References of "Skupin, Alexander 50003110"
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See detailA CutFEM Method for a Mechanistic Modelling of Astrocytic Metabolism in 3D Physiological Morphologies
Farina, Sofia UL; Voorsluijs, Valerie UL; Claus, Susanne et al

Scientific Conference (2022, June 07)

Investigating neurodegenerative diseases can be done complementary through biological and computational experiments. A good computational approach describing a simplification of the reality and focusing ... [more ▼]

Investigating neurodegenerative diseases can be done complementary through biological and computational experiments. A good computational approach describing a simplification of the reality and focusing only on some features of the problem can help getting insights on the field. The question addressed in our work is the role of astrocytes in neurodegeneration. These cells have two interesting characteristics that we want to investigate in our model: first, their role as metabolic mediator between neurons and blood vessels and second, their peculiar morphology. In fact, metabolic dysfunctions and morphological changes have been noticed in astrocyte affected by neuropathology. Computationally the main difficulty arising from solving a metabolic model into cellular shape comes from the complexity of the domain. The shape of astrocytes are very ramified, with thin branches and sharp edges. As shown in our previous work \cite{Farina}, a \cutfem{} \cite{Burman} approach is a suitable tool to deal with this issue. In our latest work we use real human three-dimensional astrocyte morphologies obtained via microscopy \cite{Salamanca} as domain to solve our system. The performed simulations highlight the effect of morphological changes on the system output. Suggesting that our model can be crucial in understanding the morphological-dependency in neuropathologies and that the spatial component cannot be neglected. [less ▲]

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See detailSingle-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson’s disease
Novak, Gabriela; Kyriakis, Dimitrios UL; Grzyb, Kamil UL et al

in Communications Biology (2022), 5(1), 1--19

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly ... [more ▼]

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD. [less ▲]

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See detailCombinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients
Capelle, Christophe M.; Ciré, Séverine; Domingues, Olivia et al

in Cell Reports Medicine (2022), 3(4), 100600

While immunopathology has been widely studied in patients with severe COVID-19, immune responses in non-hospitalized patients have remained largely elusive. We systematically analyze 484 peripheral ... [more ▼]

While immunopathology has been widely studied in patients with severe COVID-19, immune responses in non-hospitalized patients have remained largely elusive. We systematically analyze 484 peripheral cellular or soluble immune features in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 household controls. We observe a transient increase of IP10/CXCL10 and interferon-β levels, coordinated responses of dominant SARS-CoV-2-specific CD4 and fewer CD8 T cells, and various antigen-presenting and antibody-secreting cells in mild patients within 3 days of PCR diagnosis. The frequency of key innate immune cells and their functional marker expression are impaired in hospitalized patients at day 1 of inclusion. T cell and dendritic cell responses at day 1 are highly predictive for SARS-CoV-2-specific antibody responses after 3 weeks in mild but not hospitalized patients. Our systematic analysis reveals a combinatorial picture and trajectory of various arms of the highly coordinated early-stage immune responses in mild COVID-19 patients. [less ▲]

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See detailSingle-cell transcriptional profiling and gene regulatory network modeling in Tg2576 mice reveal gender-dependent molecular features preceding Alzheimer-like pathologies
Ali, Muhammad UL; Huarte, Oihane; Heurtaux, Tony UL et al

in Molecular Neurobiology (2022), in press (doi:10.1007/s12035-022-02985-2)(in press),

Alzheimer’s disease (AD) onset and progression is influenced by a complex interplay of several environmental and genetic factors, one of them gender. Pronounced gender differences have been observed both ... [more ▼]

