Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

Funding: Statement of financial support: The study was financially supported by the VIRGO consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK 03012). The authors have indicated they have no personal financial relationships relevant to this article to disclose. Data Availability Statement: The data is accessible at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69606.Peer reviewedPublisher PD

Risk Characterization For Introduction And Spread Of Multinucleate Sphere X (Msx) In Prince Edward Island, Canada

Multinucleate Sphere X (MSX) is an important pathogen of the eastern oyster (Crassostrea virginica) on the east coast of North America. This parasite is currently not present in Prince Edward Island (PEI), but there are concerns that it will spread from Cape Breton, Nova Scotia, where it was recently identified. Introduction of MSX to PEI would cause direct losses to the shellfish industry and it would have long-term implications for exports of oysters. The main goal of this study was to assess the risk of introduction and dissemination of MSX, as estimated by the number of movements of commercial oysters from three data sources. The in-degree (incoming) and out-degree (outgoing) of the contact network among bays, estuaries, and rivers were used to quantify the risks. For a single location on PEI, identification of up to 55 incoming and up to 26 outgoing movements to and from different locations within PEI were recorded. This suggests that if MSX was introduced it could be disseminated quickly. Movements of shellfish (oysters and mussels) from New Brunswick and Nova Scotia, which pose additional risks of pathogen introduction to PEI, were also identified. Two locations (New London Bay and the East-North-West River complex) were consistently ranked in the top quartile of incoming movements by the three data sources. In addition, two other locations (Bideford Area and Conway Narrows) were classified in the same quartile by only two of the data sources, suggesting that these four areas can be considered at high risk for pathogen introduction. Similarly, two locations were classified in the top quartile of outgoing movements (East-North-West River complex and Orwell Area) by the three data sources, whereas Bideford Area and Foxley River were only identified by two of the three data sources in the same quartile. These results indicate not only risk areas for pathogen introduction or dissemination, but also those areas having both high risk of introduction and high risk of dissemination (e.g., East-North-West River complex). Results of this study illustrate the potential consequences of MSX should Haplosporidium nelsoni reach PEI. Findings also highlight the need for the development of a system that captures all shellfish movements, which will be essential to mounting an effective response to pathogen introduction and mitigation of disease dissemination

In-host microevolution of Aspergillus fumigatus : a phenotypic and genotypic analysis

Acknowledgments We are thankful to Kenny Ntwari Nindorera for performing the G. mellonella survival studies. EB, AB and AW are supported by the Wellcome Trust Strategic Award (grant 097377), the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. AB was also supported by the Biotechnology and Biological Research Council (BB/K017365/1) and the Medical Research Council (MR/M026663/1). The work in this paper is funded by a BBSRC EASTBIO grant. The funders had no role in study design, data interpretation, or the decision to submit the work for publication.Peer reviewedPublisher PD

Acute Cardiac Failure due to Intra-Atrial Mass Caused by Zygomycetes in an Immunocompromised Paediatric Patient

Cardiac zygomycosis can be a critical condition with sudden onset of severe congestive heart failure followed by severe hemodynamic deterioration. We report a fatal course of disseminated fungal infection with a massive intra-atrial thrombosis caused by a zygomycete, in a five year old boy treated for acute lymphoblastic leukaemia. In addition, we discuss the literature concerning infections caused by zygomycetes involving the heart. Prognosis is poor. A high index of suspicion and an aggressive diagnostic and therapeutic approach with the prompt start of preemptive antifungal therapy are key factors to improve outcome

Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged 44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating

Memory in Fungal Pathogens Promotes Immune Evasion, Colonisation, and Infection

We are grateful to our colleagues in the medical mycology and fungal immunology communities for many stimulating and enjoyable discussions. We also thank Wai-Lum Sung for his help with the figures. The authors are directors of the Medical Research Council Centre for Medical Mycology at the University of Aberdeen led by GDB (MR/N006364/1). They are also funded by a Strategic Award from the Wellcome Trust [www.wellcome.ac.uk] led by NARG (097377). AJPB and NARG are funded by a programme grant from the UK Medical Research Council [www.mrc.ac.uk] (MR/M026663/1). NARG and GDB are supported by Wellcome Trust Investigator Awards (099215, 102705). NARG has additional awards from the Wellcome Trust (075470, 080088, 086827). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPostprin

Impact of Dose Adaptations Following Voriconazole Therapeutic Drug Monitoring in Pediatric Patients

This manuscript was derived from chapter 9 of the PhD thesis by Vincent Lempers done at Radboudumc, which can be found at: https://repository.ubn.ru.nl/bitstream/handle/2066/157075/157075.pdf?sequence=1 AW is supported by the Wellcome Trust Strategic Award (grant 097377), and the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. Funding: this study was funded by the Department of Pharmacy RadboudumcPeer reviewedPostprin

Dissecting Disease-Suppressive Rhizosphere Microbiomes by Functional Amplicon Sequencing and 10x Metagenomics

Disease-suppressive soils protect plants against soilborne fungal pathogens that would otherwise cause root infections. Soil suppressiveness is, in most cases, mediated by the antagonistic activity of the microbial community associated with the plant roots. Considering the enormous taxonomic and functional diversity of the root-associated microbiome, identification of the microbial genera and mechanisms underlying this phenotype is challenging. One approach to unravel the underlying mechanisms is to identify metabolic pathways enriched in the disease-suppressive microbial community, in particular, pathways that harbor natural products with antifungal properties. An important class of these natural products includes peptides produced by nonribosomal peptide synthetases (NRPSs). Here, we applied functional amplicon sequencing of NRPS-associated adenylation domains (A domains) to a collection of eight soils that are suppressive or nonsuppressive (i.e., conducive) to Fusarium culmorum, a fungal root pathogen of wheat. To identify functional elements in the root-associated bacterial community, we developed an open-source pipeline, referred to as dom2BGC, for amplicon annotation and putative gene cluster reconstruction through analyzing A domain co-occurrence across samples. We applied this pipeline to rhizosphere communities from four disease-suppressive and four conducive soils and found significant similarities in NRPS repertoires between suppressive soils. Specifically, several siderophore biosynthetic gene clusters were consistently associated with suppressive soils, hinting at competition for iron as a potential mechanism of suppression. Finally, to validate dom2BGC and to allow more unbiased functional metagenomics, we performed 10× metagenomic sequencing of one suppressive soil, leading to the identification of multiple gene clusters potentially associated with the disease-suppressive phenotyp

A new paediatric formulation of valaciclovir : development and bioequivalence assessment

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