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Isothiocyanates (ITCs) are typically prepared using amines and highly toxic reagents such as thiophosgene, its derivatives, or CS$_{2}$. In this work, an investigation of a multicomponent reaction (MCR) using isocyanides, elemental sulfur and amines revealed that isocyanides can be converted to isothiocyanates using sulfur and catalytic amounts of amine bases, especially DBU (down to 2 mol%). This new catalytic reaction was optimized in terms of sustainability, especially considering benign solvents such as Cyrene��� or ��-butyrolactone (GBL) under moderate heating (40 ��C). Purification by column chromatography was further optimized to generate less waste by maintaining high purity of the product. Thus, E-factors as low as 0.989 were achieved and the versatility of this straightforward procedure was shown by converting 20 different isocyanides under catalytic conditions, while obtaining moderate to high yields (34���95%).

This chapter presents an overview of novel game interaction design using brain computer interface (BCI), electroencephalography (EEG) and eye tracking.Our main goal is to highlight particular applications of these novel interfaces in digital games and accessible computing technology. We also investigate commercial offerings within these areas, such as mass-market “brain-training” games. Given the growing popularity and the relative novelty of these interfaces, this chapter reviews the current state of the art to gain an understanding of how the field may look moving forward.

Purpose The triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by brain microglia. Microglial activation, as observed in Alzheimer’s disease (AD) as well as in transgenic mice expressing human amyloid-beta, appears to increase soluble TREM2 (sTREM2) levels in CSF and brain. In this study, we used two different transgenic mouse models of AD pathology and investigated the potential of TREM2 to serve as an in vivo biomarker for microglial activation in AD. Procedures We designed and generated a bispecific antibody based on the TREM2-specific monoclonal antibody mAb1729, fused to a single-chain variable fragment of the transferrin receptor binding antibody 8D3. The 8D3-moiety enabled transcytosis of the whole bispecific antibody across the blood-brain barrier. The bispecific antibody was radiolabeled with I-125 (ex vivo) or I-124 (PET) and administered to transgenic AD and wild-type (WT) control mice. Radioligand retention in the brain of transgenic animals was compared to WT mice by isolation of brain tissue at 24 h or 72 h, or with in vivo PET at 24 h, 48 h, and 72 h. Intrabrain distribution of radiolabeled mAb1729-scFv8D3CL was further studied by autoradiography, while ELISA was used to determine TREM2 brain concentrations. Results Transgenic animals displayed higher total exposure, calculated as the AUC based on SUV determined at 24h, 48h, and 72h post injection, of PET radioligand [124I]mAb1729-scFv8D3CL than WT mice. However, differences were not evident in single time point PET images or SUVs. Ex vivo autoradiography confirmed higher radioligand concentrations in cortex and thalamus in transgenic mice compared to WT, and TREM2 levels in brain homogenates were considerably higher in transgenic mice compared to WT. Conclusion Antibody-based radioligands, engineered to enter the brain, may serve as PET radioligands to follow changes of TREM2 in vivo, but antibody formats with faster systemic clearance to increase the specific signal in relation to that from blood in combination with antibodies showing higher affinity for TREM2 must be developed to further progress this technique for in vivo use.

Herein, a more practical and efficient synthesis protocol for the preparation of uniform rod-like oligo(1,4-phenylene ethynylene)s (OPE)s is presented. Applying an iterative reaction cycle consisting of a decarboxylative coupling reaction and a saponification of an alkynyl carboxylic ester, a uniform pentamer is obtained in ten steps with 14% overall yield. The copper-free conditions prevent homocoupling until the trimer stage, resulting in a significantly easier work-up of the products. Homocoupling is observed from the tetramer stage on, but a simple variation of the work-up procedure also yields the uniform tetramer and pentamer. A thorough comparison with the commonly used and described Sonogashira approach reveals that with the new presented strategy, OPEs can be built in similar overall yield, but easier purification and in a quarter of the time. All oligomers are fully characterized by proton and carbon nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS), size-exclusion chromatography (SEC), and infrared spectroscopy (IR).

CoSn is a Pauli paramagnet with relatively flat d-bands centered about 100 meV below the Fermi energy Ef. Single crystals of CoSn lightly doped with Fe, In, or Ni are investigated using x-ray and neutron scattering, magnetic susceptibility and magnetization, ac susceptibility, specific heat and resistivity measurements. Within the rigid band approximation, hole doping with a few percent of Fe or In should move the flat bands closer to Ef, whereas electron doping with Ni should move the flat bands further away from Ef. We provide evidence that this indeed occurs. Fe and In doping drive CoSn toward magnetism, while Ni doping suppresses CoSn's already weak magnetic response. The resulting ground state is different for Fe versus In doping. For Fe-doped crystals, Co1-xFexSn, with 0.02 < x < 0.27, the magnetic and specific heat data are consistent with the formation of a spin glass, with a glass transition temperature, Tg, ranging from 1 K for x=0.02 to 10 K for x= 0.27. Powder and single crystal neutron diffraction found no evidence of long-range magnetic order below Tg with x = 0.17. For In-doped crystals, CoSn1-yIny, both the magnetic susceptibility and the Sommerfeld coefficient, gamma, increase substantially relative to pure CoSn, but with no clear indication of a magnetic transition for 0.05 < y < 0.2. CoSn crystals doped with Ni (Co0.93Ni0.07Sn) have a significantly smaller magnetic susceptibility and gamma than pure CoSn, consistent with the flat bands further from Ef., 20 pages, 10 figures

Charge density waves (CDW) are modulations of the electron density and the atomic lattice that develop in some crystalline materials at low temperature. We report an unusual example of a CDW in BaFe$_2$Al$_9$ below 100 K. In contrast to the canonical CDW phase transition, temperature dependent physical properties of single crystals reveal a first-order phase transition. This is accompanied by a discontinuous change in the size of the crystal lattice. In fact, this large strain has catastrophic consequences for the crystals causing them to physically shatter. Single crystal x-ray diffraction reveals super-lattice peaks in the low-temperature phase signaling the development of a CDW lattice modulation. No similar low-temperature transitions are observed in BaCo$_2$Al$_9$. Electronic structure calculations provide one hint to the different behavior of these two compounds; the d-orbital states in the Fe compound are not completely filled. Iron compounds are renowned for their magnetism and partly filled d-states play a key role. It is therefore surprising that BaFe$_2$Al$_9$ develops a structural modulation instead at low temperature instead of magnetic order., 34 pages, 8 figures Edits to text as well as figures 2 and 5. Added neutron diffraction (Fig. 6)

Background Statins are effective lipid-lowering drugs for the prevention of cardiovascular disease, but muscular adverse events can limit their use. Hydrophilic statins (pravastatin, rosuvastatin) may cause less muscular events than lipophilic statins (e.g. simvastatin, atorvastatin) due to lower passive diffusion into muscle cells. Objective To compare the risk of muscular events between statins at comparable lipid-lowering doses and to evaluate if hydrophilic statins are associated with a lower muscular risk than lipophilic statins. Design/Setting Propensity score-matched cohort study using data from the United Kingdom-based Clinical Practice Research Datalink (CPRD) GOLD. Patients New statin users. Cohort 1: pravastatin 20-40 mg (hydrophilic) vs simvastatin 10-20 mg (lipophilic), cohort 2: rosuvastatin 5-40 mg (hydrophilic) vs atorvastatin 10-80 mg (lipophilic), and cohort 3: simvastatin 40-80 mg vs atorvastatin 10-20 mg. Main Measures The outcome was a first record of a muscular event (myopathy, myalgia, myositis, rhabdomyolysis) during a maximum follow-up of 1 year. Key Results The propensity score-matched cohorts consisted of 1) 9,703, 2) 7,032, and 3) 37,743 pairs of statin users. Comparing the risk of muscular events between low-intensity pravastatin vs low-intensity simvastatin yielded a HR of 0.86 (95% CI 0.64-1.16). In the comparison of moderate- to high-intensity rosuvastatin vs equivalent doses of atorvastatin, we observed a HR of 1.17 (95% CI 0.88-1.56). Moderate- to high-intensity simvastatin was associated with a HR of 1.33 (95% CI 1.16-1.53), when compared with atorvastatin at equivalent doses. Limitations We could not conduct other pairwise comparisons of statins due to small sample size. In the absence of a uniform definition on the comparability of statin doses, the applied dose ratios may not fully match with all literature sources. Conclusions Our results do not suggest a systematically lower risk of muscular events for hydrophilic statins when compared to lipophilic statins at comparable lipid-lowering doses.

Searching for more sustainable materials as an alternative to petroleum-based products is of increasing interest due to different environmental issues. Cellulose and fatty acids are two very promising candidates for biobased material design. Herein, we report a sustainable synthesis of fatty acid cellulose esters (FACEs) via transesterification of cellulose with methyl-10-undecenoate in a CO

Background Low back pain (LBP) is one of the most common musculoskeletal disorders, causing significant personal and social burden. Current research is focused on the processes of the central nervous system (particularly the sensorimotor system) and body perception, with a view to developing new and more efficient ways to treat chronic low back pain (CLBP). Several clinical tests have been suggested that might have the ability to detect alterations in the sensorimotor system. These include back-photo assessment (BPA), two-point discrimination (TPD), and the movement control tests (MCT). The aim of this study was to determine whether the simple clinical tests of BPA, TPD or MCT are able to discriminate between nonspecific CLBP subjects with altered body perception and healthy controls. Methods A cross-sectional study was conducted. At one point in time, 30 subjects with CLBP and 30 healthy controls were investigated through using BPA, TPD and MCT on the lower back. Correlations among the main covariates and odds ratios for group differences were calculated. Results MCT showed an odds ratio for the presence of CLBP of 1.92, with a statistically significant p-value (0.049) and 95%CI. The TPD and BPA tests were unable to determine significant differences between the groups. Conclusions Of the three tests investigated, MCT was found to be the only suitable assessment to discriminate between nonspecific CLBP subjects and healthy controls. The MCT can be recommended as a simple clinical tool to detect alterations in the sensorimotor system of nonspecific CLBP subjects. This could facilitate the development of tailored management strategies for this challenging LBP subgroup. However, further research is necessary to elucidate the potential of all the tests to detect alterations in the sensorimotor system of CLBP subjects. Trial registration No trial registration was needed as the study contains no intervention. The study was approved by the Swiss Ethics Commission of Northwest and Central Switzerland (EKNZ) reference number 2015–243.

