Search

Abstract Current attempts to implement and apply automated control systems for the management of glucose homeostasis in individuals with diabetes are partly successful. In most semi and closed loop control systems to mimic the action of a normal pancreas in diabetes patients, insulin is administered subcutaneously. However, the parameters for insulin diffusion and transport time constants are relatively large and have wide individual variations. Therefore, deviation from a normal meal can result in suboptimal euglycemic control. Stable and reliable closed loop feedback control using continuous glucose monitoring under these conditions is difficult and needs regular interventions from the user. This article describes the translation of the endocrine physiology of a normal pancreas to an electronic equivalent. With this translation, the complex effects of a direct intravenous pulsatile method of insulin and glucagon administration can be simulated in accordance with physiological observations in a healthy subject and has been built with standard electronic components. This device is applicable for any individual and under any condition to automatically maintain the desired optimal euglycemic condition. The insulin and glucagon response control is presented in the same physiological pulsatile manner as is observed in healthy individuals.

Low-lying, tropical, coral-reef-lined coastlines are becoming increasingly vulnerable to wave-driven flooding due to population growth, coral reef degradation, and sea-level rise. Early-warning systems (EWSs) are needed to enable coastal authorities to issue timely alerts and coordinate preparedness and evacuation measures for their coastal communities. At longer timescales, risk management and adaptation planning require robust assessments of future flooding hazard considering uncertainties. However, due to diversity in reef morphologies and complex reef hydrodynamics compared to sandy shorelines, there have been no robust analytical solutions for wave runup to allow for the development of large-scale coastal wave-driven flooding EWSs and risk assessment frameworks for reef-lined coasts. To address the need for fast, robust predictions of runup that account for the natural variability in coral reef morphologies, we constructed the BEWARE-2 (Broad-range Estimator of Wave Attack in Reef Environments) meta-process modeling system. We developed this meta-process model using a training dataset of hydrodynamics and wave runup computed by the XBeach Non-Hydrostatic process-based hydrodynamic model for 440 combinations of water level, wave height, and wave period with 195 representative reef profiles that encompass the natural diversity in real-world fringing coral reef systems. Through this innovation, BEWARE-2 can be applied in a larger range of coastal settings than meta-models that rely on a parametric description of the coral reef geometry. In the validation stage, the BEWARE-2 modeling system produced runup results that had a relative root mean square error of 13 % and relative bias of 5 % relative to runup simulated by XBeach Non-Hydrostatic for a large range of oceanographic forcing conditions and for diverse reef morphologies (root mean square error and bias 0.63 and 0.26 m, respectively, relative to mean simulated wave runup of 4.85 m). Incorporating parametric modifications in the modeling system to account for variations in reef roughness and beach slope allows for systematic errors (relative bias) in BEWARE-2 predictions to be reduced by a factor of 1.5–6.5 for relatively coarse or smooth reefs and mild or steep beach slopes. This prediction provided by the BEWARE-2 modeling system is faster by 4–5 orders of magnitude than the full, process-based hydrodynamic model and could therefore be integrated into large-scale EWSs for tropical, reef-lined coasts and used for large-scale flood risk assessments.

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.

Abstract We report time resolved observations of the crystallization from liquid hydrogen, supercooled to temperatures below the melting point, using 11.2 keV X-ray diffraction from the Linac Coherent Light Source (LCLS). Changes to the metastable solid and liquid structure factors have been dynamically measured. This allows for a direct determination of the lowest energy crystal polymorphs, the stacking probabilities, as well as the liquid and solid densities and temperatures. Such measurements provide experimental evidence of an Arrhenius-like growth kinetics along the stacking direction during supercooling.

