Microcoils provide a cost-effective approach to improve detection limits for mass-limited samples. Single-sided planar microcoils are advantageous in comparison to volume coils, in that the sample can simply be placed on top. However, the considerable drawback is that the RF field that is produced by the coil decreases with distance from the coil surface, which potentially limits more complex multi-pulse NMR pulse sequences. Unfortunately, H-1 NMR alone is not very informative for intact biological samples due to line broadening caused by magnetic susceptibility distortions, and H-1-C-13 2D NMR correlations are required to provide the additional spectral dispersion for metabolic assignments in vivo or in situ. To our knowledge, double-tuned single-sided microcoils have not been applied for the 2D H-1-C-13 analysis of intact C-13 enriched biological samples. Questions include the following: Can H-1-C-13 2D NMR be performed on single-sided planar microcoils? If so, do they still hold sensitivity advantages over conventional 5 mm NMR technology for mass limited samples? Here, 2D H-1-C-13 HSQC, HMQC, and HETCOR variants were compared and then applied to C-13 enriched broccoli seeds and Daphnia magna (water fleas). Compared to 5 mm NMR probes, the microcoils showed a sixfold improvement in mass sensitivity (albeit only for a small localized region) and allowed for the identification of metabolites in a single intact D. magna for the first time. Single-sided planar microcoils show practical benefit for H-1-C-13 NMR of intact biological samples, if localized information within similar to 0.7 mm of the 1 mm I.D. planar microcoil surface is of specific interest.

Background and importanceNon-valvular atrial fibrillation (NVAF) affects 750 000 people in France and is associated with significant morbidity, use of healthcare resources and costs. The randomised controlled trial ROCKET-AF demonstrated that rivaroxaban is an efficacious alternative to warfarin in patients with NVAF. The new oral anticoagulants (NOAC) appear to have an acceptable cost effectiveness ratio in France. But is it possible that rivaroxaban could remain cost effective with the introduction of generic drugs?Aim and objectivesTo determine the price threshold for rivaroxaban to become cost effective compared with vitamin K antagonists (VKAs) in the treatment of NVAF, using real world evidence and from a French payer perspective.Material and methodsThe annual cost differences associated with rivaroxaban use compared with VKAs among NVAF patients were estimated. Clinical events reflecting the efficacy and safety of the drugs were converted into costs. Drugs costs and VKA monitoring were added to obtain a total cost. Cost differences were then calculated with a price of rivaroxaban reduced by: 20% (reduction in the price of the brand name drug when the first generic is marketed)); 32.5% (total decrease in the price of the brand name drug 18–24 months after the first generic is marketed); 60% (price of a generic compared with the brand name drug). Event rates were obtained from the pragmatic study BROTHER. The annual costs for each clinical event and for VKA monitoring were obtained from the literature (studies in French setting). The cost of medicines in 2018 came from the French National Health Insurance database.ResultsThe total cost difference associated with the use of rivaroxaban instead of VKAs were estimated at +303€ per patient per year. The total cost differences were +124€, +12€ and −234€ with price decreases of 20%, 32.5% and 60%, respectively. The threshold for a cost saving with rivaroxaban was a 34% decrease in the price of the drug.Conclusion and relevanceRivaroxaban can become cost saving with a 34% price reduction. The commercialisation of NOAC generics should allow them to play an even more important role in the treatment of NVAF.References and/or acknowledgementsNo conflict of interest.

Microcoil nuclear magnetic resonance (NMR) has been interfaced with digital microfluidics (DMF) and is applied to monitor organic reactions in organic solvents as a proof of concept. DMF permits droplets to be moved and mixed inside the NMR spectrometer to initiate reactions while using sub-microliter volumes of reagent, opening up the potential to follow the reactions of scarce or expensive reagents. By setting up the spectrometer shims on a reagent droplet, data acquisition can be started immediately upon droplet mixing and is only limited by the rate at which NMR data can be collected, allowing the monitoring of fast reactions. Here we report a cyclohexene carbonate hydrolysis in dimethylformamide and a Knoevenagel condensation in methanol/water. This is to our knowledge the first time rapid organic reactions in organic solvents have been monitored by high field DMF-NMR. The study represents a key first step towards larger DMF-NMR arrays that could in future serve as discovery platforms, where computer controlled DMF automates mixing/titration of chemical libraries and NMR is used to study the structures formed and kinetics in real time.

In recent years microcoils and related structures have been developed to increase the mass sensitivity of nuclear magnetic resonance spectroscopy, allowing this extremely powerful analytical technique to be extended to small sample volumes (<5 μl). In general, microchannels have been used to deliver the samples of interest to these microcoils; however, these systems tend to have large dead volumes and require more complex fluidic connections. Here, we introduce a two-plate digital microfluidic (DMF) strategy to interface small-volume samples with NMR microcoils. In this system, a planar microcoil is surrounded by a copper plane that serves as the counter-electrode for the digital microfluidic device, allowing for precise control of droplet position and shape. This feature allows for the user-determination of the orientation of droplets relative to the main axes of the shim stack, permitting improved shimming and a more homogeneous magnetic field inside the droplet below the microcoil, which leads to improved spectral lineshape. This, along with high-fidelity droplet actuation, allows for rapid shimming strategies (developed over decades for vertically oriented NMR tubes) to be employed, permitting the determination of reaction-product diffusion coefficients as well as quantitative monitoring of reactive intermediates. We propose that this system paves the way for new and exciting applications for in situ analysis of small samples by NMR spectroscopy.

Magnetic resonance imaging and spectroscopy are versatile methods for probing brain physiology, but their intrinsically low sensitivity limits the achievable spatial and temporal resolution. Here, we introduce a monolithically integrated NMR-on-a-chip needle that combines an ultra-sensitive 300 µm NMR coil with a complete NMR transceiver, enabling in vivo measurements of blood oxygenation and flow in nanoliter volumes at a sampling rate of 200 Hz.

In France, breast cancer currently affects one woman in eight – 54,000 new cases were detected in 2015. Among them, some women with motor disabilities as almost 100,000 women aged under 65 have to use wheelchairs. Numerous scientific studies have highlighted the positive effects of well-adapted physical activity after breast cancer surgery – it is shown to reduce fatigability, posture problems and the risk of recurrence, hence to foster a better quality of life. Several federations have adapted their sport to cancer patients; yet, most of those adaptations take no account of the possible presence of pre-existing motor problems. Solution RIPOSTE offers women with breast cancer an adapted practice of fencing, devoid of hits, which improves shoulder mobility thanks to the reflexive gesture of high parry commonly made in sabre fencing, and also corrects posture anomalies thanks to the shoulder opening required by the en garde position. Besides, the elegance of the sport helps to restore a feminine self-image, which has been severely impaired. All the fencing masters and instructors in charge of those special fencers have been specifically trained, and they are regularly re-trained. To further our action, a fencing instructor who is a member of the French National team of wheelchair athletes has just completed that course, and she has started to run fencing sessions open to every single woman who has had breast cancer – debarring none. With their oncologists' backing, wheelchair fencing could also be proposed to women with lumbar or sacrum metastases, for whom any sport involving stamping is strictly contraindicated. Thus, the French Federation of Disability Sports meets the French National Olympics and Sports Committee's wish to develop a 'sport for health' policy.

Nuclear magnetic resonance (NMR) spectroscopy enables non-invasive chemical studies of intact living matter. However, the use of NMR at the volume scale typical of microorganisms is hindered by sensitivity limitations, and experiments on single intact organisms have so far been limited to entities having volumes larger than 5 nL. Here we show NMR spectroscopy experiments conducted on single intact ova of 0.1 and 0.5 nL (i.e. 10 to 50 times smaller than previously achieved), thereby reaching the relevant volume scale where life development begins for a broad variety of organisms, humans included. Performing experiments with inductive ultra-compact (1 mm2) single-chip NMR probes, consisting of a low noise transceiver and a multilayer 150 μm planar microcoil, we demonstrate that the achieved limit of detection (about 5 pmol of 1H nuclei) is sufficient to detect endogenous compounds. Our findings suggest that single-chip probes are promising candidates to enable NMR-based study and selection of microscopic entities at biologically relevant volume scales.

With its unparalleled ability to safely generate high-contrast images of soft tissues, magnetic resonance imaging (MRI) has remained at the forefront of diagnostic clinical medicine. Unfortunately due to resolution limitations, clinical scans are most useful for detecting macroscopic structural changes associated with a small number of pathologies. Moreover, due to a longstanding inability to directly observe magnetic resonance (MR) signal behavior at the cellular level, such information is poorly characterized and generally must be inferred. With the advent of the MR microscope in 1986 came the ability to measure MR signal properties of theretofore unobservable tissue structures. Recently, further improvements in hardware technology have made possible the ability to visualize mammalian cellular structure. In the current study, we expand upon previous work by imaging the neuronal cell bodies and processes of human and porcine α-motor neurons. Complimentary imaging studies are conducted in pig tissue in order to demonstrate qualitative similarities to human samples. Also, apparent diffusion coefficient (ADC) maps were generated inside porcine α-motor neuron cell bodies and portions of their largest processes (mean=1.7±0.5μm2/ms based on 53pixels) as well as in areas containing a mixture of extracellular space, microvasculature, and neuropil (0.59±0.37μm2/ms based on 33pixels). Three-dimensional reconstruction of MR images containing α-motor neurons shows the spatial arrangement of neuronal projections between adjacent cells. Such advancements in imaging portend the ability to construct accurate models of MR signal behavior based on direct observation and measurement of the components which comprise functional tissues. These tools would not only be useful for improving our interpretation of macroscopic MRI performed in the clinic, but they could potentially be used to develop new methods of differential diagnosis to aid in the early detection of a multitude of neuropathologies.

Le but de ce travail était de comparer l'efficacité de la dissection sous-muqueuse endoscopique (DSME) et de la résection muqueuse endoscopique (RME) pour des résections ≥20mm de lésions colorectales.

