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Background In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. Aim To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). Methods Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. Results A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). Conclusion In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR. [ABSTRACT FROM AUTHOR]

[C3H3N2]+ ions have been generated under electron impact conditions from some monosubstituted pyrazoles C3H3N2R. Collision-induced dissociation (CID) mass spectra of deuterium-labelled precursors suggest that the majority of the [C3H3N2]+ ions formed from 1-nitro- and 4-bromo-pyrazole retain their cyclic structure, whereas the ions from 3(5)-bromopyrazole are mainly linear. This is confirmed by the relative values observed for the overall cross-sections for CID and for ion loss. An isotope effect of the order of 1.5-1.9 has been found for the collision-induced loss of H˙ from [C3H3N2]+, generated from 3(5)- and 4-bromopyrazole. [ABSTRACT FROM AUTHOR]

Collisionally activated dissociation (CAD) mass spectra sometimes appear to be identical in spite of the fact that the precursor ion structures are known to differ. It is shown that determination of the experimental overall cross-section for collisionally activated decomposition yields valuable extra information. After applying it to examples of known structure, [C4H5N]+·, [C5H5N]+· and [C5H5O]+, it is used to study a more complex problem, that of [C6H6]+· ions from four isomeric precursors. [ABSTRACT FROM AUTHOR]

Mass spectra of the three isomeric vinylimidazoles have been compared and the structures of the fragment ions [C3H4N2]+· and [C5H5N2]+ have been investigated by collisionally activated dissociation mass spectrometry. The greater part of the non-decomposing ions m/ z 68 from 2-vinylimidazole and from 2-imidazolecarboxylic acid methyl ester, and a minor part of this ion formed from the free acid, all have the same structure: the imidazole ring system, with hydrogens at both nitrogen atoms but none at C(2). An analogous structure, with an ethyl group at C(2), is proposed for the m/ z 93 ion from 2-vinylimidazole. [ABSTRACT FROM AUTHOR]

A standard procedure for recording and correcting collisionally activated dissociation mass spectra is proposed, and used to distinguish between the C4H5N+˙ ions formed from hydroxy- and amino-pyridines after loss of CO and HCN, respectively. It is concluded that these ions are cyclic. From the 4-isomers the 3 H-pyrrole ion is formed whereas from 2-hydroxypyridine the 1 H-pyrrole ion is formed. In the other cases, mixtures of 2 H- and either 1 H- or 3 H-pyrrole ions are generated, depending on the nature of the precursor. [ABSTRACT FROM AUTHOR]