Some insect populations are experiencing dramatic declines, endangering the crucial ecosystem services they provide. Yet, other populations appear robust, highlighting the need to better define patterns and underlying drivers of recent change in insect numbers. We examined abundance and biodiversity trends for North American butterflies using a unique citizen-science dataset that has recorded observations of over 8 million butterflies across 456 species, 503 sites, nine ecoregions, and 26 years. Butterflies are a biodiverse group of pollinators, herbivores, and prey, making them useful bellwethers of environmental change. We found great heterogeneity in butterfly species' abundance trends, aggregating near zero, but with a tendency toward decline. There was strong spatial clustering, however, into regions of increase, decrease, or relative stasis. Recent precipitation and temperature appeared to largely drive these patterns, with butterflies generally declining at increasingly dry and hot sites but increasing at relatively wet or cool sites. In contrast, landscape and butterfly trait predictors had little influence, though abundance trends were slightly more positive around urban areas. Consistent with varying responses by different species, no overall directional change in butterfly species richness or evenness was detected. Overall, a mosaic of butterfly decay and rebound hotspots appeared to largely reflect geographic variability in climate drivers. Ongoing controversy about insect declines might dissipate with a shift in focus to the causes of heterogeneous responses among taxa and sites, with climate change emerging as a key suspect when pollinator communities are broadly impacted.

In the nematic state of iron-based superconductors, twin formation often obscures the intrinsic, anisotropic, in-plane physical properties. Relatively high in-plane external magnetic fields ${H}_{\mathrm{ext}}$ greater than the typical laboratory-scale magnetic fields 10--15 T are usually required to completely detwin a sample. However, recently a very small in-plane ${H}_{\mathrm{ext}}\ensuremath{\sim}0.1$ T was found to be sufficient for detwinning the nematic domains in ${\mathrm{EuFe}}_{2}{\mathrm{As}}_{2}$. To explain this behavior, a microscopic theory based on biquadratic magnetic interactions between the Eu and Fe spins has been proposed. Here, using $^{153}\mathrm{Eu}$ nuclear magnetic resonance (NMR) measurements below the ${\mathrm{Eu}}^{2+}$ ordering temperature, we show experimental evidence of the detwinning under small in-plane ${H}_{\mathrm{ext}}$. Our NMR study also reveals the evolution of the angles between the Eu and Fe spins during the detwinning process, which provides experimental evidence for the existence of biquadratic coupling in the system.

ispartof: ACS SUSTAINABLE CHEMISTRY & ENGINEERING vol:8 issue:43 pages:16046-16047 status: published

Linear uniform oligomers synthesized via a two‐step iterative cycle are postmodified with uniform octaethylene glycol monomethyl ether and finally coupled via azide‐alkyne cycloaddition to yield uniform star‐shaped block macromolecules with a mass ranging from 10 to 14 kDa. Each of the molecules is carefully characterized by NMR, electrospray ionization mass spectrometry (ESI‐MS), and size exclusion chromatography (SEC) to underline their purity as well as their uniformity. The obtained star‐shaped macromolecules are investigated in their ability to encapsulate dye molecules by carrying out qualitative solid–liquid phase transfer experiments.

The magnetic response of $\mathrm{Ca}\mathrm{K}{({\mathrm{Fe}}_{0.949}{\mathrm{Ni}}_{0.051})}_{4}{\mathrm{As}}_{4}$ was investigated by means of the muon spin rotation/relaxation. The long-range commensurate magnetic order sets in below the N\'eel temperature ${T}_{\mathrm{N}}=50.0(5)$ K. The density-functional theory calculations have identified three possible muon stopping sites. The experimental data were found to be consistent with only one type of magnetic structure, namely, the long-range magnetic spin-vortex-crystal order with the hedgehog motif within the $ab$ plane and the antiferromagnetic stacking along the $c$ direction. The value of the ordered magnetic moment at $T\ensuremath{\approx}3$ K was estimated to be ${m}_{\mathrm{Fe}}=0.38(11){\ensuremath{\mu}}_{\mathrm{B}}$ (${\ensuremath{\mu}}_{\mathrm{B}}$ is the Bohr magneton). A microscopic coexistence of magnetic and superconducting phases accompanied by a reduction of the magnetic order parameter below the superconducting transition temperature ${T}_{\mathrm{c}}\ensuremath{\simeq}9$ K is observed. Comparison with 11, 122, and 1144 families of Fe-based pnictides points to existence of correlation between the reduction of the magnetic order parameter at $T\ensuremath{\rightarrow}0$ and the ratio of the transition temperatures ${T}_{\mathrm{c}}/{T}_{\mathrm{N}}$. Such correlations were found to be described by Machida's model for coexistence of itinerant spin-density-wave magnetism and superconductivity [K. Machida, J. Phys. Soc. Jpn. 50, 2195 (1981); S. L. Bud'ko et al., Phys. Rev. B 98, 144520 (2018)].

Quantum interference on the kagome lattice generates electronic bands with narrow bandwidth, called flat bands. Crystal structures incorporating this lattice can host strong electron correlations with nonstandard ingredients, but only if these bands lie at the Fermi level. In the six compounds with the CoSn structure type (FeGe, FeSn, CoSn, NiIn, RhPb, and PtTl) the transition metals form a kagome lattice. The two iron variants are robust antiferromagnets so we focus on the latter four and investigate their thermodynamic and transport properties. We consider these results and calculated band structures to locate and characterize the flat bands in these materials. We propose that CoSn and RhPb deserve the community's attention for exploring flat-band physics.

Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θ_{μe} mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm_{41}^{2}, excluding the 90% C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90% CL_{s} for Δm_{41}^{2}

ispartof: ACS SUSTAINABLE CHEMISTRY & ENGINEERING vol:8 issue:30 pages:11031-11032 status: published

We report the final measurement of the neutrino oscillation parameters $\Delta m^2_{32}$ and $\sin^2\theta_{23}$ using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of $23.76 \times 10^{20}$ protons on target producing $\nu_{mu}$ and $\overline{\nu_\mu}$ beams and 60.75 kt$\cdot$yr exposure to atmospheric neutrinos. The measurement of the disappearance of $\nu_{\mu}$ and the appearance of $\nu_e$ events between the Near and Far detectors yields $|\Delta m^2_{32}|=2.40^{+0.08}_{-0.09}~(2.45^{+0.07}_{-0.08}) \times 10^{-3}$ eV$^2$ and $\sin^2\theta_{23} = 0.43^{+0.20}_{-0.04} ~(0.42^{+0.07}_{-0.03})$ at 68% C.L. for Normal (Inverted) Hierarchy., Comment: 6 pages, 4 figures, 3 tables

Context Patients with type 2 diabetes mellitus (T2DM) have an increased risk of low-trauma fractures. However, the effect of antidiabetic medication in relation to glycemic control on the risk of fracture is poorly understood. Objective This work aimed to evaluate the association between the level of glycemic control, use of antidiabetic medication, and risk of low-trauma fractures in patients with newly diagnosed T2DM. Methods We conducted a nested case-control analysis among individuals registered in the Clinical Practice Research Datalink. The base population consisted of patients with newly diagnosed T2DM from 1995 to 2017. Cases were patients with a low-trauma fracture after T2DM diagnosis. We matched 4 controls to each case. Exposures of interest were glycemic control (last glycated hemoglobin [HbA1c] level before fracture) and type of diabetes treatment. We conducted conditional logistic regression analyses adjusted for several confounders. Results We identified 8809 cases and 35 219 controls. Patients with current metformin use and HbA1c levels of less than 7.0% and between 7.0-8.0% had a reduced risk of fractures (adjusted odds ratio 0.89; 95% CI, 0.83-0.96 and 0.81; 95% CI, 0.73-0.90, respectively) compared with untreated patients. However, in patients receiving metformin plus 1 or 2 other antidiabetic drugs, or insulin (alone or in addition to other antidiabetic medication), the level of glycemic control was not associated with the risk of fracture compared with untreated patients. Conclusions While patients with good or medium glycemic control receiving current metformin monotherapy had a lower risk of fracture compared with untreated patients, glycemic control in patients receiving treatment other than metformin was not associated with risk of fracture.

The synthesis of perfectly defined, monodisperse macromolecules is one of the challenges faced by polymer chemists today. Such precision synthesis requires a fundamentally different approach to conventional polymer synthesis, but in turn can unlock the door to many new applications. Therefore, we introduce here the combination of ultra-fast "click" reactions using 1,2,4-triazoline-3,5-diones (TAD) with the highly efficient and versatile Passerini three-component reaction. This new approach not only resulted in the synthesis of monodisperse, sequence-defined macromolecules of high purity and molecular weight (>7000 Da), but also offered new insights into the iterative synthesis of sequence-defined macromolecules in general, as we present a detailed comparative study of the same chemistry protocols carried out on solid phase as well as in solution.

The upper critical field of multiband superconductors is an important quantity that can reveal details about the nature of the superconducting pairing. Here we experimentally map out the complete upper-critical-field phase diagram of a stoichiometric superconductor, ${\mathrm{CaKFe}}_{4}{\mathrm{As}}_{4}$, up to $90\phantom{\rule{0.16em}{0ex}}\mathrm{T}$ for different orientations of the magnetic field and at temperatures down to $4.2\phantom{\rule{0.16em}{0ex}}\mathrm{K}$. The upper critical fields are extremely large, reaching values close to $\ensuremath{\sim}3\phantom{\rule{0.16em}{0ex}}{T}_{\mathrm{c}}$ at the lowest temperature, and the anisotropy decreases dramatically with temperature, leading to essentially isotropic superconductivity at $4.2\phantom{\rule{0.16em}{0ex}}\mathrm{K}$. We find that the temperature dependence of the upper critical field can be well described by a two-band model in the clean limit with band-coupling parameters favoring intraband over interband interactions. The large Pauli paramagnetic effects together with the presence of the shallow bands is consistent with the stabilization of an FFLO state at low temperatures in this clean superconductor.

In light of fossil fuel depletion and a general necessity for sustainable development, the synthesis of polymers from renewable resources is gaining more and more importance, yet industrially relevant radical polymerizations still struggle with the incorporation of renewable resources as the number of natural molecules containing suitable double bonds is limited. Herein, we present the sustainable synthesis of nonactivated allylic and olefinic carbonate monomers from renewable resources in a solventless one-pot transesterification reaction. We subsequently confirm the first controlled radical copolymerization of such challenging nonactivated monomers with vinyl acetate, in which molecular weights above 10 000 g·mol–1 were reached. The controlled nature of the copolymerizations was verified by the low dispersities obtained and the linear increase in molecular weights with conversion. The so-prepared copolymers were purified using sustainable extractions by supercritical carbon dioxide (scCO2), which allowe...

International audience; As we passed the 20th anniversary of the publication of the 12 principles of green chemistry, the sustainable modification of cellulose, being the most abundant biobased polymer, is certainly worth considering. Many researchers work on an efficient valorization of this renewable resource due to its manifold and promising application possibilities, but very often the use of non-sustainable approaches (i.e., solvents, reactants and modification approaches) only addresses the renewability aspect of cellulose, while neglecting most or all of the other principles of green chemistry. In this review, we have employed the use of E-factors together with basic toxicity information to compare between various approaches for homogeneous cellulose modification. This approach, though simple and certainly not overarching, can provide a quick and useful first sustainability assessment. Therefore, in order to achieve a truly sustainable modification of cellulose, its renewability combined with mild and efficient reaction protocols is crucial in order to obtain sustainable materials that are capable of reducing the overall negative impact of today’s fossil-based polymeric materials.

