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Abstract Background Neuroinflammation can modulate brain development; however, the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. To address this gap in knowledge, we evaluated the peripheral and central nervous system (CNS) immune responses to a mixed immune challenge in early postnatal rats of varying strains and sex. Methods On postnatal day 10 (P10), male and female Lewis and Brown Norway rats were injected intramuscularly with either a mix of bacterial and viral components in adjuvant, adjuvant-only, or saline. Immune responses were evaluated at 2 and 5 days post-challenge. Cytokine and chemokine levels were evaluated in serum and in multiple brain regions using a Luminex multiplex assay. Multi-factor ANOVAs were used to compare analyte levels across treatment groups within strain, sex, and day of sample collection. Numbers and activation status of astrocytes and microglia were also analyzed in the cortex and hippocampus by quantifying immunoreactivity for GFAP, IBA-1, and CD68 in fixed brain slices. Immunohistochemical data were analyzed using a mixed-model regression analysis. Results Acute peripheral immune challenge differentially altered cytokine and chemokine levels in the serum versus the brain. Within the brain, the cytokine and chemokine response varied between strains, sexes, and days post-challenge. Main findings included differences in T helper (Th) type cytokine responses in various brain regions, particularly the cortex, with respect to IL-4, IL-10, and IL-17 levels. Additionally, peripheral immune challenge altered GFAP and IBA-1 immunoreactivity in the brain in a strain- and sex-dependent manner. Conclusions These findings indicate that genetic background and sex influence the CNS response to an acute peripheral immune challenge during early postnatal development. Additionally, these data reinforce that the developmental time point during which the challenge occurs has a distinct effect on the activation of CNS-resident cells.

Treatment of locally advanced rectal cancer includes chemotherapy, radiation, and surgery but patient responses to neoadjuvant treatment are variable. We have shown that rectal tumors are comprised of multiple genetically distinct sub-clones. Unique sub-clones within tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance.Locally advanced rectal cancer patients underwent pre-treatment biopsies. At the time of surgery, tissue from the treated tumor was obtained and analyzed. Pre- and post-treatment specimens were subjected to whole exome and confirmatory deep sequencing for somatic mutations. Copy number variation was assessed using OncoScan SNP arrays. Genomic data were analyzed using PyClone to identify sub-clonal tumor population following nCRT. Alterations that persisted or were enriched in the post-treatment tumor specimen following nCRT were defined for each patient.Thirty-two samples were obtained from ten patients. PyClone identified 2 to 10 genetic sub-clones per tumor. Substantial changes in the proportions of individual sub-clones in pre- versus post-treatment tumor material were found in all patients. Resistant sub-clones recurrently contained mutations in TP53, APC, ABCA13, MUC16, and THSD4. Recurrent copy number variation was observed across multiple chromosome regions after nCRT. Pathway analysis including variant alleles and copy number changes associated with resistant sub-clones revealed significantly altered pathways, especially those linked to the APC and TP53 genes, which were the two most frequently mutated genes.Intra-tumoral heterogeneity is evident in pre-treatment rectal cancer. Following treatment, sub-clonal populations are selectively modified and enrichment of a subset of pre-treatment sub-clones is seen. Further studies are needed to define recurrent alterations at diagnosis that may contribute to resistance to nCRT.

Domain walls of topological materials may be good candidates to study topological interfacial states. Here, Huang et al. discover polar domain walls which can be manipulated by electron beams and phase domain walls where possible signature of a conducting hinge state is detected in Weyl semimetal MoTe2.

Abstract Background Bio-based production of organic acids promises to be an attractive alternative for the chemicals industry to substitute petrochemicals as building-block chemicals. In recent years, itaconic acid (IA, methylenesuccinic acid) has been established as a sustainable building-block chemical for the manufacture of various products such as synthetic resins, coatings, and biofuels. The natural IA producer Aspergillus terreus is currently used for industrial IA production; however, the filamentous fungus Aspergillus niger has been suggested to be a more suitable host for this purpose. In our previous report, we communicated the overexpression of a putative cytosolic citrate synthase citB in an A. niger strain carrying the full IA biosynthesis gene cluster from A. terreus, which resulted in the highest final titer reported for A. niger (26.2 g/L IA). In this research, we have attempted to improve this pathway by increasing the cytosolic acetyl-CoA pool. Additionally, we have also performed fermentation optimization by varying the nitrogen source and concentration. Results To increase the cytosolic acetyl-CoA pool, we have overexpressed genes acl1 and acl2 that together encode for ATP-citrate lyase (ACL). Metabolic engineering of ACL resulted in improved IA production through an apparent increase in glycolytic flux. Strains that overexpress acl12 show an increased yield, titer and productivity in comparison with parental strain CitB#99. Furthermore, IA fermentation conditions were improved by nitrogen supplementation, which resulted in alkalization of the medium and thereby reducing IA-induced weak-acid stress. In turn, the alkalizing effect of nitrogen supplementation enabled an elongated idiophase and allowed final titers up to 42.7 g/L to be reached at a productivity of 0.18 g/L/h and yield of 0.26 g/g in 10-L bioreactors. Conclusion Ultimately, this study shows that metabolic engineering of ACL in our rewired IA biosynthesis pathway leads to improved IA production in A. niger due to an increase in glycolytic flux. Furthermore, IA fermentation conditions were improved by nitrogen supplementation that alleviates IA induced weak-acid stress and extends the idiophase.

Abstract Background In vivo diffusion tensor imaging (DTI) of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis (ALS). Methods Ten mice with TDP-43 G298S overexpression under control of the Thy1.2 promoter and 10 wild type (wt) underwent longitudinal DTI scans at 11.7 T, including one baseline and one follow-up scan with an interval of about 5 months. Whole brain-based spatial statistics (WBSS) of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43 G298S mice compared to wt at the cohort level. Results were supplemented by tractwise fractional anisotropy statistics (TFAS) and histological evaluation of motor cortex for signs of neuronal loss. Results Alterations at the cohort level in TDP-43 G298S mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract. Neuronal loss in layer V of motor cortex was detected in TDP-43 G298S at the later (but not at the earlier) timepoint compared to wt. Conclusion DTI mapping of TDP-43 G298S mice demonstrated progression in motor areas M1/M2. WBSS and TFAS are useful techniques to localize TDP-43 G298S associated alterations over time in this ALS mouse model, as a biological marker.

Abstract Background Immunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8+ T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8+ T and NK cell function. Most reported preclinical studies administered N-803 intraperitoneally not subcutaneously, the current clinical route of administration. N-803 is now being evaluated clinically in combination with PD-1/PD-L1 inhibitors. However, the mechanism of action has not been fully elucidated. Here, we examined the anti­tumor efficacy and immunomodulatory effects of combining N-803 with an anti-PD-L1 antibody in preclinical models of solid carcinomas refractory to anti-PD-L1 or N-803. Methods Subcutaneous N-803 and an anti-PD-L1 monoclonal antibody were administered as monotherapy or in combination to 4T1 triple negative breast and MC38-CEA colon tumor-bearing mice. Anti-tumor efficacy was evaluated, and a comprehensive analysis of the immune-mediated effects of each therapy was performed on the primary tumor, lung as a site of metastasis, and spleen. Results We demonstrate that N-803 treatment increased PD-L1 expression on immune cells in vivo, supporting the combination of N-803 and anti-PD-L1. N-803 plus anti-PD-L1 was well-tolerated, reduced 4T1 lung metastasis and MC38-CEA tumor burden, and increased survival as compared to N-803 and anti-PD-L1 monotherapies. Efficacy of the combination therapy was dependent on both CD8+ T and NK cells and was associated with increased numbers of these activated immune cells in the lung and spleen. Most alterations to NK and CD8+ T cell phenotype and number were driven by N-803. However, the addition of anti-PD-L1 to N-803 significantly enhanced CD8+ T cell effector function versus N-803 and anti-PD-L1 monotherapies, as indicated by increased Granzyme B and IFNγ production, at the site of metastasis and in the periphery. Increased CD8+ T cell effector function correlated with higher serum IFNγ levels, without related toxicities, and enhanced anti-tumor efficacy of the N-803 plus anti-PD-L1 combination versus either monotherapy. Conclusions We provide novel insight into the mechanism of action of N-803 plus anti-PD-L1 combination and offer preclinical proof of concept supporting clinical use of N-803 in combination with checkpoint inhibitors, including for patients non- and/or minimally responsive to either monotherapy.

Expert organizations are often described as facilitators of the interactions between science and policy. In managing this boundary, they must also manage other boundaries, such as those between different knowledge systems and between different categories of actors. However, how this intersectional boundary work is performed, and what it implies, is still unexplored territory. Focusing on the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services (IPBES), this study contributes knowledge on the intersectionality of boundary work and how it influences the production of global policy-relevant knowledge. This is done by examining how IPBES socializes junior experts to become senior experts. This socialization process makes a number of norms and ideals visible and enables an analysis of how the know-how of boundary work is passed forward from one generation of experts to the next. The study analyzes three boundaries: between senior and junior experts, between science and policy, and between scientific knowledge and indigenous and local knowledge. The findings show how intersectional boundary work is crucial in the creation of expert organizations and policy-relevant knowledge. In the case of IPBES, this study shows how the institutionalization of the organization unintentionally has created restrictions for the boundary work between different knowledge systems.

Recent studies have identified the metazoan ER-resident proteins, TMEM41B and VMP1, and so structurally related VTT-domain proteins, as glycerolipid scramblases.

Study Region: Lake Urmia, Iran. Study focus: There is widespread interest in restoring drying saline lakes. At Iran’s hypersaline Lake Urmia, managers have sought a uniform target lake level of 1274.1 m above sea level to lower salinity below 263 g L−1 and recover Artemia to sufficient densities to support flamingos. We suggest that addressing a broader range of objectives will allow more flexibility for managing the lake. We define eight restoration objectives to lower salinity, sustain Artemia and flamingo populations, separate islands from each other and the mainland, reduce lakebed dust, maintain commercially valuable ions, and improve recreational access from resort beaches. We use 40 years of experimental, field, satellite, and model data to relate each objective to lake level. We describe variations through time and associated uncertainties for meeting each objective. New hydrological insights: We show that:1) Lake variations prevent setting a precise target restoration level; 2) The current target may not sufficiently lower salinity to recover Artemia to sufficient densities to support flamingos; 3) Restoration objectives do not converge to a single lake level; tradeoffs are murky; 4) Lake Urmia managers should focus on multiple ecosystem services and track how they are met as lake level varies over time; and 5) As information about the lake improves, managers should adapt their management strategies to meet the most attainable objectives.

Pulmonary fibrosis is strongly associated with telomere shortening and increased DNA damage. Key cells in the pathogenesis involve alveolar type 2 (AT2) cells, club cells and myofibroblasts; however, to what extent these cells are affected by telomere shortening and DNA damage is not yet known. We sought to determine the degree of, and correlation between, telomere shortening and DNA damage in different cell types involved in the pathogenesis of progressive fibrosing interstitial lung disease. Telomere length and DNA damage were quantified, using combined fluorescence in situ hybridisation and immunofluorescence staining techniques, in AT2 cells, club cells and myofibroblasts of controls and patients with pulmonary fibrosis and a telomerase reverse transcriptase mutation (TERT-PF), idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). In IPF and TERT-PF lungs, AT2 cells contained shorter telomeres and expressed higher DNA damage signals than club cells and myofibroblasts. In fHP lungs, club cells contained highly elevated levels of DNA damage, while telomeres were not obviously short. In vitro, we found significantly shorter telomeres and higher DNA damage levels only in AT2 surrogate cell lines treated with telomerase inhibitor BIBR1532. Our study demonstrated that in IPF and TERT-PF lungs, telomere shortening and accumulation of DNA damage primarily affects AT2 cells, further supporting the importance of AT2 cells in these diseases, while in fHP the particularly high telomere-independent DNA damage signals in club cells underscores its bronchiolocentric pathogenesis. These findings suggest that cell type-specific telomere shortening and DNA damage may help to discriminate between different drivers of fibrogenesis.

Background: Research in primary care is essential, but recruiting children in this setting can be complex and may cause selection bias. Challenges surrounding informed consent, particularly in an acute clinical setting, can undermine feasibility. The off-protocol use of an intervention nearing implementation has become common in pragmatic randomised controlled trials (RCTs) set in primary care. Aim: To describe how the informed consent procedure affects study inclusion and to assess how off-protocol medication prescribing affects participant selection in a paediatric RCT. Design & setting: A pragmatic RCT evaluating the cost-effectiveness of oral ondansetron in children diagnosed with acute gastroenteritis (AGE) in primary care out-of-hours services and a parallel cohort study. Method: Consecutive children aged 6 months to 6 years attending primary care out-of-hours services with AGE were evaluated to assess the feasibility of obtaining informed consent, the off-protocol use of ondansetron, and other inclusion and exclusion criteria. Results: The RCT's feasibility was reduced by the informed consent procedure because 39.0% (n = 325/834) of children were accompanied by only one parent. GPs prescribed ondansetron off-protocol to 34 children (4.1%) of which 19 children were eligible for the RCT. RCT-eligible children included in the parallel cohort study had fewer risk factors for dehydration than children in the RCT despite similar dehydration assessments by GPs. Conclusion: The informed consent procedure and off-protocol use of study medication affect the inclusion rate, but had little effect on selection. A parallel cohort study alongside the RCT can help evaluate selection bias, and a pilot study can reveal potential barriers to inclusion.