Circadian disruption is an important factor driving the current-day high prevalence of obesity and type-2 diabetes. While the impact of incorrect timing of caloric intake on circadian disruption is widely acknowlegded, the contribution of incorrect timing of physical activity remains relatively understudied. Here, we modeled the incorrect timing of physical activity in nightshift workers in male Wistar rats, by restricting running wheel access to the innate inactive (light) phase (LR). Controls included no wheel access (NR); access only during the innate active (dark) period (DR); or unrestricted (ad libitum) access (ALR). LR did not shift the phase of the muscle or liver clock, but dampened the muscle clock amplitude. As our previous study demonstrated that light-phase restricted feeding did shift the liver clock, but made the muscle clock arrhythmic, we next combined the time restriction of wheel and food access to either the light phase (LRLF) or dark phase (DRDF). LRLF produced a ∼12 h shift in the majority of clock gene rhythms in both skeletal muscle and liver. On the other hand, DRDF was most effective in reducing body weight and the accumulation of fat mass. Therefore, in order to shift the muscle clock in male Wistar rats, synergy between the timing of feeding and physical activity is necessary. These findings may contribute to further improve the design of lifestyle strategies that try to limit metabolic misalignment caused by circadian disruption.

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

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).

CO2 is a valuable resource, life on Earth depends on it. Rather than wasting it to the atmosphere, or burying it underground, CO2 can be combined with water and turned into valuable chemicals and fuels, the process being powered by renewable electricity. Renewable electricity generated by wind and photovoltaics (PV) is making big strides, but is limited by ill-matched supply and demand. In addition, electricity only makes up 20% to 30% of total energy demand. Domestic heating, high temperature/pressure Industrial processes and mobility/transportation gobble up the rest. Mobility and transportation prove particularly difficult to decarbonise. Aviation is a case in point. Battery-powered aircraft are unlikely to become feasible by 2050. Hydrogen has too low an energy density and is haunted by safety issues. Current policy, therefore, is directed at bio fuels. One problem, there is not enough of it. The Fuel vs. Food vs. Flora trilemma of bio-based fuel is unlikely to gain public acceptance. By converting renewable electricity into fuel, power to molecules (P2M), two birds are killed with one stone: providing fuel for long haul transportation and enabling long-term, large-scale energy storage to cover the seasonal mismatch between supply and demand of renewable electricity. Feedstock consists of air-captured carbon or nitrogen and water. Chemically combined, it creates a liquid fuel with greatly enhanced energy density, such as kerosene or ammonia, or gaseous fuel like methane which can replace natural gas in the existing gas network. Direct air capture of CO2 is currently being commercialised. The conversion technology of water and CO2 by electrolysis has recently been extended to novel plasma technology, the sub ject of this paper. For CO2 splitting by plasmolysis, the reduced electric field has been identified as the key parameter explaining and improving the energy efficiency. Energy efficiency by plasmolysis is similar to that of electrolysis, but offers advantages in energy density, upscaling and switching in response to intermittent power with no use of scarce material. A simple model explains the inverse relation between energy efficiency and particle conversion and relates input microwave power to CO2 gas density, plasma dimension and ionisation degree, allowing design parameters for a 100 kW pilot reactor to be specified. Recycling CO2 in combination with P2M is a game-changing technology to meet overall CO2 emission reduction targets. It takes advantage of existing, inexpensive infrastructure for energy storage, transport and distribution. Existing internal combustion engine technology can be maintained where necessary. Close coupled to a remote solar array or an off-shore wind farm it offers a solution to decentralised renewable fuel production at the renewable electricity source.

3D-structures of proteins and potential ligands are the cornerstones of rational drug design. The first brick to build upon is selecting a protein target and finding out whether biologically active compounds are known. Both tasks require more information than the structures themselves provide. For this purpose we have built a web resource bridging protein and ligand databases. It consists of three parts: i) A data warehouse on annotation of protein structures that integrates many well-known databases such as Swiss-Prot, SCOP, ENZYME and others. ii) A conformational library of structures of approved drugs. iii) A conformational library of ligands from the PDB, linking the realms of proteins and small molecules.

Background: 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 = 216), 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.

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