INTRODUCTION Since the first application of magnetic resonance microscopy (MRM) on large single cells (1), MRM has developed over the last 25 years as a complementary microimaging technique with a variety of applications ranging from materials to biological tissues (2). Several large single cells have been successfully imaged (3). Recently, using new surface microcoils to improve sensitivity, we performed the first MRM of neurons in mammalian tissue (4). Although it offers the potential to study tissues in vivo, the inherently low sensitivity of nuclear magnetic resonance (NMR) has limited MRM to the detection of only two cellular compartments—the cytoplasm and nucleus—in relatively large cells: i.e. frog ova (~1mm diameter) (1) and Aplysia californica neurons (~ 300-350 μm diameter) (5). However, it has so far been assumed that the structures observed in the MRM correspond to the nuclear and cytoplasmic compartments. In this work, we report the extension of the new microcoil technology to improve MRM of Aplysia californica neurons, and—for the first time—present correlative light microscopy including Nissl and fluorescent staining methods to label specific cellular substructures. These studies are also a precursor to the examination of the effects of collagenase on the MR signals in these neurons. METHODS MRM was performed using commercially available 500μm diameter (Serial # B6370) microcoils provided by Bruker Biospin. The MR studies were conducted on a 600 MHz (14.1T) Bruker Biospin system. In the standard protocol, extracted ganglia are placed in a collagenase solution to soften membranes thus aiding cell extraction (3). However, in the present study, collagenase digestion was omitted (see discussion). After isolation by gross dissection, L7 neurons (n=2) of Aplysia californica were fixed in a 4% Formaldehyde solution for no less than 24h, and then washed in PBS buffer (137mM NaCl; 2.7mM KCl; 10mM Na2HPO4; 1.8mM KH2PO4: pH 7.4) to remove fixative before imaging so that T2 relaxation is restored to pre-fixation levels for improved SNR. The slices were then embedded in 3% of agarose. Neurons were sectioned into 50 μm thick slices using a Vibratome. MRM was performed using a 2D diffusion-weighted image sequence (7.8 μm in-plane resolution, 200μm slice width, b= 1500 s/mm, TR/TE = 2000/20 ms, NEX=100, acquisition time = 7hrs8min). Following MRM, slices were stained with PKH 67 for detection of the plasma membrane, and DAPI for detection of the nucleus. Additionally, a separate slice adjacent to the MR imaged slice was stained with Nissl (0.5% cresyl violet, 0.3% glacial acetic acid, in ddH2O) to delineate the cytoplasm through labeling of the endoplasmic reticulum (ER).

Thanks to its proven utility in both clinical and research applications, diffusion tensor tractography (DTT) is regularly employed as a means of delineating white-matter tracts. While successful efforts have been made to validate tractographic predictions, comparative methods which would permit the validation of such predictions at microscopic resolutions in complex biological tissues have remained elusive. In a previous study, we attempted to validate for the first time such predictions at microscopic resolutions in rat and pig spinal cords using a semi-quantitative analysis method. In the current study, we report improved quantitative analysis methods that can be used to determine the accuracy of DTT through comparative histology and apply these techniques for the first time to human tissue (spinal cord) samples. Histological images are down-sampled to resolutions equivalent to our magnetic resonance microscopy (MRM) and converted to binary maps using an automated thresholding tool. These maps (n=3) are co-registered to the MRM allowing us to quantify the agreement based on the number of pixels which contain tracts common to both imaging datasets. In our experiments, we find that—on average—89% of imaging pixels predicted by DTT to contain in-plane white-matter tract structure correspond to physical tracts identified by histology. In addition, angular analysis comparing the orientation of fiber tracts measured in histology to their corresponding in-plane primary eigenvector components is presented. Thus, as well as demonstrating feasibility in human tissue, we report a robust agreement between imaging datasets taken at microscopic resolution and confirm the primary eigenvector's role as a fundamental parameter with clear physical correlates in the microscopic regime.

Patients et Méthodes: 37 patients (23H; 14 F) d'âge médian 68 ans (extrêmes: 38–82) ont été traités entre 2005 et 2010. Le générateur VIO 200 (ERBE) et divers bistouris étaient employés: Needle- (1), TT- (1), Flex- et IT- (1), Flex- (6), Flex- et Hook- (9) (Olympus), Hybrid- (ERBE) (1) Flush- (9), Ball-Tipped Flush-Knives (9) (Fujinon). Un embout distal (Olympus), du Sigmavisc (Life Europe), du sérum salé, une pince Coagrasper (Olympus) était utilisés et, 10 fois, une insufflation de CO2.

J. J. Flint, B. Hansen, S. Portnoy, C. H. Lee, M. A. King, M. Fey, F. Vincent, P. Vestergaard-Poulsen, and S. J. Blackband Neuroscience, University of Florida, Gainesville, Fl, United States, McKnight Brain Institute, University of Florida, Gainesville, Fl, United States, Center for Functionally Integrative Neuroscience, University of Aarhus, Aarhus, Denmark, Electrical Engineering, University of Florida, Gainesville, Fl, United States, Pharmacology and Therapeutics, University of Florida, Gainesville, Fl, United States, Bruker Biospin, National High Magnetic Field Laboratory, Talahassee, Fl, United States