Rapid diagnostic tests (RDTs) have the potential to identify infectious diseases quickly, minimize disease transmission, and could complement and improve surveillance and control of infectious and vector-borne diseases during outbreaks. The U.S. Defense Threat Reduction Agency's Joint Science and Technology Office (DTRA-JSTO) program set out to develop novel point-of-need RDTs for infectious diseases and deploy them for home use with no training. The aim of this formative study was to address two questions: 1) could community members in Iquitos, Peru and Phnom Penh, Cambodia competently use RDTs of different levels of complexity at home with visually based instructions provided, and 2) if an RDT were provided at no cost, would it be used at home if family members displayed febrile symptoms? Test kits with written and video (Peru only) instructions were provided to community members (Peru [n = 202]; Cambodia [n = 50]) or community health workers (Cambodia [n = 45]), and trained observers evaluated the competency level for each of the several steps required to successfully operate one of two multiplex RDTs on themselves or other consenting participant (i.e., family member). In Iquitos, >80% of residents were able to perform 11/12 steps and 7/15 steps for the two- and five-pathogen test, respectively. Competency in Phnom Penh never reached 80% for any of the 12 or 15 steps for either test; the percentage of participants able to perform a step ranged from 26-76% and 23-72%, for the two- and five-pathogen tests, respectively. Commercially available NS1 dengue rapid tests were distributed, at no cost, to households with confirmed exposure to dengue or Zika virus; of 14 febrile cases reported, six used the provided RDT. Our findings support the need for further implementation research on the appropriate level of instructions or training needed for diverse devices in different settings, as well as how to best integrate RDTs into existing local public health and disease surveillance programs at a large scale.

Breast tumors commonly harbor low mutational burden, low PD-L1 expression, defective antigen processing/presentation, and an immunosuppressive tumor microenvironment (TME). In a malignancy mostly refractory to checkpoint blockade, there is an unmet clinical need for novel combination approaches that increase tumor immune infiltration and tumor control. Preclinical data have guided the development of this clinical trial combining 1) BN-Brachyury (a poxvirus vaccine platform encoding the tumor associated antigen brachyury), 2) bintrafusp alfa (a bifunctional protein composed of the extracellular domain of the TGF-βRII receptor (TGFβ “trap”) fused to a human IgG1 anti-PD-L1), 3), entinostat (a class I histone deacetylase inhibitor), and 4) T-DM1 (ado-trastuzumab emtansine, a standard of care antibody-drug conjugate targeting HER2). We hypothesize that this tetratherapy will induce a robust immune response against HER2+ breast cancer with improved response rates through 1) expanding tumor antigen-specific effector T cells, natural killer cells, and immunostimulatory dendritic cells, 2) improving antigen presentation, and 3) decreasing inhibitory cytokines, regulatory T cells, and myeloid-derived suppressor cells. In an orthotopic HER2+ murine breast cancer model, tetratherapy induced high levels of antigen-specific T cell responses, tumor CD8+ T cell/Treg ratio, and augmented the presence of IFNγ- or TNFα-producing CD8+ T cells and IFNγ/TNFα bifunctional CD8+ T cells with increased cytokine production. Similar effects were observed in tumor CD4+ effector T cells. Based on this data, a phase 1b clinical trial evaluating the stepwise addition of BN-Brachyury, bintrafusp alfa, T-DM1 and entinostat in advanced breast cancer was designed. Arm 1 (TNBC) receives BN-Brachyury + bintrafusp alfa. Arm 2 (HER2+) receives T-DM1 + BN-Brachyury + bintrafusp alfa. After safety is established in Arm 2, Arm 3 (HER2+) will receive T-DM1 + BN-Brachyury + bintrafusp alfa + entinostat. Reimaging will occur every 2 cycles (1 cycle = 21 days). Arms 2 and 3 undergo research biopsies at baseline and after 2 cycles to evaluate changes within the TME. Peripheral immune responses will be evaluated. Co-primary objectives are response rate and safety. All arms employ a safety assessment in the initial six patients and a 2-stage Simon design for clinical efficacy (Arm 1 if ≥ three responses of eight then expand to 13 patients; Arms 2 and 3 if ≥ four responses of 14 then expand to 19 patients per arm). Secondary objectives include progression-free survival and changes in tumor infiltrating lymphocytes. Exploratory analyses include changes in peripheral immune cells and cytokines. To our knowledge, the combination of a vaccine, an anti-PD-L1 antibody, entinostat, and T-DM1 has not been previously evaluated in the preclinical or clinical setting. This trial (NCT04296942) is open at the National Cancer Institute (Bethesda, MD).

Introduction Early recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.Aim To describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.Methods The RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.Conclusion The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.

Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients.Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed.Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years.Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD.Trial registration:ClinicalTrials.gov with ID NCT03449589. Registered 28, February 2018.

Changes in funerary practices are key to the understanding of social transformations of past societies. Over the course of the Nordic Bronze Age, funerary practices changed from inhumation to cremation. The aim of this study is to shed light on this fundamental change through a cross-examination of archaeometric provenance data and archaeological discussions of the context and layouts of early cremation graves. To this end, we conducted 19 new provenance analyses of strontium isotopes from Early Nordic Bronze age contexts in Thisted County and Zealand and Late Bronze Age contexts from Thisted County and Vesthimmerland (Denmark). These data are subsequently compared with data from other extant relevant studies, including those from Late Bronze Age Fraugde on the Danish island of Fyn. Overall, the variations within our provenience data suggest that the integration and establishment of cremation may not have had a one-to-one relationship with in-migration to Nordic Bronze Age Denmark. Moreover, there seems to be no single blanket scenario which dictated the uptake of cremation as a practice within this part of Southern Scandinavia. By addressing habitus in relation to the deposition of cremations as juxtaposed with these provenance data¸ we hypothesize several potential pathways for the uptake of cremation as a new cultural practice within the Danish Nordic Bronze Age and suggest that this may have been a highly individual process, whose tempo may have been dictated by the specificities of the region(s) concerned.

