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Abstract: LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy, and non-specific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in eleven families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified twelve distinct homozygous loss-of-function variants in sixteen individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor (“ear-of-the-lynx” sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain, and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the “ear of the lynx” sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Introduction In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need.Methods and analysis We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×106, 10×106 and 15×106 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes.Ethics and dissemination Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations.Trial registration numbers NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).

Abstract Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88−1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73−2.38; p = 0.44). Grade 3−4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p

ABSTRACTBackground: During peacekeeping missions, military personnel may be involved in or exposed to potentially morally injurious experiences (PMIEs), such as an inability to intervene due to a limited mandate. While exposure to such morally transgressive events has been shown to lead to moral injury in combat veterans, research on moral injury in peacekeepers is limited.Objective: We aimed to determine patterns of exposure to PMIEs and associated outcome- and exposure-related factors among Dutch peacekeepers stationed in the former Yugoslavia during the Srebrenica genocide.Method: Self-report data were collected among Dutchbat III veterans (N = 431). We used Latent Class Analysis to identify subgroups of PMIE exposure as assessed by the Moral Injury Scale–Military version. We investigated whether deployment location, posttraumatic stress disorder (PTSD), posttraumatic growth, resilience, and quality of life differentiated between latent classes.Results: The analysis identified a three-class solution: a high exposure class (n = 79), a moderate exposure class (n = 261), and a betrayal and powerlessness-only class (n = 135). More PMIE exposure was associated with deployment location and higher odds of having probable PTSD. PMIE exposure was not associated with posttraumatic growth. Resilience and quality of life were excluded from analyses due to high correlations with PTSD.Conclusions: Peacekeepers may experience varying levels of PMIE exposure, with more exposure being associated with worse outcomes 25 years later. Although no causal relationship may be assumed, the results emphasize the importance of better understanding PMIEs within peacekeeping.

Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr−/− atherogenic mice transplanted with Acod1−/− bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1−/− mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.

Background: Knowledge of fasting or Nil Per Os (NPO) guidelines is an essential component of nursing care in the preoperative period. Aim: To describe registered nurses’ (RNs) knowledge and management of the preoperative NPO period. Setting: Selected surgical wards in a tertiary hospital in the Western Cape, South Africa. Methods: Quantitative descriptive, cross-sectional study utilising a structured questionnaire. The population consisted of RNs working in selected surgical wards. Convenience sampling was used and adequate knowledge was determined as ≥ 90%. Results: The response rate was 100%. Of the 68 participants, 48 (70.6%) held a diploma and 20 (29.4%) held a degree as the highest academic qualification achieved. Sixty-one (89.7%) participants knew the correct reason for keeping patients NPO. Sixty-five (95.6%) knew the correct answer for the NPO time for solids while only 27 (39.7%) knew the correct answer for clear fluids. Only 30 (44.1%), 26 (38.2%) and 33 (48.5%) participants, respectively, answered the questions about oral analgesia, oral antibiotics and chronic medication administration during the NPO period correctly. Significantly more degree participants knew the correct answer for the fasting time for non-human milk (p = 0.005) and more diploma participants would administer chronic medication during the NPO period (p = 0.037). Conclusion: Inadequate knowledge of NPO times for various fluids and unsatisfactory practice of medication administration for oral and chronic medication require attention. Contribution: This study highlights the importance that ongoing education is needed to ensure that patients receive the most up-to-date evidence-based care during the NPO period.

Abstract One of the core questions of quantum physics is how to reconcile the unitary evolution of quantum states, which is information-preserving and time-reversible, with evolution following the second law of thermodynamics, which, in general, is neither. The resolution to this paradox is to recognize that global unitary evolution of a multi-partite quantum state causes the state of local subsystems to evolve towards maximum-entropy states. In this work, we experimentally demonstrate this effect in linear quantum optics by simultaneously showing the convergence of local quantum states to a generalized Gibbs ensemble constituting a maximum-entropy state under precisely controlled conditions, while introducing an efficient certification method to demonstrate that the state retains global purity. Our quantum states are manipulated by a programmable integrated quantum photonic processor, which simulates arbitrary non-interacting Hamiltonians, demonstrating the universality of this phenomenon. Our results show the potential of photonic devices for quantum simulations involving non-Gaussian states.

Objective To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.Design Phase 3b multicentre, double-blind, randomised placebo-controlled trial.Setting Twenty-one hospitals in the UK.Participants Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.Intervention Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.Main outcome measure The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.Secondary outcome measures The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.Results 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.Conclusions The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.Trial registration number Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

As the most abundant animals on earth, nematodes are a dominant component of the soil community. They play critical roles in regulating biogeochemical cycles and vegetation dynamics within and across landscapes and are an indicator of soil biological activity. Here, we present a comprehensive global dataset of soil nematode abundance and functional group composition. This dataset includes 6,825 georeferenced soil samples from all continents and biomes. For geospatial mapping purposes these samples are aggregated into 1,933 unique 1-km pixels, each of which is linked to 73 global environmental covariate data layers. Altogether, this dataset can help to gain insight into the spatial distribution patterns of soil nematode abundance and community composition, and the environmental drivers shaping these patterns.

For more than five decades, research has been conducted at Ny-Ålesund, in Svalbard, Norway, to understand the structure and functioning of High-Arctic ecosystems and the profound impacts on them of environmental change. Terrestrial, freshwater, glacial and marine ecosystems are accessible year-round from Ny-Ålesund, providing unique opportunities for interdisciplinary observational and experimental studies along physical, chemical, hydrological and climatic gradients. Here, we synthesize terrestrial and freshwater research at Ny-Ålesund and review current knowledge of biodiversity patterns, species population dynamics and interactions, ecosystem processes, biogeochemical cycles and anthropogenic impacts. There is now strong evidence of past and ongoing biotic changes caused by climate change, including negative effects on populations of many taxa and impacts of rain-on-snow events across multiple trophic levels. While species-level characteristics and responses are well understood for macro-organisms, major knowledge gaps exist for microbes, invertebrates and ecosystem-level processes. In order to fill current knowledge gaps, we recommend (1) maintaining monitoring efforts, while establishing a long-term ecosystem-based monitoring programme; (2) gaining a mechanistic understanding of environmental change impacts on processes and linkages in food webs; (3) identifying trophic interactions and cascades across ecosystems; and (4) integrating long-term data on microbial, invertebrate and freshwater communities, along with measurements of carbon and nutrient fluxes among soils, atmosphere, freshwaters and the marine environment. The synthesis here shows that the Ny-Ålesund study system has the characteristics needed to fill these gaps in knowledge, thereby enhancing our understanding of High-Arctic ecosystems and their responses to environmental variability and change.

We aimed to study the risks of relapse and long term disability in children with non-MS acquired demyelinating syndromes (ADS). In this prospective, multi-centre study, from the 14 UK pediatric neurology centres, children (<16 years) experiencing a first episode of ADS were recruited from 2010 to 2014. Case report forms were collected prospectively. A total of 269 children were recruited and followed up for a median of 7.2 years. Median age at onset was 9y (IQR 9.5–14.5, 126 females). At last follow-up, 46 (18 %) had MS, 4 AQP4-Ab NMOSD and 206 (80 %) had other ADS, of which 27 (13 %) relapsed. Relapsing MOGAD was the diagnosis in 12/27, 6 were seronegative and 9 did not have antibodies tested. Frequency of relapse differed according to first presentation in non-MS ADS, being least likely in transverse myelitis (p = 0.025). In the non-MS group, MOG-Ab was predictive of relapse (HR = 8.42; p < 0.001) occurring 8 times as often decreasing over time. Long-term difficulties did not differ between children with monophasic vs relapsing diseases. The risk of relapse in non-MS ADS depends on initial diagnosis, and MOG-Ab positivity. Long-term difficulties are observed regardless of relapses and are determined by presenting phenotype. [ABSTRACT FROM AUTHOR]

Integrated photonics is an essential technology for optical quantum computing. Universal, phase-stable, reconfigurable multimode interferometers (quantum photonic processors) enable manipulation of photonic quantum states and are one of the main components of photonic quantum computers in various architectures. In this paper, we report the realization of the largest quantum photonic processor to date. The processor enables arbitrary unitary transformations on its 20 input modes with an amplitude fidelity of $F_{\text{Haar}} = 97.4\%$ and $F_{\text{Perm}} = 99.5\%$ for Haar-random and permutation matrices, respectively, an optical loss of 2.9 dB averaged over all modes, and high-visibility quantum interference with $V_{\text{HOM}}=98\%$. The processor is realized in $\mathrm{Si_3N_4}$ waveguides and is actively cooled by a Peltier element.

This study used tree data from field plots in urban areas to describe forest structure in urban areas throughout California. The plot data were used with numerical models to calculate several ecosystem services produced by trees. A series of transfer functions were calculated to scale-up results from the plots to the landscape using urban tree canopy (UTC) mapped at 1-m resolution for each combination of 6 land use classes and climate zones. California's UTC covered 15% of the urban area and contained 173.2 million trees, five per city resident. UTC per capita was lowest among U.S. states (90.8 m2), indicating ample opportunity for tree planting. Oaks were the most abundant taxon (22%) and overall plantings were youthful. The annual value of ecosystem services was estimated at $8.3 billion and the urban forests asset value was $181 billion. Assuming an average annual per tree management cost of $19 and benefit of $47.83, $2.52 in benefit was returned for every dollar spent. The threat posed by Invasive Shot Hole Borer (Euwallacea sp.) illustrates that urban forests are a relatively fragile resource whose contributions to human health and well-being can be suddenly jeopardized. One scenario projected that should Southern California cities lose 50% (11.6 million) of all susceptible trees, the value of ecoservices foregone over 10 years was $616.6 million. The approximate cost of removing and replacing the trees was $15.9 billion. Strategies to reduce the risk of catastrophic loss by increasing the resilience of California's urban forests are discussed.

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding "big data" that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them.

In this paper, we present and reflect upon a creative and participatory approach for engaging citizens in imagining desirable “zero”-waste futures that include different values and perspectives. The approach emerged through a 4-month collaboration involving academic researchers and creative professionals and was prototyped in a formerly industrial neighborhood of Utrecht (het Werkspoorkwartier), currently being developed as a creative circular manufacturing area. With our approach, we inquire into and provide an alternative to predominant technology-centered policy visions, which portray the issues of waste as objective challenges that can be addressed through data-driven technological solutions. Such visions neglect many other perspectives and values, particularly those of citizens that face the issue of waste in everyday life, thus providing only a narrow vision of how the future might look like. To gather and articulate different perspectives on alternative “zero”-waste futures, we focus on citizen-science-inspired and speculative design methods to engage people and stimulate imagining futures that bring to light diverse values and perspectives. In the development of the methods, we work in close collaboration with creative practitioners, both in terms of anchoring the research in a real-world context and in terms of combining our different types of expertise. Reflecting on the project, we discuss the potential of our transdisciplinary approach and the co-produced methods to intervene in how we see and imagine alternative futures. We do so by taking “translation” as an analytical lens to understand how different meanings and visions are created through experiential, material, and affective modes of expression. Specifically, we will analyze the translations that occur in the processes of moving from abstract data to matters of concern, and from desirable futures to actionable presents. Looking at these multiple processes through the lens of translation will serve to investigate how different future imaginaries are generated through different materials and modalities of translation, offering different forms of engagement in shaping inclusive urban futures. Translation here will be conceptualized less as a perfect transference of information and more as an open-ended process of paying attention to different values, and identifying those matters for which to care for in our urban futures.

