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Seven plant certified reference materials (NIST SRM1515 Apple Leaves, NIST SRM1547 Peach Leaves, BCR-129 Hay Powder, BCR-670 Aquatic Plant, GBW07603 Bush Twigs and Leaves, GBW10015 Spinach Leaves and NCS ZC73036a Green Tea) were analysed for their mass fractions of 48 elements by inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS): Li, Be, Na, Mg, Al, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Y, Nb, Mo, Ag, Cd, Sb, Te, Ba, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Ta, Tl, Pb, Bi, Th, U. Special focus was put on the determination of technology-critical elements (TCEs), to which, e.g. Li, Be, Ga, Ge, Nb, Sb, Ta, Tl, Bi, and the rare-earth elements (REEs, lanthanides and Y) are counted. Closed-vessel microwave digestion was performed using HNO3, H2O2 and HBF4. The average bias for certified values is − 1% ± 13% (SD). Limits of detection (xL) in the measured solutions lie between 13 fg g−1 (Tb) and 52 ng g−1 (Ca). This article seeks to provide an optimised measurement procedure for the determination of element mass fractions of emerging importance in environmental samples, which are challenging to analyse with more traditional techniques such as single-quad ICP-MS. In addition, it aims to improve the characterisation of commonly used plant reference materials by providing mass fraction data for rarely studied elements. Graphical abstract

Data submitted over the past 25 years to GeoPT, the highly successful proficiency-testing programme for the geochemical analysis of geological materials, organized by the International Association of Geoanalysts, provides a valuable resource that permits detailed investigation of contrasting results associated with different sample preparation and measurement principles. Highlighted issues include: recurring problems with the dissolution of the refractory minerals zircon and chromite, which produces a large dispersion in data obtained when acid digestion is involved; issues related to different XRF sample preparation methods, whereby significant divergence of pressed powder pellet results compared with those from fused glass disks is observed; high relative dispersion of data both at low mass fractions, and those higher than normally found in silicate rocks, due to incomplete method validation, in particular due to an over-confidence in estimating reporting limits and to the employment of limited working ranges. In addition, an example for Sr in an ancient pegmatite with extremely high Rb abundance is presented. The ICP-MS results amount, only to a third of the XRF results, severely underestimated due to the disregard of the radiogenic ingrowth from 87Rb decay. Recommendations are made both for improving data quality and the selection of test materials for future GeoPT rounds.

Funder: Medical University of Vienna, Micro- and nanoplastics (MNPs) are recognized as emerging contaminants, especially in food, with unknown health significance. MNPs passing through the gastrointestinal tract have been brought in context with disruption of the gut microbiome. Several molecular mechanisms have been described to facilitate tissue uptake of MNPs, which then are involved in local inflammatory and immune responses. Furthermore, MNPs can act as potential transporters ("vectors") of contaminants and as chemosensitizers for toxic substances ("Trojan Horse effect"). In this review, we summarize current multidisciplinary knowledge of ingested MNPs and their potential adverse health effects. We discuss new insights into analytical and molecular modeling tools to help us better understand the local deposition and uptake of MNPs that might drive carcinogenic signaling. We present bioethical insights to basically re-consider the "culture of consumerism." Finally, we map out prominent research questions in accordance with the Sustainable Development Goals of the United Nations.

Background: In clinical routine, not every patient who is offered genetic counselling and diagnostics in order to investigate a familial cancer risk predisposition opts for it. Little is known about acceptance of counselling and testing in newly diagnosed breast cancer cases in Germany. Methods: All primary breast cancer cases and patients with DCIS (ductal carcinoma in situ) treated at the University Hospital of Dresden between 2016 and 2019 were included. The number of tumor board recommendations for genetic counselling on the basis of the GC-HBOC risk criteria was recorded. Acceptance was analyzed by number of cases with counselling in the GC-HBOC-Center Dresden. Results: Of 996 primary breast cancer and DCIS cases, 262 (26.3%) were eligible for genetic counselling. Recommendation for genetic counselling was accepted by 64.1% (168/262). Of these 90.5% (152/168) opted for molecular genetic analysis. The acceptance rate for counselling increased between 2016 and 2019 from 58.3 to 72.6%. Altogether, 20.4% (31/152) patients were found to carry a pathogenic variant in the breast cancer genes BRCA1 or BRCA2. Conclusion: Acceptance of recommendation is increasing as clinical consequences augment. Optimization in providing information about hereditary cancer risk and in accessibility of counselling and testing is required to further improve acceptance of recommendation.

