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Introduction Serological SARS-CoV-2 assays have an important role in guiding the pandemic response. This research aimed to compare the performance of 2 antinucleocapsid assays. Methods Serum from 49 HCWs was analysed at baseline and 6 months using the Abbott diagnostics SARS-CoV-2 IgG assay and the Roche Diagnostics Elecsys Anti-SARS-CoV-2 total antibody assay. Results At baseline, 14/49 participants (29%) demonstrated antibody reactivity using the Abbott assay. At 6 months, 4/14 participants (29%) continued to demonstrate reactivity. A total of 14/49 (29%) participants had detectable antibodies at baseline using the Roche assay. In total, 13/14 (93%) of participants demonstrated antibody reactivity at 6 months. The Abbott assay showed a statistically significant difference in the signal-to-threshold values of baseline reactive samples when repeated at 6 months (p = 0.001). This was not seen with the Roche assay (p = 0.51). Conclusion In this small study, the Roche Diagnostics Elecsys Anti-SARS-CoV-2 total antibody assay appears superior in performance to the Abbott diagnostics SARS-CoV-2 IgG assay in accurately detecting participants with a history of confirmed COVID-19 disease at 6 months follow-up. This finding should be born in mind in the planning of future seroprevalence studies, especially when considering the use of anti-nucleocapsid assays.

Human herpesvirus 8 (HHV-8) seroprevalence varies geographically and between subpopulations. High seroprevalence rates have been ascribed to men who have sex with men (MSM), African migrants, and HIV-infected individuals. The objective of this study was to determine the seroprevalence of HHV-8 in an Irish population, including specific risk groups. A cross-sectional study of 200 blood donors and 200 genitourinary medicine (GUM) and infectious diseases (ID) clinic patients was performed, with testing for Immunoglobulin G (IgG) antibodies to HHV-8 lytic antigens using a commercial indirect fluorescence assay (Scimedx Corp.). Verification was performed at the Centers for Disease Control and Prevention (CDC). All 200 blood donor samples were negative for HHV-8 IgG antibodies. 21% of GUM and ID patients were positive for HHV-8 IgG antibodies. One hundred of these patients were MSM, 35% of whom were HHV-8 seropositive (46% of HIV-positive MSM and 24% of HIV-negative MSM). Of 100 heterosexual patients, only 7% were HHV-8 seropositive. The absence of seropositivity in 200 Irish blood donors may suggest that Ireland has a low overall population HHV-8 seroprevalence. The proportion of HHV-8 seropositivity in the MSM population was significantly higher than in the heterosexual population and most marked in HIV-positive MSM.

Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to Mtb DnaE1 requires the DNA substrate such that nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on Mtb DnaE1.

Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of

SUMMARYNatural products provide a rich source of potential antimicrobials for use in treating infectious diseases for which drug resistance has emerged. Foremost among these is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to Mtb DnaE1 requires the DNA substrate such that nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on Mtb DnaE1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies are an excellent indicator of past COVID-19 infection. As the COVID-19 pandemic progresses, retained sensitivity over time is an important quality in an antibody assay that is to be used for the purpose of population seroprevalence studies. We compared 5,788 health care worker (HCW) serum samples by using two serological assays (Abbott SARS-CoV-2 anti-nucleocapsid immunoglobulin G (IgG) and Roche anti-SARS-CoV-2 anti-nucleocapsid total antibody) and a subset of samples (all Abbott assay positive or grayzone, n = 485) on Wantai SARS-CoV-2 anti-spike antibody enzyme-linked immunosorbent assay (ELISA). For 367 samples from HCW with a previous PCR-confirmed SARS-CoV-2 infection, we correlated the timing of infection with assay results. Overall, seroprevalence was 4.2% on Abbott and 9.5% on Roche. Of those with previously confirmed infection, 41% (150/367) and 95% (348/367) tested positive on Abbott and Roche, respectively. At 21 weeks (150 days) after confirmed infection, positivity on Abbott started to decline. Roche positivity was retained for the entire study period (33 weeks). Factors associated (P ≤ 0.050) with Abbott seronegativity in those with previous PCR-confirmed infection included sex (odds ratio [OR], 0.30 male ; 95% confidence interval [CI], 0.15 to 0.60), symptom severity (OR 0.19 severe symptoms; 95% CI, 0.05 to 0.61), ethnicity (OR, 0.28 Asian ethnicity; 95% CI, 0.12 to 0.60), and time since PCR diagnosis (OR, 2.06 for infection 6 months previously; 95% CI, 1.01 to 4.30). Wantai detected all previously confirmed infections. In our population, Roche detected antibodies up to at least 7 months after natural infection with SARS-CoV-2. This finding indicates that the Roche total antibody assay is better suited than Abbott IgG assay to population-based studies. Wantai demonstrated high sensitivity, but sample selection was biased. The relationship between serological response and functional immunity to SARS-CoV-2 infection needs to be delineated. IMPORTANCE As the COVID-19 pandemic progresses, retained sensitivity over time is an important quality in an antibody assay that is to be used for the purpose of population seroprevalence studies. There is a relative paucity of published literature in this field to help guide public health specialists when planning seroprevalence studies. In this study, we compared results of 5,788 health care worker blood samples tested by using two assays (Roche and Elecsys, anti-nucleocapsid antibody) and by testing a subset on a third assay (Wantai enzyme-linked immunosorbent assay [ELISA] anti-spike antibody). We found significant differences in the performance of these assays, especially with distance in time from PCR-confirmed COVID-19 infection, and we feel these results may significantly impact the choice of assay for others conducting similar studies.

SARS-CoV-2 antibodies are an excellent indicator of past COVID-19 infection. As the COVID-19 pandemic progresses, retained sensitivity over time is an important quality in an antibody assay that is to be used for the purpose of population seroprevalence studies.We compared 5788 healthcare worker (HCW) serum samples on two serological assays (Abbott SARS-CoV-2 anti-nucleocapsid IgG and Roche Anti-SARS-CoV-2 anti-nucleocapsid Total Antibody) and a subset of samples (all Abbott assay positive or grayzone, n=485) on Wantai SARS-CoV-2 anti-spike Antibody ELISA. For 367 samples from HCW with previous PCR-confirmed SARS-CoV-2 infection we correlated the timing of infection with assay results.Overall seroprevalence was 4.2% on Abbott, 9.5% on Roche. Of those with previously confirmed infection, 41% (150/367) and 95% (348/367) tested positive on Abbott and Roche respectively. At 21 weeks (150 days) after confirmed infection, positivity on Abbott started to decline. Roche positivity was retained for the entire study period (33 weeks). Factors associated (P≤ 0.050) with Abbott seronegativity in those with previous PCR-confirmed infection included sex (male OR0.30;95%CI0.15-0.60), symptom severity (OR0.19 severe symptoms;95%CI0.05-0.61), ethnicity (OR0.28 Asian ethnicity;95%CI0.12-0.60) and time since PCR diagnosis (OR2.06 for infection 6 months previously;95%CI1.01-4.30. Wantai detected all previously confirmed infections.In our population, Roche detected antibodies up to at least seven months after natural infection with SARS-CoV-2. This may indicate that Roche is better suited than Abbott to population-based studies. Wantai demonstrated high sensitivity but sample selection was biased. The relationship between serological response and functional immunity to SARS-CoV-2 infection needs to be delineated.

A code to study beam power deposition on the internal components of the DIII-D and EAST neutral beamlines has been developed. The predictions that the code makes are found to be in good agreement with water flow calorimetry measurements for all components except the magnet region. The code is used to predict the power loading on new components being designed for a major beamline upgrade. The shortcomings of the code’s treatment of the magnet region are addressed by utilizing a particle trajectory tracing code and invoking the hypothesis that incomplete space charge neutralization is responsible for the discrepancy.

