Effectiveness and safety of betrixaban extended prophylaxis for venous thromboembolism compared with standard-duration prophylaxis intervention in acute medically ill patients : a systematic literature review and network meta-analysis

Aims: To determine the clinical effectiveness and safety of venous thromboembolism (VTE) prophylaxis using US- and Europe-approved anticoagulants relative to extended-duration VTE prophylaxis with betrixaban. Low molecular weight heparins (LMWHs), unfractionated heparin (UFH), fondaparinux sodium and placebo were each compared to betrixaban, as standard-duration VTE prophylaxis for hospitalized, non-surgical patients with acute medical illness at risk of VTE. Materials and methods: A systematic literature review was conducted up to June 2019 to identify randomized controlled trials (RCTs) of VTE prophylaxis in hospitalized, non-surgical patients with acute medical illness at risk of VTE. Studies that reported the occurrence of VTE events (including death) and, where possible, major bleeding, from treatment initiation to 20–50 days thereafter were retrieved and extracted. A Bayesian fixed effect network meta-analysis was used to estimate efficacy and safety of betrixaban compared with standard-duration VTE prophylaxis. Results: Seven RCTs were analyzed which compared betrixaban, LMWHs, UFH, fondaparinux sodium, or placebo. There were significantly higher odds (median odds [95% credible interval]) of VTE with LMWHs (1.38 [1.12–1.70]), UFH (1.60 [1.05–2.46]), and placebo (2.37 [1.55–3.66]) compared with betrixaban. There were significantly higher odds of VTE-related death with placebo (7.76 [2.14–34.40]) compared with betrixaban. No significant differences were observed for the odds of major bleeding with all comparators, VTE-related death with any active standard-duration VTE prophylaxis, or of VTE with fondaparinux sodium, compared with betrixaban. Limitations and conclusions: In this indirect comparison, betrixaban was shown to be an effective regimen with relative benefits compared with LMWHs and UFH. This indicates that betrixaban could reduce the burden of VTE in at-risk hospitalized patients with acute medical illness who need extended prophylaxis, though without direct comparative evidence, stronger conclusions cannot be drawn

Lifting the lid: a clinical audit on commode cleaning

Many healthcare-associated infections (HCAIs) are preventable by infection control procedures designed to interrupt the transmission of organisms from a source. Commodes are in use constantly throughout healthcare facilities. Therefore commode surfaces are constantly handled, and any pathogens present have the potential to be transferred to not only other surfaces but also, more importantly, to patients, thus compromising patient safety. In order to examine the effectiveness and thoroughness of cleaning commodes an audit was undertaken to assess compliance with evidence-based practice. This audit demonstrates a cycle which includes defining best practice, implementing best practice, monitoring best practice and taking action to improve practice. The audit results confirmed an issue that the authors had long suspected. That is, that commodes allocated to individual patients are not always cleaned after every use. Using adenosine triphosphate (ATP) bioluminescence as an indicator of organic soiling also demonstrated that commodes that were considered clean were not always cleaned to a high standard. Implementing the audit recommendations improves staff knowledge through education, standardises cleaning procedures and ultimately improves patient safety

Self-recognition and Ca2+-dependent carbohydrate–carbohydrate cell adhesion provide clues to the Cambrian explosion

Author Posting. © The Authors, 2009. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Molecular Biology and Evolution 26 (2009): 2551-2561, doi:10.1093/molbev/msp170.The Cambrian explosion of life was a relatively short period ca. 540 million years ago that marked a generalized acceleration in the evolution of most animal phyla, but the trigger of this key biological event remains elusive. Sponges are the oldest extant Precambrian metazoan phylum and thus a valid model to study factors that could have unleashed the rise of multicellular animals. One such factor is the advent of self/non-self recognition systems, which would be evolutionarily beneficial to organisms to prevent germ cell parasitism or the introduction of deleterious mutations resulting from fusion with genetically different individuals. However, the molecules responsible for allorecognition probably evolved gradually before the Cambrian period, and some other (external) factor remains to be identified as the missing triggering event. Sponge cells associate through calcium-dependent, multivalent carbohydrate-carbohydrate interactions of the g200 glycan found on extracellular proteoglycans. Single molecule force spectroscopy analysis of g200-g200 binding indicates that calcium affects the lifetime (+Ca/-Ca: 680 s/3 s) and bond reaction length (+Ca/-Ca: 3.47 Å/2.27 Å). Calculation of mean g200 dissociation times in low and high calcium within the theoretical framework of a cooperative binding model indicates the non-linear and divergent characteristics leading to either disaggregated cells or stable multicellular assemblies, respectively. This fundamental phenomenon can explain a switch from weak to strong adhesion between primitive metazoan cells caused by the well documented rise in ocean calcium levels at the end of Precambrian time. We propose that stronger cell adhesion allowed the integrity of genetically uniform animals composed only of “self” cells, facilitating genetic constitutions to remain within the metazoan individual and be passed down inheritance lines. The Cambrian explosion might have been triggered by the coincidence in time of primitive animals endowed with self/non-self recognition, and of a surge in sea water calcium that increased the binding forces between their calcium-dependent cell adhesion molecules.D.A. and A.K. acknowledge financial support from the Collaborative Research Center SFB 613 from the Deutsche Forschungsgemeinschaft (DFG), and X.F.-B. acknowledges financial support from grants BIO2002-00128, BIO2005-01591, and CSD2006-00012 from the Ministerio de Ciencia y Tecnología, Spain, which included Fondo Europeo de Desarrollo Regional funds, and from grant 2005SGR-00037 from the Generalitat de Catalunya, Spain