Alzheimer’s disease (AD) onset and progression is influenced by a complex interplay of several environmental and genetic factors, one of them gender. Pronounced gender differences have been observed both in the relative risk of developing AD and in clinical disease manifestations. A molecular level understanding of these gender disparities is still missing, but could provide important clues on cellular mechanisms modulating the disease and reveal new targets for gender-oriented disease-modifying precision therapies. We therefore present here a comprehensive single-cell analysis of disease-associated molecular gender differences in transcriptomics data from the neocortex, one of the brain regions most susceptible to AD, in one of the most widely used AD mouse models, the Tg2576 model. Cortical areas are also most commonly used in studies of post-mortem AD brains. To identify disease-linked molecular processes that occur before the onset of detectable neuropathology, we focused our analyses on an age with no detectable plaques and microgliosis. Cell-type specific alterations were investigated at the level of individual genes, pathways, and gene regulatory networks. The number of differentially expressed genes (DEGs) was not large enough to build context-specific gene regulatory networks for each individual cell type, and thus, we focused on the study of cell types with dominant changes and included analyses of changes across the combination of cell types. We observed significant disease-associated gender differences in cellular processes related to synapse organization and axonogenesis, and identified a limited set of transcription factors, including Egr1 and Klf6, as key regulators of many of the disease-associated and gender-dependent gene expression changes in the model. Overall, our analyses revealed significant celltype-specific gene expression changes in individual genes, pathways and subnetworks, including gender-specific and gender-dimorphic changes in both upstream transcription factors and their downstream targets, in the Tg2576 AD model before the onset of overt disease. This opens a window into molecular events that could determine gender-susceptibility to AD, and uncovers tractable target candidates for potential gender-specific precision medicine for AD. [less ▲]

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See detailGeneration of two human induced pluripotent stem cell lines from fibroblasts of Parkinson’s disease patients carrying the ILE368ASN mutation in PINK1 (LCSBi002) and the R275W mutation in Parkin (LCSBI004)
Novak, Gabriela; Finkbeiner, Steven; Skibinski, Gaia et al

in Stem Cell Research (2022), 61

Mutations in PINK1 and Parkin are two of the main causes of recessive early-onset Parkinson’s disease (PD). We generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of a 64-year-old ... [more ▼]

Mutations in PINK1 and Parkin are two of the main causes of recessive early-onset Parkinson’s disease (PD). We generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of a 64-year-old male patient with a homozygous ILE368ASN mutation in PINK1, who experienced disease onset at 33 years, and from fibroblasts of a 61-year-old female patient heterozygous for the R275W mutation in Parkin, who experienced disease onset at 44 years. Array comparative genomic hybridization (aCGH) determined genotypic variation in each line. The cell lines were successfully used to generate midbrain dopaminergic neurons, the neuron type primarily affected in PD. [less ▲]

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See detailMechanisms to buffer variability in cell regulation motifs close to criticality
Proverbio, Daniele UL; Noronha Montanari, Arthur UL; Skupin, Alexander UL et al

E-print/Working paper (2022)

Bistable biological regulatory systems need to cope with stochastic noise to fine-tune their function close to bifurcation points. Here, we study stability properties of this regime in generic systems to ... [more ▼]

Bistable biological regulatory systems need to cope with stochastic noise to fine-tune their function close to bifurcation points. Here, we study stability properties of this regime in generic systems to demonstrate that cooperative interactions buffer system variability, hampering noise-induced regime shifts. Our analysis also shows that, in the considered cooperativity range, impending regime shifts can be generically detected by statistical early warning signals from distributional data. Our generic framework, based on minimal models, can be used to extract robustness and variability properties of more complex models and empirical data close to criticality. [less ▲]

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See detailModel-based assessment of COVID-19 epidemic dynamics by wastewater analysis
Proverbio, Daniele UL; Kemp, Francoise UL; Magni, Stefano UL et al

in Science of the Total Environment (2022), 827

Continuous surveillance of COVID-19 diffusion remains crucial to control its diffusion and to anticipate infection waves. Detecting viral RNA load in wastewater samples has been suggested as an effective ... [more ▼]

Continuous surveillance of COVID-19 diffusion remains crucial to control its diffusion and to anticipate infection waves. Detecting viral RNA load in wastewater samples has been suggested as an effective approach for epidemic monitoring and the development of an effective warning system. However, its quantitative link to the epidemic status and the stages of outbreak is still elusive. Modelling is thus crucial to address these challenges. In this study, we present a novel mechanistic model-based approach to reconstruct the complete epidemic dynamics from SARS-CoV-2 viral load in wastewater. Our approach integrates noisy wastewater data and daily case numbers into a dynamical epidemiological model. As demonstrated for various regions and sampling protocols, it quantifies the case numbers, provides epidemic indicators and accurately infers future epidemic trends. Following its quantitative analysis, we also provide recommendations for wastewater data standards and for their use as warning indicators against new infection waves. In situations of reduced testing capacity, our modelling approach can enhance the surveillance of wastewater for early epidemic prediction and robust and cost-effective real-time monitoring of local COVID-19 dynamics. [less ▲]

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See detailMorphological principles of neuronal mitochondria
Mendelsohn, Rachel; Garcia, Guadalupe C.; Bartol, Thomas M. et al

in Journal of Comparative Neurology (2022), 530(6), 886--902

In the highly dynamic metabolic landscape of a neuron, mitochondrial membrane architectures can provide critical insight into the unique energy balance of the cell. Current theoretical calculations of ... [more ▼]

In the highly dynamic metabolic landscape of a neuron, mitochondrial membrane architectures can provide critical insight into the unique energy balance of the cell. Current theoretical calculations of functional outputs like adenosine triphosphate and heat often represent mitochondria as idealized geometries, and therefore, can miscalculate the metabolic fluxes. To analyze mitochondrial morphology in neurons of mouse cerebellum neuropil, 3D tracings of complete synaptic and axonal mitochondria were constructed using a database of serial transmission electron microscopy (TEM) tomography images and converted to watertight meshes with minimal distortion of the original microscopy volumes with a granularity of 1.64 nanometer isotropic voxels. The resulting in-silico representations were subsequently quantified by differential geometry methods in terms of the mean and Gaussian curvatures, surface areas, volumes, and membrane motifs, all of which can alter the metabolic output of the organelle. Finally, we identify structural motifs present across this population of mitochondria, which may contribute to future modeling studies of mitochondrial physiology and metabolism in neurons. [less ▲]

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See detailMicroglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies
Fixemer, Sonja UL; Ameli, Corrado UL; Hammer, Gaël et al

in Acta Neuropathologica Communications (2022), 10(1), 36

The cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration ... [more ▼]

The cellular alterations of the hippocampus lead to memory decline, a shared symptom between Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) patients. However, the subregional deterioration pattern of the hippocampus differs between AD and DLB with the CA1 subfield being more severely affected in AD. The activation of microglia, the brain immune cells, could play a role in its selective volume loss. How subregional microglia populations vary within AD or DLB and across these conditions remains poorly understood. Furthermore, how the nature of the hippocampal local pathological imprint is associated with microglia responses needs to be elucidated. To this purpose, we employed an automated pipeline for analysis of 3D confocal microscopy images to assess CA1, CA3 and DG/CA4 subfields microglia responses in post-mortem hippocampal samples from late-onset AD (n = 10), DLB (n = 8) and age-matched control (CTL) (n = 11) individuals. In parallel, we performed volumetric analyses of hyperphosphorylated tau (pTau), amyloid-β (Aβ) and phosphorylated α-synuclein (pSyn) loads. For each of the 32,447 extracted microglia, 16 morphological features were measured to classify them into seven distinct morphological clusters. Our results show similar alterations of microglial morphological features and clusters in AD and DLB, but with more prominent changes in AD. We identified two distinct microglia clusters enriched in disease conditions and particularly increased in CA1 and DG/CA4 of AD and CA3 of DLB. Our study confirms frequent concomitance of pTau, Aβ and pSyn loads across AD and DLB but reveals a specific subregional pattern for each type of pathology, along with a generally increased severity in AD. Furthermore, pTau and pSyn loads were highly correlated across subregions and conditions. We uncovered tight associations between microglial changes and the subfield pathological imprint. Our findings suggest that combinations and severity of subregional pTau, Aβ and pSyn pathologies transform local microglia phenotypic composition in the hippocampus. The high burdens of pTau and pSyn associated with increased microglial alterations could be a factor in CA1 vulnerability in AD. [less ▲]

