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Green Public Procurement can incentivize commercial investment in developing and adapting environmentally friendly products and services. However, the complexity of green aspects is a large obstacle for German procurers to include them in their tenders. Moreover, rigid public structures constitute an additional hurdle. The participation of engaged citizens in the public procurement process can counteract these obstacles. People-Public-Private Partnerships integrate engaged citizens and their expertise as end-users into the procurement process to support procurers. Due to the increasing public concern with regard to environmental issues, the potential for introducing People-Public-Private Partnerships is particularly high for Green Public Procurement. Eine Umweltfreundliche Offentliche Beschaffung kann die Anreize von Unternehmen erhohen in die Entwicklung und Adaption von umweltfreundlichen Produkten und Dienstleistungen zu investieren. People-Public-Private-Partnerships integrieren die engagierte Bevolkerung und ihre Expertise als Endnutzende zur Unterstutzung der Beschaffenden in den Beschaffungsprozess. Insbesondere aufgrund des zunehmenden offentlichen Interesses an umweltrelevanten Themen ist das Potenzial fur die Einfuhrung von People-Public-PrivatePartnerships innerhalb der Umweltfreundlichen Offentlichen Beschaffung hoch. Dieser Losungsansatz wurde von Schulerinnen des St. Raphael Gymnasiums in Heidelberg fur den Schulerwettbewerb YES! Young Economic Summit analysiert und weiterentwickelt.

Eine Umweltfreundliche Öffentliche Beschaffung kann die Anreize von Unternehmen erhöhen in die Entwicklung und Adaption von umweltfreundlichen Produkten und Dienstleistungen zu investieren. People-Public-Private-Partnerships integrieren die engagierte Bevölkerung und ihre Expertise als Endnutzende zur Unterstützung der Beschaffenden in den Beschaffungsprozess. Insbesondere aufgrund des zunehmenden öffentlichen Interesses an umweltrelevanten Themen ist das Potenzial für die Einführung von People-Public-Private-Partnerships innerhalb der Umweltfreundlichen Öffentlichen Beschaffung hoch. Dieser Lösungsansatz wurde von Schüler:innen des St. Raphael Gymnasiums in Heidelberg für den Schülerwettbewerb YES! Young Economic Summit analysiert und weiterentwickelt. Green Public Procurement can incentivize commercial investment in developing and adapting environmentally friendly products and services. However, the complexity of green aspects is a large obstacle for German procurers to include them in their tenders. Moreover, rigid public structures constitute an additional hurdle. The participation of engaged citizens in the public procurement process can counteract these obstacles. People-Public-Private Partnerships integrate engaged citizens and their expertise as end-users into the procurement process to support procurers. Due to the increasing public concern with regard to environmental issues, the potential for introducing People-Public-Private Partnerships is particularly high for Green Public Procurement.

Macrophages are essential players in the process of fracture healing, acting by remodeling of the extracellular matrix and enabling vascularization. Whilst activated macrophages of M1-like phenotype are present in the initial pro-inflammatory phase of hours to days of fracture healing, an anti-inflammatory M2-like macrophage phenotype is supposed to be crucial for the induction of downstream cascades of healing, especially the initiation of vascularization. In a mouse-osteotomy model, we provide a comprehensive characterization of vessel (CD31 , Emcn ) and macrophage phenotypes (F4/80, CD206, CD80, Mac-2) during the process of fracture healing. To this end, we phenotype the phases of vascular regeneration-the expansion phase (d1-d7 after injury) and the remodeling phase of the endothelial network, until tissue integrity is restored (d14-d21 after injury). Vessels which appear during the bone formation process resemble type H endothelium (CD31 Emcn ), and are closely connected to osteoprogenitors (Runx2 , Osx ) and F4/80 macrophages. M1-like macrophages are present in the initial phase of vascularization until day 3 post osteotomy, but they are rare during later regeneration phases. M2-like macrophages localize mainly extramedullary, and CD206 macrophages are found to express Mac-2 during the expansion phase. VEGFA expression is initiated by CD80 cells, including F4/80 macrophages, until day 3, while subsequently osteoblasts and chondrocytes are main contributors to VEGFA production at the fracture site. Using Longitudinal Intravital Microendoscopy of the Bone (LIMB) we observe changes in the motility and organization of CX3CR1 cells, which infiltrate the injury site after an osteotomy. A transient accumulation, resulting in spatial polarization of both, endothelial cells and macrophages, in regions distal to the fracture site, is evident. Immunofluorescence histology followed by histocytometric analysis reveals that F4/80 CX3CR1 myeloid cells precede vascularization.

