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Candida auris is an emerging pathogen in health care-associated infections. In contrast to many other countries with rising numbers of C. auris, only seven cases have been reported in Germany from 2015 to 2017, mostly from patients who received prior medical treatment abroad. We therefore established a mandatory screening for C. auris colonisation at our tertiary care centre for all patients who were admitted as international patients or previously hospitalised in a foreign country within the past 6 months.Colonisation of patients was assessed using a previously established screening protocol for multidrug resistant bacteria. Since 2017, all screening samples were additionally analysed for C. auris using CHROMagar Candida (CHROMagar, Paris, France). Yeast isolates were identified using matrix-assisted laser ionisation time-of-flight (MALDI TOF), except for C. albicans (identified by the typical green colour on chromogenic agar). Data were analysed retrospectively.Our study cohort included 655 patients and an overall number of 1399 samples. Fifty-three patients were colonised with Candida species (C. albicans, n = 37; C. glabrata, n = 14; others n = 9). No case of C. auris was detected. Candida spp. were mainly detected from respiratory samples (5.4% positive) and gastrointestinal specimen (5.2%). Laboratory costs were 14,689 € and analyses resulted in 98.7 h of additional technician's work.No colonisation with C. auris was detected among patients with previous hospitalisation abroad. Universal C. auris screening of patients with any contact to foreign health care does not seem to be cost-effective in our setting and more targeted screening strategies have to be developed.

Objective To examine the efficacy of hyperimmunoglobulin (HIG) treatment in women with a recent primary cytomegalovirus (CMV) infection up to 14 weeks' gestation. Methods This is an ongoing observational study conducted at the prenatal medicine departments of the University Hospitals of Tubingen, Bonn, Cologne and Erlangen, Germany, as well as at the Laboratory Prof. Gisela Enders and Colleagues in Stuttgart, Germany and the Institute for Medical Virology at the University of Tubingen, Tubingen, Germany. Enrolment criteria were the presence of confirmed recent primary CMV infection in the first trimester and a gestational age at first HIG administration of ≤ 14 weeks. The following inclusion criteria indicated a recent primary infection: low anti-immunoglobulin (Ig)-G levels, low anti-CMV-IgG avidity in the presence of a positive CMV-IgM test and no positive reactivity or just seroconversion anti-gB2-IgG-reactivity. HIG administration was started as soon as possible within a few days after the first visit. HIG was administered intravenously at a dose of 200 IU/kg maternal body weight and repeated every 2 weeks until about 18 weeks' gestation. The primary outcome was maternal-fetal transmission at the time of amniocentesis. Multivariate logistic regression analysis was used to determine significant covariates that could predict maternal-fetal transmission. Results We included 149 pregnancies (153 fetuses) that completed the treatment. Median maternal age and weight were 32.0 years and 65.0 kg, respectively. Median gestational age at the time of first referral to one of the four centers was 9.4 weeks. Median anti-CMV-IgG level, anti-CMV-IgM index and CMV-IgG avidity were 5.7 U/mL, 2.5 and 22.3%, respectively. HIG treatment was started at a median gestational age of 10.6 weeks and ended at a median of 17.9 weeks. Within this time frame, HIG was administered on average four times in each patient. Amniocentesis was carried out at a median gestational age of 20.4 weeks. In 143 (93.5%) of the 153 cases, the fetus was not infected. Maternal-fetal transmission occurred in 10 cases (6.5% (95% CI, 3.2-11.7%)). On uni- and multivariate logistic regression analysis, the level of anti-IgM index was the only factor associated significantly with maternal-fetal transmission at amniocentesis. However, only four (40.0%) of the 10 cases with maternal-fetal transmission had an anti-IgM index above 11.4, which corresponds to the 95th centile of pregnancies without transmission. Conclusions HIG is a treatment option to prevent maternal-fetal transmission in pregnancy with a primary CMV infection. However, HIG treatment seems to be beneficial primarily in women with a recent primary infection in the first trimester or during the periconceptional period, and when it is administered at a biweekly dose of 200 IU/kg. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: Melanoma is the leading cause of skin cancer-related deaths worldwide. While there have been significant improvements in the treatment of advanced melanoma in the past decade, biomarker development lagged behind. OBJECTIVES: The majority of liquid-biopsy biomarkers rely on the analyses of oncogenic mutations, however, about 20% percent of melanoma patients are wild-type. Therefore, validation of universal predictive and prognostic biomarkers is urgently needed. METHODS: We analyzed plasma samples in a discovery cohort (n = 20) and expansion cohort (n = 166) of metastatic melanoma patients and healthy donors (n = 116). Total plasma circulating cell-free DNA (cfDNA) concentrations were measured on the Qubit® platform using assays for single-(ss) and double (ds)-stranded DNA, DNA-spectrophotometry, and RNase P qPCR. We explored the diagnostic, predictive and prognostic potential of cfDNA concentration by bio-statistical methods and established a cfDNA threshold for risk stratification. RESULTS: Our selected best method was Qubit® dsDNA assay which quantified higher plasma cfDNA concentrations in melanoma patients than in healthy controls (AUC 72%). Measurement of baseline cfDNA concentration revealed that high cfDNA was associated with presence of metastases and higher AJCC stage (P < 0.05). Furthermore, high baseline cfDNA was an indicator of shorter overall survival in patients with oncogenic mutations (HR 2.12, P = 0.0008), and in wild-type patients (HR 5.55, P < 0.0001). CONCLUSIONS: We provide evidence that total cfDNA can be used as a biomarker for melanoma irrespective of the tumor genotype and can provide information on tumor load, risk of progression, and risk of death.

