Development and Validation of a Risk Score for Febrile Neutropenia After Chemotherapy in Patients With Cancer: The FENCE Score

Background: Febrile neutropenia (FN) after chemotherapy causes a high burden of morbidity and mortality. We aimed to develop and validate a risk score to predict FN in the first cycle of chemotherapy. Methods: We included patients with solid cancers and diffuse large B-cell lymphomas at Rigshospitalet, University of Copenhagen, 2010-2016. Predictors of FN were analyzed using Poisson regression and random split-sampling. Results: Among 6294 patients in the derivation cohort, 360 developed FN. Female sex, older age, cancer type, disease stage, low albumin, elevated bilirubin, low creatinine clearance, infection before chemotherapy, and number of and type of chemotherapy drugs predicted FN. Compared with those at low risk (n = 2520, 40.0%), the incidence rate ratio of developing FN was 4.8 (95% confidence interval [CI] = 2.9 to 8.1), 8.7 (95% CI = 5.3 to 14.1) and 24.0 (95% CI = 15.2 to 38.0) in the intermediate (n = 1294, 20.6%), high (n = 1249, 19.8%) and very high (n = 1231, 19.6%) risk groups, respectively, corresponding to a number needed to treat with granulocyte colony-stimulating factors to avoid one FN event in the first cycle of 284, 60, 34 and 14. The discriminatory ability (Harrell's C-statistic = 0.80, 95% CI = 0.78 to 0.82) was similar in the validation cohort (n = 3163) (0.79, 95% CI = 0.75 to 0.82). Conclusion: We developed and internally validated a risk score for FN in the first cycle of chemotherapy. The FENCE score is available online and provides good differentiation of risk groups

Incidence Rates and Risk Factors of Clostridioides difficile Infection in Solid Organ and Hematopoietic Stem Cell Transplant Recipients

BACKGROUND: Transplant recipients are an immunologically vulnerable patient group and are at elevated risk of Clostridioides difficile infection (CDI) compared with other hospitalized populations. However, risk factors for CDI post-transplant are not fully understood. // METHODS: Adults undergoing solid organ (SOT) and hematopoietic stem cell transplant (HSCT) from January 2010 to February 2017 at Rigshospitalet, University of Copenhagen, Denmark, were retrospectively included. Using nationwide data capture of all CDI cases, the incidence and risk factors of CDI were assessed. // RESULTS: A total of 1687 patients underwent SOT or HSCT (1114 and 573, respectively), with a median follow-up time (interquartile range) of 1.95 (0.52–4.11) years. CDI was diagnosed in 15% (164) and 20% (114) of the SOT and HSCT recipients, respectively. CDI rates were highest in the 30 days post-transplant for both SOT and HSCT (adjusted incidence rate ratio [aIRR], 6.64; 95% confidence interval [CI], 4.37–10.10; and aIRR, 2.85; 95% CI, 1.83–4.43, respectively, compared with 31–180 days). For SOT recipients, pretransplant CDI and liver and lung transplant were associated with a higher risk of CDI in the first 30 days post-transplant, whereas age and liver transplant were risk factors in the later period. Among HSCT recipients, myeloablative conditioning and a higher Charlson Comorbidity Index were associated with a higher risk of CDI in the early period but not in the late period. // CONCLUSIONS: Using nationwide data, we show a high incidence of CDI among transplant recipients. Importantly, we also find that risk factors can vary relative to time post-transplant

Phagocytosis of Streptococcus pyogenes by all-trans retinoic acid-differentiated HL-60 cells: roles of azurophilic granules and NADPH oxidase.

BACKGROUND: New experimental approaches to the study of the neutrophil phagosome and bacterial killing prompted a reassessment of the usefulness of all-trans retinoic acid (ATRA)-differentiated HL-60 cells as a neutrophil model. HL-60 cells are special in that they possess azurophilic granules while lacking the specific granules with their associated oxidase components. The resulting inability to mount an effective intracellular respiratory burst makes these cells more dependent on other mechanisms when killing internalized bacteria. METHODOLOGY/PRINCIPAL FINDINGS: In this work phagocytosis and phagosome-related responses of ATRA-differentiated HL-60 cells were compared to those earlier described in human neutrophils. We show that intracellular survival of wild-type S. pyogenes bacteria in HL-60 cells is accompanied by inhibition of azurophilic granule-phagosome fusion. A mutant S. pyogenes bacterium, deficient in M-protein expression, is, on the other hand, rapidly killed in phagosomes that avidly fuse with azurophilic granules. CONCLUSIONS/SIGNIFICANCE: The current data extend our previous findings by showing that a system lacking in oxidase involvement also indicates a link between inhibition of azurophilic granule fusion and the intraphagosomal fate of S. pyogenes bacteria. We propose that differentiated HL-60 cells can be a useful tool to study certain aspects of neutrophil phagosome maturation, such as azurophilic granule fusion

The elusive archaeology of Kongo urbanism: the case of Kindoki, Mbanza Nsundi (Lower Congo, DRC)

We present here results, analyses and an in-depth historical contextualisation of the fieldwork undertaken in 2012 and 2013 at the Kindoki site in the Lower Congo (DRC). This site is linked with Mbanza Nsundi, one of the Kongo Kingdom's provincial capitals, which turns out to be archaeologically 'elusive'. Pinpointing its location proved to be particularly challenging. To this end, a historically-informed excavation methodology was developed that was never implemented in Central Africa before. We combined a strategy of systematic test pits with a large-scale 50 m grid approach. A cemetery was identified on Kindoki Hill with distinct but contemporaneous quarters of a 16th-17thcenturies settlement on both sides. The cemetery itself contains mainly 18th-century burials, in all likelihood of successive Nsundi rulers. The foreign, especially Portuguese, ceramics excavated on the hilltop and the hundreds of Venetian and likely Bavarian beads found in the graves are indicative of Mbanza Nsundi's connection to trade routes linking the Atlantic coast with the Pool region. The most striking discovery is that of a previously unknown type of comb-impressed pottery, from a pit with a calibrated radiocarbon date AD 1294-1393 (2 sigma). This suggests that a settlement had been developing at Kindoki since at least the 14th century, which allows us, for the very first time, to spatially bridge Kongo history and 'prehistory'. For the entire Lower Congo region only three 14C dates posterior to AD 1000 were available before the start of the KongoKing project, twelve have been added for just Kindoki

Broad host range plasmids can invade an unexpectedly diverse fraction of a soil bacterial community

Conjugal plasmids can provide microbes with full complements of new genes and constitute potent vehicles for horizontal gene transfer. Conjugal plasmid transfer is deemed responsible for the rapid spread of antibiotic resistance among microbes. While broad host range plasmids are known to transfer to diverse hosts in pure culture, the extent of their ability to transfer in the complex bacterial communities present in most habitats has not been comprehensively studied. Here, we isolated and characterized transconjugants with a degree of sensitivity not previously realized to investigate the transfer range of IncP- and IncPromA-type broad host range plasmids from three proteobacterial donors to a soil bacterial community. We identified transfer to many different recipients belonging to 11 different bacterial phyla. The prevalence of transconjugants belonging to diverse Gram-positive Firmicutes and Actinobacteria suggests that inter-Gram plasmid transfer of IncP-1 and IncPromA-type plasmids is a frequent phenomenon. While the plasmid receiving fractions of the community were both plasmid- and donor- dependent, we identified a core super-permissive fraction that could take up different plasmids from diverse donor strains. This fraction, comprising 80% of the identified transconjugants, thus has the potential to dominate IncP- and IncPromA-type plasmid transfer in soil. Our results demonstrate that these broad host range plasmids have a hitherto unrecognized potential to transfer readily to very diverse bacteria and can, therefore, directly connect large proportions of the soil bacterial gene pool. This finding reinforces the evolutionary and medical significances of these plasmids.Fil: Klumper, Uli. Technical University of Denmark; DinamarcaFil: Riber, Leise. Universidad de Copenhagen; DinamarcaFil: Dechesne, Arnaud. Technical University of Denmark; DinamarcaFil: Sannazzaro, Analía Inés. Universidad de Copenhagen; DinamarcaFil: Hansen, Lars H.. Universidad de Copenhagen; Dinamarca. Aarhus University. Roskilde; DinamarcaFil: Sørensen, Søren. Universidad de Copenhagen; DinamarcaFil: Smets, Barth F. Technical University of Denmark; Dinamarc

Limited dissemination of the wastewater treatment plant core resistome

Horizontal gene transfer is a major contributor to the evolution of bacterial genomes and can facilitate the dissemination of antibiotic resistance genes between environmental reservoirs and potential pathogens. Wastewater treatment plants (WWTPs) are believed to play a central role in the dissemination of antibiotic resistance genes. However, the contribution of the dominant members of the WWTP resistome to resistance in human pathogens remains poorly understood. Here we use a combination of metagenomic functional selections and comprehensive metagenomic sequencing to uncover the dominant genes of the WWTP resistome. We find that this core resistome is unique to the WWTP environment, with <10% of the resistance genes found outside the WWTP environment. Our data highlight that, despite an abundance of functional resistance genes within WWTPs, only few genes are found in other environments, suggesting that the overall dissemination of the WWTP resistome is comparable to that of the soil resistome

Send more data: a systematic review of mathematical models of antimicrobial resistance

Abstract Background Antimicrobial resistance is a global health problem that demands all possible means to control it. Mathematical modelling is a valuable tool for understanding the mechanisms of AMR development and spread, and can help us to investigate and propose novel control strategies. However, it is of vital importance that mathematical models have a broad utility, which can be assured if good modelling practice is followed. Objective The objective of this study was to provide a comprehensive systematic review of published models of AMR development and spread. Furthermore, the study aimed to identify gaps in the knowledge required to develop useful models. Methods The review comprised a comprehensive literature search with 38 selected studies. Information was extracted from the selected papers using an adaptation of previously published frameworks, and was evaluated using the TRACE good modelling practice guidelines. Results None of the selected papers fulfilled the TRACE guidelines. We recommend that future mathematical models should: a) model the biological processes mechanistically, b) incorporate uncertainty and variability in the system using stochastic modelling, c) include a sensitivity analysis and model external and internal validation. Conclusion Many mathematical models of AMR development and spread exist. There is still a lack of knowledge about antimicrobial resistance, which restricts the development of useful mathematical models