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Holoprosencephaly (HPE) is the most common embryonic forebrain developmental anomaly. It involves incomplete or absent division of the prosencephalon into two distinct cerebral hemispheres during the early stages of organogenesis. HPE is etiologically heterogeneous, and its clinical presentation is very variable. We report a case of a 7 month old female infant, diagnosed with non-syndromic semilobar holoprosencephaly, caused by a novel, de novo pathogenic variant in ZIC2 - one of the most commonly mutated genes in non-syndromic HPE coding for the ZIC2 transcription factor. The patient presented with microcephaly, mild facial dysmorphic features, central hypotonia and spasticity on all four extremities. Ultrasound imaging demonstrated the absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna and brain MRI with confirmed the diagnosis of HPE. Early diagnosis and management are important for the prevention and treatment of complications associated with this condition.

In this paper, we investigated the impact of financial leverage on investment decisions on a sample of 811 firms from ten emerging South-Eastern European countries (Bosnia and Herzegovina, Bulgaria, Montenegro, Croatia, Greece, Romania, North Macedonia, Slovenia, Serbia and Turkey). We apply a panel regression model involving investment ratio as a dependent variable, leverage as independent variable, and control for several firm characteristics that closely determines the corporate investments. The results of the analysis show that leverage is negatively related to investment in the companies in SEE. But only long term debt has a stronger negative impact on investment for firms with low growth opportunities than for firms with high growth opportunities. These findings show supportive evidence of agency theories of corporate leverage, especially with the debt overhang theory, but did not give strong validation that leverage has a disciplining role for firms with low growth opportunities in SEE emerging markets. In addition to leverage, we found that corporate investments in the SEE countries decrease significantly with tangibility and the company size. Corporate investments in the SEE countries increase significantly with cash flow, sales, non-debt tax shield and profitability. Overall, the results slightly defer with those from the research on the case of developed markets.

The increasing use of genomic testing in neonatal intensive care units (NICU) gives rise to ethical issues. Yet little is known regarding what health professionals implementing the testing think about its ethical aspects. We therefore explored the views of Australian clinical geneticists towards ethical issues in the use of genomic testing in the Neonatal Intensive care Unit (NICU). Semi-structured interviews with 11 clinical geneticists were conducted, transcribed and analysed thematically. Four themes were identified: 1) Consent: the craft is in the conversation, which encapsulated the challenges in the consent process, and with pre-test counseling; 2) Whose autonomy and who decides? This illustrates the balancing of clinical utility and potentially harms the test, and how stakeholder interests are balanced; 3) The winds of change and ethical disruption, recognizing that while professional expertise is vital to clinical decision-making and oversight of mainstreaming, participants also expressed concern over the size of the genetics workforce and 4). Finding Solutions – the resources and mechanisms to prevent and resolve ethical dilemmas when they arise, such as quality genetic counseling, working as a team and drawing on external ethics and legal expertise. The findings highlight the ethical complexities associated with genomic testing in the NICU. They suggest the need for a workforce that has the necessary support and skills to navigate the ethical terrain, drawing on relevant ethical concepts and guidelines to balance the interests of neonates, their careers and health professionals.

Supplemental Materials Part A: Supplementary Tables and Figures Part B: Supplementary Methods Supplementary Table S1. Clinicopathological characteristics of non-malignant and prostate cancer tissue samples used for bisulfite sequencing, Illumina 27K or 450K Infinium analysis Supplementary Table S2. GABRE expression in 9 independent PC datasets available from the ONCOMINE database Supplementary Table S3: Genes downregulated more than 0.5 fold (log2) in both PC3 and DU145 cells when overexpressing miR-224 compared to scrambled transfected cells (only genes with crosshyb_type = 1 were considered). Supplementary Table S4: Genes downregulated more than 0.5 fold (log2) in both PC3 and DU145 cells when overexpressing miR-452 compared to scrambled transfected cells (only genes with crosshyb_type = 1 were considered). Supplementary Table S5. Shortlist of potential miR-224 and miR-452 target genes Supplementary Table S6. Uni- and multivariate Cox regression analyses of biochemical recurrence-free survival in two RP cohorts. Supplementary Table S7. Uni- and multivariate Cox regression analysis of GABRE, miR-224, and miR-452 expression in relation to biochemical recurrence-free survival in the Taylor et al. RP cohort. Supplementary Table S8. Uni- and multivariate Cox regression analysis of GABRE/miR-452/miR-224 and OAZ2 (predicted miR-452 target) gene expression in relation to biochemical recurrence-free survival in the Taylor et al. RP cohort. Supplementary Figure S1. Flow charts describing sample inclusion/exclusion criteria. Supplementary Figure S2. Positive correlations between miR-224, miR-452, and GABRE expression Supplementary Figure S3. Methylation patterns of 52 CpG sites in the GABRE~miR-452~miR-224 promoter associated CpG island determined by bisulfite sequencing of prostate tissue samples from adjacent non-malignant (AN, n=7), benign prostatic hyperplasia (BPH, n=4), localized PC (LPC, n=10), and primary tumor samples from patients with metastatic PC (MPC, n=10). Supplementary Figure S4. A. Bisulfite sequencing of 52 CpG sites in the GABRE promoterassociated CpG island in three nonmalignant (PrEC, BPH1, PNT1A) and six prostate cancer cell lines (22rv1, LNCaP, VCaP, DuCaP, DU145, PC3). Supplementary Figure S5. 450K Infinium data for the GABRE~miR-224~miR-452 locus and neighboring genes at Xq28. Supplementary Figure S6. Gene-set Enrichment Analysis of "Canonical Pathways" for genes down/upregulated in DU145 or PC3 cells after miR-224 or miR-452 transfection, respectively (compared to non/scr-transfected cells and corrected for transfection-related non-specific effects). Supplementary Figure S7. Association between GABRE/MYOD1 methylation levels and clinicopathological parameters in two RP patient cohorts.

