Convergence of virulence and antimicrobial resistance in increasingly prevalent Escherichia coli ST131 papGII+ sublineages

Escherichia coli lineage ST131 is an important cause of urinary tract and bloodstream infections worldwide and is highly resistant to antimicrobials. Specific ST131 lineages carrying invasiveness-associated papGII pathogenicity islands (PAIs) were previously described, but it is unknown how invasiveness relates to the acquisition of antimicrobial resistance (AMR). In this study, we analysed 1638 ST131 genomes and found that papGII+ isolates carry significantly more AMR genes than papGII-negative isolates, suggesting a convergence of virulence and AMR. The prevalence of papGII+ isolates among human clinical ST131 isolates increased dramatically since 2005, accounting for half of the recent E. coli bloodstream isolates. Emerging papGII+ lineages within clade C2 were characterized by a chromosomally integrated blaCTX-M-15 and the loss and replacement of F2:A1:B- plasmids. Convergence of virulence and AMR is worrying, and further dissemination of papGII+ ST131 lineages may lead to a rise in severe and difficult-to-treat extraintestinal infections

An end-to-end LwM2M-based communication architecture for multimodal NB-IoT/BLE devices

The wireless Internet of Things (IoT) landscape is quite diverse. For instance, Low-Power Wide-Area Network (LPWAN) technologies offer low data rate communication over long distance, whereas Wireless Personal Area Network (WPAN) technologies can reach higher data rates, but with a reduced range. For simple IoT applications, communication requirements can be fulfilled by a single technology. However, the requirements of more demanding IoT use cases can vary over time and with the type of data being exchanged. This is pushing the design towards multimodal approaches, where different wireless IoT technologies are combined and the most appropriate one is used as per the need. This paper considers the combination of Narrow Band IoT (NB-IoT) and Bluetooth Low Energy (BLE) as communication options for an IoT device that is running a Lightweight Machine to Machine/Constrained Application Protocol (LwM2M/CoAP) protocol stack. It analyses the challenges incurred by different protocol stack options, such as different transfer modes (IP versus non-IP), the use of Static Context Header Compression (SCHC) techniques, and Datagram Transport Layer Security (DTLS) security modes, and discusses the impact of handover between both communication technologies. A suitable end-to-end architecture for the targeted multimodal communication is presented. Using a prototype implementation of this architecture, an in-depth assessment of handover and its resulting latency is performed

Hospital Standardized Mortality Ratio: Consequences of Adjusting Hospital Mortality with Indirect Standardization

Background: The hospital standardized mortality ratio (HSMR) is developed to evaluate and improve hospital quality. Different methods can be used to standardize the hospital mortality ratio. Our aim was to assess the validity and applicability of directly and indirectly standardized hospital mortality ratios. Methods: Retrospective scenario analysis using routinely collected hospital data to compare deaths predicted by the indirectly standardized case-mix adjustment method with observed deaths. Discharges from Dutch hospitals in the period 2003-2009 were used to estimate the underlying prediction models. We analysed variation in indirectly standardized hospital mortality ratios (HSMRs) when changing the case-mix distributions using different scenarios. Sixty-one Dutch hospitals were included in our scenario analysis. Results: A numerical example showed that when interaction between hospital and case-mix is present and case-mix differs between hospitals, indirectly standardized HSMRs vary between hospitals providing the same quality of care. In empirical data analysis, the differences between directly and indirectly standardized HSMRs for individual hospitals were limited. Conclusion: Direct standardization is not affected by the presence of interaction between hospital and case-mix and is therefore theoretically preferable over indirect standardization. Since direct standardization is practically impossible when multiple predictors are included in the case-mix adjustment model, indirect standardization is the only available method to compute the HSMR. Before interpreting such indirectly standardized HSMRs the case-mix distributions of individual hospitals and the presence of interactions between hospital and case-mix should be assessed

Horizontally acquired papGII-containing pathogenicity islands underlie the emergence of invasive uropathogenic Escherichia coli lineages.

Escherichia coli is the leading cause of urinary tract infection, one of the most common bacterial infections in humans. Despite this, a genomic perspective is lacking regarding the phylogenetic distribution of isolates associated with different clinical syndromes. Here, we present a large-scale phylogenomic analysis of a spatiotemporally and clinically diverse set of 907 E. coli isolates, including 722 uropathogenic E. coli (UPEC) isolates. A genome-wide association approach identifies the (P-fimbriae-encoding) papGII locus as the key feature distinguishing invasive UPEC, defined as isolates associated with severe UTI, i.e., kidney infection (pyelonephritis) or urinary-source bacteremia, from non-invasive UPEC, defined as isolates associated with asymptomatic bacteriuria or bladder infection (cystitis). Within the E. coli population, distinct invasive UPEC lineages emerged through repeated horizontal acquisition of diverse papGII-containing pathogenicity islands. Our findings elucidate the molecular determinants of severe UTI and have implications for the early detection of this pathogen

The relation between prediction model performance measures and patient selection outcomes for proton therapy in head and neck cancer