The ion/molecule reactions of allyl cations and 2-methoxyallyl cations with vinyl methyl ether, 1-chloro-2-ethoxyethene and 1,2-dimethoxyethene are discussed in terms of [2+3] cycloaddition reactions. Deuterium labelling of the cations has been used for the study of the reaction mechanisms. The appearance of various product ions in these ion/molecule reactions lead to the suggestion that in reactions of allyl cations with alkenes non-cyclic [C5H5]+ product ions are formed preferentially, but that in reactions of 2-methoxyallyl cations with alkenes a significant part of the product ions are methoxycyclopentadienyl cations. These observations are ascribed to the stabilizing effect of the methoxy group with regard to the positive charge in the product ions. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate how Scheimpflug-derived parameters of eyes with Fuchs endothelial corneal dystrophy (FECD) are influenced by Descemet membrane endothelial keratoplasty (DMEK) depending on FECD severity and the presence of subclinical edema., Methods: A retrospective cohort study including 115 eyes (115 patients) that underwent DMEK for FECD and a control group of 27 eyes with nonpathological corneas was conducted. Preoperative and 6 months postoperative Scheimpflug imaging was used to analyze pachymetry, presence of tomographic features (loss of isopachs/displacement of the thinnest point/focal posterior depression), and corneal backscatter. FECD severity was based on the modified Krachmer scale and the absence/presence of subclinical edema., Results: Scheimpflug-derived pachymetry, tomographic, and corneal backscatter parameters were correlated with FECD severity, and all changed from preoperatively to postoperatively (all P < 0.05). Postoperative central corneal thickness, anterior and posterior corneal backscatter, and presence of focal posterior depression remained different from the control group (all P < 0.05). Of eyes without preoperative clinical edema (n = 75), 18.7% showed 0 or 1 tomographic feature (no edema group) and 82.4% had 2 or 3 features (subclinical edema group). Compared with the control group, postoperative best-corrected visual acuity for the "no edema" group did not differ (0.03 ± 0.12 vs. -0.02 ± 0.08 logarithm of the minimum angle of resolution, P = 0.150) but was worse for the subclinical edema group (0.06 ± 0.08 vs. -0.02 ± 0.08 logarithm of the minimum angle of resolution, P = 0.001)., Conclusions: For eyes without preoperative edema, more parameters reversed back to 'normal' levels than for eyes with (sub)clinical edema. Although most analyzed parameters correlated with FECD severity, corneal tomography might be best suited for objective grading of disease severity to aid in surgical decision-making., Competing Interests: G. R. J. Melles is a consultant for DORC International/Dutch Ophthalmic USA and SurgiCube International. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Face masks are widely used in dental practices, but little is known about the potential adverse effects of wearing a face mask, covering the mouth-and-nose area, on the condition of the eyes. During COVID-19 times, more eye-related complaints, such as irritated, burning or dry eyes, have been reported and observed as a result of the (mandatory) use of face masks, The combination of wearing a face mask and working on a computer appears to also cause more dry-eye complaints. Symptoms such as headache, double vision, blurry vision, irritated red eyes and/or dry eyes are often diagnosed under the collective term asthenopia, also called 'eye strain' in the literature in English. These work-related complaints are often accepted as 'normal', especially because they develop during the day. During the COVID-19 period, more knowledge has been gained about the use of face masks, face shields and eye health. It is therefore possible to consider whether personal protection with a face mask in the dental practice can cause eye-related complaints.

In order to expand hepatitis C virus (HCV) screening, a change in the diagnostic paradigm is warranted to improve accessibility and decrease costs, such as utilizing dried blood spot (DBS) collection. In our study, blood from 68 patients with chronic HCV infection was spotted onto DBS cards and stored at the following temperatures for one week: -80 °C, 4 °C, 21 °C, 37 °C, and alternating 37 °C and 4 °C; to assess whether temperature change during transportation would affect sensitivity. Sample was eluted from the DBS cards and tested for HCV antibodies (HCV-Ab) and HCV core antigen (core-Ag). HCV-Abs were detected from 68/68 DBS samples at -80 °C, 4 °C, 21 °C, and 67/68 at 37 °C and alternating 37 °C and 4 °C. Sensitivity of core-Ag was as follows: 94% (-80 °C), 94% (4 °C), 91% (21 °C), 93% (37 °C), and 93% (37 °C/4 °C). Not only did temperature not greatly affect sensitivity, but sensitivities are higher than previously reported, and support the use of this assay as an alternative to HCV RNA. We then completed a head-to-head comparison ( n = 49) of venous versus capillary samples, and one versus two DBS. No difference in core-Ag sensitivity was observed by sample type, but there was an improvement when using two spots. We conclude that HCV-Abs and core-Ag testing from DBS cards has high diagnostic accuracy and could be considered as an alternative to HCV RNA in certain settings.