BackgroundMilitary members and police officers often operate in high stakes situations and under high levels of physical and psychological stress. Consequently, they may be confronted with morally injurious experiences and develop moral injury. Most treatments for moral injury are cognitive-behavioral, face-to-face treatments, which may be supported by online interventions. Online interventions have shown promise in the treatment of trauma-related psychopathology, but few such interventions for moral injury yet exist.ObjectiveTo develop and conduct a preliminary evaluation of an online treatment module for moral injury in treatment-seeking military veterans and police officers, to be used in conjunction with regular face-to-face treatment.MethodAn online module was developed based on the moral injury literature, using elements from seven existing treatments. A preliminary evaluation was conducted using both quantitative and qualitative methods, and focusing on perceived feasibility, acceptability and engagement of the module, as well as potential benefits and harms. The concept module was evaluated by 15 assessors, including patient representatives, multidisciplinary caregivers and experts.ResultsThe module was rated favorably, with mean evaluation scores ranging from 7.9 to 8.8 on a 10-point scale. Several suggestions for improvement were made, especially concerning privacy issues, safety instructions, patient-therapist collaborations, and role plays, and the module was adapted accordingly.ConclusionUsing input from literature, patient representatives and experts, we developed an online treatment module for moral injury in military veterans and police officers, to be used in conjunction with face-to-face therapy. Acceptability and feasibility will be further examined in a future pilot study.

Background: Central nervous system (CNS) disorders benefit from ongoing monitoring to assess disease progression and treatment efficacy. Mobile health (mHealth) technologies offer a means for the remote and continuous symptom monitoring of patients. Machine Learning (ML) techniques can process and engineer mHealth data into a precise and multidimensional biomarker of disease activity. Objective: This narrative literature review aims to provide an overview of the current landscape of biomarker development using mHealth technologies and ML. Additionally, it proposes recommendations to ensure the accuracy, reliability, and interpretability of these biomarkers. Methods: This review extracted relevant publications from databases such as PubMed, IEEE, and CTTI. The ML methods employed across the selected publications were then extracted, aggregated, and reviewed. Results: This review synthesized and presented the diverse approaches of 66 publications that address creating mHealth-based biomarkers using ML. The reviewed publications provide a foundation for effective biomarker development and offer recommendations for creating representative, reproducible, and interpretable biomarkers for future clinical trials. Conclusion: mHealth-based and ML-derived biomarkers have great potential for the remote monitoring of CNS disorders. However, further research and standardization of study designs are needed to advance this field. With continued innovation, mHealth-based biomarkers hold promise for improving the monitoring of CNS disorders.

Abstract TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1–50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

There has been an increasing interest in urban forests and the levels of biodiversity they contain. Currently there are no spatially explicit maps of tree species richness in urban areas. This research tests and identifies GIS and remote sensing metrics (climate, area, productivity, three-dimensional structure) hypothesized to be associated with species richness in native forests and identifies methods that can be applied to predict and map tree species richness in cities. We quantified tree species richness, floristic composition, and structure in 28 1-ha plots in the city of Los Angeles. Climate and remote sensing metrics from high-resolution aerial imagery (10 cm), QuickBird (60 cm), Landsat (30 m), MODIS (250 m), and airborne lidar (2 m) were collected for each plot. There were 1208 individual stems and 108 trees identified to species. Species richness ranged from 2 to 31 species per ha and averaged 17 species per ha. Tree canopy cover from QuickBird explained the highest portion of variance (54%) in tree species richness followed by NDVI from Landsat (42%). Tree species richness can be higher in residential urban forests than native forests in the United States. Spatially explicit species richness maps at 1 ha can be created and tested for cities in order to identify both hotspots and coldspots of tree species richness and changes in species richness over time.

The original version of this article unfortunately contained a mistake. One of the authors name was incorrectly listed as “Darrell E. Jenerette” and should be corrected as “G. Darrel Jenerette”. The original article was corrected.

The accuracy, stability and computational efficiency of numerical methods on central processing units (CPUs) for the depth-averaged shallow water equations were well covered in the literature. A large number of these methods were already developed and compared. However, on graphics processing units (GPUs), such comparisons are relatively scarce. In this paper, we present the results of comparing two time-integration methods for the shallow water equations on structured grids. An explicit and a semi-implicit time integration method were considered. For the semi-implicit method, the performance of several iterative solvers was compared. The implementation of the semi-implicit method on a GPU in this study was a novel approach for the shallow water equations. This also holds for the repeated red black (RRB) solver that was found to be very efficient on a GPU. Additionally, the results of both methods were compared with several CPU-based software systems for the shallow water flows on structured grids. On a GPU, the simulations were 25 to 75 times faster than on a CPU. Theory predicts an explicit method to be best suited for a GPU due to the higher level of inherent parallelism. It was found that both the explicit and the semi-implicit methods ran efficiently on a GPU. For very shallow applications, the explicit method was preferred because the stability condition on the time step was not very restrictive. However, for deep water applications, we expect the semi-implicit method to be preferred.