The sulfoximine group has been reported as a versatile and beneficial functionality for pharmaceutical or agrochemical entities. Herein, we report the Csp2–H sulfoximidation of electron-rich arenes ­under the irradiation of blue light using an organic acridinium photocatalyst and molecular oxygen or peroxodisulfates as terminal oxidants. The method allows for the late-stage introduction of various sulfoximines onto complex bioactive compounds showing high functional group compatibility without the need for prefunctionalization.

Unexplained iron-deficiency anemia is an important marker for colorectal cancer (CRC). Our objectives were as follows: (a) to assess whether the association between anemia and CRC can be detected on the 'Clinical Practice Research Datalink', (b) to evaluate the timing between laboratory changes and CRC detection, and (c) to analyze its association with survival. We conducted a case-control study on patients with an incident CRC diagnosis during 2008-2012 and a 1 : 1-matched control group. We compared anemia markers serum ferritin (SF), hemoglobin (Hb), mean corpuscular volume (MCV), and red blood cell count between cases and controls using conditional logistic regression. We assessed survival in CRC cases. SF values up to 20 ng/ml were associated with an odds ratio [OR (95% confidence interval)] of 10.66 (6.88-16.51) compared with SF values of 101-300 ng/ml when restricted to measurements up to 180 days before the CRC diagnosis. For measurements taken at 1 year or earlier before the diagnosis, the OR was 2.02 (1.57-2.61). For Hb values less than 9 g/dl compared with Hb values of 13.0-15.9 g/dl the corresponding ORs were 74.25 (34.69-158.91) and 2.19 (1.31-3.67), respectively. The corresponding ORs for MCV values up to 80 fl compared with MCV values of 86-95 fl were 13.94 (10.31-18.85) and 1.89 (1.51-2.36), respectively. Low levels of these markers were only weakly associated with survival. Hb, MCV, and SF levels substantially dropped only shortly before the CRC diagnosis. Although slightly more cases had anemia markers compared with controls at 1 year or earlier before the diagnosis, most cases still had normal values. The Clinical Practice Research Datalink is well-suited to detect associations between low Hb, MCV, and SF levels and CRC.

High-grade glioma (HGG) is associated with poor prognosis. Drug repurposing evolves as new modality to improve standard therapy. The antidiabetic drug metformin has been found to inhibit glioma cell growth in vitro and in vivo. The aim of the present retrospective cohort study was to evaluate the survival of patients with HGG with or without treatment with metformin, based on a large cohort of a cancer registry. The analysis included 1,093 patients with HGG diagnosed between 1998 and 2013 from the population-based clinical cancer registry Regensburg (Germany), which covers 2.1 Mio inhabitants and 98% of all cancer diagnoses. We performed multivariable adjusted Cox-regression analyses. Hazard Ratios (HRs) with 95% Confidence Intervals (CIs) for overall survival (OS) and progression-free survival (PFS) of patients with HGG with or without treatment with metformin were obtained. Use of metformin was associated with a significantly better overall and progression-free survival of patients with WHO grade III glioma (HR for OS = 0.30; 95% CI = 0.11-0.81, HR for PFS = 0.29; 95% CI = 0.11-0.78), while there were no significant relations with OS (HR = 0.83; 95% CI = 0.57-1.20) or PFS (HR = 0.85; 95% CI = 0.59-1.22) in patients with WHO grade IV glioma. In conclusion, use of metformin is associated with better overall and progression-free survival of patients with WHO grade III. Possible underlying mechanisms include the higher prevalence of IDH mutations in WHO grade III glioma, which might sensitize to the metabolic drug metformin.

Background The shift from inpatient to ambulatory care has resulted in an increase in home care patients. Little is known regarding medication safety associated with patient transfer from hospital to home care. Objective To evaluate medication-related problems in patients transferring from hospital to home care in Switzerland. Setting A non-for-profit home care organization in the city of Lucerne/Switzerland. Methods We conducted a prospective observational study, including patients aged ≥ 64 years and receiving ≥ 4 medications at hospital discharge. Two structured questionnaires assessing the transfer process were completed by home care nurses. Prescription quality was assessed using a PCNE Type 2b Medication Review. Main outcome measures The quality of the transfer process was measured comparing agreed-upon with reported parameters. Prescription quality was analyzed assessing the unambiguity of the prescription. Potentially inappropriate medications (Priscus® list), contraindications, duplications and interactions, and clinical pharmacist-identified potential medication-related problems were collected. Results Study patients (n = 100) received 8.6 ± 3.5 regularly administered medications. Only 5/100 patients had a complete set of written discharge information. At the time of the first visit, 13/100 patients had no written medication information available. Discharge medication prescriptions were clear to nurses in 62% of patients. In 20 patients, the required medications were unavailable, resulting in 19 medication errors. Assessment by a clinical pharmacist revealed only 33/100 patients had a clear discharge prescription. Of a total of 984 prescribed drugs, 16% were considered to be ambiguous, 22 (2.2%) were potentially inappropriate. 7/984 drugs were contraindicated, 8 were duplicates. Conclusion In addition to the known risk factors in patients transferring from hospital to home care (age, polymedication, multiple providers), 3 major problems impacted upon medication safety: fragmented communication, unreliable medication availability and a poor prescription quality. Clinical pharmacists are an important option to improve medication safety ass.

