Positronium Laser Cooling via the 1

We report on laser cooling of a large fraction of positronium (Ps) in free flight by strongly saturating the 1^{3}S-2^{3}P transition with a broadband, long-pulsed 243 nm alexandrite laser. The ground state Ps cloud is produced in a magnetic and electric field-free environment. We observe two different laser-induced effects. The first effect is an increase in the number of atoms in the ground state after the time Ps has spent in the long-lived 2^{3}P states. The second effect is one-dimensional Doppler cooling of Ps, reducing the cloud's temperature from 380(20) to 170(20) K. We demonstrate a 58(9)% increase in the fraction of Ps atoms with v_{1D}<3.7×10^{4} ms^{-1}.

Thoracic impedance pneumography in propofol-sedated patients undergoing percutaneous endoscopic gastrostomy (PEG) placement in gastrointestinal endoscopy: A prospective, randomized trial.

STUDY OBJECTIVE: To assess the efficacy of an ECG-based method called thoracic impedance pneumography to reduce hypoxic events in endoscopy. DESIGN: This was a single center, 1:1 randomized controlled trial. SETTING: The trial was conducted during the placement of percutaneous endoscopic gastrostomy (PEG). PATIENTS: 173 patients who underwent PEG placement were enrolled in the present trial. Indication was oncological in most patients (89%). 58% of patients were ASA class II and 42% of patients ASA class III. INTERVENTIONS: Patients were randomized in the standard monitoring group (SM) with pulse oximetry and automatic blood pressure measurement or in the intervention group with additional thoracic impedance pneumography (TIM). Sedation was performed with propofol by gastroenterologists or trained nurses. MEASUREMENTS: Hypoxic episodes defined as SpO2 < 90% for >15 s were the primary endpoint. Secondary endpoints were minimal SpO2, apnea >10s/>30s and incurred costs. MAIN RESULTS: Additional use of thoracic impedance pneumography reduced hypoxic episodes (TIM: 31% vs SM: 49%; p = 0.016; OR 0.47; NNT 5.6) and elevated minimal SpO2 per procedure (TIM: 90.0% ± 8.9; SM: 84.0% ± 17.6; p = 0.007) significantly. Apnea events >10s and > 30s were significantly more often detected in TIM (43%; 7%) compared to SM (1%; 0%; p < 0.001; p = 0.014) resulting in a time advantage of 17 s before the occurrence of hypoxic events. As a result, adjustments of oxygen flow were significantly more often necessary in SM than in TIM (p = 0.034) and assisted ventilation was less often needed in TIM (2%) compared with SM (9%; p = 0.053). Calculated costs for the additional use of thoracic impedance pneumography were 0.13$ (0.12 €/0.11 £) per procedure. CONCLUSIONS: Additional thoracic impedance pneumography reduced the quantity and extent of hypoxic events with less need of assisted ventilation. Supplemental costs per procedure were negligible. KEY WORDS: thoracic impedance pneumography, capnography, sedation, monitoring, gastrointestinal endoscopy, percutaneous endoscopic gastrostomy.

The measurement of photocathode transverse energy distribution curves (TEDCs) using the transverse energy spread spectrometer (TESS) experimental system.

The minimum achievable particle beam emittance in an electron accelerator depends strongly on the intrinsic emittance of the photocathode electron source. This is measurable as the mean longitudinal and transverse energy spreads in the photoemitted electron beam (MLE and MTE respectively); consequently, MLE and MTE are notable figures of merit for photocathodes used as electron sources in particle accelerators. The overall energy spread is defined by the sum of the MTE and the MLE, and the minimization of MTE is crucial to reduce emittance and thus generate a high-brightness electron beam. Reducing the electron beam emittance in an accelerator that drives a Free-Electron Laser (FEL) delivers a significant reduction in the saturation length for an x-ray FEL, thus reducing the machine's construction footprint and operating costs while increasing the x-ray beam brightness. The ability to measure the transverse energy distribution curve of photoelectrons emitted from a photocathode is a key enabler in photocathode research and development that has prompted the Accelerator Science and Technology Centre (ASTeC) at the STFC Daresbury Laboratory to develop the Transverse Energy Spread Spectrometer to make these crucial measurements. We present details of the design for the upgraded TESS instrument with measured data for copper (100), (110), and (111) single-crystal photocathodes illuminated at UV wavelengths around 266 nm.

Non-invasive beam profile monitor for medical accelerators.

A beam profile monitor based on a supersonic gas-curtain is currently under development for transverse profile diagnostics of electron and proton beams in the High Luminosity LHC. This monitor uses a thin supersonic gas curtain that crosses the primary beam to be characterized under an angle of 45 degrees. The fluorescence caused by the interaction between the beam and gas-curtain is detected using a specially designed imaging system to determine the 2D transverse profile of the primary beam. Another prototype monitor based on beam induced ionization is installed at The Cockcroft Institute. This paper presents the design features of both the monitors, the gas-jet curtain formation and various experimental tests, including profile measurements of an electron beam, using helium, nitrogen and neon as gases. Such a non-invasive online beam profile monitor would be highly desirable also for medical LINAC's and storage rings as it can characterize the beam without stopping machine operation. The paper discusses opportunities for simplifying the monitor design for integration into a medical accelerator and expected monitor performance.

A novel simulation and analysis algorithm for high resolution optical transition radiation imaging.

The use of optical transition radiation (OTR) for charged particle beam imaging is a well-established and commonly used technique. As such, simulations of the images expected from an arbitrary transverse beam profile are important in both the design of such OTR imaging systems and the analysis of the data. However OTR image simulations of high-energy, low-emittance particle beams, that are becoming commonplace within accelerator physics, can be extremely challenging to produce and limited in their account of practical factors. In this paper we systematically show how high-energy OTR image simulations can be carried out using low-energy parameters, whilst providing little deviation in the resulting transverse beam profiles. Simulations require significantly less resources and can be combined with further analysis techniques, which would otherwise be too costly to be practically viable. Using this methodology as a basis for OTR simulations, we present a new method of analyzing OTR transverse beam profile data for high-energy, low-emittance beams. In contrast to previous work, this algorithm includes the effects of a finite bandwidth and directly allows the inclusion of optical effects, such as chromatic aberration.

Measurement of the longitudinal energy distribution of electrons in low energy beams using electrostatic elements.

The Transverse Energy Spread Spectrometer (TESS) was designed primarily to study the mean transverse energy spread of electrons emitted from photocathode electron sources at both room and liquid nitrogen temperatures as a function of quantum efficiency through analysis of the photoemission footprint. By reconfiguring the potentials applied to different detector elements, TESS can also be used to measure the mean longitudinal energy spread of photoemitted electrons. Initial plans were to use electrostatic wire meshes as a retarding element which prevents the detection of electrons with insufficient energy to overcome a variable potential barrier. However, this method has proved impractical and a new method has been proposed in which the photocathode bias potential is swept (effectively from a state of no electron emission to full emission) and the emitted photocurrent is then detected by using a photoemitted charge collector. In this article, we present the TESS set-up and analyze this new method to measure the longitudinal energy distribution curve. Experimental results are presented and compared to simulated results by utilising a custom designed tracking code.

Dual-grating dielectric accelerators driven by a pulse-front-tilted laser.

This paper investigates numerically dual-grating dielectric laser-driven accelerators driven by a pulse-front-tilted (PFT) laser, which extends the interaction length and boosts the electrons' energy gain. The optical system necessary to generate PFT laser beams with an ultrashort pulse duration of 100 fs is also studied in detail. Through two-dimensional particle-in-cell simulations, we show that such a PFT laser effectively increases the energy gain by (91±25) % compared to that of a normally incident laser with a waist radius of 50 µm for a 100-period dual-grating structure.

The efficacy and safety of direct acting antiviral treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection.

BACKGROUND: Direct antiviral therapies for chronic hepatitis C virus (HCV) infection have expanded treatment options for neglected patient populations, including elderly patients who are ineligible/intolerant to receive interferon (IFN)-based therapy. AIM: To investigate the efficacy, tolerability and potential for drug-drug interactions (DDIs) of IFN-free treatment in patients aged ≥65 years in a large real-world cohort. METHODS: A total of 541 patients were treated with different combinations of direct antiviral agents (DAAs: ledipasvir/sofosbuvir ±ribavirin; daclatasvir/sofosbuvir ±ribavirin; paritaprevir/ombitasvir ±dasabuvir ±ribavirin or simeprevir/sofosbuvir ±ribavirin in genotype 1/4, and daclatasvir/sofosbuvir ±ribavirin or sofosbuvir/ribavirin in genotype 2/3). Efficacy, safety and potential DDIs were analysed and compared between patients aged <65 years (n = 404) and patients aged ≥65 years (n = 137) of whom 41 patients were ≥75 years. RESULTS: Sustained virological response rates were 98% and 91% in patients aged ≥65 years and <65 years, respectively. Elderly patients took significantly more concomitant medications (79% vs. 51%; P < 0.0001). The number of concomitant drugs per patient was highest in patients ≥65 years with cirrhosis (median, three per patient; range, 0-10). Based on the hep-druginteractions database, the proportion of predicted clinically significant DDIs was significantly higher in elderly patients (54% vs. 28%; P < 0.0001). The number of patients who experienced treatment-associated adverse events was similar between the two age groups (63% vs. 65%; P = n.s.). CONCLUSIONS: Elderly patients are at increased risk for significant DDIs when treated with DAAs for chronic HCV infection. However, with careful pre-treatment assessment of concomitant medications, on-treatment monitoring or dose-modifications, significant DDIs and associated adverse events can be avoided.

Alveolar and serum concentrations of imipenem in two lung transplant recipients supported with extracorporeal membrane oxygenation.

Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly used in patients with respiratory failure who fail conventional treatment. Postoperative pneumonia is the most common infection after lung transplantation (40%). Imipenem is frequently used for empirical treatment of nosocomial pneumonia in the intensive care unit. Nevertheless, few data are available on the impact of ECMO on pharmacokinetics, and no data on imipenem dosing during ECMO. Currently, no guidelines exist for antibiotic dosing during ECMO support. We report the cases of 2 patients supported with venovenous ECMO for refractory acute respiratory distress syndrome following single lung transplantation for pulmonary fibrosis, treated empirically with 1 g of imipenem intravenously every 6 h. Enterobacter cloacae was isolated from the respiratory sample of Patient 1 and Klebsiella pneumoniae was isolated from the respiratory sample of Patient 2. Minimum inhibitory concentrations of the 2 isolated strains were 0.125 and 0.25 mg/L, respectively. Both patients were still alive on day 28. This is the first report, to our knowledge, of imipenem concentrations in lung transplantation patients supported with ECMO. This study confirms high variability in imipenem trough concentrations in patients on ECMO and with preserved renal function. An elevated dosing regimen (4 g/24 h) is more likely to optimize drug exposure, and therapeutic drug monitoring is recommended, where available. Population pharmacokinetic studies are indicated to develop evidence-based dosing guidelines for ECMO patients.

Modulation of replication efficacy of the hepatitis C virus replicon Con1 by site-directed mutagenesis of an NS4B aminoterminal basic leucine zipper.

The hepatitis C virus (HCV) nonstructural protein 4B (NS4B) is assumed to function as a membrane anchor and protein hub for the viral replication complex. The aim of the current work was to modulate HCV replication efficacy in the subgenomic Con1 replicon by mutations of specific sites within the aminoterminal-located basic leucine zipper (bZIP), a candidate motif for protein-protein interactions involving NS4B. Mutational sites and amino acid substitutes were determined by in-silico sequence analyses of the NS4B-bZIP motif in 357 isolates of HCV genotype 1b from the euHCVdB and LosAlamos database and consecutive analysis of conserved physico-chemical properties at bZIP specific positions. Mutants with predicted minor, medium or major reduction of replication efficacy were tested in the pFKI389neo/NS3-3'/ET plasmid replicon model. Four sites (L25, T29, V39 and W43) of crucial importance for bZIP-mediated protein interaction with predicted apolarity of respective amino acid positions were selected for mutational studies. Substitutes with physico-chemical properties matching the predicted requirements either well (T29A), moderately (L25W, V39W), or insufficiently (T29E, W43E) were associated with slightly improved, moderate and marked decreased replication efficacy, respectively. Spontaneous (T29G) and adaptive (A28G, E40G) mutations occurred in the T29E mutation isolate only and were associated with marked reduction of replication efficacy. The bZIP motif region of NS4B is crucial for RNA replication in the subgenomic Con1 replicon system. RNA replication efficacy can be modulated by site-directed mutagenesis at specific bZIP functional sites. New adaptive amino acid mutations were identified within the HCV NS4B protein.

Clinical relevance of HCV antiviral drug resistance.

The approval of direct-acting antiviral agents (DAAs) against the hepatitis C virus (HCV) NS3 protease revolutionized antiviral therapy in chronic hepatitis C. They mark the beginning of an era with drugs designed to inhibit specific viral proteins involved in the virus life cycle rather than the nonspecific antiviral activity of interferon. Upcoming generations of antivirals are expected that lead to viral eradication in most patients who undergo treatment with hope held for years that HCV can be cured without interferon. Antiviral drug resistance plays a key role in DAA-treatment failure. Knowledge on molecular escape mechanisms of resistant variants, their time to wild-type reversal and potential persistence is of upmost importance to design treatment strategies for patients with previous DAA-treatment failure.

Extension of the measurement capabilities of the quadrupole resonator.

The quadrupole resonator, designed to measure the surface resistance of superconducting samples at 400 MHz has been refurbished. The accuracy of its RF-dc compensation measurement technique is tested by an independent method. It is shown that the device enables also measurements at 800 and 1200 MHz and is capable to probe the critical RF magnetic field. The electric and magnetic field configuration of the quadrupole resonator are dependent on the excited mode. It is shown how this can be used to distinguish between electric and magnetic losses.

Comparison of envelope 2 CD81 binding regions in PBMC-derived versus serum-derived hepatitis C virus isolates: higher conservation of CD81 region 2 in PBMC isolates.

UNLABELLED: The aim of the present study was to investigate the variability of hepatitis C virus (HCV) CD81 binding regions (CD81-1/2) in peripheral blood mononuclear cells (PBMC)-derived and serum-derived HCV-RNA samples. HCV-RNA was isolated from PBMC (104 cells) and serum samples from 37 patients chronically infected with HCV genotype 1a/1b (n=21/16). The hypervariable regions 1/2 (amino acid 384-410, amino acid 474-482) and regions CD81-1/2 (amino acid 474-494, amino acid 522-551) were analysed. Mutational frequency of amino acid sequences was compared between PBMC-derived and serum-derived HCV variants as well as local accumulation of mutations. Furthermore, CD81 was quantified on PBMC. Mutational frequency was not different between PBMC-derived and serum-derived HCV variants. A trend to lower mutational frequency in genotype 1a PBMC variants compared with serum-derived variants was observed in region CD81-2 (5%vs 10%). Smoothed mutational frequency analysis showed a significantly lower variability within genotype 1a CD81-2 in PBMC-derived compared to serum-derived HCV-RNA (P=0.026). CD81 expression on PBMC was not correlated with the number of mutations within the CD81 binding regions. CONCLUSION: A higher conservation was observed in region CD81-2 in PBMC-derived versus serum-derived HCV-RNA indicating selection of HCV variants on PBMC. The variability in the CD81 binding regions appeared to be independent from CD81 expression.

Effect of ribavirin on the frequency of RNase L cleavage sites within the hepatitis C viral genome.

The mechanisms of synergy in antiviral activity of interferon-alpha and ribavirin in treating chronic hepatitis C virus (HCV) infection are still unknown. Interferon-alpha indirectly induces cleavage of viral RNA by RNase L at UU/UA dinucleotides. There is evidence that HCV genomes with a higher number of UU/UA dinucleotides are more sensitive to interferon-alpha. As a guanosine analogue, ribavirin exerts a mutagenic effect promoting G-to-A and C-to-U transitions. This study investigates whether ribavirin-induced mutagenesis causes a higher frequency of UU/UA dinucleotides in the viral progeny sequences. Increased mutational frequencies in favour of G-to-A and C-to-U transitions during ribavirin treatment was reported by Hofmann et al. (Gastroenterology 2007;132:921-930). Overall, 937 nucleotide sequences from that publication were reanalysed for RNase L cleavage sites. These included HCV NS3 quasispecies from three patients with ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone (n = 7) or in combination with interferon-alpha (n = 7) at baseline and during treatment; NS5B quasispecies from a subgenomic HCV replicon system after 24, 48 and 72 h of cultivation with or without ribavirin or with levovirin. For NS3 quasispecies during ribavirin monotherapy and NS5B quasispecies from patients who received ribavirin alone or in combination with interferon-alpha, analysis of RNase L cleavage sites did not reveal changes during treatment or differences between treatment regimes. Similarly, RNaseL cleavage sites from NS5B quasispecies of the HCV replicon did not differ significantly between time points or treatments. In conclusion, Ribavirin-induced mutagenesis did not increase RNase L cleavage sites (UU/UA dinucleotides) within the HCV NS3 or NS5B encoding regions.

Primary actinomycosis of the liver mimicking malignancy.

A 71-year old women presented with fever, a significant loss of body weight and abdominal pain in the upper right quadrant since approximately six months. Abdominal ultrasonography and magnetic resonance imaging (MRI) showed an irregularly shaped, inhomogeneous and hypointense lesion of the right liver lobe (6 x 8 cm in segment 7 and 8) with multiple satellite lesions. Irregular shape, hypovascular presentation during gadolinium enhancement, hypointensity in T 1-weighted images and dilation of peripheral bile ducts were suggestive for cholangiocarcinoma or metastasis. However, histological investigations revealed a rare case of primary actinomycosis of the liver which was successfully treated with antibiotics.

[Myocarditis or subendocardial myocardial infarction: role of MRI illustrated by a case report]. / Myopéricardite ou nécrose sous-endocardique: apport de l'imagerie par résonance magnétique illustré par un cas clinique.

A 50-year-old male patient treated with mesalazine for Crohn's disease was admitted in our unit for a chest pain, associated with nonspecific ST depression or ECG and troponin elevation. Coronarography showed minimal changes while SPECT imagery suggested a posterobasal subendocardial infarction, so that the diagnosis was unclear between ischemic disease and mesalazine-induced myocarditis. Eventually, MRI demonstrated clearly a subendocardial posterior infarction eliciting the diagnosis of mesalazine-induced myocarditis. This case report illustrates, in our opinion, that MRI is of invaluable interest in evaluating the characteristics of myocardium, and must be the cornerstone in the diagnosis of myocardial diseases.

Somatic hypermutation and mRNA expression levels of the BCL-6 gene in patients with hepatitis C virus-associated lymphoproliferative diseases.

Chronic hepatitis C virus (HCV) infection leads to mixed cryoglobulinaemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Aberrant somatic hypermutation and deregulation of the oncogene BCL-6 is associated with lymphomagenesis. Recently, HCV was shown to induce BCL-6 mutations in vitro. The BCL-6 gene (area B) was cloned and sequenced from peripheral blood mononuclear cells (PBMC) of 21 chronically HCV-infected patients with or without MC and B-NHL, and six healthy controls. Mutational frequencies, genetic complexity and diversity were calculated. BCL-6 mRNA from PBMC was quantified by real-time polymerase chain reaction, and additional sustained virologic responders to antiviral therapy and HBV patients served as controls. The overall/recurrent mutational frequencies tended to be lower in MC and B-NHL patients when compared with controls (P = 0.15 and 0.06, respectively). Genetic complexity was significantly lower in MC and B-NHL patients (P = 0.025). BCL-6 mRNA concentration was decreased in all HCV patients when compared with healthy controls, sustained virologic responder and HBV patients (P = 0.005). Although HCV can induce BCL-6 mutations in vitro, lower mutational frequencies and decreased BCL-6 mRNA expression in vivo suggest no major role of aberrant somatic hypermutation in HCV-associated MC and B-NHL.

Correlation of amino acid variations within nonstructural 4B protein with initial viral kinetics during interferon-alpha-based therapy in HCV-1b-infected patients.

Chronic hepatitis C is a major cause of liver cirrhosis leading to chronic liver failure and hepatocellular carcinoma. Different hepatitis C virus (HCV) proteins have been associated with resistance to interferon-alpha-based therapy. However, the exact mechanisms of virus-mediated interferon resistance are not completely understood. The importance of amino acid (aa) variations within the HCV nonstructural (NS)4B protein for replication efficiency and viral decline during the therapy is unknown. We investigated pretreatment sera from 42 patients with known outcome to interferon-based therapy. The complete NS4B gene was amplified and sequenced. Mutational analyses of predicted conformational, functional, structural and phylogenetic properties of the deduced aa sequences were performed. The complete NS4B protein was highly conserved with a median frequency of 0.015 +/- 0.009 aa exchanges (median +/- SD, 4.00 +/- 2.31). Especially within the predicted transmembranous domains of the NS4B protein, the mean number of aa variations was low (median frequency, 0.013 +/- 0.013). Neither the number of aa variations nor specific aa exchanges were correlated with HCV RNA serum concentration at baseline. A rapid initial HCV RNA decline of >/=1.5 log(10) IU/mL at week 2 of interferon-based therapy was associated with a higher frequency of nonconservative aa exchanges within the complete NS4B protein in comparison with patients with a nonrapid HCV RNA decline (median frequency, 0.011 +/- 0.005 vs 0.004 +/- 0.003, P = 0.006). Overall, the aa sequence of the NS4B protein was highly conserved, indicating an important role for replication in vivo. Amino acid variations with relevant changes of physicochemical properties may influence replication efficiency, associated with a rapid early virological response.

Mutations in the putative HCV-E2 CD81 binding regions and correlation with cell surface CD81 expression.

The hepatitis C virus (HCV) envelope (E)2 protein interacts with the cellular receptor CD81 leading to modulation of B and T cell function. Recently, a higher binding affinity of subtype 1a in comparison with 1b derived E2 proteins for CD81 in vitro was described. The importance of mutations within the putative CD81 binding regions of different HCV geno-/subtypes in correlation with CD81 expression is unknown. In the present study, CD81 expression on blood lymphocytes of patients with chronic hepatitis C infected with different HCV geno-/subtypes were analysed by fluorescence activated cell sorter analyses. In addition, the putative CD81 binding regions on the E2 gene comprising the hypervariable region (HVR)2 were analysed by direct sequencing. CD81 expression on CD8(+) T-lymphocytes from patients infected with subtype 1a (n = 6) was significantly higher in comparison with subtype 1b (n = 12) and 3 (n = 5) infected patients before and during antiviral therapy (P = 0.006; P = 0.021, respectively). Sequencing of the putative CD81 binding regions in the E2 protein comprising the HVR2 (codon 474-495 and 522-552 according to the HCV-1a prototype HCV-H) showed a highly conserved motif within HVR2 for subtype 1a isolates and an overall low number of mutations within the putative CD81 binding regions, whereas numerous mutations were detected for subtype 1b isolates (12.0 vs 23.6%). HCV-3 isolates showed an intermediate number of mutations within the putative binding sites (19.2%; P = 0.022). In conclusion, the highly conserved sequence within HVR2 and putative CD81 binding sites of subtype 1a isolates previously associated with a high CD81 binding affinity in vitro is correlated with high CD81 expression on CD8(+) T-lymphocytes in vivo.

High-throughput simultaneous determination of plasma water deuterium and 18-oxygen enrichment using a high-temperature conversion elemental analyzer with isotope ratio mass spectrometry.

This paper presents a high-throughput method for the simultaneous determination of deuterium and oxygen-18 (18O) enrichment of water samples isolated from blood. This analytical method enables rapid and simple determination of these enrichments of microgram quantities of water. Water is converted into hydrogen and carbon monoxide gases by the use of a high-temperature conversion elemental analyzer (TC-EA), that are then transferred on-line into the isotope ratio mass spectrometer. Accuracy determined with the standard light Antartic precipitation (SLAP) and Greenland ice sheet precipitation (GISP) is reliable for deuterium and 18O enrichments. The range of linearity is from 0 up to 0.09 atom percent excess (APE, i.e. -78 up to 5725 delta per mil (dpm)) for deuterium enrichment and from 0 up to 0.17 APE (-11 up to 890 dpm) for 18O enrichment. Memory effects do exist but can be avoided by analyzing the biological samples in quintuplet. This method allows the determination of 1440 samples per week, i.e. 288 biological samples per week.