Purpose: Available tools for prostate cancer diagnosis and prognosis are suboptimal and novel biomarkers are urgently needed. Here, we investigated the regulation and biomarker potential of the GABRE∼miR-452∼miR-224 genomic locus.Experimental Design: GABRE/miR-452/miR-224 transcriptional expression was quantified in 80 nonmalignant and 281 prostate cancer tissue samples. GABRE∼miR-452∼miR-224 promoter methylation was determined by methylation-specific qPCR (MethyLight) in 35 nonmalignant, 293 prostate cancer [radical prostatectomy (RP) cohort 1] and 198 prostate cancer tissue samples (RP cohort 2). Diagnostic/prognostic biomarker potential of GABRE∼miR-452∼miR-224 methylation was evaluated by ROC, Kaplan–Meier, uni- and multivariate Cox regression analyses. Functional roles of miR-224 and miR-452 were investigated in PC3 and DU145 cells by viability, migration, and invasion assays and gene-set enrichment analysis (GSEA) of posttransfection transcriptional profiling data.Results:GABRE∼miR-452∼miR-224 was significantly downregulated in prostate cancer compared with nonmalignant prostate tissue and had highly cancer-specific aberrant promoter hypermethylation (AUC = 0.98). Functional studies and GSEA suggested that miR-224 and miR-452 inhibit proliferation, migration, and invasion of PC3 and DU145 cells by direct/indirect regulation of pathways related to the cell cycle and cellular adhesion and motility. Finally, in uni- and multivariate analyses, high GABRE∼miR-452∼miR-224 promoter methylation was significantly associated with biochemical recurrence in RP cohort 1, which was successfully validated in RP cohort 2.Conclusion: The GABRE∼miR-452∼miR-224 locus is downregulated and hypermethylated in prostate cancer and is a new promising epigenetic candidate biomarker for prostate cancer diagnosis and prognosis. Tumor-suppressive functions of the intronic miR-224 and miR-452 were demonstrated in two prostate cancer cell lines, suggesting that epigenetic silencing of GABRE∼miR-452∼miR-224 may be selected for in prostate cancer. Clin Cancer Res; 20(8); 2169–81. ©2014 AACR.

Aims In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children’s deaths as part of an inquiry into the mother’s convictions. Methods and results Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. Conclusion A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths., Graphical Abstract

