Partitioning climate projection uncertainty with multiple large ensembles and CMIP5/6

Partitioning uncertainty in projections of future climate change into contributions from internal variability, model response uncertainty and emissions scenarios has historically relied on making assumptions about forced changes in the mean and variability. With the advent of multiple single-model initial-condition large ensembles (SMILEs), these assumptions can be scrutinized, as they allow a more robust separation between sources of uncertainty. Here, the framework from Hawkins and Sutton (2009) for uncertainty partitioning is revisited for temperature and precipitation projections using seven SMILEs and the Coupled Model Intercomparison Project CMIP5 and CMIP6 archives. The original approach is shown to work well at global scales (potential method bias < 20 %), while at local to regional scales such as British Isles temperature or Sahel precipitation, there is a notable potential method bias (up to 50 %), and more accurate partitioning of uncertainty is achieved through the use of SMILEs. Whenever internal variability and forced changes therein are important, the need to evaluate and improve the representation of variability in models is evident. The available SMILEs are shown to be a good representation of the CMIP5 model diversity in many situations, making them a useful tool for interpreting CMIP5. CMIP6 often shows larger absolute and relative model uncertainty than CMIP5, although part of this difference can be reconciled with the higher average transient climate response in CMIP6. This study demonstrates the added value of a collection of SMILEs for quantifying and diagnosing uncertainty in climate projections

Healthy or Environmentally Friendly? Meat Consumption Practices of Green Consumers in Vietnam and Switzerland

High meat consumption is a phenomenon in both developed countries such as Switzerland and emerging countries such as Vietnam. This high meat consumption is associated with environmental, social, and health consequences. Drawing upon social practice theory, this study explores the influence of social practices on the meat consumption of green consumers, as a growing number of consumers in both countries want to eat healthy and sustainably but still have different needs and face different barriers. Data were collected from online group discussions. For green consumers, meat consumption was found to convey certain meanings and depends, among other things, on the information available. The consumption decision in Vietnam is strongly influenced by health and food safety, whereas negative environmental consequences are important in Switzerland. Social and cultural aspects also play a major part in the decision to eat or abstain from meat in both countries. Meat is a non-negotiable part of any special occasion meal in Vietnam and is often eaten at social gatherings in Switzerland. We argue that meat consumption is linked to social status in both countries, but family influence is stronger in Vietnam than in Switzerland. Interventions, such as policy measures that are adapted to regional, cultural, and consumer group specificities and focus on social practices rather than individual behavior, are a promising means to promote meat reduction

Assessing observational constraints on future European climate in an out-of-sample framework

Observations are increasingly used to constrain multi-model projections for future climate assessments. This study assesses the performance of five constraining methods, which have previously been applied to attempt to improve regional climate projections from CMIP5-era models. We employ an out-of-sample testing approach to assess the efficacy of these constraining methods when applied to “pseudo-observational” datasets to constrain future changes in the European climate. These pseudo-observations are taken from CMIP6 simulations, for which future changes were withheld and used for verification. The constrained projections are more accurate and broadly more reliable for regional temperature projections compared to the unconstrained projections, especially in the summer season, which was not clear prior to this study. However, the constraining methods do not improve regional precipitation projections. We also analysed the performance of multi-method projections by combining the constrained projections, which are found to be competitive with the best-performing individual methods and demonstrate improvements in reliability for some temperature projections. The performance of the multi-method projection highlights the potential of combining constraints for the development of constraining methods

Identification of a New Chemical Class of Antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potentia

Self-reported sleep disturbances in renal transplant recipients

Abstract Background: Poor sleep quality (SQ) and daytime sleepiness (DS) are common in renal transplant (RTx) recipients; however, related data are rare. This study describes the prevalence and frequency of self-reported sleep disturbances in RTx recipients. Methods: This cross-sectional study included 249 RTx recipients transplanted at three Swiss transplant centers. All had reported poor SQ and / or DS in a previous study. With the Survey of Sleep (SOS) self-report questionnaire, we screened for sleep and health habits, sleep history, main sleep problems and sleep-related disturbances. To determine a basis for preliminary sleep diagnoses according to the International Classification of Sleep Disorders (ICSD), 164 subjects were interviewed (48 in person, 116 via telephone and 85 refused). Descriptive statistics were used to analyze the data and to determine the frequencies and prevalences of specific sleep disorders. Results: The sample had a mean age of 59.1 ± 11.6 years (60.2% male); mean time since Tx was 11.1 ± 7.0 years. The most frequent sleep problem was difficulty staying asleep (49.4%), followed by problems falling asleep (32.1%). The most prevalent sleep disturbance was the need to urinate (62.9%), and 27% reported reduced daytime functionality. Interview data showed that most suffered from the first ICSD category: insomnias

