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Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disk herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological MGO signaling as a mechanism underlying neuropathy improvement. We found that mice injected with MGO displayed nocifensive behaviors, whereas mice prefed a ketogenic diet were resistant to mechanical allodynia elicited by MGO. In addition, levels of circulating MGO were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body β-hydroxybutyrate (β-HB). Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared with chow-fed control mice. Recent studies also suggest that ketone bodies contribute to MGO detoxification, consistent with a negative correlation between β-HB and MGO. To assess whether ketone bodies modified MGO-evoked nociception through direct MGO detoxification, we coincubated either acetoacetate or β-HB with MGO before injection. Mice receiving intraplantar MGO injection exhibit increased nociceptive behavior (lifting, licking, biting, and scratching), which was significantly reduced by coincubation with either acetoacetate or β-HB. Methylglyoxal increased phospho-extracellular signal-regulated kinase-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or β-HB. These results suggest that a ketogenic diet and ketone bodies ameliorate MGO-evoked nociception, partially through detoxification of MGO, and provide rationale for therapeutic intervention with a ketogenic diet in MGO-driven pathologies.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Daiichi Sankyo Europe GmbH Background Based on results of multiple randomised controlled trials, direct oral anticoagulants (DOACs) are frequently used to reduce stroke risk in patients with atrial fibrillation (AF). The hypothesis is that in the real-world setting DOACs are effective in reducing the risk of stroke but ensuring continuous use is essential because of the rapid decline in anticoagulation activity when doses are omitted. Purpose The aim of this study was to assess the relationship between non-adherence, discontinuation of DOAC treatment and incidence of ischaemic stroke. Methods A nested case-control study was conducted in the InGef database, an anonymised healthcare claims database in Germany. AF patients starting DOACs between drug approval date and 31/12/2018 were included. We restricted to patients aged ≥45, ≥1 year database history, ≥1 year follow-up and at least two DOAC dispensings after cohort entry date (CED) (date of first dispensing). Patients with an ischaemic stroke during follow-up were selected as cases and compared with matched controls (matched on age +/- 5 years, sex, year of CED and CHA₂DS₂-VASc-score at CED). Controls were assigned the index date (date of first stroke diagnosis) of the corresponding case. Adherence to treatment was assessed among current users (DOAC use at or within 30 days before index date) and defined as proportion of days covered (PDC) ≥80% during CED and index date. Persistent users were defined as those with continuous DOAC use from CED to index date. We also assessed the effect of current, recent (DOAC use within 30-365 days before index date) and past use (DOAC use more than 1 year before index date). Odds ratios (ORs) with 95% confidence intervals (CIs) for ischaemic stroke were determined in logistic regression models. Results 900 cases and 3,570 controls were included. Among cases and controls, mean ± sd age was 80 ± 8 years and 49% were male. Current users who were non-adherent had a significant 1.21 higher odds (95% CI 1.01-1.45) of ischaemic stroke compared to adherent users. Similar results were observed in twice-daily (BID) users (OR 1.42 (1.15-1.75)). However, among once-daily (QD) users, the odds was not different between the adherent and non-adherent users (OR 0.99 (95% CI 0.58-1.69)). The risk of ischaemic stroke was significantly higher among non-persistent users compared to persistent users (OR 1.91 (95% CI 1.64-2.22)). Similar findings were observed among QD and BID users. The comparison of past and recent users to current users showed that the OR became higher the longer a patient had stopped DOAC use. Conclusion Both non-adherence and non-persistence were found to increase the risk of ischaemic stroke, showing that continuous use is essential for both BID and QD users. In BID users, there seems to be a stronger association between non-adherence and risk of stroke than in QD users. An explanation might be the higher degree of difficulty in adhering to a BID than QD regimen.

To describe new onset of generalized seizures in 3 young dogs following cessation of a benzodiazepine-containing sedation protocol to facilitate mechanical ventilation (MV) for hypoxemia.Three dogs under 5 months of age underwent MV due to severe hypoxemia. All 3 dogs were sedated with a constant rate infusion of benzodiazepines as part of their sedation protocol to facilitate MV. All 3 dogs had an acute onset of generalized seizures within 36 hours of sedation cessation and weaning from MV. All 3 dogs' seizures were successfully managed with a slow, tapering course of benzodiazepines. One dog was additionally treated with levetiracetam at the time of initial seizure activity, which was discontinued 1 year following discharge and absence of ongoing seizure activity. All 3 dogs were discharged successfully with no reports of ongoing seizures or neurologic deficits after discharge.Young dogs managed with benzodiazepines to facilitate MV may have acute onset of generalized seizures following cessation, which can be successfully managed with short-term benzodiazepine therapy. The 3 cases in this series demonstrated a positive outcome and were successfully managed following acute onset of generalized seizure activity post-MV.

A planar 2-D antenna array capable of mapping a full-hemisphere space to frequencies around 6 GHz is presented. It was designed using composite right-/left-handed transmission lines for the series feed network as well as for the radiating elements, thus achieving size reduction and beam steering control simplification compared to other approaches. Stripline fabrication technology is utilized to eliminate the undesired feed network radiation. A via-less unit cell reduces sensitivity to via misplacement. The result is an antenna that can be used for radar or imaging applications with the appropriate transmit/receive circuitry. Validation is provided by pattern measurements and successful detection of reflective targets.

Background Data on safety of Factor-Xa inhibitors and phenprocoumon in patients with non-valvular atrial fibrillation (NVAF) and renal disease is scarce. Among others, our study aimed to investigate the safety risks of fatal bleeding and intracranial haemorrhage (ICH) in new users of Factor-Xa inhibitors vs. phenprocoumon, the vitamin-K antagonist (VKA) of choice in Germany. Methods We conducted a new user cohort study (one year washout period) in patients with NVAF and renal disease. German claims data between January 1st, 2013 and June 30th, 2017 were utilized and a multiple Cox-regression was performed to calculate confounder-adjusted hazard ratios (HRs) for the risk of fatal bleeding and ICH in Factor-Xa inhibitors and phenprocoumon initiators. Additionally, a propensity score matching and an inverse probability of treatment weight analysis were performed as sensitivity analyses. Cases of fatal bleeding were defined as hospitalization with a primary hospital discharge diagnoses for bleeding with documented death as reason for hospital discharge or within 30 days after hospital discharge. Results The overall population comprised 23,552 phenprocoumon initiators, 22,338 rivaroxaban initiators and 16,201 apixaban initiators, where the number of patients with renal disease initiating these agents were 7,289 for phenprocoumon, 5,121 patients for rivaroxaban 15mg or 20mg and 4,750 patients for apixaban 2.5mg or 5mg, respectively. In the confounder-adjusted analysis, a beneficial effect for rivaroxaban and apixaban over phenprocoumon was observed for the risk of ICH and fatal bleeding (figure 1) for both the overall and renal disease population. Hazard ratios for rivaroxaban and the risk of ICH were calculated as 0.57 (0.43; 0.75) for the overall population and 0.62 (0.37; 1.01) for the renal disease population where hazard ratios for apixaban were calculated as 0.43 (0.31; 0.60) for the overall population and 0.41 (0.23; 0.74) for the renal disease population, respectively. There was not sufficient data to conduct the analyses for edoxaban. Figure 1 Conclusion This large retrospective database study conducted in Germany confirms the safety profile of rivaroxaban and apixaban over VKA in patients overall and specifically in patients with renal disease when assessing the risk of ICH and fatal bleeding. Our study adds evidence in a relevant subgroup of patients where anticoagulation is often challenging. Acknowledgement/Funding This study was funded by Bayer AG

Background Data on safety and effectiveness of Factor-Xa inhibitors and phenprocoumon in patients with non-valvular atrial fibrillation (NVAF) and malignant diseases is scarce. Among others, our study aimed to investigate the safety and effectiveness in new users of Factor-Xa inhibitors vs. phenprocoumon, the vitamin-K antagonist (VKA) of choice in Germany. Methods We conducted a new user cohort study (one year washout period) in patients with NVAF and malignant diseases. German claims data between January 1st, 2013 and June 30th, 2017 were utilized and a multiple Cox-regression was performed to calculate confounder-adjusted hazard ratios (HRs) for the risk of ischemic stroke (IS)/systemic embolism (SE), intracranial haemorrhage (ICH) as well as renal function worsening, defined by end stage renal disease (ESRD) or dialysis and acute kidney injury (AKI) in Factor-Xa inhibitors and phenprocoumon initiators. Diagnoses of malignant diseases were assessed over the one-year baseline period. Results The population comprised 3,779 phenprocoumon initiators, 3,386 rivaroxaban initiators, 2,697 apixaban initiators and 434 edoxaban initiators. In the confounder-adjusted analysis, no difference related to the risk of IS/SE was found for rivaroxaban and edoxaban vs. phenprocoumon, where apixaban showed a numerically increased risk for stroke (figure 1). Point estimates related to the risk of ICH showed the expected beneficial effects for both, rivaroxaban and apixaban. A strong beneficial effect was observed for rivaroxaban when assessing the risk of renal function worsening. Hazard ratios related to the risk of ESRD/dialysis and AKI were 0.27 (0.10; 0.69) and 0.64 (0.38; 1.06), respectively. For apixaban, only the ESRD/dialysis showed a reduction in risk when compared to phenprocoumon, HR 0.42 (0.19; 0.94). Conclusion This retrospective database study conducted in Germany adds evidence on the effectiveness and safety profile of Factor-Xa inhibitors over VKA in patients with NVAF and malignant diseases, a critical subgroup of patients where anticoagulation is challenging. However, apixaban showed a numerically increased risk for IS/SE compared to phenprocoumon. Both, rivaroxaban and apixaban showed a risk reduction for renal function worsening within the study period of 63% and 48%, respectively compared to phenprocoumon. Only rivaroxaban showed a risk reduction of 36% for AKI. Acknowledgement/Funding The study was funded by Bayer AG

Background Data on the effectiveness and safety of Factor-Xa non-vitamin-K oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF) and renal disease is scarce. Among others, our study aimed to investigate the risk of renal function worsening in new users of NOACs vs. phenprocoumon with renal disease. Methods We conducted a new user cohort study (one year washout period) in patients with NVAF overall and additionally with renal disease defined by either an extended list of ICD-10 codes (definition 1) or chronic kidney disease (CKD) stages 3 or 4 (definition 2). German claims data between January 1st, 2013 and June 30th, 2017 were utilized and a multiple Cox-regression was performed to calculate confounder-adjusted hazard ratios (HRs) for the risk of end stage renal disease (ESRD)/dialysis and acute kidney injury in new users of NOACs (rivaroxaban, apixaban and edoxaban) vs. new users of phenprocoumon. Results In the overall population 22,339 patients initiating rivaroxaban, 16,201 patients initiating apixaban, 2,828 patients initiating edoxaban and 23,552 patients initiating phenprocoumon were included. NOAC patients with renal disease (definition 1) initiating reduced doses comprised 2,121 initiators of rivaroxaban, 2,507 of apixaban and 292 of edoxaban. 7,289 patients of phenprocoumon were identified. Patients with CKD (definition 2) initiating reduced doses of Factor-Xa inhibitors comprised 1,216 initiators of rivaroxaban, 1,522 of apixaban, 166 of edoxaban and 3,513 of phenprocoumon. In the confounder-adjusted analysis, a beneficial effect for both, rivaroxaban and apixaban over phenprocoumon was seen for the risk of ESRD/dialysis for all populations (overall, renal definition 1 and renal definition 2). In addition, in the CKD population we found a statistically significant risk reduction related to acute kidney injury only for rivaroxaban initiators (44%). There was not sufficient data to conduct the analyses for edoxaban. Figure 1 Conclusion This is the first observational retrospective database study evaluating the effect of renal function worsening in Germany. Results indicate a beneficial effect for both, reduced doses of rivaroxaban and apixaban related to renal function worsening over time when compared to phenprocoumon. This effect was more pronounced for the risk reduction with rivaroxaban related to ESRD /dialysis and specifically also related to a significant risk reduction for AKI. Acknowledgement/Funding The study was funded by Bayer AG

Background Atypical hyperadrenocorticism (AHAC) is considered when dogs have clinical signs of hypercortisolemia with normal hyperadrenocorticism screening tests. Hypothesis/Objectives To compare cortisol concentrations and adrenal gland size among dogs with pituitary‐dependent hyperadrenocorticism (PDH), atypical hyperadrenocorticism (AHAC), and healthy controls. Animals Ten healthy dogs, 7 dogs with PDH, and 8 dogs with AHAC. Method Dogs were prospectively enrolled between November 2011 and January 2013. Dogs were diagnosed with PDH or AHAC based on clinical signs and positive screening test results (PDH) or abnormal extended adrenal hormone panel results (AHAC). Transverse adrenal gland measurements were obtained by abdominal ultrasound. Hourly mean cortisol (9 samplings), sum of hourly cortisol measurements and adrenal gland sizes were compared among the 3 groups. Results Hourly (control, 1.4 ± 0.6 μg/dL; AHAC, 2.9 ± 1.3; PDH, 4.3 ± 1.5) (mean, SD) and sum (control, 11.3 ± 3.3; AHAC, 23.2 ± 7.7; PDH, 34.7 ± 9.9) cortisol concentrations differed significantly between the controls and AHAC (P