Background: Normal-tissue complication probability (NTCP) models predict complication risk in patients receiving radiotherapy, considering radiation dose to healthy tissues, and are used to select patients for proton therapy, based on their expected reduction in risk after proton therapy versus photon radiotherapy (ΔNTCP). Recommended model evaluation measures include area under the receiver operating characteristic curve (AUC), overall calibration (CITL), and calibration slope (CS), whose precise relation to patient selection is still unclear. We investigated how each measure relates to patient selection outcomes. Methods: The model validation and consequent patient selection process was simulated within empirical head and neck cancer patient data. By manipulating performance measures independently via model perturbations, the relation between model performance and patient selection was studied. Results: Small reductions in AUC (-0.02) yielded mean changes in ΔNTCP between 0.9–3.2 %, and single-model patient selection differences between 2–19 %. Deviations (-0.2 or +0.2) in CITL or CS yielded mean changes in ΔNTCP between 0.3–1.4 %, and single-model patient selection differences between 1–10 %. Conclusions: Each measure independently impacts ΔNTCP and patient selection and should thus be assessed in a representative sufficiently large external sample. Our suggested practical model selection approach is considering the model with the highest AUC, and recalibrating it if needed

A trial like ALIC4E: why design a platform, response-adaptive, open, randomised controlled trial of antivirals for influenza-like illness?

ALIC4E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for influenza-like illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC4E is an open-label trial

Expert Guidance on Target Product Profile Development for AMR Diagnostic Tests

Diagnostics are widely considered crucial in the fight against antimicrobial resistance (AMR), which is expected to kill 10 million people annually by 2030. Nevertheless, there remains a substantial gap between the need for AMR diagnostics versus their development and implementation. To help address this problem, target product profiles (TPP) have been developed to focus developers’ attention on the key aspects of AMR diagnostic tests. However, during discussion between a multisectoral working group of 51 international experts from industry, academia and healthcare, it was noted that specific AMR-related TPPs could be extended by incorporating the interdependencies between the key characteristics associated with the development of such TPPs. Subsequently, the working group identified 46 characteristics associated with six main categories (i.e., Intended Use, Diagnostic Question, Test Description, Assay Protocol, Performance and Commercial). The interdependencies of these characteristics were then identified and mapped against each other to generate new insights for use by stakeholders. Specifically, it may not be possible for diagnostics developers to achieve all of the recommendations in every category of a TPP and this publication indicates how prioritising specific TPP characteristics during diagnostics development may influence (or not) a range of other TPP characteristics associated with the diagnostic. The use of such guidance, in conjunction with specific TPPs, could lead to more efficient AMR diagnostics development

Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA-trial): Rationale and design of a multicenter randomized clinical trial

Background: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. Methods: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. Discussion: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. Trial registration:NCT02657044(Clinicaltrials.gov), registered January 8, 2016

Heart-type Fatty acid-binding protein in Acute Myocardial infarction Evaluation (FAME): Background and design of a diagnostic study in primary care

<p>Abstract</p> <p>Background</p> <p>Currently used biomarkers for cardiac ischemia are elevated in blood plasma after a delay of several hours and therefore unable to detect acute coronary syndrome (ACS) in a very early stage. General practitioners (GPs), however, are often confronted with patients suspected of ACS within hours after onset of complaints. This ongoing study aims to evaluate the added diagnostic value beyond clinical assessment for a rapid bedside test for heart-type fatty-acid binding protein (H-FABP), a biomarker that is detectable as soon as one hour after onset of ischemia.</p> <p>Methods</p> <p>Participating GPs perform a blinded H-FABP rapid bedside test (Cardiodetect^®) in patients with symptoms suggestive of ACS such as chest pain or discomfort at rest. All patients, whether referred to hospital or not, undergo electrocardiography (ECG) and venapunction for a plasma troponin test within 12–36 hours after onset of complaints. A final diagnosis will be established by an expert panel consisting of two cardiologists and one general practitioner (blinded to the H-FABP test result), using all available patient information, also including signs and symptoms. The added diagnostic value of the H-FABP test beyond history taking and physical examination will be determined with receiver operating characteristic curves derived from multivariate regression analysis.</p> <p>Conclusion</p> <p>Reasons for presenting the design of our study include the prevention of publication bias and unacknowledged alterations in the study aim, design or data-analysis. To our knowledge this study is the first to assess the diagnostic value of H-FABP <it>outside </it>a hospital-setting. Several previous hospital-based studies showed the potential value of H-FABP in diagnosing ACS. Up to now however it is unclear whether these results are equally promising when the test is used in primary care. The first results are expected in the end of 2008.</p