Most monoclonal antibodies (MAbs), including immune checkpoint inhibitor MAbs, are delivered intravenously (i.v.) to patients. Recent clinical studies have demonstrated that some anti-PD1 MAbs may also be delivered subcutaneously (s.c.), with clinical outcomes similar of those obtained with i.v.-delivered agents. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap”) fused to the heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti-PDL1), was designed to target two key immunosuppressive pathways in the tumor microenvironment (TME). Bintrafusp alfa is currently being administered i.v. in clinical studies. The studies reported here demonstrate that systemic or s.c. delivery of bintrafusp alfa, each administered at five different doses, induces similar anti-tumor effects in breast and colorectal carcinoma models. An interrogation of the TME for CD8+ and CD4+ T cells, regulatory T cells (Tregs), monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic (G) MDSCs showed similar levels and phenotype of each cell subset when bintrafusp alfa was given systemically or s.c. Subcutaneous administration of bintrafusp alfa also sequestered TGFβ in the periphery at similar levels seen with systemic delivery. To our knowledge, this is the most comprehensive preclinical evaluation of any checkpoint inhibitor MAb given s.c. vs systemically, and the first to demonstrate this phenomenon using a bifunctional agent. These studies provide preclinical rationale to explore s.c. approaches for bintrafusp alfa in the clinic.

Intracellular alpha-synuclein has numerous effects on different functions of the cell. Although it is expressed in a wide spectrum of cell types from different lineages, most of our knowledge about it was generated by studying neuronal or glial cells. However, the role of immune cells in Parkinson’s disease and related synucleinopathies has recently emerged. Altered immune cell phenotypes and functions have been reported not only in animal models, but also in human disease. While the response of immune cells to extracellular alpha-synuclein has been thoroughly studied, insights into the effects of endogenously expressed or taken-up alpha-synuclein on the function of immune cells remain scarce. Such insights may prove to be important for understanding the complex cellular and molecular events resulting in neurodegeneration and aid the development of novel therapies. We review the current state of knowledge about how alpha-synuclein and its pathologic manifestations affect the phenotype and function of peripheral and central nervous system (CNS) immune cells, and discuss the potential of this topic for advancing our understanding of synucleinopathies.

The aggregation of α-synuclein (α-syn) is inseparably connected to Parkinson’s disease (PD). It is now well-established that certain forms of α-syn aggregates, oligomers and fibrils, can exert neurotoxicity in synucleinopathies. With the exception of rare familial forms, the vast majority of PD cases are idiopathic. Understanding the earliest molecular mechanisms that cause initial α-syn misfolding could help to explain why PD affects only some individuals and others not. Factors that chaperone the transition of α-syn’s physiological to pathological function are of particular interest, since they offer opportunities for intervention. The relationship between α-syn and lipids represents one of those factors. Membrane interaction is crucial for normal cellular function, but lipids also induce the aggregation of α-syn, causing cell toxicity. Also, disease-causing or risk-factor mutations in genes related to lipid metabolism like PLA2G6, SCARB2 or GBA1 highlight the close connection between PD and lipids. Despite the clear link, the ambivalent interaction has not been studied sufficiently so far. In this review, we address how α-syn interacts with lipids and how they can act as key factor for orchestrating toxic conversion of α-syn. Furthermore, we will discuss a scenario in which initial α-syn aggregation is determined by shifts in lipid/α-syn ratio as well as by dyshomeostasis of membrane bound/unbound state of α-syn.

This supplementary data is supportive to the research article entitled ‘Cost-effectiveness of lung cancer screening with low-dose computed tomography (LDCT) in heavy smokers: A micro-simulation modelling study’ (Yihui Du et al. 2020). This supplementary contains a description of the model input and the related model output data that were not included in the research article. The input data used for the tumour growth model and the self-detected tumour size model are provided. The output data of this article include the data used for cost-effectiveness analysis of lung cancer LDCT screening with the Dutch and international discount rates, the data of the sensitivity analysis, and the data of the model validation.

As we approach the Decade of Ecosystem Restoration (2021–2030), there is renewed focus on improving wetland restoration practices to reestablish the habitat and climate mitigation functions and services that wetlands provide. A first step in restoring these functions and services is to reestablish the native vegetation structure and composition through strategic seed-based approaches. These approaches should be driven by ecological, genetic, and evolutionary principles, along with consideration for economics, logistics, and other social constraints. Effective seed-based approaches must consider the chosen species, seed sourcing, dormancy break and germination requirements, seed enhancement technologies, potential invaders, seeding densities, and long-term monitoring. Choice of species should reflect historical plant communities and future environmental conditions, species that support functional goals including invasion resistance, and seed availability constraints. Furthermore, seeds should be sourced to ensure ample genetic diversity to support multifunctionality and evolutionary capacity while also considering the broad natural dispersal of many wetland species. The decision to collect wild seeds or purchase seeds will also impact species choice and genetic diversity, which can have cascading effects for functional goals. To ensure seedling establishment, seed dormancy should be addressed through dormancy breaking treatments and the potentially narrow germination requirements of some species will require targeted sowing timing and location to align with safe sites. Other seed enhancements such as priming and coatings are poorly developed for wetland restoration and their potential for improving establishment is unknown. Because wetlands are highly invasion prone, potential invaders and their legacies should be addressed. Seeding densities should strike a balance between outcompeting invaders and preserving valuable seed resources. Invader control and long-term monitoring is key to improving revegetation and restoration. Here, we review scientific advances to improve revegetation outcomes, and provide methods and recommendations to help achieve the desired goals. Gaps in knowledge about seed-based wetland restoration currently exist, however, and untested practices will certainly increase risks in future efforts. These efforts can be used to better understand the ecological, genetic, and evolutionary processes related to wetland seeds, which will bring us one step closer to seed-based restoration of functions and services needed for human and ecological communities.