On the DIII-D National Fusion Facility tokamak plasma diagnostics continue to improve and experiments increase in complexity. Hence the utility of dynamic control of the beam energy (and therefore also the injected torque, ion heating fraction, etc.) has become apparent. Here we report on upgrades that have been incorporated into the DIII-D Plasma Control System (PCS) and Neutral Beam Injection (NBI) systems in order to allow the beam acceleration voltage (Vaccel) to be varied continuously in a ≤20 kV range during a shot for the first time, generating new capabilities such as smooth plasma transitions and controllable interactions with Alfven waves.

BackgroundWe initiated an emergency department (ED) opt-out screening programme for HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) at our hospital in Dublin, Ireland. The objective of this study was to determine screening acceptance, yield and the impact on follow-up care.MethodsFrom July 2015 through June 2018, ED patients who underwent phlebotomy and could consent to testing were tested for HIV, HBV and HCV using an opt-out approach. We examined acceptance of screening, linkage to care, treatment and viral suppression using screening programme data and electronic health records. The duration of follow-up ranged from 1 to 36 months.ResultsOver the 36-month study period, there were 140 550 ED patient visits, of whom 88 854 (63.2%, 95% CI 63.0% to 63.5%) underwent phlebotomy and 54 817 (61.7%, 95% CI 61.4% to 62.0%) accepted screening for HIV, HBV and HCV, representing 41 535 individual patients. 2202 of these patients had a positive test result. Of these, 267 (12.1%, 95% CI 10.8% to 13.6%) were newly diagnosed with an infection and 1762 (80.0%, 95% CI 78.3% to 81.7%) had known diagnoses. There were 38 new HIV, 47 new HBV and 182 new HCV diagnoses. 81.5% (95% CI 74.9% to 87.0%) of known patients who were not linked were relinked to care after screening. Of the new diagnoses, 86.2% (95% CI 80.4 to 90.8%) were linked to care.ConclusionAlthough high proportions of patients had known diagnoses, our programme was able to identify many new infected patients and link them to care, as well as relink patients with known diagnoses who had been lost to follow-up.

The standard of care for fit patients with Mantle Cell Lymphoma (MCL) includes cytarabine containing induction treatment and consolidation with BEAM (Carmustine, Etoposide, Cytarabine and Melphalan). Chemo-refractory cases have a poorer prognosis and are candidates for allogenic stem cell transplantation (allo-SCT). Targeted therapy, such as BTK-inhibitors or BCL-mimetics can be used to bridge patients to SCT. COVID-19, a novel coronavirus has the potential to cause life threatening immune dysregulation and cytokine release syndrome (CRS) resulting in respiratory failure. Haematology patients, particularly post allogenic stem cell transplant, are high risk for developing CRS due to T-lymphopenia. PD, a 55-year-old male, with chemo-refractory MCL tested positive for COVID-19 day + 45 post allo-SCT after presenting with mild gastrointestinal symptoms and remained positive for 70 days. At day + 92 relapse was confirmed by CT and axillary node biopsy. Ibrutinib, a BTK inhibitor, was commenced with resolution of symptoms and a negative test within 20 days. With minimal reduction in adenopathy, Ibrutinib was stopped at day +110, while Cytarabine and Venetoclax (BCL-mimetic) were commenced with Donor lymphocyte infusion at day +145 resulting in complete remission. Ibrutinib’s therapeutic role against COVID-19 is now being investigated in clinical trials.

The Hepatitis B vaccine is highly effective for the prevention of hepatitis B (HBV) infection. We report the development of chronic HBV infection (Genotype F) in a vaccinated immunocompetent individual with an anti-HBsAb of 35 mIU/mL post completion of vaccine series. HBV vaccine is based on recombinant proteins of genotype-A and D (predominant genotypes in Europe). It may not be as effective for the prevention of more genetically diverse viruses such as genotype F (predominant genotype in Central and South America). Healthcare providers and patients should be aware that the HB vaccine does not confer 100% protection against HBV infection, even in the setting of protective antibody levels. Partners of individuals infected with non-A or -D genotypes should be advised to consider additional precautions to prevent transmission even in the setting protective antibody levels. Surveillance of circulating HBV genotypes should be undertaken to inform public health policy in relation to prevention of HB in high-risk groups such as men who have sex with men.