Background: Direct-acting antivirals for chronic hepatitis C (HCV) infection have reduced the need for on-treatment HCV RNA monitoring. We assessed the accuracy and cost implications of using HCV core antigen testing to replace HCV RNA testing for confirmation of diagnosis, on-treatment monitoring, and determination of sustained virological response (SVR)., Methods: In a retrospective screening cohort study, de-identified residual serum from unselected samples were obtained from commercial laboratories in Ontario, Canada. Samples from each 5-year age-sex band from birth years 1945-74 collected from Aug 1, 2014, to Feb 28, 2015, were included. All samples that tested positive for HCV antibodies, and 10% of samples that tested negative for HCV antibodies, were tested for HCV core antigen and HCV RNA. A retrospective clinical cohort study was also done using blood samples from patients with confirmed HCV infection collected at four tertiary academic centres: one in Canada, two in Germany, and one in the USA. For assessment of SVR, we included samples from patients who started direct-acting antiviral-based treatment (excluding telaprevir and boceprevir) with or without peginterferon, ribavirin, or both, from Jan 1, 2014, to March 31, 2015. To ensure inclusion of adequate numbers for analysis, patients who relapsed after any treatment regimen were included. Serum samples included in the study were from baseline, week 4 on-treatment (only for patients treated with direct-acting antivirals), end of treatment, and week 12 or 24 of follow-up. The sensitivity and specificity of core antigen testing as a diagnostic tool was assessed in the screening cohort, using HCV RNA as a reference. The sensitivity and specificity of core antigen testing as well as its concordance with HCV RNA testing in the clinical cohort was assessed at baseline, week 4 on-treatment, and at weeks 12 or 24 after the end of treatment in patients undergoing therapy with direct-acting antivirals. The cost-effectiveness of core antigen testing with and without confirmatory HCV RNA testing for negative samples was also assessed., Findings: From 10 006 samples in the screening cohort, 75 of 80 viraemic (HCV RNA-positive) samples tested positive for HCV core antigen (sensitivity 94%, 95% CI 86-98), and none of the 993 HCV RNA-negative samples tested positive for HCV core antigen (specificity 100%, 95% CI 94-100). The five viraemic samples that tested negative for HCV core antigen had low corresponding HCV RNA concentrations. In the clinical cohort, two (1%) of 202 baseline samples tested negative for HCV core antigen; one had a low HCV RNA concentration (468 IU/mL), the other had a high HCV RNA concentration (>2 000 000 IU/mL). By week 4 of treatment, HCV core antigen concentrations decreased in all patients but were not predictive of SVR. Although there was good concordance between HCV RNA and HCV core antigen results at 12 weeks after the end of treatment (r=0·97; p<0·0001), three of the 148 patients who achieved SVR at 12 weeks tested HCV core antigen positive. 12 weeks after the end of treatment, HCV core antigen was undetectable in one (1%) of 71 samples from patients who were identified as having relapsed according to HCV RNA detection. On-treatment and end-of-treatment testing of core antigen or HCV RNA provided little clinical value. The use of HCV core antigen testing as a confirmatory diagnostic strategy was cost saving relative to HCV RNA testing, with a reduction of CAD$0·29-3·70 per patient screened depending on whether HCV RNA testing was used to confirm HCV core antigen-negative results., Interpretation: These data support the use of HCV core antigen testing to document HCV viraemia in a cost-saving diagnostic algorithm. In a treatment setting, HCV core antigen testing can be used instead of HCV RNA testing for diagnosis and documentation of treatment adherence, but it might not be adequate to determine SVR. This approach might improve access to care, particularly in low-income and middle-income countries., Funding: Abbott Diagnostics and Toronto Centre for Liver Disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Concern has arisen about the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs). To identify patients at risk for HCC, we evaluated serum levels of immune mediators before, during, and after DAA treatment of HCV infection. Our study included 13 patients who developed HCC within 18 months after treatment (3 with HCC recurrence and 10 with new HCC) and 10 patients who did not develop HCC (controls), within at least 24 months of treatment (median, 26 months). We identified a set of 12 immune mediators (cytokines, growth factors, and apoptosis markers) whose levels were significantly higher in serum before DAA treatment of patients who eventually developed de novo HCC compared with controls. A panel of 9 cytokines, measured in serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21), identified patients who developed de novo HCC with an area under the receiver operating characteristic curve value higher than 0.8. Further analyses of changes in levels of inflammatory cytokines during DAA treatment also provides important information about HCV-induced carcinogenesis and the effects of DAAs., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background & Aims: Direct-acting antivirals (DAAs) have revolutionized treatment for patients with chronic hepatitis C virus (HCV) infection, leading to a high rates of sustained virologic response. This study assessed the real-world safety and effectiveness of DAA-based antiviral therapy for the treatment of cirrhotic patients with chronic HCV infection., Methods: This international, multicenter cohort study included all consecutive patients with chronic HCV infection and cirrhosis who underwent antiviral therapy with second-generation DAAs. Data on all patients were analyzed to assess treatment response. Predictors of hepatic decompensation during antiviral therapy were assessed using Cox proportional hazards regression analyses., Results: Until June 2015, 433 cirrhotic patients with chronic HCV infection started DAA-based treatment. Their mean age was 57.8 (±8.7) years, 277 (64.0%) patients were male, and 114 (26.3%) had a Child-Pugh (CP) score of B/C cirrhosis. The sustained virologic response rate at 12 weeks was similar among patients with a CP score of A (261 of 304 [85.9%]) and a CP score of B/C (83 of 101 [82.2%]; P = .37). A baseline albumin level less than 35 g/L (hazard ratio [HR], 3.11; 95% confidence interval [CI], 1.23-7.84; P = .005), baseline MELD score of 14 or higher (HR, 1.63; 95% CI, 1.03-2.61; P = .037), and HCV genotype 3 (HR, 2.05; 95% CI, 1.09-3.88; P = .033) were associated independently with hepatic decompensation during antiviral treatment among patients with a CP score of B/C., Conclusions: This large cohort study showed that therapy is safe and effective in patients with compensated (CP score of A) cirrhosis. For patients with decompensated (CP score of B/C) cirrhosis, albumin level less than 35 g/L, MELD score of 14 or greater, and HCV genotype 3 are important risk factors for hepatic decompensation during DAA-based treatment. Therefore, these patients require close monitoring during antiviral therapy or treatment should be deferred until after transplantation., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Mucosal-associated invariant T (MAIT) cells comprise a subpopulation of T cells that can be activated by bacterial products and cytokines to produce IFN-γ. Since little is known on MAIT cells during HCV infection, we compared their phenotype and function in comparison to HIV and HCV/HIV co-infected patients, and determined the effect of IFN-α-based and direct-acting antiviral therapy on MAIT cells of HCV patients., Methods: Blood samples from patients with chronic HCV (CHCV), virologically suppressed HIV, acute HCV/HIV co-infection (AHCV/HIV) and healthy individuals were examined by flowcytometry for phenotype and function of MAIT and NK cells., Results and Conclusions: Compared to healthy individuals, the frequency of CD161+Vα7.2+ MAIT cells was significantly decreased in patients with CHCV, HIV and AHCV/HIV co-infection. CD38 expression on MAIT cells was increased in AHCV/HIV patients. MAIT cells were responsive to IFN-α in vitro as evidenced by enhanced frequencies of IFN-γ producing cells. IFN-α-based therapy for CHCV decreased the frequency of IFN-γ+ MAIT cells, which was still observed 24 weeks after successful therapy. Importantly, even after successful IFN-α-based as well as IFN-α-free therapy for CHCV, decreased frequencies of MAIT cells persisted. We show that the frequencies of MAIT cells are reduced in blood of patients with CHCV, HIV and in AHCV/HIV co-infection compared to healthy individuals. Successful therapy for CHCV did not normalize MAIT cell frequencies at 24 weeks follow up. The impact of HIV and HCV infection on the numbers and function of MAIT cells warrant further studies on the impact of viral infections and the antimicrobial function of MAIT cells.