OBJECTIVE To examine the efficacy of biweekly hyperimmunoglobulin (HIG) administration to prevent maternal-fetal transmission of cytomegalovirus (CMV) in women with primary first-trimester CMV infection. METHODS This was a prospective observational study of women with confirmed primary CMV infection in the first trimester who had the first HIG administration at or before 14 weeks' gestation. All women had biweekly HIG treatment until 20 weeks' gestation at a dose of 200 IU/kg of maternal body weight. Each subject underwent amniocentesis at least 6 weeks after first presentation at about 20 weeks. Primary outcome was maternal-fetal transmission at the time of amniocentesis, and secondary outcome was the frequency of congenital CMV infection at birth. The results were compared with a historic cohort of women with first-trimester CMV infection who did not undergo HIG treatment and who had amniocentesis at about 20 weeks. RESULTS Subjects were 40 pregnant women with a primary CMV infection, with a median gestational age at first presentation of 9.6 (range, 5.1-14.3) weeks. On average, HIG administration started at 11.1 weeks and continued until 16.6 weeks. Within this interval, HIG was administered between two and six times in each patient. While CMV immunoglobulin-G (IgG) monitoring showed periodic fluctuations during biweekly HIG administration cycles, high CMV-IgG avidity indices remained stable over the whole treatment period. Maternal-fetal transmission before amniocentesis occurred in only one of the 40 cases (2.5% (95% CI, 0-13.2%)). At delivery, two additional subjects were found to have had late-gestation transmission. Considering all three cases with maternal-fetal transmission, the transmission rate was 7.5% (95% CI, 1.6-20.4%) in our 40 cases. All infected neonates were asymptomatic at birth. The matched historical control group consisted of 108 pregnancies. Thirty-eight transmissions (35.2% (95% CI, 26.2-45.0%)) occurred in the control group, which was significantly higher (P

Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions.

Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope™ is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScope™ was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web-based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScope™ have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScope™ registry.

OBJECTIVE: To examine the efficacy of biweekly hyperimmunoglobulin (HIG) administration to prevent maternal-fetal transmission of cytomegalovirus (CMV) in women with primary first-trimester CMV infection. METHODS: This was a prospective observational study of women with confirmed primary CMV infection in the first trimester who had the first HIG administration at or before 14 weeks' gestation. All women had biweekly HIG treatment until 20 weeks' gestation at a dose of 200 IU/kg of maternal body weight. Each subject underwent amniocentesis at least 6 weeks after first presentation at about 20 weeks. Primary outcome was maternal-fetal transmission at the time of amniocentesis, and secondary outcome was the frequency of congenital CMV infection at birth. The results were compared with a historic cohort of women with first-trimester CMV infection who did not undergo HIG treatment and who had amniocentesis at about 20 weeks. RESULTS: Subjects were 40 pregnant women with a primary CMV infection, with a median gestational age at first presentation of 9.6 (range, 5.1-14.3) weeks. On average, HIG administration started at 11.1 weeks and continued until 16.6 weeks. Within this interval, HIG was administered between two and six times in each patient. While CMV immunoglobulin-G (IgG) monitoring showed periodic fluctuations during biweekly HIG administration cycles, high CMV-IgG avidity indices remained stable over the whole treatment period. Maternal-fetal transmission before amniocentesis occurred in only one of the 40 cases (2.5% (95% CI, 0-13.2%)). At delivery, two additional subjects were found to have had late-gestation transmission. Considering all three cases with maternal-fetal transmission, the transmission rate was 7.5% (95% CI, 1.6-20.4%) in our 40 cases. All infected neonates were asymptomatic at birth. The matched historical control group consisted of 108 pregnancies. Thirty-eight transmissions (35.2% (95% CI, 26.2-45.0%)) occurred in the control group, which was significantly higher (P

Human T cells carrying γδ T-cell receptors (TCRs) represent a minor population relative to those with αβ TCRs. There has been much interest recently in the possibility of using these γδ T-cells in cancer therapy because they can kill tumor cells in vitro in an MHC-unrestricted manner, and possess potential regulatory capability and antigen-presenting capacity. The presence of γδ T-cells in late-stage melanoma patients and their relationship with survival has not been extensively explored, although relatively lower percentages of total γδ T-cells and Vδ2+ cells have been reported. Here, we present a detailed analysis of associations of γδ T-cell subsets and differentiation stages with survival in Stage IV patients, compared with CD4+ and CD8+ αβ T-cells. We found an increased Vδ1:Vδ2-ratio and a decreased CD4:CD8-ratio in patients compared to healthy controls, on the basis both of relative frequencies and absolute cell counts per μL blood. Nonetheless, Kaplan-Meier analyses showed that a higher than median frequency of Vδ1+ cells was negatively associated with survival, whereas there were no positive or negative associations with frequencies of Vδ2+ cells. Correlations of cell differentiation status with survival revealed a negative association of early-differentiated Vδ1+ T cells with survival, both on the basis of relative frequencies and absolute counts. There was also a positive correlation between the frequencies of early-differentiated CD8+ αβ T-cells and survival. Our findings suggest peripheral blood frequencies of Vδ1+ T-cells as a potential prognostic marker in melanoma. The mechanisms by which higher abundance of Vδ1+ cells are associated with poorer survival require determination.

The development of realistic neuroanatomical models of peripheral nerves for simulation purposes requires the reconstruction of the morphology of the myelinated fibres in the nerve, including their nodes of Ranvier. Currently, this information has to be extracted by semimanual procedures, which severely limit the scalability of the experiments. In this contribution, we propose a supervised machine learning approach for the detailed reconstruction of the geometry of fibres inside a peripheral nerve based on its high-resolution serial section images. Learning from sparse expert annotations, the algorithm traces myelinated axons, even across the nodes of Ranvier. The latter are detected automatically. The approach is based on classifying the myelinated membranes in a supervised fashion, closing the membrane gaps by solving an assignment problem, and classifying the closed gaps for the nodes of Ranvier detection. The algorithm has been validated on two very different datasets: (i) rat vagus nerve subvolume, SBFSEM microscope, 200 × 200 × 200 nm resolution, (ii) rat sensory branch subvolume, confocal microscope, 384 × 384 × 800 nm resolution. For the first dataset, the algorithm correctly reconstructed 88% of the axons (241 out of 273) and achieved 92% accuracy on the task of Ranvier node detection. For the second dataset, the gap closing algorithm correctly closed 96.2% of the gaps, and 55% of axons were reconstructed correctly through the whole volume. On both datasets, training the algorithm on a small data subset and applying it to the full dataset takes a fraction of the time required by the currently used semiautomated protocols. Our software, raw data and ground truth annotations are available at http://hci.iwr.uni-heidelberg.de/Benchmarks/. The development version of the code can be found at https://github.com/RWalecki/ATMA.

Meeting Programme Prof David O'Hagan [University of St Andrews, UK]—Enzymatic C–18F Bond Synthesis: A New Strategy for PET Synthesis. Dr Michael Carroll [University of Newcastle, UK]—Studies Towards 6-[18F]Fluoro-m-tyramine using Iodonium Salts. Dr John Gardiner [University of Manchester, UK]—Methods Towards Isotopomer-Versatile Synthesis of 13C-Labelled Carbohydrates. Prof William Lockley [University of Surrey, UK]—Some New Catalytic Systems for Isotope-Exchange Labelling. Dr David Rustidge [Scynexis Europe, UK]—14C-Synthesis—Not Always as Easy as it Looks. Dr Richard Hartley [University of Glasgow, UK]—The Potential for using Titanium Alkylidene Chemistry in Solid-Phase Radiochemical Synthesis. Dr Ian Wilson [Turku Imanet, Finland]—Transition of PET Tracers from Clinical Research Tools to Commercial Diagnostics. Dr Simon Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine. Dr John Herbert [Sanofi-Aventis, UK]—Towards Robust Conditions for Iridium-mediated Exchange. Dr Conor Barry [University of Bristol, UK]—Total Synthesis of Clavosolide A.

A Ce(III)/Cu(I)-catalytic system mediates the reaction of aryl- and alkylaldehydes (I) and (IV) with o-phenylenediamine (II) to the title compounds in good yields.

Summary Because published reports indicate that the antibiotic colistin (COL) has antifungal properties, this study investigated the antifungal in vitro activity of COL as single agent and in combination with the antifungal compounds voriconazole (VRC), caspofungin (CAS) and amphotericin B (AMB) against Scedosporium/Pseudallescheria spp., Exophiala dermatitidis and Geosmithia argillacea. In total, susceptibility was determined for 77 Scedosporium/Pseudallescheria spp., 82 E. dermatitidis and 17 G. argillacea isolates. The minimal inhibitory concentrations (MICs) of COL and the antifungals as single compound and in combination were determined with MIC test strips. Drug interactions were detected by crossing the MIC test strips at a 90o angle. The fractional inhibitory concentration index was used to categorise the drugs’ interaction. The MIC50 value of COL was 12 μg ml−1 for S. prolificans, 16 μg ml−1 for P. apiosperma, 16 μg ml−1 for P. boydii, 12 μg ml−1 for E. dermatiditis and 6 μg ml−1 for G. argillacea. VRC was the most active drug in combination without any antagonism with the exception of few P. boydii isolates. COL as single agent and in most combinations with antifungals exhibits in vitro antifungal activity against filamentous ascomycetes occurring in cystic fibrosis patients and may offer a novel therapeutic option, especially for multidrug-resistant S. prolificans.

Aim: To investigate neurodevelopmental outcome and hearing in preterm children with breast milk transmitted human cytomegalovirus (HCMV) infection. Methods: Forty-one preterm children (born before 32 weeks of gestation or birth weight Results: In both groups, irrespective of the presence or absence of a history of HCMV infection, performance in assessments of cognitive and motor function was within the normal range. However, significant differences between the HCMV-positive and the HCMV-negative group were found in both motor and cognitive function, with poorer performance in the HCMV-positive group. There were no significant differences in anthropometric parameters, and all 20 HCMV-positive children had normal hearing function. Conclusions: In this study, cognitive and motor function in preterm children with early postnatally acquired HCMV infection transmitted via breast milk was within the normal range. However, the findings suggest that their outcome is poorer than outcome in preterm children without HCMV infection. These findings need to be replicated in larger scale studies.

We propose a Bayesian smoothness prior in the spectral fitting of MRS images which can be used in addition to commonly employed prior knowledge. By combining a frequency-domain model for the free induction decay with a Gaussian Markov random field prior, a new optimization objective is derived that encourages smooth parameter maps. Using a particular parameterization of the prior, smooth damping, frequency and phase maps can be obtained whilst preserving sharp spatial features in the amplitude map. A Monte Carlo study based on two sets of simulated data demonstrates that the variance of the estimated parameter maps can be reduced considerably, even below the Cramer-Rao lower bound, when using spatial prior knowledge. Long-TE 1H MRSI at 1.5 T of a patient with a brain tumor shows that the use of the spatial prior resolves the overlapping peaks of choline and creatine when a single voxel method fails to do so. Improved and detailed metabolic maps can be derived from high-spatial-resolution, short-TE 1H MRSI at 3 T. Finally, the evaluation of four series of long-TE brain MRSI data with various signal-to-noise ratios shows the general benefit of the proposed approach.

We aimed to identify those pediatric patients undergoing ABMT with CMV EOD who developed GCV resistance. Forty-seven patients were analyzed following ABMT. Prospective post-transplant CMV monitoring was performed weekly for the detection of viral leukocyte DNAaemia, viral plasma DNAaemia, and viral DNAuria by PCR. Plasma DNAaemia was confirmed from whole blood by the detection of CMV pp67 late mRNA using NASBA technology. In the cases of persistence of viral DNA in plasma, and positive viral RNA detection in blood, CMV drug resistance screening by comprehensive PCR-based RFLP and sequencing of the viral UL97 gene were performed retrospectively. Thirty of the 47 (63.82%) patients showed active CMV infection with 27/30 (74.4%) patients belonging to the D+R+ group and 25/30 with proven viral replication. In total, 2/30 (6.6%) children developed CMV pneumonia proven by immunohistochemistry. Screening of the viral UL97 gene revealed in one of these two cases (1/30, 3.3%) the simultaneous presence of two point mutations in codon 460 (M460V, M460I) conferring GCV resistance. The CMV seroprevalence (81%) and the incidence of active infection (63.8%) in Mexican children undergoing ABMT are very high.