In this paper, we present the results of beam physics experimental and modeling efforts aimed at learning from and building on the experience of the DIII-D off-axis neutral beam upgrade and other neutral beam system upgrades such as those at JET. The modeling effort includes electrostatic accelerator modeling (using a Poisson solver), gas dynamics modeling for the neutralizer and beam transport models for the beamline. Experimentally, spectroscopic and calorimetric techniques are used to evaluate the system performance. We seek to understand and ameliorate problems such as anomalous power deposition, originating from misdirected or excessively divergent beam particles, on a number of beamline components. We qualitatively and quantitatively evaluate possible project risks such as neutralization efficiency deficit and high voltage hold off associated with increasing the beam energy up to 105 keV.

Central venous catheter (CVC) tip cultures are useful in the assessment of a patient with a potential catheter-related bloodstream infection (CRBSI). However, these results can be misleading particularly in the absence of concomitant peripheral and central line blood cultures. Catheter tip cultures should not be submitted to the laboratory unless CRBSI is suspected as the predictive value of culture results depends on the pretest probability of CRBSI. A positive CVC tip culture does not usually warrant further investigation or therapy (except in the case of Staphylococcus aureus and possibly Candida sp) while a negative catheter tip culture in isolation does not definitively exclude CRBSI. Clinicians can use alternative criteria for the diagnosis of CRBSI that do not require catheter tip cultures if necessary. Further research into the significance of CVC tip cultures in the absence of concomitant bacteraemia is required.

New results from MAST are presented that focus on validating models in order to extrapolate to future devices. Measurements during start-up experiments have shown how the bulk ion temperature rise scales with the square of the reconnecting field. During the current ramp up models are not able to correctly predict the current diffusion. Experiments have been performed looking at edge and core turbulence. At the edge detailed studies have revealed how filament characteristic are responsible for determining the near and far SOL density profiles. In the core the intrinsic rotation and electron scale turbulence have been measured. The role that the fast ion gradient has on redistributing fast ions through fishbone modes has led to a redesign of the neutral beam injector on MAST Upgrade. In H-mode the turbulence at the pedestal top has been shown to be consistent with being due to electron temperature gradient modes. A reconnection process appears to occur during ELMs and the number of filaments released determines the power profile at the divertor. Resonant magnetic perturbations can mitigate ELMs provided the edge peeling response is maximised and the core kink response minimised. The mitigation of intrinsic error fields with toroidal mode number n>1 has been shown to be important for plasma performance., 34 pages, 10 figures. This is an author-created, un-copyedited version of an article submitted for publication in Nuclear Fusion. IoP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it

Objectives Studies suggest 2 per 1000 people in Dublin are living with HIV, the level above which universal screening is advised. We aimed to assess the feasibility and acceptability of a universal opt-out HIV, Hepatitis B and Hepatitis C testing programme for Emergency Department patients and to describe the incidence and prevalence of blood-borne viruses in this population. Methods An opt-out ED blood borne virus screening programme was piloted from March 2014 to January 2015. Patients undergoing blood sampling during routine clinical care were offered HIV 1&2 antibody/antigen assay, HBV surface antigen and HCV antibody tests. Linkage to care where necessary was co-ordinated by the study team. New diagnosis and prevalence rates were defined as the new cases per 1000 tested and number of positive tests per 1000 tested respectively. Results Over 45 weeks of testing, of 10,000 patient visits, 8,839 individual patient samples were available for analysis following removal of duplicates. A sustained target uptake of >50% was obtained after week 3.97(1.09%), 44(0.49%) and 447(5.05%) HIV, Hepatitis B and Hepatitis C tests were positive respectively. Of these, 7(0.08%), 20(0.22%) and 58(0.66%) were new diagnoses of HIV, Hepatitis B and Hepatitis C respectively. The new diagnosis rate for HIV, Hepatitis B and Hepatitis C was 0.8, 2.26 and 6.5 per 1000 and study prevalence for HIV, Hepatitis B and Hepatitis C was 11.0, 5.0 and 50.5 per 1000 respectively. Conclusions Opt-out blood borne viral screening was feasible and acceptable in an inner-city ED. Blood borne viral infections were prevalent in this population and newly diagnosed cases were diagnosed and linked to care. These results suggest widespread blood borne viral testing in differing clinical locations with differing population demographic risks may be warranted.

BK polyomavirus (family Polyomaviridae) may cause hemorrhagic cystitis (BKV-HC) in hematopoietic stem cell transplant recipients. Eleven complete BKV genomes (GenBank accession numbers: JN192431-JN192441) were sequenced from urine samples of allogenic hematopoietic stem cell transplant recipients and compared to complete BKV genomes in the published literature. Of the 11 isolates, seven (64%) were subgroup Ib-1, three (27%) isolates belonged to subgroup Ib-2 and a single isolate belonged to subtype III. The analysis of single-nucleotide polymorphisms in this study showed that isolates could be subclassified into subtypes I–IV and subgroups Ib-1 and Ib-2 on the basis of VP1 of the first part of the Large T-antigen (LTag). The non-coding control region (NCCR) of the 11 isolates was also sequenced. These sequences showed that there was consistent sequence homology within subgroups Ib-1 and Ib-2. Two new mutations were described in the isolates, GC at O84 in isolate SJH-LG-310, and a deletion at R2-7 in isolate SJH-LG-309. No known transcription factor is thought to be present at the site of either of these mutations. There were no rearrangements seen in isolates and this may be because the patients were not followed up over time. There were five nucleotide positions at which subgroup Ib-1 isolated differed from subgroup Ib-2 isolates in the NCCR sequence, O41, P18, P31, R4, and S18. The mutation O41 is present in the promoter granulocyte/macrophage stimulating factor) gene and the P31 mutation is present in the NF-1 gene. J. Med. Virol. 84: 1037–1048, 2012. © 2012 Wiley Periodicals, Inc.

Electron and ion heating characteristics during merging reconnection start-up on the MAST spherical tokamak have been revealed in detail using a 130 channel yttrium aluminum garnet (YAG) and a 300 channel Ruby-Thomson scattering system and a new 32 chord ion Doppler tomography diagnostic. Detailed 2D profile measurements of electron and ion temperature together with electron density have been achieved for the first time and it is found that electron temperature forms a highly localized hot spot at the X point and ion temperature globally increases downstream. For the push merging experiment when the guide field is more than 3 times the reconnecting field, a thick layer of a closed flux surface form by the reconnected field sustains the temperature profile for longer than the electron and ion energy relaxation time ~4-10 ms, both characteristic profiles finally forming a triple peak structure at the X point and downstream. An increase in the toroidal guide field results in a more peaked electron temperature profile at the X point, and also produces higher ion temperatures at this point, but the ion temperature profile in the downstream region is unaffected.

The JET neutral beam injection (NBI) system is undergoing an upgrade of both beam power and pulse duration, which will be completed in 2011. In order to obtain an early assessment of the performance of the upgraded injectors, two positive ion neutral injectors (PINIs) with modified ion source and accelerator configuration were installed on Octant 8 Neutral Injector Box and successfully commissioned in summer 2009. Both PINIs were routinely delivering ∼2 MW of deuterium neutral beam power during the JET experimental campaign in autumn 2009. These early tests allowed us to predict with confidence that the JET NBI upgrade objective of injecting 34 MW of total deuterium neutral beam power into the JET plasma will be achieved.

Recent advances in the development of the copper facilitated Suzuki–Miyaura reaction are described. Improvements include expansion of substrate scope to include aryl chlorides and polyhalo aryl boronates. It was found that use of S-Phos and X-Phos could accomplish the coupling of 2-pyridyl boronates to aryl chlorides and bromides in shorter reaction times and in higher yield than previously described with DPPF.