Ruimtelijke organisatie en adaptatiefenomenen in twee-species- biofilms

Een aantal bacteriën maakt gebruik van een vorm van communicatie die quo rum sensing (QS) genoemd wordt en die gebaseerd is op de productie van k leine signaalmoleculen. Wanneer de concentratie van deze bacteriën toene emt, zal de accumulatie aan moleculen leiden tot een groepsrespons waarb ij specifieke fenotypes zoals biofilmvorming, de productie van extracell ulaire hydrolytische enzymen of virulentiefactoren geïnduceerd worden. I n voorgaand onderzoek werd van Serratia plymuthica RVH1, een biofilmv ormende bacterie die geïsoleerd werd uit een omgeving waar voedsel verwe rkt wordt al aangetoond dat QS door deze bacterie gebruikt word voor de productie van een extracellulair protease, chitinase en nuclease, een an timicrobiële component (AC) en de overgang van een gemengde zuren fermen tatie naar butaandiol productie. Gedurende het voorliggende onderzoek he bben we de focus gelegd op de rol van QS tijdens interacties van RVH1 me t andere bacteriën omdat van zulke QS afhankelijke eigenschappen verwach t word dat ze belangrijk zijn voor de competitiviteit van bacteriën in e en natuurlijke omgeving. Van het QS systeem van RVH1 en van de productie van de antimicrobiële co mponent werd aangetoond dat ze geen invloed hebben op biofilmvorming doo r deze stam. Tijdens competitie met Escherichia coli echter, werd zow el in vloeibare culturen als dubbelspeciesbiofilms een duidelijk inverse correlatie aangetoond tussen het celaantal van deze laatste bacterie en AC productie door verschillende RVH1 mutanten die specifiek geraakt war en in hun QS systeem of AC productie. Een hoge productie aan AC leidde t ot een snelle en complete verdrijving van E. coli uit beide systemen terwijl een verminderde productie of de afwezigheid van productie respec tievelijk resulteerden in een verhoogde overlevingskans en coexistentie. Deze prominente rol van de AC gedurende competitie-experimenten leidde t ot een meer diepgaande genetische studie. Verschillende genen betrokken bij AC productie werden geïdentificeerd en suggereerden een complexe str uctuur die structurele elementen bevat van zowel polyketide als niet rib osomale peptide origine. Expressie analyse van deze genen suggereerde da t de productie van het basismolecule QS gereguleerd verloopt, terwijl ve rdere modificatiestappen die nodig zijn voor de volledige activiteit van het molecule communicatieonafhankelijk zijn. Het activiteitsspectrum va n de AC omvat een uitgebreide reeks grampositieve en gramnegatieve bacte riën waaronder een aantal belangrijke multiresistente menselijke pathoge nen zoals Pseudomonas aeruginosa en Staphylococcus aureus. De genen betrokken bij de butaandiolfermentatie en regulatie werden geïd entificeerd en we toonden aan dat de omschakeling van fermentatie tot ge mengde zuren naar fermentatie met butaandiol als eindproduct niet enkel QS afhankelijk verloopt, maar dat deze ook geïnduceerd wordt door een la ge pH. Door deze dubbele regulatie is het organisme in staat maximaal te profiteren van de hogere energieopbrengst die gepaard gaat met de ferme ntatie tot gemengde zuren terwijl een letale verzuring van de omgeving n aar het einde van de exponentiële groei vermeden wordt. Op deze manier w orden maximale groei en optimaal overleven gegarandeerd. Hoewel een splI mutant in een flow cell systeem biofilms vormt die ni et van die van een wild type stam zijn te onderscheiden, werd de invloed van de diverse QS gereguleerde fenotypes op biofilmvorming meer diepgaa nd onderzocht onder verschillende condities. Zoals verwacht beïnvloedde geen enkel van deze fenotypes biofilmvorming in flow cells. In een batch -systeem echter, waar geen aanvoer van nutriënten en afvoer van af valstoffen plaatsvindt, leidde een verminderde butaandiolproductie tot e en reductie in biofilmmassa die rechtstreeks gecorreleerd was met de ver zuring van het medium. Wanneer in deze experimenten glucose vervangen we rd door L-arabinose werd een bijkomend QS gereguleerd fenotype ontdekt d at dominant was ten opzichte van het butaandiol-afhankelijk effect en re sulteerde in een toename in biofilmmassa voor de splI mutant ten opzi chte van de wild type stam. Initiële aanwijzingen suggereren dat dit fen otype gerelateerd is met de productie van een extracellulair polysacchar ide waarvan de productie negatief gecontroleerd wordt door QS. Cocultivatie van RVH1 met melkzuurbacteriën toonde aan dat butaandiolfer mentatie leidde tot een verminderde verzuring van het medium wat resulte erde in een verhoogde overlevingskans voor RVH1. Afhankelijk van welke m elkzuurbacteriën aanwezig waren in de gemengde cultuur, deed AC producti e de balans verder doorslaan in het voordeel van RVH1, resulterend in de verdrijving van AC gevoelige melkzuurbacteriën. Samenvattend biedt dit werk nieuwe inzichten in verschillende, veelal QS gereguleerde, mechanismen die bijdragen tot de competitiviteit van S. p lymuthica RVH1. Dit draagt bij tot een beter begrip van de ecologie v an bacteriële ecosystemen waaronder deze die belangrijk zijn voor de voe dingsindustrie.status: publishe