The type I interferon response is an important innate antiviral pathway. Recognition of viral RNA by RIG-I-like receptors (RLRs) activates a signaling cascade that leads to type I interferon (IFN-α/β) gene transcription. Multiple proteins in this signaling pathway (e.g. RIG-I, MDA5, MAVS, TBK1, IRF3) are regulated by (de)ubiquitination events. Most viruses have evolved mechanisms to counter this antiviral response. The leader protease (Lpro) of foot-and-mouth-disease virus (FMDV) has been recognized to reduce IFN-α/β gene transcription; however, the exact mechanism is unknown. The proteolytic activity of Lpro is vital for releasing itself from the viral polyprotein and for cleaving and degrading specific host cell proteins, such as eIF4G and NF-κB. In addition, Lpro has been demonstrated to have deubiquitination/deISGylation activity. Lpro's deubiquitination/deISGylation activity and the cleavage/degradation of signaling proteins have both been postulated to be important for reduced IFN-α/β gene transcription. Here, we demonstrate that TBK1, the kinase that phosphorylates and activates the transcription factor IRF3, is cleaved by Lpro in FMDV-infected cells as well as in cells infected with a recombinant EMCV expressing Lpro. In vitro cleavage experiments revealed that Lpro cleaves TBK1 at residues 692-694. We also observed cleavage of MAVS in HeLa cells infected with EMCV-Lpro, but only observed decreasing levels of MAVS in FMDV-infected porcine LFPK αVβ6 cells. We set out to dissect Lpro's ability to cleave RLR signaling proteins from its deubiquitination/deISGylation activity to determine their relative contributions to the reduction of IFN-α/β gene transcription. The introduction of specific mutations, of which several were based on the recently published structure of Lpro in complex with ISG15, allowed us to identify specific amino acid substitutions that separate the different proteolytic activities of Lpro. Characterization of the effects of these mutations revealed that Lpro's ability to cleave RLR signaling proteins but not its deubiquitination/deISGylation activity correlates with the reduced IFN-β gene transcription.

Objective: Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8+ T cell memory formation through a microRNA (miR) dependent mechanism.Methods: Phenotypes of CD8+ T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry. A microarray analysis was used to screen for differences in miR expression. Sorted CD8+ cells were in vitro stimulated with nicotine and analyzed for transcription of miRs and genes related to memory programming by qPCR.Results: CD27+CD107a−CD8+ T cells, defining a naïve-memory population, had low expression of PD-1. Additionally, the CD27+ population was more frequent in smokers (p = 0.0089). Smokers were recognized by differential expression of eight miRs. Let-7c-5p, let-7d-5p and let-7e-5p, miR-92a-3p, miR-150-5p, and miR-181-5p were up regulated, while miR-3196 and miR-4723-5p were down regulated. These miRs were predicted to target proteins within the FOXO-signaling pathway involved in CD8+ memory programming. Furthermore, miR-92a-3p was differentially expressed in CD8+ cells with naïve-memory predominance. Nicotine exposure of CD8+ cells induced the expression of miR-150-5p and miR-181a-5p in the naïve-memory cells in vitro. Additionally, nicotine exposure inverted the ratio between mRNAs of proteins in the FOXO pathway and their targeting miRs.Conclusions: Smokers have a high prevalence of CD8+ T cells with a naïve-memory phenotype. These cells express a miR profile that interacts with the memory programming conducted through the FOXO pathway.

Capacity building has been identified as being of importance for the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES). As the IPBES is becoming an influential expert organization, it is essential to examine what capacity building means in its context, what capacities it has built, and what implications these capacities have. This study explores these issues by focusing on the IPBES's general strategy for capacity building, the IPBES's fellowship programme and to what extent there are additional capacity building needs that can be addressed. The study shows that the IPBES has focused its capacity building efforts on the science side of the science-policy interface while, thus far, it has neglected to build capacities on the policy side of the interface. The study provides insight into how capacity building for the science-policy interface sets preconditions for science-policy relations at different levels and scales within biodiversity and ecosystem services and beyond.

Background Anti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two αPD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+αPD-L1 combination.Methods The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+αPD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN).Results We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+αPD-L1. Compared with N-803+αPD-L1, N-809 enhanced natural killer (NK) and CD8+ T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8+ T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8+ T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+αPD-L1, N-809 reduced immunosuppressive regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME.Conclusions Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8+ T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including Treg, M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma.

This paper provides a discussion of the increasing amount of mobility data from the Early Nordic Bronze Age (Early NBA), c. 1600-1100 BCE with particular focus on NBA II and III (c. 1500-1100 BCE). As a male-oriented study, the intent is to develop current perspectives on gender roles in the Early NBA in relation to mobility. In order to achieve our aim, we conducted strontium isotope analyses and radiocarbon dating combined with an in-depth archaeological investigation of grave goods obtained from two male burials from the Vejle region, SE Jutland. To contextualise the case study results, we also conducted network analyses of male gear from burials and ritual deposits on a regional scale, which reveal differentiated roles among men in the upper social echelon. The warrior emerged as an overall identity for high-ranking males whilst differences in male weaponry interestingly suggest that a minimum of three kinds of warriors were distinguished, reflecting social roles in war and society. The results suggest that one of the individuals was local while the other might have moved. The overall aim is to demonstrate that robust results regarding gendered mobilities will depend on the combination of several methods, datasets and scales of inquiry.

During infection neuraminidase desialylates platelets and induces their rapid clearance from circulation. The underlying molecular basis, particularly the role of platelet glycoprotein (GP)Ibα therein, is not clear. Utilizing genetically altered mice we report that the extracellular domain of GPIbα, but neither von Willebrand factor nor ADAM17 (a disintegrin and metalloprotease 17), is required for platelet clearance induced by intravenous injection of neuraminidase. Lectin binding to platelets following neuraminidase injection over time revealed that the extent of desialylation of O-glycans correlates with the decrease of platelet count in mice. Injection of α2,3-neuraminidase reduces platelet counts in wild-type but not in transgenic mice expressing only a chimeric GPIbα that misses most of its extracellular domain. Neuraminidase treatment induces unfolding of the O-glycosylated mechanosensory domain in GPIbα as monitored by single-molecule force spectroscopy, increases the exposure of the ADAM17 shedding cleavage site in the mechanosensory domain on the platelet surface, and induces ligand-independent GPIb-IX signaling in human and murine platelets. These results suggest that desialylation of O-glycans of GPIbα induces unfolding of the mechanosensory domain, subsequent GPIb-IX signaling including amplified desialylation of N-glycans, and eventually rapid platelet clearance. This new molecular mechanism of GPIbα-facilitated clearance could potentially resolve many puzzling and seemingly contradicting observations associated with clearance of desialylated or hyposialylated platelets.

