Publications by authors named "Andreas Gleiss"

97 Publications

Comparison of Iron Dosing Strategies in Patients Undergoing Long-Term Hemodialysis: A Randomized Controlled Trial.

Clin J Am Soc Nephrol 2021 Oct 1;16(10):1512-1521. Epub 2021 Sep 1.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Background And Objectives: Whether iron supplementation in patients on hemodialysis could be delivered by less frequent but higher single doses compared with the currently more common higher-frequency schedules of lower single iron doses is unknown.

Design, Setting, Participants, & Measurements: We carried out an open-label, randomized, controlled noninferiority trial over 40 weeks in patients on prevalent hemodialysis (=142). We administered in total 2 g iron as 100 mg iron sucrose biweekly in a continuous (20 × 100 mg) fashion or 500 mg ferric carboxymaltose every 10 weeks in a periodic (4 × 500 mg) fashion. The primary end point was the change in hemoglobin at week 40 from baseline with a noninferiority margin of -0.8 g/dl. Secondary end points were changes in ferritin, transferrin, transferrin saturation, and erythropoiesis-stimulating agent use.

Results: In total, 108 patients completed the study. At 40 weeks, hemoglobin changed by -0.27 g/dl (95% confidence interval, -0.64 to 0.09) in the iron sucrose arm and by -0.74 g/dl (95% confidence interval, -1.1 to -0.39) in the ferric carboxymaltose arm compared with baseline. Noninferiority was not established in the per-protocol population as hemoglobin changes compared with baseline differed by -0.47 g/dl (95% confidence interval, -0.95 to 0.01) in the ferric carboxymaltose arm compared with the iron sucrose arm. Proportional changes from baseline to week 40 differed by -31% (98.3% confidence interval, -52 to -0.1) for ferritin, by 1% (98.3% confidence interval, -7 to 10) for transferrin, and by -27% (98.3% confidence interval, -39 to -13) for transferrin saturation in the ferric carboxymaltose arm compared with the iron sucrose arm. Erythropoiesis-stimulating agent dosing did not differ between groups. The overall number of adverse events was similar; however, more infections were observed in the iron sucrose arm.

Conclusions: An equal cumulative dose of ferric carboxymaltose administered less frequently did not meet noninferiority for maintaining hemoglobin levels compared with iron sucrose administered more frequently.

Clinical Trial Registry Name And Registration Number: Comparison Study of Two Iron Compounds for Treatment of Anemia in Hemodialysis Patients (COPEFER), NCT02198495.
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http://dx.doi.org/10.2215/CJN.03850321DOI Listing
October 2021

Degrees of necessity and of sufficiency: Further results and extensions, with an application to covid-19 mortality in Austria.

Stat Med 2021 06 4;40(14):3352-3366. Epub 2021 May 4.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

The purpose of this paper is to extend to ordinal and nominal outcomes the measures of degree of necessity and of sufficiency defined by the authors for dichotomous and survival outcomes in a previous paper. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. The degrees of necessity and sufficiency, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic regression models; the measures, however, do not require any particular model. In addition, we study in detail the relationship between the proposed measures and the related explained variation summary for dichotomous outcomes, which are the common root for the developments for ordinal, nominal, and survival outcomes. We introduce and analyze the Austrian covid-19 data, with the aim of quantifying effects of age and other potentially prognostic factors on covid-19 mortality. This is achieved by standard regression methods but also in terms of the newly proposed measures. It is shown how they complement the toolbox of prognostic factor studies, in particular when comparing the importance of prognostic factors of different types. While the full model's degree of necessity is extremely high (0.933), its low degree of sufficiency (0.179) is responsible for the low proportion of explained variation (0.193).
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http://dx.doi.org/10.1002/sim.8961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207017PMC
June 2021

Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy.

Nat Commun 2021 03 22;12(1):1816. Epub 2021 Mar 22.

Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability. Intriguingly, NfL was a significant predictor to discriminate non-converting AMN from cohorts later developing CALD. In CALD, markedly amplified NfL levels reflected brain lesion severity. In rare cases, atypically low NfL revealed a previously unrecognized smoldering CALD disease course with slowly progressive myelin destruction. Upon halt of brain demyelination by hematopoietic stem cell transplantation, NfL gradually normalized. Together, our study reveals that blood NfL reflects inflammatory activity and progression in CALD patients, thus constituting a potential surrogate biomarker that may facilitate clinical decisions and therapeutic development.
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http://dx.doi.org/10.1038/s41467-021-22114-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985512PMC
March 2021

Brief High Oxygen Concentration Induces Oxidative Stress in Leukocytes and Platelets: A Randomized Cross-over Pilot Study in Healthy Male Volunteers.

Shock 2021 Sep;56(3):384-395

Department of Anesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria.

Background: Supplemental oxygen is administered routinely in the clinical setting to relieve or prevent tissue hypoxia, but excessive exposure may induce oxidative damage or disrupt essential homeostatic functions. It is speculated that oxidative stress in leukocytes and platelets may contribute to vascular diseases by promoting inflammation and cell aggregation.

Methods: In this pilot study 30 healthy male volunteers (18-65 years) were exposed to high oxygen concentration (non-rebreather mask, 8 L/min, 100% O2) and synthetic air (non-rebreather mask, 8 L/min, 21% O2) in a cross-over design for 20 min at a 3-week interval. Venous blood samples were obtained at baseline and 1, 3, and 6 h postintervention. Primary outcome was generation of reactive oxygen species in leukocytes as measured by the redox-sensitive fluorescent dye dihydrorhodamine 123. Additional outcomes were oxidative stress in platelets and platelet aggregation as measured by thromboelastography (ROTEM) and Multiplate analyses.

Findings: High oxygen exposure induced oxidative stress in leukocytes as evidenced by significantly higher mean fluorescence intensity (MFI) compared with synthetic air at 3 h postintervention (47% higher, P = 0.015) and 6 h postintervention (37% higher, P = 0.133). Oxidative stress was also detectable in platelets (33% higher MFI in comparison with synthetic air at 6 h, P = 0.024; MFI 20% above baseline at 3 h, P  = 0.036; 37% above baseline at 6 h, P = 0.002). ROTEM analyses demonstrated reduced mean clotting time 1 h postintervention compared with baseline (-4%, P = 0.049), whereas there were no significant effects on other surrogate coagulation parameters.

Conclusion: Clinically relevant oxygen exposure induces oxidative stress in leukocytes and platelets, which may influence the immune and clotting functions of these cells.
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http://dx.doi.org/10.1097/SHK.0000000000001728DOI Listing
September 2021

Circulating bioactive sclerostin levels in an Austrian population-based cohort.

Wien Klin Wochenschr 2021 Feb 5. Epub 2021 Feb 5.

Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Background: Circulating serum sclerostin levels are supposed to give a good estimation of the levels of this negative regulator of bone mass within bone. Most studies evaluating total serum sclerostin found different levels in males compared to females and in older compared to younger subjects. Besides an ELISA detecting total sclerostin an ELISA determining bioactive sclerostin has been developed. The aim of this study was to investigate serum levels of bioactive sclerostin in an Austrian population-based cohort.

Methods: We conducted a cross-sectional observational study in 235 healthy subjects. Using the bioactive ELISA assay (Biomedica) bioactive sclerostin levels were evaluated.

Results: Serum levels of bioactive sclerostin were higher in men than in women (24%). The levels correlated positively with age (r = 0.47). A positive correlation could also be detected with body mass index and bone mineral density.

Conclusion: Using the ELISA detecting bioactive sclerostin our results are consistent with data in the literature obtained by different sclerostin assays. The determination of sclerostin concentrations in peripheral blood thus appears to be a robust parameter of bone metabolism.
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http://dx.doi.org/10.1007/s00508-021-01815-0DOI Listing
February 2021

Diagnostic Value of Serum Acid-Labile Subunit Alone and in combination with IGF-I and IGFBP-3 in the Diagnosis of Growth Hormone Deficiency.

Horm Res Paediatr 2020 18;93(6):371-379. Epub 2020 Dec 18.

Comprehensive Center for Pediatrics, Division of Pulmology, Allergology and Endocrinology, Medical University of Vienna, Vienna, Austria,

Background: The acid-labile subunit (ALS) is a crucial factor in the tertiary complex. IGF-I and IGFBP-3 are routinely measured during the diagnostic work-up for growth hormone deficiency (GHD). The aim of the study is to evaluate the relevance of serum ALS as an additional biomarker in the diagnosis of GHD.

Methods: Ninety-one children undergoing standard diagnostic work-up for GHD were included in this retrospective study. Inclusion criteria were evidence-based auxological cutoffs, IGF-I and IGFBP-3 <-2 SDS at first presentation, at least 1 growth hormone (GH) stimulation test, and IGF-I, IGFBP-3, and ALS measurements on the same day. Statistical analysis was performed by ROC as well as by odds ratio calculations.

Results: Forty-seven of 90 participants presented with peak GH values under the cutoff of 7 ng/mL. AUC from a model containing only IGF-I was 0.76 and 0.68 when using only ALS. A model containing IGF-I, IGFBP-3, and ALS (AUC = 0.77) did not improve the result compared to the combination of IGF-I/IGFBP-3 (0.77) or IGF-I/ALS (0.76). Furthermore, the variation in the outcome (GH peak
Conclusion: Determination of serum ALS alone or in combination with IGF-I and IGFBP-3 did not improve definition of biochemical GHD in a cohort of short children and adolescents with suspected growth disorder. However, performance of IGFBP-3 in this context was not statistically superior to ALS.
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http://dx.doi.org/10.1159/000512336DOI Listing
October 2021

Influence of socioeconomic status on cognitive outcome after childhood arterial ischemic stroke.

Dev Med Child Neurol 2021 04 18;63(4):465-471. Epub 2020 Dec 18.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Aim: To determine whether socioeconomic status (SES) is a stronger predictor for cognitive outcome after childhood arterial ischemic stroke compared to clinical factors.

Method: We investigated perceptual reasoning, executive functions, language, memory, and attention in 18 children and adolescents (12 males, six females, median age at testing 13y 4mo, range 7y-17y 5mo) after arterial ischemic stroke; collected sociodemographic information (education of parents, household income); and used clinical information (initial lesion volume, residual lesion volume, age at stroke, time since stroke). Linear regression models were used to investigate the potential influence of SES and clinical parameters on cognitive abilities.

Results: SES had a moderate effect on all cognitive outcome parameters except attention by explaining 41.9%, 37.9%, 38.0%, and 22.5% of variability in perceptual reasoning, executive functions, language, and memory respectively. Initial lesion volume was the only clinical parameter that showed moderate importance on cognitive outcome (33.1% and 25.6% of the variability in perceptual reasoning and memory respectively). Overall, SES was a stronger predictor of cognitive outcome than clinical factors.

Interpretation: Future paediatric studies aiming at clinical predictors of cognitive outcome should control their analyses for SES in their study participants. The findings of the present study further point to the need for more attention to the treatment of children with low SES.

What This Paper Adds: Socioeconomic status (SES) explains up to 42% of variance in cognitive outcome after childhood arterial ischemic stroke. SES is a stronger predictor of outcome than clinical factors.
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http://dx.doi.org/10.1111/dmcn.14779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986130PMC
April 2021

Use of Clopidogrel, Prasugrel, or Ticagrelor and Patient Outcome after Acute Coronary Syndrome in Austria from 2015 to 2017.

J Clin Med 2020 Oct 23;9(11). Epub 2020 Oct 23.

Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Background: Dual antiplatelet therapy improves patient outcome after acute coronary syndrome (ACS), but prescription differences of P2Y12 inhibitor treatments exist. The aim of the present investigation was to study the long-term utilization and patient outcomes of clopidogrel, prasugrel, and ticagrelor in patients with ACS from 2015 to 2017 in Austria.

Methods: Data from 13 Austrian health insurance funds of patients with a hospital discharge diagnosis of ACS for the years 2015 to 2017 were analyzed. The primary end point was to investigate the recurrence of ACS or death.

Results: Of 49,124 P2Y12 inhibitor-naive patients with a hospital discharge diagnosis of ACS, 25,147 subjects filled a P2Y12 inhibitor prescription within 30 days after the index event. Of these patients, 10,626 (42.9%) subjects had a prescription for clopidogrel, 4788 (19.3%) for prasugrel, and 9383 (37.8%) for ticagrelor. Ticagrelor was the most frequently prescribed P2Y12 inhibitor among patients below 70 years old, and clopidogrel in those aged ≥70 years. Occurrence of an endpoint was highest in elderly patients. After adjustment for age, sex, and pre-existing medication as proxy for comorbidity, the hazard ratio for ACS or death for prasugrel vs. clopidogrel of 0.70 (95% CI: 0.61; 0.79) was similar to that of ticagrelor vs. clopidogrel (0.70; 95% CI: 0.64; 0.77).

Conclusion: Prescription of ticagrelor or prasugrel after ACS were associated with a lower risk of ACS recurrence or death compared to clopidogrel.
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http://dx.doi.org/10.3390/jcm9113398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690682PMC
October 2020

Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer.

Oncol Lett 2020 Nov 17;20(5):252. Epub 2020 Sep 17.

Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, A-1090 Vienna, Austria.

Genetic variations in the organic-anion-transporting polypeptide (OATP)-encoding solute carrier of organic anions () genes can promote cancer development and progression. The overexpression of solute carrier organic anion transporter family member 4A1 (OATP4A1), a transporter for steroid hormones, prostaglandins, and bile acids, has been previously associated with tumor recurrence and progression in colorectal cancer (CRC). Therefore, the present study aimed to investigate the association between 2 frequent single nucleotide polymorphisms (SNPs) in (rs34419428, R70Q; rs1047099G, V78I) and CRC predisposition. Following restriction fragment length polymorphism-PCR analysis in 178 patients with CRC [Union for International Cancer Control (UICC) stage I/II] and 65 healthy controls, no significant difference was observed in allele frequency and the number of heterozygous/homozygous individuals between the groups. Notably, the R70Q minor allele was identified to be associated with the V78I minor allele in the genome. Comparing of the individual genotypes of CRC patients to clinical data, including sex, UICC-stage and relapse revealed no increased risk for CRC. In addition, the OATP4A1 immunoreactivity assay in paraffin-embedded CRC and adjacent non-tumorous mucosa sections, examined using quantitative microscopy image analysis, did not reveal any association with these polymorphisms. No significant differences were observed in the expression levels, localization, and sodium fluorescein transport capacity among the OATP4A1 variants, which was studied using functional assays in Sf9-insect and A431 tumor cells overexpressing the 2 single and a double mutant OATP4A1 SNP variants. These results suggested that the 2 most frequent polymorphisms located in the first intracellular loop of OATP4A1 do not associate with CRC predisposition and tumor recurrence. They are unlikely to affect the outcome of CRC in patients.
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http://dx.doi.org/10.3892/ol.2020.12115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509609PMC
November 2020

Hypofractionated stereotactic photon radiotherapy of choroidal melanoma: 20-year experience.

Acta Oncol 2021 Feb 24;60(2):207-214. Epub 2020 Sep 24.

Department of Ophthalmology, Medical University of Vienna, Vienna, Austria.

Background: To evaluate the long-term results after hypofractionated stereotactic photon radiotherapy (SRT) in patients with choroidal melanoma treated between 1997 and 2016.

Material And Methods: A total of 335 patients (183 male and 152 female) with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated with linear accelerator-based SRT at the Medical University of Vienna. All patients received five fractions with either 10, 12 or 14 Gy per fraction. A complete ophthalmic examination including visual acuity and measurement of the tumor base and height using standardized A- and B-scan ultrasonography was performed every 3 months in the first 2 years, every 6 months until 5 years and yearly thereafter. Early and late adverse side effects were assessed at every follow-up visit.

Results: The median overall follow-up was 78.6 months (39.1 to 113.7 months). Local tumor control was 95.4% after 10 and 12 years, respectively. Fifty-four patients developed metastatic disease, and 31 died during the follow-up. Mean visual acuity decreased from 0.55 Snellen at baseline to 0.05 Snellen at the last individual follow-up. Ischemic retinopathy (192/335cases) and optic neuropathy (174/335cases) were the most common radiogenic side effects, followed by radiogenic cataract ( = 127), neovascular glaucoma ( = 71) and corneal epithelium defects ( = 49). Enucleation was performed in 54 patients mostly due to neovascular glaucoma ( = 41) or tumor recurrence ( = 10) during the study period. The eye retention rate was 79.7% after 10 and 12 years.

Conclusion: Hypofractionated stereotactic photon radiotherapy showed a high rate of local tumor control for choroidal melanoma and an acceptable rate of radiogenic side effects.
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http://dx.doi.org/10.1080/0284186X.2020.1820572DOI Listing
February 2021

The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans.

J Clin Med 2020 Aug 14;9(8). Epub 2020 Aug 14.

Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.

Anemia in chronic kidney disease (CKD) is an almost universal complication of this condition. Fibroblast growth factor 23 (FGF23), a key-player in mineral metabolism, is reportedly associated with anemia and hemoglobin levels in non-dialysis CKD patients. Here, we sought to further characterize this association while taking into account the biologically active, intact fraction of FGF23, iron metabolism, and erythropoietin (EPO). Hemoglobin, EPO, iron, and mineral metabolism parameters, including both intact and c-terminal-FGF23 (iFGF23 and cFGF23, respectively) were measured cross-sectionally in 225 non-dialysis CKD patients (stage 1-5, median eGFR: 30 mL/min./1.73m) not on erythropoiesis stimulating agents or intravenous iron therapy. Statistical analysis was performed by multiple linear regression. After adjustment for eGFR and other important confounders, only cFGF23 but not iFGF23 was significantly associated with hemoglobin levels and this association was largely accounted for by iron metabolism parameters. cFGF23 but not iFGF23 was also associated with mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), again in dependence on iron metabolism parameters. Similarly, EPO concentrations were associated with cFGF23 but not iFGF23, but their contribution to the association of cFGF23 with hemoglobin levels was marginal. In pre-dialysis CKD patients, the observed association of FGF23 with hemoglobin seems to be restricted to cFGF23 and largely explained by the iron status.
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http://dx.doi.org/10.3390/jcm9082640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463779PMC
August 2020

Effects of roflumilast on arterial stiffness in COPD (ELASTIC): A randomized trial.

Respirology 2021 02 28;26(2):153-160. Epub 2020 Jul 28.

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Otto-Wagner-Hospital and Sigmund Freud University, Medical School, Vienna, Austria.

Background And Objective: Cardiovascular risk is substantially increased in patients with COPD and can be quantified via arterial stiffness. The PDE-IV inhibitor roflumilast revealed a potential reduction of COPD-related cardiovascular risk. We aimed to investigate the effects of roflumilast on arterial stiffness by quantification of pulse wave velocity (PWV) in stable COPD.

Methods: In this randomized placebo-controlled trial, 80 COPD patients received roflumilast or placebo for 24 weeks. The primary outcome was the change in cf-PWV. Secondary outcomes comprised markers of vascular function (e.g. Aix and RHI), systemic inflammation (e.g. IL-6 and TNF-α) and clinical characteristics of COPD (e.g. CAT and 6MWT).

Results: A total of 33 and 34 patients completed the roflumilast and placebo arm, respectively (age, median (IQR): 64.5 (61-69.5) vs 64.5 (56-72) years; FEV , median (IQR): 34.5 (25.5-48.6) vs 35.3 (27-46.8) % predicted; 6MWT, median (IQR): 428 (340-558) vs 456 (364-570) m). Change from baseline PWV did not show a significant difference between roflumilast and placebo (+5.0 (95% CI: -2.0 to +13.0) vs 0.0 (95% CI: -7.0 to +7.0)%, P = 0.268). Roflumilast did not improve markers of vascular function or systemic inflammation. We observed a significant improvement in change from baseline 6MWT with roflumilast versus placebo (+53.0 (95% CI: +19.1 to +86.9) vs -0.92 (95% CI: -35.1 to +33.3) m, P = 0.026).

Conclusion: Our study revealed no beneficial effects of roflumilast on arterial stiffness. Further studies are needed to test a potential improvement of exercise capacity with roflumilast in COPD.
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http://dx.doi.org/10.1111/resp.13914DOI Listing
February 2021

Circulating Myostatin Levels Decrease Transiently after Implantation of a Hip Hemi-Arthroplasty.

Gerontology 2020 26;66(4):393-400. Epub 2020 May 26.

Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.

Introduction: Muscle and bone metabolism are both important for the healing of fractures and the regeneration of injured muscle tissue. The aim of this investigation was to evaluate myostatin and other regulating factors in patients with hip fractures who underwent hemi-arthroplasty.

Methods: Serum levels of myostatin (MSTN), follistatin (FSTN), dickkopf-1 (Dkk1), and periostin (PSTN) as well as markers of bone turnover were evaluated in patients with hip fractures before surgery and twice in the 2 weeks after surgery. These parameters were also evaluated in age- and gender-matched subjects without major musculoskeletal injury.

Results: MSTN was transiently reduced; its opponent FSTN was transiently increased. Dkk1, the negative regulator of bone mass, and PSTN, a marker of subperiosteal bone formation, increased after surgery. With regard to markers of bone turnover, resorption was elevated during the entire period of observation whereas the early bone formation marker N-terminal propeptide of type I collagen was elevated 12 days after surgery.

Conclusions: Unexpectedly, MSTN, a negative regulator of muscle growth, was reduced after surgery compared with before surgery. As musculoskeletal markers are altered during bone healing, they do not reflect general bone metabolism after fracture or joint arthroplasty. This is important because many elderly patients receive treatment for osteoporosis.
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http://dx.doi.org/10.1159/000507731DOI Listing
September 2020

Does the tutors' academic background influence the learning objectives in problem-based learning?

GMS J Med Educ 2020 17;37(1):Doc8. Epub 2020 Feb 17.

Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria.

Problem-based learning (PBL) is an essential element of the curriculum of the Medical University of Vienna (MUV) and is performed in an eight steps model with: clarifying, defining, analysing, shifting & sorting, identifying learning objectives, going to learn and coming back to talk and feedback. With an annual intake of up to 740 students the MUV has to recruit PBL tutors from various academic backgrounds including undergraduate near-peer students. Therefore, we were interested to see whether a tutor's academic background had an influence on the resulting PBL sessions as reflected by the percentage of learning objectives (LOs) which were actually achieved in relation to the intended LOs. For each PBL session "intended learning objectives" (ILOs) were defined. ILOs were communicated to all tutors by means of PBL session guides in order to provide homogenous learning opportunities to all students. However, it was not mandatory to reach all ILOs. The PBL coordination regarded a range of two thirds to three quarters of ILOs as a desirable goal. For analysis we retrieved data concerning ILOs, characteristics of tutors and PBL groups from the institution's PBL quality assurance system. From 2012-2014, 216 PBL groups were facilitated by 106 tutors with different academic backgrounds. On average, 70.8% (95% CI: 69.2-72.5%) of the ILOs were achieved; MUV clinicians reached 74.3% (70.8-77.8%), MUV non-clinicians 74.2% (71.7-76.6%), external faculty (clinicians and non-clinicians) 68.6% (64.4-72.8%), and near-peer students 64.7% (61.8-67.7%). Statistically significant differences were found between near-peer students and MUV clinicians (p<.001) as well as MUV non-clinicians (p<.001). ILOs were reached within a satisfactory range. However, groups taught by near-peer students reached significantly fewer ILOs than groups taught by MUV faculty tutors. This finding raises the question whether tutor training for near-peer students should be intensified. Also, further research is needed to explore the group dynamics of student-led PBL groups.
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http://dx.doi.org/10.3205/zma001301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105758PMC
October 2020

TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin.

Pain 2020 07;161(7):1532-1541

Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

Tissue acidosis due to ischemia occurs under several pathological conditions and is believed to contribute to pain in these circumstances. TRPV1, TRPA1, and ASICs are known to be sensitive to acidic pH. Addressing their possible role in acidosis perception, the respective antagonists BCTC, A-967079, and amiloride were injected in the volar forearm skin of 32 healthy volunteers. To investigate possible redundancies between channels, a full-factorial study design was used. Injections were performed in a prerandomized, double-blind, and balanced design. Each injection included a three-step pH protocol from pH 7.0 over pH 6.5 to pH 6.0 with a step duration of 90 seconds. Pain was reported by volunteers on a numerical scale every 10 seconds during injections. Confirming the primary hypothesis, the combination of all 3 antagonists reduced acid-induced pain at pH 6.0. Because of the full-factorial design, it could be concluded that BCTC alone, but not A-967079 or amiloride, or any combination thereof, was responsible for the observed effects, suggesting TRPV1 as primary sensor for pH 6.0-induced pain. Surprisingly, A-967079 even enhanced pain induced by pH 6.0. In cultured mouse dorsal root ganglion neurons, TPRV1 dependence of pH 6-induced calcium responses could be confirmed. Responses of hTRPV1 to acidic stimulation showed a maximum around pH6, providing an explanation for the pH-dependent inhibition by BCTC. A-967079 sensitizes pH responses is a TRPA1-responsive dorsal root ganglion neuron population, and a direct effect of A-967079 on hTRPA1 and hTRPV1 was excluded. In conclusion, inhibiting TRPV1-mediated acidosis-induced pain could be a symptomatic and potentially also a disease-modifying approach.
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http://dx.doi.org/10.1097/j.pain.0000000000001848DOI Listing
July 2020

The role of prescription drugs in female overactive bladder syndrome-A population-wide cohort study.

Pharmacoepidemiol Drug Saf 2020 02 5;29(2):189-198. Epub 2019 Dec 5.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria.

Purpose: Overactive bladder (OAB) syndrome has severe effects on quality of life. Certain drugs are known risk factors for OAB but have not been investigated in a population-wide cohort. The objective of this study was to investigate the role of prescription drugs in the etiology of the OAB.

Methods: Retrospective cohort study using a population-wide database of 4 185 098 OAB-naïve women followed Strengthening the Reporting of Observational Studies in Epidemiology guidelines. We investigated the subscription use of anticholinergic medication and 188 chemical substances, which are suspected triggers for OAB (trigger medications [TMs]). We hypothesized a relationship between the prescription for one or more TM and the prescription for anticholinergic medication against OAB (marker medication [MM]).

Results: The use of MM in Austria increased from 2009 to 2012 on average by 0.025 percentage points per year (95% confidence interval [CI]: 0.015-0.036). In December 2012, 1 in 123 women filled a prescription for any MM, equaling an average utilization of 0.84%. The relative risk of filling a prescription for a MM 6 months after filling a prescription for a TM was 2.70 (95% CI: 2.64-2.77). All investigated medication classes showed a higher risk for the prescription for MM. Medication from classes "genitourinary system and sex hormones" and "systemic anti-infectives" caused the highest increase in risk (109% and 89%, respectively). Prescriptions for class "cardiovascular system" caused the lowest increase in the risk (15%).

Conclusion: Certain prescription medications are a significant risk factor for the need to take anticholinergic medication as a consequence.
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http://dx.doi.org/10.1002/pds.4920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027558PMC
February 2020

Short-time effect of intravitreal injections on retinal vascular oxygenation and vessel diameter in patients with diabetic macular oedema or neovascular age-related macular degeneration.

Acta Ophthalmol 2020 May 25;98(3):e301-e308. Epub 2019 Oct 25.

Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria.

Purpose: To investigate the short-time effect of intravitreal injections (IVI) of the vascular endothelial growth factor inhibitors ranibizumab and aflibercept on retinal arterial and venous oxygen saturation (SO2a and SO2v), arteriovenous oxygen saturation difference (AVD) and vessel diameter (VDa and VDv) in patients with diabetic macular oedema (DME) and patients with choroidal neovascularization (CNV) due to age-related macular degeneration.

Methods: Uncontrolled prospective observational study in 100 eyes. Retinal vessel oxygen saturation and diameters were assessed using a retinal oximeter before and minutes after IVI of ranibizumab or aflibercept.

Results: 40 eyes with CNV and 34 eyes with DME were included in the analysis. At baseline, SO2a and SO2v were significantly higher in DME (p = 0.043 and p = 0.009, respectively). After IVI, SO2a significantly decreased in CNV and DME eyes by 2.6% (p = 0.016) and 4.6% (p = 0.002) and SO2v decreased by 14.0% (p = 0.004) and 12.4% (p = 0.017), respectively. However, a significant increase in AVD was only found in CNV (15.7%, p = 0.001). VDa decreased significantly only in DME by 5.7% (p = 0.010). No medication-specific disease effect was found and vice versa.

Conclusions: The observed changes can be interpreted as signs of increased metabolic demand during the physiological stress after an IVI. The abnormal arterial constriction and the abolished increase in AVD seen only in eyes with DME indicate an impairment of vascular autoregulation and oxygen distribution and a reduced neuroretinal metabolism in the diabetic retina with a significant impact on inner retinal oxygen consumption shortly after IVI.
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http://dx.doi.org/10.1111/aos.14276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216886PMC
May 2020

Prognostic Value of Right Ventricular Dysfunction and Tricuspid Regurgitation in Patients with Severe Low-Flow Low-Gradient Aortic Stenosis.

Sci Rep 2019 10 10;9(1):14580. Epub 2019 Oct 10.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

Long and mid-term data in Low-Flow Low-Gradient Aortic Stenosis (LFLG-AS) are scarce. The present study sought to identify predictors of outcome in a sizeable cohort of patients with LFLG-AS. 76 consecutive patients with LFLG-AS (defined by a mean gradient <40 mmHg, an aortic valve area ≤1 cm and an ejection fraction ≤50%) were prospectively enrolled and followed at regular intervals. Events defined as aortic valve replacement (AVR) and death were assessed and overall survival was determined. 44 patients underwent AVR (10 transcatheter and 34 surgical) whilst intervention was not performed in 32 patients, including 9 patients that died during a median waiting time of 4 months. Survival was significantly better after AVR with survival rates of 91.8% (CI 71.1-97.9%), 83.0% (CI 60.7-93.3%) and 56.3% (CI 32.1-74.8%) at 1,2 and 5 years as compared to 84.3% (CI 66.2-93.1%), 52.9% (CI 33.7-69.0%) and 30.3% (CI 14.6-47.5%), respectively, for patients managed conservatively (p = 0.017). The presence of right ventricular dysfunction (HR 3.47 [1.70-7.09]) and significant tricuspid regurgitation (TR) (HR 2.23 [1.13-4.39]) independently predicted overall mortality while the presence of significant TR (HR 3.40[1.38-8.35]) and higher aortic jet velocity (HR 0.91[0.82-1.00]) were independent predictors of mortality and survival after AVR. AVR is associated with improved long-term survival in patients with LFLG-AS. Treatment delays are associated with excessive mortality, warranting urgent treatment in eligible patients. Right ventricular involvement characterized by the presence of TR and/or right ventricular dysfunction, identifies patients at high risk of mortality under both conservative management and after AVR.
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http://dx.doi.org/10.1038/s41598-019-51166-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787042PMC
October 2019

Retinal and Corneal Neurodegeneration and Their Association with Systemic Signs of Peripheral Neuropathy in Type 2 Diabetes.

Am J Ophthalmol 2020 01 19;209:197-205. Epub 2019 Sep 19.

Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria. Electronic address:

Purpose: To determine the extent of retinal and corneal neurodegeneration and investigate the association with intraepidermal neuronal loss and diabetic peripheral neuropathy (DPN) in type 2 diabetes.

Design: Prospective, cross-sectional study.

Methods: Single-center study of 94 patients with type 2 diabetes patients (157 eyes), divided into groups: the groups without diabetic retinopathy (DR) (n = 68); the nonproliferative DR (NPDR) group (n = 48); and the proliferative DR (PDR) group (n = 41). Patients were imaged with optical coherence tomography and confocal microscopy for macular and peripapillary neuroretinal layer thicknesses and corneal nerve length/density, respectively. Distal leg skin punch biopsies and 2 neurological scores were used to depict intraepidermal nerve fiber density (IENFD) and clinical DPN.

Results: Among neuroretinal layers, solely the peripapillary retinal nerve fiber layer was decreased in PDR (96 μm; 95% confidence interval [CI], 92-100 μm) versus no DR (103 μm; 95% CI, 100-106 μm) eyes and only after exclusion of outliers (P = .01). Corneal nerve fiber length and density were statistically significantly reduced in the NPDR group (23.0 mm/mm; 95% CI, 20.0-26.00 mm/mm and 14.3 mm; 95% CI, 14.5-16.63 mm, respectively) and the PDR group (18.6 mm/mm; 95% CI, 14.9-22.30 mm/mm and 11.7 mm; 95% CI, 10.2-13-3 mm, respectively) versus the no DR group (25.5 mm/mm; 95% CI, 23.3-27.70 mm/mm and 15.6 mm; 95% CI, 14.5-16.6 mm, respectively), and in the PDR versus the NPDR group. IENFD was statistically significantly reduced in the NPDR (2.0/mm; 95% CI, 1.4-2.7/mm) and PDR stage (1.4/mm; 95% CI, 0.9-2.1/mm) versus in eyes without DR (3.6/mm; 95% CI, 2.9-4.6/mm). A low correlation between intraepidermal and corneal fiber loss was found with both neurological scores (P < .05).

Conclusions: Retinal neurodegenerative changes may develop independently of the microvascular alterations defining DR. Corneal and intraepidermal neuronal loss is more pronounced in advanced stages of DR, indicating a positive severity correlation between DR and DPN.
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http://dx.doi.org/10.1016/j.ajo.2019.09.010DOI Listing
January 2020

Quantifying degrees of necessity and of sufficiency in cause-effect relationships with dichotomous and survival outcomes.

Stat Med 2019 10 6;38(23):4733-4748. Epub 2019 Aug 6.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

We suggest measures to quantify the degrees of necessity and of sufficiency of prognostic factors for dichotomous and for survival outcomes. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. Necessity and sufficiency can be seen as the two faces of causation, and this symmetry and equal relevance are reflected by the suggested measures. The measures provide an approximate, in some cases an exact, multiplicative decomposition of explained variation as defined by Schemper and Henderson for censored survival and for dichotomous outcomes. The measures, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic or Cox regression models; the measures, however, do not require any particular model. The measures of the degree of necessity implicitly generalize the established attributable fraction or risk for dichotomous prognostic factors and dichotomous outcomes to continuous prognostic factors and to survival outcomes. In a setting with multiple prognostic factors, they provide marginal and partial results akin to marginal and partial odds and hazard ratios from multiple logistic and Cox regression. Properties of the measures are explored by an extensive simulation study. Their application is demonstrated by three typical real data examples.
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http://dx.doi.org/10.1002/sim.8331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771968PMC
October 2019

Quantifying degrees of necessity and of sufficiency in cause-effect relationships with dichotomous and survival outcomes.

Stat Med 2019 10 6;38(23):4733-4748. Epub 2019 Aug 6.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

We suggest measures to quantify the degrees of necessity and of sufficiency of prognostic factors for dichotomous and for survival outcomes. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. Necessity and sufficiency can be seen as the two faces of causation, and this symmetry and equal relevance are reflected by the suggested measures. The measures provide an approximate, in some cases an exact, multiplicative decomposition of explained variation as defined by Schemper and Henderson for censored survival and for dichotomous outcomes. The measures, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic or Cox regression models; the measures, however, do not require any particular model. The measures of the degree of necessity implicitly generalize the established attributable fraction or risk for dichotomous prognostic factors and dichotomous outcomes to continuous prognostic factors and to survival outcomes. In a setting with multiple prognostic factors, they provide marginal and partial results akin to marginal and partial odds and hazard ratios from multiple logistic and Cox regression. Properties of the measures are explored by an extensive simulation study. Their application is demonstrated by three typical real data examples.
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http://dx.doi.org/10.1002/sim.8331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771968PMC
October 2019

Effects of high-intensity interval training on platelet function in cardiac rehabilitation: a randomised controlled trial.

Heart 2020 01 17;106(1):69-79. Epub 2019 Jul 17.

Institute of Physiology, Medical University of Vienna, Wien, Austria.

Objective: To compare effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on platelet function in patients undergoing cardiac rehabilitation, as hyper-reactive platelets are involved in atherogenesis and atherothrombosis.

Methods: In this single-centre parallel group randomised controlled trial, male patients after an acute coronary syndrome under dual antiplatelet therapy performed MICT or HIIT+MICT for 12 weeks. Main outcome was platelet reactivity measured by the half-maximal concentration (EC) of platelet agonist thrombin receptor-activating peptide-6 (TRAP-6) in terms of P-selectin expression. EC was determined at baseline, after 6 and 12 weeks, each time at physical rest and on exertion.

Results: 82 patients were randomised to MICT or HIIT+MICT. Mean (95% CI) baseline ECvalues at physical rest were 6.7 µM (6.3 µM to 7.0 µM) TRAP-6. After 6/12 weeks, 36/33 MICT and 34/28 HIIT+MICT patients were examined. HIIT+MICT patients had 0.9 µM (0.4 µM to 1.4 µM)/0.5 µM (-0.1 µM to 1.0 µM) higher ECvalues than MICT ones, and the propensity of their platelets to form aggregates with monocytes was significantly lower after 12 weeks. Short-term strenuous physical exertion was generally associated with platelet activation and an ECreduction of 0.7 µM (0.6 µM to 0.8 µM). HIIT+MICT patients tended to be fitter after 12 weeks. No serious harms were observed.

Conclusions: Including HIIT in cardiac rehabilitation seems to confer additional benefits compared with MICT alone, which should be confirmed in clinical trials with hard endpoints. Exertion-induced platelet activation and hyper-reactivity occur despite dual antiplatelet therapy.

Trial Registration Number: NCT02930330; Results.
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http://dx.doi.org/10.1136/heartjnl-2019-315130DOI Listing
January 2020

Body mass index and height in 11- to 16-year-old Austrian students attending two different school types with divergent socioeconomic backgrounds.

Wien Klin Wochenschr 2019 Jul 1;131(13-14):337-346. Epub 2019 Apr 1.

Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

Background: In developed countries high socioeconomic status (SES) is associated with lower body mass index (BMI) and greater height compared with low SES.

Aim: To investigate differences in BMI/height in adolescent students from two different school types with divergent SES backgrounds.

Methods: A total of 4579 students (2313 female), aged 11-16 years, attending either low SES vocation-directed secondary schools (VSS) or high SES secondary academic schools (AHS) were compared. Potential differences were investigated using ANCOVA models including sex, school type, geographical region and degree of urbanicity.

Results: At all ages between 11 and 16 years the BMI of students attending VSS was significantly higher than that of students attending AHS (mean +0.87kg/m). The AHS students were on average taller (mean +0.93cm; p<0.001), without statistically significant age-specific differences. The taller height contributed to lower BMI by approximately 25%. Short stature, overweight and obesity were 2.3-fold, 1.8-fold and 2.5-fold, respectively more frequent in VSS than in AHS students. The BMI was higher in students in Vienna than in communities with >100,000 (p<0.001) and 20,000-100,000 (p=0.045) but similar to communities with <20,000 inhabitants.

Conclusion: These findings suggest that differences in BMI and height between students reflect early SES-based grouping into school types according to the academic level of the schools they attend.
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http://dx.doi.org/10.1007/s00508-019-1479-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647492PMC
July 2019

Treatment of Diabetic Macular Edema with Intravitreal Antivascular Endothelial Growth Factor and Prompt versus Deferred Focal Laser during Long-Term Follow-Up and Identification of Prognostic Retinal Markers.

J Ophthalmol 2018 1;2018:3082560. Epub 2018 Oct 1.

Department of Ophthalmology, Hietzing Hospital, Wolkersbergenstrasse 1, Vienna, Austria.

Purpose: Long-term follow-up of patients with diabetic macular edema (DME) treated with intravitreal antivascular endothelial growth factor (anti-VEGF) combined focal laser and identification of prognostic morphological characteristics.

Methods: Prospective clinical trial (50 treatment-naive eyes) with DME randomized 1 : 1 receiving intravitreal ranibizumab (0.5 mg/0.05 ml) and prompt grid laser compared with ranibizumab and deferred laser. Morphological characteristics potentially relevant for prognosis were assessed at baseline, month 6, month 9, and years 1, 2, 3, 4, and 5 of follow-up.

Results: Although functional results were slightly higher in the prompt group at week 12 (0.5; 20/40 Snellen (SD = 0.04, 0.3 logMAR) versus 0.4; 20/50 Snellen (SD = 0.04, logMAR: 0.4), =0.4) and month 9 (prompt group: 0.5; 20/40 Snellen (SD = 0.03, 0.3 logMAR) versus deferred group: 0.4; 20/50 Snellen (SD = 0.04, 0.4 logMAR), =0.4), these were statistically insignificant. There was no significant benefit regarding functionality during long-term follow-up in the prompt group compared to the deferred group. BCVA in the eyes with clusters of hyperreflective foci in the central macular region was inferior compared with the eyes without these alterations at year 5 (0.39; 20/50 Snellen, (SD = 0.25, 0.4 logMAR) versus 0.63; 20/80 Snellen (SD = 0.22, 0.2 logMAR), < 0.01).

Conclusion: Grid laser and ranibizumab therapy are effective in DME management during the long-term follow-up. Intraretinal hyperreflective material in SD-OCT is negatively related to BCVA.
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http://dx.doi.org/10.1155/2018/3082560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188720PMC
October 2018

Myostatin and other musculoskeletal markers in lung transplant recipients.

Clin Exp Med 2019 Feb 13;19(1):77-85. Epub 2018 Oct 13.

Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria.

Recipients of lung transplantation (LuTx) may experience impaired muscle function and bone metabolism even after rehabilitation. We investigated the potential use of musculoskeletal markers in identifying the impairment of muscle function and bone function in these patients. Biochemical parameters, bodily functions, and lung function of 37 LuTx recipients were evaluated at the time of their discharge from the hospital stay and about 6 months later. The biomarkers were also assessed in 30 healthy age and gender distribution-matched controls. Compared to controls, the negative muscle regulator myostatin was elevated in LuTx recipients at baseline and follow-up, whereas its opponent follistatin only showed a group-specific difference at follow-up. LuTx recipients had reduced serum levels of sclerostin and increased levels of dickkopf 1 and periostin. Lung function and physical function were improved during follow-up. The change in lung function was correlated with the change in chair-rising time and the 6-min walking test. At follow-up, all musculoskeletal markers of LuTx recipients differed from those of controls, thus reflecting their still reduced lung function and bodily functions. Among the tested biomarkers, myostatin, sclerostin, dickkopf 1, and periostin were useful to detect impaired musculoskeletal function in LuTx recipients. Myostatin may serve as a target of treatment in the future.
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http://dx.doi.org/10.1007/s10238-018-0532-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394594PMC
February 2019

Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer.

Front Pharmacol 2018 7;9:842. Epub 2018 Aug 7.

Institute of Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

High-grade serous ovarian cancer (HGSOC) is considered the most deadly and frequently occurring type of ovarian cancer and is associated with various molecular compositions and growth patterns. Evaluating the mRNA expression pattern of the organic anion transporters (OATPs) encoded by genes may allow for improved stratification of HGSOC patients for targeted invention. The expression of mRNA and genes coding for putative functionally related ABC-efflux pumps, enzymes, pregnane-X-receptor, and (coding for estrogen receptors ERα and ERß) and HER-2 were assessed using RT-qPCR. The expression levels were assessed in a cohort of 135 HGSOC patients to elucidate the independent impact of the expression pattern on the overall survival (OS). For identification of putative regulatory networks, Graphical Gaussian Models were constructed from the expression data with a tuning parameter K varying between meaningful borders (Pils et al., 2012; Auer et al., 2015, 2017; Kurman and Shih Ie, 2016; Karam et al., 2017; Labidi-Galy et al., 2017; Salomon-Perzynski et al., 2017; Sukhbaatar et al., 2017). The final value used ( = 4) was determined by maximizing the proportion of explained variation of the corresponding LASSO Cox regression model for OS. The following two networks of directly correlated genes were identified: (i) with implicated in estrogen homeostasis; and (ii) two ABC-efflux pumps in the immune regulation () with and . Combining LASSO Cox regression and univariate Cox regression analyses, coding for OATP5A1, an estrogen metabolite transporter located in the cytoplasm and plasma membranes of ovarian cancer cells, was identified as significant and independent prognostic factor for OS (HR = 0.68, CI 0.49-0.93; = 0.031). Furthermore, results indicated the benefits of patients with high expression by adding 5.1% to the 12.8% of the proportion of explained variation (PEV) for clinicopathological parameters known for prognostic significance (FIGO stage, age and residual tumor after debulking). Additionally, overlap with previously described signatures that indicated a more favorable prognosis for ovarian cancer patients was shown for , the network as well as . Furthermore, expression of and , which are important for PGE degradation, was associated with the non-miliary peritoneal tumor spreading. In conclusion, the present findings suggested that and the related molecules identified as potential biomarkers in HGSOC may be useful for the development of novel therapeutic strategies.
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http://dx.doi.org/10.3389/fphar.2018.00842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090214PMC
August 2018

Optimizing Treatment Sequence for Late-line Metastatic Colorectal Cancer Patients Using Trifluridine/Tipiracil and Regorafenib.

Clin Colorectal Cancer 2018 12 8;17(4):274-279. Epub 2018 Jun 8.

Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Treatment sequencing for patients with refractory metastatic colorectal cancer (mCRC) has been highly debated. The thymidine-based nucleoside trifluridine/tipiracil (TAS-102) and the multikinase inhibitor regorafenib have demonstrated clinical benefits in randomized phase III trials compared with placebo. However, limited data are available on the most optimal therapy sequence involving TAS-102 and regorafenib.

Patients And Methods: In the present retrospective, observational, real-life study, clinical data on mCRC patients treated with TAS-102 or an alternative salvage treatment at the Medical University of Vienna and University Hospital Zurich were collected from January 2013 to December 2016.

Results: A total of 85 patients whose disease had progressed during fluoropyrimidine-based therapy (FBT) with or without an antibody were included. The disease control rate in patients treated with TAS-102 after FBT-based treatment was 24% compared with 35% in patients treated with regorafenib after FBT-based treatment (adjusted odds ratio, 1.75; 95% confidence interval, 0.41-7.47; P = .449). The progression-free survival (PFS) and overall survival (OS) for patients treated with TAS-102 was 2.8 months (quartile, 2.0-4.8 months) and 15.9 months, respectively. When the data were analyzed according to the subgroups of patients with or without an FBT-free period, the TAS-102-treated patients with a previous FBT-free interval had a PFS of 3.1 months and OS of 17.7 months compared with a PFS of 2.2 months and OS of 8.1 months for patients who received TAS-102 immediately after FBT.

Conclusion: Our results have confirmed the efficacy of TAS-102 and regorafenib in the real-life setting. The treatment sequence analysis showed a tendency for longer PFS and OS for TAS-102-treated patients after an FBT-free interval. Prospective randomized data are needed to gain more information about the most beneficial therapy sequence in the salvage treatment of mCRC.
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http://dx.doi.org/10.1016/j.clcc.2018.05.012DOI Listing
December 2018

Optimizing Treatment Sequence for Late-line Metastatic Colorectal Cancer Patients Using Trifluridine/Tipiracil and Regorafenib.

Clin Colorectal Cancer 2018 12 8;17(4):274-279. Epub 2018 Jun 8.

Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Treatment sequencing for patients with refractory metastatic colorectal cancer (mCRC) has been highly debated. The thymidine-based nucleoside trifluridine/tipiracil (TAS-102) and the multikinase inhibitor regorafenib have demonstrated clinical benefits in randomized phase III trials compared with placebo. However, limited data are available on the most optimal therapy sequence involving TAS-102 and regorafenib.

Patients And Methods: In the present retrospective, observational, real-life study, clinical data on mCRC patients treated with TAS-102 or an alternative salvage treatment at the Medical University of Vienna and University Hospital Zurich were collected from January 2013 to December 2016.

Results: A total of 85 patients whose disease had progressed during fluoropyrimidine-based therapy (FBT) with or without an antibody were included. The disease control rate in patients treated with TAS-102 after FBT-based treatment was 24% compared with 35% in patients treated with regorafenib after FBT-based treatment (adjusted odds ratio, 1.75; 95% confidence interval, 0.41-7.47; P = .449). The progression-free survival (PFS) and overall survival (OS) for patients treated with TAS-102 was 2.8 months (quartile, 2.0-4.8 months) and 15.9 months, respectively. When the data were analyzed according to the subgroups of patients with or without an FBT-free period, the TAS-102-treated patients with a previous FBT-free interval had a PFS of 3.1 months and OS of 17.7 months compared with a PFS of 2.2 months and OS of 8.1 months for patients who received TAS-102 immediately after FBT.

Conclusion: Our results have confirmed the efficacy of TAS-102 and regorafenib in the real-life setting. The treatment sequence analysis showed a tendency for longer PFS and OS for TAS-102-treated patients after an FBT-free interval. Prospective randomized data are needed to gain more information about the most beneficial therapy sequence in the salvage treatment of mCRC.
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http://dx.doi.org/10.1016/j.clcc.2018.05.012DOI Listing
December 2018

Early ultrasonographic tumor regression after linear accelerator stereotactic fractionated photon radiotherapy of choroidal melanoma as a predictor for metastatic spread.

Radiother Oncol 2018 Jun 8;127(3):385-391. Epub 2018 May 8.

Department of Ophthalmology and Optometry, Medical University of Vienna, Austria.

Background And Purpose: During extended follow-up (of up to 15 years), approximately fifty percent of patients with choroidal melanoma will develop metastatic disease and eventually die. Thus, continuing research on prognostic factors, early detection and treatment is necessary. Height regression rates both after plaque brachytherapy and proton beam irradiation have been shown to have prognostic value. The purpose of this study was to analyze the influence of early tumor regression rate after treatment of choroidal melanoma with LINAC stereotactic fractionated radiotherapy (SFRT) as an independent risk factor for metastasis.

Material And Methods: 256 patients with choroidal melanoma treated with LINAC SFRT were included. Follow-up included standardized echography yielding apical height, smallest and largest basal linear diameter, tumor volume and mean reflectivity. The influence of baseline measurements and of a longitudinal, normalized area under the curve coefficient (NAC) of the latter marker on metastasis risk was assessed.

Results: NAC for tumor thickness at months 3, 6, and 12 had a statistically significant (p < 0.001) non-linear effect on risk of metastasis. Additionally, ultrasonographic baseline tumor dimensions, but not internal reflectivity were found to be statistically significant risk factors for metastasis.

Conclusions: Our results demonstrate a non-linear influence of regression rate of choroidal melanoma as independent risk factor of metastatic disease after LINAC SFRT. These prove the clinical experience that, in comparison to rather slow regressions, very quick and very slow early tumor responses to LINAC SFRT are associated with a significantly higher metastasis risk.
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http://dx.doi.org/10.1016/j.radonc.2018.04.019DOI Listing
June 2018
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