Comparison of two region-of-interest placement methods for histogram analysis of apparent diffusion coefficient maps for glioma grading.

Objectives: We assessed the value of histogram analysis (HA) of apparent diffusion coefficient (ADC) maps for grading low-grade (LGG) and high-grade (HGG) gliomas. Methods: We compared the diagnostic performance of two region-of-interest (ROI) placement methods (ROI 1: the entire tumor; ROI 2: the tumor excluding cystic and necrotic portions). We retrospectively evaluated 54 patients with supratentorial gliomas (18 LGG and 36 HGG). All subjects underwent standard 3T contrast-enhanced magnetic resonance imaging. Histogram parameters of ADC maps calculated with the two segmentation methods comprised mean, median, maxi-mum, minimum, kurtosis, skewness, entropy, standard deviation (sd), mean of positive pixels (mpp), uniformity of positive pixels, and their ratios (r) between lesion and normal white matter. They were compared using the independent t-test, chi-square test, or Mann-Whitney U test. For statistically significant results, receiver operating characteristic curves were constructed, and the optimal cutoff value, sensitivity, and specificity were determined by maximizing Youden's index. Results: The ROI 1 method resulted in significantly higher rADC mean, rADC median, and rADC mpp for LGG than for HGG; these parameters had value for predicting the histological glioma grade with a cutoff (sensitivity, specificity) of 1.88 (77.8%, 61.1%), 2.25 (44.4%, 97.2%), and 1.88 (77.8%, 63.9%), respectively. The ROI 2 method resulted in significantly higher ADC mean, ADC median, ADC mpp, ADC sd, ADC max, rADC median, rADC mpp, rADC mean, rADC sd, and rADC max for LGG than for HGG, while skewness was lower for LGG than for HGG (0.27 [0.98] vs 0.91 [0.81], p = 0.014). In ROI 2, ADC median, ADC mpp, ADC mean, rADC median, rADC mpp, and rADC mean performed well in differentiating glioma grade with cutoffs (sensitivity, specificity) of 1.28 (77.8%, 88.9%), 1.28 (77.8%, 88.9%), 1.25 (77.8%, 91.7%), 1.81 (83.3%, 91.7%), 1.74 (83.3%, 91.7%), and 1.81 (83.3%, 91.7%), respectively. Conclusions: HA parameters had value for grading gliomas. Ex-cluding cystic and necrotic portions of the tumor for measuring HA parameters was preferable to using the entire tumor as the ROI. In this segmentation, rADC median showed the highest performance in predicting histological glioma grade, followed by rADC mpp, rADC mean, ADC median, ADC mpp, and ADC mean.

Evaluation of anatomical factors affecting stress urinary incontinence in female patients via dynamic pelvic floor magnetic resonance imaging.

Objective: To evaluate the anatomical factors affecting stress urinary incontinence (SUI) in female patients via dynamic pelvic floor magnetic resonance imaging (DP-MRI). Methods: This prospective study was conducted on 43 female patients, including 22 patients with SUI (disease group) and 21 patients without SUI (control group). All patients underwent DP-MRI. The length, volume, transverse/anteroposterior diameter, and outer/inner layer thickness of the urethra were measured on static (T2W) pulse sequences. Urethral angle, posterior urethro-vesical angle (PUVA), bladder neck-pubococcygeal angle, and position of the bladder neck and cervix relative to the pubococcygeal line were measured on dynamic (Cine) pulse sequences at rest and during evacuation phase. These parameters were compared between the groups to evaluate which anatomical factors affected SUI. The area under the ROC curve (AUC) and threshold of the sensitivity and specificity of these parameters for the diagnosis of SUI were calculated. Results: The mean age of the patients was 57.3±13.8 years (disease group: 53.9±12.6 years; control group: 60.8±14.4 years). The mean number of childbirths was 2.2±0.65, and vaginal delivery accounted for 73% in each group. There was no significant difference between the two groups in terms of length, transverse diameter, outer layer thickness of the urethra, urethral angle, bladder neck-pubococcygeal angle, position of bladder neck relative to the pubococcygeal line in both resting and evacuation phases (p>0.05). There was a significant difference between the two groups regarding volume (p=0.014), anteroposterior diameter (p=0.01), inner layer thickness of the urethra (p=0.04), and PUVA (p<0.001) at rest and evacuation phases and cervix position at evacuation phase (p=0.001). The AUC of the PUVA for SUI diagnosis was 0.9 at rest and 0.98 during evacuation phases. For the threshold 133.5° at rest phase and 153.5° at evacuation phase, the sensitivity and specificity of PUVA were 0.86 and 0.86 at rest phase and 0.91 and 0.95 at evacuation phase, respectively. Conclusions: PUVA was the anatomical factor that had the greatest effect on SUI and provided high sensitivity and specificity for SUI diag-nosis.

Rhodium-Catalyzed Asymmetric Synthesis of 1,2-Disubstituted Allylic Fluorides.

Although there are many methods for the asymmetric synthesis of monosubstituted allylic fluorides, construction of enantioenriched 1,2-disubstituted allylic fluorides has not been reported. To address this gap, we report an enantioselective synthesis of 1,2-disubstituted allylic fluorides using chiral diene-ligated rhodium catalyst, Et3 N ⋅ 3HF as a source of fluoride, and Morita Baylis Hillman (MBH) trichloroacetimidates. Kinetic studies show that one enantiomer of racemic MBH substrate reacts faster than the other. Computational studies reveal that both syn and anti π-allyl complexes are formed upon ionization of allylic substrate, and the syn complexes are slightly energetically favorable. This is in contrast to our previous observation for formation of monosubstituted π-allyl intermediates, in which the syn π-allyl conformation is strongly preferred. In addition, the presence of an electron-withdrawing group at C2 position of racemic MBH substrate renders 1,2-disubstituted π-allyl intermediate formation endergonic and reversible. To compare, formation of monosubstituted π-allyl intermediates was exergonic and irreversible. DFT calculations and kinetic studies support a dynamic kinetic asymmetric transformation process wherein the rate of isomerization of the 1,2-disubstituted π-allylrhodium complexes is faster than that of fluoride addition onto the more reactive intermediate. The 1,2-disubstituted allylic fluorides were obtained in good yields, enantioselectivity, and branched selectivity.

Heparan Sulfate-Mimicking Glycopolymers Bind SARS-CoV-2 Spike Protein in a Length- and Sulfation Pattern-Dependent Manner.

Heparan sulfate-mimicking glycopolymers, composed of glucosamine (GlcN)-glucuronic acid (GlcA) repeating units, bind to the receptor-binding subunit (S1) and spike glycoprotein (S) domains of the SARS-CoV-2 spike protein in a length- and sulfation pattern-dependent fashion. A glycopolymer composed of 12 repeating GlcNS6S-GlcA units exhibits a much higher affinity to the S1 protein (IC50 = 13 ± 1.1 nM) compared with the receptor-binding domain (RBD). This glycopolymer does not interfere in angiotensin-converting enzyme 2 binding of the RBD. Although this compound binds strongly to the S1/membrane-fusion subunit (S2) junction (KD = 29.7 ± 4.18 nM), it does not shield the S1/S2 site from cleavage by furin-a behavior contrary to natural heparin. This glycopolymer lacks iduronic acid, which accounts for 70% of heparin. Further, this compound, unlike natural heparin, is well defined in both sulfation pattern and length, which results in fewer off-target interactions with heparin-binding proteins. The results highlight the potential of using polymeric heparan sulfate (HS) mimetics for the therapeutic agent development.

Overcoming the Potential Window-Limited Functional Group Compatibility by Alternating Current Electrolysis.

The functional group compatibility of an electrosynthetic method is typically limited by its potential reaction window. Here, we report that alternating current (AC) electrolysis can overcome such potential window-limited functional group compatibility. Using alkene heterodifunctionalization as a model system, we design and demonstrate a series of AC-driven reactions that add two functional groups sequentially and separately under the cathodic and anodic pulses, including chloro- and bromotrilfuoromethylation as well as chlorosulfonylation. We discovered that the oscillating redox environment during AC electrolysis allows the regeneration of the redox-active functional groups after their oxidation or reduction in the preceding step. As a result, even though redox labile functional groups such as pyrrole, quinone, and aryl thioether fall in the reaction potential window, they are tolerated under AC electrolysis conditions, leading to synthetically useful yields. The cyclic voltammetric study has confirmed that the product yield is limited by the extent of starting material regeneration during the redox cycling. Our findings open a new avenue for improving functional group compatibility in electrosynthesis and show the possibility of predicting the product yield under AC electrolysis from voltammogram features.

Scope and Mechanistic Probe into Asymmetric Synthesis of α-Trisubstituted-α-Tertiary Amines by Rhodium Catalysis.

Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition-metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium-catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π-σ-π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin-Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between ß-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched-linear >99:1, up to 99% enantiomeric excess).

Pelvic arteriovenous malformation mimicking benign prostatic hyperplasia: A case report.

Pelvic arteriovenous malformation is a rare vascular abnormality, espescially in male patients, and is difficult to treat because of its nature supplied by multiple arterial feeders. We report a 70-year-old male patient admitted due to symptoms of benign prostatic hyperplasia. Ultrasound was performed initially, and no other abnormalities were found other than an enlarged prostate. CT scan later demonstrated a pelvic arteriovenous malformation adjacent to the prostate, with multiple arterial feeders from the right internal iliac artery. Angiography confirmed the diagnosis, and transaterial embolization was successfully done. The symptoms disappeared several days later, and the patient remained asymptompmatic during follow-up.

Diagnostic and antibiotic stewardship lessons: an outpatient assessment of symptomatic reflex urinalysis ordering accuracy using an electronic best-practice alert.

BACKGROUND: It is not well known how reliably clinicians order reflex urinalysis to microscopy and culture (rUA-cx) for outpatient urinary tract infection (UTI) workup. Antibiotic appropriateness cannot be fully appreciated until the prevalence of UTIs and asymptomatic bacteriuria (ASB) are realized. OBJECTIVE: This quality improvement study has two major aims, first to determine UTI symptom accuracy for rUA-cx ordering and second, to confirm UTI and ASB cases by integrating rUA-cx and cascaded urinalysis results. Antibiotic utilization and diagnostic coding were secondarily linked to UTIs and ASB. METHODS: An electronic best-practice alert informed the ordering of two rUA-cx options: symptomatic- rUA-cx specifically for dysuria, frequency, urgency, costovertebral pain, suprapubic pain or fever versus non-specific-rUA-cx for vague complaints. UTI symptoms were verified by chart review. Confirmed UTI was defined as a significant culture with UTI symptoms and ASB as a significant culture without UTI symptoms. RESULTS: rUA-cx (2065) were prospectively collected over 6 months from female patients at risk for uncomplicated UTIs. Symptomatic-rUA-cx and non-specific-rUA-cx were associated with UTI symptoms for 53% (809/1527) and 20% (107/538), respectively. Overall, 44% (916/2065) of all rUA-cx had UTI symptoms. rUA-cx were overordered by a factor of 9 (2065/225) for every confirmed UTI. The UTI-to-ASB relative ratio was 2.6 (225/86). Regarding UTI-relevant antibiotics, 39% (214/553) were appropriately associated with UTI whereas only 22% (74/339) of inappropriate antibiotics were captured by the ASB definition, underestimating the problem 4-fold. CONCLUSIONS: UTI and ASB remain challenging to categorize despite a meticulous method that applied acceptable criteria.

Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies.

Heparan sulfate (HS) contains variably repeating disaccharide units organized into high- and low-sulfated domains. This rich structural diversity enables HS to interact with many proteins and regulate key signaling pathways. Efforts to understand structure-function relationships and harness the therapeutic potential of HS are hindered by the inability to synthesize an extensive library of well-defined HS structures. We herein report a rational and expedient approach to access a library of 27 oligosaccharides from natural aminoglycosides as HS mimetics in 7-12 steps. This strategy significantly reduces the number of steps as compared to the traditional synthesis of HS oligosaccharides from monosaccharide building blocks. Combined with computational insight, we identify a new class of four trisaccharide compounds derived from the aminoglycoside tobramycin that mimic natural HS and have a strong binding to heparanase but a low affinity for off-target platelet factor-4 protein.

Charge and Solvent Effects on the Redox Behavior of Vanadyl Salen-Crown Complexes.

The incorporation of charged groups proximal to a redox active transition metal center can impact the local electric field, altering redox behavior and enhancing catalysis. Vanadyl salen (salen = N,N'-ethylenebis(salicylideneaminato)) complexes functionalized with a crown ether containing a nonredox active metal cation (V-Na, V-K, V-Ba, V-La, V-Ce, and V-Nd) were synthesized. The electrochemical behavior of this series of complexes was investigated by cyclic voltammetry in solvents with varying polarity and dielectric constant (ε) (acetonitrile, ε = 37.5; N,N-dimethylformamide, ε = 36.7; and dichloromethane, ε = 8.93). The vanadium(V/IV) reduction potential shifted anodically with increasing cation charge compared to a complex lacking a proximal cation (ΔE1/2 > 900 mV in acetonitrile and >700 mV in dichloromethane). In contrast, the reduction potential for all vanadyl salen-crown complexes measured in N,N-dimethylformamide was insensitive to the magnitude of the cationic charge, regardless of the electrolyte or counteranion used. Titration studies of N,N-dimethylformamide into acetonitrile resulted in cathodic shifting of the vanadium(V/IV) reduction potential with increasing concentration of N,N-dimethylformamide. Binding constants of N,N-dimethylformamide (log(KDMF)) for the series of crown complexes show increased binding affinity in the order of V-La > V-Ba > V-K > (salen)V(O), indicating an enhancement of Lewis acid/base interaction with increasing cationic charge. The redox behavior of (salen)V(O) and (salen-OMe)V(O) (salen-OMe = N,N'-ethylenebis(3-methoxysalicylideneamine) was also investigated and compared to the crown-containing complexes. For (salen-OMe)V(O), a weak association of triflate salt at the vanadium(IV) oxidation state was observed through cyclic voltammetry titration experiments, and cation dissociation upon oxidation to vanadium(V) was identified. These studies demonstrate the noninnocent role of solvent coordination and cation/anion effects on redox behavior and, by extension, the local electric field.

Stereoselective glycosylation reactions with 2-deoxyglucose: a computational study of some catalysts.

2-Deoxy glycosides are important components of many oligosaccharides with antibiotic and anti-cancer activity, but their synthesis can be very challenging. Phenanthrolines and substituted pyridines promote stereoselective glycosylation of 1-bromo sugars via a double SN2 mechanism. Pyridine reacting with α-bromo, 2-deoxyglucose was chosen to model this reaction. The first step involves displacement of bromide by pyridine which can be rate limiting because bromide ion is poorly solvated in the non-polar solvents used for these reactions. We examined a series of small molecules to bind bromide and stabilize this transition state. Geometry optimization and vibrational frequencies were calculated using M06-2X/6-31+G(d,p) and SMD implicit solvation for diethyl ether. More accurate energies were obtained with M06-2X/aug-cc-pVTZ and implicit solvation. Urea, thiourea, guanidine and cyanoguanidine bind bromide more strongly than alkylamines, (NH2CH2CH2)nNH3-n. Compared to the uncatalyzed reaction, urea, thiourea and cyanoguanidine lower the free energy of the transition state by 3 kcal/mol while guanidine lowers the barrier by 2 kcal/mol.

Phenanthroline Catalysis in Stereoselective 1,2-cis Glycosylations.

The National Research Council's report in 2012 recognized glycosidic bond forming (glycosylation) reactions as critical due to the central importance of carbohydrates to the glycosciences. This report emphasized the need for the development of reproducible and broadly applicable glycosylation technologies to facilitate the stereoselective synthesis of biomedically relevant glycan libraries for tool development and for research applications by nonspecialists. In response to this report with NIH Common Fund support, the publications of new catalytic diastereoselective glycosylation protocols, some with broad generality under mild conditions, have been recently reported by our group and others. These recent discoveries have also advanced the understanding of the glycosylation reaction mechanism involving the coupling of a sugar electrophile bearing a leaving group at its C1-anomeric center with an alcohol nucleophile. This glycosidic bond forming reaction can lead to a mixture of two stereoisomers that differ in the configuration of the anomeric center.In our group, we discovered that readily available phenanthroline, a rigid and planar organic compound with two fused pyridine rings, could be utilized as a nucleophilic catalyst to promote highly diastereoselective glycosylation of an alcohol nucleophile with a sugar bromide electrophile. The phenanthroline catalysis process allows access to a myriad of high yielding and diastereoselective 1,2-cis pyranosides and furanosides. This catalyst-controlled approach has been applied to the synthesis of a potential vaccine adjuvant α-glucan octasaccharide. For pyranosyl bromide electrophiles, an extensive mechanistic investigation illustrated that two phenanthrolinium ion intermediates, a 4C1 chair-liked equatorial-conformer and a B2,5 boat-like axial-conformer, are formed in a ratio of 2:1 (equatorial/axial). To obtain high levels of axial-1,2-cis selectivity, a Curtin-Hammett scenario was proposed wherein interconversion of the 4C1 equatorial-conformer and B2,5 axial-conformer is more rapid than nucleophilic addition. Hydroxyl attack takes place from the axial-face of the more reactive 4C1 chairlike equatorial intermediate to afford an axial-1,2-cis glycoside product. The phenanthroline catalysis system is applicable to a number of furanosyl bromide electrophiles to provide the challenging 1,2-cis substitution products in good yield and diastereoselectivity. NMR experiments and density-functional theory (DFT) calculations support an associative mechanism in which the rate-determining step takes place from an invertive displacement of the faster reacting furanosyl phenanthrolinium ion intermediate with an alcohol nucleophile. Overall, this work stands at the underdeveloped intersection of operationally simple conditions, catalysis, and stereocontrolled glycosidic bond formation, each of which represents an important theme in the preparation of biologically important oligosaccharides and glycopeptides for applications to human health and medicine.

Depolymerization of Rice Straw Lignin into Value-Added Chemicals in Sub-Supercritical Ethanol.

Depolymerization of lignin is an important step to obtain a lignin monomer for the synthesis of functional chemicals. In the context of more lignin produced from biomass and pulp industry, converting real lignin with low purity is still required more studies. In this study, the influence of solvent composition and reaction parameters such as binary solvents ratio, time, and temperature, the solvent-to-lignin ratio on the depolymerization of rice straw lignin was investigated carefully. Essential lignin-degraded products including liquid product (LP), char (solid), and gas were obtained, and their yields were directly influenced by reaction conditions. Results show that the maximum lignin conversion rate of 92% and LP yield of 66% was under the condition of 275°C, 30 min, 75 : 1 (mL solvent/1 g lignin), and ethanol 50%. Gas chromatography-mass spectroscopy (GC-MS) analysis was used for the analysis of the depolymerization products and identified 11 compounds which are mainly phenolic compounds such as 2-ethylphenol, 3-ethylphenol, phenol, methyl 2,4,6-trimethylbenzoate. The structure changes of LP and char in various conditions were analyzed using Fourier-transform infrared (FTIR).

Heparan Sulfate Mimicking Glycopolymer Prevents Pancreatic ß Cell Destruction and Suppresses Inflammatory Cytokine Expression in Islets under the Challenge of Upregulated Heparanase.

Diabetes is a chronic disease in which the levels of blood glucose are too high because the body does not effectively produce insulin to meet its needs or is resistant to insulin. ß Cells in human pancreatic islets produce insulin, which signals glucogen production by the liver and causes muscles and fat to uptake glucose. Progressive loss of insulin-producing ß cells is the main cause of both type 1 and type 2 diabetes. Heparan sulfate (HS) is a ubiquitous polysaccharide found at the cell surface and in the extracellular matrix (ECM) of a variety of tissues. HS binds to and assembles proteins in ECM, thus playing important roles in the integrity of ECM (particularly basement membrane), barrier function, and ECM-cell interactions. Islet HS is highly expressed by the pancreatic ß cells and critical for the survival of ß cells. Heparanase is an endoglycosidase and cleaves islet HS in the pancreas, resulting in ß-cell death and oxidative stress. Heparanase could also accelerate ß-cell death by promoting cytokine release from ECM and secretion by activated inflammatory and endothelial cells. We demonstrate that HS-mimicking glycopolymer, a potent heparanase inhibitor, improves the survival of cultured mouse pancreatic ß cells and protects HS contents under the challenge of heparanase in human pancreatic islets. Moreover, this HS-mimicking glycopolymer reduces the expression levels of cytokines (IL8, IL1ß, and TNFα) and the gene encoding Toll-like Receptor 2 (TLR2) in human pancreatic islets.

Stereoselective 1,2-cis Furanosylations Catalyzed by Phenanthroline.

Stereoselective formation of the 1,2-cis furanosidic linkage, a motif of many biologically relevant oligosaccharides and polysaccharides, remains an important synthetic challenge. We herein report a new stereoselective 1,2-cis furanosylation method promoted by phenanthroline catalysts under mild and operationally simple conditions. NMR experiments and density functional theory calculations support an associative mechanism in which the rate-determining step occurs from an inverted displacement of the faster-reacting phenanthrolinium ion intermediate with an alcohol nucleophile. The phenanthroline catalysis system is applicable to a number of furanosyl bromide donors to provide the challenging 1,2-cis substitution products in good yield with high anomeric selectivities. While arabinofuranosyl bromide provides ß-1,2-cis products, xylo- and ribofuranosyl bromides favor α-1,2-cis products.

Morphological Component Analysis of Functional MRI Brain Networks.

OBJECTIVE: Sparse representations have been utilized to identify functional connectivity (FC) of networks, while ICA employs the assumption of independence among the network sources to demonstrate FC. Here, we investigate a sparse decomposition method based on Morphological Component Analysis and K-SVD dictionary learning - MCA-KSVD - and contrast the effect of the sparsity constraint vs. the independency constraint on FC and denoising. METHODS: Using a K-SVD algorithm, fMRI signals are decomposed into morphological components which have sparse spatial overlap. We present simulations when the independency assumption of ICA fails and MCA-KSVD recovers more accurate spatial-temporal structures. Denoising performance of both methods is investigated at various noise levels. A comprehensive experimental study was conducted on resting-state and task fMRI. RESULTS: Validations show that ICA is advantageous when network components are well-separated and sparse. In such cases, the MCA-KSVD method has modest value over ICA in terms of network delineation but is significantly more effective in reducing spatial and temporal noise. Results demonstrate that the sparsity constraint yields sparser networks with higher spatial resolution while suppressing weak signals. Temporally, this localization effect yields higher contrast-to-noise ratios (CNRs) of time series. CONCLUSION: While marginally improving the spatial decomposition, MCA-KSVD denoises fMRI data much more effectively than ICA, preserving network structures and improving CNR, especially for weak networks. SIGNIFICANCE: A sparsity-based decomposition approach may be useful for investigating functional connectivity in noisy cases. It may serve as an efficient decomposition method for reduced acquisition time and may prove useful for detecting weak network activations.

[Interest of the use of the "MYDEFI" smartphone application to help reduce alcohol consumption in the involvement of pharmacists in the prevention of at-risk consumption: Results of a survey in the Hauts-de-France]. / Intérêt de l'utilisation de l'application smartphone « MYDEFI ¼ d'aide à la réduction de la consommation d'alcool dans l'implication des pharmaciens dans la prévention de la consommation à risque : résultats d'une enquête dans les Hauts-de-France.

OBJECTIVES: Evaluate the interest in the MyDéfi application as a tool to help pharmacists identify and manage excessive alcohol consumption, as well as their perception and knowledge of alcohol and their possible role in its management. METHODS: Prospective mixed qualitative and quantitative study, based on face-to-face semi-directive interviews. RESULTS: The 101 pharmacists interviewed in Hauts-de-France region considered that the detection of alcohol consumption was part of their mission, even if it is a difficult subject, and that they had received specific training in alcohology during their university training. Only 12% were aware of early screening and brief intervention on alcohol. Several obstacles were mentioned, such as the lack of training and confidentiality, and difficulties related to patient specificities. Forty-one percent said that the pharmacy was not suitable and almost 72% said that the MyDéfi application could be useful for screening and 91% would recommend the application as one of the best supports, easy to advise with a personalised follow-up. For 32%, the application is accessible to patients (40% think that the main drawback of the application is inaccessibility and 27% its cost). CONCLUSION: Pharmacists consider that excessive alcohol use is a major problem that should mobilise them but many do not feel ready to offer brief interventions. After seeing how the MyDéfi application worked, the majority considered that it could help them in their prevention mission.

Propagating Error through Traveling-Wave Ion Mobility Calibration.

Native mass spectrometry (MS) is used to elucidate the stoichiometry of protein complexes and quantify binding interactions by maintaining native-like, noncovalent interactions in the gas phase. However, ionization forces proteins into specific conformations, losing the solution-phase dynamics associated with solvated protein structures. Comparison of gas-phase structures to those in solution, or to other gas-phase ion populations, has many biological implications. For one, analyzing the variety of conformations that are maintained in the gas-phase can provide insight into a protein's solution-phase energy landscape. The gas-phase conformations of proteins and complexes can be investigated using ion mobility (IM) spectrometry. Specifically, drift tube (DT)-IM utilizes uniform electric fields to propel a population of gas-phase ions through a region containing a neutral gas. By measuring the mobility (K) of gas-phase ions, users are able to calculate an average momentum transfer cross section (DTCCS), which provides structural information on the ion. Conversely, in traveling-wave ion mobility spectrometry (TWIMS), TWCCS values cannot be derived directly from an ion's mobility but must be determined following calibration. Though the required calibration adds uncertainty, it is common to report only an average and standard deviation of the calculated TWCCS, accounting for uncertainty associated with replicate measurements, which is a fraction of the overall uncertainty. Herein, we calibrate a TWIMS instrument and derive TWCCSN2 and TWCCSN2→He values for four proteins: cytochrome c, ubiquitin, apo-myoglobin, and holo-myoglobin. We show that compared to reporting only the standard deviation of TWCCS, propagating error through the calibration results in a significant increase in the number of calculated TWCCS values that agree within experimental error with literature values (DTCCS). Incorporating this additional uncertainty provides a more thorough assessment of a protein ion's gas-phase conformations, enabling the structures sampled by native IM-MS to be compared against other reported structures, both experimental and computational.

Phenanthroline-Catalyzed Stereoselective Formation of α-1,2-cis 2-Deoxy-2-Fluoro Glycosides.

Phenanthroline is a heterocyclic aromatic organic compound and commonly used in coordination chemistry acting as a bidentate ligand. The C4 and C7 positions of phenanthroline can often be substituted to change the binding capabilities of the ligand. Recently, there has been a push in the field of chemistry to create environmental-friendly chemical methodologies by utilizing catalysts and minimizing solvent. Herein, we have illustrated how, at high concentrations with minimal use of solvent, the C4 and C7 positions of phenanthroline can be tuned to develop an efficient and stereoselective catalyst for the formation of α-1,2-cis-fluorinated glycosides. By activating 2-deoxy-2-fluoro glycosyl halides with phenanthroline-based catalysts, we have been able to achieve glycosylations with high levels of α-selectivities and moderate to high yields. The catalytic system has been applied to several glycosyl halide electrophiles with a range of glycosyl nucleophilic acceptors. The proposed mechanism for this catalytic glycosylation system has been investigated by density functional theory calculations, indicating that the double SN2 displacement pathways with phenanthroline catalysts have lower barriers and ensure stereoselective formation of α-1,2-cis-2-fluoro glycosides.

Alkyl Radical-Free Cu(I) Photocatalytic Cross-Coupling: A Theoretical Study of Anomerically Specific Photocatalyzed Glycosylation of Pyranosyl Bromide.

Previously, we reported a visible light-activated Cu(I) photocatalyst capable of facilitating C-O bond formation of glycosyl bromides and aliphatic alcohols with a high degree of diastereoselectivity. This catalyst functions equally well in the presence of radical traps, suggesting an entirely inner sphere mechanism atypical for heteroleptic Cu photocatalysis. Further, experimental estimates put the chromophore reducing power at -1.30 V vs Ag/AgCl. This is much more positive than the ∼-2.0 V vs Ag/AgCl onset observed for irreversible reduction of glycosyl bromides in our experiments. Theoretical investigations were undertaken to explain the function of the catalyst. Outer sphere electron transfer from a chromophore to substrate was discounted based on thermodynamics and electron transfer barriers determined by Marcus theory and non-equilibrium solvation calculations. Unactivated and activated chromophores were found to disproportionate to Cu(0) and Cu(II) species. The resulting Cu(0) species undergoes oxidative addition with a glycosyl bromide generating a Cu(II) species. Addition of a nucleophilic alcohol and oxidation of the Cu(II) species to Cu(III) result in rapid reductive elimination forming products and resetting the catalytic cycle.