Granular aluminium nanojunction fluxonium qubit.

Mesoscopic Josephson junctions, consisting of overlapping superconducting electrodes separated by a nanometre-thin oxide layer, provide a precious source of nonlinearity for superconducting quantum circuits. Here we show that in a fluxonium qubit, the role of the Josephson junction can also be played by a lithographically defined, self-structured granular aluminium nanojunction: a superconductor-insulator-superconductor Josephson junction obtained in a single-layer, zero-angle evaporation. The measured spectrum of the resulting qubit, which we nickname gralmonium, is indistinguishable from that of a standard fluxonium. Remarkably, the lack of a mesoscopic parallel plate capacitor gives rise to an intrinsically large granular aluminium nanojunction charging energy in the range of tens of gigahertz, comparable to its Josephson energy. We measure coherence times in the microsecond range and we observe spontaneous jumps of the value of the Josephson energy on timescales from milliseconds to days, which offers a powerful diagnostics tool for microscopic defects in superconducting materials.

Fluorescent annulated imidazo[4,5-c]isoquinolines via a GBB-3CR/imidoylation sequence - DNA-interactions in pUC-19 gel electrophoresis mobility shift assay.

Herein we report the development of a sequential synthesis route towards annulated imidazo[4,5-c]isoquinolines comprising a GBB-3CR, followed by an intramolecular imidoylative cyclisation. X-Ray crystallography revealed a flat 3D structure of the obtained polyheterocycles. Thus, we evaluated their interactions with double-stranded DNA by establishing a pUC-19 plasmid-based gel electrophoresis mobility shift assay, revealing a stabilising effect on ds-DNA against strand-break inducing conditions.

Cost-effectiveness of immediate total-body CT in patients with severe trauma (REACT-2 trial).

BACKGROUND: The effect of immediate total-body CT (iTBCT) on health economic aspects in patients with severe trauma is an underreported issue. This study determined the cost-effectiveness of iTBCT compared with conventional radiological imaging with selective CT (standard work-up (STWU)) during the initial trauma evaluation. METHODS: In this multicentre RCT, adult patients with a high suspicion of severe injury were randomized in-hospital to iTBCT or STWU. Hospital healthcare costs were determined for the first 6 months after the injury. The probability of iTBCT being cost-effective was calculated for various levels of willingness-to-pay per extra patient alive. RESULTS: A total of 928 Dutch patients with complete clinical follow-up were included. Mean costs of hospital care were €25 809 (95 per cent bias-corrected and accelerated (bca) c.i. €22 617 to €29 137) for the iTBCT group and €26 155 (€23 050 to €29 344) for the STWU group, a difference per patient in favour of iTBCT of €346 (€4987 to €4328) (P = 0.876). Proportions of patients alive at 6 months were not different. The proportion of patients alive without serious morbidity was 61.6 per cent in the iTBCT group versus 66.7 per cent in the STWU group (difference -5.1 per cent; P = 0.104). The probability of iTBCT being cost-effective in keeping patients alive remained below 0.56 for the whole group, but was higher in patients with multiple trauma (0.8-0.9) and in those with traumatic brain injury (more than 0.9). CONCLUSION: Economically, from a hospital healthcare provider perspective, iTBCT should be the diagnostic strategy of first choice in patients with multiple trauma or traumatic brain injury.

The design and manufacture of 3D-printed adjuncts for powered air-purifying respirators.

Spurred in part by literature published in the immediate aftermath of the severe acute respiratory syndrome epidemic in 2003, powered air-purifying respirators have seen increased use worldwide during the COVID-19 pandemic. Whereas these devices provide excellent protection of the user, there is an added element of risk during doffing and cleaning of the device. An additional layer of barrier protection, in the form of a polypropylene gown, to be worn over the hood and motor belt, can be used to minimise this risk. However, the device entrains air perpendicular to the lie of the gown, resulting in the impermeable material being sucked into the air intake, and partial occlusion of flow. In this report, we describe a clinical-academic partnership whereby a bespoke filter guard was designed to disrupt airflow and prevent gown entrainment, thereby enabling full barrier protection of both the device and user. This intervention was simple, cheap, scalable and able to be mass produced.

High rates of clinically relevant incidental findings by total-body CT scanning in trauma patients; results of the REACT-2 trial.

OBJECTIVES: To determine whether there is a difference in frequency and clinical relevance of incidental findings detected by total-body computed tomography scanning (TBCT) compared to those by the standard work-up (STWU) with selective computed tomography (CT) scanning. METHODS: Trauma patients from five trauma centres were randomized between April 2011 and January 2014 to TBCT imaging or STWU consisting of conventional imaging with selective CT scanning. Incidental findings were divided into three categories: 1) major finding, may cause mortality; 2) moderate finding, may cause morbidity; and 3) minor finding, hardly relevant. Generalized estimating equations were applied to assess differences in incidental findings. RESULTS: In total, 1083 patients were enrolled, of which 541 patients (49.9 %) were randomized for TBCT and 542 patients (50.1 %) for STWU. Major findings were detected in 23 patients (4.3 %) in the TBCT group compared to 9 patients (1.7 %) in the STWU group (adjusted rate ratio 2.851; 95%CI 1.337-6.077; p < 0.007). Findings of moderate relevance were detected in 120 patients (22.2 %) in the TBCT group compared to 86 patients (15.9 %) in the STWU group (adjusted rate ratio 1.421; 95%CI 1.088-1.854; p < 0.010). CONCLUSIONS: Compared to selective CT scanning, more patients with clinically relevant incidental findings can be expected by TBCT scanning. KEY POINTS: • Total-body CT scanning in trauma results in 1.5 times more incidental findings. • Evaluation by TBCT in trauma results in more patients with incidental findings. • In every category of clinical relevance, TBCT detects more incidental findings.

Investigation of Hungarian mushrooms for antibacterial activity and synergistic effects with standard antibiotics against resistant bacterial strains.

UNLABELLED: This study aimed to screen the antibacterial activity of 160 extracts of 40 mushroom species, collected in Hungary, against 11 standard bacterial strains and 9 clinical isolates. The further objective of this work was to evaluate the capacity of active fungal extracts to potentiate the action of antibiotics against resistant pathogens. Disc-diffusion method was applied for screening of antibacterial activity of extracts. Microdilution method was used to determine minimum inhibitory concentrations. The active extracts were applied to different resistant micro-organisms (multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa, vancomycin-resistant Enterococcus faecium and MRSA), combined with commercial drugs. The synergism between extracts and antibiotics was assessed by double-disc synergy assay and determination of fractional inhibitory concentration (FIC) with checkerboard technique. From 40 mushrooms included in this experiment, 16 species exhibited antibacterial effects with moderate to high potential. In general the chloroform extracts proved to be most active, while the aqueous and aqueous-methanolic extracts demonstrated low or no activity. Fistulina hepatica, Tapinella atrotomentosa (syn. Paxillus atrotomentosus) and Rhodocybe popinalis were the most active species; moreover, they can potentiate the action of cefuroxime against MRSA. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, 160 organic (n-hexane, chloroform and 50% methanol) and aqueous extracts of 40 mushroom species were submitted to antibacterial screening assay. The antibacterial capacity of 18 species has been examined for the first time. Nineteen extracts of 16 species showed antibacterial effects with moderate to high potential. The extracts of Fistulina hepatica, Tapinella atrotomentosa and Rhodocybe popinalis exhibited not only broad antibacterial spectrum, but also synergistic activity with cefuroxime against MRSA. Our screening study proved that mushroom species are promising sources of potential antimicrobial molecules. The results serve as good starting point for selection of fungal species for detailed pharmacological and chemical investigation.

Manual adjustment of tube voltage from 120 to 100 kVp during abdominal CT in patients with body weights ≤75 kg: assessment of image quality and radiation dose in a prospective, randomised trial.

AIM: To assess image quality and radiation dose in patients with body weights ≤75 kg undergoing abdominal computed tomography (CT) with a tube voltage of either 120 or 100 kVp. MATERIALS AND METHODS: Eighty patients weighing ≤75 kg were prospectively assigned to receive either 120 or 100 kVp abdominal CT in the portal-venous phase. Attenuation values of abdominal organs and image noise were measured, and the contrast-to-noise ratios (CNRs) were calculated. Subjective image quality was assessed by three independent radiologists. Radiation exposure was assessed by size-specific dose estimate (SSDE). RESULTS: The mean attenuation of the kidney increased by 20% at 100 kVp (p<0.0001), and the mean image noise was 27% higher in the 100 kVp (p=0.003). The CNR did not significantly differ between the groups (120 kVp, 6.6±2.8; 100 kVp, 7.4±3.6; p=0.26). Except for subjective image noise (p<0.001), no other subjective quality parameters (e.g., contrast, artefacts) were significantly different between the two groups (p between 0.094 and 0.761). The mean SSDE in the 100-kVp group (9.8±1.8 mGy) was reduced by 19% compared to the 120-kVp group (12.1±1.8 mGy; p<0.0001). CONCLUSION: Manual reduction of tube voltage from the standard 120 to 100 kVp for portal-venous phase CT in patients with body weights ≤75 kg resulted in a 19% dose reduction while maintaining objective and subjective image quality.