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See detailStress hormone signalling inhibits Th1 polarization in a CD4 T-cell-intrinsic manner via mTORC1 and the circadian gene PER1
Capelle, Christophe M.; Chen, Anna; Zeng, Ni et al

in Immunology (2022), 165(4), 428--444

Stress hormones are believed to skew the CD4 T-cell differentiation towards a Th2 response via a T-cell-extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that ... [more ▼]

Stress hormones are believed to skew the CD4 T-cell differentiation towards a Th2 response via a T-cell-extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show that both adrenergic- and glucocorticoid-mediated stress signalling pathways play a CD4 naïve T-cell-intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced the Th1 programme and cytokine production by inhibiting mTORC1 signalling via two parallel mechanisms. Stress hormone signalling inhibited mTORC1 in naïve CD4 T cells (1) by affecting the PI3K/AKT pathway and (2) by regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signalling, thus reducing Th1 differentiation. This previously unrecognized cell-autonomous mechanism connects stress hormone signalling with CD4 T-cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1. [less ▲]

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See detailCOVID-19 Crisis Management in Luxembourg: Insights from an Epidemionomic Approach
Burzynski; Machado, Joel; Aalto, Atte UL et al

in Economics and Human Biology (2021), 43

We develop an epidemionomic model that jointly analyzes the health and economic responses to the COVID-19 crisis and to the related containment and public health policy measures implemented in Luxembourg ... [more ▼]

We develop an epidemionomic model that jointly analyzes the health and economic responses to the COVID-19 crisis and to the related containment and public health policy measures implemented in Luxembourg. The model has been used to produce nowcasts and forecasts at various stages of the crisis. We focus here on two key moments in time, namely the deconfinement period following the first lockdown, and the onset of the second wave. In May 2020, we predicted a high risk of a second wave that was mainly explained by the resumption of social life, low participation in large-scale testing, and reduction in teleworking practices. Simulations conducted 5 months later reveal that managing the second wave with moderately coercive measures has been epidemiologically and economically effective. Assuming a massive third (or fourth) wave will not materialize in 2021, the real GDP loss due to the second wave will be smaller than 0.4 percentage points in 2020 and 2021. [less ▲]

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See detailA new brain organoid model to study Parkinson’s Disease
Bolognin, Silvia UL; Smits, Lisa UL; Nickels, Sarah Louise UL et al

in Biomedical Science and Engineering (2021)

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See detailSingle‑nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell‑type‑specific gene regulatory variation
Gui, Yujuan; Grzyb, Kamil UL; Thomas, Melanie UL et al

in Epigenetics and Chromatin (2021)

Background: Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and ... [more ▼]

Background: Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression in a cell-type-specific manner depending on the chromatin structure and accessibility. Results: We report 20,658 single-nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell-type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell-type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Conclusions: Our data set provides an extensive resource to study gene regulation in mesencephalon and provides insights into control of cell identity in the midbrain and identifies cell-type-specific regulatory variation possibly underlying phenotypic and behavioural differences between mouse strains. [less ▲]

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See detailModelling COVID-19 dynamics and potential for herd immunity by vaccination in Austria, Luxembourg and Sweden
Kemp, Francoise UL; Proverbio, Daniele UL; Aalto, Atte UL et al

in Journal of Theoretical Biology (2021)

Against the COVID-19 pandemic, non-pharmaceutical interventions have been widely applied and vaccinations have taken off. The upcoming question is how the interplay between vaccinations and social ... [more ▼]

