Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends ...testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.
The functionalization of C(sp3)−H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the ...development of new reactions based on C−H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition‐metal‐catalyzed C−H activation, 1,n‐hydrogen atom transfer, and transition‐metal‐catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3)−H bonds. For each strategy, the scope, the reactivity of different C−H bonds, the position of the reacting C−H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C−H functionalization reactions and inspire future research in this area.
The targeted functionalization of C(sp3)−H bonds streamlines chemical synthesis and allows the use of simple starting materials. This Review discusses the strength and weakness of the three main approaches: transition‐metal‐catalyzed C−H activation, 1,n‐hydrogen atom transfer, and transition‐metal‐catalyzed carbene/nitrene transfer.
Visible light photoredox catalysis enables direct γ- C(sp3)–H alkylation of saturated aliphatic carbonyl compounds. Electron-deficient alkenes are used as the coupling partners in this reaction. ...Distinguished site selectivity is controlled by the predominant 1,5-hydrogen atom transfer of an amidyl radical generated in situ.
Unlike other fluoride-based caries preventive agents, silver diamine fluoride (SDF) can simultaneously prevent and arrest coronal and root dentine caries. The profound clinical success of SDF has ...drawn many clinicians and researchers to study the mechanism of SDF in arresting dentine caries. This critical review discusses how silver and fluoride contribute to caries arrest, in terms of their effects on bacteria as well as on the mineral and organic content of dentine. Silver interacts with bacterial cell membrane and bacterial enzymes, which can inhibit bacterial growth. Silver can also dope into hydroxyapatite and have an antibacterial effect on silver-doped hydroxyapatite. Furthermore, silver is also a strong inhibitor of cathepsins and inhibits dentine collagen degradation. Early studies proposed that silver hardened caries lesions by forming silver phosphate. However, recent studies found that little silver phosphate remained on the arrested dentine lesion. The principal silver precipitate was silver chloride, which could not contribute to the significant hardening of the arrested lesions. On the other hand, fluoride enhances mineral formation by forming fluorohydroxyapatite with reduced solubility. A significant increase in microhardness occurs with an elevated level of calcium and phosphorus but not silver on the surface layer of the arrested dentine caries lesion following SDF treatment. Fluoride also inhibits matrix metalloproteinases activities and therefore inhibits dentine collagen degradation. The combination of silver and fluoride in an alkaline solution has a synergistic effect in arresting dentine caries. The alkaline property of SDF provides an unfavorable environment for collagen enzyme activation. Understanding the mechanisms of SDF in arresting dentine caries helps clinicians to develop appropriate protocols for the use of SDF in clinical care.
We report measurements of the vacuum ultraviolet (VUV) emission spectra of a microwave-discharge hydrogenflow lamp (MDHL), a common tool in astrochemistry laboratories working on ice VUV ...photoprocessing. The MDHL provides hydrogen Ly- alpha (121.6 nm) and H sub(2) molecular emission in the 110-180 nm range. We show that the spectral characteristics of the VUV light emitted in this range, in particular the relative proportion of Ly- alpha to molecular emission bands, strongly depend on the pressure of H sub(2) inside the lamp, the lamp geometry (F type versus T type), the gas used (pure H sub(2) versus H sub(2) seeded in He), and the optical properties of the window used (MgF sub(2) versus CaF sub(2)). These different configurations are used to study the VUV irradiation of CO ice at 14 K. In contrast to the majority of studies dedicated to the VUV irradiation of astrophysical ice analogs, which have not taken into consideration the emission spectrum of the MDHL, our results show that the processes induced by photons in CO ice from a broad energy range are different and more complex than the sum of individual processes induced by monochromatic sources spanning the same energy range, as a result of the existence of multistate electronic transitions and discrepancy in absorption cross sections between parent molecules and products in the Ly- alpha and H sub(2) molecular emission ranges.
Chemically modified biomacromoleculesi.e., proteins, nucleic acids, glycans, and lipidshave become crucial tools in chemical biology. They are extensively used not only to elucidate cellular ...processes but also in industrial applications, particularly in the context of biopharmaceuticals. In order to enable maximum scope for optimization, it is pivotal to have a diverse array of biomacromolecule modification methods at one’s disposal. Chemistry has driven many significant advances in this area, and especially recently, numerous novel visible-light-induced photochemical approaches have emerged. In these reactions, light serves as an external source of energy, enabling access to highly reactive intermediates under exceedingly mild conditions and with exquisite spatiotemporal control. While UV-induced transformations on biomacromolecules date back decades, visible light has the unmistakable advantage of being considerably more biocompatible, and a spectrum of visible-light-driven methods is now available, chiefly for proteins and nucleic acids. This review will discuss modifications of native functional groups (FGs), including functionalization, labeling, and cross-linking techniques as well as the utility of oxidative degradation mediated by photochemically generated reactive oxygen species. Furthermore, transformations at non-native, bioorthogonal FGs on biomacromolecules will be addressed, including photoclick chemistry and DNA-encoded library synthesis as well as methods that allow manipulation of the activity of a biomacromolecule.
Summary
Background
Cases of severe drug hypersensitivity, demonstrating a variable spectrum of cutaneous and systemic involvement, are reported under various names, especially drug reaction with ...eosinophilia and systemic symptoms (DRESS). Case definition and overlap with other severe cutaneous adverse reactions (SCAR) are debated.
Objectives
To analyse the spectrum of signs and symptoms of DRESS and distribution of causative drugs in a large multicentre series.
Patients and methods
RegiSCAR, a multinational registry of SCAR, prospectively enrolled 201 potential cases from 2003 to mid‐2009. Using a standardized scoring system, 117 cases were validated as showing probable or definite DRESS.
Results
The male/female ratio was 0·80; females were borderline significantly younger than males. Next to the ubiquitous exanthema, the main features were eosinophilia (95%), visceral involvement (91%), high fever (90%), atypical lymphocytes (67%), mild mucosal involvement (56%) and lymphadenopathy (54%). The reaction was protracted in all but two patients; two patients died during the acute phase. Drug causality was plausible in 88% of cases. Antiepileptic drugs were involved in 35%, allopurinol in 18%, antimicrobial sulfonamides and dapsone in 12% and other antibiotics in 11%. The median time interval after drug intake was 22 days (interquartile range 17–31) for all drugs with (very) probable causality, with differences between drugs.
Conclusion
This prospective observational study supports the hypothesis that DRESS is an original phenotype among SCAR in terms of clinical and biological characteristics, causative drugs, and time relation. The diversity of causative drugs was rather limited, and mortality was lower than that suggested by prior publications.
What's already known about this topic?
DRESS is a hypersensitivity reaction, characterized by a variable combination of symptomatic and asymptomatic features.
What does this study add?
DRESS is an original phenotype among severe cutaneous adverse reactions in terms of clinical and biological characteristics, drugs, time relation, and course.
Besides eosinophilia, other haematological abnormalities are frequent.
The diversity of causative drugs is rather limited.
The prodromal period is quite variable, introducing risk of protopathic bias, especially for antibiotics and NSAIDs.
This 30-mo randomized clinical trial compared the effectiveness of 2 concentrations (12% or 38%) of silver diamine fluoride (SDF) and 2 periodicity of application (once or twice a year) in arresting ...cavitated dentin caries in primary teeth. Children aged 3 to 4 y who had at least 1 active cavitated caries lesion were enrolled and randomly allocated into 4 groups for intervention. Group 1 had 12% SDF applied annually (every 12 mo), group 2 had 12% SDF applied semiannually (every 6 mo), group 3 had 38% SDF applied annually, and group 4 had 38% SDF applied semiannually. Clinical examinations were performed semiannually in kindergarten by a single examiner to investigate whether the SDF-treated caries became arrested. A total of 888 children with 4,220 decayed tooth surfaces received SDF application at baseline, and 799 (90.0%) children with 3,790 surfaces (89.8%) were evaluated at the 30-mo examination. The caries arrest rates were 55.2%, 58.6%, 66.9%, and 75.7% for groups 1, 2, 3, and 4, respectively (P < 0.001). Caries treated with 38% SDF had a higher chance of becoming arrested than those treated with 12% SDF (odds ratio OR, 1.98; 95% confidence interval CI, 1.51–2.60, P < 0.001). The interaction between frequency of SDF application and visible plaque index (VPI) score was significant (P = 0.017). Among those children who received annual SDF application, children with a higher VPI score had a lower chance to have their caries become arrested (OR, 0.59, 95% CI, 0.49–0.72). In conclusion, SDF at a concentration of 38% is more effective than that of 12% in arresting active caries in primary teeth. For children with poor oral hygiene, caries arrest rate of SDF treatment can be increased by increasing the frequency of application from annually to semiannually (ClinicalTrials.gov NCT02385474).
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