Activated-platelet targeting of CD39 as a potential way forward. The quest for efficient antithrombotic therapy without associated bleeding complications.

UNLABELLED: Antiplatelet therapy is given to millions of patients and has saved numerous lives. However, it is also associated with complications including fatal bleedings. Clinically used antiplatelet drugs seem to follow the rule of an inherent link of improved anti-thrombotic potency with increased risk of bleeding complications. Therefore, there is an ongoing quest to develop drugs that are able to break this link that has prevented many patients from receiving antiplatelet protection and has resulted in substantial mortality and morbidity. We describe a new antiplatelet approach that is based on an recombinant antibody protein, a drug format that has recently attracted major interest. Two unique components are genetically combined in this molecule: 1) The ecto-nucleoside triphosphate diphosphohydrolase NTPDase CD39, which enzymatically degrades ATP and ADP to AMP, which is then further degraded to adenosine by the endothelially expressed CD73. Thereby, the platelet activating ADP is reduced and replaced by the platelet inhibiting adenosine resulting in a strong antiplatelet effect. 2) A single-chain antibody (scFv) that specifically binds to the activated GPIIb/IIIa receptor and thus allows targeting to activated platelets. The described fusion protein results in strong enrichment of CD39's antiplatelet effect, resulting in potent inhibition of platelet adhesion and aggregation and thrombosis in mice. The activated platelet targeting allows using a low systemic concentration that does not interfere with normal haemostasis and thus does not cause bleeding time prolongation in mice. CONCLUSION: We describe a new antiplatelet approach that promises to deliver strong localized antithrombotic effects without associated bleeding problems.

Comparison of Optimized 3D-SPACE and 3D-TSE Sequences at 1.5T MRCP in the Diagnosis of Choledocholithiasis.

PURPOSE: The aim of the study was to evaluate whether or not MRCP using a 3D-SPACE sequence allows for better image quality and a higher level of diagnostic confidence than a conventional 3D-TSE sequence at 1.5 T regarding the diagnosis of choledocholithiasis in a routine clinical setting. MATERIALS AND METHODS: 3D-SPACE and 3D-TSE sequences were performed in 42 consecutive patients with suspected choledocholithiasis undergoing MRCP. Evaluation of image quality and diagnostic confidence was done on the pancreaticobiliary tree which was subdivided into 10 segments. They were scored and statistically evaluated separately for visibility and diagnostic certainty by three radiologists with differing levels of experience on a five-point scale of 1 to 5 and -2 to 2, respectively. Student t-test was performed, and the interobserver agreement was also calculated. RESULTS: Image quality for each segment was significantly better for the 3D-SPACE sequence compared to the 3D-TSE sequence (4.48 ±â€Š0.94 vs. 3.98 ±â€Š1.20; 5-point scale p < 0.01). Diagnostic confidence for the reporting radiologist was also significantly better for 3D-SPACE than for 3D-TSE (1.68 ±â€Š0.56 vs. 1.46 ±â€Š0.70; 3-point scale; p < 0.01). The interobserver agreement was high in both sequences, 0.62 - 0.83 and 0.64 - 0.82, respectively. CONCLUSION: The optimized 3D-SPACE sequence allows for better image quality in 1.5 T MRCP examinations and leads to a higher diagnostic confidence for choledocholithiasis compared to the conventional 3D-TSE sequence. KEY POINTS: • 3D-SPACE allows for better image quality in 1.5 T MRCP.• This leads to a higher diagnostic confidence particularly in the periampullary region.• 3D-SPACE should be considered to substitute conventional 3D-TSE sequences in clinical routine MRCP.

Pharmacological insight into the anti-inflammatory activity of sesquiterpene lactones from Neurolaena lobata (L.) R.Br. ex Cass.

