Code-Sharing in Cost-of-Illness Calculations: An Application to Antibiotic-Resistant Bloodstream Infections

Data Availability Statement: The linked JANIS-DPC dataset analyzed for this study is not fully available due to patient identifiable data being present. However, JANIS does provide surveillance data in its open report available. Requests to access the datasets should be directed to https://janis.mhlw.go.jp/english/about/index.html.Copyright © 2020 Naylor, Yamashita, Iwami, Kunisawa, Mizuno, Castro-Sánchez, Imanaka, Ahmad and Holmes. Background: More data-driven evidence is needed on the cost of antibiotic resistance. Both Japan and England have large surveillance and administrative datasets. Code sharing of costing models enables reduced duplication of effort in research. Objective: To estimate the burden of antibiotic-resistant Staphylococcus aureus bloodstream infections (BSIs) in Japan, utilizing code that was written to estimate the hospital burden of antibiotic-resistant Escherichia coli BSIs in England. Additionally, the process in which the code-sharing and application was performed is detailed, to aid future such use of code-sharing in health economics. Methods: National administrative data sources were linked with voluntary surveillance data within the Japan case study. R software code, which created multistate models to estimate the excess length of stay associated with different exposures of interest, was adapted from previous use and run on this dataset. Unit costs were applied to estimate healthcare system burden in 2017 international dollars (I$). Results: Clear supporting documentation alongside open-access code, licensing, and formal communication channels, helped the re-application of costing code from the English setting within the Japanese setting. From the Japanese healthcare system perspective, it was estimated that there was an excess cost of I$6,392 per S. aureus BSI, whilst oxacillin resistance was associated with an additional I$8,155. Conclusions: S. aureus resistance profiles other than methicillin may substantially impact hospital costs. The sharing of costing models within the field of antibiotic resistance is a feasible way to increase burden evidence efficiently, allowing for decision makers (with appropriate data available) to gain rapid cost-of-illness estimates.HPRU-2012-1004

Code-sharing in Cost-of-illness Calculations: An Application to Antibiotic-Resistant Bloodstream Infections

Background: More data-driven evidence is needed on the cost of antibiotic resistance. Both Japan and England have large surveillance and administrative datasets. Code sharing of costing models enables reduced duplication of effort in research. Objective: To estimate the burden of antibiotic-resistant Staphylococcus aureus bloodstream infections (BSIs) in Japan, utilizing code that was written to estimate the hospital burden of antibiotic-resistant Escherichia coli BSIs in England. Additionally, the process in which the code-sharing and application was performed is detailed, to aid future such use of code-sharing in health economics. Methods: National administrative data sources were linked with voluntary surveillance data within the Japan case study. R software code, which created multistate models to estimate the excess length of stay associated with different exposures of interest, was adapted from previous use and run on this dataset. Unit costs were applied to estimate healthcare system burden in 2017 international dollars (I$). Results: Clear supporting documentation alongside open-access code, licensing and formal communication channels, helped the re-application of costing code from the English setting within the Japanese setting. From the Japanese healthcare system perspective, it was estimated that there was an excess cost of I$6,392 per S. aureus BSI, whilst oxacillin resistance was associated with an additional I$8,155. Conclusions: S. aureus resistance profiles other than methicillin may substantially impact hospital costs. The sharing of costing models within the field of antibiotic resistance is a feasible way to increase burden evidence efficiently, allowing for decision makers (with appropriate data available) to gain rapid cost-of-illness estimates

Comparison of national strategies to reduce methicillin-resistant Staphylococcus aureus (MRSA) infections in Japan and England

Background National responses to healthcare-associated infections vary between high-income countries but when analysed for contextual comparability, interventions can be assessed for transferability. Aim To identify learning from country-level approaches to addressing meticillin-resistant Staphylococcus aureus (MRSA) in Japan and England. Methods A longitudinal analysis (2000-17), comparing epidemiological trends and policy interventions. Data from 441 textual sources concerning infection prevention and control (IPC), surveillance, and antimicrobial stewardship interventions were systematically coded for: type - mandatory requirements, recommendations, or national campaigns; method - restrictive, persuasive, structural in nature; level of implementation - macro (national), meso (organisational), micro (individual) levels. Healthcare organisational structures and role of media were also assessed. Findings In England significant reduction has been achieved in number of reported MRSA bloodstream infections. In Japan, in spite of reductions, MRSA remains a predominant infection. Both countries face new threats in the emergence of drug-resistant Escherichia coli. England has focused on national mandatory and structural interventions, supported by a combination of outcomes-based incentives and punitive mechanisms, and multidisciplinary IPC hospital teams. Japan has focused on (non-mandatory) recommendations and primarily persuasive interventions, supported by process-based incentives, with voluntary surveillance. Areas for development in Japan include resourcing of dedicated data management support and implementation of national campaigns for healthcare professionals and the public. Conclusion Policy interventions need to be relevant to local epidemiological trends, while acceptable within health system cultures and public expectations. Cross-national learning can help inform the right mix of interventions to create sustainable and resilient systems for future infection and economic challenges