Plastic fragments, weathered into or released in the form of micro- and nanoplastics, are persistent and widespread in the environment, and it is anticipated that they have negative environmental impacts. This necessitates immediate efforts for management strategies throughout the entire plastics lifecycle. This opinion paper was initiated by the EU COST Action CA20101 PRIORITY, which focuses on the need to develop an effective global networking platform dealing with research, implementation, and consolidation of ways to address the worldwide challenges associated with micro- and nanoplastics pollution in the environment., Microplastics, 1 (2), ISSN:2673-8929

The characterization of Zr-containing dispersoids in aluminum alloys is challenging due to their broad size distribution, low volume fraction, and heterogeneous distribution within the grains. In this work, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) were compared to scanning electron microscopy (SEM) and transmission electron microscopy (TEM) regarding their capability to characterize Zr-containing dispersoids in aluminum alloys. It was demonstrated that both scattering techniques are suitable tools to characterize dispersoids in a multi-phase industrial 7xxx series aluminum alloy. While SAXS is more sensitive than SANS due to the high electron density of Zr-containing dispersoids, SANS has the advantage of being able to probe a much larger sample volume. The combination of both scattering techniques allows for the verification that the contribution from dispersoids can be separated from that of other precipitate phases such as the S-phase or GP-zones. The size distributions obtained from SAXS, SANS and TEM showed good agreement. The SEM-derived size distributions were, however, found to significantly deviate from those of the other techniques, which can be explained by considering the resolution-limited restrictions of the different techniques.

Background: Prophylactic mastectomies in carriers of mutations in BRCA1 or BRCA2 are becoming increasingly more accepted. We investigated the outcome after prophylactic mastectomy, especially regarding satisfaction with the procedure, in a monocenter study. Methods:BRCA1/2 mutation carriers and non-carriers with elevated pedigree-based cancer risk were followed prospectively in a structured surveillance program between 2000 and 2017. A retrospective telephone survey was conducted among all patients with documented prophylactic mastectomy. Complications and satisfaction with the decision for prophylactic mastectomy were recorded. Results: 39 patients who opted for a prophylactic mastectomy (38 BRCA1/2 mutation carriers and 1 non-carrier) were interviewed. Mostly nipple-sparing mastectomy with reconstruction was performed (87%). Half of the patients (22/39; 56.4%) had a history of unilateral breast cancer. The median time since prophylactic mastectomy was 5.6 years. While 61.5% did not report any complications, flap loss was seen in 15% (3/20) and moderate limitations in everyday life were present in 20% (7/35). An improvement in quality of life was noticed by 82% after prophylactic mastectomy and no patient expressed regret with regard to the decision. Conclusions: Prophylactic mastectomy is a procedure with risk for long-term complications in some cases. Our results confirm high satisfaction with the decision and improved quality of life.

Introduction The clinical implications of genetic variants in BRCA1/2 in healthy and affected individuals are considerable. Variant interpretation, however, is especially challenging for missense variants. The majority of them are classified as variants of unknown clinical significance (VUS). Computational (in-silico) predictive programs are easy to access, but represent only one tool out of a wide range of complemental approaches to classify VUS. With this single-center study, we aimed to evaluate the impact of in-silico analyses in a spectrum of different BRCA1/2 missense variants. Methods We conducted mutation analysis of BRCA1/2 in 523 index patients with suspected hereditary breast and ovarian cancer (HBOC). Classification of the genetic variants was performed according to the German Consortium (GC)-HBOC database. Additionally, all missense variants were classified by the following three in-silico prediction tools: SIFT, Mutation Taster (MT2) and PolyPhen2 (PPH2). Results Overall 201 different variants, 68 of which constituted missense variants were ranked as pathogenic, neutral, or unknown. The classification of missense variants by in-silico tools resulted in a higher amount of pathogenic mutations (25% vs. 13.2%) compared to the GC-HBOC-classification. Altogether, more than fifty percent (38/68, 55.9%) of missense variants were ranked differently. Sensitivity of in-silico-tools for mutation prediction was 88.9% (PPH2), 100% (SIFT) and 100% (MT2). Conclusion We found a relevant discrepancy in variant classification by using in-silico prediction tools, resulting in potential overestimation and/or underestimation of cancer risk. More reliable, notably gene-specific, prediction tools and functional tests are needed to improve clinical counseling.

Determination of mutation status of BRCA1 and BRCA2 has become part of the clinical routine. However, the spectrum of genetic variants differs between populations. The aim of this study was to deliver a comprehensive description of all detected variants. In families fulfilling one of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) criteria for genetic testing, one affected was chosen for analysis. DNA of blood lymphocytes was amplified by PCR and prescreened by DHPLC. Aberrant fragments were sequenced. All coding exons and splice sites of BRCA1 and BRCA2 were analyzed. Screening for large rearrangements in both genes was performed by MLPA. Of 523 index patients, 121 (23.1%) were found to carry a pathogenic or likely pathogenic (class 4/5) mutation. A variant of unknown significance (VUS) was detected in 73/523 patients (13.9%). Two mutations p.Gln1756Profs*74 and p.Cys61Gly comprised 42.3% (n = 33/78) of all detected pathogenic mutations in BRCA1. Most of the other mutations were unique mutations. The most frequently detected mutation in BRCA2 was p.Val1283Lys (13.9%; n = 6/43). Altogether, 101 different neutral genetic variants were counted in BRCA1 (n = 35) and in BRCA2 (n = 66). The two most frequently detected mutations are founder mutations in Poland and Czech Republic. More similarities seem to be shared with our direct neighbor countries compared to other European countries. For comparison of the extended genotype, a shared database is needed.

580 Background: DTCs in the bone marrow are observed in up to 30% at primary diagnosis of BC and their presence is an independent prognostic factor for reduced survival. It was shown that antiresorptive therapy eradicates DTCs and improves prognosis in DTC-positive BC patients (pts). In the GeparX phase III prospective randomized trial, denosumab (a monoclonal IgG2-anti-RANKL-antibody) was investigated as add-on treatment to neoadjuvant chemotherapy (NACT) with two different nab-paclitaxel schedules in early high-risk primary BC. In a translational substudy, we analyzed for the first time the influence of short-term denosumab treatment (24 weeks) on the presence of DTCs. Methods: A total of 167 pts from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive pts were re-analyzed for DTCs after NACT±Denosumab. Results: Overall, 60/167 pts (35.9%) treated with NACT±Denosumab had a pathological complete response (pCR; 55.4% in TNBC, 43.3% in HER2+, 15.3% in HR+/HER2-). At baseline, 43/167 pts (25.7%) were DTC-positive and 41 of those were available for re-analysis of DTCs after NACT±Denosumab. DTC eradication was observed in 77.8% after NACT+Denosumab and in 69.6% after NACT alone (p = 0.726). Due to the limited number of pts eligible for DTC-re-analysis after NACT, a subtype specific analysis for the effect of denosumab was not possible. There was no significant association between pCR and i) the presence of DTCs at baseline (37.1% DTC-negative vs 32.6% positive, p = 0.71) or ii) the eradication of DTCs after NACT±Denosumab (36.7% vs 27.3%, p = 0.72). Notably, in TNBC, we observed a tendency that DTC-positivity at baseline or DTC-persistence after NACT could be associated with reduced pCR rate (40.0% in DTC-positive vs. 66.7% in DTC-negative pts, p = 0.16; 25% in DTC-persistent pts vs. 50% in DTC-eradicated pts, p = 0.59). Conclusions: Denosumab in addition to NACT does not improve pCR, but the suspected effect of denosumab on DTC eradication should be further analyzed in TNBC. Key words: GeparX trial, denosumab, disseminated tumor cells, bone marrow, neoadjuvant chemotherapy. Funding: GeparX and DTC substudy were financially supported by Amgen and Celgene. Clinical trial information: NCT02682693 .

