The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA’s blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body’s natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.

Reconfiguration events in turbulent mixed convection, i.e. the superposition of thermal and forced flow contributions, at the two different Richardson numbers $Ri=1.5$ and $Ri=3.7$ and similar Rayleigh numbers of $Ra \approx 10^8$ are investigated with tomographic particle image velocimetry in combination with local temperature measurements. For both cases, the three-dimensional velocity fields reflect diagonally aligned large-scale circulations (LSC) switching their alignment by rotating their axes around a pivot located at the centre of the LSC, while the temperatures perform a translation movement of the structures in agreement with earlier temperature-based investigations. For the high $Ri$ case, the switching process of the observed spontaneous reconfigurations is induced by a reversing thermal flow contribution while the forced flow contribution is constant. Furthermore, it is shown that a secondary roll structure, which drives the reconfiguration process in Rayleigh–Bénard convection, also exists in mixed convection. However, in the latter, the flow reversals are triggered by different structures which accumulate and release their kinetic energy according to a proper orthogonal decomposition analysis. In contrast, for the low $Ri$ case, the structure formation during continuous reconfigurations is governed by a Taylor- or Görtler-type instability. This means that the forced convection substantially affects the reconfiguration mechanism of these structures. Therefore, the reconfigurations cannot be described by a simple superposition of structures associated with the two flow contributions as for the high $Ri$.

Multi-Robot System (MRS) is composed of a group of robots that work cooperatively. However, Multi-Agent System (MAS) is computational systems consisting of a group of agents that interact with each other to solve a problem. The central difference between MRS and MAS is that in the first case, the agent is a robot, and in the second, it is a software. Analyzing the scientific literature, it is possible to notice that few studies address the integration between MAS and MRS. In order to achieve the interdisciplinary integration, the theoretical background of these areas must be considered in this paper, so that the integration can be applied using a case study of decentralized MRS. The objective of this MRS is to track and surround a stationary target. Also, it has been implemented and validated in the robot simulator called Virtual Robot Experimentation Platform (V-REP). In the validation of the proposed MRS, a scenario with three robots and a stationary target were defined. In the tracking task, the robot can detect the target whose position is not known a priori. When the detection occurs, the V-REP informs the target position to the robot because the environment is discretized into a grid of rectangular cells. After that, all the robots are directed to the target, and the surround task is realized. In this task, a mathematical model with direct communication between the robots was used to keep the robots equidistant therefrom and from each other.

A partly destabilised Na-richterite has been found in an olivine-nephelinite from Morocco. The riehterite crystal (600 × 420 μm) is surrounded by a reaction zone (400-700 μm) of K- and Si-rich glass containing small (<50 μm) olivine (Fo80-83%) and endiopside crystals. Outwards, another zone is formed of normal magmatic minerals and circumscribes the original crystal, indicating that the destabilisation event took place at the end of the crystallisation sequence. Estimated ascent time of about 100 hours would have completely decomposed an isolated richterite crystal, which suggests that the amphibole was originally included in a xenolith. A mass-balance calculation shows that the fichterite isovolumic decomposition was accompanied by exchanges with the magma. The loss of Na from the reaction zone and the gain of AI from the magma allowed the precipitation of an analcime-rich zone observed around the destabilised amphibole and the concentration of K in the reaction zone glass. Compositional variations, Fe and Ti increase and Mg, Ca and F decrease at the richterite edge are interpreted as the result of a diffusion process. No alkali gradients are observed. The diffusion phenomenon lasted less than 100 hours and ceased to be operative at a temperature of 900-950°C i.e. just below the solidus temperature. Diffusion coefficients for the amphibole are proposed: e.g 10−9 cm2 s−1 for K2O and 10−10 for FeO at 900°C

Objectives: The aim of this study was to investigate the relationship of psychological variables to cognitive performance validity test (PVT) results in mixed forensic and nonforensic clinical samples. Methods: Participants included 183 adults who underwent comprehensive neuropsychological examination. Criterion groups were formed, that is, Credible Group or Noncredible Group, based upon their performance on the Word Memory Test and other stand-alone and embedded PVT measures. Results: Multivariate logistic regression analysis identified three significant predictors of cognitive performance validity. These included two psychological constructs, for example, Cogniphobia (perception that cognitive effort will exacerbate neurological symptoms), and Symptom Identity (perception that current symptoms are the result of illness or injury), and one contextual factor (forensic). While there was no interaction between these factors, elevated scores were most often observed in the forensic sample, suggesting that these independently contributing intrinsic psychological factors are more likely to occur in a forensic environment. Conclusions: Illness perceptions were significant predictors of cognitive performance validity particularly when they reached very elevated levels. Extreme elevations were more common among participants in the forensic sample, and potential reasons for this pattern are explored. (JINS, 2018, 24, 1–11)