An engineering upgrade to the neutral beam system at the DIII-D tokamak [J. L. Luxon, Nucl. Fusion 42, 614 (2002)] enables time-dependent programming of the beam voltage and current. Initial application of this capability involves pre-programmed beam voltage and current injected into plasmas that are known to be susceptible to instabilities that are driven by energetic ( E ≥ 40 keV) beam ions. These instabilities, here all Alfven eigenmodes (AEs), increase the transport of the beam ions beyond a classical expectation based on particle drifts and collisions. Injecting neutral beam power, P beam ≥ 2 MW, at reduced voltage with increased current reduces the drive for Alfvenic instabilities and results in improved ion confinement. In lower-confinement plasmas, this technique is applied to eliminate the presence of AEs across the mid-radius of the plasmas. Simulations of those plasmas indicate that the mode drive is decreased and the radial extent of the remaining modes is reduced compared to a higher beam voltage case. In higher-confinement plasmas, this technique reduces AE activity in the far edge and results in an interesting scenario of beam current drive improving as the beam voltage reduces from 80 kV to 65 kV.An engineering upgrade to the neutral beam system at the DIII-D tokamak [J. L. Luxon, Nucl. Fusion 42, 614 (2002)] enables time-dependent programming of the beam voltage and current. Initial application of this capability involves pre-programmed beam voltage and current injected into plasmas that are known to be susceptible to instabilities that are driven by energetic ( E ≥ 40 keV) beam ions. These instabilities, here all Alfven eigenmodes (AEs), increase the transport of the beam ions beyond a classical expectation based on particle drifts and collisions. Injecting neutral beam power, P beam ≥ 2 MW, at reduced voltage with increased current reduces the drive for Alfvenic instabilities and results in improved ion confinement. In lower-confinement plasmas, this technique is applied to eliminate the presence of AEs across the mid-radius of the plasmas. Simulations of those plasmas indicate that the mode drive is decreased and the radial extent of the remaining modes is reduced compared to a higher b...

The JET neutral beam (NB) heating system is being upgraded as a part of the ongoing JET Enhancement Programme. This is one of the largest upgrades of the JET machine carried out within the EFDA-JET framework. The main goals of the project are to increase the NB power delivered to JET plasma, to increase the beam pulse duration and to improve the availability and reliability of the JET NB system. The upgrade of the system is being carried out through the modification of the two existing neutral injector boxes (NIBs), each equipped with up to eight positive ion neutral injectors (PINIs). Significant changes of the JET NB system will be carried out within the next few years and will include modification of all PINIs, modification or replacement of various beamline components and corresponding instrumentation, procurement and installation of new high voltage power supply (HVPS) units and corresponding control systems and refurbishment of the 36 kV power distribution. Various physics, engineering and planning issues related to this project, as well as the current status of the project are discussed in detail. Particular attention is given to the results of a PINI prototype test, which are of crucial importance for the successful completion of the entire enhancement programme. Upon the completion of the project in 2009/2010, JET NB system should be capable of delivering more than 34 MW of deuterium beam power into the JET plasma for a duration of up to 20 s with improved reliability. This will significantly enhance overall capabilities of the JET machine in support of ITER development.

To realise a high yield H− (or D−) ion source capable of long pulse operation for the ITER neutral beam heating system, it is vital to understand and optimise the plasma parameters in the ion source. Calculating the electron energy distribution function (EEDF) in a non-Maxwellian plasma using conventional Langmuir probe numerical techniques is prone to error and generally produces poor results. Using a technique developed by Boyd and Twiddy [R.L.F. Boyd, N.D. Twiddy, Proc. R. Soc. A 53 (1959) 250] in the 1950s a new Langmuir probe system has been developed. This paper presents a detailed account of the experimental method, apparatus, software and analysis. The impact of the development is demonstrated by comparing data obtained from the ITER Negative Ion Beam Development Test Stand at CEA Cadarache using this method with similar data obtained with conventional methods.

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).

We report on a study of the neutralization process in the DIII-D neutral beam system. Measurements of the neutralization efficiency are compared to theoretically predicted values and the potential for neutralization efficiency deficit is explored. A molecular spectroscopic technique is used to measure the neutralizer gas temperature and the results are used in a Monte-Carlo mode to study the neutralizer gas dynamics.

