Xanthomonas rydalmerensis sp. nov., a non-pathogenic member of Group 1 Xanthomonas.

Five bacterial isolates were isolated from Fragaria × ananassa in 1976 in Rydalmere, Australia, during routine biosecurity surveillance. Initially, the results of biochemical characterisation indicated that these isolates represented members of the genus Xanthomonas. To determine their species, further analysis was conducted using both phenotypic and genotypic approaches. Phenotypic analysis involved using MALDI-TOF MS and BIOLOG GEN III microplates, which confirmed that the isolates represented members of the genus Xanthomonas but did not allow them to be classified with respect to species. Genome relatedness indices and the results of extensive phylogenetic analysis confirmed that the isolates were members of the genus Xanthomonas and represented a novel species. On the basis the minimal presence of virulence-associated factors typically found in genomes of members of the genus Xanthomonas, we suggest that these isolates are non-pathogenic. This conclusion was supported by the results of a pathogenicity assay. On the basis of these findings, we propose the name Xanthomonas rydalmerensis, with DAR 34855T = ICMP 24941 as the type strain.

Integrative and Conjugative Elements and Prophage DNA as Carriers of Resistance Genes in Erysipelothrix rhusiopathiae Strains from Domestic Geese in Poland.

Goose erysipelas is a serious problem in waterfowl breeding in Poland. However, knowledge of the characteristics of Erysipelothrix rhusiopathiae strains causing this disease is limited. In this study, the antimicrobial susceptibility and serotypes of four E. rhusiopathiae strains from domestic geese were determined, and their whole-genome sequences (WGSs) were analyzed to detect resistance genes, integrative and conjugative elements (ICEs), and prophage DNA. Sequence type and the presence of resistance genes and transposons were compared with 363 publicly available E. rhusiopathiae strains, as well as 13 strains of other Erysipelothrix species. Four strains tested represented serotypes 2 and 5 and the MLST groups ST 4, 32, 242, and 243. Their assembled circular genomes ranged from 1.8 to 1.9 kb with a GC content of 36-37%; a small plasmid was detected in strain 1023. Strains 1023 and 267 were multidrug-resistant. The resistance genes detected in the genome of strain 1023 were erm47, tetM, and lsaE-lnuB-ant(6)-Ia-spw cluster, while strain 267 contained the tetM and ermB genes. Mutations in the gyrA gene were detected in both strains. The tetM gene was embedded in a Tn916-like transposon, which in strain 1023, together with the other resistance genes, was located on a large integrative and conjugative-like element of 130 kb designated as ICEEr1023. A minor integrative element of 74 kb was identified in strain 1012 (ICEEr1012). This work contributes to knowledge about the characteristics of E. rhusiopathiae bacteria and, for the first time, reveals the occurrence of erm47 and ermB resistance genes in strains of this species. Phage infection appears to be responsible for the introduction of the ermB gene into the genome of strain 267, while ICEs most likely play a key role in the spread of the other resistance genes identified in E. rhusiopathiae.

Investigating the Orientation of an Interfacially Adsorbed Monoclonal Antibody and Its Fragments Using Neutron Reflection.

Interfacial adsorption is a molecular process occurring during the production, purification, transport, and storage of antibodies, with a direct impact on their structural stability and subsequent implications on their bioactivities. While the average conformational orientation of an adsorbed protein can be readily determined, its associated structures are more complex to characterize. Neutron reflection has been used in this work to investigate the conformational orientations of the monoclonal antibody COE-3 and its Fab and Fc fragments at the oil/water and air/water interfaces. Rigid body rotation modeling was found to be suitable for globular and relatively rigid proteins such as the Fab and Fc fragments but less so for relatively flexible proteins such as full COE-3. Fab and Fc fragments adopted a 'flat-on' orientation at the air/water interface, minimizing the thickness of the protein layer, but they adopted a substantially tilted orientation at the oil/water interface with increased layer thickness. In contrast, COE-3 was found to adsorb in tilted orientations at both interfaces, with one fragment protruding into the solution. This work demonstrates that rigid-body modeling can provide additional insights into protein layers at various interfaces relevant to bioprocess engineering.

Understanding the Stabilizing Effect of Histidine on mAb Aggregation: A Molecular Dynamics Study.

Histidine, a widely used buffer in monoclonal antibody (mAb) formulations, is known to reduce antibody aggregation. While experimental studies suggest a nonelectrostatic, nonstructural (relating to secondary structure preservation) origin of the phenomenon, the underlying microscopic mechanism behind the histidine action is still unknown. Understanding this mechanism will help evaluate and predict the stabilizing effect of this buffer under different experimental conditions and for different mAbs. We have used all-atom molecular dynamics simulations and contact-based free energy calculations to investigate molecular-level interactions between the histidine buffer and mAbs, which lead to the observed stability of therapeutic formulations in the presence of histidine. We reformulate the Spatial Aggregation Propensity index by including the buffer-protein interactions. The buffer adsorption on the protein surface leads to lower exposure of the hydrophobic regions to water. Our analysis indicates that the mechanism behind the stabilizing action of histidine is connected to the shielding of the solvent-exposed hydrophobic regions on the protein surface by the buffer molecules.

In-Membrane Nanostructuring of Cationic Amphiphiles Affects Their Antimicrobial Efficacy and Cytotoxicity: A Comparison Study between a De Novo Antimicrobial Lipopeptide and Traditional Biocides.

Cationic biocides have been widely used as active ingredients in personal care and healthcare products for infection control and wound treatment for a long time, but there are concerns over their cytotoxicity and antimicrobial resistance. Designed lipopeptides are potential candidates for alleviating these issues because of their mildness to mammalian host cells and their high efficacy against pathogenic microbial membranes. In this study, antimicrobial and cytotoxic properties of a de novo designed lipopeptide, CH3(CH2)12CO-Lys-Lys-Gly-Gly-Ile-Ile-NH2 (C14KKGGII), were assessed against that of two traditional cationic biocides CnTAB (n = 12 and 14), with different critical aggregation concentrations (CACs). C14KKGGII was shown to be more potent against both bacteria and fungi but milder to fibroblast host cells than the two biocides. Biophysical measurements mimicking the main features of microbial and host cell membranes were obtained for both lipid monolayer models using neutron reflection and small unilamellar vesicles (SUVs) using fluorescein leakage and zeta potential changes. The results revealed selective binding to anionic lipid membranes from the lipopeptide and in-membrane nanostructuring that is distinctly different from the co-assembly of the conventional CnTAB. Furthermore, CnTAB binding to the model membranes showed low selectivity, and its high cytotoxicity could be attributed to both membrane lysis and chemical toxicity. This work demonstrates the advantages of the lipopeptides and their potential for further development toward clinical application.

Breast Implant-associated Anaplastic Large Cell Lymphoma: An Evidence-based Systematic Review.

OBJECTIVE: This evidence-based systematic review synthesizes and critically appraises current clinical recommendations and advances in the diagnosis and treatment of BIA-ALCL. This review also aims to broaden physician awareness across diverse specialties, particularly among general practitioners, breast surgeons, surgical oncologists, and other clinicians who may encounter patients with breast implants in their practice. BACKGROUND: BIA-ALCL is an emerging and treatable immune cell cancer definitively linked to textured-surface breast implants. Although the National Comprehensive Cancer Network (NCCN) consensus guidelines and other clinical recommendations have been established, the evidence supporting these guidelines has not been systematically studied. The purpose of this evidence-based systematic review is to synthesize and critically appraise current clinical guidelines and recommendations while highlighting advances in diagnosis and treatment and raising awareness for this emerging disease. METHODS: This evidence-based systematic review evaluated primary research studies focusing on the diagnosis and treatment of BIA-ALCL that were published in PubMed, Google Scholar, and other scientific databases through March 2020. RESULTS AND CONCLUSIONS: The clinical knowledge of BIA-ALCL has evolved rapidly over the last several years with major advances in diagnosis and treatment, including en bloc resection as the standard of care. Despite a limited number of high-quality clinical studies comprised mainly of Level III and Level V evidence, current evidence aligns with established NCCN consensus guidelines. When diagnosed and treated in accordance with NCCN guidelines, BIA-ALCL carries an excellent prognosis.

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. METHODS: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. FINDINGS: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. INTERPRETATION: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. FUNDING: Menarini, Ipsen, and Teijin Pharma Ltd.

Electrolyte/Dye/TiO2 Interfacial Structures of Dye-Sensitized Solar Cells Revealed by In Situ Neutron Reflectometry with Contrast Matching.

The nature of an interfacial structure buried within a device assembly is often critical to its function. For example, the dye/TiO2 interfacial structure that comprises the working electrode of a dye-sensitized solar cell (DSC) governs its photovoltaic output. These structures have been determined outside of the DSC device, using ex situ characterization methods; yet, they really should be probed while held within a DSC since they are modulated by the device environment. Dye/TiO2 structures will be particularly influenced by a layer of electrolyte ions that lies above the dye self-assembly. We show that electrolyte/dye/TiO2 interfacial structures can be resolved using in situ neutron reflectometry with contrast matching. We find that electrolyte constituents ingress into the self-assembled monolayer of dye molecules that anchor onto TiO2. Some dye/TiO2 anchoring configurations are modulated by the formation of electrolyte/dye intermolecular interactions. These electrolyte-influencing structural changes will affect dye-regeneration and electron-injection DSC operational processes. This underpins the importance of this in situ structural determination of electrolyte/dye/TiO2 interfaces within representative DSC device environments.

Markov Chain Modeling of Surfactant Critical Micelle Concentration and Surface Composition.

A Markov chain (MC) model has been used to model the following binary surfactant mixtures: linear alkylbenzenesulfonate (LAS4)/octaethylene glycol monododecyl ether (C12E8) at 10 and 25 °C, LAS6/acidic sophorolipid (AS), C12Betaine/C12Maltoside, sodium lauryl ether sulfate (SLES2)/C12E8, and rhamnolipid (R1)/LAS6. The critical micellar concentration and the composition of the adsorbed layer, for each system, can be modeled using the same monomer reactivity ratio values, g1 and g2. This implies that the interactions between the surfactants in the bulk solution and at the interface are the same, within error. For the LAS4/C12E8 system at 25 °C, the ranges of g1 and g2 values which can model both sets of data are within 0.03-0.05 and 1.55-2.10, respectively; g1 ≪ g2 implies that C12E8 is significantly more surface active than LAS4. The MC model indicates a negative change in the free energy upon mixing for all of the surfactant systems, consistent with the literature. The interfacial mixing behavior of LAS4/SLES2 is inferred from the results of the MC analysis of the LAS4/C12E8 and SLES2/C12E8 systems, which share a common surfactant partner in C12E8, and the prediction is in line with the published data.

Interfacial Adsorption of a Monoclonal Antibody and Its Fab and Fc Fragments at the Oil/Water Interface.

The physical stability of a monoclonal antibody (mAb) solution for injection in a prefilled syringe may in part depend on its behavior at the silicone oil/water interface. Here, the adsorption of a mAb (termed COE-3) and its fragment antigen-binding (Fab) and crystallizable (Fc) at the oil/water interface was measured using neutron reflection. A 1.4 ± 0.1 µm hexadecane oil film was formed on a sapphire block by a spin-freeze-thaw process, retaining its integrity upon contact with the protein solutions. Measurements revealed that adsorbed COE-3 and its Fab and Fc fragments retained their globular structure, forming layers that did not penetrate substantially into the oil phase. COE-3 and Fc were found to adsorb flat-on to the interface, with denser 45 and 42 Å inner layers, respectively, in contact with the oil and a more diffuse 17-21 Å outer layer caused by fragments adsorbing in a tilted manner. In contrast, Fab fragments formed a uniform 60 Å monolayer. Monolayers were formed under all conditions studied (10-200 ppm, using three isotopic contrasts), although changes in packing density across the COE-3 and Fc layers were observed. COE-3 had a higher affinity to the interface than either of its constituent fragments, while Fab had a lower interfacial affinity consistent with its higher net surface charge. This study extends the application of high-resolution neutron reflection measurements to the study of protein adsorption at the oil/water interface using an experimental setup mimicking the protein drug product in a siliconized prefilled syringe.

Missed opportunities for oral cancer screening in Australia.

OBJECTIVES: Most patients with oral cancer lack early symptoms, therefore most present with advanced stage of disease. Early detection of oral cancer and oral potentially malignant disorders (OPMDs) in the asymptomatic phase via an opportunistic oral cancer screening examination is important as survival rates are significantly improved if the disease is treated at an earlier stage. The objective is to identify opportunities to achieve early stage diagnosis of oral cancer in Australian patients. MATERIALS AND METHODS: A cohort of 103 patients newly diagnosed with oral cancer were surveyed at a tertiary hospital Head and Neck Clinic. Patient awareness, knowledge, risk factors and diagnostic delay in oral cancer diagnosis were investigated. The asymptomatic period before diagnosis was studied to identify opportunities for improving opportunistic screening rates in Australia. RESULTS: Australian patients have poor awareness of oral cancer with 46% having never heard of oral cancer, and poor knowledge of risk factors for oral cancer. Only 7% were diagnosed in the asymptomatic phase and all by dental practitioners. Once symptomatic, median diagnostic delay was 9 weeks. In the asymptomatic phase before diagnosis, patients attended general medical practitioners far more often than general dental practitioners. Both groups rarely discussed risk factors for oral cancer (<10%) or performed opportunistic oral cancer screening examinations (<10%) with their patients. CONCLUSION: Asymptomatic diagnosis of oral cancer at an earlier stage of disease is possible in the primary medical setting but increased awareness and knowledge are required in both patients and health practitioners.

Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study.

BACKGROUND: The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months. METHODS: ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation. Changes in left ventricular ejection fraction (LVEF), left ventricular mass (LVM), left atrial diameter (LAD), aortic root diameter (AoRD), E:A, and E deceleration time (EDT) were compared between study arms. Analyses were performed using t-tests and multivariate linear regression. RESULTS: Ninety two patients were included (50 medical versus 42 revascularization). There was no difference between arms in any baseline echocardiographic parameter. Comparisons of longitudinal changes in echocardiographic measurements were: δLVEF medical 0.8 ± 8.7% versus revascularization - 2.8 ± 6.8% (p = 0.05), δLVM - 2.9 ± 33 versus - 1.7 ± 39 g (p = 0.9), δLAD 0.1 ± 0.4 versus 0.01 ± 0.5 cm (p = 0.3), δAoRD 0.002 ± 0.3 versus 0.06 ± 0.3 cm (p = 0.4), δE:A - 0.0005 ± 0.6 versus 0.03 ± 0.7 (p = 0.8), δEDT - 1.1 ± 55.5 versus - 9.0 ± 70.2 ms (p = 0.6). In multivariate models, there were no differences between treatment groups for any parameter at 12 months. Likewise, change in blood pressure did not differ between arms (mean δsystolic blood pressure medical 0 mmHg [range - 56 to + 54], revascularization - 3 mmHg [- 61 to + 59], p = 0.60). CONCLUSIONS: This sub-study did not show any significant differences in cardiac structure and function accompanying renal revascularization in ASTRAL. Limitations include the small sample size, the relative insensitivity of echocardiography, and the fact that a large proportion of ASTRAL patient population had only modest renal artery stenosis as described in the main study.

IMG/VR: a database of cultured and uncultured DNA Viruses and retroviruses.

Viruses represent the most abundant life forms on the planet. Recent experimental and computational improvements have led to a dramatic increase in the number of viral genome sequences identified primarily from metagenomic samples. As a result of the expanding catalog of metagenomic viral sequences, there exists a need for a comprehensive computational platform integrating all these sequences with associated metadata and analytical tools. Here we present IMG/VR (https://img.jgi.doe.gov/vr/), the largest publicly available database of 3908 isolate reference DNA viruses with 264 413 computationally identified viral contigs from >6000 ecologically diverse metagenomic samples. Approximately half of the viral contigs are grouped into genetically distinct quasi-species clusters. Microbial hosts are predicted for 20 000 viral sequences, revealing nine microbial phyla previously unreported to be infected by viruses. Viral sequences can be queried using a variety of associated metadata, including habitat type and geographic location of the samples, or taxonomic classification according to hallmark viral genes. IMG/VR has a user-friendly interface that allows users to interrogate all integrated data and interact by comparing with external sequences, thus serving as an essential resource in the viral genomics community.

Determination of PMMA Residues on a Chemical-Vapor-Deposited Monolayer of Graphene by Neutron Reflection and Atomic Force Microscopy.

Chemical vapor deposition (CVD) is now a well-established method for creating monolayer graphene films. In this method, poly(methyl methacrylate) (PMMA) films are often coated onto monolayer graphene films to make them mechanically robust enough for transfer and further handling. However, it is found that PMMA is hard to remove entirely, and any residual polymers remaining can affect graphene's properties. We demonstrate here a method to determine the amount of PMMA remaining on the graphene sheet fabricated from CVD by a combined study of Raman scattering, atomic force microscopy, and neutron reflection. Neutron reflectivity is a powerful technique which is particularly sensitive to any interfacial structure, so it is able to investigate the density profile of the residual PMMA in the direction perpendicular to the graphene film surface. After the standard process of PMMA removal by acetone-IPA cleaning, we found that the remaining PMMA film could be represented as a two-layer model: an inner layer with a thickness of 17 Å and a roughness of 1 Å mixed with graphene and an outer diffuse layer with an average thickness of 31 Å and a roughness of 4 Å well mixed with water. On the basis of this model analysis, it was demonstrated that the remaining PMMA still occupied a significant fraction of the graphene film surface.

Temperature Resistant Binary SLES/Nonionic Surfactant Mixtures at the Air/Water Interface.

Surface compositions of adsorbed monolayers at the air/water interface, formed from binary surfactant mixtures in equilibrium, have been studied using neutron reflectivity at three discrete temperatures: 10, 25, and 40 °C. The binary compositions studied are sodium lauryl dodecyl ether sulfate (SLES EO3)/C12E n, where n = 6 and 8, at a fixed concentration of 2 mM with and without the addition of 0.1 M NaCl. Without NaCl, the nonionic surfactant dominates at the interface and nonideal mixing behavior is observed. This is modeled using the pseudophase approximation with a quadratic expansion of the free energy of mixing. The addition of 0.1 M NaCl screens the charge interaction between the surfactants and drives the surface composition of each system closer to that of the bulk composition. However, model fits to both the micelles and surface layers suggest that nonideal mixing is still taking place, although it is difficult to establish the extent of nonideality due to the limited data quality. The effect of temperature changes on the surface adsorption and composition of the surfactant mixtures is minimal and within error, with and without NaCl, but the critical micelle concentrations are significantly affected. This indicates the dominant influence of steric hindrances and surfactant charge interactions in determining interfacial behavior for these surfactants, relative to the temperature changes. The study also highlights the delicate effect of a relatively small change in the number of EO groups on mixing behavior.

Structural Features of Reconstituted Cuticular Wax Films upon Interaction with Nonionic Surfactant C12E6.

The interaction of nonionic surfactant hexaethylene glycol monododecyl ether (C12E6) with a reconstituted cuticular wheat wax film has been investigated by spectroscopic ellipsometry and neutron reflection (NR) to help understand the role of the leaf wax barrier during pesticide uptake, focusing on the mimicry of the actions adjuvants impose on the physical integrity and transport of the cuticular wax films against surfactant concentration. As the C12E6 concentration was increased up to the critical micelle concentration (CMC = 0.067 mM), an increasing amount of surfactant mass was deposited onto the wax film. Alongside surface adsorption, C12E6 was also observed to penetrate the wax film, which is evident from the NR measurements using fully protonated and chain-deuterated surfactants. Furthermore, surfactant action upon the model wax film was found to be physically reversible below the CMC, as water rinsing could readily remove the adsorbed surfactant, leaving the wax film in its original state. Above the CMC, the detergency action of the surfactant became dominant, and a significant proportion of the wax film was removed, causing structural damage. The results thus reveal that both water and C12E6 could easily penetrate the wax film throughout the concentration range measured, indicating a clear pathway for the transport of active ingredients while the removal of the wax components above the CMC must have enhanced the transport process. As the partial removal of the wax film could also expose the underlying cutaneous substrate to the environment and undermine the plant's health, this study has a broad implication to the roles of surfactants in crop care.

Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).

BACKGROUND: Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting. METHOD: Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR). RESULTS: In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81-1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81-1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001). INTERPRETATION: In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759.

Adsorption at the Air-Water Interface in Biosurfactant-Surfactant Mixtures: Quantitative Analysis of Adsorption in a Five-Component Mixture.

The composition of the air-water adsorbed layer of a quinary mixture consisting of three conventional surfactants, octaethylene glycol monododecyl ether (C12E8), dodecane-6-p-sodium benzene sulfonate (LAS6), and diethylene glycol monododecyl ether sodium sulfate (SLE2S), mixed with two biosurfactants, the rhamnolipids l-rhamnosyl-l-rhamnosyl-ß-hydroxydecanoyl-ß-hydroxydecanoyl, R2, and l-rhamnosyl-ß-hydroxydecanoyl-ß-hydroxydecanoyl, R1, has been measured over a range of compositions above the mixed critical micelle concentration. Additional measurements on some of the subsets of ternary and binary mixtures have also been measured by NR. The results have been analyzed using the pseudophase approximation (PPA) in conjunction with an excess free energy, GE, that depends on the quadratic and cubic terms in the composition. The compositions of the binary, ternary, and quinary mixtures could all be fitted to two sets of interaction parameters between the pairs of surfactants, one for micelles and one for adsorption. No ternary interactions or ternary corrections were required. Because the system contains two strongly anionic surfactants, the PPA can be extended, in practice, to ionic surfactants, contrary to the prevailing view. The values of the interaction parameters show that the quinary mixture, SLE2S-LAS6-C12E8-R1-R2, which is known to be a highly effective surfactant system, is characterized by a sequence of strong surface but weak micellar interactions. About half of the minima in GE for the strong surface interactions occur well away from the regular solution value of 0.5.

Impact of Electrolyte on Adsorption at the Air-Water Interface for Ternary Surfactant Mixtures above the Critical Micelle Concentration.

The composition of the air-water adsorbed layer of the ternary surfactant mixture, octaethylene monododecyl ether, C12E8, sodium dodecyl 6-benzenesulfonate, LAS, and sodium dioxyethylene glycol monododecyl sulfate, SLES, and of each of the binary mixtures, with varying amounts of electrolyte, has been studied by neutron reflectivity. The measurements were made above the mixed critical micelle concentration. In the absence of electrolyte adsorption is dominated by the nonionic component C12E8 but addition of electrolyte gradually changes this so that SLES and LAS dominate at higher electrolyte concentrations. The composition of the adsorbed layer in both binary and ternary mixtures can be quantitatively described using the pseudo-phase approximation with quadratic and cubic interactions in the excess free energy of mixing (GE) at both the surface and in the micelles. A single set of parameters fits all the experimental data. A similar analysis is effective for a mixture in which SDS replaces SLES. Addition of electrolyte weakens the synergistic SLES-C12E8 and LAS-C12E8 interactions, consistent with them being dominated by electrostatic interactions. The SLES-LAS (and SDS-LAS) interaction is moderately strong at the surface and is little affected by addition of electrolyte, suggesting that it is controlled by structural or packing factors. Most of the significant interactions in the mixtures are unsymmetrical with respect to composition, with the minimum in GE at the 1:2 or 2:1 composition. There is a small structural contribution to the LAS-C12E8 interaction that leads to a minimum intermediate in composition between 1:2 and 1:1 (LAS:C12E8) and to a significant residual GE in strong electrolyte.

Video Voiding Device for Diagnosing Lower Urinary Tract Dysfunction in Men.

We introduce a novel diagnostic Visual Voiding Device (VVD), which has the ability to visually document urinary voiding events and calculate key voiding parameters such as instantaneous flow rate. The observation of the urinary voiding process along with the instantaneous flow rate can be used to diagnose symptoms of Lower Urinary Tract Dysfunction (LUTD) and improve evaluation of LUTD treatments by providing subsequent follow-up documentations of voiding events after treatments. The VVD enables a patient to have a urinary voiding event in privacy while a urologist monitors, processes, and documents the event from a distance. The VVD consists of two orthogonal cameras which are used to visualize urine leakage from the urethral meatus, urine stream trajectory, and its break-up into droplets. A third, lower back camera monitors a funnel topped cylinder where urine accumulates that contains a floater for accurate readings regardless of the urine color. Software then processes the change in level of accumulating urine in the cylinder and the visual flow properties to calculate urological parameters. Video playback allows for reexamination of the voiding process. The proposed device was tested by integrating a mass flowmeter into the setup and simultaneously measuring the instantaneous flow rate of a predetermined voided volume in order to verify the accuracy of VVD compared to the mass flowmeter. The VVD and mass flowmeter were found to have an accuracy of ±2 and ±3% relative to full scale, respectively. A VVD clinical trial was conducted on 16 healthy male volunteers ages 23-65.