Publications by authors named "Alexandra Graf"

99 Publications

Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.

NPJ Vaccines 2020 Jul 24;5(1):67. Epub 2020 Jul 24.

Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

The aim of this prospective study was to characterize the humoral immune response to TBE vaccination after hematopoietic stem cell transplantation (HSCT). Nineteen adult patients 11-13 months after HSCT and 15 age-matched immunocompetent adults received up to three TBE vaccinations. Antibodies against TBE virus were measured by neutralization test (NT). As primary endpoint, the antibody response (NT titer of ≥10 and at least a twofold increase from baseline 4 weeks after second vaccination) was compared between patients and controls using Fisher exact test. Prior vaccination, 15 (79%) HSCT patients still had detectable neutralizing antibodies. At primary endpoint, the antibody response was significantly lower in patients than in controls (35% versus 93%; p < 0.001). The CD4+ cell count was a predictor for an antibody response in patients (p = 0.019). Interestingly, the majority of HSCT patients still had detectable antibodies prior vaccination. Following vaccination, antibody response in HSCT patients was associated with the CD4+ cell count.
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http://dx.doi.org/10.1038/s41541-020-00215-1DOI Listing
July 2020

Fractional heat shock protein 27 urine excretion as a short-term predictor in acute exacerbation of chronic obstructive pulmonary disease.

Ann Transl Med 2021 Jan;9(2):117

Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Austria.

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is characterized by episodes of acute exacerbations. Finding a systemic biomarker that reliably predicts outcome after an acute exacerbation remains a major challenge. Heat shock protein 27 (HSP27) has been previously studied in COPD, however, urine excretion trajectory and prognostic value after an exacerbation is unknown.

Methods: In this retrospective post hoc analysis of a prospective study that included 253 COPD patients who were hospitalized for acute exacerbation, 207 patients were analyzed. Urine and serum were sampled at admission, discharge, and 180 days after discharge; urine excretion trajectory was analyzed and correlated with clinicopathological and survival data.

Results: HSP27 urine excretion increased after an exacerbation episode [1.8% admission, 1.8% discharge, 2.3% 180 days after discharge (P=0.091)]. In severely ill patients (GOLD IV) this course was even more distinct [1.6% admission, 2.1% discharge, 2.8% 180 days after discharge (P=0.007)]. Furthermore, fractional HSP27 urine excretion at discharge was increased in GOLD IV patients (P=0.031). In Kaplan-Meier and univariable Cox proportional hazard models patients with HSP27 urine excretion below 0.845% showed significantly worse survival at 30, 90 and 180 days after discharge. In a multivariable Cox proportional hazard model including established COPD outcome parameters fractional HSP27 urine excretion remained a significant predictor of survival at 30 and 90 days after discharge. Comparing this model to our already published model that includes HSP27 serum concentration we could show that fractional HSP27 urine excretion performs better in short-term survival.

Conclusions: Our findings provide novel information about fractional HSP27 urine excretion trajectory in acute exacerbation of COPD. Fractional HSP27 urine excretion may be significantly reduced during an episode of acute exacerbation in COPD patients and may be used as a predictor of short-term all-cause mortality.
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http://dx.doi.org/10.21037/atm-20-3683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867877PMC
January 2021

Lessons from low seroprevalence of SARS-CoV-2 antibodies in schoolchildren: A cross-sectional study.

Pediatr Allergy Immunol 2021 Jan 29. Epub 2021 Jan 29.

Department of Pediatrics and Adolescent Medicine, Klinik Ottakring, Vienna, Austria.

Background: Children are discussed as hidden SARS-CoV-2 virus reservoir because of predominantly mild or even asymptomatic course of disease. The objective of this cross-sectional study in May-July 2020 was to assess the prevalence of SARS-CoV-2 antibodies and virus RNA in schoolchildren, consistent with previous infection by contact tracing.

Methods: School authorities approached parents for voluntary participation. Interested families were contacted by the study team. A nasal and oropharyngeal swab, a blood sample, and a questionnaire were employed. Primary endpoint was the frequency of SARS-CoV-2 real-time PCR (RT-PCR) and antibody-positive children. Antibody positivity was assessed by a highly sensitive first-line ELISA, and a neutralization assay and two other immunoassays as confirmatory assays.

Results: Of 2069 children (median age 13 years, IQR 10-15), 2 cases (0.1%) tested positive for SARS-CoV-2 RNA and 26 cases (1.3%) tested positive for specific antibodies. SARS-CoV-2-specific antibodies exhibited detectable virus-neutralizing activity in 92% (24 of 26 samples). Seropositivity was associated with a history of mild clinical symptoms in 14 children (53.8%), while 12 children (46.2%) remained asymptomatic. Among 13 seropositive children being tested concomitantly with their siblings, only one pair of siblings was seropositive. Contact tracing revealed adult family members and school teachers as potential index cases.

Conclusion: In schoolchildren, the infection rate with SARS-CoV-2 is low and associated with a mild or asymptomatic course of disease. Virus spreading seemed to occur more likely in intergenerational contacts than among siblings in the same household. The presence of neutralizing SARS-CoV-2 antibodies in children may reflect protective adaptive immunity.
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http://dx.doi.org/10.1111/pai.13459DOI Listing
January 2021

The Microbiome of Leonardo da Vinci's Drawings: A Bio-Archive of Their History.

Front Microbiol 2020 20;11:593401. Epub 2020 Nov 20.

Department of Biotechnology, Institute of Microbiology and Microbial Biotechnology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.

Seven emblematic Leonardo da Vinci's drawings were investigated through third generation sequencing technology (Nanopore). In addition, SEM analyses were carried out to acquire photographic documentation and to infer the nature of the micro-objects removed from the surface of the drawings. The Nanopore generated microbiomes can be used as a "bio-archive" of the drawings, offering a kind of fingerprint for current and future biological comparisons. This information might help to create a biological catalog of the drawings (cataloging), a microbiome-fingerprint for each single analyzed drawing, as a reference dataset for future studies (monitoring) and last but not least a bio-archive of the history of each single object (added value). Results showed a relatively high contamination with human DNA and a surprising dominance of bacteria over fungi. However, it was possible to identify typical bacteria of the human microbiome, which are mere contaminants introduced by handling of the drawings as well as other microorganisms that seem to have been introduced through vectors, such as insects and their droppings, visible through the SEM analyses. All drawings showed very specific bio-archives, but a core microbiome of bacteria and fungi that are repeatedly found in this type of material as true degraders were identified, such as members of the phyla , , and among bacteria, and fungi belonging to the classes and . In addition, some similarities were observed that could be influenced by their geographical location (Rome or Turin), indicating the influence of this factor and denoting the importance of environmental and storage conditions on the specific microbiomes.
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http://dx.doi.org/10.3389/fmicb.2020.593401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718017PMC
November 2020

Oral probiotics to reduce vaginal group B streptococcal colonization in late pregnancy.

Sci Rep 2020 11 12;10(1):19745. Epub 2020 Nov 12.

Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

This study aimed to evaluate the potential of oral probiotics to eradicate vaginal GBS colonization during the third trimester of pregnancy. We screened 1058 women for GBS colonization at 33-37 gestational weeks using a combination of vaginal-to-rectal swab and culture-based methods. Women who tested GBS positive were randomized to either the verum group, receiving a dietary probiotic supplement of four viable strains of Lactobacillus twice-daily for 14 days, or to the placebo group. Women underwent follow-up smears, whereat GBS colonization upon follow-up was considered the primary endpoint. We found that 215 women (20.3%) were positive for GBS upon screening, of which 82 (38.1%) were eligible for study inclusion; 41 (50%) of these were randomized to the verum and placebo groups each. After treatment, 21/33 (63.6%) members of the verum group, and 21/27 (77.8%) of the placebo group were still GBS positive (p = 0.24). Four (9.8%) women in the verum group and one (2.4%) in the placebo group experienced preterm birth (p = 0.20); smokers showed significantly higher rates of preterm birth (p = 0.03). Hence, the findings did not support the hypothesis that oral probiotics can eradicate GBS during pregnancy, although we observed a trend toward reduced GBS persistence after probiotic intake.
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http://dx.doi.org/10.1038/s41598-020-76896-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665007PMC
November 2020

Correction to: Drusen characteristics of type 2 macular neovascularization in age-related macular degeneration.

BMC Ophthalmol 2020 Oct 27;20(1):430. Epub 2020 Oct 27.

Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12886-020-01699-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592543PMC
October 2020

Detection rate of diabetic macular microaneurysms comparing dye-based angiography and optical coherence tomography angiography.

Sci Rep 2020 10 1;10(1):16274. Epub 2020 Oct 1.

Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.

Diabetic maculopathy (DM) is a microvascular dysfunction clinically characterized by microaneurysms (MA) leading to edema and central visual deprivation. This prospective explorative study investigated 27 eyes of 17 patients with DM by fluorescein/indocyanine green angiography (FA/ICGA; SPECTRALIS HRA-OCT, Heidelberg Engineering) and by swept source-optical coherence tomography angiography (SS-OCTA; DRI-OCT Triton Plus, Topcon) to identify clinically relevant MAs. The SS-OCTA cubes were split into the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) according to the automated segmentation. The images of all modalities were superimposed for alignment by an Early Treatment Diabetic Retinopathy Study grid overlay and compared to each other. In total, the mean number of MAs in FA was 33.4 ± 22 (standard deviation) (median 27.5 [q1:21.75;q3:38.25]), in ICGA 24.9 ± 16.9 (17.5 [14;35]), in the SCP 6.5 ± 3.7 (5.5 [3.75;9.25]) and in the DCP 18.1 ± 10.5 (18.5 [10.75;23.5]). Mixed effects models between ICGA and the DCP were borderline significant (p = 0.048; 95% confidence interval 0.21 to 13.49), whereas all other imaging methods differed significantly. Quantitative analysis of MAs in DM showed a plausible agreement between ICGA and the DCP in SS-OCTA. These findings contribute to the imaging methodology in DM.
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http://dx.doi.org/10.1038/s41598-020-73516-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530679PMC
October 2020

Remodeling the Skeletal Muscle Extracellular Matrix in Older Age-Effects of Acute Exercise Stimuli on Gene Expression.

Int J Mol Sci 2020 Sep 25;21(19). Epub 2020 Sep 25.

Research Unit for Orthopaedic Sports Medicine and Injury Prevention, Private University for Health Sciences, Medical Informatics and Technology, Hall 6060, Austria.

With advancing age, the skeletal muscle extracellular matrix (ECM) undergoes fibrotic changes that may lead to increased muscle stiffness, injury susceptibility and strength loss. This study tested the potential of different exercises to counter these changes by stimulating the activity of genes associated with ECM remodeling. Twenty-six healthy men (66.9 ± 3.9 years) were stratified to two of four groups, performing unilateral (i) conventional resistance exercise, (ii) conventional resistance exercise followed by self-myofascial release (CEBR), (iii) eccentric-only exercise (ECC) or (iv) plyometric jumps (PLY). The non-trained leg served as control. Six hours post-exercise, vastus lateralis muscle biopsy samples were analyzed for the expression of genes associated with ECM collagen synthesis (COL1A1), matrix metallopeptidases (collagen degradation; MMPs) and peptidase inhibitors (TIMP1). Significant between-group differences were found for MMP3, MMP15 and TIMP1, with the greatest responses in MMP3 and TIMP1 seen in CEBR and in MMP15 in ECC. MMP9 (3.24-3.81-fold change) and COL1A1 (1.47-2.40-fold change) were increased in CEBR and PLY, although between-group differences were non-significant. The expression of ECM-related genes is exercise-specific, with CEBR and PLY triggering either earlier or stronger remodeling than other stimuli. Training studies will test whether execution of such exercises may help counter age-associated muscle fibrosis.
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http://dx.doi.org/10.3390/ijms21197089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583913PMC
September 2020

Drusen characteristics of type 2 macular neovascularization in age-related macular degeneration.

BMC Ophthalmol 2020 Sep 25;20(1):381. Epub 2020 Sep 25.

Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.

Background: Type 2 macular neovascularization (MNV) is supposed to be a rare condition in age-related macular degeneration (AMD). The main purpose of this study was to assess accompanying factors of type 2 MNV in AMD.

Methods: Retrospective data analysis of eyes previously diagnosed with neovascular AMD in a tertiary eye care center (Medical Retina Unit, Rudolf Foundation Hospital, Vienna, Austria) between June 2008 and December 2017. Drusen subtypes, fibrosis, atrophy and subfoveal choroidal thickness (SFCT) of both eyes in patients with type 2 MNV lesions were categorized based on multimodal imaging.

Results: Type 2 MNV was diagnosed in 27 (3.2%) of 835 eyes (749 patients). Drusen characteristics in type 2 MNV were observed as followed: drusen < 63 μm in 2 eyes (7.4%), drusen ≥63 μm in 10 eyes (37%), subretinal drusenoid deposits (SDD) in 8 eyes (29.6%), cuticular drusen in 2 eye (7.4%) and no drusen were evident in 10 eyes (37%). Drusen distribution in 23 fellow eyes was detected as followed: drusen < 63 μm in 2 eyes (8.7%), drusen ≥63 μm in 9 eyes (39.1%), SDD in 5 eyes (21.7%), cuticular drusen in 1 eye (4.3%) and no drusen were evident in 9 eyes (39.1%). Mean SFCT was 140 ± 49 μm in affected eyes and 152 ± 41 μm in the fellow eyes. Patients with drusen or SDD were significantly younger (mean 70.88 ± 6.85, p = 0.04) than patients without deposits (mean 77.40 ± 5.74).

Conclusions: Type 2 MNV remains a rare entity in AMD. It was frequently seen in the absence of drusen, a hallmark of AMD. These findings contribute to the heterogeneity of phenotypes related to pure type 2 lesions.
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http://dx.doi.org/10.1186/s12886-020-01651-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519492PMC
September 2020

Erratum: Author Correction: Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.

NPJ Vaccines 2020 31;5:79. Epub 2020 Aug 31.

Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

[This corrects the article DOI: 10.1038/s41541-020-00215-1.].
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http://dx.doi.org/10.1038/s41541-020-00230-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459277PMC
August 2020

The effect of oral Δ-9-tetrahydrocannabinol on the minimal alveolar concentration of sevoflurane: A randomised, controlled, observer-blinded experimental study.

Eur J Anaesthesiol 2021 01;38(1):58-63

From the Division of General Anaesthesia and Intensive Care Medicine, University Department of Anaesthesia, Intensive Care Medicine and Pain Medicine (JM, WP, JB-S, LI, TH), Clinical Department of Laboratory Medicine, Analytical Toxicology (BR, TS) and Institute of Medical Statistics, Medical University of Vienna, Vienna, Austria (AG).

Background: Cannabis has increasingly been used for medical and recreational purposes. The main pharmacological compound in cannabis is tetrahydrocannabinol (THC), which has sedative, anxiolytic and analgesic effects. In some animal models, THC has also been shown to reduce the minimum alveolar concentration (MAC) of halothane and cyclopropane, but its effect on sevoflurane, currently the most commonly used inhalational anaesthetic agent, has not been investigated.

Objective: To investigate the effect of THC on the MAC of sevoflurane in rats.

Methods: Observer-blinded, randomised controlled trial.

Setting: Centre for Biomedical Research of the Medical University of Vienna, 2019.

Individuals: Thirty-eight adult Wistar rats.

Interventions: The rats were allocated randomly into one of two groups. Group A received THC 10 mg kg and group B received the corresponding volume of placebo via gastric gavage (administration through a tube placed in the distal oesophagus). The rats were then individually anaesthetised in an airtight sevoflurane-flooded chamber, and the MAC in both groups was determined using Dixon's up-and-down method. Blood samples were drawn to measure serum concentrations of THC.

Main Outcome Measures: The primary outcome was the MAC of sevoflurane in Groups A and B.

Results: The bootstrap estimate of the MAC of sevoflurane was 2.1 (95% confidence interval 1.8 to 2.4) vol% in the THC group and 2.8 (95% confidence interval 2.7 to 2.9) vol% in the placebo group, corresponding to a significant MAC reduction of 26% in response to THC.

Conclusion: Gastric administration of THC 10 mg kg significantly reduced the MAC of sevoflurane by 26%.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1097/EJA.0000000000001295DOI Listing
January 2021

Comparison of macular neovascularization lesion size by the use of Spectral-Domain Optical Coherence Tomography Angiography and Swept-Source Optical Coherence Tomography Angiography versus Indocyanine Green Angiography.

Acta Ophthalmol 2020 Aug 24. Epub 2020 Aug 24.

Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.

Purpose: To compare the lesion sizes of macular neovascularization (MNV) imaged with spectral-domain (SD) and swept-source (SS) optical coherence tomography angiography (OCTA) as well as indocyanine green angiography (ICGA).

Methods: In this prospective, observational case series, patients showing a secured diagnosis of MNV on ICGA or Fluorescein Angiography, were imaged by SD-OCTA and SS-OCTA on the same day. Lesion size was measured on 3 × 3-mm and 6 × 6-mm scans using the Maestro 2 SD-OCTA (Topcon Corporation, Tokyo Japan) and the Triton SS-OCTA device (Topcon Corporation, Tokyo Japan) and compared to ICGA (Spectralis HRA, Heidelberg, Germany).

Results: Twenty eyes from 20 patients (11 females, 55%) were enrolled. The neovascularization area measured on 6 × 6-mm SD-OCTA was lower compared to that outlined on SS-OCTA, however, not reaching statistical significance (p = 0.094). Regarding 3 × 3-mm measurements, the median lesion sizes between the two OCTA devices were comparable (p = 0.492). Indocyanine green angiography depicted a larger lesion area than both OCTA devices, however, not reaching statistical significance.

Conclusion: SD-OCTA tends to show smaller areas of MNV extension than SS-OCTA regarding 6 × 6 mm scans. The lesion size of MNV can be very well compared between the different devices, emphasizing the use of OCTA for monitoring neovascular area. Lesion measurements on SS-OCTA correlate better with ICGA than SD-OCTA.
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http://dx.doi.org/10.1111/aos.14572DOI Listing
August 2020

Pseudohyphal differentiation in Komagataella phaffii: investigating the FLO gene family.

FEMS Yeast Res 2020 Aug;20(5)

Austrian Centre of Industrial Biotechnology, Muthgasse 11, 1190 Vienna, Austria.

Many yeasts differentiate into multicellular phenotypes in adverse environmental conditions. Here, we investigate pseudohyphal growth in Komagataella phaffii and the involvement of the flocculin (FLO) gene family in its regulation. The K. phaffii FLO family consists of 13 members, and the conditions inducing pseudohyphal growth are different from Saccharomyces cerevisiae. So far, this phenotype was only observed when K. phaffii was cultivated at slow growth rates in glucose-limited chemostats, but not upon nitrogen starvation or the presence of fusel alcohols. Transcriptional analysis identified that FLO11, FLO400 and FLO5-1 are involved in the phenotype, all being controlled by the transcriptional regulator Flo8. The three genes exhibit a complex mechanism of expression and repression during transition from yeast to pseudohyphal form. Unlike in S. cerevisiae, deletion of FLO11 does not completely prevent the phenotype. In contrast, deletion of FLO400 or FLO5-1 prevents pseudohyphae formation, and hampers FLO11 expression. FAIRE-Seq data shows that the expression and repression of FLO400 and FLO5-1 are correlated to open or closed chromatin regions upstream of these genes, respectively. Our findings indicate that K. phaffii Flo400 and/or Flo5-1 act as upstream signals that lead to the induction of FLO11 upon glucose limitation in chemostats at slow growth and chromatin modulation is involved in the regulation of their expression.
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http://dx.doi.org/10.1093/femsyr/foaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419694PMC
August 2020

Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.

NPJ Vaccines 2020 24;5:67. Epub 2020 Jul 24.

Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

The aim of this prospective study was to characterize the humoral immune response to TBE vaccination after hematopoietic stem cell transplantation (HSCT). Nineteen adult patients 11-13 months after HSCT and 15 age-matched immunocompetent adults received up to three TBE vaccinations. Antibodies against TBE virus were measured by neutralization test (NT). As primary endpoint, the antibody response (NT titer of ≥10 and at least a twofold increase from baseline 4 weeks after second vaccination) was compared between patients and controls using Fisher exact test. Prior vaccination, 15 (79%) HSCT patients still had detectable neutralizing antibodies. At primary endpoint, the antibody response was significantly lower in patients than in controls (35% versus 93%;  < 0.001). The CD4+ cell count was a predictor for an antibody response in patients ( = 0.019). Interestingly, the majority of HSCT patients still had detectable antibodies prior vaccination. Following vaccination, antibody response in HSCT patients was associated with the CD4+ cell count.
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http://dx.doi.org/10.1038/s41541-020-00215-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381595PMC
July 2020

Brain Tissue Oxygen Response as Indicator for Cerebral Lactate Levels in Aneurysmal Subarachnoid Hemorrhage Patients.

J Neurosurg Anesthesiol 2020 07 21. Epub 2020 Jul 21.

Department of Neurosurgery, Johannes Kepler University, Linz, Austria.

Background: Early detection of cerebral ischemia and metabolic crisis is crucial in critically ill subarachnoid hemorrhage (SAH) patients. Variable increases in brain tissue oxygen tension (PbtO2) are observed when the fraction of inspired oxygen (FiO2) is increased to 1.0. The aim of this prospective study was to evaluate whether a 3-minute hyperoxic challenge can identify patients at risk for cerebral ischemia detected by cerebral microdialysis.

Methods: Twenty consecutive severe SAH patients undergoing continuous cerebral PbtO2 and microdialysis monitoring were included. FiO2 was increased to 1.0 for 3 minutes (the FiO2 challenge) twice a day and PbtO2 responses during the FiO2 challenges were related to cerebral microdialysis-measures, ie, lactate, the lactate-pyruvate ratio, and glycerol. Multivariable linear and logistic regression models were created for each outcome parameter.

Results: After predefined exclusions, 274 of 400 FiO2 challenges were included in the analysis. Lower absolute increases in PbtO2 ([INCREMENT]PbtO2) during FiO2 challenges were significantly associated with higher cerebral lactate concentration (P<0.001), and patients were at higher risk for ischemic lactate levels >4 mmol/L (odds ratio 0.947; P=0.04). Median (interquartile range) [INCREMENT]PbtO2 was 7.1 (4.6 to 12.17) mm Hg when cerebral lactate was >4 mmol/L and 10.2 (15.76 to 14.24) mm Hg at normal lactate values (≤4 mmol/L). Median [INCREMENT]PbtO2 was significantly lower during hypoxic than during hyperglycolytic lactate elevations (4.6 vs. 10.6 mm Hg, respectively; P<0.001). Lactate-pyruvate ratio and glycerol levels were mainly determined by baseline characteristics.

Conclusions: A 3-minute FiO2 challenge is an easy to perform and feasible bedside diagnostic tool in SAH patients. The absolute increase in PbtO2 during the FiO2 challenge might be a useful surrogate marker to estimate cerebral lactate concentrations and might be used to identify patients at risk for impending ischemia.
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http://dx.doi.org/10.1097/ANA.0000000000000713DOI Listing
July 2020

Optimized multiple testing procedures for nested sub-populations based on a continuous biomarker.

Stat Methods Med Res 2020 10 30;29(10):2945-2957. Epub 2020 Mar 30.

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

An important step in the development of targeted therapies is the identification and confirmation of sub-populations where the treatment has a positive treatment effect compared to a control. These sub-populations are often based on continuous biomarkers, measured at baseline. For example, patients can be classified into biomarker low and biomarker high subgroups, which are defined via a threshold on the continuous biomarker. However, if insufficient information on the biomarker is available, the a priori choice of the threshold can be challenging and it has been proposed to consider several thresholds and to apply appropriate multiple testing procedures to test for a treatment effect in the corresponding subgroups controlling the family-wise type 1 error rate. In this manuscript we propose a framework to select optimal thresholds and corresponding optimized multiple testing procedures that maximize the expected power to identify at least one subgroup with a positive treatment effect. Optimization is performed over a prior on a family of models, modelling the relation of the biomarker with the expected outcome under treatment and under control. We find that for the considered scenarios 3 to 4 thresholds give the optimal power. If there is a prior belief on a small subgroup where the treatment has a positive effect, additional optimization of the spacing of thresholds may result in a large benefit. The procedure is illustrated with a clinical trial example in depression.
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http://dx.doi.org/10.1177/0962280220913071DOI Listing
October 2020

Seven-Year Visual and Anatomical Outcomes of Intravitreal Vascular Endothelial Growth Factor Inhibition for Neovascular Age-Related Macular Degeneration.

J Ophthalmol 2020 14;2020:8345850. Epub 2020 Feb 14.

Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.

Purpose: To evaluate 7-year visual and anatomical outcomes of intravitreal injections (IVI) with antivascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD) based on a personalized pro re nata (PRN) regimen.

Methods: Anonymized data of 124 consecutive eyes in 121 patients with treatment-naïve nAMD were initially collected in 2010. Of those, 45 received anti-VEGF IVI at least every 6months until 2017 in one single center in Austria and hence were retrospectively analyzed. All eyes had been initiated on a loading dose of 3 monthly IVI with different anti-VEGF agents followed by a PRN regimen in the first year. At year 2, monitoring as well as therapeutic intervention could be prolonged every 2weeks up to intervals of 3months without capping treatment. Primary outcome measure was the change of visual acuity (VA) assessed by Early Treatment Diabetic Retinopathy Study charts at 4 meters (ETDRS) in letters-counting every correctly read letter-and converted to Snellen. Secondary outcome measures were number of injections and change of central retinal thickness (CMT) from baseline.

Results: Mean baseline VA was 20/63 + 1 (0.63 ± 0.26 ETDRS) and declined to 20/100 + 2 (0.45 ± 0.33) with an overall loss of 9 letters ETDRS after 7years ( = 0.001). An average of 3.5 ± 1.9 IVI was given per year and eye. Mean CMT at baseline was 322 ± 95 m, decreased by 52 m, decreased by 52 m, decreased by 52 m, decreased by 52 m to 270 ± 70 m within the first year, and remained below baseline at year 7 (271 ± 106 m;  = 0.001). An average of 3.5 ± 1.9 IVI was given per year and eye. Mean CMT at baseline was 322 ± 95 m, decreased by 52 m to 270 ± 70 m within the first year, and remained below baseline at year 7 (271 ± 106 m; < 0.001).

Conclusions: Our data confirm an absolute vision loss in eyes compromised by nAMD after 7 years of continuous VEGF inhibition. The visual decline was significantly related to baseline VA as well as the number of injections. We suggest following patients thoroughly independent of the initial VA and a greater incentive for the physician to treat.
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http://dx.doi.org/10.1155/2020/8345850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042519PMC
February 2020

A subcellular proteome atlas of the yeast Komagataella phaffii.

FEMS Yeast Res 2020 02;20(1)

Austrian Centre of Industrial Biotechnology (ACIB), Muthgasse 11, 1190 Vienna, Austria.

The compartmentalization of metabolic and regulatory pathways is a common pattern of living organisms. Eukaryotic cells are subdivided into several organelles enclosed by lipid membranes. Organelle proteomes define their functions. Yeasts, as simple eukaryotic single cell organisms, are valuable models for higher eukaryotes and frequently used for biotechnological applications. While the subcellular distribution of proteins is well studied in Saccharomyces cerevisiae, this is not the case for other yeasts like Komagataella phaffii (syn. Pichia pastoris). Different to most well-studied yeasts, K. phaffii can grow on methanol, which provides specific features for production of heterologous proteins and as a model for peroxisome biology. We isolated microsomes, very early Golgi, early Golgi, plasma membrane, vacuole, cytosol, peroxisomes and mitochondria of K. phaffii from glucose- and methanol-grown cultures, quantified their proteomes by liquid chromatography-electrospray ionization-mass spectrometry of either unlabeled or tandem mass tag-labeled samples. Classification of the proteins by their relative enrichment, allowed the separation of enriched proteins from potential contaminants in all cellular compartments except the peroxisomes. We discuss differences to S. cerevisiae, outline organelle specific findings and the major metabolic pathways and provide an interactive map of the subcellular localization of proteins in K. phaffii.
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http://dx.doi.org/10.1093/femsyr/foaa001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981350PMC
February 2020

Heat shock protein 27 as a predictor of prognosis in patients admitted to hospital with acute COPD exacerbation.

Cell Stress Chaperones 2020 01 9;25(1):141-149. Epub 2019 Dec 9.

Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.

Episodes of acute exacerbations are major drivers of hospitalisation and death from COPD. To date, there are no objective biomarkers of disease activity or biomarkers to predict patient outcome. In this study, 211 patients hospitalised for an acute exacerbation of COPD have been included. At the time of admission, routine blood tests have been performed including complete blood count, C-reactive protein, cardiac troponin T and NT-proBNP. Heat shock protein 27 (HSP27) serum concentrations were determined at time of admission, discharge and 180 days after discharge by ELISA. We were able to demonstrate significantly increased HSP27 serum concentrations in COPD patients at time of admission to hospital as compared to HSP27 concentrations obtained 180 days after discharge. In univariable Cox regression analyses, a HSP27 serum concentration ≥ 3098 pg/mL determined at admission was a predictor of all-cause mortality at 90 days, 180 days, 1 year and 3 years. In multivariable analyses, an increased HSP27 serum concentration at admission retained its prognostic ability with respect to all-cause mortality for up to 1-year follow-up. However, an increased HSP27 serum concentration at admission was not an independent predictor of long-term all-cause mortality at 3 years. Elevated serum HSP27 concentrations significantly predicted short-term mortality in patients admitted to hospital with acute exacerbation of COPD and could help to improve outcomes by identifying high-risk patients.
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http://dx.doi.org/10.1007/s12192-019-01057-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985059PMC
January 2020

Strong Signs for a Weak Wall in Tricuspid Aortic Valve Associated Aneurysms and a Role for Osteopontin in Bicuspid Aortic Valve Associated Aneurysms.

Int J Mol Sci 2019 Sep 26;20(19). Epub 2019 Sep 26.

Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria.

Central processes in the pathogenesis of TAV- (tricuspid aortic valve) and BAV- (bicuspid aortic valve) associated ascending thoracic aortic aneurysm (ATAA) development are still unknown. To gain new insights, we have collected aortic tissue and isolated smooth muscle cells of aneurysmal tissue and subjected them to in situ and in vitro analyses. We analyzed aortic tissue from 78 patients (31 controls, 28 TAV-ATAAs, and 19 BAV-ATAAs) and established 30 primary smooth muscle cell cultures. Analyses included histochemistry, immuno-, auto-fluorescence-based image analyses, and cellular analyses including smooth muscle cell contraction studies. With regard to TAV associated aneurysms, we observed a strong impairment of the vascular wall, which appears on different levels-structure and dimension of the layers (reduced media thickness, increased intima thickness, atherosclerotic changes, degeneration of aortic media, decrease of collagen, and increase of elastic fiber free area) as well as on the cellular level (accumulation of fibroblasts/myofibroblasts, and increase in the number of smooth muscle cells with a reduced alpha smooth muscle actin (α-SM actin) content per cell). The pathological changes in the aortic wall of BAV patients were much less pronounced-apart from an increased expression of osteopontin (OPN) in the vascular wall which stem from smooth muscle cells, we observed a trend towards increased calcification of the aortic wall (increase significantly associated with age). These observations provide strong evidence for different pathological processes and different disease mechanisms to occur in BAV- and TAV-associated aneurysms.
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http://dx.doi.org/10.3390/ijms20194782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802355PMC
September 2019

Relationship between Neovascular Density in Swept Source-Optical Coherence Tomography Angiography and Signs of Activity in Exudative Age-Related Macular Degeneration.

J Ophthalmol 2019 9;2019:4806061. Epub 2019 Jul 9.

Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.

Purpose: To assess the relationship between signs of activity in exudative neovascular age-related macular degeneration (nAMD) following anti-vascular endothelial growth factor (anti-VEGF) treatment and morphology of choroidal neovascularization (CNV) based on neovascular density as imaged using swept source-optical coherence tomography angiography (SS-OCTA) in a qualitative manner.

Methods: A single-cohort retrospective data analysis from one tertiary eye care center. Seventy-seven eyes of 72 patients were included and their charts reviewed which had been started on intravitreal injections with anti-VEGF for nAMD at least one year prior to enrollment. Clinically active disease was evaluated by slit-lamp fundus examination and spectral domain-OCT B-scans. Morphological appearance in SS-OCTA was characterized based on 5 different criteria and subsequently divided into 3 groups: predominantly hyperdense, minimally hyperdense, and hypodense lesions.

Results: Fifty-eight eyes (75%) were considered clinically active and 19 eyes (25%) clinically inactive. CNV was depicted in 71 eyes (92%) by SS-OCTA and separated accordingly into predominantly hyperdense (32%), minimally hyperdense (34%), and hypodense lesions (34%). A borderline significant difference in the probability of neovascular activity for predominantly hyperdense lesions compared to hypodense lesions was detected (=0.05).

Conclusions: Hyperdense choroidal neovascularization based on qualitative assessment of flow density showed a significant relation to active disease. Inactivity could not be matched adequately. This study demonstrated the potential usefulness of SS-OCTA for guidance of treatment in age-related macular degeneration.
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http://dx.doi.org/10.1155/2019/4806061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652027PMC
July 2019

Assessment of urban microbiome assemblies with the help of targeted in silico gold standards.

Biol Direct 2018 10 12;13(1):22. Epub 2018 Oct 12.

Department Bioengineering, University of Applied Sciences FH Campus Wien, Vienna, Austria.

Background: Microbial communities play a crucial role in our environment and may influence human health tremendously. Despite being the place where human interaction is most abundant we still know little about the urban microbiome. This is highlighted by the large amount of unclassified DNA reads found in urban metagenome samples. The only in silico approach that allows us to find unknown species, is the assembly and classification of draft genomes from a metagenomic dataset. In this study we (1) investigate the applicability of an assembly and binning approach for urban metagenome datasets, and (2) develop a new method for the generation of in silico gold standards to better understand the specific challenges of such datasets and provide a guide in the selection of available software.

Results: We applied combinations of three assembly (Megahit, SPAdes and MetaSPAdes) and three binning tools (MaxBin, MetaBAT and CONCOCT) to whole genome shotgun datasets from the CAMDA 2017 Challenge. Complex in silico gold standards with a simulated bacterial fraction were generated for representative samples of each surface type and city. Using these gold standards, we found the combination of SPAdes and MetaBAT to be optimal for urban metagenome datasets by providing the best trade-off between the number of high-quality genome draft bins (MIMAG standards) retrieved, the least amount of misassemblies and contamination. The assembled draft genomes included known species like Propionibacterium acnes but also novel species according to respective ANI values.

Conclusions: In our work, we showed that, even for datasets with high diversity and low sequencing depth from urban environments, assembly and binning-based methods can provide high-quality genome drafts. Of vital importance to retrieve high-quality genome drafts is sequence depth but even more so a high proportion of the bacterial sequence fraction too achieve high coverage for bacterial genomes. In contrast to read-based methods relying on database knowledge, genome-centric methods as applied in this study can provide valuable information about unknown species and strains as well as functional contributions of single community members within a sample. Furthermore, we present a method for the generation of sample-specific highly complex in silico gold standards.

Reviewers: This article was reviewed by Craig Herbold, Serghei Mangul and Yana Bromberg.
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http://dx.doi.org/10.1186/s13062-018-0225-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889603PMC
October 2018

Recent advances in methodology for clinical trials in small populations: the InSPiRe project.

Orphanet J Rare Dis 2018 10 25;13(1):186. Epub 2018 Oct 25.

Warwick Medical School, University of Warwick, Coventry, UK.

Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project. This paper summarizes the main results of the project, which was completed in 2017.The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods for small population clinical trials using a Bayesian decision-theoretic framework to compare costs with potential benefits, developed approaches for targeted treatment trials, enabling simultaneous identification of subgroups and confirmation of treatment effect for these patients, worked on early phase clinical trial design and on extrapolation from adult to pediatric studies, developing methods to enable use of pharmacokinetics and pharmacodynamics data, and also developed improved robust meta-analysis methods for a small number of trials to support the planning, analysis and interpretation of a trial as well as enabling extrapolation between patient groups. In addition to scientific publications, we have contributed to regulatory guidance and produced free software in order to facilitate implementation of the novel methods.
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http://dx.doi.org/10.1186/s13023-018-0919-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203217PMC
October 2018

Influence of age, BMI and parity on the success rate of midurethral slings for stress urinary incontinence.

PLoS One 2018 16;13(8):e0201167. Epub 2018 Aug 16.

Department of Obstetrics and Gynaecology, Division of General Gynaecology and Gynaecologic Oncology, Medical University of Vienna, Vienna, Austria.

Aims: Our aim was to evaluate, in a second data analysis of the prospective randomized controlled trial conducted by Austrian Urogynaecology Working Group, the effect of age, BMI and parity at the time of surgery on short- and long-term outcomes of women primarily treated for SUI (stress urinary incontinence) with midurethral slings.

Methods: In the original study 554 patients received randomly a retropubic (TVT) or a transobturator midurethral (TVT-O) sling procedure. 480 (87%) and 277 (50%) patients were available for a follow-up efficacy evaluation at 3 months and 5 years respectively.

Results: Higher age and BMI at surgery appear to lead to a larger probability to have a positive stress test 5 years after surgery, but not after 3 months. Older patients seem to have a worse perception of improvement 5 years after surgery as compared to younger ones, as described by the PGI-I score. Age and BMI do not affect significantly the quality of life of women surgically treated for SUI, as reflected by the results of King´s Health Questionnaire. Parity does not seem to have any effect on objective and subjective surgical outcomes.

Conclusions: Higher age and BMI at surgery have a detrimental influence on the objective cure rate at 5 years after midurethral sling surgery; higher age also has a negative influence on subjective long-term outcomes. However, these demographic parameters do not influence significantly the quality of life of patients after anti-incontinence surgery. Parity does not show any significant influence on success rate of midurethral sling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201167PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095512PMC
February 2019

Robustness of testing procedures for confirmatory subpopulation analyses based on a continuous biomarker.

Stat Methods Med Res 2019 06 11;28(6):1879-1892. Epub 2018 Jun 11.

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

With the advent of personalized medicine, clinical trials studying treatment effects in subpopulations are receiving increasing attention. The objectives of such studies are, besides demonstrating a treatment effect in the overall population, to identify subpopulations, based on biomarkers, where the treatment has a beneficial effect. Continuous biomarkers are often dichotomized using a threshold to define two subpopulations with low and high biomarker levels. If there is insufficient information on the dependence structure of the outcome on the biomarker, several thresholds may be investigated. The nested structure of such subpopulations is similar to the structure in group sequential trials. Therefore, it has been proposed to use the corresponding critical boundaries to test such nested subpopulations. We show that for biomarkers with a prognostic effect that is not adjusted for in the statistical model, the variability of the outcome may vary across subpopulations which may lead to an inflation of the family-wise type 1 error rate. Using simulations we quantify the potential inflation of testing procedures based on group sequential designs. Furthermore, alternative hypotheses tests that control the family-wise type 1 error rate under minimal assumptions are proposed. The methodological approaches are illustrated by a trial in depression.
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http://dx.doi.org/10.1177/0962280218777538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566459PMC
June 2019

Association of anterior and posterior occlusal planes with different Angle and skeletal classes in permanent dentitions : A lateral cephalometric radiograph study.

J Orofac Orthop 2018 Jul 17;79(4):267-276. Epub 2018 May 17.

Austrian Cluster for Hard Tissue and Biomaterial Research, Karl Donath Laboratory, Medical University of Vienna, Sensengasse 2a, 1090, Vienna, Austria.

Objectives: Malocclusions affect about two-thirds of the population and orthodontic treatment is justified in 65% of these. However, the associations between anterior and posterior occlusal plane (AOP, POP) inclinations and Angle classification are lacking.

Patients And Methods: In a retrospective study, lateral cephalometric radiograph tracings of 230 previously untreated Caucasians, aged 13 to 49 years, yielded inclines of the bisector occlusal plane, AOP, and POP. All inclinations were referenced to the Sella-Nasion line and the Frankfort horizontal and were assigned to the Angle classification as well as skeletal groups (retrognathic, neutral, prognathic). Quantile regressions were calculated.

Results: In the skeletal groups the angles between Sella-Nasion line and both AOP and POP were significantly different between the groups (p < 0.01), showing steep inclines in skeletal class II and flat inclines in skeletal class III. The angles Frankfort horizontal-to-POP and Frankfort horizontal-to-AOP showed the same trends but only the latter differed significantly between the groups (p = 0.02). Among the Angle groups, AOP inclinations did not differ significantly for both reference planes whereas POP inclinations were significantly different (p = 0.01 to Frankfort horizontal, p = 0.02 to Sella-Nasion). Angle class I patients showed the flattest POP.

Conclusion: Occlusal plane inclines, measured to Sella-Nasion, were more consistent than those referenced to Frankfort horizontal. Sella-Nasion related anterior and posterior occlusal plane inclinations were steep in skeletal class II and flat in skeletal class III patients over all quantiles. Using the Angle classification, anterior and posterior occlusal plane inclinations did not follow this principle.
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http://dx.doi.org/10.1007/s00056-018-0139-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061169PMC
July 2018

Strength training increases skeletal muscle quality but not muscle mass in old institutionalized adults: a randomized, multi-arm parallel and controlled intervention study.

Eur J Phys Rehabil Med 2018 Dec 7;54(6):921-933. Epub 2018 Mar 7.

Research Platform Active Ageing, University of Vienna, Vienna, Austria.

Background: Age related loss of skeletal muscle mass is accompanied by changes in muscle quality leading to impairment of functional status.

Aim: This study investigated the effect of resistance training and nutritional supply on muscle mass and muscle quality in very old institutionalized adults.

Design: Prospective, randomized, multi-arm parallel and controlled intervention study.

Setting: This study was conducted in five retirement care facilities.

Population: This subgroup of the Vienna Active Ageing Study included 54 women and men (82.4±6.0 years) with impaired health status. Participants were randomly assigned either to elastic band resistance training (N.=16), training with nutritional supplementation (N.=21) or control group (N.=17).

Methods: Health status was assessed at baseline with functional tests, cognitive status, nutritional status, sum of medications as well as sum of diseases. Skeletal muscle mass, determined by dual-energy X-ray absorptiometry, isokinetic knee extension and flexion force and handgrip strength were assessed at baseline and after 6 months. Muscle quality of lower extremities was defined as ratio of the extensor (MQ_LE (Ext.)) or flexor strength (MQ_LE (Flex.)) to lean leg mass. Muscle quality of upper extremity was defined as ratio of handgrip strength to lean arm mass. Follow-up examinations were performed after 12 and 18 months of intervention.

Results: Muscle quality, but not muscle mass, showed significant correlations to functional tests at baseline (0.300 - 0.614, P<0.05). Resistance training significantly enhanced muscle quality of lower extremity after 6 months (MQ_LE (Ext.) +19.8%, MQ_LE (Flex.) +30.8%, P<0.05). Nutritional supplementation could not further increase the training effect. Participants with lower muscle quality at baseline benefit most from the training intervention. Skeletal muscle mass was not changed by any intervention.

Conclusions: Resistance training with elastic bands improved muscle quality in very old people. Additional nutritional supplementation was not able to further improve the effects obtained by training alone.

Clinical Rehabilitation Impact: Elastic band resistance training could be safely used to improve muscle quality even in old people with impaired health status. Weak and chronically ill participants benefit most from this training.
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http://dx.doi.org/10.23736/S1973-9087.18.04930-4DOI Listing
December 2018

Microscopic biliary and perineural invasion and clinical outcome after neoadjuvant bevacizumab-based chemotherapy and liver resection in patients with colorectal liver metastases.

Eur J Surg Oncol 2018 Jan 26;44(1):139-147. Epub 2017 Nov 26.

Department of General Surgery, Medical University Vienna, Austria.

Background: The value of microscopic biliary and perineural invasion as prognostic biomarkers in patients with resectable colorectal liver metastases (CLM) who undergo neoadjuvant chemotherapy and liver resection is still unclear. This retrospective study was performed to elucidate this issue.

Methods: Histologic slides of resected CLM of patients who underwent neoadjuvant bevacizumab-based chemotherapy and liver resection were investigated with respect to biliary and perineural invasion. Presence of invasion was correlated with radiologic and histologic response, recurrence-free survival (RFS) and overall survival (OS).

Results: One hundred forty-one patients were enrolled. There was a significant association between biliary and perineural invasion, respectively (P = 0.001). Moreover, both biliary and perineural invasion were associated with bilobar metastatic spread and higher number of metastases, while perineural invasion was also associated with a higher Fong score. No significant association was found with response. In univariable analysis, biliary and perineural invasion were associated with shorter RFS (median 10.1 vs. 13.5 months, HR 2.09, P = 0.010 and 7.6 vs. 14.0, HR 2.23, P = 0.001, respectively). Biliary invasion was also associated with shorter OS (median 32.8 months vs. not reached, HR 2.78, P = 0.010), however these results did not remain significant in multivariable analysis.

Conclusions: In patients with resectable colorectal liver metastases undergoing neoadjuvant bevacizumab-based chemotherapy and liver resection, biliary and perineural invasion are associated with higher tumor load but may not be prognostic biomarkers.
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http://dx.doi.org/10.1016/j.ejso.2017.11.018DOI Listing
January 2018

The dosage-dependent effect exerted by the NM23-H1/H2 homolog NDK-1 on distal tip cell migration in C. elegans.

Lab Invest 2018 02 18;98(2):182-189. Epub 2017 Sep 18.

Department of Biological Anthropology, ELTE Eötvös Loránd University, Budapest, Hungary.

Abnormal regulation of cell migration and altered rearrangement of the cytoskeleton are fundamental properties of metastatic cells. The first identified metastasis suppressor NM23-H1, which displays nucleoside-diphosphate kinase (NDPK) activity is involved in these processes. NM23-H1 inhibits the migratory and invasive potential of some cancer cells. Correspondingly, numerous invasive cancer cell lines (eg, breast, colon, oral, hepatocellular carcinoma, and melanoma) display low endogenous NM23 levels. In this review, we summarize mechanisms, which are linked to the anti-metastatic activity of NM23. In human cancer cell lines NM23-H1 was shown to regulate cytoskeleton dynamics through inactivation of Rho/Rac-type GTPases. The Drosophila melanogaster NM23 homolog abnormal wing disc (AWD) controls tracheal and border cell migration. The molecular function of AWD is well characterized in both processes as a GTP supplier of Shi/Dynamin whereby AWD regulates the level of chemotactic receptors on the surface of migrating cells through receptor internalization, by its endocytic function. Our group studied the role of the sole group I NDPK, NDK-1 in distal tip cell (DTC) migration in Caenorhabditis elegans. In the absence of NDK-1 the migration of DTCs is incomplete. A half dosage of NDPK as present in ndk-1 (+/-) heterozygotes results in extra turns and overshoots of migrating gonad arms. Conversely, an elevated NDPK level also leads to incomplete gonadal migration owing to a premature stop of DTCs in the third phase of migration, where NDK-1 acts. We propose that NDK-1 exerts a dosage-dependent effect on the migration of DTCs. Our data derived from DTC migration in C. elegans is consistent with data on AWD's function in Drosophila. The combined data suggest that NDPK enzymes control the availability of surface receptors to regulate cell-sensing cues during cell migration. The dosage of NDPKs may be a coupling factor in cell migration by modulating the efficiency of receptor recycling.
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http://dx.doi.org/10.1038/labinvest.2017.99DOI Listing
February 2018