Summary Objectives: To compare the quality of care regarding the use of elective percutaneous coronary interventions (PCIs) in the inpatient and outpatient setting and to evaluate different methods of confounder control in this context. Methods: Based on data of three statutory health insurances including more than nine million insurance members, a retrospective cohort study between 2005 and 2009 was conducted. The occurrence of myocardial infarction, stroke, further coronary intervention and death was ascertained following the first PCI in the study period, which was preceded by a one-year period without a PCI. A Cox proportional hazard model was used to assess the influence of the setting of the elective PCI on the risk for complications after the PCI for each outcome separately. Age, sex, the number of diseases of the Elixhauser comorbidity measure, past acute coronary syndrome, coronary artery disease, dyslipidemia, past stroke, past coronary artery bypass surgery and the year of the PCI were included as covariables. The analyses were repeated in a propensity score matched cohort as well as in inverse probability of treatment weighted analyses. Results: The cohort comprised 4,269 patients with an outpatient PCI and 26,044 patients with an inpatient PCI. The majority of the analyses revealed no statistically significant effect of the setting of the PCI on the risk of myocardial infarction, stroke and further coronary interventions, whereas a reduced mortality risk was observed for out-patient PCIs. Similar results were obtained in the propensity score analyses. Conclusions: The analysis revealed that the adjusted risk for complications following an elective PCI is similar between the inpatient and the outpatient setting. For mortality the risk differed but this might be explained by residual or unmeasured confounding. The different methods applied in this study revealed mostly similar results. Since our study only covered one aspect of quality of care in the field of PCI and did not consider drug treatment in hospital or in the outpatient setting, further studies are needed which include these aspects.

A 3D space-to-frequency mapping array comprised of a composite right/left-hand (CRLH) feed network and CRLH leaky-wave antennas (LWAs) is presented for microwave frequencies. Highly directive pencil beams can be scanned by varying frequency in a small footprint network with only passive CRLH structures. Simulation results are provided as demonstration.

A series feed network concept based on a distributed CRLH stripline and couplers is proposed for frequency scanning phase array applications. The characteristics of such a network, which includes a smaller footprint, are discussed and compared to the traditional transmission line series feed network. Design details of an implementation centered around 6GHz are provided, along with measurements results of the standalone network and as a feed for a 4 element antenna array, for validation of the core idea.

Cost-effectiveness of shoulder arthroscopy was analyzed and assessed by the days off work as part of the indirect costs. We retrospectively evaluated a group of 266 inpatients on sick leave after arthroscopic shoulder surgery. Mean duration till return to full duty was 9.5 days, the mean sick leave benefit was € 485. There was a statistically significant difference in the mean time to return to work between the older (age50) and the younger group (age under 50). Secondary data analysis of sick leave and sickness benefits as indirect costs of medical treatment seems to be well suited to provide essentiell information to health care policy makers and those charged with distributing disability funds.Am Beispiel der minimal-invasiven Schulterchirurgie werden die Arbeitsunfähigkeitstage als ein Teil der indirekten Kosten abgebildet und in die Bewertung der Wirtschaftlichkeit der Behandlungsmethode mit einbezogen. Für 266 Versicherte wurde die Dauer der Arbeitsunfähigkeit nach einer stationär durchgeführten Schulterarthroskopie bestimmt. Die Dauer und Höhe der Krankengeldzahlungen betrugen im Durchschnitt pro Teilnehmer 9,5 Tage bzw. 485,00 €. Versicherte, die maximal 50 Jahre alt waren, hatten signifikant mehr Krankengeldtage als Versicherte über 50 Jahre. Krankengeldzahlungen als indirekte Kosten einer Krankenbehandlung konnten effizient über Sekundärdatenanalysen erhoben und bewertet werden.