Assessing observational constraints on future European climate in an out-of-sample framework

Observations are increasingly used to constrain multi-model projections for future climate assessments. This study assesses the performance of five constraining methods, which have previously been applied to attempt to improve regional climate projections from CMIP5-era models. We employ an out-of-sample testing approach to assess the efficacy of these constraining methods when applied to “pseudo-observational” datasets to constrain future changes in European climate. These pseudo-observations are taken from CMIP6 simulations, for which future changes were withheld and used for verification. The constrained projections are more accurate and broadly more reliable for regional temperature projections compared to the unconstrained projections, especially in the summer season, which was not clear prior to this study. However, the constraining methods do not improve regional precipitation projections. We also analysed the performance of multi-method projections, by combining the constrained projections, which are found to be competitive with the best performing individual methods and demonstrate improvements in reliability for some temperature projections. The performance of the multi-method projection highlights the potential of combining constraints for the development of constraining methods

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

Nutzen für BürgerInnen und Verwaltung durch einen Smart Service-orientierten Gestaltungsansatz

Mit der Digitalisierung und der Servitisierung (d. h. der Service Transformation) überlagern sich zwei Entwicklungen mit ausgeprägtem Potenzial für die Schaffung von Nutzen für Menschen und Organisationen in der Wirtschaft, der Verwaltung und somit der Gesellschaft insgesamt. Die konzeptionellen Ansätze für die digitale Service-Transformation in Unternehmen sind Gegenstand intensiver Forschung und Innovation sowie durch zahlreiche Best-Practice-Ansätze belegt. Das Ziel dieses Kapitels besteht darin, eine Service-orientierte Perspektive auf Themen der öffentlichen Verwaltung anhand einer Literaturanalyse und ausgewählten Beispielen in der Schweiz einzunehmen sowie die Gestaltungsprinzipien für die Smart Service Innovation aus diesem Blickwinkel zu diskutieren und den daraus resultierenden Nutzen für BürgerInnen und Verwaltung abzuleiten

Quantifying uncertainty in European climate projections using combined performance-independence weighting

Uncertainty in model projections of future climate change arises due to internal variability, multiple possible emission scenarios, and different model responses to anthropogenic forcing. To robustly quantify uncertainty in multi-model ensembles, inter-dependencies between models as well as a models ability to reproduce observations should be considered. Here, a model weighting approach, which accounts for both independence and performance, is applied to European temperature and precipitation projections from the CMIP5 archive. Two future periods representing mid- and end-of-century conditions driven by the high-emission scenario RCP8.5 are investigated. To inform the weighting, six diagnostics based on three observational estimates are used to also account for uncertainty in the observational record. Our findings show that weighting the ensemble can reduce the interquartile spread by more than 20% in some regions, increasing the reliability of projected changes. The mean temperature change is most notably impacted by the weighting in the Mediterranean, where it is found to be 0.35 °C higher than the unweighted mean in the end-of-century period. For precipitation the largest differences are found for Northern Europe, with a relative decrease in precipitation of 2.4% and 3.4% for the two future periods compared to the unweighted case. Based on a perfect model test, it is found that weighting the ensemble leads to an increase in the investigated skill score for temperature and precipitation while minimizing the probability of overfitting

Open reduction and fixation of medial Moore type II fractures of the tibial plateau by a direct dorsal approach

INTRODUCTION: Moore type II Entire Condyle fractures of the tibia plateau represent a rare and highly unstable fracture pattern that usually results from high impact traumas. Specific recommendations regarding the surgical treatment of these fractures are sparse. We present a series of Moore type II fractures treated by open reduction and internal fixation through a direct dorsal approach. PATIENTS AND METHODS: Five patients (3 females, 2 males) with Entire Condyle fractures were retrospectively analyzed after a mean follow-up period of 39 months (range 12-61 months). Patient mean age at the time of operation was 36 years (range 26-43 years). Follow-up included clinical and radiological examination. Furthermore, all patient finished a SF36 and Lysholm knee score questionnaire. RESULTS: Average range of motion was 127/0/1 degrees with all patients reaching full extension at the time of last follow up. Patients reached a mean Lysholm score of 81.2 points (range 61-100 points) and an average SF36 of 82.36 points (range 53.75-98.88 points). One patient sustained deep wound infection after elective implant removal 1 year after the initial surgery. Overall all patients were highly satisfied with the postoperative result. CONCLUSION: The direct dorsal approach to the tibial plateau represents an adequate method to enable direct fracture exposure, open reduction, and internal fixation in posterior shearing medial Entire Condyle fractures and is especially valuable when also the dorso-lateral plateau is depressed