Pseudomonas aeruginosa Pili and Flagella Mediate Distinct Binding and Signaling Events at the Apical and Basolateral Surface of Airway Epithelium

Pseudomonas aeruginosa, an important opportunistic pathogen of man, exploits numerous factors for initial attachment to the host, an event required to establish bacterial infection. In this paper, we rigorously explore the role of two major bacterial adhesins, type IV pili (Tfp) and flagella, in bacterial adherence to distinct host receptors at the apical (AP) and basolateral (BL) surfaces of polarized lung epithelial cells and induction of subsequent host signaling and pathogenic events. Using an isogenic mutant of P. aeruginosa that lacks flagella or utilizing beads coated with purified Tfp, we establish that Tfp are necessary and sufficient for maximal binding to host N-glycans at the AP surface of polarized epithelium. In contrast, experiments utilizing a P. aeruginosa isogenic mutant that lacks Tfp or using beads coated with purified flagella demonstrate that flagella are necessary and sufficient for maximal binding to heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPGs) at the BL surface of polarized epithelium. Using two different cell-free systems, we demonstrate that Tfp-coated beads show highest binding affinity to complex N-glycan chains coated onto plastic plates and preferentially aggregate with beads coated with N-glycans, but not with single sugars or HS. In contrast, flagella-coated beads bind to or aggregate preferentially with HS or HSPGs, but demonstrate little binding to N-glycans. We further show that Tfp-mediated binding to host N-glycans results in activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and bacterial entry at the AP surface. At the BL surface, flagella-mediated binding to HS activates the epidermal growth factor receptor (EGFR), adaptor protein Shc, and PI3K/Akt, and induces bacterial entry. Remarkably, flagella-coated beads alone can activate EGFR and Shc. Together, this work provides new insights into the intricate interactions between P. aeruginosa and lung epithelium that may be potentially useful in the development of novel treatments for P. aeruginosa infections

The Evolution of Extracellular Matrix

We present a perspective on the molecular evolution of the extracellular matrix (ECM) in metazoa that draws on research publications and data from sequenced genomes and expressed sequence tag libraries. ECM components do not function in isolation, and the biological ECM system or “adhesome” also depends on posttranslational processing enzymes, cell surface receptors, and extracellular proteases. We focus principally on the adhesome of internal tissues and discuss its origins at the dawn of the metazoa and the expansion of complexity that occurred in the chordate lineage. The analyses demonstrate very high conservation of a core adhesome that apparently evolved in a major wave of innovation in conjunction with the origin of metazoa. Integrin, CD36, and certain domains predate the metazoa, and some ECM-related proteins are identified in choanoflagellates as predicted sequences. Modern deuterostomes and vertebrates have many novelties and elaborations of ECM as a result of domain shuffling, domain innovations and gene family expansions. Knowledge of the evolution of metazoan ECM is important for understanding how it is built as a system, its roles in normal tissues and disease processes, and has relevance for tissue engineering, the development of artificial organs, and the goals of synthetic biology

