HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

NF-B signalling is crucial for cellular responses to inflammation but has also been associated with the hypoxia response. NF-B and HIF transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1beta modulates NF-kappaB transcriptional response, very little is understood regarding how HIF-1beta contributes to NF-kappaB signalling. Here, we demonstrate that HIF-1beta is required for full NF-kappaB activation in cells following canonical and non-canonical stimuli. We found that HIF-1beta specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1beta binds to the TRAF6 gene and controls its expression independently of HIF-1alpha. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1beta. These results indicate that HIF-1beta is an important regulator of NF-kappaB with consequences for homeostasis and human disease.</jats:p

Effect of individual- and group-level antibiotic exposure on MRSA isolation: a multilevel analysis

Objectives: To observe the relative role of individual and group-level antimicrobial selective pressure on subsequent methicillin-resistant Staphylococcus aureus (MRSA) isolation in a university hospital. Methods: For this purpose, 18 596 patients were included in a retrospective statistical analysis, applying multilevel modelling with discrete time intervals at the lowest level. Individual-level and hospital group variables on antimicrobial exposure and MRSA colonization pressure were collected from computerized databases. Results: The simultaneous hospital group- and individual-level analysis showed individual exposure to fluoroquinolones and collective exposure to penicillins to be associated with MRSA isolation after adjustment for colonization pressure and other potential confounders. Conclusions: These results support efforts to reduce prescriptions of selected antimicrobial drug classes such as fluoroquinolones and show the added value of multilevel analysis for research on the adverse outcomes of antibiotic prescribin

Use of intranasal mupirocin to prevent methicillin-resistant Staphylococcus aureus infection in intensive care units

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) causes severe morbidity and mortality in intensive care units (ICUs) worldwide. The purpose of this study was to determine whether intranasal mupirocin prophylaxis is useful to prevent ICU-acquired infections with MRSA. MATERIALS AND METHODS: We conducted a 4-year observational retrospective study in a 15-bed adult medical ICU. During the first 2-year period mupirocin ointment was included in the MRSA control programme; during the second, mupirocin was not used. The main endpoint was the number of endogenous ICU-acquired infections with MRSA. RESULTS: The number of endogenous acquired infections was significantly higher during the second period than during the first (11 versus 1; P = 0.02), although there was no significant difference in the total number of patients infected with MRSA between the two periods. We also observed that nasal MRSA decolonisation was significantly higher in the mupirocin period than in mupirocin-free period (P = 0.002). CONCLUSION: Our findings suggest that intranasal mupirocin can prevent endogenous acquired MRSA infection in an ICU. Further double-blind, randomised, placebo-controlled studies are needed to demonstrate its cost-effectiveness and its impact on resistance

Research activities to improve the utilization of antibiotics in Africa

There is a need to improve the rational use of antibiotics across continents including Africa. This has resulted in initiatives in Botswana including treatment guidelines and the instigation of Antibiotic Stewardship Programs (ASPs). The next steps involve a greater understanding of current antibiotic utilization and resistance patterns (AMR). This resulted in a 2-day meeting involving key stakeholders principally from Botswana to discuss key issues including AMR rates as well as ASPs in both the public and private sectors. Following this, the findings will be used to plan future studies across Africa including point prevalence studies. The findings will be presented in July 2016 at the next Medicines Utilization Research in Africa meeting will ideally serve as a basis for planning future pertinent interventional studies to enhance the rational use of antibiotics in Botswana and wider

Antifungal therapy in European hospitals : data from the ESAC point-prevalence surveys 2008 and 2009

The study aimed to identify targets for quality improvement in antifungal use in European hospitals and determine the variability of such prescribing. Hospitals that participated in the European Surveillance of Antimicrobial Consumption Point Prevalence Surveys (ESACPPS) were included. The WHO Anatomical Therapeutic Chemical (ATC) classification for ‘antimycotics for systemic use’ (J02) 2009 version was used. Demographic data and information about indications and diagnoses were collected in 2008 and 2009. From 99 053 patients, 29 324 (29.6%) received antimicrobials. Antifungals represented 1529 of 40 878 (3.7%) antimicrobials. Antifungals were mainly (54.2%) administered orally. Hospital-acquired infections represented 44.5% of indications for antifungals followed by medical prophylaxis at 31.2%. The site of infection was not defined in 36.0% of cases but the most commonly targeted sites were respiratory (19.2%) and gastrointestinal (18.8%). The most used antifungal was fluconazole (60.5%) followed by caspofungin (10.5%). Antifungal–antibacterial combinations were frequently used (77.5%). The predominance of fluconazole use in participating hospitals could result in an increase in prevalence of inherently resistant fungi, increasing the need for newer antifungals. Although acknowledging that antifungal prophylaxis in the immunocompromised host needs further exploration, repetitive surveys using ESAC-PPS methodology may help to monitor the effects of interventions set to regulate antifungal use.The ESAC project was supported by a grant from the European Centre for Disease Prevention and Control (ECDC; Grant Agreement 2007/001).peer-reviewe

Hypoxia activates IKK-NF-κB and the immune response in <em>Drosophila melanogaster</em>