We evaluated the immunological responses of lymph-node involved (stage III) melanoma patients to adjuvant dendritic cell vaccination with subsets of naturally occurring dendritic cells (nDCs). Fifteen patients with completely resected stage III melanoma were randomized to receive adjuvant dendritic cell vaccination with CD1c+ myeloid dendritic cells (cDC2s), plasmacytoid dendritic cells (pDCs) or the combination. Immunological response was the primary endpoint and secondary endpoints included safety and survival. In 80% of the patients, antigen-specific CD8+ T cells were detected in skin test-derived T cells and in 55% of patients, antigen-specific CD8+ T cells were detectable in peripheral blood. Functional interferon-γ-producing T cells were found in the skin test of 64% of the patients. Production of nDC vaccines meeting release criteria was feasible for all patients. Vaccination only induced grade 1–2 adverse events, mainly consisting of fatigue. In conclusion, adjuvant dendritic cell vaccination with cDC2s and/or pDCs is feasible, safe and induced immunological responses in the majority of stage III melanoma patients.

In this paper we report on the development of an inventory that measures global citizenship among adolescents. The methodology used consists of cognitive interviews for questionnaire design and explorative and confirmatory factor analyses among several datasets. The resulting Global Citizenship Inventory (GCI) includes a global citizenship behaviour index and three scales measuring principles underlying global citizenship: human equality, mutual dependency in the world, and the shared responsibility for solving global issues. The behaviour index measures behaviour connected to efficient use of energy and water, mobility, recycling and handling waste, search for information and expressing an opinion on global issues, donating to charity, and volunteering. The results provide support for our theoretical constructs regarding global citizenship.

Abstract The maximum temperature (Tmax) and subsequent exhumation reflect the relations between advective and conductive heat transport, which in turn depend on the tectonic evolution. To unravel these relations in an orogen, precise Tmax data need to be combined with relative time information for the displacements of adjacent units. We present new Tmax data based on Raman spectroscopy of carbonaceous material (RSCM) and zircon fission track (FT) data, which are combined with previous data and then discussed jointly. We follow this approach in the Central Alps at the western edge of the Lepontine dome. Our analysis indicates two main tectono-metamorphic domains in this area: domain A comprises the Lower Helvetic units involving the Aar Massif; domain B is situated south of the Helvetic main thrust, in the footwall of the Simplon line. In domain A, thrusted Helvetic units were overprinted mainly by reverse faulting in the Aar Massif. The thermal evolution is related to the inversion of the former Doldenhorn basin. Tectonic transport during inversion brought into contact units with substantially different Tmax. Temperature gradients were then reduced by conductive heat transfer, but thermal overprinting during cooling involved subsequent vertical movements as well. Zircon FT data yield apparent ages between 12 and 18 Ma in the external part, but 8–9 Ma in the internal part of the Aar Massif. The youngest ages are taken as the cooling at a given temperature, whereas the other data are discussed as being only partially resetted along a temperature path in the partial annealing zone of the zircon FT. When combined with age data for Tmax and apatite FT data from the literature, the youngest group exhibits exhumation rates between 0.5 and 1.2 km/Ma in the time range between 20 Ma and today. In all of domain B, Tmax was significantly higher than in domain A. In domain B the estimated rates of exhumation are 0.8–1.0 km/Ma for the post-20 Ma time interval. Despite of different temperature evolution, the exhumation rates are similar in both domains. The study shows the necessity to combine detailed tectonic data to interpret the T–t evolution of such an area.

Abstract Background Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). Methods In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. Results Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1–2 toxicity. Conclusions Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. Trial registration ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.

Abstract Background Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. Results We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age. Conclusions These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.