Aim: To evaluate the enteral feeding practice of preterm infants

There is a polarity in the literature as to whether companies do or do not postpone investment decisions in the light of regulatory uncertainty. In the case of flexible regulation characterized by a high degree and discontinuous resolution of uncertainty, we show that companies do not necessarily postpone investment decisions. We trace this observation back to three motivations: securing competitive resources, leveraging complementary resources, and alleviating institutional pressure. We connect these motivations to fundamental principles of the resource-based view and institutional theory and further show the existence of a regime where institutionally motivated and resource-based actions are not necessarily decoupled. We base our research on a case study covering 80 per cent of the German power generation industry which faces regulatory uncertainty from the European CO2 Emission Trading Scheme.

We present a photon-by-photon analysis framework for the evaluation of data from single-molecule fluorescence spectroscopy (SMFS) experiments using a Markov-modulated Poisson process (MMPP). A MMPP combines a discrete (and hidden) Markov process with an additional Poisson process reflecting the observation of individual photons. The algorithmic framework is used to automatically analyze the dynamics of the complex formation and dissociation of Cu 2+ ions with the bi-dentate ligand 2,2'-bipyridine-4,4'dicarboxylic acid in aqueous media. The process of association and dissociation of Cu 2+ ions is monitored with SMFS. The dcbpy-DNA conjugate can exist in two or more distinct states which influence the photon emission rates. The advantage of a photon-by-photon analysis is that no information is lost in preprocessing steps. Different model complexities are investigated in order to best describe the recorded data and to determine transition rates on a photon-by-photon basis. The main strength of the method is that it allows to detect intermittent phenomena which are masked by binning and that are difficult to find using correlation techniques when they are short-lived.

Spectral images offer more information on complex probes than either conventional imagery (yielding only one or few measurements per voxel) or conventional spectroscopy (resulting in only one or a few spectra per probe) can. Spectral imaging is thus starting to become ubiquitous in areas ranging from materials science and process control to remote sensing and medicine. However, the information concealed in the massive amount of data generated by spectral imaging is not as easily accessible as in conventional (gray value or color) images and as in conventional spectroscopy, hence calling for new methods to analyze and visualize spectral images. Broadly speaking, analysis methods can be classified in terms of the information used in the training phase, and by the extent to which they use spatial context in the analysis. This article gives a brief overview of ‘unsupervised’ methods that require sample spectral images during the training stage as well as specification of a degree of complexity of the sample, either in terms of number of cluster centers or intrinsic dimensionality of the data [principal component analysis (PCA)]. ‘Supervised’ methods, on the other hand, require a training set in which a class membership, or label, is available for each pixel. Our discussion includes methods that deal well with the high dimensionality and high degree of correlation among individual features, such as partial least squares (PLS) and linear discriminant analysis (LDA). All of the above methods ignore the spatial context when applied to individual spectra. Often, the label map can be assumed to exhibit some spatial coherence, a fact that can help in classifying low quality spectra and that can be exploited using conditional or Markov random fields. The methods are illustrated using examples from automated process control and quantitative medical diagnostics. Copyright © 2009 John Wiley & Sons, Ltd.

Besides the diagnostic evaluation of a spectrum, the assessment of its quality and a check for plausibility of its information remains a highly interactive and thus time-consuming process in MR spectroscopic imaging (MRSI) data analysis. In the automation of this quality control, a score is proposed that is obtained by training a machine learning classifier on a representative set of spectra that have previously been classified by experts into evaluable data and nonevaluable data. In the first quantitative evaluation of different quality measures on a test set of 45,312 long echo time spectra in the diagnosis of brain tumor, the proposed pattern recognition (using the random forest classifier) separated high- and low-quality spectra comparable to the human operator (area-under-the-curve of the receiver-operator-characteristic, AUC >0.993), and performed better than decision rules based on the signal-to-noise-ratio (AUC