Personalized embryo transfer reduces success rates because endometrial receptivity analysis fails to accurately identify the window of implantation.

After more than a decade of increasingly widespread clinical use, personalized embryo transfer guided by endometrial receptivity analysis (ERA) remains controversial and unproven. One key element missing from the historical literature is the recognition that potential benefits from personalized embryo transfer are entirely dependent on the accuracy and predictive value of the ERA test. Results from the first comprehensive clinical trial, designed in a way that allowed independent evaluation of both potential benefits of personalized embryo transfer and the predictive value of the ERA test upon which it is based, were recently published. However, the authors failed to conduct an appropriate analysis or recognize the significance of their results. Here, we present a simple reanalysis of data from this otherwise excellent randomized controlled trial, demonstrating for the first time that the ERA was unable to identify the window of implantation as purported and that, as a result, personalized embryo transfer based on the ERA actually reduced rather than increased the birth rates. Based on these results and the lack of any contradictory evidence, it is our opinion that all clinical use of ERA-guided personalized embryo transfer should be discontinued immediately, outside of a controlled experimental setting with appropriate informed consent of all participating patients.

Carrier envelope phase sensitivity of photoelectron circular dichroism.

We report on a combined experimental and numerical study of photoelectron circular dichroism (PECD) induced by intense few-cycle laser pulses, using methyloxirane as the molecular example. Our experiments reveal a remarkably pronounced sensitivity of the PECD strength of double-ionization on the carrier-envelope phase (CEP) of the laser pulses. By comparison to the simulations, which reproduce the measured CEP-dependence for specific orientations of the molecules in the lab frame, we attribute the origin of the observed CEP-dependence of PECD to the CEP-induced modulation of ionization from different areas of the wave functions of three dominant orbitals.

Short-range organization and photophysical properties of CdSe quantum dots coupled with aryleneethynylenes.

Hybrid organic-inorganic nanomaterials composed of organic semiconductors and inorganic quantum dots (QDs) are promising candidates for opto-electronic devices in a sustainable internet of things. Especially their ability to combine the advantages of both compounds in one material with new functionality, the energy-efficient production possibility and the applicability in thin films with little resource consumption are key benefits of these materials. However, a major challenge one is facing for these hybrid materials is the lack of a detailed understanding of the organic-inorganic interface which hampers the widespread application in devices. We advance the understanding of this interface by studying the short-range organization and binding motif of aryleneethynylenes coupled to CdSe QDs as an example system with various experimental methods. Clear evidence for an incorporation of the organic ligands in between the inorganic QDs is found, and polarization-modulation infrared reflection-absorption spectroscopy is shown to be a powerful technique to directly detect the binding in such hybrid thin-film systems. A monodentate binding and a connection of neighboring QDs by the aryleneethynylene molecules is identified. Using steady-state and time resolved spectroscopy, we further investigated the photophysics of these hybrid systems. Different passivation capabilities resulting in different decay dynamics of the QDs turned out to be the main influence of the ligands on the photophysics.

3D printed versus commercial models in undergraduate conservative dentistry training.

INTRODUCTION: The treatment of carious lesions is one of the most fundamental competencies in daily dental practice. However, many commercially available training models lack in reality regarding the simulation of pathologies such as carious lesions. 3D printed models could provide a more realistic simulation. This study provides an exemplary description of the fabrication of 3D printed dental models with carious lesions and assesses their educational value compared to commercially available models in conservative dentistry. MATERIALS AND METHODS: A single-stage, controlled cohort study was conducted within the context of a curricular course. A stereolithographic model was obtained from an intraoral scan and then printed using fused deposition modelling. These models were first piloted by experts and then implemented and compared against commercial models in a conservative dentistry course. Experts and students evaluated both models using a validated questionnaire. Additionally, a cost analysis for both models was carried out. RESULTS: Thirteen dentists and twenty-seven 5th year dental students participated in the study. The 3D printed models were rated significantly more realistic in many test areas. In particular, the different tactility and the distinction in colour was rated positively in the 3D printed models. At 28.29€ (compared to 112.36€), the 3D printed models were exceptionally cost-efficient. CONCLUSIONS: 3D printed dental models present a more realistic and cost-efficient alternative to commercial models in the undergraduate training of conservative dentistry.

