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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.

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.

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).

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background Habitual intake of long‐chain omega‐3 fatty acids, especially eicosapentaenoic and docosahexaenoic acid (EPA+DHA) from fish, has been associated with a lower risk of fatal coronary heart disease (CHD) in population‐based studies. Whether that is also the case for patients with CHD is not yet clear. We studied the associations of dietary and circulating EPA+DHA and alpha‐linolenic acid, a plant‐derived omega‐3 fatty acids, with long‐term mortality risk after myocardial infarction. Methods and Results We analyzed data from 4067 Dutch patients with prior myocardial infarction aged 60 to 80 years (79% men, 86% on statins) enrolled in the Alpha Omega Cohort from 2002 to 2006 (baseline) and followed through 2018. Baseline intake of fish and omega‐3 fatty acids were assessed through a validated 203‐item food frequency questionnaire and circulating omega‐3 fatty acids were assessed in plasma cholesteryl esters. Hazard ratios (HRs) with 95% CIs were obtained from Cox regression analyses. During a median follow‐up period of 12 years, 1877 deaths occurred, of which 515 were from CHD and 834 from cardiovascular diseases. Dietary intake of EPA+DHA was significantly inversely associated with only CHD mortality (HR, 0.69 [0.52–0.90] for >200 versus ≤50 mg/d; HR, 0.92 [0.86–0.98] per 100 mg/d). Similar results were obtained for fish consumption (HRCHD, 0.74 [0.53–1.03] for >40 versus ≤5 g/d; Ptrend: 0.031). Circulating EPA+DHA was inversely associated with CHD mortality (HR, 0.71 [0.53–0.94] for >2.52% versus ≤1.29%; 0.85 [0.77–0.95] per 1‐SD) and also with cardiovascular diseases and all‐cause mortality. Dietary and circulating alpha‐linolenic acid were not significantly associated with mortality end points. Conclusions In a cohort of Dutch patients with prior myocardial infarction, higher dietary and circulating EPA+DHA and fish intake were consistently associated with a lower CHD mortality risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03192410.

Objective: Out-of-hospital cardiac arrest (OHCA) occurrence has been shown to exhibit a circadian rhythm, following the circadian rhythm of acute myocardial infarction (AMI) occurrence. Diabetes mellitus (DM) is associated with changes in circadian rhythm. We aimed to compare the temporal variation of OHCA occurrence over the day and week between OHCA patients with DM and those without. Methods: In two population-based OHCA registries (Amsterdam Resuscitation Studies [ARREST] 2010–2016, n = 4163, and Danish Cardiac Arrest Registry [DANCAR], 2010–2014, n = 12,734), adults (≥18y) with presumed cardiac cause of OHCA and available medical history were included. Single and double cosinor analysis was performed to model circadian variation of OHCA occurrence. Stratified analysis of circadian variation was performed in patients with AMI as immediate cause of OHCA. Results: DM patients (22.8% in ARREST, 24.2% in DANCAR) were older and more frequently had cardiovascular risk factors or previous cardiovascular disease. Both cohorts showed 24 h-rhythmicity, with significant amplitudes in single and double cosinor functions (P-range

Background: Disruption in circadian rhythms is associated with cardiovascular disease and may play a role in socioeconomic differences in cardiovascular disease prevalence. However, it is unclear whether low SES is associated with a lower diurnal rhythm in autonomic activity markers. We investigated the association between SES and the amplitude of the daily fluctuation of heart rate. Methods: We included data of 450 participants of a HELIUS sub-study in Amsterdam, the Netherlands. Participants wore an Actiheart monitor (CamNtech), a chest-worn monitor which measures heart rate every 15 s for several days. Cosinor analysis was performed on the time series of heart rate within each participant. We analyzed the association between the cosinor parameters (amplitude, midline and peak time of the diurnal HR rhythm) and SES indicators (education, occupational class and a proxy of income) in multivariate linear regression models, adjusting for age, sex and ethnicity. Results: There was a clear diurnal rhythm in the average heart rates, with a peak between noon and 18:00 and a trough between 04:00 and 06:00. This rhythm was present for all categories of education, occupation and income proxy. The estimates for the cosinor parameters did not differ consistently and significantly between categories of education, occupation or income proxy. Conclusions: We did not find any consistent evidence to support our hypothesis of a diminished amplitude in the diurnal variation of heart rate in individuals with lower SES. Future studies should explore SES differences in the diurnal variation in markers of autonomic activity other than heart rate.