Unstable decay and state selection II

The decay of unstable states when several metastable states are available for occupation is investigated using path-integral techniques. Specifically, a method is described which allows the probabilities with which the metastable states are occupied to be calculated by finding optimal paths, and fluctuations about them, in the weak noise limit. The method is illustrated on a system described by two coupled Langevin equations, which are found in the study of instabilities in fluid dynamics and superconductivity. The problem involves a subtle interplay between non-linearities and noise, and a naive approximation scheme which does not take this into account is shown to be unsatisfactory. The use of optimal paths is briefly reviewed and then applied to finding the conditional probability of ending up in one of the metastable states, having begun in the unstable state. There are several aspects of the calculation which distinguish it from most others involving optimal paths: (i) the paths do not begin and end on an attractor, and moreover, the final point is to a large extent arbitrary, (ii) the interplay between the fluctuations and the leading order contribution are at the heart of the method, and (iii) the final result involves quantities which are not exponentially small in the noise strength. This final result, which gives the probability of a particular state being selected in terms of the parameters of the dynamics, is remarkably simple and agrees well with the results of numerical simulations. The method should be applicable to similar problems in a number of other areas such as state selection in lasers, activationless chemical reactions and population dynamics in fluctuating environments.Comment: 28 pages, 6 figures. Accepted for publication in Phys. Rev.

Genome landscapes and bacteriophage codon usage

Across all kingdoms of biological life, protein-coding genes exhibit unequal usage of synonmous codons. Although alternative theories abound, translational selection has been accepted as an important mechanism that shapes the patterns of codon usage in prokaryotes and simple eukaryotes. Here we analyze patterns of codon usage across 74 diverse bacteriophages that infect E. coli, P. aeruginosa and L. lactis as their primary host. We introduce the concept of a `genome landscape,' which helps reveal non-trivial, long-range patterns in codon usage across a genome. We develop a series of randomization tests that allow us to interrogate the significance of one aspect of codon usage, such a GC content, while controlling for another aspect, such as adaptation to host-preferred codons. We find that 33 phage genomes exhibit highly non-random patterns in their GC3-content, use of host-preferred codons, or both. We show that the head and tail proteins of these phages exhibit significant bias towards host-preferred codons, relative to the non-structural phage proteins. Our results support the hypothesis of translational selection on viral genes for host-preferred codons, over a broad range of bacteriophages.Comment: 9 Color Figures, 5 Tables, 53 Reference

Detecting Horizontally Transferred and Essential Genes Based on Dinucleotide Relative Abundance

Various methods have been developed to detect horizontal gene transfer in bacteria, based on anomalous nucleotide composition, assuming that compositional features undergo amelioration in the host genome. Evolutionary theory predicts the inevitability of false positives when essential sequences are strongly conserved. Foreign genes could become more detectable on the basis of their higher order compositions if such features ameliorate more rapidly and uniformly than lower order features. This possibility is tested by comparing the heterogeneities of bacterial genomes with respect to strand-independent first- and second-order features, (i) G + C content and (ii) dinucleotide relative abundance, in 1 kb segments. Although statistical analysis confirms that (ii) is less inhomogeneous than (i) in all 12 species examined, extreme anomalies with respect to (ii) in the Escherichia coli K12 genome are typically co-located with essential genes

CANGAROO-III Observation of TeV Gamma Rays from the vicinity of PSR B1 706-44

Observation by the CANGAROO-III stereoscopic system of the Imaging Cherenkov Telescope has detected extended emission of TeV gamma rays in the vicinity of the pulsar PSR B1706$-$44. The strength of the signal observed as gamma-ray-like events varies when we apply different ways of emulating background events. The reason for such uncertainties is argued in relevance to gamma-rays embedded in the "off-source data", that is, unknown sources and diffuse emission in the Galactic plane, namely, the existence of a complex structure of TeV gamma-ray emission around PSR B1706$-$44.Comment: 10 pages, 13 figures, to be published in Ap

A Pivotal Role of Vitamin B9 in the Maintenance of Regulatory T Cells In Vitro and In Vivo

Dietary factors regulate immunological function, but the underlying mechanisms remain elusive. Here we show that vitamin B9 is a survival factor for regulatory T (Treg) cells expressing high levels of vitamin B9 receptor (folate receptor 4). In vitamin B9-reduced condition in vitro, Treg cells could be differentiated from naïve T cells but failed to survive. The impaired survival of Treg cells was associated with decreased expression of anti-apoptotic Bcl2 and independent of IL-2. In vivo depletion of dietary vitamin B9 resulted in the reduction of Treg cells in the small intestine, a site for the absorption of dietary vitamin B9. These findings provide a new link between diet and the immune system, which could maintain the immunological homeostasis in the intestine

CANGAROO-III observation of TeV gamma rays from the unidentified gamma-ray source HESS J1614-518

We report the detection, with the CANGAROO-III imaging atmospheric Cherenkov telescope array, of a very high energy gamma-ray signal from the unidentified gamma-ray source HESS J1614-518, which was discovered in the H.E.S.S. Galactic plane survey. Diffuse gamma-ray emission was detected above 760 GeV at the 8.9 sigma level during an effective exposure of 54 hr from 2008 May to August. The spectrum can be represented by a power-law: 8.2+-2.2_{stat}+-2.5_{sys}x10^{-12}x (E/1TeV)^{-Gamma} cm^{-2} s^{-1} TeV^{-1} with a photon index Gamma of 2.4+-0.3_{stat}+-0.2_{sys}, which is compatible with that of the H.E.S.S. observations. By combining our result with multi-wavelength data, we discuss the possible counterparts for HESS J1614-518 and consider radiation mechanisms based on hadronic and leptonic processes for a supernova remnant, stellar winds from massive stars, and a pulsar wind nebula. Although a leptonic origin from a pulsar wind nebula driven by an unknown pulsar remains possible, hadronic-origin emission from an unknown supernova remnant is preferred.Comment: 9 pages, 7 figures, accepted for publication in Ap