Purpose: To investigate the agreement in dry eye care management between general practitioners (GPs) and optometrists in the Netherlands., Methods: A web-based survey was used to investigate the agreement in symptoms associated with dry eye, causes of developing dry eye, and investigative techniques used in practice, between GPs and optometrists. Additional questions surveyed knowledge of the latest research, and co-management of dry eye disease in primary healthcare. The anonymised questionnaire contained 16 forced-choice questions with Likert scales, and was sent to 1471 general medical practitioners and 870 registered optometrists. The response data was stored on an online database, and was converted directly to text format for analysis using SPSS 21 statistical analysis software., Results: 138 optometrists and 93 GPs responded to the survey (Cronbach α=0.885, optometrists, and 0.833, GPs). Almost no agreement was found for all the questions: a statistically significant difference (Chi-square p<0.0001) was found between the optometrists and GPs in the use of investigative techniques, associating symptoms, causes of dry eye (p>0.0001), and dry eye symptoms, except for 'burning sensation of the eye' and 'irritation of the eye' as agreed symptoms, and agreement that dry eye is an age-related disease., Conclusions: As the optometrist and the GP are the gatekeepers for secondary healthcare, the fundamental differences in the methods of investigation and interpretation of dry eye-related symptoms, the possible cause of developing dry eye disease, and the therapy given by GPs and optometrists in the Netherlands, may have a significant impact on consistency of patient care., (Copyright © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Ageing is an important factor that affects visual functioning. In the Netherlands the average age in healthcare facilities is on increase. The current study is a preliminary literature review regarding the influence of light on the visual functioning of the aging workforce and their related tasks.

