RadaR (Rapid analysis of diagnostic and antimicrobial patterns in R) - an interactive open source software tool

Background: Analysing outcome and quality of care indicators for infectious patients in an entire hospital requires processing large datasets, accounting for numerous patient parameters and treatment guidelines. Rapid, reproducible and adaptable analyses usually require substantial technical expertise. We describe a dashboard tool (RadaR) allowing user-friendly, intuitive and interactive analysis of large datasets without prior in-depth knowledge. This tool was developed for studying the effect of taking blood cultures on length of stay (LOS) and antibiotic consumption in patients receiving intravenous (IV) antibiotics at an academic tertiary referral hospital. RadaR handled a modelling dataset of more than 80,000 patients (eight years, 59 sub-specialties, 35 different antibiotic agents). Materials/methods: RadaR was built in R (version 3.4.2), an open source programming language using Shiny package (version 1.0.5), a web application framework for R. Analytical graphs are generated with ggplot2 and survminer packages. The source code and additional required R packages for RadaR can be found at github.com/ceefluz/radar with a running example at ceefluz.shinyapps.io/radar. Results: RadaR visualizes analytical graphs in an interactive manner within seconds. Users can control different input variables: time of blood culture taken, study year, patient age, specialty, admission route and antibiotic agents. For a predefined grouping variable (e.g. blood cultures taken vs. not taken) in the selected patient population RadaR automatically calculates the following: LOS distribution, animated LOS distribution over time, Kaplan-Meier estimates for hospital discharge, frequencies and ratios in antibiotic prescriptions, antibiotic consumption (in DDD) and mortality. Stratification can be done for (sub-)specialties, admission route, age, gender, admissions per quarter and antibiotic agent. Moreover, multiple logistic and Cox regression analysis in RadaR allows to investigate the grouping variable further. Finally, datasets of identified groups can easily be downloaded for further analysis. Conclusions: This tool enables intuitive, rapid and reproducible quality of care pattern analysis of infectious patients without prior software experience. Hence, it facilitates understanding and communication of important trends, performances and patient outcome. We have started using RadaR to investigate blood culture use at our institution. However, due to its open source nature this tool can be easily adapted to different objectives and settings

Diagnostic stewardship: sense or nonsense?!

The right test at the right time for the right patient to answer the right questions and to start the right treatment - many important decisions have to be made involving multiple medical specialists. The importance of appropriate and timely diagnostics to guide this process (stewardship) are obvious but are often neglected in classic stewardship concepts of infection management.We describe the approach of a multidisciplinary, intertwined stewardship concept with a focus on diagnostics, where medical specialists in general and medical microbiologists in particular closely interact for optimal quality of care and patient safety in successful infection management. Diagnostics in medical microbiology laboratories are advancing fast with regards to new technologies and improved workflows. Yet, diagnostics in infection management is broader than this and cover many clinical areas where communication and interaction are the key to make the best use of knowledge and expertise that all specialisms can contribute to patient care. These aspects are demonstrated in two cases of patients with prosthetic joint infections with two very different outcomes

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development.

In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development

Random glucose sampling as screening tool for diabetes among disadvantaged tuberculosis patients residing in urban slums in India.

Recently, a two-step diagnostic algorithm to diagnose diabetes among TB patients was proposed comprising random glucose and point-of-care HbA1c. This study evaluates the first part of this algorithm among disadvantaged TB patients. http://ow.ly/UI7d30nK1UN

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation