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A novel magnetic liquid silicone rubber composite core design applicable to wireless power transfer (WPT) for medical applications is presented. As a case study, the integration of WPT, including the proposed cores for the coils, with ventricular-assist devices (VADs) was investigated. This facilitates transferring 4.6 W of power wirelessly through the skin layer, which, thus, allows to disposal of the transcutaneous cable that connects the extracorporal batteries to the implanted blood pump. To enhance the coupling coefficient and consequently increase the WPT efficiency, the geometry of the cores was optimized. This reduces the temperature increase in the implant area. The field and thermal simulations were carried out with CST software. The electrical properties of the proposed design as obtained by simulation were validated by measurements. The simulation results perfectly coincide with the measured results. Finally, a new optimized design with additional high permeability core inserts is introduced to further increase the coupling coefficient. The results indicate that the coupling coefficient is increased from 0.31 to 0.52 with the optimized design compared to the case without cores. Moreover, by fixing the initial temperature as 37 °C, the maximum temperature is decreased from 38.19 °C to 37.27 °C while keeping the transferred power fixed. Its high magnetic conductivity, biocompatibility, low-loss property, flexibility, and Qi-standard compatibility make the proposed WPT design an excellent candidate for the wireless powering of heart-assist devices, such as VADs.

Objectives. Galectin-3 (gal-3) is a mediator of extracellular matrix metabolism and reflects an ongoing cardiac fibrotic process. The aim of this study was to determine the potential use of gal-3 in evaluating the structural and functional parameters of the right ventricle as determined by echocardiography. Design. Ninety-one patients undergoing routine echocardiography were prospectively enrolled in this monocentric study. Serum samples for gal-3 and aminoterminal pro-brain natriuretic peptide (NT-proBNP) were collected within 24 h of echocardiographic examination. Patients were arbitrarily divided into subgroups based on right ventricular function as measured by tricuspid annular plane systolic excursion (TAPSE) and these included TAPSE >24 mm (n = 23); TAPSE 18-24 mm (n = 55); TAPSE ≤17 mm (n = 13); permitting the detailed statistical analysis of derived data. Results. Serum levels of gal-3 in all patients correlated with age (r = 0.36. p

Etching pores in the basal plane of graphene by wet-chemical methods with a certain size-control reflects a synthetic challenge. Here, a facile and controllable method is presented to produce solution-processible porous-graphene derivatives. The derivative of graphene oxide, here oxo-functionalized graphene (oxo-G) with a controlled density of in-plane vacancy defects is chosen as a precursor. Hydroxyl radicals are generated, which etch pores into the basal plane of oxo-G, preferably starting at defect sites. Thereby, solution-processible flakes of oxo-G with μm-size lateral dimensions and pores with tunable diameters between 5 nm and 500 nm are accessible. Moreover, a plausible mechanism for the growth of pores is proposed based on AFM, TEM, UV–vis spectroscopy, FTIR spectroscopy, XPS, solid-state NMR spectroscopy and statistical Raman spectroscopy. In first approximation, the electrophilic addition and oxidation reaction between hydroxyl radicals and oxo-G close to defect-sites is the basis for etching. The porous graphene materials may act as membranes or tunable two-dimensional materials.

Biological pretreatment of lignocellulose by white-rot fungi is an environmentally friendly alternative to chemical and physical approaches to enhance enzymatic saccharification. However, inefficient lignin degradation and substantial cellulose consumption during fungal pretreatment can cause low sugar yields. In this study, the combined action of CuSO4 and MnSO4 effectively improved the degree and selectivity of delignification during solid-state fungal pretreatment of poplar wood by Phanerochaete chrysosporium. Compared to pretreatment without this supplementation, a 1.9 fold higher lignin degradation and 2.4 times higher delignification selectivity value were obtained due to the increased and prolonged manganese peroxidase activity. Enzymatic saccharification of supplemented pretreated wood resulted in a 2.9 times higher glucose yield compared to the non-supplemented system. This study has demonstrated that the combined application of Mn2+ and Cu2+ can significantly improve the fungal pretreatment process and that the beneficial effect of Cu2+ on delignification is not restricted to laccase-producing fungi.

A novel and very simple to perform electrochemical approach for the synthesis of several N‐cyanosulfilimines in good to excellent yields was established. This method provides access to biologically relevant sulfoximines by consecutive oxidation using electro‐generated periodate. This route can be easily scaled‐up to gram quantities. The S,N coupling is carried out at an inexpensive carbon anode by direct oxidation of sulfide. Therefore, the designed process is atom economic and represents a new “green route” for the synthesis of sulfilimines and sulfoximines., A novel, robust and scalable electrochemical route for synthesis of N‐cyanosulfilimines is described. The reaction provides good to excellent yields for dialkyl and alkylaryl sulfilimines. Compared to established routes no external oxidizers or strong bases are required. The synthesis provides access to biologically relevant sulfoximines by further oxidation using electro‐generated periodate.

Background Biliary phosphatidylcholine (PtdC) concentration plays a role in the pathogenesis of bile duct diseases. In vivo phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) at 7 T offers the possibility to assess this concentration noninvasively with high spectral resolution and signal intensity. Purpose Comparison of PtdC levels of cholangiopathic patient groups to a control group using a measured T1 relaxation time of PtdC in healthy subjects. Study type Case control. Subjects Two patient groups with primary sclerosing cholangitis (PSC, 2f/3 m; age: 43 ± 7 years) and primary biliary cholangitis (PBC, 4f/2 m; age: 57 ± 6 years), and a healthy control group (CON, 2f/3 m; age: 38 ± 7 years). Ten healthy subjects for the assessment of the T1 relaxation time of PtdC. Field strength/sequence A 3D phase-encoded pulse-acquire 31 P-MRSI sequence for PtdC quantification and a 1D image-selected in vivo 31 P spectroscopy for T1 estimation at 7 T, and a T2-weighted half-Fourier single-shot turbo spin echo MRI sequence for volumetry at 3 T. Assessment Calculation of gallbladder volumes and PtdC concentration in groups using hepatic gamma-adenosine triphosphate signal as an internal reference and correction for insufficient relaxation of PtdC with a T1 value assessed in healthy subjects. Statistical tests Group comparison of PtdC content and gallbladder volumes of the PSC/PBC and CON group using Student's t-tests with a significance level of 5%. Results PtdC T1 value of 357 ± 85 msec in the gallbladder. Significant lower PtdC content for the PSC group, and for the female subgroup of the PBC group compared to the CON group (PSC/CON: 5.74 ± 0.73 mM vs. 9.64 ± 0.97 mM, PBC(f)/CON: 5.77 ± 1.44 mM vs. 9.64 ± 0.97 mM). Significant higher gallbladder volumes of the patient groups compared to the CON group (PSC/CON: 66.3 ± 15.8 mL vs. 20.9 ± 2.2 mL, PBC/CON: 49.8 ± 18.2 mL vs. 20.9 ± 2.2 mL). Data conclusion This study demonstrated the application of a 31 P-MRSI protocol for the quantification of PtdC in the human gallbladder at 7 T. Observed differences in PtdC concentration suggest that this metabolite could serve as a biomarker for specific hepatobiliary disorders. Level of evidence 2 TECHNICAL EFFICACY STAGE: 3.

Purpose As the number of intravitreal injections (IVI) increases annually, this study aimed to assess the anatomical and functional outcomes following rhegmatogenous retinal detachment (RRD) surgery for IVI-associated RRD (IVARD). Methods All non-vitrectomized eyes developing IVARD since 2007 in two European vitreoretinal centers (Department of Ophthalmology, LMU Munich, Germany, and Eye Clinic Luigi Sacco, University of Milan, Milan, Italy) were included. Main outcomes were primary and secondary retinal attachment rate after surgery, rate of proliferative vitreoretinopathy (PVR), and final functional result. Ten years of incidence rates per injection were calculated for one center. Results Fifty-two eyes of 52 patients comprised the study. Primary anatomic success rate was 83% (n = 43) and secondary 96% (n = 50). PVR was observed in all uveitic eyes (n = 3), in eyes with postoperative cystoid macular edema (n = 2), and in 8 of 9 eyes that received the dexamethasone implant (DEX). Age, number of prior injections, duration of symptoms, or time between last IVI and RRD did not show any statistically significant differences with regard to presence of PVR or not. Mean BCVA improved in 28 cases, remained stable in 16 cases, and worsened in 8 cases. The RRD incidence rate was statistically significant higher for DEX and ocriplasmin compared with that for anti-VEGF agents. Conclusion The anatomical result after one surgical intervention seems acceptable, but the final visual outcome remains rather poor, because of the underlying macular disease. In our population, injection with DEX is associated with higher IVARD rate, presence and development of PVR, and recurrent RRD in comparison with anti-VEGF agents.

Previous work from this group utilized a HYSYS simulator to predict the performance of an ethylene oxidative dehydrogenation (ODH) production facility using alternative diluents and separation technology not currently used in the standard industrial process. An ODH process system has been previously modeled with ethane being fed along with air into a reactor with simultaneous mixing with pure methane to lower the product gas temperature. The methane feed was later separated from the other product gases and eventually fed into a recycle stream. This process was fairly expensive due to the use of a demethanizer within the process recycle stream. Safety and operational improvements for the ODH process was another aspect of this analysis that yielded interesting results. By the inclusion of storage vessels before and after the ODH reactor, the reactor unit can operate even in the event of an upstream or downstream failure, resulting in less downtime for the process. This current work has investigated the development of membrane-based separation technology for the production of ethylene for the oxidative dehydrogenation (ODH) reaction of ethane using a HYSYS simulator with MEMCAL extension software in concert with economic and safety analyses. The application of polymer-membrane separation and non-cryogenic distillation alternatives, such as bottom-flash, heat-pump assisted and low-temperature distillation, were simulated and evaluated individually and in-tandem with membrane separation.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 are involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We explored the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events (MAKE) after cardiac surgery. Methods: We compared the predictive value of plasma NGAL, hepcidin-25, and plasma NGAL:hepcidin-25 with that of serum creatinine (Cr) and urinary output and protein for primary-endpoint MAKE (acute kidney injury [AKI] stages 2 and 3, persistent AKI >48 hours, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses. Results: At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, plasma interleukin-6, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77, 0.79, 0.74, and 0.74, respectively) and AKI (0.73, 0.89, 0.70, and 0.69). For AKI prediction, plasma NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00-0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC

OBJECTIVE: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss. METHODS: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion). RESULTS: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 μm respectively). CONCLUSION: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.

Design of experiment (DoE) is a powerful statistical tool in establishing improved chemical processes. An optimization and scale-up of the electrochemical reduction of l-cystine to l-cysteine is pr...

Purpose There is an ongoing controversial debate about the effectiveness of laser treatments in chronic central serous chorioretinopathy (cCSC). We performed a prospective non-randomized interventional study to learn about the effects of a subthreshold laser treatment (Topcon Endpoint Management™, Topcon Healthcare Inc., Tokyo, Japan) in patients with cCSC. Methods Patients with cCSC and a minimum symptom duration of 4 months were included and treated with a standardized laser pattern covering the macular area. Retreatment was performed every 3 months if persistent subretinal fluid was observed. The primary endpoint was resolution of subretinal fluid at 6 months. Further outcome parameters included best corrected visual acuity, microperimetry, central macular and subfoveal choroidal thickness. Results A total of 42 eyes of 39 patients were included. Mean patient age was 48 ± 10.6 years (range 25–67). Mean symptomatic time before inclusion into the study was 134 ± 133.4 weeks (16–518). Before inclusion, 78.6% of the patients had failed to resolve subretinal fluid under mineralocorticoid receptor antagonists and 14.3% had a recurrence after half-dose photodynamic therapy. Complete resolution of subretinal fluid was observed in 42.9% at 6 months and in 53.8% at 12 months after baseline. Central retinal thickness decreased from 398 ± 135 µm to 291 ± 68 µm (p Conclusion The results show that the investigated laser treatment is effective in reducing subretinal fluid and leads to an improvement of functional parameters.

Abstract The highly complex raw milk matrix challenges the sample preparation for amplicon-sequencing due to low bacterial counts and high amounts of eukaryotic DNA originating from the cow. In this study, we optimized the extraction of bacterial DNA from raw milk for microbiome analysis and evaluated the impact of cycle numbers in the library-PCR. The selective lysis of eukaryotic cells by proteinase K and digestion of released DNA before bacterial lysis resulted in a high reduction of mostly eukaryotic DNA and increased the proportion of bacterial DNA. Comparative microbiome analysis showed that a combined enzymatic and mechanical lysis procedure using the DNeasy® PowerFood® Microbial Kit with a modified protocol was best suitable to achieve high DNA quantities after library-PCR and broad coverage of detected bacterial biodiversity. Increasing cycle numbers during library-PCR systematically altered results for species and beta-diversity with a tendency to overrepresentation or underrepresentation of particular taxa. To limit PCR bias, high cycle numbers should thus be avoided. An optimized DNA extraction yielding sufficient bacterial DNA and enabling higher PCR efficiency is fundamental for successful library preparation. We suggest that a protocol using ethylenediaminetetraacetic acid (EDTA) to resolve casein micelles, selective lysis of somatic cells, extraction of bacterial DNA with a combination of mechanical and enzymatic lysis, and restriction of PCR cycles for analysis of raw milk microbiomes is optimal even for samples with low bacterial numbers. Key points • Sample preparation for high-throughput 16S rRNA gene sequencing of raw milk microbiota. • Reduction of eukaryotic DNA by enzymatic digestion. • Shift of detected microbiome caused by high cycle numbers in library-PCR.

Molecular aggregation alters the optical properties of a system as fluorescence may be activated or quenched. This is usually described within the well-established framework of H- and J-aggregates. While H-aggregates show nonfluorescent blueshifted absorption bands with respect to the isolated monomer, J-aggregates are fluorescent displaying a redshifted peak. In this publication, we employ a combined approach of experiment and theory to study the complex aggregation features and photophysical properties of diaminodicyanoquinone derivatives, which show unusual and puzzling nonfluorescent redshifted absorption bands upon aggregation. Our theoretical analysis demonstrates that stable aggregates do not account for the experimental observations. Instead, we propose an unprecedented mechanism involving metastable dimeric species formed from stable dimers to generate nonfluorescent J-aggregates. These results represent a novel kind of aggregation-induced optical effect and may have broad implications for the photophysics of dye aggregates.

The central role of cupric superoxide intermediates proposed in hormone and neurotransmitter biosynthesis by noncoupled binuclear copper monooxygenases like dopamine-β-monooxygenase has drawn significant attention to the unusual methionine ligation of the Cu(M) (“Cu(B)”) active site characteristic of this class of enzymes. The copper–sulfur interaction has proven critical for turnover, raising still-unresolved questions concerning Nature’s selection of an oxidizable Met residue to facilitate C–H oxygenation. We describe herein a model for Cu(M), [((TMG)N(3)S)Cu(I)](+) ([1](+)), and its O(2)-bound analog [((TMG)N(3)S)Cu(II)(O(2)(•−))](+) ([1·O(2)](+)). The latter is the first reported cupric superoxide with an experimentally proven Cu–S bond which also possesses demonstrated hydrogen atom abstraction (HAA) reactivity. Introduction of O(2) to a precooled solution of the cuprous precursor [1]B(C(6)F(5))(4) (−135 °C, 2-methyltetrahydrofuran (2-MeTHF)) reversibly forms [1·O(2)]B(C(6)F(5))(4) (UV/vis spectroscopy: λ(max) 442, 642, 742 nm). Resonance Raman studies (413 nm) using (16)O(2) [(18)O(2)] corroborated the identity of [1·O(2)](+) by revealing Cu–O (446 [425] cm(−1)) and O–O (1105 [1042] cm(−1)) stretches, and extended X-ray absorption fine structure (EXAFS) spectroscopy showed a Cu–S interatomic distance of 2.55 Å. HAA reactivity between [1·O(2)](+) and TEMPO–H proceeds rapidly (1.28 × 10(−1) M(−1) s(−1), −135 °C, 2-MeTHF) with a primary kinetic isotope effect of k(H)/k(D) = 5.4. Comparisons of the O(2)-binding behavior and redox activity of [1](+) vs [2](+), the latter a close analog of [1](+) but with all N atom ligation (i.e., N(3)S vs N(4)), are presented.

Scanning electron microscopy shows that the microstructure, in particular the overall grain size, of chemical vapor deposited silicon carbide coatings depends on the deposition temperature. So far, the influence of the microstructure on the mechanical properties of such coatings is not well described in literature. To investigate the influence of the deposition temperature on the mechanical properties of the coating, nanoindentation is used in this work. Since the measurement results of nanoindentation can be affected by the substrate material, the contribution of the substrate material is taken into account utilizing a finite element model. The model is then employed to generate information about elastic and plastic properties of the coating by inverse simulation. To evaluate the fracture toughness of the coating, the generated material model is used in a cohesive-zone based formulation of the fracture process during indentation at higher loads. The results of this model allow determining the fracture toughness of silicon carbide coatings deposited at different temperatures.

Levetiracetam is an active pharmaceutical ingredient widely used to treat epilepsy. We describe a new synthesis of levetiracetam by a dynamic kinetic resolution and a ruthenium-catalysed ex-cell anodic oxidation. For the enzymatic resolution, we tailored a high throughput screening method to identify Comamonas testosteroni nitrile hydratase variants with high (S)-selectivity and activity. Racemic nitrile was applied in a fed-batch reaction and was hydrated to (S)-(pyrrolidine-1-yl)butaneamide. For the subsequent oxidation to levetiracetam, we developed a ligand-free ruthenium-catalysed method at a low catalyst loading. The oxidant was electrochemically generated in 86% yield. This route provides a significantly more sustainable access to levetiracetam than existing routes.

Lignin represents the largest renewable feedstock of aromatic moieties in nature. However, its valorisation towards organic chemicals poses a challenging task. We herein report the selective electrochemical depolymerisation of several technically relevant organosolv lignins to aromatic fine chemicals with a simple two-electrode arrangement using caustic soda as electrolyte. Vanillin, syringaldehyde, the corresponding ketones and guaiacol were obtained with a combined maximum of 7.8 wt% isolated yield. Deeper insight in the process was provided by FT-IR, HSQC NMR and 31P NMR analyses of the lignins.

Collisions of N+ and N2+ with C3 hydrocarbons, represented by a self assembled monolayer of propanethiol on a polcrystalline gold surface, were investigated by experiments over the incident energy range between 5 eV and 100 eV. For N+, formation of HCN+ is observed at incident energies of projectile ions as low as 20 eV. In the case of N2+ projectile ions, the yield of HCN+ increased above zero only at incident energies of about 50 eV. This collision energy in the laboratory frame corresponds to an activation energy of about 3 eV to 3.5 eV. In the case of N+ projectile ions, the yield of HCN+ was large for most of the incident energy range, but decreased to zero at incident energies below 20 eV. This may indicate a very small energy threshold for the surface reaction between N+ and C3 hydrocarbons of a few tenths of an eV. Such a threshold for the formation of HCN+ may exist also for collisions of N+ with an adsorbed mixture of hydrocarbon molecules.

Formamidine represents a versatile building block in synthetic organic chemistry. We developed a new electrochemical synthesis of formamidine acetate by cathodic reduction of cyanamide in an aqueous electrolyte and in high yield. The crude product could be used for further conversions, such as to pyrimidines without purification. Compared to established synthetic routes neither prior processing of cyanamide was necessary, nor precious transition-metal catalyst were required, nor any reagent waste was produced, and only biocompatible and sustainable solvents were employed for this process, following the requirements of green chemistry.

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5′-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

OBJECTIVE Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP). RESEARCH DESIGN AND METHODS Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90–180 min (MR1), and 300–390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques. RESULTS Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg−1 min−1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg−1 min−1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (−3.28 ± 0.49 vs. −2.53 ± 0.56 μmol kg−1 min−1; P = n.s.) or T2DM-P and T2DM-D (−0.74 ± 0.23 vs. −1.21 ± 0.33 μmol kg−1 min−1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg−1 min−1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed. CONCLUSIONS The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.

Access to large, annotated samples represents a considerable challenge for training accurate deep-learning models in medical imaging. Although at present transfer learning from pre-trained models can help with cases lacking data, this limits design choices and generally results in the use of unnecessarily large models. Here we propose a self-supervised training scheme for obtaining high-quality, pre-trained networks from unlabelled, cross-modal medical imaging data, which will allow the creation of accurate and efficient models. We demonstrate the utility of the scheme by accurately predicting retinal thickness measurements based on optical coherence tomography from simple infrared fundus images. Subsequently, learned representations outperformed advanced classifiers on a separate diabetic retinopathy classification task in a scenario of scarce training data. Our cross-modal, three-stage scheme effectively replaced 26,343 diabetic retinopathy annotations with 1,009 semantic segmentations on optical coherence tomography and reached the same classification accuracy using only 25% of fundus images, without any drawbacks, since optical coherence tomography is not required for predictions. We expect this concept to apply to other multimodal clinical imaging, health records and genomics data, and to corresponding sample-starved learning problems. The thickness of the retina is an important medical indicator for diabetic retinopathy. Holmberg and colleagues present a self-supervised deep-learning method that uses cross-modal data to predict retinal thickness maps from easily obtainable fundus images.

A fast and mild synthesis procedure for nanoparticles that consist of CaWO4:Eu3+, Sm3+ and exhibit persistent luminescence is described here. Using co-precipitation in diethylene glycol and subsequently heating afforded a barely crystalline product which shows no afterglow. After a short 30 min annealing step, the increased crystallinity leads to visible persistent luminescence. A correlation between crystallinity of the product and the persistence of the luminescence is clearly demonstrated. Because of preferred red emission due to the doped Eu3+ ions, these nanoparticles can be employed in bio-imaging as demonstrated here.

Legumes associate with root colonizing rhizobia that provide fixed nitrogen to its plant host in exchange for recently fixed carbon. There is a lack in understanding how individual plants modulate carbon allocation to a nodulated root system as a dynamic response to abiotic stimuli. One reason is that most approaches are based on destructive sampling, making quantification of localized carbon allocation dynamics in the root system difficult. We established an experimental workflow for routinely using non-invasive Positron Emission Tomography (PET) to follow the allocation of leaf-supplied 11C tracer towards individual nodules in a three-dimensional (3D) root system of pea (Pisum sativum). Nitrate was used for triggering the shutdown of biological nitrogen fixation (BNF) expected to rapidly affect carbon allocation dynamics in the root-nodule system. This nitrate treatment lead to a reduction of 11C tracer allocation to nodules by 40% – 47% in 5 treated plants while the variation in control plants was less than 11%. The established experimental pipeline enabled for the first time that several plants could consistently be labelled and measured using 11C tracer in a PET approach to quantify C-allocation to individual nodules following a BNF shutdown. This demonstrates the strength of using 11C tracers in a PET approach for non-invasive quantification of dynamic carbon allocation in several growing plants over several days. A major advantage of the approach is the possibility to investigate carbon dynamics in small regions of interest in a 3D system such as nodules in comparison to whole plant development.One sentence summaryPositron Emission Tomography for quantification of carbon allocation dynamics in individual nodules within a 3D root system revealed strong effect of nitrate on carbon allocation.

Copper(I) complexes with the macrocyclic thioether ligands 1,4,8,11-tetrathiacyclotetradecane (tetrathiacyclam, 14-S4) and 1,8-dithia-4,11-diazacyclotetradecane (dithiacyclam, 14-N2S2) were synthesized and structurally characterized. While the copper(I) complexes showed no reactivity towards dioxygen, the formation of “dioxygen adduct complexes” could be spectroscopically detected with ozone using low temperature stopped-flow techniques. Furthermore, it was possible to synthesize and characterize iron(II) and cobalt(II) complexes with the tetrathiacyclam ligand. No 'dioxygen adduct' intermediates were observed when these complexes were reacted with dioxygen or ozone. Depending on the reaction conditions, the coordination of the metal ions could be controlled (endo- vs exo-coordination and cis- vs trans-coordination) and in addition to mononuclear complexes, also coordination polymers were obtained.