Against the COVID-19 pandemic, non-pharmaceutical interventions have been widely applied and vaccinations have taken off. The upcoming question is how the interplay between vaccinations and social measures will shape infections and hospitalizations. Hence, we extend the Susceptible-Exposed-Infectious-Removed (SEIR) model including these elements. We calibrate it to data of Luxembourg, Austria and Sweden until 15 December 2020. Sweden results having the highest fraction of undetected, Luxembourg of infected and all three being far from herd immunity in December. We quantify the level of social interaction, showing that a level around 1/3 of before the pandemic was still required in December to keep the effective reproduction number Refft below 1, for all three countries. Aiming to vaccinate the whole population within 1 year at constant rate would require on average 1,700 fully vaccinated people/day in Luxembourg, 24,000 in Austria and 28,000 in Sweden, and could lead to herd immunity only by mid summer. Herd immunity might not be reached in 2021 if too slow vaccines rollout speeds are employed. The model thus estimates which vaccination rates are too low to allow reaching herd immunity in 2021, depending on social interactions. Vaccination will considerably, but not immediately, help to curb the infection; thus limiting social interactions remains crucial for the months to come. [less ▲]

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See detailA cut finite element method for spatially resolved energy metabolism models in complex neuro-cell morphologies with minimal remeshing
Farina, Sofia UL; Claus, Susanne; Hale, Jack UL et al

in Advanced Modeling and Simulation in Engineering Sciences (2021), 8

A thorough understanding of brain metabolism is essential to tackle neurodegenerative diseases. Astrocytes are glial cells which play an important metabolic role by supplying neurons with energy. In ... [more ▼]

A thorough understanding of brain metabolism is essential to tackle neurodegenerative diseases. Astrocytes are glial cells which play an important metabolic role by supplying neurons with energy. In addition, astrocytes provide scaffolding and homeostatic functions to neighboring neurons and contribute to the blood–brain barrier. Recent investigations indicate that the complex morphology of astrocytes impacts upon their function and in particular the efficiency with which these cells metabolize nutrients and provide neurons with energy, but a systematic understanding is still elusive. Modelling and simulation represent an effective framework to address this challenge and to deepen our understanding of brain energy metabolism. This requires solving a set of metabolic partial differential equations on complex domains and remains a challenge. In this paper, we propose, test and verify a simple numerical method to solve a simplified model of metabolic pathways in astrocytes. The method can deal with arbitrarily complex cell morphologies and enables the rapid and simple modification of the model equations by users also without a deep knowledge in the numerical methods involved. The results obtained with the new method (CutFEM) are as accurate as the finite element method (FEM) whilst CutFEM disentangles the cell morphology from its discretisation, enabling us to deal with arbitrarily complex morphologies in two and three dimensions. [less ▲]

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See detailRoles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics
Martinez Arbas, Susana UL; Narayanasamy, Shaman UL; Herold, Malte et al

in Nature Microbiology (2021), 6(1), 123--135

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We ... [more ▼]

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE–host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR–Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid–host and phage–host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant ‘Candidatus Microthrix parvicella’ population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes. [less ▲]

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See detailThe benefits, costs and feasibility of a low incidence COVID-19 strategy
Czypionka, T.; Iftekhar, E.; Prainsack, B. et al

in The Lancet Regional Health - Europe (2021), 12(100193),

In the summer of 2021, European governments removed most NPIs after experiencing prolonged second and third waves of the COVID-19 pandemic. Most countries failed to achieve immunization rates high enough ... [more ▼]

In the summer of 2021, European governments removed most NPIs after experiencing prolonged second and third waves of the COVID-19 pandemic. Most countries failed to achieve immunization rates high enough to avoid resurgence of the virus. Public health strategies for autumn and winter 2021 have ranged from countries aiming at low incidence by re-introducing NPIs to accepting high incidence levels. However, such high incidence strategies almost certainly lead to the very consequences that they seek to avoid: restrictions that harm people and economies. At high incidence, the important pandemic containment measure ‘test-trace-isolate-support’ becomes inefficient. At that point, the spread of SARS-CoV-2 and its numerous harmful consequences can likely only be controlled through restrictions. We argue that all European countries need to pursue a low incidence strategy in a coordinated manner. Such an endeavour can only be successful if it is built on open communication and trust. [less ▲]

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