Multifaceted effects of public regional policy measures on regional living conditions. Evidence from German redistribution policies and European Cohesion Policy.

The place a person lives in significantly affects the living standards and life chances of this person. Peripheral and economically weak regions within highly developed countries appear to offer their residents fewer opportunities, due to economic constraints, such as unemployment and lower wages, weaker regional amenities (e.g. such as weaker infrastructure and educational opportunities) or social challenge, such as increased risks for social marginalization, poverty and premature mortality. These constraints affect the daily lives of people living in these regions. Thus, peripheral and structurally lagging regions tend to appear less attractive and economic and social disparities to primarily dynamic metropolitan areas foster social polarization. Socioeconomic trends such as structural change, the new geography of jobs or ageing tend to reinforce within-country inequalities. The theoretical considerations in this thesis illustrate that reducing regional disparities and promoting spatially equivalent living conditions is an important topic in regional science because of its economic, social and political implications. Regional redistributive policy such as structural investment funds and fiscal equalization schemes aim to make less developed regions more attractive and to increase economic and non-economic life-chances. But how effective are those policies? While there is a long tradition of examining economic growth effects of regional policies, there is a lack of scientific research and knowledge on effects that are not directly related to the economic output growth, such as the regional quality of life. This thesis aims to contribute to the literature on the efficacy of regional policy interventions dedicated to less developed regions by presenting novel empirical findings that focus on regional outcomes measures beyond regional economic output growth. Spatial vectorautoregressive panel models (SpVARs) are used to empirically assess the effects of regional policy measures. These models have the advantage of being flexible, accounting for indirect effects between variables, time lags between subsidies payments and regional effects and allowing for the evaluation of multidimensional policy outcomes within the same model. Another goal of this thesis is to further develop the SpVAR approach into an explicitly spatial design that adequately accounts for spatial spillovers and spatial interdependencies between variables and allows to estimate additional impulse response functions that estimate effects occurring in neighboring regions. This cumulative dissertation contains four stand-alone research papers in addition to an overarching introduction and a concluding chapter. The first paper analyzes the effects of the German Fiscal equalization scheme and the structural fund GRW at the level of German labor market regions. The paper shows, that fiscal equalization scheme grants have a significant positive effect on regional net migration rates for persons under 50 years of age. This particularly applies for regions with low endogenous fiscal capacities, which can be described as structurally lagging behind. It is argued that the dynamic development of net migration rates can be used as an indicator of the development of the individually perceived quality of life in the regions. By preventing out-migration from structurally lagging regions, it is found that equalization grants contribute to the goal of spatial equity, although no evidence for promoting regional economic growth is found. This is not found for the GRW policy. The second paper analyzes the multifaceted effects of European Structural and Investment Funds (ESIF’s) in European NUTS-2 regions. The paper finds that the European Regional Development Fund (ERDF) can support regional productivity and employment growth as well as household income growth, which should have a positive impact on the people’s material living standards. The effects of ERDF subsidies are particularly present in less developed regions, while no robust regional responses to subsidies are found for the European Social Fund (ESF) and the Cohesion Fund. In contrast to the first paper, no effects on net migration rates are found. The third article focuses on GRW effects at the regional level of German counties and independent cities. It emphasizes wage developments at different quantiles of the wage distribution as possible effects from GRW subsidies in order to investigate the extent to which possible productivity and income effects of GRW subsidies are transmitted to employees. Industry subsidies are found to have partially positive effects at different levels of the wage distribution in East Germany, while effects in the West are limited to the upper end of the wage distribution. Infrastructure subsidies appear to have higher efficacy on wages than firm subsidies in the industrial scheme, but are also limited to East Germany and to the service sector. The empirical findings suggest that the policies under investigation in this thesis have different transmission channels. The occurrence and strength of effects is heterogeneous and differs across policies. All three empirical findings suggest that effects are higher in less developed regions. Thus, they seem to depend on regional preconditions as well as on the policy frameworks. The final paper presents a novel spatio-temporal panel vector autoregressive approach as an extended spatial econometric method to correctly analyze spatial spillover effects in the SpVAR systems used in this thesis. The paper does not primarily aim to provide new empirical insights, but to extend the spatial dimension of SpVAR models by capturing the full cross-regional interdependencies and spatial spillover between variables over time, which allows to estimate policy effects in neighboring and economically connected regions. It is shown, that positive responses of variable shocks in regions can induce negative effects in neighboring regions through substitution effects. The findings presented should be of particular interest to policy makers, as relevant policy implications can be drawn. Based on the empirical findings, spatially redistributive policies can support the regional development of less developed regions and thus the quality of life and material living standards in these regions under certain circumstances. First, unconditional policy grants from fiscal equalization appear to be more effective than structural investment funds in increasing regional net migration rates and promoting non-material living conditions. Second, the high conditionality of effects in favor of regions with low economic strength indicates that policies should be even more tailored to these regions to be most effective. Finally, policymakers and researchers need to consider spatially indirect effects, since positive effects in subsidized regions may entail negative effects in neighboring regions

Goodpasture's Syndrome and Silica: A Case Report and Literature Review

We report a case of Goodpasture's syndrome following chronic low level and an acute, high level of exposure to crystalline silica. A 38-year-old male tilesetter was admitted to the emergency room with dyspnea and respiratory failure. He reported that his symptoms had developed over the previous week after inhaling a large amount of dust while dry-sanding and sweeping a silica-based product used to fill cracks in a cement floor. Over the following days, his pulmonary function declined and he developed acute renal failure. Tests of antiglomerular basement membrane antibody were positive and renal biopsy revealed global glomerulonephritis. He was diagnosed with Goodpasture's syndrome and treated with steroids, plasmapheresis, and hemodialysis. This man had a history of childhood asthma and a remote, one pack-year history of cigarette use. He used the flooring product for seven years prior to the inciting event, however, previous jobs had utilized significantly smaller amounts. Goodpasture's syndrome and other autoimmune diseases have been reported in association with silica exposure. The acute onset following high level silica exposure in this previously healthy man, suggest that clinicians should investigate silica exposure as a causal factor in cases of Goodpasture's syndrome

Host Autophagy Combating S. aureus: α-Toxin Will Be Tolerated

Autophagy regulates the degradation of both cellular components and invading intracellular pathogens. In this issue of Cell Host & Microbe, Maurer et al. (2015) reveal that cellular autophagy decreases host sensitivity to Staphylococcus aureus α-toxin via reduced expression of the toxin receptor ADAM10, thus rendering the host tolerant to disease

Staphylococcus aureus toxin suppresses antigen-specific T cell responses

Staphylococcus aureus remains a leading cause of human infection. These infections frequently recur when the skin is a primary site of infection, especially in infants and children. In contrast, invasive staphylococcal disease is less commonly associated with reinfection, suggesting that tissue-specific mechanisms govern the development of immunity. Knowledge of how S. aureus manipulates protective immunity has been hampered by a lack of antigen-specific models to interrogate the T cell response. Using a chicken egg OVA-expressing S. aureus strain to analyze OVA-specific T cell responses, we demonstrated that primary skin infection was associated with impaired development of T cell memory. Conversely, invasive infection induced antigen-specific memory and protected against reinfection. This defect in adaptive immunity following skin infection was associated with a loss of DCs, attributable to S. aureus α-toxin (Hla) expression. Gene- and immunization-based approaches to protect against Hla during skin infection restored the T cell response. Within the human population, exposure to α-toxin through skin infection may modulate the establishment of T cell-mediated immunity, adversely affecting long-term protection. These studies prompt consideration that vaccination targeting S. aureus may be most effective if delivered prior to initial contact with the organism

Endothelial ADAM10 utilization defines a molecular pathway of vascular injury in mice with bacterial sepsis

The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin-mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in pathogenesis. Mice harboring an endothelium-specific knockout of ADAM10 were protected against lethal Pseudomonas aeruginosa and Streptococcus pneumoniae sepsis, yet remained fully susceptible to group B streptococci and Candida albicans sepsis. These studies illustrate a previously unknown role for ADAM10 in sepsis-associated endothelial injury and suggest that understanding pathogen-specific divergent host pathways in sepsis may enable more precise targeting of disease

Prognostic significance of early platelet dynamics in Staphylococcus aureus bacteremia