This research was supported by the European Commission's Horizon 2020 Framework Programme (ACTRIS2 (grant agreement no. 654109)), the University of Helsinki, the Finnish Meteorological Institute, the Department of Science and Innovation of South Africa, the Academy of Finland Centre of Excellence programme (project no. 272041), the Academy of Finland project Greenhouse gas, aerosol and albedo variations in the changing Arctic (project no. 269095), the Novel Assessment of Black Carbon in the Eurasian Arctic: From Historical Concentrations and Sources to Future Climate Impacts (NABCEA, project no. 296302), the Korea Meteorological Administration Research and Development Program "Development of Monitoring and Analysis Techniques for Atmospheric Composition in Korea" (grant no. KMA2018-00522), the National Research Foundation of Korea (grant no. 2017R1D1A1B06032548), the Korea Meteorological Administration Research and Development Program (grant no. KMI2018-01111), the Taiwan Environmental Protection Administration, the China Meteorological Administration, the National Scientific Foundation of China (41675129, 41875147), the National Key R&D Program of the Ministry of Science and Technology of the People's Republic of China (grant no. 2016YFC0203305 and 2018YFC0213204), the Chinese Academy of Meteorological Sci-ences (2020KJ001), the Innovation Team for Haze-fog Observation and Forecasts of MOST and CMA, CNRS-INSU, the French Ministry for Research under the ACTRIS-FR national research infrastructure, the French Ministry of the Environment, MeteoSwiss (GAW-CH aerosol monitoring programme), the Swiss State Secretariat for Education, Research and Innovation (SERI), the Ministry of Education, Youth and Sports of CR within National Sustainability Program I (NPU I, grant no. LO1415), ERDF "ACTRISCZ RI" (grant no. CZ.02.1.01/0.0/0.0/16_013/0001315), CRISOL (CGL2017-85344-R MINECO/AEI/FEDER, UE), TIGAS-CM (Madrid Regional Government Y2018/EMT-5177), AIRTECCM (Madrid Regional Government P2018/EMT4329), REDMAAS2020 (RED2018-102594-T CIENCIA), Red de Excelencia ACTRIS-ESPANA (CGL2017-90884-REDT), the Spanish Ministry of Economy, Industry and Competitiveness, FEDER funds (project HOUSE, grant no. CGL2016-78594-R), the Generalitat de Catalunya (AGAUR 2017 SGR41 and the DGQA), the National Institute for Aerospace Technology, the Ministerio Espanol de Economia, Industria y Competitividad (MINECO), the Spanish Ministry of Economy and Competitiveness (projects no. CGL2016-81092-R, CGL2017-90884-REDT, RTI2018-097864-BI00 and PGC2018-098770-B-I00), the Andalusia Regional Government (project no. P18-RT-3820), the PANhellenic infrastructure for Atmospheric Composition and climate change (MIS 5021516), Research and Innovation Infrastructure, Competitiveness, Entrepreneurship and Innovation (grant no. NSRF 20142020), the Italian Ministry of Research and Education, the Norwegian Environment Agency, Swedish FORMAS, the Swedish Research Council (VR), the Magnus Bergvall foundation, the Marta och Erik Holmberg foundation, and the Swedish EPA., Aerosol particles are a complex component of the atmospheric system which influence climate directly by interacting with solar radiation, and indirectly by contributing to cloud formation. The variety of their sources, as well as the multiple transformations they may undergo during their transport (including wet and dry deposition), result in significant spatial and temporal variability of their properties. Documenting this variability is essential to provide a proper representation of aerosols and cloud condensation nuclei (CCN) in climate models. Using measurements conducted in 2016 or 2017 at 62 ground-based stations around the world, this study provides the most up-to-date picture of the spatial distribution of particle number concentration (N-tot) and number size distribution (PNSD, from 39 sites). A sensitivity study was first performed to assess the impact of data availability on N-tot's annual and seasonal statistics, as well as on the analysis of its diel cycle. Thresholds of 50% and 60% were set at the seasonal and annual scale, respectively, for the study of the corresponding statistics, and a slightly higher coverage (75 %) was required to document the diel cycle. Although some observations are common to a majority of sites, the variety of environments characterizing these stations made it possible to highlight contrasting findings, which, among other factors, seem to be significantly related to the level of anthropogenic influence. The concentrations measured at polar sites are the lowest (similar to 10(2) cm(-3)) and show a clear seasonality, which is also visible in the shape of the PNSD, while diel cycles are in general less evident, due notably to the absence of a regular day-night cycle in some seasons. In contrast, the concentrations characteristic of urban environments are the highest (similar to 10(3)-10(4) cm(-3)) and do not show pronounced seasonal variations, whereas diel cycles tend to be very regular over the year at these stations. The remaining sites, including mountain and non-urban continental and coastal stations, do not exhibit as obvious common behaviour as polar and urban sites and display, on average, intermediate N-tot (similar to 10(2)-10(3) cm(-3)). Particle concentrations measured at mountain sites, however, are generally lower compared to nearby lowland sites, and tend to exhibit somewhat more pronounced seasonal variations as a likely result of the strong impact of the atmospheric boundary layer (ABL) influence in connection with the topography of the sites. ABL dynamics also likely contribute to the diel cycle of N-tot observed at these stations. Based on available PNSD measurements, CCN-sized particles (considered here as either >50 nm or >100 nm) can represent from a few percent to almost all of N-tot, corresponding to seasonal medians on the order of similar to 10 to 1000 cm(-3), with seasonal patterns and a hierarchy of the site types broadly similar to those observed for N-tot. Overall, this work illustrates the importance of in situ measurements, in particular for the study of aerosol physical properties, and thus strongly supports the development of a broad global network of near surface observatories to increase and homogenize the spatial coverage of the measurements, and guarantee as well data availability and quality. The results of this study also provide a valuable, freely available and easy to use support for model comparison and validation, with the ultimate goal of contributing to improvement of the representation of aerosol-cloud interactions in models, and, therefore, of the evaluation of the impact of aerosol particles on climate., European Commission's Horizon 2020 Framework Programme (ACTRIS2) 654109, University of Helsinki, Finnish Meteorological Institute, Department of Science and Innovation of South Africa, Academy of Finland 272041, Academy of Finland project Greenhouse gas, aerosol and albedo variations in the changing Arctic 269095, Novel Assessment of Black Carbon in the Eurasian Arctic: From Historical Concentrations and Sources to Future Climate Impacts (NABCEA) 296302, Korea Meteorological Administration Research and Development Program "Development of Monitoring and Analysis Techniques for Atmospheric Composition in Korea" KMA2018-00522, National Research Foundation of Korea 2017R1D1A1B06032548, Korea Meteorological Administration Research and Development Program KMI2018-01111, Taiwan Environmental Protection Administration, China Meteorological Administration, National Natural Science Foundation of China (NSFC) 41675129 41875147, National Key R&D Program of the Ministry of Science and Technology of the People's Republic of China 2016YFC0203305 2018YFC0213204, Chinese Academy of Meteorological Sciences 2020KJ001, Innovation Team for Haze-fog Observation and Forecast of MOST Innovation Team for Haze-fog Observation and Forecast of CMA Innovation Team for Haze-fog Observation and Forecast of CNRS-INSU, French Ministry for Research under the ACTRIS-FR national research infrastructure, French Ministry of the Environment, MeteoSwiss (GAW-CH aerosol monitoring programme), Swiss State Secretariat for Education, Research and Innovation (SERI), Ministry of Education, Youth and Sports of CR within National Sustainability Program I (NPU I) LO1415, ERDF "ACTRISCZ RI" CZ.02.1.01/0.0/0.0/16_013/0001315, CRISOL CGL2017-85344, TIGAS-CM (Madrid Regional Government) Y2018/EMT-5177, AIRTECCM (Madrid Regional Government) P2018/EMT4329, REDMAAS2020 RED2018-102594-T, Red de Excelencia ACTRIS-ESPANA CGL2017-90884-REDT, Spanish Ministry of Economy, Industry and Competitiveness, FEDER funds CGL2016-78594-R, Generalitat de Catalunya, General Electric AGAUR 2017 SGR41, National Institute for Aerospace Technology, Ministerio Espanol de Economia, Industria y Competitividad (MINECO) Spanish Government CGL2017-90884-REDT CGL2016-81092-R RTI2018-097864-BI00 PGC2018-098770-B-I00, Andalusia Regional Government P18-RT-3820, PANhellenic infrastructure for Atmospheric Composition and climate change MIS 5021516, Research and Innovation Infrastructure, Competitiveness, Entrepreneurship and Innovation NSRF 20142020, Ministry of Education, Universities and Research (MIUR), Norwegian Environment Agency, Swedish FORMAS, Swedish Research Council, Magnus Bergvall foundation, Marta och Erik Holmberg foundation, Swedish EPA

Objectives T o evaluate the value of multiparametric MRI (mpMRI) for the prediction of prostate cancer (PCA) aggressiveness. Methods In this single center cohort study, consecutive patients with histologically confirmed PCA were retrospectively enrolled. Four different ISUP grade groups (1, 2, 3, 4–5) were defined and fifty patients per group were included. Several clinical (age, PSA, PSAD, percentage of PCA infiltration) and mpMRI parameters (ADC value, signal increase on high b-value images, diameter, extraprostatic extension [EPE], cross-zonal growth) were evaluated and correlated within the four groups. Based on combined descriptors, MRI grading groups (mG1–mG3) were defined to predict PCA aggressiveness. Results In total, 200 patients (mean age 68 years, median PSA value 8.1 ng/ml) were analyzed. Between the four groups, statistically significant differences could be shown for age, PSA, PSAD, and for MRI parameters cross-zonal growth, high b-value signal increase, EPE, and ADC (p p p = 0.09). A mixed linear model demonstrated the strongest prediction of the respective ISUP grade group for the MRI grading system (p Conclusions MpMRI yields relevant pre-biopsy information about PCA aggressiveness. A combination of quantitative and qualitative parameters (MRI grading groups) provided the best prediction of the biopsy ISUP grade group and may improve clinical pathway and treatment planning, adding useful information beyond PI-RADS assessment category. Due to the high prevalence of higher grade PCA in patients within mG3, an early re-biopsy seems indicated in cases of negative or post-biopsy low-grade PCA. Key Points • MpMRI yields relevant pre-biopsy information about prostate cancer aggressiveness. • MRI grading in addition to PI-RADS classification seems to be helpful for a size independent early prediction of clinically significant PCA. • MRI grading groups may help urologists in clinical pathway and treatment planning, especially when to consider an early re-biopsy.