Loess is common in the Mid-Atlantic region of the United States south of the Late Wisconsinan glacial border particularly along rivers draining the glaciated areas of Pennsylvania, New Jersey, and New York. The broadest deposits occur on the flat landscapes of the Delmarva Peninsula in Maryland where two episodes of deposition have been identified. The earlier Miles Point Loess has a limited distribution and is buried by the more widespread Paw Paw Loess. OSL and 14C dates place deposition of the Miles Point Loess during MIS 3. The well developed paleosol formed in the Miles Point Loess acts as a stratigraphic marker. The Paw Paw Loess buries Clovis age cultural materials which date deposition to the end of the Pleistocene. Loess deposits and paleosols are critical in understanding regional landscape evolution, Late Pleistocene environments, and early North American cultural history. Mapping the extent of loess in the Mid-Atlantic using the Natural Resources Conservation Service’s gSSURGO database overrepresents loess in some areas and underrepresents in others.

Objectives: Tackling ethical dilemmas faced by reimbursement decision makers requires deeper understanding of values on which health technology assessment (HTA) agencies are founded and how trade-offs are made. This was explored in this study including the case of rare disease.

Methods: Representatives from eight HTA explored values on which institutions are founded using a narrative approach and reflective multicriteria (developed from EVIDEM, criteria derived from ethical imperatives of health care). Trade-offs between criteria and the impact of incorporating defined priorities (including for rare diseases) were explored through a quantitative values elicitation exercise.

Results: Participants reported a diversity of substantive and procedural values with a common emphasis on scientific excellence, stakeholder involvement, independence, and transparency. Examining the ethical imperatives behind EVIDEM criteria was found to be useful to further explore substantive values. Most criteria were deemed to reflect institutions’ values, while 70 percent of the criteria were reported by at least half of participants to be considered formally by their institutions. The quantitative values elicitation highlighted the difficulty to balance imperatives of “alleviating or preventing patient suffering,” “serving the whole population equitably,” “upholding healthcare system sustainability,” and “making decisions informed by evidence and context” but may help share the ethical reasoning behind decisions. Incorporating “Priorities” (including for rare diseases) helped reveal trade-offs from other criteria and their underlying ethical imperatives.

Conclusions: Reflective multicriteria are useful to explore substantive values of HTAs, reflect how these values and their ethical underpinnings can be operationalized into criteria, and explore the ethical reasoning at the heart of the healthcare debate.

Within the framework of core-drilling through the permafrost of the active rock glacier Murtèl–Corvatsch in the Swiss Alps, subfossil stem remains of seven different bryophyte species were found at a depth of 6 m below surface and about 3 m below the permafrost table in samples from massive ice. The composition of the moss species points to the former growth of the recovered mosses in the nearest surroundings of the drill site. A total of 127 pollen and spores captured by the mosses and representing 23 taxa were determined. The local vegetation during deposition time must be characterized as a moss-rich alpine grassland meadow rich in Cyperaceae, Poaceae, Chenopodiaceae and Asteraceae, comparable to today’s flora present around the study site. For l4C analysis, accelerator mass spectrometry had to be used due to the small sample mass (about 0.5 mg Carbon content). The mean conventional 14C age of 2250 ± 100 years (1σ variability) corresponds to ranges in the calibrated calendar age of 470–170 BC and 800 BC to AD 0 at statistical probabilities of 68% and 95%, respectively. This result is compared with the present-day flow field as determined by high-precision photogrammetry and with information about the thickness, vertical structure and flow of the permafrost from borehole measurements. Total age of the rock glacier as a landform is on the order of 104 years; the development of the rock glacier most probably started around the onset of the Holocene, when the area it now occupies became definitely deglaciated. The bulk of the ice/rock mixture within the creeping permafrost must be several thousand years old. Characteristic average values are estimated for (1) surface velocities through time (cm a-1), (2) long-term ice and sediment accretion rates (mm a-1) on the debris cone from which the rock glacier develops, (3) retreat rates (1–2 mm a-1) of the cliff which supplies the debris to the debris cone and rock glacier, and (4) ice content of the creeping ice/rock mixture (50–90% by volume). The pronounced supersaturation of the permafrost explains the steady-state creep mode of the rock glacier.