Environmental factors, such as high airflow and low relative humidity, are known to promote dry eye symptoms during reading tasks in office workers. These symptoms are associated with an adverse impact on daily activities at work. This study reports on the relationship between eye symptoms and environmental factors in 294 employees at one office location.

In the discovery of new enzymes genomic and cDNA expression libraries containing thousands of differential clones are generated to obtain biodiversity. These libraries need to be screened for the activity of interest. Removing so-called empty and redundant clones significantly reduces the size of these expression libraries and therefore speeds up new enzyme discovery. Here, we present a sensitive, generic workflow for high throughput screening of successful microbial protein over-expression in microtiter plates containing a complex matrix based on mass spectrometry techniques. MALDI-LTQ-Orbitrap screening followed by principal component analysis and peptide mass fingerprinting was developed to obtain a throughput of ∼12,000 samples per week. Alternatively, a UHPLC-MS(2) approach including MS(2) protein identification was developed for microorganisms with a complex protein secretome with a throughput of ∼2000 samples per week. TCA-induced protein precipitation enhanced by addition of bovine serum albumin is used for protein purification prior to MS detection. We show that this generic workflow can effectively reduce large expression libraries from fungi and bacteria to their minimal size by detection of successful protein over-expression using MS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Here, we report the identification and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F(po) = 4%) and possessed off-target activity at the hERG ion channel (pK(i) = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC(50) = 8.0; hERG pK(i) < 4; F(po) = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.

Recently, a new class (often referred to as SPRMs: selective progesterone receptor modulators) of progesterone receptor ligands with mixed agonist/antagonist properties has been described. Such compounds are envisaged, for example, as treatment for endometriosis, uterine fibroids, and leiomyomas. Existing SPRMs include Asoprisnil 1 and Uliprisnil acetate 2. In our hands, however, these compounds proved to have a predominantly or exclusively antagonistic in vitro profile, which may make this type of compound less attractive, for example, as contraceptives. We therefore aimed at a class of mixed-profile compounds that would show a more evenly balanced agonist/antagonist profile. A novel class of 11beta-[4-(heteroaryl)phenyl]-substituted pregnanes was identified that displayed the desired balance. Contrary to known SPRMs, this novel class of MPP (mixed-profile progestagen) was found to have a truly mixed activity, including a sizeable agonist component.

Anemotaxis in the predatory mite Phytoseiulus persimilis (both well-fed and starved), has previously been studied on a wire grid under slight turbulent airflow conditions yielding weak, yet distinct, gradients in wind speed and odour concentration (Sabelis and Van der Weel 1993). Such conditions might have critically influenced the outcome of the study. We repeated these experiments, under laminar airflow conditions on a flat surface in a wind tunnel, thereby avoiding variation in wind speed and odour concentration. Treatments for starved and well-fed mites were (1) still-air without herbivore-induced plant volatiles (HIPV) (well-fed mites only), (2) an HIPV-free air stream, and (3) an air stream with HIPV (originating from Lima bean plants infested by two-spotted spider mites, Tetranychus urticae). Well-fed mites oriented in random directions in still-air without HIPV. In an air stream, starved mites always oriented upwind, whether plant odours were present or not. Well-fed mites oriented downwind in an HIPV-free air stream, but in random directions in an air stream with HIPV. Only under the last treatment our results differed from those of Sabelis and Van der Weel (1993).