Sialidase preparations are applied in structural and functional studies on sialoglycans, in the production of sialylated therapeutic proteins and synthetic substrates for use in biochemical research, etc. They are obtained mainly from pathogenic microorganisms; therefore, the demand for apathogenic producers of sialidase is of exceptional importance for the safe production of this enzyme. Here, we report for the first time the presence of a sialidase gene and enzyme in the saprophytic actinomycete

β-galactosidase is an enzyme with dual activity and important industrial application. As a hydrolase, the enzyme eliminates lactose in milk, while as a trans-galactosidase it produces prebiotic galactooligosaccharides (GOS) with various degrees of polymerization (DP). The aim of the present study is the molecular characterization of β-galactosidase from a Bulgarian isolate

Increased TLR7 signaling leading to type-I IFN production is an important contributor to human systemic lupus erythematosus (SLE). PACSIN1, a molecule that regulates synaptic vesicle recycling, has been linked to TLR7/9-mediated type I interferon production in mice, but the underlying mechanism is unknown. We undertook this study to explore pathogenicity and underlying mechanism of a de novo PACSIN1 missense variant identified in a child with SLE.PACSIN1 Q59K de novo and null variants were introduced into a human pDC cell line and mice by CRISPR/Cas9 editing. The effects of the variants on TLR7/9 signaling in human and mouse cells, as well as PACSIN1 mRNA and interferon signature in SLE patients, were assessed by real-time PCR and flow cytometry. Mechanisms were investigated by luciferase reporter assays, RNA interference, co- immunoprecipitation, and immunofluorescence.We established that PACSIN1 forms a trimolecular complex with TRAF4 and TRAF6 important for the regulation of type I-IFN. The Q59K mutation in PACSIN1 augments binding to N-WASP whilst it decreases binding to TRAF4, leading to unrestrained TRAF6-mediated activation of type-I IFN. Intriguingly, PACSIN1 Q59K increased TLR7 but not TLR9 signaling in human cells, leading to elevated IFN-β and interferon-inducible genes. Untreated SLE patients had high PACSIN1 expression in peripheral blood cells that correlated positively with interferon-related genes. Introduction of the Pacsin1 Q59K into mice caused increased surface TLR7 and Trail expression in B cells.PACSIN1 Q59K increases IFN-β activity via impairing TRAF4-mediated inhibition of TLR7 signaling, possibly contributing to SLE risk. This article is protected by copyright. All rights reserved.

To determine the capability of Gadolinium-free arterial spin labelling (ASL) sequences as novel, contrast-free, non-invasive alternative perfusion imaging method to differentiate prostate cancer (PCA) from benign prostate tissue compared to conventional DCE MRI.Thirty men with histologically confirmed PCA were included in this prospectively enrolled single center cohort study. All patients received multiparametric MRI (T2, DWI, DCE) at 3 T with additional ASL of the PCA lesion. Primary endpoint was differentiability of PCA versus benign prostate tissue by signal intensities (SI) and contrast ratios (CR) in ASL in comparison to DCE. For DCE also Signal-Enhancement-Ratio (SER) of native and early contrast enhancement SI was assessed. Secondary objectives were differences regarding PCA localisation in peripheral (PZ) or transition zone (TZ) and PCA detection.In both, ASL and DCE, average SI of PCA differed significantly from SI in benign tissue in the TZ and PZ (p 0,01, respectively). ASL had significantly higher CR discerning PCA and benign tissue in PZ and TZ (PZ = 5.19; TZ = 6.45) compared to DCE SI (PZ = 1.61; TZ = 1.43) and DCE SER (PZ = 1.59; TZ = 1.43) (p 0.01, respectively). In subjective evaluation, PCA could be detected in ASL in 28 patients, compared to 29 in DCE.ASL had significantly higher CR differentiating PCA from benign tissue in PZ and TZ compared to DCE. Visual detection of PCA does not differ significantly between the two sequences. As perfusion gadolinium-based contrast media is seen more critical in the last few years, ASL seems to be a promising alternative to DCE in PCA detection.

Das Prostatakarzinom (PCa) ist die haufigste Krebserkrankung und die zweithaufigste Krebstodesursache bei Mannern in Industrielandern. Es gibt keine allgemein akzeptierte PCa-Fruherkennungsstrategie. Aus den Erfahrungen verschiedener internationaler Screeningstudien wurde 2014 die deutsche „Prostate Cancer Early Detection Study Based on a Baseline PSA Value in Young Men“ (PROBASE) etabliert. Basierend auf den positiven Ergebnissen retrospektiver Kohortenanalysen soll die PROBASE-Studie nachweisen, dass eine Fruherkennungsstrategie nach Risikozuordnung durch einen Basiswert fur das prostataspezifische Antigen (PSA) im Alter von 45 oder 50 Jahren eine Alternative zum populationsbasierten Screening darstellen kann. Grundsatzlich gibt es mehrere Ansatze, das populationsbezogene Screening des PCa zu verbessern. Bekannte Risikofaktoren fur ein PCa sind z. B. das Alter, eine bestimmte genetische Pradisposition (BRCA 1/2) und andere Keimbahnmutationen sowie einzelne somatische Mutationen. Die PROBASE-Studie konzentriert sich auf das Alter und die Bestimmung eines Basis-PSA Insgesamt 23.301 Teilnehmer wurden in den Studienarm A randomisiert. Die PSA-Baseline-Tests im Studienarm A kategorisierten 89,18 % der Teilnehmer in die niedrige, 9,32 % in die intermediare und 1,48 % in die hohe Risikogruppe. Damit entsprach die Risikozuordnung exakt der bislang berichteten Verteilung. Das vom Basis-PSA abhangige risikoadaptierte PSA-Screening hat das Potenzial, durch verlangerte Testintervalle in der Niedrigrisikogruppe das hohe Ausmas der Uberdiagnostik und letztlich auch der Ubertherapie insignifikanter PCa des populationsbasierten Screenings zu reduzieren. Parallel zu PROBASE werden aktuell mehrere risikoadaptierte Screeningstrategien weltweit getestet, deren Auswertung ebenfalls erst in einigen Jahren zu erwarten sein wird.

PROBASE is a population-based, randomized trial of 46 495 German men recruited at age 45 to compare effects of risk-adapted prostate cancer (PCa) screening starting either immediately at age 45, or at a deferred age of 50 years. Based on prostate-specific antigen (PSA) levels, men are classified into risk groups with different screening intervals: low-risk (3 ng/ml, recommendation for immediate biopsy). Over the first 6 years of study participation, attendance rates to scheduled screening visits varied from 70.5% to 79.4%, depending on the study arm and risk group allocation, in addition 11.2% to 25.4% of men reported self-initiated PSA tests outside the PROBASE protocol. 38.5% of participants had a history of digital rectal examination or PSA testing prior to recruitment to PROBASE, frequently associated with family history of PCa. These men showed higher rates (33% to 57%, depending on subgroups) of self-initiated PSA testing in-between PROBASE screening rounds. In the high-risk groups (both arms), the biopsy acceptance rate was 64% overall, but was higher among men with screening PSA ≥4 ng/ml (>71%) and with PIRADS ≥3 findings upon multiparameter magnetic resonance imaging (mpMRI) (>72%), compared with men with PSA ≥3 to 4 ng/ml (57%) or PIRADS score ≤ 2 (59%). Overall, PROBASE shows good acceptance of a risk-adapted PCa screening strategy in Germany. Implementation of such a strategy should be accompanied by a well-structured communication, to explain not only the benefits but also the harms of PSA screening. in press

Encapsulation of a selected DNA molecule in a cell has important implications for bionanotechnology. Non-viral proteins that can be used as nucleic acid containers include proteinaceous subcellular bacterial microcompartments (MCPs) that self-assemble into a selectively permeable protein shell containing an enzymatic core. Here, we adapted a propanediol utilization (Pdu) MCP into a synthetic protein cage to package a specified DNA segment in vivo, thereby enabling subsequent affinity purification. To this end, we engineered the LacI transcription repressor to be routed, together with target DNA, into the lumen of a Strep-tagged Pdu shell. Sequencing of extracted DNA from the affinity-isolated MCPs shows that our strategy results in packaging of a DNA segment carrying multiple LacI binding sites, but not the flanking regions. Furthermore, we used LacI to drive the encapsulation of a DNA segment containing operators for LacI and for a second transcription factor.

This study analyzes the value of dynamic contrast-enhanced MRI (DCE) of the prostate on 1.5 T and 3 T examinations in patients within PI-RADS category 4.In this retrospective, bi-centric, cohort study all consecutive patients classified as PI-RADS 4 in mpMRI with 100 verified prostate cancers (PCa) in subsequent MRI/US-guided fusion biopsy were included for 1.5 T and 3 T, each. PCa detection in index lesions (IL) upgraded to PI-RADS 4 based on positive DCE findings was compared between 1.5 T and 3 T. Secondary objectives are subgroup analysis of PZ lesions and comparison of ISUP grade group distribution between 1.5 T and 3 T.In total, 293 patients within PI-RADS category 4, including 152 (mean 66 ± 8y; median PSA 6.4 ng/ml;116 PZ IL) in the 1.5 T group and 141 (mean 65 ± 8y; median PSA 7.2 ng/ml;100 PZ IL) in the 3 T group were included. Overall amount of PCa (66 % vs 71 %; p = 0.346) and portion of upgraded IL (28 % vs 21 %; p = 0.126) did not differ significantly. At 1.5 T PCa detection was higher in upgraded PZ lesions compared to 3 T (23 % vs 14 %; p = 0.048). The amount of upgraded PZ lesions with ISUP grade group 2-5 PCa was significantly higher at 1.5 T versus 3 T (13.8 % vs 4.0 %; p = 0.007). 33 % (11/33; 1.5 T) and 32 % (10/31; 3 T) of the ISUP grade group 1 PCa of the PZ lesions were detected in upgraded lesions (10% of all PZ index lesions, respectively).DCE enabled the detection of a substantial amount of additional clinically significant PCa in prostate mpMRI at 1.5 T. The effect was smaller at 3 T and was accompanied in relation to 1.5 T by higher risk of overdiagnosis due to detection of additional low-risk PCa.

Primary retroperitoneal lymph node dissection (RPLND) for clinical stage (CS) IIA/B seminoma without adjuvant treatment is an experimental treatment to avoid radiotherapy- or chemotherapy-related toxicity from standard treatment.The PRIMETEST trial aimed to prospectively evaluate the oncological efficacy and surgical safety of primary RPLND.PRIMETEST is a single-arm, single-center prospective phase 2 trial. Patients with seminoma, unilateral retroperitoneal lymph node metastases5 cm, and human chorionic gonadotropin levels5 mU/ml were included. Patients with CS IIA/B seminoma at initial diagnosis, and recurrence under active surveillance or following adjuvant carboplatin for CS I disease were eligible.Unilateral open or robot-assisted primary RPLND was performed. The primary endpoint of the study was progression-free survival (PFS) after 36 mo. The trial was considered positive if30% of patients experienced a recurrence.Between 2016 and 2021, 33 patients were accrued (nine with primary CS IIA/B, 19 recurrences during active surveillance, and five recurrences following adjuvant carboplatin). Thirteen and 20 patients had CS IIA and IIB, respectively. Open and robot-assisted RPLND procedures were performed in 14 (42%) and 19 (58%) patients, respectively. After a median follow-up of 32 mo (interquartile range 23-46), ten recurrences were detected (30%, 95% confidence interval: 16-49%); thus, the primary endpoint was not met. Infield recurrences occurred in three of ten patients. The current analysis of risk factors could not identify the predictors of recurrence. Three of 33 patients (9%) presented with pN0.The PRIMETEST trial did not meet its primary endpoint. Nevertheless, PFS of 70% after a median follow-up of 32 mo suggests this approach to be of interest for highly selected patients. Selection criteria, however, need to be defined and validated in a larger prospective cohort of patients. Until then, surgery alone for the treatment of patients with CS IIA/B seminoma cannot be recommended outside of a clinical trial setting.In this study, we investigated primary surgery as an alternative to conventional treatment (chemotherapy or radiation therapy) in patients with metastatic seminoma. The primary objective of the study, to prevent at least 30% of patients from recurrence, was not met. However, certain patients may benefit from this approach and thereby avoid chemotherapy or radiation therapy. Predictive factors need to be analyzed to better select patients for this surgery-only approach.

Real-time PCR (Polymerase Chain Reaction) or qPCR is a method by which the amount of the PCR product can be determined in real-time, and is very useful for investigating gene expression. The main advantages of qPCR are that it provides fast and high-throughput detection and quantification of target DNA sequences in different matrices. The lower time of amplification is facilitated by the simultaneous amplification and visualization of newly formed DNA amplicons. The development and application of molecular methods for the detection of pathogens has significantly changed the diagnosis and control of plant diseases, various environmental samples, including hosts tissues, soil, water and air. With real-time PCR method, it is possible not only to identify and detect the presence or absence of the target pathogen, but it is also possible to quantify the amount present in the sample allowing the quantitative assessment of the number of the pathogen in the sample. Detection and accurate identification of plant pathogens is one of the most important strategies for controlling plant diseases to initiate preventive or curative measures. Plum pox virus (PPV), the agent of sharka, is the most devastating virus infecting stone fruits. The PPV control is mainly based on prevention, and its quick and reliable detection is considered crucial in this strategy. In this study DAS-ELISA and real-time PCR were compared for evaluating their potentialities and limits for large scale surveys. Plum (Prunus domestica L.) hosts and apricot (Prunus armeniaca L.) samples from several different locations were included in laboratory test analyzes, plant organs (phloem, buds, flowers, leaves and fruits) and parts of them, different seasons (spring, summer and winter period 2017/20), presence or absence of symptoms were considered for comparison. Using DAS-ELISA tests and a universal set of antibodies (BIOREBA), have proved the presence of virus of Plum pox in all examined samples, especially from samples collected in summer, but also in virus status examination in winter and early spring season. The examination found high concentrations of viral antigens in plant samples (OD 2.912-2.752, for 30 min / 405 nm). Real-time PCR show amplification plot for positive PPV samples on plums and apricot.

Introduction Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits. Case presentation A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Conclusion Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.

The North Atlantic Treaty Organization (NATO) is the premier and only security alliance uniting 30 countries and growing with many partner states in the provision of collective security and against threats posed by conflict and natural disasters. Security of countries and communities is increasingly threatened by a broad spectrum of unconventional types of war and disease threats - from hybrid and asymmetric to multi-domain and peer-to-peer/near-peer conflict. The NATO Centre of Excellence for Military Medicine (MILMED COE) is the centre of gravity for medical best practices and promotion of medical doctrine across the NATO alliance. Disaster medicine is multidisciplinary and in NATO, multinational, requiring best practices that are driven by data and evidence to prevent death on the battlefield and prepare for future conflicts. "Vigorous Warrior" is a live military and disaster medicine exercise series using both civilian and military actors across all sectors of health focused on health security and identifying lessons learned to ready the alliance for future threats. In this brief report, we make the case that the Vigorous Warrior exercise exposes gaps, highlights challenges and generates an evidence base to make NATO military medicine systems more robust, more efficient and in provision of best medical practices. We specifically argue that clinical data capture must be duplicated and continuous across the alliance to ensure evidence-based medicine stays current in NATO military medical doctrine.

Robotic assisted retroperitoneal lymph node dissection in patients with testicular cancer is controversial. Lately, unusual recurrence patterns with adverse outcomes after robotic assisted retroperitoneal lymph node dissection have been published. In this report we determine the feasibility, safety and early oncologic outcome of robotic assisted retroperitoneal lymph node dissection in patients with small volume metastatic testicular cancer.We retrospectively evaluated 27 consecutive patients with small volume metastatic testicular cancer (October 2010 to November 2019) who underwent robotic assisted retroperitoneal lymph node dissection (unilateral modified template). Intraoperative and postoperative complications as well as early oncologic outcomes are reported. Surgery was performed in the primary metastatic setting in 22 (81%), post-chemotherapy in 4 (15%) and for late relapse in 1 patient (4%). Initial clinical stage was IIA for 14 (52%), IIB for 12 (43%) and III for 1 (4%) patient.Median operative time, blood loss and length of hospital stay were 175 minutes, 50 ml and 4 days, respectively. Expectedly, viable tumor was found in 21/27 patients (78%) and 6 patients (22%) showed fibrosis, necrosis or no tumor. Overall 3 (11%) patients experienced intraoperative (Satava II) and 1 (4%) postoperative (Clavien-Dindo IIIb) complications, respectively. Median followup was 16.5 months (3-69), and 3 (11%) patients experienced relapse outside of the surgical field after 12, 22 and 36 months.In highly selected patients with low volume metastatic testicular cancer robotic assisted retroperitoneal lymph node dissection may be indicated, and appears to be technically feasible and comparable with open surgery in terms of complications and early oncologic safety. Prospective data collection in larger series is necessary to clarify the role and specific indications of this approach.

We present the first lasing results of SwissFEL, a hard X-ray free-electron laser (FEL) that recently came into operation at the Paul Scherrer Institute in Switzerland. SwissFEL is a very stable, compact and cost-effective X-ray FEL facility driven by a low-energy and ultra-low-emittance electron beam travelling through short-period undulators. It delivers stable hard X-ray FEL radiation at 1-A wavelength with pulse energies of more than 500 μJ, pulse durations of ~30 fs (root mean square) and spectral bandwidth below the per-mil level. Using special configurations, we have produced pulses shorter than 1 fs and, in a different set-up, broadband radiation with an unprecedented bandwidth of ~2%. The extremely small emittance demonstrated at SwissFEL paves the way for even more compact and affordable hard X-ray FELs, potentially boosting the number of facilities worldwide and thereby expanding the population of the scientific community that has access to X-ray FEL radiation. The first lasing results at SwissFEL, an X-ray free-electron laser, are presented, highlighting the facility’s unique capabilities. A general comparison to other major facilities is also provided.

This study aims to give an overview of the status of Erwinia amylovora, isolated from pear (Pyrus communis), wild pear (Pyrus pyraster), apple (Malus silvestris), and quince trees (Cydonia oblonga) from different localities in the Republic of North Macedonia, for the period 2015-2019. Classical biochemical analyses coupled to modern molecular diagnostic tools such as PCR and Real Time PCR were used for the determination of bacteria. Symptomatic fruit trees were no-ticed in almost all investigated localities in Republic of North Macedonia. The most expressed symptoms were recorded during the intensive growth of the shoots. Isolated strains elicited HR in tobacco, necrosis of pear seedlings, and immature pear fruits. Strains possess typical biochemical characteristics com-pared with the positive control, such as non-fluorescent, anaerobic (oxidase negative), levan production, and catalase enzymatic activity, doesn’t hydrolyze gelatine, aesculin, and starch, produce acid from sucrose, fructose, and galac-tose, etc. Amplification of the total bacterial DNA originating from apple, pear, wild pear, and quince trees using PCR followed by agarose electrophoresis, showed that PCR patterns for all investigated native strains are identical to the European reference strain (LMG 1883). TaqMan qPCR was used to quantify E. amylovora DNA from different host plants and locations, during the investigated period. The results indicate that the disease incidence is sporadic and crop dam-ages are of medium economic significance. E. amylovora in the Republic of North Macedonia was identified as a causal agent of fire blight on pear, wild pear, apple, and quince trees in young and old fruit orchards.

Збирката раскази „Викајте ме Естебан“ од Лејла Каламуиќ во оригинал на босански јазик („Zovite me Esteban“) е издадена во 2015 г., а во 2017 г. излегува од печат и преводот на македонски. Станува збор за автобиографска збирка и интимно четиво на една од најчитаните современи (квир) авторки денес во Босна и Херцеговина. Самиот оригинал изобилува со елементи особено интересни за проучување на повеќе јазични рамништа, а преводот, умешно следејќи ја мислата на Каламуиќ, одлично ја пресликува содржината на македонски јазик. Тргнувајќи oд тоа како „потстанарите“ Rat и Mir, на македонски стануваат Ратко и Мирко, преку басамаците и меаната во расказите каде што главни ликови се бабите и дедовците, сѐ до особено интересните преводи на дел од колоквијалната лексика, во овој труд правиме избор на повпечатливите преводни решенија, кои придонесуваат едно вакво емотивно и богато, а, сепак, минималистичко дело, да се почувствува „домашно“ на македонски јазик.

PURPOSE This study aims to analyze the ability of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to distinguish between prostate cancer (PCa) and benign lesions in transition zone (TZ) and peripheral zone (PZ) using different methods for arterial input function (AIF) determination. Study endpoints are identification of a standard AIF method and optimal quantitative perfusion parameters for PCa detection. METHODS DCE image data of 50 consecutive patients with PCa who underwent multiparametric MRI were analyzed retrospectively with three different methods of AIF acquisition. First, a region of interest was manually defined in an artery (AIFm); second, an automated algorithm was used (AIFa); and third, a population-based AIF (AIFp) was applied. Values of quantitative parameters after Tofts (Ktrans, ve, and kep) in PCa, PZ, and TZ in the three different AIFs were analyzed. RESULTS Ktrans and kep were significantly higher in PCa than in benign tissue independent from the AIF method. Whereas in PZ, Ktrans and kep could differentiate PCa (P.001), in TZ only kep using AIFpdemonstrated a significant difference (P = .039). The correlations of the perfusion parameters that resulted from AIFm and AIFa were higher than those that resulted from AIFp, and the absolute values of Ktrans, kep, and ve were significantly lower when using AIFp. The values of quantitative perfusion parameters for PCa were similar regardless of whether PCa was located in PZ or TZ. CONCLUSION Ktrans and kep were able to differentiate PCa from benign PZ independent of the AIF method. AIFaseems to be the most feasible method of AIF determination in clinical routine. For TZ, none of the quantitative perfusion parameters provided satisfying results.

Toxic ingredients in food can lead to serious food-related diseases. Such compounds are bacterial toxins (Shiga-toxin, listeriolysin, Botulinum toxin), mycotoxins (aflatoxin, ochratoxin, zearalenone, fumonisin), pesticides of different classes (organochlorine, organophosphate, synthetic pyrethroids), heavy metals, and natural antinutrients such as phytates, oxalates, and cyanide-generating glycosides. The generally regarded safe (GRAS) status and long history of lactic acid bacteria (LAB) as essential ingredients of fermented foods and probiotics make them a major biological tool against a great variety of food-related toxins. This state-of-the-art review aims to summarize and discuss the data revealing the involvement of LAB in the detoxification of foods from hazardous agents of microbial and chemical nature. It is focused on the specific properties that allow LAB to counteract toxins and destroy them, as well as on the mechanisms of microbial antagonism toward toxigenic producers. Toxins of microbial origin are either adsorbed or degraded, toxic chemicals are hydrolyzed and then used as a carbon source, while heavy metals are bound and accumulated. Based on these comprehensive data, the prospects for developing new combinations of probiotic starters for food detoxification are considered.

Background To assess the diagnostic value of an additional late-phase PET/CT scan after urination as part of 68 Ga-PSMA-11 PET/CT for the restaging of patients with biochemically recurrent prostate cancer (BCR). Methods This retrospective trial included patients with BCR following radical prostatectomy, who underwent standard whole-body early-phase PET/CT performed 105 ± 45 min and an additional late-phase PET/CT performed 159 ± 13 min after injection of 68 Ga-PSMA-11. Late-phase PET/CT covered a body volume from below the liver to the upper thighs and was conducted after patients had used the bathroom to empty their urinary bladder. Early- and late-phase images were evaluated regarding lesion count, type, localisation, and SUVmax. Reference standard was histopathology and/or follow-up imaging. Results Whole-body early-phase PET/CT detected 93 prostate cancer lesions in 33 patients. Late-phase PET/CT detected two additional lesions in two patients, both local recurrences. In total, there were 57 nodal, 28 bone, and 3 lung metastases, and 7 local recurrences. Between early- and late-phase PET/CT, lymph node metastases showed a significant increase of SUVmax from 14.5 ± 11.6 to 21.5 ± 17.6 (p = 0.00007), translating to a factor of + 1.6. Benign lymph nodes in the respective regions showed a significantly lower increase of SUVmax of 1.4 ± 0.5 to 1.7 ± 0.5 (p = 0.0014, factor of + 1.2). Local recurrences and bone metastases had a SUVmax on late-phase PET/CT that was + 1.7 and + 1.1 times higher than the SUVmax on early-phase PET/CT, respectively. Conclusion In patients with BCR following radical prostatectomy, an additional abdomino-pelvic late-phase 68 Ga-PSMA-11 PET/CT scan performed after emptying the urinary bladder may help to detect local recurrences missed on standard whole-body 68 Ga-PSMA-11 PET/CT. Lymph node metastases show a higher SUVmax and a stronger increase of SUVmax than benign lymph nodes on late-phase PET/CT, hence, biphasic 68 Ga-PSMA-11 PET/CT might help to distinguish between malignant and benign nodes. Bone metastases, and especially local recurrences, also demonstrate a metabolic increase over time.

The treatment of agricultural areas with pesticides is an indispensable approach to improve crop yields and cannot be avoided in the coming decades. At the same time, significant amounts of pesticides remain in food and their ingestion causes serious damage such as neurological, gastrointestinal, and allergic reactions; cancer; and even death. However, during the fermentation processing of foods, residual amounts of pesticides are significantly reduced thanks to enzymatic degradation by the starter and accompanying microflora. This review concentrates on foods with the highest levels of pesticide residues, such as milk, yogurt, fermented vegetables (pickles, kimchi, and olives), fruit juices, grains, sourdough, and wines. The focus is on the molecular mechanisms of pesticide degradation due to the presence of specific microbial species. They contain a unique genetic pool that confers an appropriate enzymological profile to act as pesticide detoxifiers. The prospects of developing more effective biodetoxification strategies by engaging probiotic lactic acid bacteria are also discussed.

Efficient data storage and query processing systems play a vital role in many different research areas. Blockchain technology and distributed ledgers attract massive attention and trigger multiple projects in various industries. Nevertheless, blockchain still lacks the features of a Database Management System (DBMS or simply databases), such as high throughput, low latency, and high capacity. For that purpose, there have been many proposed approaches for handling data storage and query processing solutions in the blockchain. This paper presents a complete overview of many different DBMS types and how these systems can be used to implement, enhance, and further improve blockchain technology. More concretely, we give an overview of 10 transactional, an extensive overview of 14 analytical, 9 hybrids, i.e., translytical, and 13 blockchain DBMSs. We explain how database technology has influenced the development of blockchain technology by unlocking different features, such as Atomicity, Consistency, Isolation, and Durability (ACID), transaction consistency, rich queries, real-time analysis, and low latency. Using a relaxation approach analogous to the one used to prove the Consistency, Availability, Partition tolerance (CAP)-theorem, we postulate a “Decentralization, Consistency, and Scalability (DCS)-satisfiability conjecture” and give concrete strategies for achieving the relaxed DCS conditions. We also provide an overview of the different DBMSs, emphasizing their architecture, storage manager, query processing, and implementation.

To evaluate if follow-up mpMRI scans of patients in PI-RADS category 3 are safe enough to omit or delay prostate biopsy in the future and to determine an optimal control interval. This retrospective single center study includes consecutive PI-RADS category 3 patients with one or more follow-up mpMRI (T2WI, DWI, DCE) and subsequent MRI-targeted and systematic TRUS-guided biopsy between 2012 and 2018. Primary study objective was the verification of a significant PI-RADS category upgrade in follow-up mpMRI in patients with subsequent PCA positive biopsy versus patients with negative biopsy. Further objectives were development of the PI-RADS category and clinical parameters between initial and follow-up mpMRI in the context of histopathologic results and time interval. Eighty-nine patients (median PSA 6.6 ng/ml; PSAD 0.13 ng/ml/ml) were finally included (follow-up period 31 ± 18 months). 19 cases had PCA (median PSA 7.8 ng/ml; PSAD 0.14 ng/ml/ml). 4 cases had csPCA (median PSA 5.4 ng/ml; PSAD 0.13 ng/ml/ml) for which there was a significant PI-RADS upgrade after 12–24 months (mean 3.75; p = 0.01) compared to patients without PCA (mean 2.74). Without PCA the mean PI-RADS category decreased after 25–36 months (mean 2.74; p = 0.02). Clinical parameters did not change significantly except a PSAD increase for PCA patients after 24 months. Patients within PI-RADS category 3 may not need prompt biopsy since those with PCA reliably demonstrate a PI-RADS category upgrade in follow-up mpMRI after 12–24 months. PI-RADS 3 patients with negative biopsy do not benefit from follow-up mpMRI earlier than 24 months.

In the framework of COST CA16217 “European Network of multidisciplinary research to improve the Urinary Stents (ENIUS)”, WG3 group worked on the validation of protocols for new stent designs. In this chapter, we address a methodology on clinical evaluation of urinary stents as well as the importance of clinical data and patients’ feedback regarding urinary stents. This methodology is meant to provide guidance on clinical aspects of urinary stent development, thus assisting all stakeholders in innovation and improvement of new stents designs during clinical investigation in both, pre- and post-market evaluation. In addition, as part of the methodology for urinary stents development, we were also focused to effective determination of any undesirable side effects that can appear in stented patients. That is the reason we performed analysis of all tools developed in order to obtain and deliver such information from the patients who underwent urinary stent placement and suggest a newer approach in obtaining this feedback through The Urinary Stent Related Health (UriSteRH) questionnaire.