In wild and domestic animals, gastrointestinal parasites can have significant impacts on host development, condition, health, reproduction and longevity. Improving our understanding of the causes and consequences of individual-level variation in parasite load is therefore of prime interest. Here we investigated the relationship between strongyle fecal egg count (FEC) and body condition in a unique, naturalized population of horses that has never been exposed to anthelmintic drugs (Sable Island, Nova Scotia, Canada). We first quantified variation in FEC and condition for 447 individuals according to intrinsic (sex, age, reproductive status, social status) and extrinsic (group size, location, local density) variables. We then quantified the repeatability of measurements obtained over a field season and tested for covariance between FEC and condition. FECs were high relative to other horse populations (mean eggs per gram ± SD = 1543·28 ± 209·94). FECs generally decreased with age, were higher in lactating vs non-lactating females, and unexpectedly lower in males in some part of the island. FECs and condition were both spatially structured, with patterns depending on age, sex and reproductive status. FECs and condition were both repeatable. Most notably, FECs and condition were negatively correlated, especially in adult females.

The immune response to leishmaniasis is complex, and the result of infection depends on both the genetic composition of the Leishmania species and the immunity of the host. Clinical and experimental evidence suggest that the activation of B cells leads to exacerbation of visceral leishmaniasis. However, the role of B-1 cells (a subtype of B lymphocytes) in the pathogenesis of experimental visceral leishmaniasis has not yet been elucidated. In this study, we investigated the importance of B-1 cells in experimental infection with Leishmania. (L.) chagasi. Our results showed that BALB/XID mice (X-linked immunodeficient mice which are genetically deficient in B-1 cells) infected with L. (L.) chagasi for 45 days had a significant reduction in parasite load in the spleen when compared with control mice. Cytokine analysis showed that the BALB/XID mice had lower amounts of IL-10 in their sera compared with control group. In addition, the transfer of B-1 cells from wild type mice into IL-10KO animals led to an increase in susceptibility to L. (L.) chagasi infection in the IL-10KO mice, suggesting that the IL-10 produced by these cells is important in experimental infection. Our results suggest that B-1 cells may play an important role in susceptibility to L. (L.) chagasi.

The Hawaiian Archipelago contains some of the best surveyed black coral populations on the globe; however, most previous surveys have grouped all black coral species into a single category. As a result, the unique ecological features of individual species have not been identified. This study mapped the spatial distribution of eight antipatharian species (Antipathes griggi, Antipathes grandis, Cirrhipathes cf. anguina, Stichopathes echinulata, Stichopathes? sp., Aphanipathes verticillata, Acanthopathes undulata and Myriopathes cf. ulex) found in shallow-waters (<150 m) along the Hawaiian Archipelago, and compared data on substrate type, depth and temperature among species. All black coral species were exclusively recorded on hard substrates and were generally widely distributed along the Hawaiian Islands. Additionally, antipatharian species were found at overlapping depths and temperatures, although there were significant differences in the mean depths and temperatures between most species. In cases where species did not have significant differences in mean depths, the overlapping species had different colony and polyp morphologies, which may serve to minimize competition by allowing species to grow most efficiently under particular current regimes. This study represents one of the first to map the spatial distribution of sympatric antipatharian species, and indicates that individual species exploit unique environments in terms of depth and temperature or have unique morphologies to avoid overlap.

We analyse the first-order asymptotic growth of

\[ a_{n}=\int_{0}^{1}\prod_{j=1}^{n}4\sin^{2}(\pi jx)\, dx. \]

Despite its extreme geographical isolation, numerous expeditions have surveyed the marine flora and fauna of Johnston Atoll. However, historical information about the marine biodiversity of Johnston is mostly limited to SCUBA surveys in shallow-waters (<30 m), and submersible observations in deeper waters (100–500 m). Extensive coral reefs, known as mesophotic coral ecosystems, exist between these two depth ranges at Johnston, but have remained largely unexplored. We used closed-circuit rebreathers to survey eleven sites at mesophotic depths (32–78 m) surrounding Johnston Atoll. A total of 130 species were recorded, including 99 species of fish, 15 species of corals, nine species of macroalgae, three species of echinoderms, three species of sponges and one species of squat lobster. Most species recorded during our mesophotic surveys have previously been recorded on shallow-water (<30 m) reefs at Johnston, with the exception of one black coral, one zoanthid, one squat lobster, two macroalgae, three sponges, and 22 fish, which represent new records for the atoll. As noted in previous studies, our surveys found a near absence of endemism, and recorded high proportions of species that are also known from the Hawaiian Archipelago. The similarity between the mesophotic biodiversity of Johnston Atoll and Hawaiʻi provides further support for the strong connectivity between these two locations highlighted in previous studies.

Non-n-ampleness as denned by Pillay [20] and Evans [5] is preserved under analysability. Generalizing this to a more general notion of Σ-ampleness, this gives an immediate proof for all simple theories of a weakened version of the Canonical Base Property (CBP) proven by Chatzidakis [4] for types of finite SU-rank. This is then applied to the special case of groups.