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.

Abstract Background Circulating odd-chain fatty acids pentadecanoic (15:0) and heptadecanoic acid (17:0) are considered to reflect dairy intake. In cohort studies, higher circulating 15:0 and 17:0 were associated with lower type 2 diabetes risk. A recent randomized controlled trial in humans suggested that fiber intake also increased circulating 15:0 and 17:0, potentially resulting from fermentation by gut microbes. We examined the associations of dairy and fiber intake with circulating 15:0 and 17:0 in patients with a history of myocardial infarction (MI). Methods We performed cross-sectional analyses in a subsample of 869 Dutch post-MI patients of the Alpha Omega Cohort who had data on dietary intake and circulating fatty acids. Dietary intakes (g/d) were assessed using a 203-item food frequency questionnaire. Circulating 15:0 and 17:0 (as % of total fatty acids) were measured in plasma phospholipids (PL) and cholesteryl esters (CE). Spearman correlations (r s ) were computed between intakes of total dairy, dairy fat, fiber, and circulating 15:0 and 17:0. Results Patients were on average 69 years old, 78% was male and 21% had diabetes. Total dairy intake comprised predominantly milk and yogurt (69%). Dairy fat was mainly derived from cheese (47%) and milk (15%), and fiber was mainly from grains (43%). Circulating 15:0 in PL was significantly correlated with total dairy and dairy fat intake (both r s = 0.19, p

Abstract Background The emphasis on impact factors and the quantity of publications intensifies competition between researchers. This competition was traditionally considered an incentive to produce high-quality work, but there are unwanted side-effects of this competition like publication pressure. To measure the effect of publication pressure on researchers, the Publication Pressure Questionnaire (PPQ) was developed. Upon using the PPQ, some issues came to light that motivated a revision. Method We constructed two new subscales based on work stress models using the facet method. We administered the revised PPQ (PPQr) to a convenience sample together with the Maslach Burnout Inventory (MBI) and the Work Design Questionnaire (WDQ). To assess which items best measured publication pressure, we carried out a principal component analysis (PCA). Reliability was sufficient when Cronbach’s alpha > 0.7. Finally, we administered the PPQr in a larger, independent sample of researchers to check the reliability of the revised version. Results Three components were identified as ‘stress’, ‘attitude’, and ‘resources’. We selected 3 × 6 = 18 items with high loadings in the three-component solution. Based on the convenience sample, Cronbach’s alphas were 0.83 for stress, 0.80 for attitude, and 0.76 for resources. We checked the validity of the PPQr by inspecting the correlations with the MBI and the WDQ. Stress correlated 0.62 with MBI’s emotional exhaustion. Resources correlated 0.50 with relevant WDQ subscales. To assess the internal structure of the PPQr in the independent reliability sample, we conducted the principal component analysis. The three-component solution explains 50% of the variance. Cronbach’s alphas were 0.80, 0.78, and 0.75 for stress, attitude, and resources, respectively. Conclusion We conclude that the PPQr is a valid and reliable instrument to measure publication pressure in academic researchers from all disciplinary fields. The PPQr strongly relates to burnout and could also be beneficial for policy makers and research institutions to assess the degree of publication pressure in their institute.