Bacterial Flagella: Twist and Stick, or Dodge across the Kingdoms

The flagellum organelle is an intricate multiprotein assembly best known for its rotational propulsion of bacteria. However, recent studies have expanded our knowledge of other functions in pathogenic contexts, particularly adherence and immune modulation, e.g., for Salmonella enterica, Campylobacter jejuni, Pseudomonas aeruginosa, and Escherichia coli. Flagella-mediated adherence is important in host colonisation for several plant and animal pathogens, but the specific interactions that promote flagella binding to such diverse host tissues has remained elusive. Recent work has shown that the organelles act like probes that find favourable surface topologies to initiate binding. An emerging theme is that more general properties, such as ionic charge of repetitive binding epitopes and rotational force, allow interactions with plasma membrane components. At the same time, flagellin monomers are important inducers of plant and animal innate immunity: variation in their recognition impacts the course and outcome of infections in hosts from both kingdoms. Bacteria have evolved different strategies to evade or even promote this specific recognition, with some important differences shown for phytopathogens. These studies have provided a wider appreciation of the functions of bacterial flagella in the context of both plant and animal reservoirs

The Second Type VI Secretion System of Pseudomonas aeruginosa Strain PAO1 Is Regulated by Quorum Sensing and Fur and Modulates Internalization in Epithelial Cells

The genome of Pseudomonas aeruginosa PAO1 contains three type VI secretion systems (T6SSs) called H1-, H2-, and H3-T6SS. The H1-T6SS secretes three identified toxins that target other bacteria, providing a fitness advantage for P. aeruginosa, and likely contributes to bacterial pathogenesis in chronic infections. However, no specific substrates or defined roles have been described for the two other systems. Here, we demonstrate that the expression of H2-T6SS genes of strain PAO1 is up-regulated during the transition from exponential to stationary phase growth and regulated by the Las and Rhl quorum sensing systems. In addition, we identify two putative Fur boxes in the promoter region and find that H2-T6SS transcription is negatively regulated by iron. We also show that the H2-T6SS system enhances bacterial uptake into HeLa cells (75% decrease in internalization with a H2-T6SS mutant) and into lung epithelial cells through a phosphatidylinositol 3-kinase-dependent pathway that induces Akt activation in the host cell (50% decrease in Akt phosphorylation). Finally, we show that H2-T6SS plays a role in P. aeruginosa virulence in the worm model. Thus, in contrast to H1-T6SS, H2-T6SS modulates interaction with eukaryotic host cells. Together, T6SS can carry out different functions that may be important in establishing chronic P. aeruginosa infections in the human host

Assessment of rescue opioid use in patients with post-bunionectomy pain treated with diclofenac potassium liquid-filled capsules

Joyce S Willens,1 Iwona Bucior,2 Shay Bujanover,2 Neel Mehta3 1Villanova University, Villanova, PA, 2Depomed, Inc., Newark, CA, 3Weill-Cornell Pain Medicine Center, New York, NY, USA Abstract: When used in multimodal analgesia for acute pain, nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the requirement for opioids during the perioperative period. To provide more insight into pain treatment during the outpatient period, we examined the use of opioid rescue medication (RM) and described the relationship between pain intensity and RM use in patients with acute pain after bunionectomy. Patients received placebo or 25 mg of a liquid-filled capsule version of the NSAID diclofenac potassium (DPLFC; n=188 patients/group) every 6 hours during the 48-hour inpatient period through the end of outpatient dosing on day 4. Opioid RM (hydrocodone/acetaminophen tablets, 5 mg/500 mg) was available as needed, but taken at least 1 hour post-study medication. Fewer patients taking DPLFC versus placebo requested opioid RM during the inpatient period (4.8%–44.7% versus 25.0%–90.4%) and also during the outpatient period (3.7%–16.0% versus 13.1%–46.4%). Moderate or severe pain after surgery (P=0.0307 and P=0.0002, respectively) or at second dose (P=0.0006 and P=0.0002, respectively) was predictive of RM use. Patients taking RM (placebo/DPLFC) reported more adverse events (RM 55.7%/40.6%; no RM 29.4%/26.0%). Most adverse events in the RM group were opioid-related. In summary, this study shows that DPLFC lowers the requirement for opioids, which is associated with a reduction in the occurrence of treatment side effects, while maintaining adequate analgesia for patients with moderate acute pain in both the outpatient and outpatient periods. Patients with more severe pain are more likely to use RM, but they still use fewer opioids when treated with DPLFC. This suggests that multimodal treatment using DPLFC and an opioid may offer an important clinical benefit in the treatment of acute pain, including in the home environment. Keywords: nonsteroidal anti-inflammatory drugs, diclofenac, opioids, opioid sparing, acute pai

Strong specific binding forces between adhesive extracellular proteoglycan carbohydrates

Bucior I, Garcia-Manyes S, Ros R, et al. Strong specific binding forces between adhesive extracellular proteoglycan carbohydrates. FEBS JOURNAL. 2005;272(Suppl. 1):340