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Abstract Background Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease. Methods The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes. Results In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes. Conclusion Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets. Trial registration The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

The large majority of patients with HER2-positive metastatic breast cancer (MBC) will eventually develop resistance to anti-HER2 therapy and die of this disease. Despite, relatively high levels of stromal tumor infiltrating lymphocytes (sTILs), PD1-blockade has only shown modest responses. Monalizumab targets the inhibitory immune checkpoint NKG2A, thereby unleashing NK- and CD8 T cells. We hypothesized that monalizumab synergizes with trastuzumab by promoting antibody-dependent cell-mediated cytotoxicity.In the phase II MIMOSA-trial, HER2-positive MBC patients were treated with trastuzumab and 750 mg monalizumab every two weeks. Following a Simon's two-stage design, 11 patients were included in stage I of the trial.Treatment was well tolerated with no dose-limiting toxicities. No objective responses were observed. Therefore, the MIMOSA-trial did not meet its primary endpoint.In summary, despite the strong preclinical rationale, the novel combination of monalizumab and trastuzumab does not induce objective responses in heavily pre-treated HER2-positive MBC patients.

Controversy exists around owned dogs’ impacts in public open spaces, with concerns about dogs’ impact on wildlife, including birds. Leashing dogs in public open spaces offers a tractable way of reducing dogs’ deleterious impacts on birds. Although dogs in public spaces are often unleashed, some dogs roam freely, whilst other unleashed dogs remain close to their owners. It is currently unknown whether birds can perceive and incorporate subtle differences in the leash status of approaching, but non-roaming, dogs into their escape decisions. We compare escape responses of a common urban bird, the magpie-lark Grallina cyanoleuca, in parks in Melbourne, Australia, to standardized approaches by a walker and a dog, which was either leashed or not leashed (but with the dog at the same distance from the walker). Flight-initiation distances, the distance between the lark and dog when escape commenced, did not vary between treatments. However, the unleashed dog evoked more intense responses (mostly flying away) than the leashed dog (mostly walking away). Thus, this species appears to perceive unleashed dogs as especially threatening, independent of their roaming behavior. Our findings suggest that leashing may be an effective way to reduce dog disturbance to wildlife, even for non-roaming dogs.

Objectives To assess the effectiveness, cost-effectiveness and return on investment of individual placement and support (IPS) implemented through a reimbursement strategy on a nationwide scale compared with traditional vocational rehabilitation (TVR) regarding sustainable participation in competitive employment in individuals with severe mental illness receiving sickness or disability benefits.Methods An observational study was conducted using administrative data regarding all Dutch individuals receiving sickness or disability benefits in the period 2012–2019. Exact matching and difference-in-difference fixed-effect estimations were performed to handle the non-randomised nature of the data. The matched sample consisted of 863 IPS and 16 466 TVR participants. The primary effect measure was the proportion of individuals having worked for at least 48 hours per month in competitive employment (ie, for 12 hours or more per week); the proportion of individuals having worked in competitive employment for at least 1 hour per month was also evaluated. Cost-effectiveness and return on investment were assessed from the societal perspective (intervention, sickness/disability benefit and healthcare costs) and payer perspective (sickness/disability benefit costs).Results IPS led to a statistically significant higher probability of being competitively employed for at least 12 hours per week of 3.7% points (95% CI 0.8% to 6.7%) to 7.5% points (95% CI 3.8% to 11.3%) and of being competitively employed for at least 1 hour per month of 4.7% points (95% CI 1.6% to 7.7%) to 8.9% points (95% CI 5.2 to 12.6%) from 6 to 36 months after starting the intervention. From the societal and payer perspective, IPS was—on average—less costly and more effective than TVR and return-on-investment estimates showed that IPS was—on average—cost saving (eg, societal perspective: ∆C: −364 (95% CI −3977 to 3249); ∆E: 0.104 (95% CI 0.046 to 0.164); benefit–cost ratio: 2.1 (95% CI −14.8 to 19.1)), but the uncertainty surrounding these estimates was large.Conclusions IPS implemented through a reimbursement strategy on a nationwide scale is more effective and potentially cost-effective than TVR in people with severe mental illness receiving sickness or disability benefits. Based on these results, the implementation of IPS by a wide scale reimbursement strategy could be promoted to enhance sustainable participation in competitive employment in these individuals. Future economic evaluations should strive for a more robust sample size and a long follow-up period.

Summary: Consumption of fructo- (FOS) and galacto-oligosaccharides (GOS) has health benefits which have been linked in part to short-chain fatty acids (SCFA) production by the gut microbiota. However, detailed knowledge of this process in the human intestine is lacking. We aimed to determine the acute fermentation kinetics of a FOS:GOS mixture in healthy males using a naso-intestinal catheter for sampling directly in the ileum or colon. We studied the fate of SCFA as substrates for glucose and lipid metabolism by the host after infusion of 13C-SCFA. In the human distal ileum, no fermentation of FOS:GOS, nor SCFA production, or bacterial cross-feeding was observed. The relative composition of intestinal microbiota changed rapidly during the test day, which demonstrates the relevance of postprandial intestinal sampling to track acute responses of the microbial community toward interventions. SCFA were vividly taken up and metabolized by the host as shown by incorporation of 13C in various host metabolites.

Summary: Background: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (

ObjectiveThis study explores the intricate relationship between cognitive functioning and aggression, with a specific focus on individuals prone to reactive or proactive aggression. The purpose of the study was to identify important neuropsychological constructs and suitable tests for comprehending and addressing aggression.MethodsAn international panel of 32 forensic neuropsychology experts participated in this three-round Delphi study consisting of iterative online questionnaires. The experts rated the importance of constructs based on the Research Domain Criteria (RDoC) framework. Subsequently, they suggested tests that can be used to assess these constructs and rated their suitability.ResultsThe panel identified the RDoC domains Negative Valence Systems, Social Processes, Cognitive Systems and Positive Valence Systems as most important in understanding aggression. Notably, the results underscore the significance of Positive Valence Systems in proactive aggression and Negative Valence Systems in reactive aggression. The panel suggested a diverse array of 223 different tests, although they noted that not every RDoC construct can be effectively measured through a neuropsychological test. The added value of a multimodal assessment strategy is discussed.ConclusionsThis research advances our understanding of the RDoC constructs related to aggression and provides valuable insights for assessment strategies. Rather than suggesting a fixed set of tests, our study takes a flexible approach by presenting a top-3 list for each construct. This approach allows for tailored assessment to meet specific clinical or research needs. An important limitation is the predominantly Dutch composition of the expert panel, despite extensive efforts to diversify.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true endogenous pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t13 = -6.03, p

The COVID-19 pandemic presents a serious public health challenge in all countries. However, repercussions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on future global health are still being investigated, including the pandemic's potential effect on the emergence and spread of global antimicrobial resistance (AMR). Critically ill COVID-19 patients may develop severe complications, which may predispose patients to infection with nosocomial bacterial and/or fungal pathogens, requiring the extensive use of antibiotics. However, antibiotics may also be inappropriately used in milder cases of COVID-19 infection. Further, concerns such as increased biocide use, antimicrobial stewardship/infection control, AMR awareness, the need for diagnostics (including rapid and point-of-care diagnostics) and the usefulness of vaccination could all be components shaping the influence of the COVID-19 pandemic. In this publication, the authors present a brief overview of the COVID-19 pandemic and associated issues that could influence the pandemic's effect on global AMR.

Akifumi Kishi,1– 3 Hans PA Van Dongen4,5 1Graduate School of Education, The University of Tokyo, Tokyo, Japan; 2Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 3Japan Science and Technology Agency, PRESTO, Saitama, Japan; 4Sleep and Performance Research Center, Washington State University, Spokane, WA, USA; 5Department of Translational Medicine and Physiology, Washington State University, Spokane, WA, USACorrespondence: Akifumi Kishi, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan, Tel +81-3-5841-3415, Fax +81-3-5841-3418, Email kishi@p.u-tokyo.ac.jpIntroduction: Evaluating the dynamic structure of sleep may yield new insights into the mechanisms underlying human sleep physiology.Methods: We analyzed data from a 12-day, 11-night, strictly controlled laboratory study with an adaptation night, 3 iterations of a baseline night followed by a recovery night after 36 h of total sleep deprivation, and a final recovery night. All sleep opportunities were 12 h in duration (22:00– 10:00) and recorded with polysomnography (PSG). The PSG records were scored for the sleep stages: rapid eye movement (REM) sleep; non-REM (NREM) stage 1 sleep (S1), stage 2 sleep (S2), and slow wave sleep (SWS); and wake (W). Phenotypic interindividual differences were assessed using indices of dynamic sleep structure – specifically sleep stage transitions and sleep cycle characteristics – and intraclass correlation coefficients across nights.Results: NREM/REM sleep cycles and sleep stage transitions exhibited substantial and stable interindividual differences that were robust across baseline and recovery nights, suggesting that mechanisms underlying the dynamic structure of sleep are phenotypic. In addition, the dynamics of sleep stage transitions were found to be associated with sleep cycle characteristics, with a significant relationship between the length of sleep cycles and the degree to which S2-to-W/S1 and S2-to-SWS transitions were in equilibrium.Discussion: Our findings are consistent with a model for the underlying mechanisms that involves three subsystems – characterized by S2-to-W/S1, S2-to-SWS, and S2-to-REM transitions – with S2 playing a hub-like role. Furthermore, the balance between the two subsystems within NREM sleep (S2-to-W/S1 and S2-to-SWS) may serve as a basis for the dynamic regulation of sleep structure and may represent a novel target for interventions aiming to improve sleep.Keywords: polysomnography, sleep stage transitions, NREM/REM sleep cycles, ultradian rhythm, sleep phenotype

Using a conceptual model, we examine how hydraulically controlled exchange flows in silled fjords affect the relationship between the basal glacier melt and the features of warm intermediate Atlantic Water (AW) outside the fjords. We show that an exchange flow can be forced to transit into the hydraulic regime if the AW interface height decreases, the AW temperature increases, or the production of glacially modified water is boosted by subglacial discharge. In the hydraulic regime, the heat transport across the sill becomes a rate-limiting factor for the basal melt, which is suppressed. An interplay between processes near the ice–ocean boundary and the hydraulically controlled exchange flow determines the melt dynamics, and the sensitivity of the basal melt to changes in the AW temperature is reduced. The model results are discussed in relation to observations from the Petermann, Ryder, and 79∘ N glaciers in northern Greenland.

Abstract Background Plant immunity relies on the perception of immunogenic signals by cell-surface and intracellular receptors and subsequent activation of defense responses like programmed cell death. Under certain circumstances, the fine-tuned innate immune system of plants results in the activation of autoimmune responses that cause constitutive defense responses and spontaneous cell death in the absence of pathogens. Results Here, we characterized the onset of leaf death 12 (old12) mutant that was identified in the Arabidopsis accession Landsberg erecta. The old12 mutant is characterized by a growth defect, spontaneous cell death, plant-defense gene activation, and early senescence. In addition, the old12 phenotype is temperature reversible, thereby exhibiting all characteristics of an autoimmune mutant. Mapping the mutated locus revealed that the old12 phenotype is caused by a mutation in the Lectin Receptor Kinase P2-TYPE PURINERGIC RECEPTOR 2 (P2K2) gene. Interestingly, the P2K2 allele from Landsberg erecta is conserved among Brassicaceae. P2K2 has been implicated in pathogen tolerance and sensing extracellular ATP. The constitutive activation of defense responses in old12 results in improved resistance against Pseudomonas syringae pv. tomato DC3000. Conclusion We demonstrate that old12 is an auto-immune mutant and that allelic variation of P2K2 contributes to diversity in Arabidopsis immune responses.

Understanding calving processes and their controls is of importance for reducing uncertainty in sea level rise estimates. The impact of tidal fluctuations and frontal melt on calving patterns has been researched through both modelling and observational studies but remains uncertain and may vary from glacier to glacier. In this study, we isolate various different impacts of tidal fluctuations on a glacier terminus to understand their influence on the timing of calving events in a model of Kronebreen, Svalbard, for the duration of 1 month. In addition, we impose a simplified frontal melt parameterisation onto the calving front in order to allow for an undercut to develop over the course of the simulations. We find that calving events show a tidal signal when there is a small or no undercut, but, after a critical point, undercut-driven calving becomes dominant and drowns out the tidal signal. However, the relationship is complex, and large calving events show a tidal signal even with a large modelled undercut. The modelled undercut sizes are then compared to observational profiles, showing that undercuts of up to ca. 25 m are plausible but with a more complex geometry being evident in observations than that captured in the model. These findings highlight the complex interactions occurring at the calving front of Kronebreen and suggest further observational data and modelling work is needed to fully understand the hierarchy of controls on calving.