The Small Negative Ion Facility (SNIF) at CCFE has been undergoing continuous development and enhancement to both improve operational reliability and increase diagnostic capability. SNIF uses a CW 13.56MHz, 5kW RF driven volume source with a 30kV triode accelerator. Improvement and characterisation work includes: Installation of a new “L” type RF matching unit, used to calculate the load on the RF generator. Use of the electron suppressing biased insert as a Langmuir probe under different beam extraction conditions. Measurement of the hydrogen Fulcher molecular spectrum, used to calculate gas temperature in the source. Beam optimisation through parameter scans, using copper target plate and visible cameras, with results compared with AXCEL-INP to provide beam current estimate. Modelling of the beam power density profile on the target plate using ANSYS to estimate beam power and provide another estimate of beam current. This work is described, and has allowed an estimation of the extracted beam current of approximately 6mA (4mA/cm2) at 3.5kW RF power and a source pressure of 0.6Pa.

The Mega Ampère Spherical Tokamak (MAST) programme is strongly focused on addressing key physics issues in preparation for operation of ITER as well as providing solutions for DEMO design choices. In this regard, MAST has provided key results in understanding and optimizing H-mode confinement, operating with smaller edge localized modes (ELMs), predicting and handling plasma exhaust and tailoring auxiliary current drive. In all cases, the high-resolution diagnostic capability on MAST is complemented by sophisticated numerical modelling to facilitate a deeper understanding. Mitigation of ELMs with resonant magnetic perturbations (RMPs) with toroidal mode number n RMP = 2, 3, 4, 6 has been demonstrated: at high and low collisionality; for the first ELM following the transition to high confinement operation; during the current ramp-up; and with rotating n RMP = 3 RMPs. n RMP = 4, 6 fields cause less rotation braking whilst the power to access H-mode is less with n RMP = 4 than n RMP = 3, 6. Refuelling with gas or pellets gives plasmas with mitigated ELMs and reduced peak heat flux at the same time as achieving good confinement. A synergy exists between pellet fuelling and RMPs, since mitigated ELMs remove fewer particles. Inter-ELM instabilities observed with Doppler backscattering are consistent with gyrokinetic simulations of micro-tearing modes in the pedestal. Meanwhile, ELM precursors have been strikingly observed with beam emission spectroscopy (BES) measurements. A scan in beta at the L–H transition shows that pedestal height scales strongly with core pressure. Gyro-Bohm normalized turbulent ion heat flux (as estimated from the BES data) is observed to decrease with increasing tilt of the turbulent eddies. Fast ion redistribution by energetic particle modes depends on density, and access to a quiescent domain with ‘classical’ fast ion transport is found above a critical density. Highly efficient electron Bernstein wave current drive (1 A W−1) has been achieved in solenoid-free start-up. A new proton detector has characterized escaping fusion products. Langmuir probes and a high-speed camera suggest filaments play a role in particle transport in the private flux region whilst coherence imaging has measured scrape-off layer (SOL) flows. BOUT++ simulations show that fluxes due to filaments are strongly dependent on resistivity and magnetic geometry of the SOL, with higher radial fluxes at higher resistivity. Finally, MAST Upgrade is due to begin operation in 2016 to support ITER preparation and importantly to operate with a Super-X divertor to test extended leg concepts for particle and power exhaust.

An effective synthesis of [Psi[CH(2)NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K(a) = 5.2 x 10(3) M(-1)) and a 35-fold reduction in affinity for D-Ala-D-Ala (K(a) = 4.8 x 10(3) M(-1)), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 microg/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to d-Ala-d-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics.