Abstract Nuts and vegetable oils are important sources of fat and of a wide variety of micronutrients and phytochemicals. Following their intake, several of their constituents, as well as their derived metabolites, are found in blood circulation and in urine. As a consequence, these could be used to assess the compliance to a dietary intervention or to determine habitual intake of nuts and vegetable oils. However, before these metabolites can be widely used as biomarkers of food intake (BFIs), several characteristics have to be considered, including specificity, dose response, time response, stability, and analytical performance. We have, therefore, conducted an extensive literature search to evaluate current knowledge about potential BFIs of nuts and vegetable oils. Once identified, the strengths and weaknesses of the most promising candidate BFIs have been summarized. Results from selected studies have provided a variety of compounds mainly derived from the fatty fraction of these foods, but also other components and derived metabolites related to their nutritional composition. In particular, α-linolenic acid, urolithins, and 5-hydroxyindole-3-acetic acid seem to be the most plausible candidate BFIs for walnuts, whereas for almonds they could be α-tocopherol and some catechin-derived metabolites. Similarly, several studies have reported a strong association between selenium levels and consumption of Brazil nuts. Intake of vegetable oils has been mainly assessed through the measurement of specific fatty acids in different blood fractions, such as oleic acid for olive oil, α-linolenic acid for flaxseed (linseed) and rapeseed (canola) oils, and linoleic acid for sunflower oil. Additionally, hydroxytyrosol and its metabolites were the most promising distinctive BFIs for (extra) virgin olive oil. However, most of these components lack sufficient specificity to serve as BFIs. Therefore, additional studies are necessary to discover new candidate BFIs, as well as to further evaluate the specificity, sensitivity, dose-response relationships, and reproducibility of these candidate biomarkers and to eventually validate them in other populations. For the discovery of new candidate BFIs, an untargeted metabolomics approach may be the most effective strategy, whereas for increasing the specificity of the evaluation of food consumption, this could be a combination of different metabolites.

Macrophages are highly plastic, key regulators of inflammation. Deregulation of macrophage activation can lead to excessive inflammation as seen in inflammatory disorders like atherosclerosis, obesity, multiple sclerosis and sepsis. Targeting intracellular metabolism is considered as an approach to reshape deranged macrophage activation and to dampen the progression of inflammatory disorders. ATP citrate lyase (Acly) is a key metabolic enzyme and an important regulator of macrophage activation. Using a macrophage-specific Acly-deficient mouse model, we investigated the role of Acly in macrophages during acute and chronic inflammatory disorders. First, we performed RNA sequencing to demonstrate that Acly-deficient macrophages showed hyperinflammatory gene signatures in response to acute LPS stimulation in vitro. Next, we assessed endotoxin-induced peritonitis in myeloid-specific Acly-deficient mice and show that, apart from increased splenic Il6 expression, systemic and local inflammation were not affected by Acly deficiency. Also during obesity, both chronic low-grade inflammation and whole-body metabolic homeostasis remained largely unaltered in mice with Acly-deficient myeloid cells. Lastly, we show that macrophage-specific Acly deletion did not affect the severity of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. These results indicate that, despite increasing inflammatory responses in vitro, macrophage Acly deficiency does not worsen acute and chronic inflammatory responses in vivo. Collectively, our results indicate that caution is warranted in prospective long-term treatments of inflammatory disorders with macrophage-specific Acly inhibitors. Together with our earlier observation that myeloid Acly deletion stabilizes atherosclerotic lesions, our findings highlight that therapeutic targeting of macrophage Acly can be beneficial in some, but not all, inflammatory disorders.

Aluminum oxide (Al2O3) is an emerging material in integrated photonics. It exhibits a very broad transparency window from the UV to the mid-IR, very low propagation losses and a high solubility for rare-earth ions leading to optical gain in different spectral ranges. Al2O3 can be deposited by different wafer-level deposition techniques, including atomic layer deposition and reactive magnetron sputtering, being compatible with the monolithic integration onto passive integrated photonics platforms, such as Si3N4, to which it provides optical amplification and lasing. When deposited at low temperatures, it is also compatible with integration onto CMOS chips. In this review, the state-of-the-art on the deposition, integration and device development in this photonic platform is described.

Background Current investigations into physical behaviour in Muscular Dystrophy (MD) have focussed largely on physical activity (PA). Negative health behaviours such as sedentary behaviour (Physical Behaviour) and sitting time (Posture Classification) are widely recognised to negatively influence health, but by contrast are poorly reported, yet could be easier behaviours to modify. Methods 14 ambulant men with MD and 12 healthy controls (CTRL) subjects completed 7-days of free-living with wrist-worn accelerometry, assessing physical behaviour (SB or PA) and Posture Classification (Sitting or Standing), presented at absolute (minutes) or relative (% Waking Hours). Participant body composition (Fat Mass and Fat Free Mass) were assessed by Bioelectrical Impedance, while functional status was assessed by 10 m walk test and a functional scale (Swinyard Scale). Results Absolute Sedentary Behaviour (2.2 Hours, p = 0.025) and Sitting Time (1.9 Hours, p = 0.030 was greater in adults with MD compared to CTRL and Absolute Physical Activity (3.4 Hours, p < 0.001) and Standing Time (3.2 Hours, p < 0.001) was lower in adults with MD compared to CTRL. Absolute hours of SB was associated with Fat Mass (Kg) (R = 0.643, p < 0.05) in ambulatory adults with MD, Discussion This study has demonstrated increased Sedentary Behaviour (2.2 hours) and Sitting time (1.9 Hours) in adults with MD compared to healthy controls. Extended waking hours in sitting and SB raises concerns with regards to progression of potential cardio-metabolic diseases and co-morbidities in MD.

BackgroundCurrent investigations into physical behaviour in Muscular Dystrophy (MD) have focussed largely on physical activity (PA). Negative health behaviours such as sedentary behaviour (Physical Behaviour) and sitting time (Posture Classification) are widely recognised to negatively influence health, but by contrast are poorly reported, yet could be easier behaviours to modify.Methods14 ambulant men with MD and 12 healthy controls (CTRL) subjects completed 7-days of free-living with wrist-worn accelerometry, assessing physical behaviour (SB or PA) and Posture Classification (Sitting or Standing), presented at absolute (minutes) or relative (% Waking Hours). Participant body composition (Fat Mass and Fat Free Mass) were assessed by Bioelectrical Impedance, while functional status was assessed by 10 m walk test and a functional scale (Swinyard Scale).ResultsAbsolute Sedentary Behaviour (2.2 Hours, p = 0.025) and Sitting Time (1.9 Hours, p = 0.030 was greater in adults with MD compared to CTRL and Absolute Physical Activity (3.4 Hours, p < 0.001) and Standing Time (3.2 Hours, p < 0.001) was lower in adults with MD compared to CTRL. Absolute hours of SB was associated with Fat Mass (Kg) (R = 0.643, p < 0.05) in ambulatory adults with MD.DiscussionThis study has demonstrated increased Sedentary Behaviour (2.2 hours) and Sitting time (1.9 Hours) in adults with MD compared to healthy controls. Extended waking hours in sitting and SB raises concerns with regards to progression of potential cardio-metabolic diseases and co-morbidities in MD.

BackgroundDe novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).Methods and findingsSeventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.ConclusionsConcentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Tissue resident intestinal macrophages are known to exhibit an anti-inflammatory phenotype and produce little pro-inflammatory cytokines upon TLR ligation, allowing symbiotic co-existence with the intestinal microbiota. However, upon acute events such as epithelial damage and concomitant influx of microbes, these macrophages must be able to quickly mount a pro-inflammatory response while more inflammatory macrophages are recruited from the blood stream simultaneously. Here, we show that dietary intake of vitamin A is required for the maintenance of the anti-inflammatory state of tissue resident intestinal macrophages. Interestingly, these anti-inflammatory macrophages were characterized by high levels of Dectin-1 expression. We show that Dectin-1 expression is enhanced by the vitamin A metabolite retinoic acid and our data suggests that Dectin-1 triggering might provide a switch to induce a rapid production of pro-inflammatory cytokines. In addition, Dectin-1 stimulation resulted in an altered metabolic profile which is linked to a pro-inflammatory response. Together, our data suggests that presence of vitamin A in the small intestine enhances an anti-inflammatory phenotype as well as Dectin-1 expression by macrophages and that this anti-inflammatory phenotype can rapidly convert toward a pro-inflammatory state upon Dectin-1 signaling.

Even though a lot of attention has been directed towards risk management, disruptions are inevitably present within supply chains and should therefore be successfully managed if organizations are to thrive in today’s ever-changing world. How organizations respond to these disruptions has an impact on the relationship between the parties involved. This study explored what factors influenced buyer-supplier relationships in either a strengthening or weakening manner within a disruption context. A generic qualitative research approach was used to gather data by conducting semi-structured interviews with 24 participants that consisted of 3PLs and clients who have experienced a recent disruption between each other. This study reported on the relational factors within pre-, during- and post- disruption phases. A total of 18 strengthening factors were identified with the majority being classified into the during-disruption phase. The factors that added to existing disruption literature included having a mutual business understanding, problem solving ability and an introspective focus when resolving disruptions. Twelve weakening factors emerged from the data. Common business problems, a lack of, or weak prior relationship, no mutual business understanding and the occurrence and late detection of the disruption are novel findings. Practitioners gain value from this study as it equips them to manage supply chain disruptions successfully by highlighting important strengthening and weakening relational factors to consider when working with supply chain members to resolve disruptions. The study contributes to the body of knowledge by being one of the first empirical studies conducted on the relational effects of supply chain disruptions in a developing country context.

The effects of feeding behavior and diet composition, as well as their possible interactions, on daily (clock) gene expression rhythms have mainly been studied in the liver, and to a lesser degree in white adipose tissue (WAT), but hardly in other metabolic tissues such as skeletal muscle (SM) and brown adipose tissues (BAT). We therefore subjected male Wistar rats to a regular chow or free choice high-fat-high sugar (fcHFHS) diet in combination with time restricted feeding (TRF) to either the light or dark phase. In SM, all tested clock genes lost their rhythmic expression in the chow light fed group. In the fcHFHS light fed group rhythmic expression for some, but not all, clock genes was maintained, but shifted by several hours. In BAT the daily rhythmicity of clock genes was maintained for the light fed groups, but expression patterns were shifted as compared with ad libitum and dark fed groups, whilst the fcHFHS diet made the rhythmicity of clock genes become more pronounced. Most of the metabolic genes in BAT tissue tested did not show any rhythmic expression in either the chow or fcHFHS groups. In SM Pdk4 and Ucp3 were phase-shifted, but remained rhythmically expressed in the chow light fed groups. Rhythmic expression was lost for Ucp3 whilst on the fcHFHS diet during the light phase. In summary, both feeding at the wrong time of day and diet composition disturb the peripheral clocks in SM and BAT, but to different degrees and thereby result in a further desynchronization between metabolically active tissues such as SM, BAT, WAT and liver. Keywords: Soleus muscle (SM), Brown adipose tissue (BAT), free choice High-fat High-sugar (fcHFHS), Time-restricted feeding (TRF), desynchronization

Abstract Background Premature infants are highly vulnerable to infection. This is partly attributable to the preterm immune system, which differs from that of the term neonate in cell composition and function. Multiple studies have found differential DNA methylation (DNAm) between preterm and term infants’ cord blood; however, interpretation of these studies is limited by the confounding factor of blood cell composition. This study evaluates the epigenetic impact of preterm birth in isolated hematopoietic cell populations, reducing the concern of cell composition differences. Methods Genome-wide DNAm was measured using the Illumina 450K array in T cells, monocytes, granulocytes, and nucleated red blood cells (nRBCs) isolated from cord blood of 5 term and 5 preterm ( 0.10) discovered between preterm and term infants compared to the

This essay was originally published in The Routledge Handbook of New Security Studies (Burgess, 2010), and has since become a key reference point in debates on the finance-security nexus. It is reproduced here as a starting point for the present forum, which aims to further advance efforts to conceptualise the relations between finance and security.