Prevalence of Alaria alata mesocercariae in wild boars from Brandenburg, Germany.

Since 2002, Alaria (A.) alata mesocercariae (AM) have been found during routine Trichinella inspection of wild boars in many European countries. To date, human infection with AM through consumption of undercooked or raw AM infested wild boar meat cannot be excluded. In Germany, data on the parasite's prevalence in wild boars are scarce. To better understand temporal and spatial fluctuations of this parasite, this study investigated the prevalence of AM in wild boars in the German federal state of Brandenburg during three hunting seasons from 2017 to 2020. In total, 28.3% (100/354, 95% CI: 23.3-33.3%) of all wild boars sampled in eight counties of Brandenburg were tested positive for AM by Alaria alata mesocercariae migration technique (AMT). AM were detected in wild boars from seven different counties. Samples from one county (Havelland) tested completely negative for AM (0/16). Prevalences of the seven AM positive counties of Brandenburg ranged from 11.5 (3/26, 95% CI: 2.5-30.1%) in Märkisch-Oderland to 64.1% (25/39, 95% CI: 47.2-78.8%) in Uckermark. An association between sex and A. alata positivity could not be determined. A statistically significant increase in frequency of older AM positive wild boars was observed (p = 0.001). For a nationwide assessment of the prevalence of A. alata in wild boars and the risk for consumers of ingesting viable AM by consumption of raw or undercooked AM infested wild boar meat, further long-term studies in different regions of Germany are needed.

Regulatory Impact of the C-Terminal Tail on Charge Transfer Pathways in Drosophila Cryptochrome.

Interconnected transcriptional and translational feedback loops are at the core of the molecular mechanism of the circadian clock. Such feedback loops are synchronized to external light entrainment by the blue light photoreceptor cryptochrome (CRY) that undergoes conformational changes upon light absorption by an unknown photoexcitation mechanism. Light-induced charge transfer (CT) reactions in Drosophila CRY (dCRY) are investigated by state-of-the-art simulations that reveal a complex, multi-redox site nature of CT dynamics on the microscopic level. The simulations consider redox-active chromophores of the tryptophan triad (Trp triad) and further account for pathways mediated by W314 and W422 residues proximate to the C-terminal tail (CTT), thus avoiding a pre-bias to specific W-mediated CT pathways. The conducted dissipative quantum dynamics simulations employ microscopically derived model Hamiltonians and display complex and ultrafast CT dynamics on the picosecond timescale, subtly balanced by the electrostatic environment of dCRY. In silicio point mutations provide a microscopic basis for rationalizing particular CT directionality and demonstrate the degree of electrostatic control realized by a discrete set of charged amino acid residues. The predicted participation of CT states in proximity to the CTT relates the directionality of CT reactions to the spatial vicinity of a linear interaction motif. The results stress the importance of CTT directional charge transfer in addition to charge transfer via the Trp triad and call for the use of full-length CRY models including the interactions of photolyase homology region (PHR) and CTT domains.

FLIm and Raman Spectroscopy for Investigating Biochemical Changes of Bovine Pericardium upon Genipin Cross-Linking.

Biomaterials used in tissue engineering and regenerative medicine applications benefit from longitudinal monitoring in a non-destructive manner. Label-free imaging based on fluorescence lifetime imaging (FLIm) and Raman spectroscopy were used to monitor the degree of genipin (GE) cross-linking of antigen-removed bovine pericardium (ARBP) at three incubation time points (0.5, 1.0, and 2.5 h). Fluorescence lifetime decreased and the emission spectrum redshifted compared to that of uncross-linked ARBP. The Raman signature of GE-ARBP was resonance-enhanced due to the GE cross-linker that generated new Raman bands at 1165, 1326, 1350, 1380, 1402, 1470, 1506, 1535, 1574, 1630, 1728, and 1741 cm-1. These were validated through density functional theory calculations as cross-linker-specific bands. A multivariate multiple regression model was developed to enhance the biochemical specificity of FLIm parameters fluorescence intensity ratio (R2 = 0.92) and lifetime (R2 = 0.94)) with Raman spectral results. FLIm and Raman spectroscopy detected biochemical changes occurring in the collagenous tissue during the cross-linking process that were characterized by the formation of a blue pigment which affected the tissue fluorescence and scattering properties. In conclusion, FLIm parameters and Raman spectroscopy were used to monitor the degree of cross-linking non-destructively.

Coupled excitation energy and charge transfer dynamics in reaction centre inspired model systems.

Functional operation conditions of reaction centre core complexes require the tight coupling of exciton states to concomitant charge separation. Rigorous theoretical treatment of such integrated excitation energy transfer (EET) and charge transfer (CT) dynamics is particularly challenging due to (i) appreciable system sizes, (ii) inter-site and system-bath couplings of similar magnitude that render the Born-Markov approximation invalid, (iii) substantial reorganization energies of CT states, and (iv) the presence of complex structured spectral densities due to vibrational modes of the surroundings. We present numerical simulations on bacterial reaction centre (bRC) inspired model systems that utilize the recently developed MACGIC-iQUAPI method [Richter et al., J. Chem. Phys., 2017, 146, 214101]. The simulations demonstrate that the method provides a rigorous framework for the investigation of such integrated EET-CT dynamics. First, the applicability of the MACGIC-iQUAPI method is explored for a transition from monotonically decaying to oscillatory system-bath influence coefficients, a behavior inherently imposed by structured bath spectral densities. Tightly coupled EET and CT dynamics is further addressed for an excitonic subsystem that resembles strong coupling of special pair states and serves as donor towards a generic bridge-acceptor system. By solving the dissipative quantum dynamics of such bRC inspired model systems, the quenching of excitonic coherence on the hundreds of femtoseconds timescale is explored via a variation of the bridge state energetics, resembling a continuous transition from sequential to superexchange mediated CT regimes. Further, the simulations explore the influence of resonant vibrational modes on the quenching of excitonic coherence via CT. The results reveal a moderate influence of vibrational mode on charge separation dynamics in regimes of biologically relevant EET and CT dynamics.

The DNA double-strand "breakome" of mouse spermatids.

De novo germline mutations arise preferentially in male owing to fundamental differences between spermatogenesis and oogenesis. Post-meiotic chromatin remodeling in spermatids results in the elimination of most of the nucleosomal supercoiling and is characterized by transient DNA fragmentation. Using three alternative methods, DNA from sorted populations of mouse spermatids was used to confirm that double-strand breaks (DSB) are created in elongating spermatids and repaired at later steps. Specific capture of DSB was used for whole-genome mapping of DSB hotspots (breakome) for each population of differentiating spermatids. Hotspots are observed preferentially within introns and repeated sequences hence are more prevalent in the Y chromosome. When hotspots arise within genes, those involved in neurodevelopmental pathways become preferentially targeted reaching a high level of significance. Given the non-templated DNA repair in haploid spermatids, transient DSBs formation may, therefore, represent an important component of the male mutation bias and the etiology of neurological disorders, adding to the genetic variation provided by meiosis.

Imaging the He2 quantum halo state using a free electron laser.

Quantum tunneling is a ubiquitous phenomenon in nature and crucial for many technological applications. It allows quantum particles to reach regions in space which are energetically not accessible according to classical mechanics. In this "tunneling region," the particle density is known to decay exponentially. This behavior is universal across all energy scales from nuclear physics to chemistry and solid state systems. Although typically only a small fraction of a particle wavefunction extends into the tunneling region, we present here an extreme quantum system: a gigantic molecule consisting of two helium atoms, with an 80% probability that its two nuclei will be found in this classical forbidden region. This circumstance allows us to directly image the exponentially decaying density of a tunneling particle, which we achieved for over two orders of magnitude. Imaging a tunneling particle shows one of the few features of our world that is truly universal: the probability to find one of the constituents of bound matter far away is never zero but decreases exponentially. The results were obtained by Coulomb explosion imaging using a free electron laser and furthermore yielded He2's binding energy of [Formula: see text] neV, which is in agreement with most recent calculations.

Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin.

Isoliquiritigenin (1) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation. In order to enable the use of 1 for in vivo studies without the use of toxic carriers or cosolvents, a phosphate prodrug strategy was implemented relying on the availability of phenol groups in the molecule. In this study, a phosphate group was added to position C-4 of 1, leading to the more water-soluble prodrug 2 and its ammonium salt 3, which possesses increased stability compared to 2. Herein are reported the synthesis, characterization, solubility, and stability of phosphate prodrug 3 in biological medium in comparison to 1, as well as new results on its anti-inflammatory properties in vivo. As designed, the solubility of prodrug 3 was superior to that of the parent natural product 1 (9.6 mg/mL as opposed to 3.9 µg/mL). Prodrug 3 as an ammonium salt was also found to possess excellent stability as a solid and in aqueous solution, as opposed to its phosphoric acid precursor 2.

Coarse-grained representation of the quasi adiabatic propagator path integral for the treatment of non-Markovian long-time bath memory.

The description of non-Markovian effects imposed by low frequency bath modes poses a persistent challenge for path integral based approaches like the iterative quasi-adiabatic propagator path integral (iQUAPI) method. We present a novel approximate method, termed mask assisted coarse graining of influence coefficients (MACGIC)-iQUAPI, that offers appealing computational savings due to substantial reduction of considered path segments for propagation. The method relies on an efficient path segment merging procedure via an intermediate coarse grained representation of Feynman-Vernon influence coefficients that exploits physical properties of system decoherence. The MACGIC-iQUAPI method allows us to access the regime of biological significant long-time bath memory on the order of hundred propagation time steps while retaining convergence to iQUAPI results. Numerical performance is demonstrated for a set of benchmark problems that cover bath assisted long range electron transfer, the transition from coherent to incoherent dynamics in a prototypical molecular dimer and excitation energy transfer in a 24-state model of the Fenna-Matthews-Olson trimer complex where in all cases excellent agreement with numerically exact reference data is obtained.

The paradox of falling job satisfaction with rising job stickiness in the German nursing workforce between 1990 and 2013.

BACKGROUND: Literature reports a direct relation between nurses' job satisfaction and their job retention (stickiness). The proper planning and management of the nursing labor market necessitates the understanding of job satisfaction and retention trends. The objectives of the study are to identify trends in, and the interrelation between, the job satisfaction and job stickiness of German nurses in the 1990-2013 period using a flexible specification for job satisfaction that includes different time periods and to also identify the main determinants of nurse job stickiness in Germany and test whether these determinants have changed over the last two decades. METHODS: The development of job stickiness in Germany is depicted by a subset of data from the German Socio-Economic Panel (1990-2013), with each survey respondent assigned a unique identifier used to calculate the year-to-year transition probability of remaining in the current position. The changing association between job satisfaction and job stickiness is measured using job satisfaction data and multivariate regressions assessing whether certain job stickiness determinants have changed over the study period. RESULTS: Between 1990 and 2013, the job stickiness of German nurses increased from 83 to 91%, while their job satisfaction underwent a steady and gradual decline, dropping by 7.5%. We attribute this paradoxical result to the changing association between job satisfaction and job stickiness; that is, for a given level of job (dis)satisfaction, nurses show a higher stickiness rate in more recent years than in the past, which might be partially explained by the rise in part-time employment during this period. The main determinants of stickiness, whose importance has not changed in the past two decades, are wages, tenure, personal health, and household structure. CONCLUSIONS: The paradoxical relation between job satisfaction and job stickiness in the German nursing context could be explained by historical downsizing trends in hospitals, an East-West German nurse compensation gap, and an increase in the proportion of nurses employed on a part-time basis. A clearer analysis of each of these trends is thus essential for the development of evidence-based policies that enhance the job satisfaction and efficiency of the German nursing workforce.

