Browsing by Subject "AGENTS"

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  • Purmonen, Timo; Puolakka, Kari; Mishra, Dinesh; Gunda, Praveen; Martikainen, Janne (2019)
    Aim: This study assesses the cost-effectiveness of secukinumab vs currently licensed biologics for the treatment of ankylosing spondylitis (AS) from the Finnish health care system perspective. Methods: A semi-Markov model compared secukinumab with adalimumab, adalimumab biosimilar, certolizumab pegol, etanercept, etanercept biosimilar, golimumab, and infliximab in a biologic-naive population over a lifetime horizon. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to assess the treatment response. Efficacy inputs were obtained from the network meta-analysis, and other model inputs were obtained from the published literature and Finnish sources. Main study outcomes included quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratio in terms of cost per QALY gained. Robustness of results was confirmed by sensitivity analyses and alternative scenario analyses. Results: Secukinumab achieved highest QALYs (13.1) at lowest expected lifetime cost (ss279,872) vs other comparators in biologic-naive AS patients in the base case analysis, thus it dominated other biologics. Golimumab had a second highest QALYs (12.9) at the total cost of ss309,551. Results were sensitive to variation in BASDAI 50 response for secukinumab, baseline Bath Ankylosing Spondylitis Functional Index (BASFI) score across all drugs, change in BASDAI and BASFI scores, and discount rates as observed in the one-way sensitivity analyses. Secukinumab was either dominant or cost-effective treatment in different alternative scenarios. Conclusion: Secukinumab presented itself to be the dominant (ie, less costly and more effective) treatment vs other comparators for the biologic-naive patients with AS in Finland.
  • Serim, Baris; Jacucci, Giulio (ACM, 2019)
    The term implicit interaction is often used to denote interactions that differ from traditional purposeful and attention demanding ways of interacting with computers. However, there is a lack of agreement about the term's precise meaning. This paper develops implicit interaction further as an analytic concept and identifies the methodological challenges related to HCI's particular design orientation. We first review meanings of implicit as unintentional, attentional background, unawareness, unconsciousness and implicature, and compare them in regards to the entity they qualify, the design motivation they emphasize and their constructive validity for what makes good interaction. We then demonstrate how the methodological challenges can be addressed with greater precision by using an updated, intentionality-based definition that specifies an input-effect relationship as the entity of implicit. We conclude by identifying a number of new considerations for design and evaluation, and by reflecting on the concepts of user and system agency in HCI.
  • Al-Ani, Anas Aaqel Salim Salim; Stape, Thiago Henrique Scarabello; Mutluay, Murat; Tjäderhane, Leo; Tezvergil-Mutluay, Arzu (2019)
    Objective: To understand dimethyl sulfoxide (DMSO) interaction with distinct methacrylate monomer blends and the impact on polymer formation by investigating the combined relationship among degree of resin hydrophilicity, presence of DMSO and specific physico/mechanical properties. Methods: One hydrophobic (R2) and one hydrophilic (R5) methacrylate-based resins with different monomer compositions were solvated in ascending DMSO concentrations (0, 0.01, 0.1, 1, 5, and 10 w/w %). Neat resins (0 w/w % DMSO) were used as controls. The degree of conversion was determined by Fourier-transform infrared spectroscopy. Polymer crosslinking density was indirectly measured by a modified ethanol-water two-stage solvation technique and the biaxial flexural strength was measured after 24 h and 30 days of water storage at 37 degrees C. Water sorption and solubility were gravimetrically assisted during 28 days of water storage to determine the kinetics of water-polymer interactions. Data were analyzed by ANOVA and Tukey test (alpha = 0.05). Results: Incorporation of high DMSO-concentrations significantly increased the degree of conversion of all tested formulations, specifically for the hydrophobic resin (p <0.05). Despite the increase in degree of monomer conversion, higher water sorption/solubility values and lower biaxial flexure strengths were detected as a result of reductions in polymer crosslink density (p <0.05). In general, low DMSO-concentrations had no impact on the biaxial flexural strength, crosslinking density and water sorption/solubility (p <0.05). Conclusion: DMSO-monomer ratio and monomer composition are critical for new dental methacrylate-based adhesive formulations. High DMSO incorporation hampers physico/mechanical properties of methacrylate bonding resins, albeit to a lesser extend when hydrophilic resins are employed. Nonetheless, DMSO-solvated hydrophobic adhesives extensively outperform their hydrophilic correspondents. DMSO incorporation of 1 w/w % may constitute a secure threshold regardless of monomer composition.
  • Durcik, Martina; Lovison, Denise; Skok, Žiga; Durante Cruz, Cristina; Tammela, Päivi; Tomašič, Tihomir; Benetto Tiz, Davide; Draskovits, Gábor; Nyerges, Ákos; Pál, Csaba; Ilaš, Janez; Peterlin Mašič, Lucija; Kikelj, Danijel; Zidar, Nace (2018)
    The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coil and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coil gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 mu M against Enterococcus faecalis, and 3.13 mu M against wild type S. aureus, methicillinresistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PA beta N) is 4.6 mu M. (C) 2018 Elsevier Masson SAS. All rights reserved.
  • Aly, Ashraf A.; El-Sheref, Essmat M.; Brown, Alan B.; Braese, Stefan; Nieger, Martin; Abdelhafez, El-Shinnaa M. N. (2019)
    A new one pot reaction of substituted thiosemicarbazides with 2-bromoacetophenone and carbonyl compounds gave 2-hydrazonothiazoles in good yields. The structures of the isolated compounds were corroborated by NMR, IR, mass spectra and elemental analyses in addition to X-ray structure determination. [GRAPHICS] .
  • Hokynar, Kati; Kurkela, Satu; Nieminen, Tea; Saxen, Harri; Vesterinen, Eero J.; Mannonen, Laura; Pietikäinen, Risto; Puolakkainen, Mirja (2019)
    Community-acquired pneumonia (CAP) is a common disease responsible for significant morbidity and mortality. However, the definite etiology of CAP often remains unresolved, suggesting that unknown agents of pneumonia remain to be identified. The recently discovered members of the order Chlamydiales, Chlamydia-related bacteria (CRB), are considered as possible emerging agents of CAP. Parachlamydia acanthamoebae is the most studied candidate. It survives and replicates inside free-living amoeba, which it might potentially use as a vehicle to infect animals and humans. A Mycoplasma pneumoniae outbreak was observed in Kymenlaakso region in Southeastern Finland during August 2017-January 2018. We determined the occurrence of Chlamydiales bacteria and their natural host, free-living amoeba in respiratory specimens collected during this outbreak with molecular methods. Altogether, 22/278 (7.9%) of the samples contained Chlamydiales DNA. By sequence analysis, majority of the CRBs detected were members of the Parachlamydiaceae family. Amoebal DNA was not detected within the sample material. Our study further proposes that Parachlamydiaceae could be a potential agent causing atypical CAP in children and adolescents.
  • Vaara, Martti (2019)
    Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized permeabilizer derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up.
  • Vaara, Martti (2019)
    The discovery of polymyxins, highly basic lipodecapeptides, was published independently by three laboratories in 1947. Their clinical use, however, was abandoned in the sixties because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were discovered. Now polymyxins have resurged as the last-resort drugs against extremely multi-resistant strains, even though their nephrotoxicity forces clinicians to administer them at doses that are lower than those required for optimal efficacy. As their therapeutic windows are very narrow, the use of polymyxins has received lots of justified criticism. To address this criticism, consensus guidelines for the optimal use of polymyxins have just been published. Quite obviously, too, improved polymyxins with increased efficacy and lowered nephrotoxicity would be more than welcome. Over the last few years, more than USD 40 million of public money has been used in programs that aim at the design of novel polymyxin derivatives. This perspective article points out that polymyxins do have potential for further development and that the novel derivatives already now at hand might offer major advantages over the old polymyxins.
  • Pirnay, Jean-Paul; Blasdel, Bob G.; Bretaudeau, Laurent; Buckling, Angus; Chanishvili, Nina; Clark, Jason R.; Corte-Real, Sofia; Debarbieux, Laurent; Dublanchet, Alain; De Vos, Daniel; Gabard, Jerome; Garcia, Miguel; Goderdzishvili, Marina; Gorski, Andrzej; Hardcastle, John; Huys, Isabelle; Kutter, Elizabeth; Lavigne, Rob; Merabishvili, Maia; Olchawa, Ewa; Parikka, Kaarle J.; Patey, Olivier; Pouilot, Flavie; Resch, Gregory; Rohde, Christine; Scheres, Jacques; Skurnik, Mikael; Vaneechoutte, Mario; Van Parys, Luc; Verbeken, Gilbert; Zizi, Martin; Van den Eede, Guy (2015)
    The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allowsa timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.
  • Aly, Ashraf A.; Hassan, Alaa A.; AbdAl-Latif, El-Shimaa S. M.; Ibrahim, Mahmoud A. A.; Bräse, Stefan; Nieger, Martin (2018)
    Reaction of hydrazinecarbothioamides with 2-bromoacetophenones furnished the formation of thiazole-, bis-thiazole-, pyrazole- and 1,3,4-thiadiazole- derivatives in good yields. The mechanism was discussed. The structures of products were proved by MS, IR, NMR, elemental analyses and X-ray structure analyses. [GRAPHICS] .
  • Paradis, D.; Meny, C.; Juvela, M.; Noriega-Crespo, A.; Ristorcelli, I. (2019)
    Context. Some Galactic molecular clouds show signs of dust evolution as compared to the diffuse interstellar medium, most of the time through indirect evidence such as color ratios, increased dust emissivity, or scattering (coreshine). These signs are not a feature of all Galactic clouds. Moreover, molecular clouds in the Large Magellanic Cloud (LMC) have been analyzed in a previous study based on Spitzer and IRIS data, at 4' angular resolution, with the use of one single dust model, and did not show any signs of dust evolution. Aims. In this present analysis we investigate the dust properties associated with the different gas phases (including the ionized phase this time) of the LMC molecular clouds at 1' angular resolution (four times greater than the previous analysis) and with a larger spectral coverage range thanks to Herschel data. We also ensure the robustness of our results in the framework of various dust models. Methods. We performed a decomposition of the dust emission in the infrared (from 3.6 to 500 mu m) associated with the atomic, molecular, and ionized gas phases in the molecular clouds of the LMC. The resulting spectral energy distributions were fitted with four distinct dust models. We then analyzed the model parameters such as the intensity of the radiation field and the relative dust abundances, as well as the slope of the emission spectra at long wavelengths. Results. This work allows dust models to be compared with infrared data in various environments for the first time, which reveals important differences between the models at short wavelengths in terms of data fitting (mainly in the polycyclic aromatic hydrocarbon bands). In addition, this analysis points out distinct results according to the gas phases, such as dust composition directly affecting the dust temperature and the dust emissivity in the submillimeter and different dust emission in the near-infrared (NIR). Conclusions. We observe direct evidence of dust property evolution from the diffuse to the dense medium in a large sample of molecular clouds in the LMC. In addition, the differences in the dust component abundances between the gas phases could indicate different origins of grain formation. We also point out the presence of a NIR-continuum in all gas phases, with an enhancement in the ionized gas. We favor the hypothesis of an additional dust component as the carrier of this continuum.
  • Tyrrell, Jonathan M.; Aboklaish, Ali F.; Walsh, Timothy R.; Vaara, Timo; Vaara, Martti (2019)
    The antibiotic crisis has reinstated polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective derivatives of polymyxins such as NAB739. Simultaneously, polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare. Here we show that NAB739 sensitizes the PMR strains to rifampin, a classic "anti-Gram-positive" antibiotic excluded by the intact outer membrane (OM) permeability barrier, as well as to retapamulin, the surrogate of lefamulin, an antibiotic under development against Gram-positive bacteria. Polymyxin B was used as a comparator. The combination of NAB739 and rifampin was synergistic against ten out of eleven PMR strains of Escherichia coll. (Fractional Synergy Indices, FICs, 0.14-0.19) and that of NAB739 and retapamulin against all the tested eleven strains (FICs 0.19-0.25). Against PMR Klebsiella pneumoniae (n = 7), the FICs were 0.13-0.27 for NAB739 + rifampin and 0.14-0.28 for NAB739 + retapamulin. Against Acinetobacter baumannii (n = 2), the combination of NAB739 and rifampin had the FIC of 0.09-0.19. Furthermore, NAB739 and meropenem were synergistic (FICs 0.25-0.50) against four out of five PMR strains that were simultaneously resistant to meropenem.
  • Kolho, Kaija-Leena (2021)
    Inflammatory bowel disease (IBD) with pediatric onset has become more prevalent during past decades. Thus, the number of patients with moderate to severe disease subtype treated with antagonists to tumor necrosis factor alpha (TNF alpha) has concurrently risen. Most pediatric patients initially respond to these drugs but will need dose escalation during the first year of therapy. As pediatric data regarding therapeutic drug monitoring during therapy with TNF alpha-blocker adalimumab are sparse, this review focuses on the literature on therapeutic drug monitoring of infliximab and how it may guide management.
  • Matikainen, Jorma; Lehtinen, Markku; Pelttari, Eila; Elo, Hannu (2015)