Independently of the preparation method, for cluster cations of aliphatic amino acids, the protonated form MnH+ is always the dominant species. This is a surprising fact considering that in the gas phase, they dissociate primarily by the loss of 45 Da, i.e., the loss of the carboxylic group. In the present study, we explore the dissociation dynamics of small valine cluster cations Mn+ and their protonated counterparts MnH+ via collision-induced dissociation experiments and ab initio calculations with the aim to elucidate the formation of MnH+-type cations from amino acid clusters. For the first time, we report the preparation of valine cluster cations Mn+ in laboratory conditions, using a technique of cluster ion assembly inside He droplets. We show that the Mn+ cations cooled down to He droplet temperature can dissociate to form both Mn-1H+ and [Mn-COOH]+ ions. With increasing internal energy, the Mn-1H+ formation channel becomes dominant. Mn-1H+ ions then fragment nearly exclusively by monomer loss, describing the high abundance of protonated clusters in the mass spectra of amino acid clusters.

Three strains of a Gram-stain-positive, catalase-negative, facultative anaerobic, and coccoid species were isolated from German bulk tank milk. Phylogenetic analyses based on the 16S rRNA gene sequences indicated that the three strains (WS4937T, WS4759 and WS5303) constitute an independent phylogenetic lineage within the family Aerococcaceae with Facklamia hominis CCUG 36813T (93.7–94.1 %) and Eremococcus coleocola M1831/95/2T (93.5 %) as most closely related type species. The unclassified strains demonstrated variable growth with 6.5 % (w/v) NaCl and tolerated pH 6.5–9.5. Growth was observed from 12 to 39 °C. Their cell-wall peptidoglycan belongs to the A1α type (l-Lys-direct) consisting of alanine, glutamic acid and lysine. The predominant fatty acids were C16 : 1 ω9c, C16 : 0 and C18 : 1 ω9c and in the polar lipids profile three glycolipids, a phospholipid, phosphatidylglycerol, phosphoglycolipid and diphosphatidylglycerol were found. The G+C content of strain WS4937T was 37.4 mol% with a genome size of ~3.0 Mb. Based on phylogenetic, phylogenomic and biochemical characterizations, the isolates can be demarcated from all other genera of the family Aerococcaceae and, therefore, the novel genus Fundicoccus gen. nov. is proposed. The type species of the novel genus is Fundicoccus ignavus gen. nov., sp. nov. WS4937T (=DSM 109652T=LMG 31441T).

Rocaglates, rocaglamides, and related flavagline natural products exert their remarkable anticancer activity through inhibition of eukaryotic initiation factor 4A (eIF4A) but generally display suboptimal drug-like properties. In our efforts to identify potent drug-like eIF4A inhibitors, we developed synthetic strategies for diastereoselectively functionalizing the C1 position of aza-rocaglamide scaffolds (cf. 14 and 18), which proceed via retention or inversion of configuration at C1 depending on the C2 substituent (cf. 15 and 21) and ultimately enabled the discovery of novel and potent eIF4A inhibitors such as 25.

Summary Background Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis. Methods The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5–15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints–erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4–6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov , NCT02573012 . Findings Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35–0·73) with tapered prednisone and −0·08 (–0·27 to 0·12) with continued prednisone (difference 0·61 [0·35–0·88]; p Interpretation In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose. Funding F Hoffmann-La Roche.

A novel approach towards the activation of different arenes and purines including caffeine and theophylline is presented. The simple, safe and scalable electrochemical synthesis of 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP) aryl ethers was conducted using an easy electrolysis setup with boron‐doped diamond (BDD) electrodes. Good yields up to 59 % were achieved. Triethylamine was used as a base as it forms a highly conductive media with HFIP, making additional supporting electrolytes superfluous. The synthesis was optimized using Design of Experiment (DoE) techniques giving a detailed insight to the significance of the reaction parameters. The mechanism was investigated by cyclic voltammetry (CV). Subsequent transition metal‐catalyzed as well as metal‐free functionalization led to interesting motifs in excellent yields up to 94 %., An alternative route for the activation of different arenes including caffeine and theophylline, optimized by design of experiment techniques is presented. We provide a simple electroorganic protocol using BDD electrodes in undivided cells for the synthesis of aryl 1,1,1,3,3,3‐hexafluoroisopropyl ethers. The value of these fluorinated ethers for subsequent functionalization with a variety of nucleophiles has been proved (see scheme).

Objective: This study aims to evaluate the in vitro antioxidant, anti-inflammatory activities of the aqueous and hydroethanolic extracts recipe of Alchornea cordifolia and Antrocaryon klaineanum. A preliminary phytochemical screening was carried out. Methods: The total phenols content was determined by the Folin Ciocalteu reagent method, while the antioxidant activity of both extracts was characterized by the 2-2diphenyl-1-picrilhidrazil (DPPH) and β-carotene assays. The anti-inflammatory activity of the extracts was evaluated as the inhibition of Bovine Serum Albumin (BSA) denaturation and antiproteinase activity. Results: The aqueous extracts of Alchornea cordifolia and Antrocaryon klaineanum contained more polyphenols [270 mg Ascorbic acid equivalent (AAE)/g dry weight (dw)] than the hydroethanolic recipe extract (262.41 mg AAE/g dw) at the same concentration level. On the other hand, the aqueous and hydroethanolic recipe extract had the same radical scavenging activity with the antiradical power of 0.851 and 0.830, respectively. Similarly, the recipe extract had the same reducing activity with reducing the power of 94.2±2.03 mg EAA/g dw and 97.4±4.16 mg EAA/g dw for the aqueous and hydroethanolic recipe extract of Alchornea cordifolia and Antrocaryon klaineanum respectively. For the anti-inflammatory activity it was observed that both extracts possess the same activity as Diclofenac® with an IC50 of 50.21 μg/ml. The phytochemical screening of the extracts revealed the presence of alkaloids, flavonoids, carbohydrates, phenols and tannins, which may account for their activities. Conclusion: The plant recipe extract studied possess antioxidant and anti-inflammatory potentials, which may be beneficiary to its consumers.

Background Previous in vivo proton MR spectroscopy (MRS) studies have demonstrated the possibility of quantifying amide groups of conjugated bile acids (NHCBA), olefinic lipids and cholesterol (OLC), choline-containing phospholipids (CCPLs), taurine and glycine conjugated bile acids (TCBA, GCBA), methylene group of lipids (ML), and methyl groups of bile acids, lipids, and cholesterol (BALC1.0, BALC0.9, and TBAC) in the gallbladder, which may be useful for the study of cholestatic diseases and cholangiopathies. However, these studies were performed at 1.5T and 3T, and higher magnetic fields may offer improved spectral resolution and signal intensity. Purpose To develop a method for gallbladder MRS at 7T. Study type Retrospective, technical development. Population Ten healthy subjects (five males and five females), two patients with primary biliary cholangitis (PBC) (one male and one female), and one patient with primary sclerosing cholangitis (PSC) (female). Field strength/sequence Free-breathing single-voxel MRS with a modified stimulated echo acquisition mode (STEAM) sequence at 7T. Assessment Postprocessing was based on the T2 relaxation of water in the gallbladder and in the liver. Concentrations of biliary components were calculated using water signal. All data were corrected for T2 relaxation times measured in healthy subjects. Statistical tests The range of T2 relaxation time and concentration per bile component, and the resulting mean and standard deviation, were calculated. Results The concentrations of gallbladder components in healthy subjects were: NHCBA: 93 ± 66 mM, OLC: 154 ± 124 mM, CCPL: 42 ± 17 mM, TCBA: 48 ± 35 mM, GCBA: 67 ± 32 mM, ML: 740 ± 391 mM, BALC1.0: 175 ± 92 mM, BALC0.9: 260 ± 138 mM, and TBAC: 153 ± 90 mM. Mean concentrations of all bile components were found to be lower in patients. Data conclusion This work provides a protocol for designing future MRS investigations of the bile system in vivo. Evidence level 2 TECHNICAL EFFICACY STAGE: 1.

Purpose A critical shortage of small-volume parenteral solutions in late 2017 led hospitals to develop strategies to ensure availability for critical patients, including administration of antibiotics as intravenous push (IVP). Minimal literature has been published to date that assesses the safety of administration of beta-lactams via this route. Therefore, the purpose of this study was to evaluate the safety of IVP administration of select beta-lactam antibiotics. Methods We performed a retrospective review of IVP administrations of aztreonam, ceftriaxone, cefepime, and meropenem at two campuses of the New York University Langone Health system after October 2017. Patients receiving surgical prophylaxis or more than one IVP antibiotic simultaneously were excluded. The primary endpoint was adverse events (ADE) following IVP administration of antibiotics. Results We evaluated 1000 patients who received IVP aztreonam (n = 43), ceftriaxone (n = 544), cefepime (n = 368) or meropenem (n = 45). There were 10 (1%) ADE observed, 5 of which were allergic reactions. Four ADE were neurotoxicity related to IVP cefepime. Based on the Naranjo score, 1 adverse event was “probably” and 3 were “possibly” related to cefepime IVP administration. Lastly, only 1 report of phlebitis was observed with the use of IVP ceftriaxone. Conclusions The use of IVP as an alternative to intravenous piggyback (IVPB) during times of drug shortage for select beta-lactam antibiotics appears to be safe, and ADE are similar to those previously described for IVPB administration. Future studies evaluating clinical outcomes between IVP and IVPB administration may be of benefit.

Power-to-Gas approaches comprise different activities to store electric power in form of gaseous energy carriers like hydrogen or methane. The synthesis of SNG (substitute natural gas) and its injection into the natural gas grid allows the utilization of the well-established infrastructure for natural gas storage, distribution and utilization without the need for further changes to the energy system. At the Engler-Bunte-Institut research focuses on catalytic methanation in catalytically coated metallic honeycomb reactors and in slurry bubble column reactors with the aim of evaluating alternative reactor concepts offering optimized heat transfer characteristics as well as maximizing the possibility of dynamic operation. Both concepts are attractive for small to medium scale power-to-gas applications. Hence, a scale-up was performed for bothreactor concepts with the aim of implementation on commercial scale.

We report the synthesis and spectroscopic characteristics of two different sets of carbon dots (CDs) formed by hydrothermal reaction between citric acid and polyethylenimine (PEI) or 2,3-diaminopyridine (DAP). Although the formation of amide-based species and the presence of citrazinic acid type derivates assumed to be responsible for a blue emission is confirmed for both CDs by elemental analysis, infrared spectroscopy, and mass spectrometry, a higher abundance of sp2-hybridized nitrogen is observed for DAP-based CDs, which causes a red-shift of the n-π* absorption band relative to the one of PEI-based CDs. These CD systems possess high photoluminescence quantum yields (QY) of ∼40% and ∼48% at neutral pH, demonstrating a possible tuning of the optical properties by the amine precursor. pH-Dependent spectroscopic studies revealed a drop in QY to < 9% (pH ∼ 1) and < 21% (pH ∼ 12) for both types of CDs under acidic and basic conditions. In contrast, significant differences in the pH-dependency of the n-π* transitions are found for both CD types which are ascribed to different (de)protonation sequences of the CD-specific fluorophores and functional groups using zeta potential analysis.

Eight facultatively anaerobic rod-shaped bacteria were isolated from raw milk and two other dairy products. Results of phylogenetic analyses based on 16S rRNA gene sequences showed that the isolates are placed in a distinct lineage within the family Propionibacteriaceae with Propioniciclava sinopodophylli and Propioniciclava tarda as the closest relatives (94.6 and 93.5 % similarity, respectively). The cell-wall peptidoglycan contained meso-diaminopimelic acid, alanine and glutamic acid and was of the A1γ type (meso-DAP-direct). The major cellular fatty acid was anteiso-C15 : 0 and the major polar lipids were diphosphatidylglycerol, phosphatidyglycerol and three unidentified glycolipids. The quinone system contained predominantly menaquinone MK-9(H4). The G+C content of the genomic DNA of strain VG341T was 67.7 mol%. The whole-cell sugar pattern contained ribose, rhamnose, arabinose and galactose. On the basis of phenotypic and genetic data, eight strains (VG341T, WS4684, WS4769, WS 4882, WS4883, WS4901, WS4902 and WS4904) are proposed to be classified as members of a novel species in a new genus of the family Propionibacteriaceae , for which the name Brevilactibacter flavus gen. nov., sp. nov. is proposed. The type strain is VG341T (=WS4900T=DSM 100885T=LMG 29089T) and seven additional strains are WS4684, WS4769, WS4882, WS4883, WS4901, WS4902 and WS4904. Furthermore, we propose the reclassification of P. sinopodophylli as Brevilactibacter sinopodophylli comb. nov.

Background Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs). Methods Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs). Results Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60). Conclusions The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM.

Purpose To determine the anatomical and functional outcomes of an extended 6-month intravitreal anti-vascular endothelial growth factor (anti-VEGF) upload in choroidal neovascularization (CNV) secondary to chronic central serous chorioretinopathy (CSCR). Methods A retrospective database analysis was performed applying the following inclusion criteria: (1) diagnosis of CSCR, (2) diagnosis of secondary CNV, and (3) treatment of at least six consecutive injections of anti-VEGF. Outcome measures included the change of central retinal subfield thickness, remodeling of the pigment epithelium detachments, and change in visual function. Results Twenty-one eyes of 21 patients were included. Mean patient age was 65 ± 8.3 years, and 35% of the patients (n = 8) were female. Mean disease duration before diagnosis of CNV was 48 ± 25.3 months. Mean central retinal thickness decreased from 346 ± 61 to 257 ± 57 μm (p p p = 0.038). Significant CNV remodeling was observed as a decrease in pigment epithelium detachment (PED) vertical (p = 0.021) and horizontal diameter (p = 0.024) as well as PED height (p Conclusion An extended anti-VEGF upload of six consecutive injections seems to be effective in inducing CNV remodeling and fluid resorption in CNV complicating chronic CSCR.