BACKGROUND: Platelets are recognized as key immune effectors, but they are targets of bacterial virulence factors. In the present study, we aimed to examine the relationship between early platelet dynamics and the outcome of Staphylococcus aureus bacteremia (SAB). METHOD: Electronic medical records of adult patients hospitalized for SAB between July 2012 and November 2020 were retrospectively reviewed for relevant demographic, laboratory, and clinical data. The outcome endpoints were mortality and microbial persistence. RESULTS: Among the 811 patients evaluated, 29% experienced thrombocytopenia on Day 1. Platelet count nadir occurred on Days 2-3 following SAB onset, and Day 4 was a determining point of platelet count trajectory and mortality. Mortality risk was 6% or less for those with normal platelet count by Day 4 regardless of whether they experienced thrombocytopenia on Day 1, but the risk increased to 16-21% for those who experienced thrombocytopenia on Day 4 regardless of whether they had normal platelet count on Day 1 or sustained thrombocytopenia. The duration of bacteremia was prolonged by one day (median 3 d vs. 2 d) for those with sustained thrombocytopenia compared to those without. CONCLUSION: Early platelet dynamics during SAB have prognostic significance and represent an early window for potential platelet-directed therapeutic interventions to improve outcome

Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

Background: Linezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown.Methods: A lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNFα, IL1β, Interferon-γ and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses.Results: LZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1β, Interferon-γ and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy.Conclusion: LZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level.</p

Characterization and Comparison of 2 Distinct Epidemic Community-Associated Methicillin-Resistant Staphylococcus aureus Clones of ST59 Lineage.

Sequence type (ST) 59 is an epidemic lineage of community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) isolates. Taiwanese CA-MRSA isolates belong to ST59 and can be grouped into 2 distinct clones, a virulent Taiwan clone and a commensal Asian-Pacific clone. The Taiwan clone carries the Panton-Valentine leukocidin (PVL) genes and the staphylococcal chromosomal cassette mec (SCCmec) VT, and is frequently isolated from patients with severe disease. The Asian-Pacific clone is PVL-negative, carries SCCmec IV, and a frequent colonizer of healthy children. Isolates of both clones were characterized by their ability to adhere to respiratory A549 cells, cytotoxicity to human neutrophils, and nasal colonization of a murine and murine sepsis models. Genome variation was determined by polymerase chain reaction of selected virulence factors and by multi-strain whole genome microarray. Additionally, the expression of selected factors was compared between the 2 clones. The Taiwan clone showed a much higher cytotoxicity to the human neutrophils and caused more severe septic infections with a high mortality rate in the murine model. The clones were indistinguishable in their adhesion to A549 cells and persistence of murine nasal colonization. The microarray data revealed that the Taiwan clone had lost the ø3-prophage that integrates into the β-hemolysin gene and includes staphylokinase- and enterotoxin P-encoding genes, but had retained the genes for human immune evasion, scn and chps. Production of the virulence factors did not differ significantly in the 2 clonal groups, although more α-toxin was expressed in Taiwan clone isolates from pneumonia patients. In conclusion, the Taiwan CA-MRSA clone was distinguished by enhanced virulence in both humans and an animal infection model. The evolutionary acquisition of PVL, the higher expression of α-toxin, and possibly the loss of a large portion of the β-hemolysin-converting prophage likely contribute to its higher pathogenic potential than the Asian-Pacific clone

Phenotypic and genotypic characterization of linezolid-resistant Enterococcus faecium from the USA and Pakistan

OBJECTIVES: Linezolid is an important therapeutic option for the treatment of infections caused by VRE. Linezolid is a synthetic antimicrobial and resistance to this antimicrobial agent remains relatively rare. As a result, data on the comparative genomics of linezolid resistance determinants in Enterococcus faecium are relatively sparse. METHODS: To address this knowledge gap in E. faecium, we deployed phenotypic antibiotic susceptibility testing and Illumina WGS on hospital surface (environmental) and clinical isolates from the USA and Pakistan. RESULTS: We found complete concordance between isolate source country and mechanism of linezolid resistance, with all the US isolates possessing a 23S rRNA gene mutation and the Pakistan isolates harbouring two to three acquired antibiotic resistance genes. These resistance genes include the recently elucidated efflux-pump genes optrA and poxtA and a novel cfr-like variant. Although there was no difference in the linezolid MIC between the US and Pakistan isolates, there was a significant difference in the geometric mean of the MIC between the Pakistan isolates that had two versus three of the acquired antibiotic resistance genes. In five of the Pakistan E. faecium that possessed all three of the resistance genes, we found no difference in the local genetic context of poxtA and the cfr-like gene, but we identified different genetic contexts surrounding optrA. CONCLUSIONS: These results demonstrate that E. faecium from different geographical regions employ alternative strategies to counter selective pressure of increasing clinical linezolid use