Juvenile dermatomyositis (JDM) is a rare autoimmune disease associated with typical skin changes and muscle weakness. Within the framework of the diagnostics, myositis-associated (MAA) and myositis-specific antibodies (MSA) can be detected. These are important for the assessment of the course of the disease and the prognosis.In this study we searched for MAA and MSA by means of a line immunoassay in 12 currently supervised JDM patients in the Rheumatism Center Sankt Augustin.In 10 of the 12 patients a total of 15 myositis antibodies were detected where 3 patients each had Mi2, SRP or NXP2 antibodies, 2 had TIF-1γ antibodies and Jo1 or Mi2β antibodies were found in 1 patient each. Of the patients two had additional PM-Scl antibodies. In the 10 patients with detected antibodies, a good phenotype-serotype correlation was found with deviation from the phenotypes described in the literature in only 3 patients.The frequent detection of certain antibodies and the good correlation with those phenotypes described in the literature, show that the determination of MSA is an important diagnostic tool to assess the course, complications and outcome and to initiate adequate therapy at an early stage.

ZusammenfassungKlassische Myositis-spezifische Autoantikörper (MSA) gegen t-RNA-Synthetasen, Mi-2 und SRP lassen sich nur selten bei juvenilen idiopathischen inflammatorischen Myopathien (JIIM) nachweisen und trugen bisher wenig zur Diagnosestellung bei. Die Entdeckung neuer MSA wie TIF-1 gamma, NXP-2, MDA5 und SAE ermöglicht eine bessere Diagnostik und serologische Klassifikation der JIIM sowie prognostische Aussagen. MSA können bei etwa 60 % der JIIM nachgewiesen werden, wobei Antikörper gegen TIF-1 gamma und NXP-2 am häufigsten sind. Diese sind vor allem mit juveniler Dermatomyositis assoziiert, wobei Patienten mit NXP-2-Antiköpern jünger sind, häufiger eine subkutane Kalzinose entwickeln und einen schwereren Krankheitsverlauf zeigen. Kinder mit MDA5-Antikörper zeigen vorwiegend Hautmanifestationen und eine milde Form der Myositis. SAE-Antikörper sind extrem selten. Die Konzentration von Antikörpern gegen Jo-1, SRP und MDA-5 korreliert mit der Krankheitsaktivität. Das erweiterte Spektrum nachweisbarer MSA könnte in Zukunft die Notwendigkeit invasiver diagnostischer Methoden wie der Muskelbiopsie reduzieren und neue Möglichkeiten zur Therapie -stratifizierung und -überwachung schaffen.

Wir berichten uber eine 32-jahrige Patientin mit seit ca. 10 Jahren entstandenen multiplen, klinisch atypischen, z. T. zystischen Basalzellkarzinomen des Gesichts, Glaukom, kantiger Schadelform mit verbreitertem Nasenrucken und Hypertelorismus. Kieferzysten, Rippenanomalien, palmoplantare Hyperkeratosen oder Gruben und andere bekannte assoziierte Symptome des Syndroms fanden sich nicht. Dagegen wurde in unserem Fall zusatzlich ein Hypophysenadenom ohne vermehrte Somatotropin-Produktion nachgewiesen.