The Combination of Micro Diaphragm Pumps and Flow Sensors for Single Stroke Based Liquid Flow Control.

With the combination of micropumps and flow sensors, highly accurate and secure closed-loop controlled micro dosing systems for liquids are possible. Implementing a single stroke based control mode with piezoelectrically driven micro diaphragm pumps can provide a solution for dosing of volumes down to nanoliters or variable average flow rates in the range of nL/min to µL/min. However, sensor technologies feature a yet undetermined accuracy for measuring highly pulsatile micropump flow. Two miniaturizable in-line sensor types providing electrical readout-differential pressure based flow sensors and thermal calorimetric flow sensors-are evaluated for their suitability of combining them with mircopumps. Single stroke based calibration of the sensors was carried out with a new method, comparing displacement volumes and sensor flow volumes. Limitations of accuracy and performance for single stroke based flow control are described. Results showed that besides particle robustness of sensors, controlling resistive and capacitive damping are key aspects for setting up reproducible and reliable liquid dosing systems. Depending on the required average flow or defined volume, dosing systems with an accuracy of better than 5% for the differential pressure based sensor and better than 6.5% for the thermal calorimeter were achieved.

Analysis of Diagnostic Findings From the European Mobile Laboratory in Guéckédou, Guinea, March 2014 Through March 2015.

BACKGROUND: A unit of the European Mobile Laboratory (EMLab) consortium was deployed to the Ebola virus disease (EVD) treatment unit in Guéckédou, Guinea, from March 2014 through March 2015. METHODS: The unit diagnosed EVD and malaria, using the RealStar Filovirus Screen reverse transcription-polymerase chain reaction (RT-PCR) kit and a malaria rapid diagnostic test, respectively. RESULTS: The cleaned EMLab database comprised 4719 samples from 2741 cases of suspected EVD from Guinea. EVD was diagnosed in 1231 of 2178 hospitalized patients (57%) and in 281 of 563 who died in the community (50%). Children aged <15 years had the highest proportion of Ebola virus-malaria parasite coinfections. The case-fatality ratio was high in patients aged <5 years (80%) and those aged >74 years (90%) and low in patients aged 10-19 years (40%). On admission, RT-PCR analysis of blood specimens from patients who died in the hospital yielded a lower median cycle threshold (Ct) than analysis of blood specimens from survivors (18.1 vs 23.2). Individuals who died in the community had a median Ct of 21.5 for throat swabs. Multivariate logistic regression on 1047 data sets revealed that low Ct values, ages of <5 and ≥45 years, and, among children aged 5-14 years, malaria parasite coinfection were independent determinants of a poor EVD outcome. CONCLUSIONS: Virus load, age, and malaria parasite coinfection play a role in the outcome of EVD.

Dilemmas in Managing Pregnant Women With Ebola: 2 Case Reports.

We report 2 cases of Ebola viral disease (EVD) in pregnant women who survived, initially with intact pregnancies. Respectively 31-32 days after negativation of the maternal blood EVD-polymerase chain reaction (PCR) both patients delivered a stillborn fetus with persistent EVD-PCR amniotic fluid positivity.

Dynamical Characteristics of Rydberg Electrons Released by a Weak Electric Field.

The dynamics of ultraslow electrons in the combined potential of an ionic core and a static electric field is discussed. With state-of-the-art detection it is possible to create such electrons through strong intense-field photoabsorption and to detect them via high-resolution time-of-flight spectroscopy despite their very low kinetic energy. The characteristic feature of their momentum spectrum, which emerges at the same position for different laser orientations, is derived and could be revealed experimentally with an energy resolution of the order of 1 meV.

The administration of oseltamivir results in reduced effector and memory CD8+ T cell responses to influenza and affects protective immunity.

