Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry

Background: Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. Method: A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time <3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. Results: During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in patient samples, but not in spiked calibrator samples. Comparison with LC-MS/MS disclosed a significant bias with higher concentrations measured by LC-MS/MS, while UPLC-MS/MS showed excellent agreement with the commercially available HPLC method. In the LC-MS/MS procedure, comparably wide and left side shifted peaks were noticed. This could be ascribed to in-source fragmentation of conjugate metabolites during electrospray ionisation. Precursor and product ion scans confirmed the assumption that the additional compounds are posaconazole glucuronides. Reducing the cone voltage led to disappearance of the glucuronide peaks. Slight modification of the LC-MS/MS method enabled separation of the main interference, leading to significantly reduced deviation. Conclusions: These results highlight the necessity to reliably eliminate interference from labile drug metabolites for correct TDM results, either by sufficient separation or selective MS conditions. The presented UPLC-MS/MS method provides a reliable and fast assay for TDM of posaconazole. Clin Chem Lab Med 2010; 48:1723-31

Theranos revisited: the trial and lessons learned

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Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease

BACKGROUND: Sphingomyelin (SM) is the major phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; thus, high levels of SM may promote atherogenesis. METHODS: We investigated in a median follow up of 6.0 years the association of SM with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) in stable and unstable patients, and its relation to other marker of atherosclerosis in 1,102 patients with angiographically documented CAD and 444 healthy controls. RESULTS AND DISCUSSION: Logistic regression analysis showed that SM categorized by median was associated with an elevated risk for CAD (HR 3.2, 95%CI 2.5–4.0, p < 0.05). SM levels were correlated with apoB (r = 0.34) and triglyceride levels (r = 0.31). In patients with stable angina (n = 614), SM categorized by median was not related to incidence of a combined endpoint (cardiovascular death and myocardial infarction) (p = 0.844 by Log-rank test). However, in patients with acute coronary syndrome (n = 488), elevated SM was related to the combined endpoint (p < 0.05 by Log-rank test), also in a multivariate Cox regression analysis including potential confounders (HR 1.8, 95%CI 1.0–3.3, p < 0.05). CONCLUSION: The results of our study reveal that 1) human plasma SM levels are a risk factor for CAD; 2) the pro-atherogenic property of plasma SM might be related to metabolism of apoB-containing or triglyceride-rich lipoproteins; and 3) plasma SM levels are a predictor for outcome of patients with acute coronary syndrome

Cost evaluation of PAGE-B risk score guided HCC surveillance in patients with treated chronic hepatitis B

BACKGROUND The PAGE-B score (Platelet Age GEnder–HBV) selects chronic hepatitis B (cHB) patients showing no relevant 5-year risk for hepatocellular carcinoma (HCC). We, therefore, explored potential cost reduction following the introduction of a PAGE-B tailored ultrasound screening in a single center cohort of cHB patients receiving stable antiviral therapy. METHODS cHB patients attending throughout the year 2018 were documented. Patients eligible for PAGE-B score were classified into high (≥18 points), intermediate (10–17 points) and low (≤9 points) HCC risk groups. Patients of the low HCC risk group could postpone HCC screening to reduce HCC screening expenses. Full costs for hepatic ultrasound were assessed. RESULTS Throughout the year cHB patients (n = 607) attended our clinic, which included PAGE-B eligible patients (n = 227, 37.4%) of whom n = 94 (15.8%) were allocated to the low HCC risk group. Sonographic HCC screening during a median exam time of 12.4 min (IQR 9.2–17.2) resulted in total costs of 22.82 Euro/exam. Additional opportunistic expenses caused by patient’s lost earnings or productivity were 15.6–17.5 €/exam and 26.7 €/exam, respectively. Following a PAGE-B tailored HCC screening at our institution annual full costs for cHB patients could be reduced by 15.51%, which equals a cost reduction by 1.91% for our total sonography unit. In comparison, 1.35% up to 7.65% of HBV-infected patients of Caucasian descent could postpone HCC screening according to population-based estimates from Germany. CONCLUSIONS PAGE-B risk score adapted screening for HCC is an efficient and cost neutral tool to reduce costs for sonography in Caucasian patients with chronic hepatitis B receiving antiviral treatment

