QUERI and implementation research: Emerging from adolescence into adulthood: QUERI Series

The Quality Enhancement Research Initiative (QUERI) program and implementation research have both come of age in the 10 years since QUERI was established. Looking forward, if QUERI and the field of implementation science are to mature successfully, we will need to address a series of challenges. First, we need to more clearly demonstrate how applying principles of implementation science leads to more effective implementation and communicate those lessons to our partners and funders. Second, we will need to engage in the ongoing debate over methodological standards in quality improvement and implementation research. Third, a program like QUERI needs to become more relevant to the daily decisions of key stakeholders. Fourth, if we hope to sustain interest in implementation science, we will need to demonstrate the business case for more effective implementation. Fifth, we need to think creatively about how to nurture the next generations of implementation researchers and front-line "connectors," who are critical for accelerating implementation. Finally, we need to strengthen the connections between implementation research and the other operational and research activities that influence change in healthcare systems

Intra-abdominal candidiasis: The importance of early source control and antifungal treatment

Intra-abdominal candidiasis (IAC) is poorly understood compared to candidemia. We described the clinical characteristics, microbiology, treatment and outcomes of IAC, and identified risk factors for mortality. We performed a retrospective study of adults diagnosed with IAC at our center in 2012-2013. Risk factors for mortality were evaluated using multi-variable logistic regression. We identified 163 patients with IAC, compared to 161 with candidemia. Types of IAC were intra-abdominal abscesses (55%), secondary peritonitis (33%), primary peritonitis (5%), infected pancreatic necrosis (5%), and cholecystitis/cholangitis (3%). Eighty-three percent and 66% of secondary peritonitis and abscesses, respectively, stemmed from gastrointestinal (GI) tract sources. C. albicans (56%) and C. glabrata (24%) were the most common species. Bacterial co-infections and candidemia occurred in 67% and 6% of patients, respectively. Seventy-two percent of patients underwent an early source control intervention (within 5 days) and 72% received early antifungal treatment. 100-day mortality was 28%, and highest with primary (88%) or secondary (40%) peritonitis. Younger age, abscesses and early source control were independent predictors of survival. Younger age, abscesses and early antifungal treatment were independently associated with survival for IAC stemming from GI tract sources. Infectious diseases (ID) consultations were obtained in only 48% of patients. Consulted patients were significantly more likely to receive antifungal treatment. IAC is a common disease associated with heterogeneous manifestations, which result in poor outcomes. All patients should undergo source control interventions and receive antifungal treatment promptly. It is important for the ID community to become more engaged in treating IAC

Control of sulphide during anaerobic treatment of S-containing wastewaters by adding limited amounts of oxygen or nitrate

Sulphide generated during anaerobic treatment of S-containing wastewaters represents an environmental problem. Adding limited amounts of oxygen or nitrate (or nitrite) to biologically (or chemically) oxidise sulphide forms a simple process level strategy to control this problem. This short review evaluates the feasibility and limitations of this strategy on the basis of the results of bioreactor studies.Sulphide generated during anaerobic treatment of S-containing wastewaters represents an environmental problem. Adding limited amounts of oxygen or nitrate (or nitrite) to biologically (or chemically) oxidise sulphide forms a simple process level strategy to control this problem. This short review evaluates the feasibility and limitations of this strategy on the basis of the results of bioreactor studies.Spanish Ministry of Education and Science; AEA Technology Environment; Nova Energie; The Swedish Gas Centre; University of Southern Denmark

Presence of intestinal Mycobacterium avium subspecies paratuberculosis (MAP) DNA is not associated with altered MMP expression in ulcerative colitis