Abstract Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. Methods This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. Discussion The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. Trial registration number The study was prospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Abstract Background The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. Methods We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. Results In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. Conclusion The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.

While landscapes are broadly sculpted by tectonics and climate, on a catchment scale, sediment size can regulate hillslope denudation rates and thereby influence the location of topographic highs and valleys. In this work, we used in situ 10Be cosmogenic radionuclide analysis to measure the denudation rates of bedrock, boulders, and soil in three granitic landscapes with different climates in Chile. We hypothesize that bedrock and boulders affect differential denudation by denuding more slowly than the surrounding soil; the null hypothesis is that no difference exists between soil and boulder or bedrock denudation rates. To evaluate denudation rates, we present a simple model that assesses differential denudation of boulders and the surrounding soil by evaluating boulder protrusion height against a two-stage erosion model and measured 10Be concentrations of boulder tops. We found that hillslope bedrock and boulders consistently denude more slowly than soil in two out of three of our field sites, which have a humid and a semi-arid climate: denudation rates range from ∼5 to 15 m Myr−1 for bedrock and boulders and from ∼8 to 20 m Myr−1 for soil. Furthermore, across a bedrock ridge at the humid site, denudation rates increase with increasing fracture density. At our lower-sloping field sites, boulders and bedrock appear to be similarly immobile based on similar 10Be concentrations. However, in the site with a Mediterranean climate, steeper slopes allow for higher denudation rates for both soil and boulders (∼40–140 m Myr−1), while the bedrock denudation rate remains low (∼22 m Myr−1). Our findings suggest that unfractured bedrock patches and large hillslope boulders affect landscape morphology by inducing differential denudation in lower-sloping landscapes. When occurring long enough, such differential denudation should lead to topographic highs and lows controlled by bedrock exposure and hillslope sediment size, which are both a function of fracture density. We further examined our field sites for fracture control on landscape morphology by comparing fracture, fault, and stream orientations, with the hypothesis that bedrock fracturing leaves bedrock more susceptible to denudation. Similar orientations of fractures, faults, and streams further support the idea that tectonically induced bedrock fracturing guides fluvial incision and accelerates denudation by reducing hillslope sediment size.

Abstract Background Person-centred care is integral to high-quality health service provision, though concepts vary and the literature is complex. Validated instruments that measure person-centred practitioner skills, and behaviours within consultations, are needed for many reasons, including in training programmes. We aimed to provide a high-level synthesis of what was expected to be a large and diverse literature through a systematic review of existing reviews of validation studies a of instruments that measure person-centred practitioner skills and behaviours in consultations. The objectives were to undertake a critical appraisal of these reviews, and to summarise the available validated instruments and the evidence underpinning them. Methods A systematic search of Medline, EMBASE, PsycINFO and CINAHL was conducted in September 2020. Systematic reviews of validation studies of instruments measuring individual practitioner person-centred consultation skills or behaviours which report measurement properties were included. Review quality was assessed with the Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. Details of the reviews, the included validation studies, and the instruments themselves are tabulated, including psychometric data, and a narrative overview of the reviews is provided. Results Four reviews were eligible for inclusion. These used different conceptualisations of person-centredness and targeted distinct, sometimes mutually exclusive, practitioners and settings. The four reviews included 68 unique validation studies examining 42 instruments, but with very few overlaps. The critical appraisal shows there is a need for improvements in the design of reviews in this area. The instruments included within these reviews have not been subject to extensive validation study. Discussion There are many instruments available which measure person-centred skills in healthcare practitioners and this study offers a guide to what is available to researchers and research users. The most relevant and promising instruments that have already been developed, or items within them, should be further studied rigorously. Validation study of existing material is needed, not the development of new measures.

Any large dataset can be analyzed in a number of ways, and it is possible that the use of different analysis strategies will lead to different results and conclusions. One way to assess whether the results obtained depend on the analysis strategy chosen is to employ multiple analysts and leave each of them free to follow their own approach. Here, we present consensus-based guidance for conducting and reporting such multi-analyst studies, and we discuss how broader adoption of the multi-analyst approach has the potential to strengthen the robustness of results and conclusions obtained from analyses of datasets in basic and applied research.