BEYOND: a randomized controlled trial comparing efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus antagonist protocol during the first ovarian stimulation cycle.

STUDY QUESTION: How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation? SUMMARY ANSWER: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS). WHAT IS KNOWN ALREADY: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively). LIMITATIONS, REASONS FOR CAUTION: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown. WIDER IMPLICATIONS OF THE FINDINGS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol. STUDY FUNDING/COMPETING INTEREST(S): The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40. TRIAL REGISTRATION DATE: 7 April 2019. DATE OF FIRST PATIENT'S ENROLMENT: 2 May 2019.

Low Temperature Dynamic Polaron Liquid in a Manganite Exhibiting Colossal Magnetoresistance.

Polarons-fermionic charge carriers bearing a strong companion lattice deformation-exhibit a natural tendency for self-localization due to the recursive interaction between electrons and the lattice. While polarons are ubiquitous in insulators, how they evolve in transitions to metallic and superconducting states in quantum materials remains an open question. Here, we use resonant inelastic x-ray scattering to track the electron-lattice coupling in the colossal magneto-resistive bi-layer manganite La_{1.2}Sr_{1.8}Mn_{2}O_{7} across its metal-to-insulator transition. The response in the insulating high-temperature state features harmonic emissions of a dispersionless oxygen phonon at small energy transfer. Upon cooling into the metallic state, we observe a drastic redistribution of spectral weight from the region of these harmonic emissions to a broad high energy continuum. In concert with theoretical calculations, we show that this evolution implies a shift in electron-lattice coupling from static to dynamic lattice distortions that leads to a distinct polaronic ground state in the low temperature metallic phase-a dynamic polaron liquid.

Prevalence of burnout among German radiologists: a call to action.

OBJECTIVES: In the presence of escalating global concerns regarding physician burnout, this study aims to analyze the prevalence and associated factors of burnout among radiologists in Germany. METHODS: A comprehensive online survey, inclusive of 73 targeted questions including a German-modified version of the Maslach Burnout Inventory, was distributed among all members of the German Radiological Society and the German Interventional Radiological Society between May and August 2023. The survey encompassed aspects of employment, workload, well-being, and coping mechanisms. Data from 172 completed surveys were analyzed, with correlations explored via crosstabs and the Pearson-chi-square test. RESULTS: In total, 76.7% of participating radiologists were identified to be burnt out. The prevalence was significantly associated with increased workload, reduced sleep quality, suboptimal working conditions, reduced job satisfaction, and the negative interplay between work, family life, and health. Median work satisfaction was described as "satisfied" while median workload was assessed as "frequently overwhelming of work." A total of 41.9% of respondents noted facing daily time pressure. Radiologists' concerns about work interfering with private family life were voiced by approximately 70%, and 73.3% highlighted the perceived negative effects on their health. CONCLUSION: The pronounced prevalence of burnout among German radiologists demonstrates an urgent, unmet need for comprehensive interventions and systemic changes. Our findings act as a catalyst for initiating targeted, multifaceted strategies and dialogs, essential for fostering a resilient and effective healthcare ecosystem. Further large-scale systematic studies should follow to analyze the findings in broad. CLINICAL RELEVANCE STATEMENT: Consistent with other countries, there is a high prevalence of burnout among radiologists in Germany. A call for further investigation is recommended to help mitigate adverse outcomes associated with physician burnout. KEY POINTS: • The prevalence of burnout has yet not been evaluated for German radiologists. • German radiologists have a high prevalence of burnout. • Steps must be implemented to engage this problem to prevent worsening.

Three-dimensional collective charge excitations in electron-doped copper oxide superconductors.

High-temperature copper oxide superconductors consist of stacked CuO2 planes, with electronic band structures and magnetic excitations that are primarily two-dimensional1,2, but with superconducting coherence that is three-dimensional. This dichotomy highlights the importance of out-of-plane charge dynamics, which has been found to be incoherent in the normal state3,4 within the limited range of momenta accessible by optics. Here we use resonant inelastic X-ray scattering to explore the charge dynamics across all three dimensions of the Brillouin zone. Polarization analysis of recently discovered collective excitations (modes) in electron-doped copper oxides5-7 reveals their charge origin, that is, without mixing with magnetic components5-7. The excitations disperse along both the in-plane and out-of-plane directions, revealing its three-dimensional nature. The periodicity of the out-of-plane dispersion corresponds to the distance between neighbouring CuO2 planes rather than to the crystallographic c-axis lattice constant, suggesting that the interplane Coulomb interaction is responsible for the coherent out-of-plane charge dynamics. The observed properties are hallmarks of the long-sought 'acoustic plasmon', which is a branch of distinct charge collective modes predicted for layered systems8-12 and argued to play a substantial part in mediating high-temperature superconductivity10-12.

CT angiography of the lower limbs: combining small field of view with large matrix size and iterative reconstruction further improves image quality of below-the-knee arteries.

BACKGROUND: Image quality and diagnostic accuracy in computed tomography angiography (CTA) reach their limits in imaging of below-the-knee vessels. PURPOSE: To evaluate whether image quality in CTA of lower limbs is further improvable by combining side-separate reconstruction with a larger matrix size and whether resulting noise can be compromised with iterative reconstruction (IR). MATERIAL AND METHODS: From CTA of the lower extremities of 26 patients (5 women, 21 men; mean age = 68.5 ± 10.3 years), the lower legs were reconstructed side-separately with different reconstruction algorithms and matrix sizes including filtered back projection (FBP) with a 512 × 512 matrix, FBP with a 1024 × 1024 matrix, IR (SAFIRE) with a 512 × 512 matrix, and IR (SAFIRE) with a 1024 × 1024 matrix. A total of 208 CT series were evaluated. Subjective image quality was assessed by two readers using a 5-point Likert scale. Image noise was assessed by measuring signal-to-noise and contrast-to-noise ratios. RESULTS: Subjective image quality was rated significantly higher when using a 1024 × 1024 matrix (P < 0.001) and could further be increased with IR. Vessel sharpness was rated significantly better with a larger matrix (P < 0.001). Visible and measured image noise was significantly higher with a 1024 × 1024 matrix but could be reduced by using IR (P < 0.001), even to a level below FBP with a 512 × 512 matrix while reconstructing with a larger matrix (P < 0.001). CONCLUSION: Image quality, image noise, and vessel sharpness can be further improved in CTA of the lower extremities with side-separate reconstruction using a 1024 × 1024 matrix size and IR.

Virtual reality simulation training in laparoscopic surgery - does it really matter, what simulator to use? Results of a cross-sectional study.

BACKGROUND: Virtual reality simulation training plays a crucial role in modern surgical training, as it facilitates trainees to carry out surgical procedures or parts of it without the need for training "on the patient". However, there are no data comparing different commercially available high-end virtual reality simulators. METHODS: Trainees of an international gastrointestinal surgery workshop practiced in different sequences on LaparoS® (VirtaMed), LapSim® (Surgical Science) and LapMentor III® (Simbionix) eight comparable exercises, training the same basic laparoscopic skills. Simulator based metrics were compared between an entrance and exit examination. RESULTS: All trainees significantly improved their basic laparoscopic skills performance, regardless of the sequence in which they used the three simulators. Median path length was initially 830 cm and 463 cm on the exit examination (p < 0.001), median time taken improved from 305 to 167 s (p < 0.001). CONCLUSIONS: All Simulators trained efficiently the same basic surgery skills, regardless of the sequence or simulator used. Virtual reality simulation training, regardless of the simulator used, should be incorporated in all surgical training programs. To enhance comparability across different types of simulators, standardized outcome metrics should be implemented.

Determinants of Cannabis Initiation and Cessation among Berlin College Students - A Longitudinal Study.

Background: As a big European city famous for its party scene, Berlin attracts college students that are a high-risk population for cannabis use and use disorder. College years are often associated with new behavior patterns, but the factors leading to cannabis initiation are rarely studied past adolescence. This study describes the longitudinal evolution of college students' cannabis use over two years and its correlates. Method: Data was collected among all students of Berlin's public colleges via two online surveys (N = 1,201, mean interval = 16 months). Multivariable binary logistic regressions were performed on four outcomes: regular use, use initiation, use reduction and use cessation. Several dimensions of covariates were used: socio-demographic factors, psychological (locus of control, impulsivity, psychiatric diagnosis), behavioral (other substance use), perceived harm, declared intention to reduce and setting of cannabis use. Results: Overall, the majority of respondents did not change their cannabis use. The factors for use initiation (impulsivity, tobacco and alcohol use) were not fully symmetric to the factors leading to cutting down/quitting (locus of control, perceived harm, tobacco use). Perceived harm had an impact on quitting, but not on reducing use. The intention to reduce did not significantly predict subsequent use behavior. Most regular users use cannabis at home, which was associated with a low probability to reduce. Conclusions: No simple symmetry exists between correlates of initiation and cessation: tobacco co-use is important for both, while impulsivity and alcohol use lead to initiation and internal locus of control facilitates cessation.

Digital Variance Angiography in Selective Lower Limb Interventions.

PURPOSE: To evaluate the potential benefits of digital variance angiography (DVA) in selective lower limb angiography and to compare the performance of 2 DVA algorithms (conventional DVA1 and the recently developed DVA2) to that of digital subtraction angiography (DSA). MATERIALS AND METHODS: From November 2019 to May 2020, 112 iodinated contrast media (ICM) and 40 carbon dioxide (CO2) angiograms were collected from 15 and 13 peripheral artery disease patients, respectively. The DVA files were retrospectively generated from the same unsubtracted source file as DSA. The objectively calculated contrast-to-noise ratio (CNR) and the subjective visual image quality of DSA, DVA1, and DVA2 images were statistically compared using the Wilcoxon signed-rank test. The images were evaluated by 6 radiologists (R.P.T., S.V., A.M.K., S.S.A., O.E., and J.S.) from 2 centers using a 5-grade Likert scale. RESULTS: Both DVA algorithms produced similar increase (at least 2-fold) in CNR values (P < .001) and significantly higher image quality scores than DSA, independent of the contrast agent used. The overall scores with ICM were 3.61 ± 0.05 for DSA, 4.30 ± 0.04 for DVA1, and 4.33 ± 0.04 for DVA2 (each P < .001 vs DSA). The scores for CO2 were 3.10 ± 0.14 for DSA, 3.63 ± 0.13 for DVA1 (P < .001 vs DSA), and 3.38 ± 0.13 for DVA2 (P < .05 vs DSA). CONCLUSIONS: DVA provides higher CNR and significantly better image quality in selective lower limb interventions irrespective of the contrast agent used. Between DVA algorithms, DVA1 is preferred because of its identical or better image quality than DVA2. DVA can potentially help the interventional decision process and its quality reserve might allow dose management (radiation/ICM reduction) in the future.

Effect of preoperative erector spinae muscles mass on postoperative outcomes in patients with left ventricular assist devices.

BACKGROUND: Frailty influences the postoperative outcomes in patients undergoing left ventricular assist device (LVAD) implantation. Recently, erector spinae muscle (ESM) mass has been proposed as a parameter to assess frailty accurately. Thus, the purpose of the present study was to evaluate whether preoperative ESM mass is associated with short- and long-term clinical outcomes in patients with LVAD. METHODS: A total of 119 consecutive patients with LVAD were enrolled between January 2010 and October 2017 at a single heart center. The ESM area, ESM index, and Hounsfield units (HU) of the ESM were calculated by computed tomography for preoperative ESM mass evaluation. We then statistically evaluated the in-hospital mortality, major adverse cardiovascular events (MACE), duration of hospital stay, and long-term survival. RESULTS: In a multivariate Cox regression analysis, ESM mass indicated no effect on all clinical outcomes. In addition, the ESM area presented a weak but significant negative linear correlation only with the duration of hospital stay (r = -0.21, p < .05). In contrast, the Model For End-stage Liver Disease (MELD) score and preoperative venous-arterial extracorporeal membrane oxygenation (va-ECMO) were significant predictive factors for in-hospital mortality (MELD score: p < .001, hazard ratio [HR] 1.1; preoperative va-ECMO: p < .01, HR 2.72) and MACE (MELD score: p < .001, HR 1.07; preoperative va-ECMO: p < .005, HR 2.62). CONCLUSION: Preoperative ESM mass might predict the length of hospital stay in patients undergoing LVAD implantation. In contrast, it had no effect on MACE, in-hospital mortality, or long-term survival in this study.

In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration.

PURPOSE: Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. METHODS: An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration ("pulsed delivery"), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5-40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. RESULTS: Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 ± 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. CONCLUSION: Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes.

Publisher Correction: Electronic structure of the parent compound of superconducting infinite-layer nickelates.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Electronic structure of the parent compound of superconducting infinite-layer nickelates.

The search continues for nickel oxide-based materials with electronic properties similar to cuprate high-temperature superconductors1-10. The recent discovery of superconductivity in the doped infinite-layer nickelate NdNiO2 (refs. 11,12) has strengthened these efforts. Here, we use X-ray spectroscopy and density functional theory to show that the electronic structure of LaNiO2 and NdNiO2, while similar to the cuprates, includes significant distinctions. Unlike cuprates, the rare-earth spacer layer in the infinite-layer nickelate supports a weakly interacting three-dimensional 5d metallic state, which hybridizes with a quasi-two-dimensional, strongly correlated state with [Formula: see text] symmetry in the NiO2 layers. Thus, the infinite-layer nickelate can be regarded as a sibling of the rare-earth intermetallics13-15, which are well known for heavy fermion behaviour, where the NiO2 correlated layers play an analogous role to the 4f states in rare-earth heavy fermion compounds. This Kondo- or Anderson-lattice-like 'oxide-intermetallic' replaces the Mott insulator as the reference state from which superconductivity emerges upon doping.

Monitoring of Erosive Tooth Wear with Intraoral Scanners In vitro.

Intraoral scanners (IOS) have been used to quantify tooth wear, but so far they have not been systematically validated for monitoring of tissue loss. The aim of this in vitro study was to investigate whether progression of tissue loss can be detected with an IOS and whether IOS values agree with those obtained with noncontacting profilometry (PRO) serving as a standard method. Model jaws were mounted in a phantom head positioned in a dental chair. Flattened areas were prepared on the non-load-bearing cusps of the first molars (model teeth; n = 16) in order to fix flat enamel samples with an experimental area and a reference area. After baseline PRO and IOS, the experimental enamel area was stepwise etched with 35% H3PO4 gel (4 × 30 s and 4 × 15 s). After each etching, PRO and IOS was performed and the vertical tissue loss between the reference and experimental areas was measured, each at the same 3 measurement points. Furthermore, cupped cusps were simulated by stepwise preparation of the load-bearing cusps of the model teeth with a spherical diamond bur, and the maximum vertical depth after each preparation step was measured only by IOS. Trios3 (3Shape, Denmark), Carestream CS3600 (Carestream, USA) and an optical profilometer (MicroProf, Fries, Germany) were used to measure the flat areas of the enamel samples, whereas only IOS were used to measure curved surfaces on the load-bearing cupped cusps of the model teeth. The IOS data were analyzed with an external software (GOM Inspect, Germany) and with the respective internal IOS software. PRO revealed a mean (±SD) tissue loss of 17.1 ± 4.7 µm after 30-s etching steps and 10.1 ± 5.1 µm after the 15-s etching steps. IOS and software types were able to detect the progression of tissue loss after each etching step (p ≤ 0.001 each); Bland-Altmann plots revealed good agreement with PRO regardless of the order of tissue loss, and no systematic difference was found. Increasing cupped lesion depths were detected by all IOS, with no significant differences between IOS and analysis methods. IOS were able to detect small amounts of tissue loss under simulated clinical conditions and seem to be a promising tool for monitoring even initial erosive tooth wear.

Iron deficiency does not impair the outcome after elective coronary artery bypass and aortic valve procedures.

BACKGROUND AND AIM OF THE STUDY: Iron deficiency (ID), a common malnutrition, has been linked to impaired prognosis in patients with congestive heart failure. It remains unclear whether ID also affects the outcome after elective cardiac surgery. METHODS: A total of 378 consecutive patients undergoing either coronary artery bypass grafting (CABG) or surgical aortic valve replacement (SAVR) were prospectively enrolled, and blood samples were taken before surgery for analysis of iron metabolism. Incidence of major adverse cardiovascular and cerebrovascular events (MACCE) was defined as the primary endpoint of the study. RESULTS: ID (ferritin < 100 ng/ml or ferritin = 100-299 ng/ml and transferrin saturation < 20%) was common in cardiac surgery patients (ID, n = 265, 70%) and related to significant decreased preoperative hemoglobin values (ID: 13.6 ± 1.6 g/dl, Non-ID: 14.3 ± 1.5 g/dl, p < 0.01). We did not observe any differences in the postoperative outcome of the two groups. The incidence of MACCE was 4.9% in patients with ID and 8.8% in Non-ID (p = 0.16). In-hospital mortality (ID: 1.9%, Non-ID: 4.4%, p = 0.17) and stroke (ID: 1.1%, Non-ID: 1.8%, p = 0.64) were also not altered by ID. In addition, intensive care unit and hospital stay, perioperative blood transfusions as well as perioperative morbidities, such as acute kidney injury, low cardiac output syndrome, major bleeding complication, and sternal wound infections were comparable in patients with and without ID. CONCLUSIONS: The majority of patients undergoing elective CABG or SAVR suffer from ID; however, we found no significant differences in regard to MACCE and postoperative morbidity between ID and non-ID patients.

Real-time in situ observations of reaction and transport phenomena during silicate glass corrosion by fluid-cell Raman spectroscopy.

Borosilicate glass is an important material used in various industries due to its chemical durability, such as for the immobilization of high-level nuclear waste. However, it is susceptible to aqueous corrosion, recognizable by the formation of surface alteration layers (SALs). Here, we report in situ fluid-cell Raman spectroscopic experiments providing real-time insights into reaction and transport processes during the aqueous corrosion of a borosilicate glass. The formation of a several-micrometre-thick water-rich zone between the SAL and the glass, interpreted as an interface solution, is detected, as well as pH gradients at the glass surface and within the SAL. By replacing the solution with a deuterated solution, it is observed that water transport through the SAL is not rate-limiting. The data support an interface-coupled dissolution-reprecipitation process for SAL formation. Fluid-cell Raman spectroscopic experiments open up new avenues for studying solid-water reactions, with the ability to in situ trace specific sub-processes in real time by using stable isotopes.

Intermediate monocytes exhibit higher levels of TLR2, TLR4 and CD64 early after congenital heart surgery.

INTRODUCTION: Congenital heart surgery with cardiopulmonary bypass (CPB) initiates an immune response which frequently leads to organ dysfunction and a systemic inflammatory response. Complications associated with exacerbated immune responses may severely impact the postoperative recovery. The objective was to describe the characteristics of monocyte subpopulations and neutrophils at the level of pattern recognition receptors (PRR) and the cytokine response after CPB in infants. METHODS: An observational cohort study was conducted between June 2016 and June 2017 of infants < 2 years of age, electively admitted for surgical correction of acyanotic congenital heart defects using CPB. Fourteen blood samples were collected sequentially and processed immediately during and up to 48 h following cardiac surgery for each patient. Flow cytometry analysis comprised monocytic and granulocytic surface expression of CD14, CD16, CD64, TLR2, TLR4 and Dectin-1 (CLEC7A). Monocyte subpopulations were further defined as classical (CD14++/CD16-), intermediate (CD14++/CD16+) and nonclassical (CD14+/CD16++) monocytes. Plasma concentrations of 14 cytokines, including G-CSF, GM-CSF, IL-1ß, IL-1RA, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, TNF-α, IFN-γ, MIP-1ß (CCL4) and TGF-ß1, were measured using multiplex immunoassay for seven points in time. RESULTS: Samples from 21 infants (median age 7.4 months) were analyzed by flow cytometry and from 11 infants, cytokine concentrations were measured. Classical and intermediate monocytes showed first receptor upregulation with an increase in CD64 expression four hours post CPB. CD64-expression on intermediate monocytes almost tripled 48 h post CPB (p < 0.0001). TLR4 was only increased on intermediate monocytes, occurring 12 h post CPB (p = 0.0406) along with elevated TLR2 levels (p = 0.0002). TLR4 expression on intermediate monocytes correlated with vasoactive-inotropic score (rs = 0.642, p = 0.0017), duration of ventilation (rs = 0.485, p = 0.0259), highest serum creatinine (rs = 0.547, p = 0.0102), postsurgical transfusion (total volume per kg bodyweight) (rs = 0.469, p = 0.0321) and lowest mean arterial pressure (rs = -0.530, p = 0.0135). Concentrations of IL-10, MIP-1ß, IL-8, G-CSF and IL-6 increased one hour post CPB. Methylprednisolone administration in six patients had no significant influence on the studied surface receptors but led to lower IL-8 and higher IL-10 plasma concentrations. CONCLUSIONS: Congenital heart surgery with CPB induces a systemic inflammatory process including cytokine response and changes in PRR expression. Intermediate monocytes feature specific inflammatory characteristics in the 48 h after pediatric CPB and TLR4 correlates with poorer clinical course, which might provide a potential diagnostic or even therapeutic target.

Process intensification for cytochrome P450 BM3-catalyzed oxy-functionalization of dodecanoic acid.

Selective oxy-functionalization of nonactivated C-H bonds is a long-standing "dream reaction" of organic synthesis for which chemical methodology is not well developed. Mono-oxygenase enzymes are promising catalysts for such oxy-functionalization to establish. Limitation on their applicability arises from low reaction output. Here, we showed an integrated approach of process engineering to the intensification of the cytochrome P450 BM3-catalyzed hydroxylation of dodecanoic acid (C12:0). Using P450 BM3 together with glucose dehydrogenase for regeneration of nicotinamide adenine dinucleotide phosphate (NADPH), we compared soluble and co-immobilized enzymes in O2 -gassed and pH-controlled conversions at high final substrate concentrations (≥40mM). We identified the main engineering parameters of process output (i.e., O2 supply; mixing correlated with immobilized enzyme stability; foam control correlated with product isolation; substrate solubilization) and succeeded in disentangling their complex interrelationship for systematic process optimization. Running the reaction at O2 -limited conditions at up to 500-ml scale (10% dimethyl sulfoxide; silicone antifoam), we developed a substrate feeding strategy based on O2 feedback control. Thus, we achieved high reaction rates of 1.86g·L-1 ·hr-1 and near complete conversion (≥90%) of 80mM (16g/L) C12:0 with good selectivity (≤5% overoxidation). We showed that "uncoupled reaction" of the P450 BM3 (~95% utilization of NADPH and O2 not leading to hydroxylation) with the C12:0 hydroxylated product limited the process efficiency at high product concentration. Hydroxylated product (~7g; ≥92% purity) was recovered from 500ml reaction in 82% yield using ethyl-acetate extraction. Collectively, these results demonstrate key engineering parameters for the biocatalytic oxy-functionalization and show their integration into a coherent strategy for process intensification.

Enzymatic activity and thermoresistance of improved microbial transglutaminase variants.

Microbial transglutaminase (MTG, EC 2.3.2.13) of Streptomyces mobaraensis is widely used in industry for its ability to synthesize isopeptide bonds between the proteinogenic side chains of glutamine and lysine. The activated wild-type enzyme irreversibly denatures at 60 °C with a pseudo-first-order kinetics and a half-life time (t1/2) of 2 min. To increase the thermoresistance of MTG for higher temperature applications, we generated 31 variants based on previous results obtained by random mutagenesis, DNA shuffling and saturation mutagenesis. The best variant TG16 with a specific combination of five of seven substitutions (S2P, S23Y, S24 N, H289Y, K294L) shows a 19-fold increased half-life at 60 °C (t1/2 = 38 min). As measured by differential scanning fluorimetry, the transition point of thermal unfolding was increased by 7.9 °C. Also for the thermoresistant variants, it was shown that inactivation process follows a pseudo-first-order reaction which is accompanied by irreversible aggregation and intramolecular self-crosslinking of the enzyme. Although the mutations are mostly located on the surface of the enzyme, kinetic constants determined with the standard substrate CBZ-Gln-Gly-OH revealed a decrease in KM from 8.6 mM (± 0.1) to 3.5 mM (± 0.1) for the recombinant wild-type MTG and TG16, respectively. The improved performance of TG16 at higher temperatures is exemplary demonstrated with the crosslinking of the substrate protein ß-casein at 60 °C. Using molecular dynamics simulations, it was shown that the increased thermoresistance is caused by a higher backbone rigidity as well as increased hydrophobic interactions and newly formed hydrogen bridges.

'Higher education' - substance use among Berlin college students.

Berlin is internationally known for its intense nightlife associated with high rates of psychoactive substance use. Previous studies conducted in other cities indicated college students as a group at high risk for substance (mis-)use that was associated with individual psychological and cognitive impairments as well as lower academic performance. The aim of this study was to provide detailed data about the substance use patterns of Berlin college students. In addition, major protective and risk factors were analysed. An online questionnaire assessing sociodemographic data and various relevant aspects of both legal and illegal substance use such as consumption pattern and frequency as well as risk-taking behaviour was developed and distributed among colleges in Berlin. A sample of 9351 participants from 17 different colleges in Berlin completed the questionnaire. The study revealed high lifetime (69.3%), past year (45.9%) and past month (28.3%) prevalence of illicit substance use in the sample. Daily tobacco-smoking, a mental disorder diagnosis, a positive screening for problematic consumption (Cage-AID), bisexual orientation and living in open relationship were main factors positively associated with the prevalence and the extent of illicit substance use. Students in Berlin appear to show higher rates of illicit substance use than was previously reported for age-matched individuals in the general German population and college students in other cities. Thus, they are a relevant target group for early prevention and intervention concerning substance use and abuse.

Pressure Effects on the 4f Electronic Structure of Light Lanthanides.

Using the satellite structure of the Lγ_{1} line in nonresonant x-ray emission spectra, we probe the high-pressure evolution of the bare 4f signature of the early light lanthanides at ambient temperature. For Ce and Pr the satellite peak experiences a sudden reduction concurrent with their respective volume collapse (VC) transitions. These new experimental results are supported by calculations using state-of-the-art extended atomic structure codes for Ce and Pr, and also for Nd, which does not exhibit a VC. Our work suggests that changes to the 4f occupation are more consistently associated with evolution of the satellite than is the reduction of the 4f moment. Indeed, we show that in the case of Ce, mixing of a higher atomic angular momentum state, driven by the increased hybridization, acts to obscure the expected satellite reduction. These measurements emphasize the importance of a unified study of a full set of microscopic observables to obtain the most discerning test of the underlying, fundamental f-electron phenomena at high pressures.