The clinical benefits of oseltamivir (Tamiflu) are well established, but the effects of antiviral treatment on the immune response are poorly understood. By use of flow cytometric analyses and the mouse model, we thoroughly investigated the impact of such a treatment on the immune response and the generation of protective immunity to influenza. We demonstrated that influenza-specific CD8(+) effector T cell recruitment was reduced up to 81% in the lungs of mice treated with oseltamivir (5 or 50 mg/kg twice daily; EC50 49 nM in vitro) compared to saline controls, but cell generation was unaffected in draining lymph nodes. Importantly, we showed that oseltamivir administration significantly decreased the pools of tissue-resident and circulating effector memory (93.7%) and central memory CD8(+) T cells (45%) compared to saline controls. During heterologous secondary infection, a decreased memory CD8(+) T cell pool combined with reduced generation of secondary influenza-specific effectors in the lymph nodes resulted in 10-fold decreased CD8(+) T cell recall responses, which increased mouse morbidity and delayed viral clearance. Furthermore, antiviral administration led to a significant 5.7-fold decreased production of functional anti-influenza antibodies. Thus, our study demonstrates that antiviral treatment affects the development of the adaptive immune response and protective immunity against influenza.

Biomarker candidates for the detection of an infectious etiology of febrile neutropenia.

PURPOSE: Infections and subsequent septicemia are major complications in neutropenic patients with hematological malignancies. Here, we identify biomarker candidates for the early detection of an infectious origin, and monitoring of febrile neutropenia (FN). METHODS: Proteome, metabolome, and conventional biomarkers from 20 patients with febrile neutropenia without proven infection (FNPI) were compared to 28 patients with proven infection, including 17 patients with bacteremia. RESULTS: Three peptides (mass to charge ratio 1017.4-1057.3; p-values 0.011-0.024), six proteins (mass to charge ratio 6881-17,215; p-values 0.002-0.004), and six phosphatidylcholines (p-values 0.007-0.037) were identified that differed in FNPI patients compared to patients with infection or bacteremia. Seven of these marker candidates discriminated FNPI from infection at fever onset with higher sensitivity and specificity (ROC-AUC 0.688-0.824) than conventional biomarkers i.e., procalcitonin, C-reactive protein, or interleukin-6 (ROC-AUC 0.535-0.672). In a post hoc analysis, monitoring the time course of four lysophosphatidylcholines, threonine, and tryptophan allowed for discrimination of patients with or without resolution of FN (ROC-AUC 0.648-0.919) with higher accuracy compared to conventional markers (ROC-AUC 0.514-0.871). CONCLUSIONS: Twenty-one promising biomarker candidates for the early detection of an infectious origin or for monitoring the course of FN were found which might overcome known shortcomings of conventional markers.

[On-site detection of bioterrorism-relevant agents : Rapid detection methods for viruses, bacteria and toxins - capabilities and limitations]. / Vor-Ort-Nachweis bioterroristisch relevanter Agenzien : Schnelle Nachweismethoden für Viren, Bakterien und Toxine ­ Potenziale und Grenzen.

In Europe, besides the threat of terrorist attacks involving conventional methods such as explosive devices and automatic weapons, there is also a potential threat of terrorist groups using non-conventional material like biological agents in the scope of future attacks. Consequently, rapid and reliable detection systems for biological agents are being developed and tested continuously to inform crisis management. For environmental detection, a broad spectrum of different laboratory-based techniques has been developed for relevant biological agents. However for environmental samples, fast and reliable on-site detection methods are desired by first responders for rapid assessment.Based on different functional principles, generic, immunological and nucleic-acid-based on-site detection methods can be distinguished. Those should be facile, fast, sensitive, and specific. However, commercially available kits usually have limited sensitivity and often have not been validated independently. Furthermore in this context, the multitude of relevant biological agents that potentially have to be considered present in complex environmental matrices poses a serious challenge for reliable detection. Therefore, detailed knowledge of the specific scope of applications and the limitations of different analytical systems is necessary to evaluate the results obtained purposefully.The aim of this article is to provide an overview of the analytical principles, benefits and limitations of prevailing on-site environmental detection systems for bioterrorism-relevant viruses, bacteria and toxins. Despite promising developments the informative value of currently available on-site tests is still limited. Thus, expert laboratories have to conduct confirmatory testing.