Securitization has a dual rationality that twins a financial sense to one of modern statecraft and national security. This forum contribution advocates a focus on material practices as a means of further exploring the entanglement of finance and security. In particular, it advances a notion of ‘chains of securitization’, arguing that such a concept provides researchers with a concrete way to analyze how ‘financial’ objects, such as derivatives, are assembled to generate (in)securities, as well as how ‘security’ objects, such as suspicious transactions, are assembled across public/private domains.

Objectives: Transcranial magnetic stimulation (TMS) is widely used to assess cortical excitability. To detect changes in excitability with longitudinal studies, it is important to validate the repeatability of excitability measures within a subject between different sessions. Repeatability studies on long intracortical inhibition (LICI) are limited and reported agreement ranges from poor to good. This study aims to evaluate the repeatability of LICI in healthy subjects using paired pulse TMS. In addition, it investigates whether LICI repeatability differs for manual and robot-guided coil positioning. Methods: Thirty healthy subjects (10 males, mean age 28.4 ± 8.2 years) were studied twice, approximately one week apart. Both motor cortices were stimulated with 50 paired pulses (intensity 120% of resting motor threshold) at interstimulus intervals (ISIs): 50, 100, 150, 200, 250 and 300 ms. In twenty subjects a figure-of-eight coil was positioned and held in place manually during both sessions, while in ten subjects a robot-navigated arm was used. LICI repeatability was assessed using the intraclass correlation coefficient (ICC). Results: For manual and robot-guided coil positioning we found a large variation in repeatability at the subject level and ISI level, ranging from poor to good agreement. On a group level, we found good repeatability for averaged LICI curves (manual: ICC = 0.91, robot-guided: ICC = 0.95), which decreased when individual curves were correlated between sessions (manual: ICC = 0.76, robot-guided: ICC = 0.84). Conclusion: For a correct interpretation of longitudinal study outcomes it is important to know the subject specific LICI repeatability and to analyze each ISI individually. Furthermore, the added value of robot-guided coil positioning for paired pulse TMS seems limited. Significance: The large variation in LICI repeatability at the subject level and ISI level should be taken into account in longitudinal studies, while robot-guided coil positioning seems unnecessary. Keywords: Transcranial magnetic stimulation, TMS, Repeatability, Long intracortical inhibition, LICI, Coil positioning

Epidemiological studies indicate that shift-workers have an increased risk of type 2 diabetes mellitus (T2DM). Glucose tolerance and insulin sensitivity both are dependent on the circadian timing system (i.e., the time-of-day) and fasting duration, in rodents as well as humans. Therefore, question is whether manipulation of the circadian timing system, for example by changing the timing of feeding and fasting, is a potential preventive treatment for T2DM. Time-restricted feeding (TRF) is well-known to have profound effects on various metabolic measures, including glucose metabolism. However, experiments that directly measure the effects of TRF on glucose tolerance and/or insulin sensitivity at different time points throughout the 24 h cycle are lacking. Here we show, in rats, that TRF in line with the circadian timing system (i.e., feeding during the active phase) improves glucose tolerance during intravenous glucose tolerance tests (ivGTT) in the active phase, as lower insulin levels were observed with similar levels of glucose clearance. However, this was not the case during the inactive phase in which more insulin was released but only a slightly faster glucose clearance was observed. Contrasting, TRF out of sync with the circadian timing system (i.e., feeding during the inactive phase) worsened glucose tolerance, although only marginally, likely because of adaptation to the 4 week TRF regimen. Our results show that TRF can improve glucose metabolism, but strict adherence to the time-restricted feeding period is necessary, as outside the regular eating hours glucose tolerance is worsened.

