Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis

AIM: To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. METHODS: Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-nai¨ve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. RESULTS: One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P = 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). CONCLUSION: In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR

Photochemically produced SO2 in the atmosphere of WASP-39b

S.-M.T. is supported by the European Research Council advanced grant EXOCONDENSE (no. 740963; principal investigator: R. T. Pierrehumbert). E.K.H.L. is supported by the SNSF Ambizione Fellowship grant (no. 193448). X.Z. is supported by NASA Exoplanet Research grant 80NSSC22K0236. O.V. acknowledges funding from the ANR project ‘EXACT’ (ANR-21-CE49-0008-01), from the Centre National d’Études Spatiales (CNES) and from the CNRS/INSU Programme National de Planétologie (PNP). L.D. acknowledges support from the European Union H2020-MSCA-ITN-2109 under grant no. 860470 (CHAMELEON) and the KU Leuven IDN/19/028 grant Escher. This work benefited from the 2022 Exoplanet Summer Program at the Other Worlds Laboratory (OWL) at the University of California, Santa Cruz, a programme financed by the Heising-Simons Foundation. T.D. is an LSSTC Catalyst Fellow. J.K. is an Imperial College Research Fellow. B.V.R. is a 51 Pegasi b Fellow. L.W. is an NHFP Sagan Fellow. A.D.F. is an NSF Graduate Research Fellow.Photochemistry is a fundamental process of planetary atmospheres that regulates the atmospheric composition and stability1. However, no unambiguous photochemical products have been detected in exoplanet atmospheres so far. Recent observations from the JWST Transiting Exoplanet Community Early Release Science Program2,3 found a spectral absorption feature at 4.05 μm arising from sulfur dioxide (SO2) in the atmosphere of WASP-39b. WASP-39b is a 1.27-Jupiter-radii, Saturn-mass (0.28 MJ) gas giant exoplanet orbiting a Sun-like star with an equilibrium temperature of around 1,100 K (ref. 4). The most plausible way of generating SO2 in such an atmosphere is through photochemical processes5,6. Here we show that the SO2 distribution computed by a suite of photochemical models robustly explains the 4.05-μm spectral feature identified by JWST transmission observations7 with NIRSpec PRISM (2.7σ)8 and G395H (4.5σ)9. SO2 is produced by successive oxidation of sulfur radicals freed when hydrogen sulfide (H2S) is destroyed. The sensitivity of the SO2 feature to the enrichment of the atmosphere by heavy elements (metallicity) suggests that it can be used as a tracer of atmospheric properties, with WASP-39b exhibiting an inferred metallicity of about 10× solar. We further point out that SO2 also shows observable features at ultraviolet and thermal infrared wavelengths not available from the existing observations.Publisher PDFPeer reviewe

Stellen de voedingsstoffen en hun verpakkingen een probleem voor de volksgezondheid? Welke analytische aanpak kunnen we best gebruiken.

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Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex(R)), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex(R)

Evaluative conditioning: missing, presumed dead

Although research into evaluative conditioning (EC) has progressed considerably over the past 30 years, there have been some doubts about the strength and reliability of conditioning effects ¿ especially when visual stimuli are used. Partly this has been due to well-documented methodological debates and empirical evidence of alternative causes of apparent learning (Field & Davey, 1999). The seeds of doubt have undoubtedly been nurtured, also by the numerous informal reports of researchers failing to obtain EC effects ¿ even when replicating previously successful paradigms. This has led some to talk of boundary conditions that could enhance or eliminate the effects in EC experiments (De Houwer, Baeyens, Vansteenwegen & Eelen, 2000). This paper summarises 12 experiments that have explored this elusive phenomenon with mixed results (even when replicating past procedures). These various experiments are used to attempt to draw conclusions about what boundary conditions might exist for evaluative conditioning