The burdens of poverty during the COVID-19 pandemic

Background: Individuals living at-risk-of-poverty have an increased risk of poor mental health. The pandemic and its societal impacts might have negative effects especially on this group widening the gap between rich and poor and also exacerbate gender gaps, which in turn might impact social cohesion. Aim: The objective of this longitudinal study was to determine if people living at-risk-of-poverty were more vulnerable to economic and psychosocial impacts of the pandemic and showed poorer mental health. Moreover, gender differences were analyzed. Method: We drew data from a sample of N = 10,250 respondents of two time points (T1 starting from October 2020, T2 starting from March 2021) of the Gutenberg COVID-19 Study. We tested for differences between people living at-risk-of-poverty and more affluent respondents regarding economic impacts, psychosocial stressors, as well as depressiveness, anxiety and loneliness, by comparing mean and distributional differences. To test for significant discrepancy, we opted for chi-square- and t-tests. Results: The analysis sample compromised N = 8,100 individuals of which 4,2% could be classified as living at-risk-of-poverty. 23% of respondents living at-risk-of-poverty had a decrease in income since the beginning of the pandemic–twice as many as those not living at-risk-of-poverty, who reported more often an increase in income. Less affluent individuals reported a decrease in working hours, while more affluent people reported an increase. Between our survey time points, we found a significant decrease in these economic impacts. Gender differences for economic changes were only found for more affluent women who worked more hours with no change in income. Less affluent respondents were more impacted by psychosocial stressors, depressiveness, anxiety, and loneliness. Gender differences were found particularly with regard to care responsibilities. Discussion: Our results indicate a widening in the gap between the rich and the poor at the beginning of the pandemic. Gender differences concerning economic changes affect more affluent women, but women in both income groups are more burdened by care responsibilities, which might indicate a heightened resurgence of gender role in times of crisis. This increase in inequality might have impacted social cohesion

The ophthalmic branch of the Gutenberg Health Study: study design, cohort profile and self-reported diseases

This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS).The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling.Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively.The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties

Frequency of cataract surgery and its impact on visual function : results from the German Gutenberg Health Study

PURPOSE To determine the frequency of cataract surgery in Germany and to evaluate its impact on visual function in an adult population. METHODS The population-based Gutenberg Health Study was conducted in Germany with its baseline examination between 2007 and 2012 and a 5-year follow-up examiantion. An ophthalmological examination including slit-lamp examination, ocular biometry, and Scheimpflug imaging was carried out. Overall and age-specific frequencies of unilateral and bilateral cataract surgery within 5 years were computed including the 95% confidential intervals [95%-CI]. Association analyses were conducted to determine social and ocular associated factors using multivariable logistic regression analysis. Vision-related quality of life was assessed using NEI VFQ-25. RESULTS A total of 10,544 people aged 35 to 74 years were bilateral phakic at baseline and had information on lens status at the 5-year examination. Of these, 168 had unilateral cataract surgery (1.6% [1.4–1.9%]), and 448 had bilateral cataract surgery (4.2% [3.9–4.7%]) in the following 5 years. The frequency of cataract surgery increased with age: 45–54-year-old subjects had twice as often cataract surgery (in at least on eye: OR = 2.32) than at age 35–44 years. The frequency further strongly increases with age (55–64 years: OR = 10.5; 65–74 years: OR = 43.8, p < 0.001). Subjects with glaucoma were more likely to have cataract surgery (OR = 2.52, p < 0.001). Visual function increased when undergoing bilateral cataract surgery. CONCLUSIONS The frequency of cataract surgery is low at younger ages and increases up to 26% at age 70–74 years. Persons with glaucoma are more likely to undergo cataract surgery at population-based level in Germany

The ophthalmic branch of the Gutenberg Health Study : study design, cohort profile and self-reported diseases

PURPOSE: This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). METHODS: The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. RESULTS: Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. CONCLUSIONS: The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties

Peripapillary retinal nerve fiber layer profile in relation to refractive error and axial length : results from the Gutenberg Health Study

Purpose: To investigate the retinal nerve fiber layer profile measured by optical coherence tomography and its relation to refractive error and axial length. Methods: The Gutenberg Health Study is a population-based study in Mainz, Germany. At the five-year follow-up examination, participants underwent optical coherence tomography, objective refraction and biometry. Peripapillary retinal nerve fiber layer (pRNFL) was segmented using proprietary software. The pRNFL profiles were compared between different refraction groups and the angle between the maxima, i.e., the peaks of pRNFL thickness in the upper and lower hemisphere (angle between the maxima of pRNFL thickness [AMR]) was computed. Multivariable linear regression analysis was carried out to determine associations of pRNFL profile (AMR) including age, sex, optic disc size, and axial length in model 1 and spherical equivalent in model 2. Results: A total of 5387 participants were included. AMR was 145.3° ± 23.4° in right eyes and 151.8° ± 26.7° in left eyes and the pRNFL profile was significant different in the upper hemisphere. The AMR decreased with increasing axial length by −5.86°/mm (95% confidence interval [CI]: [−6.44; −5.29], P < 0.001), female sex (−7.61°; 95% CI: [−8.71; −6.51], P < 0.001) and increased with higher age (0.08°/year; 95% CI: [0.03; 0.14], P = 0.002) and larger optic disc size (2.29°/mm2; 95% CI: [1.18; 3.41], P < 0.001). In phakic eyes, AMR increased with hyperopic refractive error by 2.60°/diopters (dpt) (95% CI: [2.33; 2.88], P < 0.001). Conclusions: The pRNFL profiles are related to individual ocular and systemic parameters. Translational Relevance: Biometric parameters should be considered when pRNFL profiles are interpreted in diagnostics, i.e., in glaucoma