Summary. Seborrhoeic dermatitis is a common entity that conventionally is difficult to treat. Recently, topical ketoconazole has been proven successful. To determine if other azoles, and in particular the more modern ones, are also helpful in this condition, a double-blind multicentre randomized controlled trial was performed in patients suffering from seborrhoeic dermatitis involving individuals 16 years and older without human immunodeficiency virus (HIV) infection. One hundred patients were enrolled and treated according to a random plan with either bifonazole 1 % cream or the corresponding vehicle once daily for 4 weeks. All patients were evaluated at the beginning of the study, as well as after 2 and 4 weeks, i.e. the treatment period proper, and after 6 weeks of follow-up. Clinical evaluation was based on scores of 0–3 for the following parameters: erythema, papules, infiltration, scaling, itch. In addition, mycological evaluation was performed using adequate contact plates for quantitative determination of Malassezia furfur. In the end, 92 patients were at least partially evaluable. In general, the verum preparation tended to be more efficacious, e.g. the score for erythema amounted to 0.75 after 4 weeks as compared with 0.88 in the control group, the baseline values being 2.18 and 2.04 respectively. With itch, the corresponding figures were 0.17 and 0.33 as compared with 1.42 and 1.38 before treatment. While in statistical terms there was significant difference in these parameters, such a difference was demonstrated by clinical judgement at follow-up. In the verum group (n= 37) 10 and 24 patients respectively were cured or improved; the corresponding figures for the control group (n= 43) were 9 and 23 (P=0.l). Differences in M. furfur colonization in favour of the verum preparation were not significant. Accordingly, there was no major difference in terms of the overall clinical and mycological cure rate in both groups, originally defined as a major test parameter. Bifonazole 1% cream might be helpful clinically in seborrhoeic dermatitis of non-HIV-infected patients. For definite proof of this hypothesis another confirmatory trial is needed, which should be based solely on global clinical judgement. Zusammenfassung. Das seborrhoische Ekzem ist eine haufige Erkrankung, die bislang schwer zu behandeln war. In der jungsten Vergangenheit hat sich Ketoconazol topisch als erfolgreich enviesen. Um festzustellen, ob andere und insbesondere die neueren Azole bei dieser Erkrankung ebenfalls hilfreich sind, wurde eine randomisierte Doppel-blind-Multizenter-Studie durchgefuhrt bei Patien-ten mit seborrhoischem Ekzem mit einem Mindestalter von 16 Jahren und ohne HIV-Infektion. Es sollten 100 Patienten aufgenommen werden und zufolge einem Randomplan entweder mit l%iger Bifonazol Creme oder mit der korre-spondierenden Basiscreme 1 × taglich uber vier Wochen behandelt werden. Alle Patienten musten zu Beginn evaluiert werden, des weiteren zwei und vier Wochen danach, d.h. wahrend der eigentlichen Behandlungsperiode sowie nach sechs Wochen zur Nachunter-suchung. Die klinische Bewertung grundete sich auf Scores von 0–3 fur die folgenden Parameter: Erythem, Papeln, Infiltration, Schuppung, Juckreiz. Zudem wurde eine mykologische Beurteilung angestrebt unter Einsatz von geeigneten Kontaktplatten zur quantitativen Ermittlung von Malassezia furfur. Schlieslich waren 92 Falle wenigstens teilweise auswertbar. Insgesamt envies sich die Verum-Praparation als etwas starker wirksam. So belief sich der Score-Wert fur Erythem auf 0,75 nach vier Wochen im Vergleich zu 0,88, wobei die Ausgangswerte 2,18 bzw. 2,04 lauteten. Beim Juckreiz beliefen sich die entspre-chenden Werte auf 0,17 vs. 0,33 bei Ausgangswer-ten von 1,42 vs. 1,38. Wahrend sich statistisch betrachtet kein Hinweis auf Unterschied bei diesen Parametern ergab, zeigte sich ein solcher bei der klinischen Globalbeurteilung zum Zeitpunkt der Nachuntersuchung. In der Verum-Gruppe (n= 37) wurden 10 bzw. 24 Patienten geheilt bzw. gebes-sert, wahrend die Vergleichszahlen fur die Kon-trollgruppe (n= 43) auf 9 und 23 lauteten (P= 0,1). Definitive Unterschiede bei der M. furfur-Besiedlung zeigten sich nicht. Dementsprechend ergab sich kein groserer Unterschied bei der klinischen und mykologischen Gesamtheilungsrate in den beiden Behandlungsgruppen, als dem Parameter, der ursprunglich als Hauptprufparameter festgelegt worden war. 1%ige Bifonazol-Creme durfte als hilfreich beim seborrhoischen Ekzem des nicht HIV-infizierten Patienten zu gelten haben. Um diese Hypothese endgultig abzusi-chern, bedarf es einer weiteren konfirmatorischen Studie, die sich an der klinischen Globalbewertung als Hauptprufparameter orientieren sollte.

Zusammenfassung: Spermatologische Untersuchungen wurden bei 227 Varikozelenpatienten im Alter von 19 - 23 Jahren (Durchschnittsalter 20.4 Jahre) und bei 73 Varikozelenpatienten im Alter von 24 - 40 Jahren (Durchschnittsalter 28.0 Jahre) durchgefuhrt. Die spermatologischen Befunde bei den Varikozelenpatienten wurden den Ergebnissen einer Kontrollgruppe von 55 andrologisch gesunden jungen Mannern, ohne Varikozele gegen-ubergestellt. Die einzelnen Schweregrade wirken sich unterschiedlich auf die Spermaqualitat aus. Eine verminderte Spermaqualitat weisen nur die Patienten mit den klinischen Zei-chen einer Varikozelen-Orchidopathie auf. Die schlechteste Spermaqualitat findet sich bei dem Schweregrad Varikozele in Kombination mit anderen Hodenschaden. Die Befunde in der hoheren Altersklasse deuten darauf hin, das die Hodenschadigung bei langerer Be-standsdauer der Varikozele zunimmt. Bei der Differenzierung der Spermatozoenmorpho-logie nach dem “Dusseldorfer Klassifizierungsschema” lassen sich bei den Varikozelenpatienten charakteristische Formen mit Uberstreckung des Kopfes nachweisen, bei der Varikozele mit Kombinationsschaden akrosomdefekte Spermien. Summary: Spermatologic Investigations in 300 Varicocele Patients with Different Degrees and in Diverse Age Groups Spermatologic investigations were made in 227 patients with varicocele at the age of 19 - 23 years (average age 20.4 years) and in 73 patients with varicocele at the age of 24 — 40 years (average age 28.0 years). The spermatologic findings of the patients with varicocele were compared with the results of 55 andrologic healthy young men without varicocele. The diverse degrees have a different effect to the sperm quality. Only patients with the clinical signs of the varicocele-orchidopathy present a decreased sperm quality. The degree varicocele combined with other testicular disorders shows the worst sperm quality. The results in the higher age group explain, that the damage of the testicle increases with longer duration of the varicocele. Differentiating the spermatozoal morphology according to the “Diisseldorf morphological classification” you can find characteristic forms with hyperelongation of the head in patients with varicocele and spermatozoa with acrosomal defects in the degree varicocele combined with other testicular disorders.

Zusammenfassung Differentiating of various haemodynamique types of varicocele through the bidirectional ultrasonic Doppler technique Durch die bidirektionale Ultraschall-Doppler-Untersuchung gelingt es, bei einem Teil der Varicocelenpatienten innerhalb des Scrotums eine dem Reflux gegenlaufige Stromung nachzuweisen, bei einem anderen Teil ist nur eine kurze Stromung bei Beginn des Valsalva-Manovers zu registrieren. Daraus kann auf verschiedene haemodynamische Varicocelentypen geschlossen werden, die als „Shunt-Typ” und „Drucktyp” bezeichnet werden. Untersuchungen uber die prognostische Bedeutung der unterscheidbaren Typen sollen folgen.