In rabbits (Oryctolagus cuniculus L.), pododermatitis is a chronic multifactorial skin disease that appears mainly on the plantar surface of the hind legs. In later stages, it causes pain leading to poor welfare of affected animals. Pododermatitis is commonly observed in commercial rabbit production in breeding does housed with wire mesh flooring. However, the prevalence in breeding does that are housed in groups on litter and plastic slats is not known. The aim of this cross-sectional study was to investigate the frequency, the severity and possible risk factors of pododermatitis in group housed breeding does in Switzerland on litter and plastic slats. Between June and September 2016 about 30% of all adult female breeding rabbits (1090 animals in total) were evaluated for the presence and the severity of pododermatitis on 17 commercial rabbit farms with group housing. The latter was done with a tagged visual-analogue-scale. Additionally, various animal-related (e.g. hybrid, age or body weight) and environmental risk factors (e.g. temperature, relative humidity or wet area per pen) known from the literature were recorded. The risk factors were analysed with generalized linear models, additive Bayesian network (ABN) models resulting in directed acyclic graphs (DAGs) and random forests with variable importance plots. On average, 25% of the rabbits displayed ulcerative pododermatitis likely to be painful on at least one hind leg, while the prevalence varied between farms from 4 to 49%. The age, body weight and claw-length of the animals were positively associated with pododermatitis as the most important risk factors. The best model explained 37.4% of the observed variance in the primary outcome measure for pododermatitis. These findings demonstrate that pododermatitis is prevalent in female breeding does even in group housing systems with litter and plastic slats. However, the results of this cross-sectional study also indicate that important risk factors may have been missed or were not recorded precisely enough. Thus, more in-depth research is needed to assess risk factors of pododermatitis in view of effectively preventing the occurrence of this painful disease.

Highly efficient synthesis processes for the selective catalytic oxidation of unsaturated fatty acid methyl esters (FAMEs) are described, leading to valuable renewable platform chemicals. Here keto...

Long-term use of proton pump inhibitors (PPIs) has been associated with an increased risk of Alzheimer’s disease (AD) in observational studies. The role of exposure duration, and whether this applies to other dementia subtypes, has not been explored in these studies. The aim was to study the association between long-term use of PPIs (or of histamine-2 receptor antagonists [H2RAs], as a negative control) and the risk of developing AD or vascular dementia (VaD). We conducted a case–control analysis on the UK-based Clinical Practice Research Datalink (CPRD). We identified 41,029 patients aged ≥ 65 years with newly diagnosed AD or VaD between 1998 and 2015 and matched them 1:1 to dementia-free controls on age, sex, calendar time, general practice, and number of years of recorded history. We applied conditional logistic regression analyses to calculate adjusted odds ratios (aORs), with 95% confidence intervals (CIs), of developing AD or VaD in relation to previous use of PPIs or H2RAs, categorized by exposure duration. As compared to non-use, long-term PPI use (≥ 100 prescriptions) was not associated with an increased risk of developing AD (aOR 0.88, 95% CI 0.80–0.97) or VaD (aOR 1.18, 95% CI 1.04–1.33). Neither was long-term use of H2RAs (≥ 20 prescriptions) associated with an increased risk of developing AD (aOR 0.94, 95% CI 0.87–1.02) or VaD (aOR 0.99, 95% CI 0.89–1.10). In this large, case-control analysis, we did not find any evidence for an increased risk of either AD or VaD related to PPI or H2RA use.

Background/aim GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Materials and methods Transgenic mice, 3D cultures and xenografts were used to examine the effect of mutant GATA3 expression on mammary cell proliferation. Results Mutant GATA3 accelerated tumor growth of ZR751 cell xenografts and promoted precocious lobuloalveolar development in transgenic mouse mammary glands. Conclusion GATA3 mutations, recently observed in breast cancer, encode active transcription factors, which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of ER-positive breast cancer cell lines.

Sequence-defined and information coding macromolecules suitable for data storage materials were synthesized via a combination of two multicomponent reactions. Thus, a well-established protocol based on the Passerini reaction was combined for the first time with the Biginelli reaction for monomer synthesis to explore new sequence-defined materials by exploiting the high structural variety of two multicomponent reactions. The information was encoded via the variation of six different components per repeating unit choosing from a list of more than 100 components that can potentially be applied. The structural variety of the oligomers that can achieved using this approach offers an information density of up to 24 bits per repeat unit. The information was read out via tandem mass spectrometry, wherein the predominant fragmentation processes were identified and subsequently applied for reading out the information contained within several macromolecules, i.e. by sequencing and re-establishing the structure of these macromolecules.

Herein, a novel approach is reported for the synthesis of medium- and long-chain aliphatic polyethers 2 based on the GaBr3 -catalysed reduction of polyesters 1 with TMDS as the reducing agent. Thus, various linear and branched aliphatic polyesters 1 were prepared and systematically investigated for this reduction strategy, demonstrating the applicability and versatility of this new polyether synthesis protocol. Medium- and long-chain chain polyethers were obtained from the respective polyesters without or with minor chain degradation, whereas short-chain polyesters, such as poly-l-lactide 1 i and poly[(R)-3-hydroxybutanoate] 1 j, showed major chain degradation. In this way, previously unavailable and uncommon polyethers were obtained and studied.

Flexor tendon injuries are common and pose a clinical challenge for functional restoration. The purpose of our study was to assess the adequacy of the turkey as a large animal model for flexor tendon injuries in vivo. Twenty-four male turkeys underwent surgical flexor tendon cut and repair. Turkeys were allocated to five groups postoperatively: (1) foot casted in extension and sacrificed after 3 weeks; (2) foot casted in extension and sacrificed after 6 weeks; (3) foot casted in flexion and sacrificed after 3 weeks; (4) foot casted in flexion and sacrificed after 6 weeks; and (5) foot casted in flexion for 6 weeks and then free roaming allowed for an additional 3 weeks before sacrifice. After sacrifice, digits were collected and analyzed for adhesion formation, healing at the macrolevel and histologically, and biomechanical properties-including friction, work of flexion, stiffness, and strength of repair. All turkeys survived anesthesia and surgery. Tendon rupture occurred in all extension casts and in 11% of those casted in flexion. Friction and work of flexion were significantly higher in the repaired digit than the control digit. There was a correlation between duration of immobilization and repair strength. Histologically, the tendon healed with tenocytes migrating into the gap and producing collagen fibers. We have, for the first time, studied flexor tendon injury and repair using turkeys in terms of anesthesia, surgical procedures, postoperative care, and animal husbandry. The findings regarding functional and histological results from this novel avian model were comparable to the most commonly used mammal model. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2497-2505, 2018.

Injuries of the ligaments and tendons of the ankle and foot are among the most common musculoskeletal injuries. A correct and precise description of the pathology and possible accompanying injuries is essential for treatment planning by trauma and orthopedic surgeons. While X‑ray is used to exclude fractures, ultrasound is a very useful tool to assess the ligaments and tendons. For the radiologist, magnetic resonance imaging (MRI) is invaluable regarding the correct assessment of (partial) ruptures, as well as for evaluating accompanying injuries. The aim of the present overview is to provide the most relevant facts for radiologists regarding injuries of ligaments and tendons of the ankle and foot. A description of expected MRI findings and possible pitfalls are presented. For each ligament complex or tendon, we review the anatomy, followed by relevant facts on biomechanics and typical findings in case of injury. The lateral and medial ligament complex, syndesmosis, spring ligament complex, and the Lisfranc ligament are shown in detail. The Achilles tendon and the peroneal tendons are also discussed.

This one-year collaborative study examined the role of narrative in promoting new forms of culturally responsive literacy learning in two contrasting international preschool contexts. The qualitati...

This best-practices article endorses incorporating service-learning into the foundational public speaking course. The article explains connections between service-learning and the rhetorical tradition, highlights pedagogical approaches that would benefit from a service-learning component, and discusses the benefits of service-learning for community partners and students. The remainder of the article focuses on how to implement service learning in a public speaking course, including reflection and assessment recommendations.

Context Exogenous testosterone administration may affect blood clotting, polycythaemia, and may increase atherosclerosis, though any association with cardiovascular events is unclear. While the literature is inconclusive, some studies have suggested testosterone use may increase short-term risk of cardiovascular events and stroke, and injection testosterone may convey higher risks than other dosage forms. Objective We sought to evaluate the short-term cardiovascular risk of receiving injection testosterone. Design We conducted a case-crossover analysis comparing injection testosterone exposure in the 7 days prior to an outcome event to referent windows in the past to estimate the acute association of cardiovascular outcomes with the receipt of testosterone injections. Patients We identified adult male testosterone users hospitalized with myocardial infarction (MI), stroke or a composite of MI, stroke or unstable angina in US commercial claims (2000-2013) or Medicare (2007-2010) databases. Measurements We identified testosterone use for the patients from pharmacy dispensing claims or in-office procedure codes in the insurance billing data. Results We identified 2898 commercially insured men with events and recent testosterone use, and 339 from Medicare. Injected testosterone was associated with an increased risk of adverse events (composite outcome of myocardial infarction, stroke or unstable angina) in the immediate postinjection period for the older, Medicare population only: commercial insurance, odds ratios (OR) = 0.98 (95% confidence intervals [CI]: 0.86-1.12); Medicare, OR = 1.45 (1.07, 1.98). This association was either greatly attenuated or not present when evaluating receipt of any testosterone dosage forms (injection, gel, patch, implant): commercial insurance, OR = 1.01 (0.92, 1.11); Medicare, OR = 1.26 (95% CI: 0.98-1.63). Conclusions Testosterone injections were uniquely associated with short-term risk of acute cardio- and cerebrovascular events in older adult men following injection receipt.

Glycogen debranching enzyme (AGL) and Glycogen phosphorylase (PYG) are responsible for glycogen breakdown. We have earlier shown that AGL is a regulator of bladder tumor growth. Here we investigate the role of AGL in non-small cell lung cancers (NSCLC). Short hairpin RNA (shRNA) driven knockdown of AGL resulted in increased anchorage independent and xenograft growth of NSCLC cells. We further establish that an increase in hyaluronic acid (HA) synthesis driven by Hyaluronic Acid Synthase 2 (HAS2) is critical for anchorage independent growth of NSCLC cells with AGL loss. Using gene knockdown approach against HAS2 and by using 4-methylumbelliferone (4MU), an inhibitor of HA synthesis, we show that HA synthesis is critical for growth of NSCLC cells that have lost AGL. We further show NSCLC cells without AGL expression are dependent on RHAMM for HA signaling and growth. Analysis of NSCLC patient datasets established that patients with low AGL/high HAS2 or low AGL/high RHAMM mRNA expression have poor overall survival compared to patients with high AGL/low HAS2 or high AGL/low RHAMM expression. We show for the first time that loss of AGL promotes anchorage independent growth of NSCLC cells. We further show that HAS2 driven HA synthesis and signaling via RHAMM is critical in regulating growth of these cancer cells with AGL loss. Further patients presenting with low AGL and HAS2 or RHAMM over expressing tumors might present the ideal cohort who would respond to inhibitors of HA synthesis and signaling.