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium avium </it>subspecies <it>paratuberculosis </it>(MAP) is suspected to be a causative agent in human Crohn's disease (CD). Recent evidence suggests that pathogenic mycobacteria and MAP can induce the expression of Matrix Metalloproteinases (MMP), which are the main proteases in the pathogenesis of mucosal ulcerations in inflammatory bowel disease (IBD). Within this study we assessed the prevalence of intestinal MAP specific DNA in patients with Crohn's disease, ulcerative colitis (UC), and healthy controls. We further analysed regulation patterns of MMPs in mucosal tissues of UC patients with and without intestinal MAP DNA detection.</p> <p>Methods</p> <p>Colonic biopsy samples were obtained from 63 Norwegian and German IBD patients and 21 healthy controls. RNA was quantified by quantitative real-time polymerase chain reaction (PCR) to study MMP gene expression in both pathological and healthy mucosal specimens. The presence of MAP DNA in colonic mucosa was examined using MAP specific PCR.</p> <p>Results</p> <p>MAP DNA was detected in 20% of UC patients and 33% of healthy controls but only in 7% of patients with CD. UC patients treated with corticosteroids exhibited a significantly increased frequency of intestinal MAP DNA compared to those not receiving corticosteroids. Expression of MMP-1, -2, -7, -9, -13, -19, -28 and TNF-α did not differ between UC patients with presence of intestinal MAP DNA compared to those without. MMP-2, MMP-9 and MMP-13 were significantly decreased in UC patients receiving corticosteroids.</p> <p>Conclusions</p> <p>The presence of intestinal MAP specific DNA is not associated with altered MMP expression in UC <it>in vivo</it>. Corticosteroids are associated with increased detection of intestinal MAP DNA and decreased expression of certain MMPs. Frequent detection of MAP DNA in healthy controls might be attributable to the wide environmental distribution of MAP and its presence in the food-chain.</p

Insulin Production and Signaling in Renal Tubules of Drosophila Is under Control of Tachykinin-Related Peptide and Regulates Stress Resistance

The insulin-signaling pathway is evolutionarily conserved in animals and regulates growth, reproduction, metabolic homeostasis, stress resistance and life span. In Drosophila seven insulin-like peptides (DILP1-7) are known, some of which are produced in the brain, others in fat body or intestine. Here we show that DILP5 is expressed in principal cells of the renal tubules of Drosophila and affects survival at stress. Renal (Malpighian) tubules regulate water and ion homeostasis, but also play roles in immune responses and oxidative stress. We investigated the control of DILP5 signaling in the renal tubules by Drosophila tachykinin peptide (DTK) and its receptor DTKR during desiccative, nutritional and oxidative stress. The DILP5 levels in principal cells of the tubules are affected by stress and manipulations of DTKR expression in the same cells. Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted in increased survival at either stress, whereas over-expression of these components produced the opposite phenotype. Thus, stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP5 signaling. Manipulations of S6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locally on tubules, possibly in oxidative stress regulation. Our findings are the first to demonstrate DILP signaling originating in the renal tubules and that this signaling is under control of stress-induced release of peptide hormone

Contribution of Exogenous Genetic Elements to the Group A Streptococcus Metagenome

Variation in gene content among strains of a bacterial species contributes to biomedically relevant differences in phenotypes such as virulence and antimicrobial resistance. Group A Streptococcus (GAS) causes a diverse array of human infections and sequelae, and exhibits a complex pathogenic behavior. To enhance our understanding of genotype-phenotype relationships in this important pathogen, we determined the complete genome sequences of four GAS strains expressing M protein serotypes (M2, M4, and 2 M12) that commonly cause noninvasive and invasive infections. These sequences were compared with eight previously determined GAS genomes and regions of variably present gene content were assessed. Consistent with the previously determined genomes, each of the new genomes is ∼1.9 Mb in size, with ∼10% of the gene content of each encoded on variably present exogenous genetic elements. Like the other GAS genomes, these four genomes are polylysogenic and prophage encode the majority of the variably present gene content of each. In contrast to most of the previously determined genomes, multiple exogenous integrated conjugative elements (ICEs) with characteristics of conjugative transposons and plasmids are present in these new genomes. Cumulatively, 242 new GAS metagenome genes were identified that were not present in the previously sequenced genomes. Importantly, ICEs accounted for 41% of the new GAS metagenome gene content identified in these four genomes. Two large ICEs, designated 2096-RD.2 (63 kb) and 10750-RD.2 (49 kb), have multiple genes encoding resistance to antimicrobial agents, including tetracycline and erythromycin, respectively. Also resident on these ICEs are three genes encoding inferred extracellular proteins of unknown function, including a predicted cell surface protein that is only present in the genome of the serotype M12 strain cultured from a patient with acute poststreptococcal glomerulonephritis. The data provide new information about the GAS metagenome and will assist studies of pathogenesis, antimicrobial resistance, and population genomics

RNA delivery by extracellular vesicles in mammalian cells and its applications.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications