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This dissertation aims at contributing to the literature investigating the positive and normative framework for monetary policy. It provides an assessment of macroeconomic (i.e. monetary and to some extent also fiscal) policies by focusing on two rather distinct dynamic general equilibrium environments which help shed light on a number of critical aspects regarding the dynamic conduct of monetary policy. The main questions asked are of both theoretical and empirical nature and concern the way monetary policy interacts with fiscal policy and financial markets: How does nominal government debt shape the incentives faced by monetary policy makers? What is the nature of the monetary time consistency problem when there is interaction with sequential fiscal policy makers? Can the dynamic interplay of monetary and fiscal policies explain the evolution of government debt and inflation? How can we rationalize the negative correlation between inflation and aggregate productivity observed at business cycle frequency? What role do nominal interest rates and the provision of liquidity play in this context? A unifying starting point for the set of models laid out in this thesis are specifications proposing that monetary policy does not operate in isolation, but interacts with other agents or institutions. The first two chapters concentrate on the strategic aspects underlying the interaction of monetary and fiscal policies in an economy characterized by positive amounts of government debt in nominal denomination. Specifically, in order to reexamine the time consistency properties of optimal monetary policy, chapter one poses a dynamic optimal taxation problem where not only monetary, but also fiscal policies are sequentially implemented. Starting from this scenario, the next chapter provides a positive theory of dynamic monetary-fiscal interactions and a reflection on the institution of monetary conservatism, whose role is shown to be inherently determined via its implications for the interaction with fiscal policy. The third chapter takes a different and more empirically oriented route: It elaborates on an incomplete markets environment in order to demonstrate how monetary policy systematically affects an economy's aggregate productivity. Key for this conclusion is to acknowledge that nominal fluctuations induced by monetary policy on the one hand and financial markets' capacity to intermediate scarce liquidity on the other hand interact in a way that has an important influence on corporate activity, thus affecting aggregate productivity.

We study the sustainability of public debt in a closed production economy where a benevolent government chooses fiscal policies, including haircuts on its outstanding debt, in a discretionary manner. Government bonds are held by domestic agents to smooth consumption over time and because they provide collateral and liquidity services. We characterize a recursive equilibrium where public debt amounts to a sizeable fraction of output in steady state and is nevertheless fully serviced by the government. In a calibrated economy, steady state debt amounts to around 84% of output, the government's default threshold is at around 94% of output, and the haircut on outstanding debt at this threshold is around 40%. Both reputational costs of default and contemporaneous costs due to lost collateral and liquidity are essential to generate these empirically plausible predictions.

Bovine tuberculosis (bTB) caused by Mycobacterium bovis is a transmissible disease notifiable to the World Organization for Animal Health and to European Union, with ongoing efforts of surveillance and eradication in every EU member state. In Germany, a country which has been declared officially free from bovine tuberculosis since 1997 by the EU, M. bovis infections still occur sporadically in cattle and other mammals, including humans. Here, the transmission routes of a bovine TB outbreak in a wildlife park in Germany affecting different cervid species, bison, lynx, and pot-bellied pig were followed employing whole genome sequencing (WGS) combined with spoligotyping and MIRU-VNTR-typing. One single M. bovis strain persisted from 2002 – 2015, and transmission between the park and a distantly located captive cervid farm was verified. The spoligotyping pattern remained identical while MIRU-VNTR-typing of 24 loci of the standardized panel and locus 2163a as additional locus revealed one change at locus 2165 in a strain from a fallow deer, and one at locus 2461 in isolates from red deer over the whole time period. WGS analysis confirmed close relatedness of the isolates, with a maximum of 12 SNPs detected between any two sequenced isolates. In conclusion, our data confirm a longitudinal outbreak of M. bovis in a German wildlife park and provide first insights into the dynamics of different genotyping markers in M. bovis.

Bovine tuberculosis (bTB) caused by Mycobacterium bovis is a transmissible disease notifiable to the World Organization for Animal Health and to the European Union, with ongoing efforts of surveillance and eradication in every EU member state. In Germany, a country which has been declared officially free from bovine tuberculosis since 1997 by the EU, M. bovis infections still occur sporadically in cattle and other mammals, including humans. Here, the transmission routes of a bTB outbreak in a wildlife park in Germany affecting different cervid species, bison, lynx, and pot-bellied pigs were followed by employing whole-genome sequencing (WGS) combined with spoligotyping and mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing. One single M. bovis strain persisted from 2002 to 2015, and transmission between the park and a distantly located captive cervid farm was verified. The spoligotyping patterns remained identical, while MIRU-VNTR typing of 24 loci of the standardized panel and locus 2163a as an additional locus revealed one change at locus 2165 in a strain from a fallow deer and one at locus 2461 in isolates from red deer over the whole time period. WGS analysis confirmed the close relatedness of the isolates, with a maximum of 12 single nucleotide polymorphisms (SNPs) detected between any two sequenced isolates. In conclusion, our data confirm a longitudinal outbreak of M. bovis in a German wildlife park and provide the first insights into the dynamics of different genotyping markers in M. bovis.

Using 894 phylogenetically diverse genomes of the Mycobacterium tuberculosis complex (MTBC), we simulated in silico the ability of the Hain Lifescience GenoType MTBC to differentiate the causative agents of tuberculosis. We propose a revised interpretation of this assay to reflect its strengths (e.g. it can distinguish some strains of M. canettii and variants of M. bovis that are not intrinsically resistant to pyrazinamide) and limitations (e.g. M. orygis cannot be differentiated from M. africanum). This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Molecular surveillance of multidrug-resistant tuberculosis (MDR-TB) using 24-loci MIRU-VNTR in the European Union suggests the occurrence of international transmission. In early 2014, Austria detected a molecular MDR-TB cluster of five isolates. Links to Romania and Germany prompted the three countries to investigate possible cross-border MDR-TB transmission jointly. We searched genotyping databases, genotyped additional isolates from Romania, used whole genome sequencing (WGS) to infer putative transmission links, and investigated pairwise epidemiological links and patient mobility. Ten isolates from 10 patients shared the same 24-loci MIRU-VNTR pattern. Within this cluster, WGS defined two subgroups of four patients each. The first comprised an MDR-TB patient from Romania who had sought medical care in Austria and two patients from Austria. The second comprised patients, two of them epidemiologically linked, who lived in three different countries but had the same city of provenance in Romania. Our findings strongly suggested that the two cases in Austrian citizens resulted from a newly introduced MDR-TB strain, followed by domestic transmission. For the other cases, transmission probably occurred in the same city of provenance. To prevent further MDR-TB transmission, we need to ensure universal access to early and adequate therapy and collaborate closely in tuberculosis care beyond administrative borders.

Background Tracking recent transmission is a vital part of controlling widespread pathogens such as Mycobacterium tuberculosis. Multiple methods with specific performance characteristics exist for detecting recent transmission chains, usually by clustering strains based on genotype similarities. With such a large variety of methods available, informed selection of an appropriate approach for determining transmissions within a given setting/time period is difficult. Methods This study combines whole genome sequence (WGS) data derived from 324 isolates collected 2005–2010 in Kinshasa, Democratic Republic of Congo (DRC), a high endemic setting, with phylodynamics to unveil the timing of transmission events posited by a variety of standard genotyping methods. Clustering data based on Spoligotyping, 24-loci MIRU-VNTR typing, WGS based SNP (Single Nucleotide Polymorphism) and core genome multi locus sequence typing (cgMLST) typing were evaluated. Findings Our results suggest that clusters based on Spoligotyping could encompass transmission events that occurred almost 200 years prior to sampling while 24-loci-MIRU-VNTR often represented three decades of transmission. Instead, WGS based genotyping applying low SNP or cgMLST allele thresholds allows for determination of recent transmission events, e.g. in timespans of up to 10 years for a 5 SNP/allele cut-off. Interpretation With the rapid uptake of WGS methods in surveillance and outbreak tracking, the findings obtained in this study can guide the selection of appropriate clustering methods for uncovering relevant transmission chains within a given time-period. For high resolution cluster analyses, WGS-SNP and cgMLST based analyses have similar clustering/timing characteristics even for data obtained from a high incidence setting. ; ISSN:2352-3964