TP53 is the most mutated tumor suppressor gene in human cancers and is a master regulator of a wide array of cellular processes including but not limited to cell cycle progression and DNA damage response. Due to its diverse functions, therapies specifically exploit the vulnerabilities created by TP53 loss remained elusive. We established a panel of TP53 isogenic pair cell line models by knocking out TP53 from WT cell lines and observed that CHK1/2 inhibitor prexasertib showed preferential selectivity toward TP53 KO cell lines. To thoroughly examine additional nodes which could further exploit this selective sensitivity, we carried out genome-wide prexasertib anchor screen in A549 isogenic lines employing CRISPRn, CRISPRi and CRISPRa platforms. From these functional genomics screens, we identified that targeting the anti-folate pathway genes (TYMS, DHFR) showed selective synergy with prexasertib specifically in TP53 KO cells. Secondly, a panel of iron metabolism genes was identified across different CRISPR platforms as candidate TP53 context specific synthetic lethal hits synergize with prexasertib. And lastly, additional sub-context was identified which may inform patient selection strategy for prexasertib as single agent. Citation Format: Teng Teng, Stephen Paik, Shan-chuan Zhao, Ashley Choi, Steven A. Lombardo, Shangtao Liu, Samuel R. Meier, Yi Yu, Jannik N. Anderson, Alan Huang, Fang Li, Xuewen Pan. Isogenic CRISPR anchor screens identified actionable nodes to CHK1/2 inhibitor prexasertib in TP53 mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P095.

Synthetic lethality — the genetic interaction that causes cell death when two genetic deficiencies co-occur but cell survival when each deficiency occurs alone — can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interactions by virtue of their redundant function in the cell. Here we demonstrate a paralog synthetic lethality by targeting VRK1 in VRK2-methylated glioblastoma multiforme (GBM). VRK2 is silenced by methylation in about two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells leads to cell death via cell cycle arrest in G2M and subsequent DNA damage. The lethality is dependent on the kinase activity of VRK1 and is rescued by ectopic VRK2 expression. Knockdown of VRK1 leads to robust tumor growth inhibition in VRK2-methylated glioblastoma xenografts in vivo. These results suggest that inhibiting VRK1 kinase activity could be a viable cancer therapeutic in VRK2-methylated glioblastoma. Citation Format: Julie Shields, Samuel R. Meier, Justin Engel, Madhavi Bandi, Maria L. Dam Ferdinez, Wenhai Zhang, Shan-chuan Zhao, Minjie Zhang, Ashley Choi, Yi Yu, Xuewen Pan, Brian McMillan, Brett Williams, Robert Tjin Tham Sjin, Douglas Whittington, Erik Wilker, Alan Huang, Fang Li, Natasha Emmanuel. VRK1 is a novel synthetic lethal target in VRK2-methylated glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P182.

KRAS is the most frequently mutated oncogene in human tumors and drives tumorigenesis across multiple lineages. Specifically, KRAS is mutated in about 30% of lung cancer and over 90% of pancreatic cancer. Despite recent progress in developing mutant selective KRASG12C inhibitors, patient treatment options for RAS activated cancers remain very limited. Targeting the MAPK pathway by means of MEK and ERK inhibitors has been explored as an alternative strategy for KRAS mutant cancer. However, the clinical benefit is modest due to drug resistance caused by reactivation of the MAPK pathway and potentially other pathways and/or bypass mechanisms. Here we used CRISPR-based screens to identify potential combination therapy targets to enhance trametinib response in KRAS mutant cancers. We screened in five KRAS mutant cell lines of lung and pancreatic lineages and identified both known as well as novel modulators of MEK inhibitor response. Consistent with previous reports, gene knockouts that impair the reactivation of ERK downstream of MEK inhibition scored as top hits in our drop-out screens. Knocking out MAPK1, RAF1, BRAF and PTPN11 sensitized all five cell lines to trametinib treatment supporting these as candidate drug combination targets for MAPK pathway inhibition. Our screens also identified multiple genes within the heparan sulfate pathway (EXT1, EXT2, EXTL3, XYLT2, ALG6, B3GAT3, B4GALT7 and HS2ST1) and the MAPK7 pathway (MAPK7 and MAP2K5) that sensitize multiple but not all cell lines to trametinib. As part of our target discovery platform, we further validated these screening results using various phenotypic assays. Altogether, our results suggest that resistance to MEK inhibitors is driven by reactivation of the MAPK pathway as previously demonstrated and that impairing such reactivation restores the sensitivity of KRAS mutant cancer cells to trametinib. The genetic mechanisms driving the MAPK pathway rebound are likely different in different cancers and understanding such mechanisms will be key for achieving clinical success. Citation Format: Silvia Fenoglio, Aileen M. Cristo, James Tepper, Teng Teng, Samuel R. Meier, Ashley Choi, Hongxiang Zhang, Shan-chuan Zhao, Shangtao Liu, Leanne G. Ahronian, Daniel Aird, Nikitha M. Das, Yi Yu, Robert Tjin Tham Sjin, Jannik N. Andersen, Alan Huang, Fang Li, Xuewen Pan. CRISPR screens identify sensitizers to trametinib in KRAS mutant cancer cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P183.