RATIONALE:A subset of patients with idiopathic pulmonary fibrosis (IPF) contains short leukocyte telomeres or telomere related mutations. We previously showed that alveolar type 2 cells have short telomeres in fibrotic lesions. Our objectives were to better understand how telomere shortening associates with fibrosis in IPF lung and identify a subset of patients with telomere-related disease. METHODS:Average telomere length was determined in multiple organs, basal and apical lung, and diagnostic and end-stage fibrotic lung biopsies. Alveolar type 2 cells telomere length was determined in different areas of IPF lungs. RESULTS:In IPF but not in controls, telomere length in lung was shorter than in other organs, providing rationale to focus on telomere length in lung. Telomere length did not correlate with age and no difference in telomere length was found between diagnostic and explant lung or between basal and apical lung, irrespective of the presence of a radiological apicobasal gradient or fibrosis. Fifteen out of 28 IPF patients had average lung telomere length in the range of patients with a telomerase (TERT) mutation, and formed the IPFshort group. Only in this IPFshort and TERT group telomeres of alveolar type 2 cells were extremely short in fibrotic areas. Additionally, whole exome sequencing of IPF patients revealed two genetic variations in RTEL1 and one in PARN in the IPFshort group. CONCLUSIONS:Average lung tissue telomere shortening does not associated with fibrotic patterns in IPF, however, approximately half of IPF patients show excessive lung telomere shortening that is associated with pulmonary fibrosis driven by telomere attrition.

Antimicrobial Resistance is a global crisis that veterinarians contribute to through their use of antimicrobials in animals. Antimicrobial stewardship has been shown to be an effective means to reduce antimicrobial resistance in hospital environments. Effective monitoring of antimicrobial usage patterns is an essential part of antimicrobial stewardship and is critical in reducing the development of antimicrobial resistance. The aim of this study is to describe how frequently antimicrobials were used in veterinary consultations and identify the most frequently used antimicrobials. Using VetCompass Australia, Natural Language Processing techniques, and the Australian Strategic Technical Advisory Group's (ASTAG) Rating system to classify the importance of antimicrobials, descriptive analysis was performed on the antimicrobials prescribed in consultations from 137 companion animal veterinary clinics in Australia between 2013 and 2017 (inclusive). Of the 4,400,519 consultations downloaded there were 595,089 consultations where antimicrobials were prescribed to dogs or cats. Antimicrobials were dispensed in 145 of every 1000 canine consultations; and 38 per 1000 consultations involved high importance rated antimicrobials. Similarly with cats, 108 per 1000 consultations had antimicrobials dispensed, and in 47 per 1000 consultations an antimicrobial of high importance rating was administered. The most common antimicrobials given to cats and dogs were cefovecin and amoxycillin clavulanate, respectively. The most common topical antimicrobial and high-rated topical antimicrobial given to dogs and cats was polymyxin B. This study provides a descriptive analysis of the antimicrobial usage patterns in Australia using methods that can be automated to inform antimicrobial use surveillance programs and promote antimicrobial stewardship.

BACKGROUND:Because of a lack of preference-based health-related quality of life (HRQoL) instruments suitable for infants aged 0-12 months, we previously developed the Infant QoL Instrument (IQI). The present study aimed to generate an algorithm to estimate utilities for the IQI. METHODS:Via an online survey, respondents from the general population and primary caregivers from China-Hong Kong, the UK, and the USA were presented 10 discrete choice scenarios based on the IQI classification system. An additional sample of respondents from the general population were also asked if they considered the examined health states to be worse than death. Coefficients for the IQI item levels were obtained with a conditional logit model based on the responses of the primary caregivers for IQI states only. These coefficients were then normalized using the rank-ordered logit model based on the responses from the general population who assessed "death" as a choice option. In this way, the values were rescaled from full health (1.0) to death (0.0), and consequently, they became suitable for the computation of quality-adjusted life years. RESULTS:The total sample consisted of 1409 members of the general population and 1229 primary caregivers. Results indicated that, out of the 7 IQI items ("sleeping," "feeding," "breathing," "stooling/poo," "mood," "skin," and "interaction"), "breathing" had the highest impact on the HRQoL of infants. Moreover, except for "stooling," all item levels were statistically significant. The general population sample considered none of the health states as worse than death. The utility value for the worst health state was 0.015 (State 4444444). CONCLUSIONS:The IQI is the first generic instrument to assess overall HRQoL in 0-1-year-old infants by providing values and utilities. Using discrete choice experiments, we demonstrated that it is possible to derive utilities of infant health states. The next step will be to collect IQI values in a clinical population of infants and to compare these values with those of other instruments.

BackgroundInvasive fungal infection (IFI) detection requires application of complex case definitions by trained staff. Administrative coding data (ICD-10-AM) may provide a simplified method for IFI surveillance, but accuracy of case ascertainment in children with cancer is unknown.ObjectiveTo determine the classification performance of ICD-10-AM codes for detecting IFI using a gold-standard dataset (r-TERIFIC) of confirmed IFIs in paediatric cancer patients at a quaternary referral centre (Royal Children's Hospital) in Victoria, Australia from 1st April 2004 to 31st December 2013.MethodsICD-10-AM codes denoting IFI in paediatric patients (ResultsOf 1,671 evaluable patients, 113 (6.76%) had confirmed IFI diagnoses according to gold-standard criteria, while 114 (6.82%) cases were identified using the codes. Of the clinical IFI cases, 68 were in receipt of ≥1 ICD-10-AM code(s) for IFI, corresponding to an overall sensitivity, PPV and F1 score of 60%, respectively. Sensitivity was highest for proven IFI (77% [95% CI: 58-90]; F1 = 47%) and invasive candidiasis (83% [95% CI: 61-95]; F1 = 76%) and lowest for other/unspecified IFI (20% [95% CI: 5.05-72%]; F1 = 5.00%). The most frequent misclassification was coding of invasive aspergillosis as invasive candidiasis.ConclusionICD-10-AM codes demonstrate moderate sensitivity and PPV to detect IFI in children with cancer. However, specific subsets of proven IFI and invasive candidiasis (codes B37.x) are more accurately coded.

BackgroundIn many countries, medical interventions are reimbursed on the basis of recommendations made by advisory boards and committees that apply multiple criteria in their assessment procedures. Given the diversity of these criteria, it is difficult to find common ground to determine what information is required for setting priorities.ObjectiveTo investigate whether society and patients share the same interests and views concerning healthcare priorities.MethodsWe applied a framework of discrete choice models in which respondents were presented with judgmental tasks to elicit their preferences. They were asked to choose between two hypothetical scenarios of patients receiving a new treatment. The scenarios graphically presented treatment outcomes and patient characteristics. Responses were collected through an online survey administered among respondents from the general population (N = 1,253) and patients (N = 1,389) and were analyzed using conditional logit and mixed logit models.ResultsThe respondents' preferences regarding new medical treatments revealed that they attached the most relative importance to additional survival years, age at treatment, initial health condition, and the cause of disease. Minor differences in the relative importance assigned to three criteria: age at treatment, initial health, and cause of disease were found between the general population and patient samples. Health scenarios in which patients had higher initial health-related quality of life (i.e., a lower burden of disease) were favored over those in which patients' initial health-related quality of life was lower.ConclusionsOverall, respondents within the general population expressed preferences that were similar to those of the patients. Therefore, priority-setting studies that are based on the perspectives of the general population may be useful for informing decisions on reimbursement and other types of priority-setting processes in health care. Incorporating the preferences of the general population may simultaneously increase public acceptance of these decisions.

Abstract White matter lesions (WMLs) are a common manifestation of small vessel disease (SVD) in the elderly population. They are associated with an enhanced risk of developing gait abnormalities, poor executive function, dementia, and stroke with high mortality. Hypoperfusion and the resulting endothelial damage are thought to contribute to the development of WMLs. The focus of the present study was the analysis of the microvascular bed in SVD patients with deep WMLs (DWMLs) by using double- and triple-label immunohistochemistry and immunofluorescence. Simultaneous visualization of collagen IV (COLL4)-positive membranes and the endothelial glycocalyx in thick sections allowed us to identify endothelial recession in different types of string vessels, and two new forms of small vessel/capillary pathology, which we called vascular bagging and ghost string vessels. Vascular bags were pouches and tubes that were attached to vessel walls and were formed by multiple layers of COLL4-positive membranes. Vascular bagging was most severe in the DWMLs of cases with pure SVD (no additional vascular brain injury, VBI). Quantification of vascular bagging, string vessels, and the density/size of CD68-positive cells further showed widespread pathological changes in the frontoparietal and/or temporal white matter in SVD, including pure SVD and SVD with VBI, as well as a significant effect of the covariate age. Plasma protein leakage into vascular bags and the white matter parenchyma pointed to endothelial damage and basement membrane permeability. Hypertrophic IBA1-positive microglial cells and CD68-positive macrophages were found in white matter areas covered with networks of ghost vessels in SVD, suggesting phagocytosis of remnants of string vessels. However, the overall vessel density was not altered in our SVD cohort, which might result from continuous replacement of vessels. Our findings support the view that SVD is a progressive and generalized disease process, in which endothelial damage and vascular bagging drive remodeling of the microvasculature.

Abstract Background Adherence to osteoporosis treatment is crucial for good treatment effects. However, adherence has been shown to be poor and a substantial part of the patients don’t even initiate treatment. This study aimed to gain insight into the considerations of both osteoporosis patients and general practitioners (GP) concerning intentional non-initiation of bisphosphonate treatment. Methods Osteoporosis patients and GPs were recruited from the SALT Osteoporosis Study and a transmural fracture liaison service, both carried out in the Netherlands. Using questionnaires, we identified non-starters and starters of bisphosphonate treatment. Semi-structured interviews were conducted to gain a detailed overview of all considerations until saturation of the data was reached. Starters were asked to reflect on the considerations that were brought forward by the non-starters. Interviews were open coded and the codes were classified into main themes and subthemes using an inductive approach. Results 16 non-starters, 10 starters, and 13 GPs were interviewed. We identified three main themes: insufficient medical advice, attitudes towards medication use including concerns about side effects, and disease awareness. From patients’ as well as GPs’ perspective, insufficient or ambiguous information from the GP influenced the decision of the non-starters to not start bisphosphonates. In contrast, starters were either properly informed, or they collected information themselves. Patients’ aversion towards medication, fear of side effects, and a low risk perception also contributed to not starting the medication, whereas starters were aware of their fracture risk and were confident of the outcome of the treatment. Concerns about osteoporosis treatment and its side effects were also expressed by several GPs. Some GPs appeared to have a limited understanding of the current osteoporosis guidelines and the indications for treatment. Conclusions Many reasons we found for not starting bisphosphonate treatment were related to the patients or the GPs themselves being insufficiently informed. Attitudes of the GPs were shown to play a role in the decision of patients not to start treatment. Interventions need to be developed that are aimed at GPs, and at education of patients.

Abstract Background Our aim was to design a study to evaluate the effectiveness and cost-effectiveness of adding physiotherapy to conventional treatment for children with functional constipation in primary care. Physiotherapy is focusing on improving the coordination between the pelvic floor and abdominal musculature during bowel movement, while conventional treatment is mainly focusing on symptomatic relief of symptoms, therefore, we expect the effects of physiotherapy will be more sustainable than the effects of conventional treatment. In this paper we describe the final study design and how the design was adapted, to overcome recruitment problems. Methods We designed a randomized controlled trial of children aged 4–17 years with functional constipation diagnosed by a general practitioner or pediatrician. Children in the intervention group received physiotherapy plus conventional treatment, and those in the control group received conventional treatment only. Follow-up measurements took place at 4 and 8 months. The primary outcome was treatment success defined according to the Rome-III criteria as the absence of functional constipation, with no laxative use. Secondary outcomes were absence of functional constipation irrespective of laxative use, quality of life, global perceived effect, and costs. Children were recruited from September 2014 to February 2017. Initially, we aimed to include children with recent symptom onset. However, in the first phase of enrollment we were confronted with an unforeseen recruitment problem: many children and their parents refused randomization because physiotherapy was considered too burdensome for the stage of disease. Therefore, we decided to also include children with a longer duration of symptoms. In total 134 children were included. Discussion The target number of participants is achieved. Therefore, the results may change thinking about the management of functional constipation in children. Trail registration Netherlands Trial Register (NTR4797), registered 8 September 2014.

Aim: Current dietary assessment methods are prone to subjective bias, highlighting the demand for an objective marker of fruit and vegetable (F/V) intake. Carotenoids from F/V consumption deposit in skin and adipose tissue, contributing to changes in skin colour. Results from research in females have highlighted positive associations between skin colour assessed by reflectance spectroscopy and F/V intake. The aim of this study was to determine the relationship between (i) F/V intake, (ii) carotenoid intake and skin colour in young Caucasian men. Methods: In this cross-sectional study reflectance spectroscopy was used to quantify skin colour in young Caucasian men. Skin colour was assessed at eight sun-exposed and unexposed body locations. A food frequency questionnaire was administered to assess F/V intake over the past month. Partial correlations were done to assess the associations between skin yellowness, F/V intake (grams) and carotenoid intake (milligrams), both with and without controlling for skin lightness. Results: Carotenoid intake was strongly associated with F/V intake (r = 0.8, p

Materials that combine metallic behaviour with stable electric polarization are scarce despite being proposed in the 1960s. Here the authors engineer a perovskite heterostructure where 2D polar metallic behavior coexists with built-in electric polarization from the displacement of B-site titanium cations.

Abstract Background The healthcare sector is evolving while life expectancy is increasing. These trends put greater pressure on healthcare resources, prompt healthcare reforms, and demand transparent arguments and criteria to assess the overall value of health interventions. There is no consensus on the core criteria by which to value and prioritize interventions, and individual stakeholders might value specific elements differently. The present study is based on a literature review that retrieved the most widely recognized arguments and criteria used in decision-making. The aim was to compile a smaller set of arguments and criteria that would seem most relevant to different stakeholders. Methods A literature review was performed in Medline and EMBASE. The initial search retrieved over 2000 articles and documents of relevant committees. A selection was made based on their reference to healthcare, policy issues, or social justice. Finally, 84 papers were included. Data extraction took place after appraisal of the articles. A full table was made, including all arguments and criteria found; next, identical or largely overlapping arguments were excluded. The remaining arguments and criteria were assessed for relevance and a reduced set was compiled. Results The final set included 25 arguments and criteria, categorized by type (clinical, social justice, ethical, and policy). For each argument and criterion, relevance to stakeholders was scored on three levels (not, partly, and completely relevant). Conclusions Many arguments and criteria play a role in making value judgments on health interventions, but not all are relevant to all interventions. Moreover, they may interact with each other. A viable way to deal with interacting and possibly conflicting arguments and criteria might be to arrange public discussions that would evoke different stakeholders’ perspectives.

Abstract Background Assessing quality of life among the elderly is a complex and multifaceted issue. Elderly people might find valuing and describing their personal experience of quality of life (QoL) demanding and cumbersome. This study therefore sought to determine the feasibility of administering two questionnaires in two samples of elderly people. Methods A preference-based instrument (EQ-5D + C) and a currently achieved functioning questionnaire (CAF) were utilized. Two pilot studies were performed. The first was performed in South Africa (n = 30), designed to test whether elderly respondents could complete and understand the two questionnaires and also to indicate which valuation method, visual analogue scale or time trade off they preferred. A second pilot study was performed in the Netherlands (n = 30), designed to investigate the use of both questionnaires in determining quality of life and health state valuations in a Dutch sample of elderly. Results Seventy percent of the South African respondents indicated that they preferred the visual analogue scale (VAS) method, when compared to the time trade-off (TTO). In both the South African and the Dutch pilot studies, the respondents, with different dependency levels, were able to use both questionnaires to determine health state descriptions and valuations. When ranking the profiles from fewer to more problems, the EQ-5D + C exhibits a gradual downwards trend, with a maximum of 100 and minimum VAS value of 41. The CAF also exhibits a gradual downwards trend, with a maximum of 1.00 and minimum VAS value of 36. Conclusions The results indicate that individuals from different parts of the world are able to complete, describe, and value the questionnaires. It is our recommendation that a comprehensive study should be done, which includes both the EQ-5D + C questionnaire and the CAF questionnaire, since the two questionnaires have proven to be feasible in providing information on quality of life and well-being of elderly people.

Abstract Background The amount of time spent living with disease greatly influences elderly people’s wellbeing, disability and healthcare costs, but differs by disease, age and sex. Methods We assessed how various single and combined diseases differentially affect life years spent living with disease in Dutch elderly men and women (65+) over their remaining life course. Multistate life table calculations were applied to age and sex-specific disease prevalence, incidence and death rates for the Netherlands in 2007. We distinguished congestive heart failure, coronary heart disease (CHD), breast and prostate cancer, colon cancer, lung cancer, diabetes, COPD, stroke, dementia and osteoarthritis. Results Across ages 65, 70, 75, 80 and 85, CHD caused the most time spent living with disease for Dutch men (from 7.6 years at age 65 to 3.7 years at age 85) and osteoarthritis for Dutch women (from 11.7 years at age 65 to 4.8 years at age 85). Of the various co-occurrences of disease, the combination of diabetes and osteoarthritis led to the most time spent living with disease, for both men (from 11.2 years at age 65 to 4.9 -years at age 85) and women (from 14.2 years at age 65 to 6.0 years at age 85). Conclusions Specific single and multi-morbid diseases affect men and women differently at different phases in the life course in terms of the time spent living with disease, and consequently, their potential disability. Timely sex and age-specific interventions targeting prevention of the single and combined diseases identified could reduce healthcare costs and increase wellbeing in elderly people.

The concept boundary organization has been introduced to identify and explain a specific way of organizing the interface between science and policy. Although the original meaning of the concept has been criticized, the term has come to be frequently used in studies of knowledge transfer and science-policy relations. This usage constitutes the reason for this paper, which investigates how the concept of boundary organization has come to be used and defined and explores its contribution to the discussion of the organization of the science-policy interplay. The analysis finds that despite its spread and usage, the concept boundary organization does not refer to any specific form of organization and does not per se give any guidance about how to organize science-policy interplay. Instead, boundary organization is mainly used as an empirical label when studying the governance of expertise and the management of science-policy interfaces. This finding is also true for studies of the Intergovernmental Panel on Climate Change, which describe that organization as a boundary organization without saying anything about what that label means in terms of institutional design and practical implications. However, to label an organization as a boundary organization nevertheless works performatively; it shapes an organization’s identity, may provide legitimacy, and can also stabilize the interactions between it and other organizations. Therefore, boundary organization is an important concept, but primarily as a way to facilitate interaction. Thus, the focus of research should be on analyzing how the concept is used and what its implications are for the organization studied. Keywords: Boundary organization, Science-policy interface, Institutional design, Hybrid management, IPCC

Expert organisations, such as the Intergovernmental Science-Policy Platform on Biodiversity & Ecosystem Services (IPBES), have become increasingly important in global, regional, and local efforts to manage current environmental challenges. As producers of environmental knowledge assessments, these expert organisations are epistemic authorities in their field of expertise. To achieve and maintain epistemic authority, expert organisations constantly need to reproduce and develop their expertise. By using the first cohort of IPBES’s fellowship program as a case study, the current paper examines the production of expertise and the socialisation of new experts into expert organisations. The paper also examines the importance of these socialisation processes in the institutionalisation of expert organisations. By analyzing interviews, observations, and documents, the current study explores the expected goals, the performance, and the results of the socialisation. The study shows how the fellows learned and acquired new roles and norms. The study also shows that whoever controls the socialisation process also control the production of expertise and the institutionalisation of the expert organisation.