International audience ; Conventional molecular tests for detecting Mycobacterium tuberculosis complex (MTBC) drug resistance on clinical samples cover a limited set of mutations. Whole genome sequencing (WGS) typically requires culture. Here, we evaluated the Deeplex Myc-TB targeted deep sequencing assay for prediction of resistance to 13 anti-tuberculous drugs/drug classes, directly applicable on sputum. With MTBC DNA tests, the limit of detection was 100–1000 genome copies for fixed resistance mutations. Deeplex Myc-TB captured in silico 97.1–99.3% of resistance phenotypes correctly predicted by WGS from 3651 MTBC genomes. On 429 isolates, the assay predicted 92.2% of 2369 first- and second-line phenotypes, with a sensitivity of 95.3% and specificity of 97.4%. Fifty-six of 69 (81.2%) residual discrepancies with phenotypic results involved pyrazinamide, ethambutol, and ethionamide, and low-level rifampicin- or isoniazid-resistance mutations, all notoriously prone to phenotypic testing variability. Only 2 of 91 (2.2%) resistance phenotypes undetected by Deeplex Myc-TB had known resistance-associated mutations by WGS analysis outside Deeplex Myc-TB targets. Phenotype predictions from Deeplex Myc-TB analysis directly on 109 sputa from a Djibouti survey matched those of MTBSeq/PhyResSE/Mykrobe, fed with WGS data from subsequent cultures, with a sensitivity of 93.5/98.5/93.1% and specificity of 98.5/97.2/95.3%. Most residual discordances involved gene deletions/indels and 3–12% heteroresistant calls undetected by WGS analysis, or natural pyrazinamide resistance of globally rare "M. canettii" strains then unreported by Deeplex Myc-TB. On 1494 arduous sputa from a Democratic Republic of the Congo survey, 14 902 of 19 422 (76.7%) possible susceptible or resistance phenotypes could be predicted culture-free. Deeplex Myc-TB may enable fast, tailored tuberculosis treatment.

International audience ; Conventional molecular tests for detecting Mycobacterium tuberculosis complex (MTBC) drug resistance on clinical samples cover a limited set of mutations. Whole genome sequencing (WGS) typically requires culture. Here, we evaluated the Deeplex Myc-TB targeted deep sequencing assay for prediction of resistance to 13 anti-tuberculous drugs/drug classes, directly applicable on sputum. With MTBC DNA tests, the limit of detection was 100–1000 genome copies for fixed resistance mutations. Deeplex Myc-TB captured in silico 97.1–99.3% of resistance phenotypes correctly predicted by WGS from 3651 MTBC genomes. On 429 isolates, the assay predicted 92.2% of 2369 first- and second-line phenotypes, with a sensitivity of 95.3% and specificity of 97.4%. Fifty-six of 69 (81.2%) residual discrepancies with phenotypic results involved pyrazinamide, ethambutol, and ethionamide, and low-level rifampicin- or isoniazid-resistance mutations, all notoriously prone to phenotypic testing variability. Only 2 of 91 (2.2%) resistance phenotypes undetected by Deeplex Myc-TB had known resistance-associated mutations by WGS analysis outside Deeplex Myc-TB targets. Phenotype predictions from Deeplex Myc-TB analysis directly on 109 sputa from a Djibouti survey matched those of MTBSeq/PhyResSE/Mykrobe, fed with WGS data from subsequent cultures, with a sensitivity of 93.5/98.5/93.1% and specificity of 98.5/97.2/95.3%. Most residual discordances involved gene deletions/indels and 3–12% heteroresistant calls undetected by WGS analysis, or natural pyrazinamide resistance of globally rare "M. canettii" strains then unreported by Deeplex Myc-TB. On 1494 arduous sputa from a Democratic Republic of the Congo survey, 14 902 of 19 422 (76.7%) possible susceptible or resistance phenotypes could be predicted culture-free. Deeplex Myc-TB may enable fast, tailored tuberculosis treatment.