C 18 H 22 FeO 7 cristallise dans P2 1 2 1 2 1 avec a=6,4633, b=10,7995, c=28,056 A, Z=4; affinement jusqu'a R=0,030. Une caracteristique surprenante de la structure moleculaire est une orientation non usuelle: cis «anti-sterique» des coordinats menthyloxy et Fe(CO) 4 . Les resultats experimentaux sont completes par les resultas de calculs ab initio

Mother Nature utilizes simple precursors to build up complex organic molecules efficiently. One important example is the C3 building block dihydroxyacetone phosphate, which is used in various enzyme-catalyzed reactions. Following this biosynthetic strategy the DHAP equivalent 'dioxanone' can be used in organocatalytic reactions to synthesize sugars, aminosugars, carbasugars, polyoxamic acids and sphingosines. In this respect, organocatalytic domino reactions can also be seen as biomimetic as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products. In nature, the coenzyme thiamin (vitamin B1), a natural thiazolium salt, is used in biochemical nucleophilic acylations ('Umpolung'). The catalytic active species is a nucleophilic carbene. Mimicking this approach, organocatalytic carbene catalysis has emerged to an exceptionally fruitful research area, which is used in asymmetric C-C bond formations.

A novel asymmetric synthesis of highly enantioenriched homotaurine precursors has been developed via diastereo-selective Michael addition of lithiated enantiopure sulfonates to nitroalkenes by using 1,2:5,6-di-O-isopropylidene-alpha-D-allofuranose as chiral auxiliary.

Alkylation of 1,4-cyclohexanedione monoethylene acetal SAMP-hydrazone with various electrophiles (10 examples given) and subsequent cleavage of the hydrazones with saturated oxalic acid furnished highly enantiomerically enriched alpha-alkylated mono-protected 1,4-cyclohexanedione derivatives in high yields and enantiomeric excesses of ee = 28, 80-/=99%. Reduction of the ketones gave the corresponding alcohols in good yields with high enantiomeric excesses (ee = 80-/=98%) and cis/trans-ratios of usually 85:15.

Die kardiovaskulare Risikorelevanz der Hyper- und Dyslipoproteinamien ist durch zahlreiche experimentelle, klinische und epidemiologische Studien belegt, und uber das Verhalten der Serumlipide und -lipoproteine bei koronarer Herzkrankheit (KHK) liegen zahlreiche Mitteilungen in der Literatur vor.

A new and efficient synthetis of 1,6-dioxaspiro[4,4]nonane-spiroacetals, starting from the simple building blocks acetone and oxiranes is described.

Using intestinal sleeves in vitro, we studied the effect of dietary carbohydrate on active monosaccharide uptake in mice. Dietary carbohydrate did not affect numerous parameters of intestinal structure, such as length, circumference, weight, protein content, villus dimensions and density, and area at the villus level. Mice on a carbohydrate-free diet had active D-glucose uptake relatively independent of position along the small intestine. A carbohydrate-containing diet reversibly and within 1 day stimulated uptake except in the ileum, restoring the proximal-to-distal gradient in glucose uptake normally observed. This stimulation involved a 81-116% increase in the Michaelis- Menton constant Vmax, and also an apparent increase in the Michaelis- Menton constant Km, that may however be an artifact arising from unstirred-layer effects. Active uptake of 3-O-methyl-D-glucose also increased, permeability to glucose remained unchanged, and proline uptake reversibly decreased (probably due to the lower protein content of the carbohydrate-containing diets). The effect of fasting on active monosaccharide uptake seemed largely due to withdrawal of dietary carbohydrate, rather than of calories per se. It is concluded that dietary carbohydrate causes induction of monosaccharide carriers in the intestine, along with its more familiar induction of pancreatic amylase and intestinal disaccharidases. Substrate-dependent carrier induction may be physiologically significant in maintaining the proximal-to-distal gradient of glucose transport. An appendix presents measurements of villus area as a function of position along the intestine.

Highly enantioselective α-alkylations of ketones and aldehydes using metalated chiral hydrazones of (S)- or (R)-1-amino-2-methoxymethyl-pyrrolidine (“SAMP/RAMP-hydrazones”) are described. Furthermore, reduction/N-N bond cleavage of SAMP-hydrazones leads to primary amines of (R)- or (S)-configuration with selectivities of up to 94% ee depending on the reducing agent. Proline derived chiral hydrazines can also be used efficiently as agents for chromatographic (HPLC) resolution of aldehydes. Lithiated chiral (thio)formamides and allylamines are used in asymmetric nucleophilic acylation processes and as chiral homoenolate equivalents, respectively. In addition, new simple and generally applicable syntheses of spiroacetals and α-aminoketones are presented.