Aligning development and climate goals means Africa’s energy systems will be based on clean energy technologies in the long term, but pathways to get there are uncertain and variable across countries. Although current debates about natural gas and renewables in Africa are heated, they largely ignore the substantial context specificity of the starting points, development objectives and uncertainties of each African country’s energy system trajectory. Here we—an interdisciplinary and majority African group of authors—highlight that each country faces a distinct solution space and set of uncertainties for using renewables or fossil fuels to meet its development objectives. For example, Ethiopia is headed for an accelerated green-growth pathway, but Mozambique is at a crossroads of natural gas expansion with implicit large-scale technological, economic, financial and social risks and uncertainties. We provide geopolitical, policy, finance and research recommendations to create firm country-specific evidence to identify adequate energy system pathways for development and to enable their implementation. Discussions abound regarding the future of African energy systems, yet they typically overlook the different starting points and development objectives of each country. This Perspective highlights these differences and calls for more context-specific attention to define low-carbon energy pathways.

The 'weekend effect' describes increased adverse outcomes after weekend hospitalization. We examined weekend-weekday differences in the outcome of 580 patients following renal transplantation (RTx, brain dead donors) between January 2007 and December 2014 at our center. 3-year patient and graft survival, incidence of delayed graft function (DGF), acute rejections and estimated glomerular filtration rate (eGFR, CKD-EPI) at 1 year as well as surgical complications were assessed. Of all 580 transplants, 416 (71.7%) were performed on weekdays (Monday-Friday) and 164 (28.3%) on weekends (Saturday-Sunday). 3-year patient and graft survival, frequencies of DGF, acute rejections and 1-year eGFR as well as length of hospital stay were similar between RTx patients transplanted on weekdays or weekends, respectively. However, a noticeable difference was detected with regard to surgical complications which were more frequent in RTx patients transplanted on weekends. All results remained consistent across all definitions of weekend status. Our results suggest that weekend transplant status does not affect functional short-term and long-term outcomes after RTx. The standardized protocols and operationalized processes applied in RTx might contribute to this finding and may provide a model for other medical procedures that are performed on weekends to improve efficiency and outcomes. The higher rate of surgical complications after weekend RTx needs further elaboration to fully assess the presence of a weekend effect in RTx.

ObjectivesGiant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens.MethodsA total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients’ and healthy blood donors’ (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis.ResultsTranscriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission.ConclusionsOur findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.

Introduction Anti-amyloid antibodies for the treatment of Alzheimer´s disease (AD) are currently being evaluated for approval and reimbursement in Europe. An approval brings opportunities, but also challenges to health care systems across Europe. The objective of this position paper is to provide guidance from experts in the field in terms of navigating implementation. Methods Members of the European Alzheimer's Disease Consortium and a representative of Alzheimer Europe convened to formulate recommendations covering key areas related to the possible implementation of anti-amyloid antibodies in AD through online discussions and 2 rounds of online voting with an 80% threshold for a position to be accepted. Results In total, 24 recommendations were developed covering the research landscape and priorities within research in AD following a possible approval, potential impact on health care systems and diagnostic pathways, and communication to patients about anti-amyloid antibodies. Anti-amyloid antibodies are regarded as a substantial innovation with an important clinical impact. In addition, however, new compounds with other mechanisms of action and/or route of administration are also needed. Approval of new treatments will require changes to existing patient pathways and real-world data needs to be generated. Conclusion Comprehensive guidance is provided on the potential implementation of anti-amyloid antibody therapies in Europe following possible approval. Emphasis is placed on the necessity of regularly updating recommendations as new evidence emerges in the coming years.

Progressive neurological decline in multiple sclerosis is associated with axonal loss and synaptic dysfunction in the non-demyelinated normal appearing gray matter (NAGM) and prominently in the cerebellum. In contrast to early disease stages, where synaptic and neuro-axonal pathology correlates with the extent of T cell infiltration, a prominent role of the innate immune system has been proposed for progressive MS. However, the specific contribution of microglia and astrocytes to synaptic cerebellar pathology in the NAGM– independent of an adaptive T cell response - remains largely unexplored. In the present study, we quantified synaptic changes in the cerebellar NAGM distant from demyelinated lesions in a mouse model of toxic demyelination. Proteomic analysis of the cerebellar cortex revealed differential regulation of synaptic and glutamate transport proteins in the absence of evident structural synaptic pathology or local gray matter demyelination. At the functional level, synaptic changes manifested as a reduction in frequency-dependent facilitation at the parallel fiber– Purkinje cell synapse. Further, deficiency of MyD88, an adaptor protein of the innate immune response, associated with a functional recovery in facilitation, reduced changes in the differential expression of synaptic and glutamate transport proteins, and reduced transcription levels of inflammatory cytokines. Nevertheless, the characteristics of demyelinating lesions and their associated cellular response were similar to wild type animals. Our work brings forward an experimental paradigm mimicking the diffuse synaptic pathology independent of demyelination in late stage MS and highlights the complex regulation of synaptic pathology in the cerebellar NAGM. Moreover, our findings suggest a role of astrocytes, in particular Bergmann glia, as key cellular determinants of cerebellar synaptic dysfunction.

Background During the COVID-19 pandemic and associated public health and social measures, decreasing patient numbers have been described in various healthcare settings in Germany, including emergency care. This could be explained by changes in disease burden, e.g. due to contact restrictions, but could also be a result of changes in utilisation behaviour of the population. To better understand those dynamics, we analysed routine data from emergency departments to quantify changes in consultation numbers, age distribution, disease acuity and day and hour of the day during different phases of the COVID-19 pandemic. Methods We used interrupted time series analyses to estimate relative changes for consultation numbers of 20 emergency departments spread throughout Germany. For the pandemic period (16-03-2020 – 13-06-2021) four different phases of the COVID-19 pandemic were defined as interruption points, the pre-pandemic period (06-03-2017 – 09-03-2020) was used as the reference. Results The most pronounced decreases were visible in the first and second wave of the pandemic, with changes of − 30.0% (95%CI: − 32.2%; − 27.7%) and − 25.7% (95%CI: − 27.4%; − 23.9%) for overall consultations, respectively. The decrease was even stronger for the age group of 0–19 years, with − 39.4% in the first and − 35.0% in the second wave. Regarding acuity levels, consultations assessed as urgent, standard, and non-urgent showed the largest decrease, while the most severe cases showed the smallest decrease. Conclusions The number of emergency department consultations decreased rapidly during the COVID-19 pandemic, without extensive variation in the distribution of patient characteristics. Smallest changes were observed for the most severe consultations and older age groups, which is especially reassuring regarding concerns of possible long-term complications due to patients avoiding urgent emergency care during the pandemic.

Alternating current stimulation (ACS) is an established means to manipulate intrinsic cortical oscillations. While working towards clinical impact, ACS mechanisms of action remain unclear. For ACS's well-documented influence on occipital alpha, hypotheses include neuronal entrainment as well as rebound phenomena. As a retinal origin is also discussed, we employed a novel form of ACS with the advantage that it specifically targets occipital alpha-oscillations retinofugal pathways retinofugal ACS (rACS). We aimed to confirm alpha-enhancement outlasting the duration of stimulation with 10 Hz rACS. To distinguish entrainment from rebound effects, we investigated the correlation between alpha peak frequency change and alpha-enhancement strength. We quantified the alpha band power before and after 10 Hz rACS in 15 healthy subjects. Alpha power enhancement and alpha peak frequency change were assessed over the occipital electrodes and compared to sham stimulation. RACS significantly enhanced occipital alpha power in comparison to sham stimulation ( < 0.05). Alpha peak frequency changed by a mean 0.02 Hz (± 0.04). A greater change in alpha peak frequency did not correlate with greater effects on alpha power. Our findings show an alpha-enhancement consistent with studies conducted for transcranial ACS (tACS) and contribute evidence for a retinal involvement in tACS effects on occipital alpha. Furthermore, the lack of correlation between alpha peak frequency change and alpha-enhancement strength provides an argument against entrainment effects and in favor of a rebound phenomenon.