Hypoxia, or low oxygen availability, is an important physiological and pathological stimulus for multicellular organisms. Molecularly, hypoxia activates a transcriptional programme directed at restoration of oxygen homoeostasis and cellular survival. In mammalian cells, hypoxia not only activates the HIF (hypoxia-inducible factor) family, but also additional transcription factors such as NF-κB (nuclear factor κB). Here we show that hypoxia activates the IKK–NF-κB [IκB (inhibitor of nuclear factor κB)–NF-κB] pathway and the immune response in Drosophila melanogaster. We show that NF-κB activation is required for organism survival in hypoxia. Finally, we identify a role for the tumour suppressor Cyld, as a negative regulator of NF-κB in response to hypoxia in Drosophila. The results indicate that hypoxia activation of the IKK–NF-κB pathway and the immune response is an important and evolutionary conserved response

Change-points in antibiotic consumption in the community, European Union/European Economic Area, 1997-2017

Surveillance of antibiotic consumption in the community is of utmost importance to inform and evaluate control strategies. Data on two decades of antibiotic consumption in the community were collected from 30 EU/European Economic Area (EEA) countries. This article reviews temporal trends and the presence of abrupt changes in subgroups of relevance in antimicrobial stewardship.For the period 1997-2017, data on yearly antibiotic consumption in the community, aggregated at the level of the active substance, were collected using the WHO ATC classification and expressed in DDD (ATC/DDD index 2019) per 1000 inhabitants per day. We applied a range of non-linear mixed models to assess the presence of changes in the consumption of antibacterials for systemic use (ATC group J01) and eight antibiotic subgroups.For the majority of the studied groups, a country-specific change-point model provided the best fit. Depending on the antibiotic group/subgroup and on the country, change-points were spread out between 2000 and 2013.Due to the heterogeneity in antibiotic consumption in the community across EU/EEA countries, a country-specific change-point model provided the better fit. Given the limitations of this model, our recommendation for the included countries is to carefully interpret the country-specific results presented in this article and to use the tutorial included in this series to conduct their own change-point analysis when evaluating the impact of changes in regulations, public awareness campaigns, and other national interventions to improve antibiotic consumption in the community

The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use

A standardised methodology for a combined point prevalence survey (PPS) on healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospitals developed by the European Centre for Disease Prevention and Control was piloted across Europe. Variables were collected at national, hospital and patient level in 66 hospitals from 23 countries. A patient-based and a unit-based protocol were available. Feasibility was assessed via national and hospital questionnaires. Of 19,888 surveyed patients, 7.1% had an HAI and 34.6% were receiving at least one antimicrobial agent. Prevalence results were highest in intensive care units, with 28.1% patients with HAI, and 61.4% patients with antimicrobial use. Pneumonia and other lower respiratory tract infections (2.0% of patients; 95% confidence interval (CI): 1.8-2.2%) represented the most common type (25.7%) of HAI. Surgical prophylaxis was the indication for 17.3% of used antimicrobials and exceeded one day in 60.7% of cases. Risk factors in the patient-based protocol were provided for 98% or more of the included patients and all were independently associated with both presence of HAI and receiving an antimicrobial agent. The patient-based protocol required more work than the unit-based protocol, but allowed collecting detailed data and analysis of risk factors for HAI and antimicrobial use.peer-reviewe

Temporal development of coastal ecosystems in the Baltic Sea over the past two decades

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European Surveillance of Antimicrobial Consumption (ESAC) : quality appraisal of antibiotic use in Europe

Objectives: To assess quality of outpatient antibiotic use in Europe in 2009 based on the 12 European Surveillance of Antimicrobial Consumption (ESAC) drug-specific quality indicators and to evaluate changes in quality between 2004 and 2009. Methods: Quality of outpatient antibiotic use in 2009 was compared between 32 countries by calculating the indicator values for 2009 for each of the 12 ESAC drug-specific quality indicators based on outpatient antibiotic use data expressed in defined daily doses per 1000 inhabitants per day (DID). For each of the indicators we grouped the 2009 indicator values into four quartiles. To evaluate changes in quality between 2004 and 2009, based on their respective indicator values, countries were also grouped according to the quartile distribution of the 2004 indicator values. Only countries able to deliver data for both years were included in this analysis. Results: In 2009 a difference in the quality of outpatient antibiotic use between Nordic and Southern European countries was observed. Quality of outpatient antibiotic use decreased between 2004 and 2009. In particular, there were increases in the quality indicators [J01F_DID], [J01M_DID], [J01CR_%] and [J01_B/N], i.e. the use of macrolides, lincosamides and streptogramins in DID, the use of quinolones in DID, the proportional use of combinations of penicillins, including b-lactamase inhibitors and the ratio of broad- to narrow-spectrum antibiotics. Conclusions: Quality of outpatient antibiotic use in DID decreased between 2004 and 2009. A continuous effort to improve outpatient antibiotic consumption seems to be essential to reduce outpatient antibiotic use in general and the use of broad-spectrum antibiotics in particular.peer-reviewe