Background: Disturbance of immunometabolic signaling is a key process involved in the progression of obesity. Microglia—the resident immune cells in the brain, initiate local immune responses. It is known that hypercaloric diets lead to microglial activation. Previously, we observed that hypothalamic microglial cells from mice fed high-fat diet (HFD) lose their day/night rhythm and are constantly activated. However, little is known about daily rhythmicity in microglial circadian, immune and metabolic functions, either in lean or obese conditions. Therefore, we hypothesized that HFD disturbs microglial immunometabolism in a day/night-dependent manner.Methods: Obesity was induced in Wistar rats by feeding them HFD ad libitum for the duration of 8 weeks. Microglia were isolated from HFD- and chow-fed control animals at six time points during 24 h [every 4 h starting 2 h after lights on, i.e., Zeitgeber Time 2 (ZT2)]. Gene expression was evaluated using quantitative RT-PCR. JTK_Cycle software was used to estimate daily rhythmicity. Statistical analysis was performed with two-way ANOVA test.Results: Consumption of the obesogenic diet resulted in a 40 g significantly higher body weight gain in week 8, compared to chow diet (p < 0.0001), associated with increased adiposity. We observed significant rhythmicity of circadian clock genes in microglia under chow conditions, which was partially lost in diet-induced obesity (DIO). Microglial immune gene expression also showed time-of-day differences, which were disrupted in HFD-fed animals. Microglia responded to the obesogenic conditions by a shift of substrate utilization with decreased glutamate and glucose metabolism in the active period of the animals, and an overall increase of lipid metabolism, as indicated by gene expression evaluation. Additionally, data on mitochondria bioenergetics and dynamics suggested an increased energy production in microglia during the inactive period on HFD. Finally, evaluation of monocyte functional gene expression showed small or absent effect of HFD on peripheral myeloid cells, suggesting a cell-specific microglial inflammatory response in DIO.Conclusions: An obesogenic diet affects microglial immunometabolism in a time-of-day dependent manner. Given the central role of the brain in energy metabolism, a better knowledge of daily rhythms in microglial immunometabolism could lead to a better understanding of the pathogenesis of obesity.

Background: Chronic stress is often accompanied by alterations in the diurnal rhythm of hypothalamus–pituitary–adrenal activity. However, there are limited data on the diurnal rhythmicity of breast milk glucocorticoids (GCs) among women with psychological distress. We compared mothers who sought consultation at an expertise center for pregnant women with an increased risk of psychological distress with control mothers for GC diurnal rhythmicity in milk and saliva obtained at the same time. Methods: We included 19 mothers who sought consultation at the psychiatry–obstetric–pediatric (POP) outpatient clinic and 44 control mothers. One month postpartum, mothers collected on average eight paired milk and saliva samples during a 24 h period. GC levels were measured using liquid chromatography–tandem mass spectrometry. GC rhythmicity parameters were determined with specialized software. Results: For both milk and saliva, no group differences regarding GC rhythms were found. Milk cortisol area under the curve with respect to the ground was lower in the POP group than in the control group (p = 0.02). GC levels in human milk and saliva were highly correlated within each group (p < 0.001). Conclusion: Although there were no differences between groups in GC rhythmicity, the total amount of milk cortisol was lower in the POP group. Long-term follow-up is needed to address the impact of vertical transmission of breast milk GCs.

Family routines improve family stability. However, it is unclear what impedes the formation of stable routines after life transitions. In this paper we discuss normative challenges that 10, mostly low-income, couples face in managing routines after becoming parents. Qualitative analysis revealed three themes: temporal incongruence, schedule derailment, and factors that increase task and temporal complexity. The seven sub-themes of the latter theme were transport limitations, workplace schedules, extended family involvement, child-related difficulties, health complications, incongruence between family member needs, and a composite of these factors. Results underscore the need to address context-specific family challenges related to time restrictions and scheduling.

Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

BackgroundWe aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D).Methods and findingsSixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist.ConclusionsIn a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

Background: Despite risk management efforts, supply chains have become increasingly vulnerable to disruptions. Disruptions should be successfully managed if organisations are to thrive in today’s ever-changing world. Purpose: This study explored supply chain disruptions of third-party logistics service providers (3PLs) and their clients based in South Africa by investigating the disruptions these organisations face, and how they go about managing them. Method: A generic qualitative research approach was used to gather data by conducting semi-structured interviews with 22 participants, which comprised 11 3PLs and 11 client organisations operating in South Africa. Findings: This study classified disruptions as intra-, inter- and extra-organisational. South African 3PLs and their clients face the majority of their disruptions either intra- or inter-organisationally. The focus of 3PLs and clients has shifted from risk management to disruption management. The findings show that 3PLs and their clients based in South Africa prefer disruption learning over traditional risk management as a method to better manage future disruptions. Conclusion: This study contributes to existing literature by providing insight into the specific supply chain disruptions that 3PLs and their clients based in South Africa face, according to the disruption location in the supply chain and how 3PLs and clients manage supply chain disruptions.

BackgroundDaily cyclic changes in environmental conditions are key signals for anticipatory and adaptive adjustments of most living species, including mammals. Lower ambient temperature stimulates the thermogenic activity of brown adipose tissue (BAT) and skeletal muscle. Given that the molecular components of the endogenous biological clock interact with thermal and metabolic mechanisms directly involved in the defense of body temperature, the present study evaluated the differential homeostatic responses to a cold stimulus at distinct time-windows of the light/dark-cycle.MethodsMale Wistar rats were subjected to a single episode of 3 h cold ambient temperature (4°C) at one of 6 time-points starting at Zeitgeber Times 3, 7, 11, 15, 19, and 23. Metabolic rate, core body temperature, locomotor activity (LA), feeding, and drinking behaviors were recorded during control and cold conditions at each time-point. Immediately after the stimulus, rats were euthanized and both the soleus and BAT were collected for real-time PCR.ResultsDuring the light phase (i.e., inactive phase), cold exposure resulted in a slight hyperthermia (p

Dilated cardiomyopathy amongst children (pediatric cardiomyopathy, pediatric CM) is associated with a high morbidity and mortality. Because little is known about the pathophysiology of pediatric CM, treatment is largely based on adult heart failure therapy. The reason for high morbidity and mortality is largely unknown as well as data on cellular pathomechanisms is limited. Here, we assessed cardiomyocyte contractility and protein expression to define cellular pathomechanisms in pediatric CM. Explanted heart tissue of 11 pediatric CM patients and 18 controls was studied. Contractility was measured in single membrane-permeabilized cardiomyocytes and protein expression was assessed with gel electrophoresis and western blot analysis. We observed increased Ca2+-sensitivity of myofilaments which was due to hypophosphorylation of cardiac troponin I, a feature commonly observed in adult DCM. We also found a significantly reduced maximal force generating capacity of pediatric CM cardiomyocytes, as well as a reduced passive force development over a range of sarcomere lengths. Myofibril density was reduced in pediatric CM compared to controls. Correction of maximal force and passive force for myofibril density normalized forces in pediatric CM cardiomyocytes to control values. This implies that the hypocontractility was caused by the reduction in myofibril density. Unlike in adult DCM we did not find an increase in compliant titin isoform expression in end-stage pediatric CM. The limited ability of pediatric CM patients to maintain myofibril density might have contributed to their early disease onset and severity.

Chronic kidney disease (CKD) is highly prevalent among older post-myocardial infarction (MI) patients. It is not known whether CKD is an independent risk factor for mortality in older post-MI patients with optimal cardiovascular drug-treatment. Therefore, we studied the relation between kidney function and all-cause and specific mortality among older post-MI patients, without severe heart failure, who are treated with state-of-the-art pharmacotherapy. From 2002-2006, 4,561 Dutch post-MI patients were enrolled and followed until death or January 2012. We estimated Glomerular Filtration Rate (eGFR) with cystatin C (cysC) and creatinine (cr) using the CKD-EPI equations and analyzed the relation with any and major causes of death using Cox models and restricted cubic splines. Mean (SD) for age was 69 years (5.6), 79% were men, 17% smoked, 21% had diabetes, 90% used antihypertensive drugs, 98% used antithrombotic drugs and 85% used statins. Patients were divided into four categories of baseline eGFRcysC: ≥90 (33%; reference), 60-89 (47%), 30-59 (18%), and