PURPOSE: Neurolaena lobata is a Caribbean medicinal plant used for the treatment of several conditions including inflammation. Recent data regarding potent anti-inflammatory activity of the plant and isolated sesquiterpene lactones raised our interest in further pharmacological studies. The present work aimed at providing a mechanistic insight into the anti-inflammatory activity of N. lobata and eight isolated sesquiterpene lactones, as well as a structure-activity relationship and in vivo anti-inflammatory data. METHODS: The effect of the extract and its compounds on the generation of pro-inflammatory proteins was assessed in vitro in endothelial and monocytic cells by enzyme-linked immunosorbent assay. Their potential to modulate the expression of inflammatory genes was further studied at the mRNA level. In vivo anti-inflammatory activity of the chemically characterized extract was evaluated using carrageenan-induced paw edema model in rats. RESULTS: The compounds and extract inhibited LPS- and TNF-α-induced upregulation of the pro-inflammatory molecules E-selectin and interleukin-8 in HUVECtert and THP-1 cells. LPS-induced elevation of mRNA encoding for E-selectin and interleukin-8 was also suppressed. Furthermore, the extract inhibited the development of acute inflammation in rats. CONCLUSIONS: Sesquiterpene lactones from N. lobata interfered with the induction of inflammatory cell adhesion molecules and chemokines in cells stimulated with bacterial products and cytokines. Structure-activity analysis revealed the importance of the double bond at C-4-C-5 and C-2-C-3 and the acetyl group at C-9 for the anti-inflammatory activity. The effect was confirmed in vivo, which raises further interest in the therapeutic potential of the compounds for the treatment of inflammatory diseases.

Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.

The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.

Rapid identification of sibutramine in dietary supplements using a stepwise approach.

Adulteration of botanical food supplements with undeclared synthetic drugs is a common problem. One of the most affected product groups are the slimming agents. There are no analytical protocols for the detection of synthetic adulterants from these products. The present study aimed at the development of a multistep analytical method for the quick and reliable determination of sibutramine, one of the most common adulterants among botanical food supplements. The extract of a sibutramine-containing slimming formula was analysed by colour tests, TLC, HPLC-DAD, MS and NMR. The multistep method proposed by the authors allows the quick identification of sibutramine in counterfeit samples in laboratories with different instrumentation.

Metabolic effects of mulberry leaves: exploring potential benefits in type 2 diabetes and hyperuricemia.

The leaves of Morus alba L. have a long history in Traditional Chinese Medicine and also became valued by the ethnopharmacology of many other cultures. The worldwide known antidiabetic use of the drug has been suggested to arise from a complex combination effect of various constituents. Moreover, the drug is also a potential antihyperuricemic agent. Considering that type 2 diabetes and hyperuricemia are vice-versa in each other's important risk factors, the use of mulberry originated phytotherapeutics might provide an excellent option for the prevention and/or treatment of both conditions. Here we report a series of relevant in vitro and in vivo studies on the bioactivity of an extract of mulberry leaves and its fractions obtained by a stepwise gradient on silica gel. In vivo antihyperglycemic and antihyperuricemic activity, plasma antioxidant status, as well as in vitro glucose consumption by adipocytes in the presence or absence of insulin, xanthine oxidase inhibition, free radical scavenging activity, and inhibition of lipid peroxidation were tested. Known bioactive constituents of M. alba (chlorogenic acid, rutin, isoquercitrin, and loliolide) were identified and quantified from the HPLC-DAD fingerprint chromatograms. Iminosugar contents were investigated by MS/MS, 1-deoxynojirimycin was quantified, and amounts of 2-O-alpha-D-galactopyranosyl-1-deoxynojirimicin and fagomine were additionally estimated.

[Comparison of the iCare tonometer with the Goldmann tonometer in Malawi]. / Vergleich des iCare-Tonometers mit dem Goldmann-Tonometer in Malawi.

BACKGROUND: The risk for glaucoma is 4-5 times higher in patients from sub-Saharan Africa. Thus, especially in developing countries an easy and effective method for assessing the intraocular pressure (IOP) is needed. METHODOLOGY: In this hospital-based survey 150 eyes were divided into 3 groups concerning the IOP (group I < 16 mmHg, group II 16-23 mmHg and group III > 23 mmHg) and underwent examination with ultrasound pachymetry followed by iCare tonometry (ICT) and Goldmann applanation tonometry (GAT). Agreement of the measurements by two tonometers was assessed with the Bland-Altman method and the influence of the central corneal thickness (CCT) on the ICT measurements was determined. RESULTS: The mean difference between the IOD measured with GAT and ICT was 0.84 ± 2.63 mmHg. The differences were similar in all three groups (0.77-0.97 mmHg), however, the standard deviation in group III (4.04 mmHg) was greater than in groups I (1.98 mmHg) and II (1.79 mmHg). The mean CCT was 513.51 ± 36.22 µm. CONCLUSIONS: The agreement of measurements by GAT and ICT was good for lower IOP values but less accurate in patients with higher IOP values (group III). A dependency of the CCT on the ICT measurements was observed. In comparison to other countries the lowest CCTs were found in Malawian patients.

Antibacterial properties of compounds isolated from Carpobrotus edulis.

Several compounds isolated from the plant Carpobrotus edulis were evaluated for their activity against multidrug-resistant (MDR) bacteria and their efflux pump systems. Amongst the compounds isolated, six compounds were tested, namely uvaol, ß-amyrin, oleanolic acid, catechin, epicatechin and monogalactosyldiacylglycerol. Oleanolic acid presented high antibacterial activity against a large number of bacterial strains. The triterpene uvaol was the most active compound for modulation of efflux activity by MDR Gram-positive strains.

The effect of Echinacea preparations in three laboratory tests of anxiety: comparison with chlordiazepoxide.

Echinacea preparations are traditionally used to treat upper respiratory infections and inflammations. No psychotropic effects of Echinacea have been reported so far, although some recently reported active constituents are behaviorally active. Prompted by these findings, the anxiolytic potential of five different Echinacea preparations was evaluated. Three of these decreased anxiety but two of them had a very narrow effective dose range. Only one extract decreased anxiety within a wide dose-range (3-8 mg/kg). Anxiolytic effects were consistently seen in three different tests of anxiety, the elevated plus-maze, social interaction and shock-induced social avoidance tests. No locomotor suppressant effects were seen at any dose. Noteworthy, the doses that showed anxiolytic effects in the present study were much lower than those used in the laboratory models of the traditional indications. Chlordiazepoxide robustly decreased anxiety-like behavior in all tests but suppressed locomotion at higher doses. Perceived and real risks of conventional medications increase the demand for alternative therapies, provided that these are safe and efficient. Earlier evidence shows that Echinacea preparations have an excellent safety profile, while our findings suggest for the first time that certain preparations have a considerable anxiolytic potential. Further research is required to identify factors that differentiate efficient and inefficient preparations.

Reversal of multidrug resitance by natural substances from plants.

The multidrug resistance (MDR) proteins that belong to the ATP-binding cassette superfamily such as P-glycoprotein (P-gp) and MRP1, are present in a majority of human tumors and constitute an important cause of therapeutic failure. Selective inhibitors of the MDR-efflux proteins may improve the effectiveness of cancer chemotherapy. Their mechanism of action was believed to be a competition between resistance modifiers and drugs for the same binding site of P-gp. In our previous work we studied modulation of MDR in cancer cells expressing P-gp or MRP1 by selected carotenoids, flavonoids and extracts from medically important Chinese plants. Capsanthin and capsorubin, carotenoids isolated from paprika, were identified as potent P-gp inhibitors, while lycopene, lutein, antheraxanthin and violaxanthin induced moderate effects. Among flavonoids, effective modulators were rotenone, chrysin, phloretin and sakuranetin. Some chloroform extracts of Chinese herbs were also found to inhibit MDR efflux pumps. The effects of the modulators on P-gp activity were studied by measuring rhodamine 123 uptake in several cancer cells such as the human MDR1 gene-transfected mouse lymphoma cells (L1210) and human breast cancer cells MDA-MB-231 expressing the MRP1 pump (HTB26). Additionally, the ability to alter biophysical properties of lipid bilayers by selected carotenoids was studied by differential scanning calorimetry. The antiproliferative effects as well as the MDR reversal activity of the studied compounds, applied in combination with anticancer drugs, were also discussed.

Constituents of Carpobrotus edulis inhibit P-glycoprotein of MDR1-transfected mouse lymphoma cells.

A bioassay-guided separation protocol, including the testing of the extracts, fractions and pure compounds for their ability to inhibit P-glycoprotein (the efflux pump responsible for the multidrug resistance of the used cell line) of mouse lymphoma cells containing the human efflux pump gene MDR1, led to the isolation of seven compounds from the chloroform and ethyl acetate soluble fractions of the methanolic extract of Carpobrotus edulis. The compounds were identified by 1D, 2D NMR and MS investigations as triterpens (beta-amyrin, uvaol and oleanolic acid), monogalactosyldiacylglycerol, catechin, epicatechin and procyanidin B5. Uvaol was the most effective and promising compound in the reversal of multidrug resistance in MDR mouse lymphoma cell line.