV. The comparison of data samples with and without the use of the radon abatement system demonstrates that the contribution of airborne-Rn is negligible. A radiogenic background model is built upon the extensive radiopurity screening campaign conducted by the NEXT collaboration. A spectral fit to this model yields the specific contributions of 60Co, 40K, 214Bi and 208Tl to the total background rate, as well as their location in the detector volumes. The results are used to evaluate the impact of the radiogenic backgrounds in the double beta decay analyses, after the application of topological cuts that reduce the total rate to (0.25±0.01) mHz. Based on the best-fit background model, the NEXT-White median sensitivity to the two-neutrino double beta decay is found to be 3.5σ after 1 year of data taking. The background measurement in a Qββ±100 keV energy window validates the best-fit background model also for the neutrinoless double beta decay search with NEXT-100. Only one event is found, while the model expectation is (0.75±0.12) events. [Figure not available: see fulltext.]

Contribution of microscopy for understanding the mechanism of action against trypanosomatids

Transmission electron microscopy (TEM) has proved to be a useful tool to study the ultrastructural alterations and the target organelles of new antitrypanosomatid drugs. Thus, it has been observed that sesquiterpene lactones induce diverse ultrastructural alterations in both T. cruzi and Leishmania spp., such as cytoplasmic vacuolization, appearance of multilamellar structures, condensation of nuclear DNA, and, in some cases, an important accumulation of lipid vacuoles. This accumulation could be related to apoptotic events. Some of the sesquiterpene lactones (e.g., psilostachyin) have also been demonstrated to cause an intense mitochondrial swelling accompanied by a visible kinetoplast deformation as well as the appearance of multivesicular bodies. This mitochondrial swelling could be related to the generation of oxidative stress and associated to alterations in the ergosterol metabolism. The appearance of multilamellar structures and multiple kinetoplasts and flagella induced by the sesquiterpene lactone psilostachyin C indicates that this compound would act at the parasite cell cycle level, in an intermediate stage between kinetoplast segregation and nuclear division. In turn, the diterpene lactone icetexane has proved to induce the external membrane budding on T. cruzi together with an apparent disorganization of the pericellar cytoskeleton. Thus, ultrastructural TEM studies allow elucidating the possible mechanisms and the subsequent identification of molecular targets for the action of natural compounds on trypanosomatids.Fil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Spina Zapata, Renata María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Energy calibration of the NEXT-White detector with 1% resolution near Q ββ of 136Xe

Excellent energy resolution is one of the primary advantages of electroluminescent high-pressure xenon TPCs. These detectors are promising tools in searching for rare physics events, such as neutrinoless double-beta decay (ββ0ν), which require precise energy measurements. Using the NEXT-White detector, developed by the NEXT (Neutrino Experiment with a Xenon TPC) collaboration, we show for the first time that an energy resolution of 1% FWHM can be achieved at 2.6 MeV, establishing the present technology as the one with the best energy resolution of all xenon detectors for ββ0ν searches. [Figure not available: see fulltext.