The reduction in neutralisation efficiency of positive ion beams compared to theoretical calculations has been acknowledged for some time. The effect has been ascribed to a depletion of the gas target in the neutraliser, although the cause of this has been the subject of debate. Recent measurements in the neutraliser of the JET neutral beam injection (NBI) system showed a significant increase of the gas temperature, supporting the gas heating hypothesis. This work presents direct measurement, by two methods, of the power contained in the neutral component of the JET neutral beam injection system that confirms the neutralisation shortfall. A calorimetric technique is used to compare the power within the full (i.e. ions and neutrals) and neutral beam components for the high current JET triode injectors, from which the effective gas target can be derived. The results of these measurements are confirmed by considering the response to neutral beam injection of the energy stored in the tokamak plasma. Finally, the gas heating model, combined with earlier measurements of the gas temperature in the neutraliser, is used to support the hypothesis that the target depletion is due to indirect heating of the neutraliser gas by the beam.

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF,/=95%) and diastereoselective (/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.

Neutralisation efficiency is an important issue in the design of neutral beam injection (NBI) systems for heating and fuelling fusion plasmas. The JET Neutral Beam Injectors system does not reach the efficiency that is expected on the basis of current understanding of the neutralisation process. If this neutralisation efficiency deficit could be eliminated by re-design of the neutralisers, additional neutral beam heating power would become available. The interaction of the high-energy beam ions and the gas in the neutraliser cell results in the partial neutralisation of the beam and also in the formation of a low temperature plasma inside the neutraliser. The interaction between this plasma, the neutral gas and the walls of the cell can give rise to various phenomena capable of depleting the neutral gas molecular density hence reducing the effective neutralisation target. This paper presents the results of a number of experiments that were carried out in order to measure the plasma and gas parameters inside the neutraliser. The plasma parameters were obtained using a combination of planar Langmuir probes and a novel electrical diagnostic called a ‘plasma eater’. The gas pressure was measured using hot cathode ionisation gauges and capacitance manometers. An attempt has been made to measure the neutral hydrogen gas temperature using a spectroscopic technique that requires the measurement of the intensities of the spectral lines of the hydrogen Fulcher-α system [Plasma Sources Sci. Technol. 10 (2001) 17].

The first measurement of an elevated temperature of the target gas in a neutralizer cell, resulting from interaction with the beam, is reported. Effects unique to the beam-plasma system in the neutralizer are considered with particular reference to the relevance of the experimental spectroscopic analysis technique. The gas is found to reach temperatures up to 900 K for operation with multi-megawatt positive ion beams.

In the last three years, magnetic reconnection research in the MAST spherical tokamak achieved major progress by the use of new 32 chord ion Doppler tomography and 130 channel YAG and 300 channel Ruby Thomson scattering diagnostics. In addition to the previously achieved high power plasma heating during merging, detailed full temperature profile measurements including the diffusion region have been achieved for the first time. 2D imaging measurements of ion and electron temperature profiles have revealed that magnetic reconnection mostly heats ions globally in the downstream region of outflow jet and electrons locally around the X-point. The toroidal field in MAST “over 0.3T” strongly inhibits cross-field thermal transport, and the characteristic peaked electron temperature profile around the X-point is sustained on a millisecond time scale. In contrast, ions are mostly heated in the downstream region of outflow acceleration and around the stagnation point formed by reconnected flux mostly by viscosity di...

Electrodeless radiofrequency discharges exhibit two modes of operation: a low-density mode in which the power is capacitively coupled to the plasma and which is known as the E-mode, and a higher density mode which is an inductive discharge known as the H-mode. The transition between these modes exhibits hysteresis, i.e. the E to H transition occurs at a different coil current than the reverse H to E transition. Recent theoretical results show that the hysteresis can be qualitatively understood in terms of electron power balance assuming that either the power dissipated or the power absorbed by the plasma electrons has a nonlinear dependence on the electron density. Experiments have been carried out to examine this hypothesis, both by characterizing steady-state E- and H-mode plasmas with a Langmuir probe, and by using a new approach consisting of measuring the internal plasma parameters in a pulsed discharge. In the latter case, the power is time modulated with increasing and decreasing power ramps. This approach allows us to investigate the hysteresis in detail and to study the dynamics of the transition. A number of time-resolved diagnostics including Langmuir probes, current and voltage sensors, optical emission and B-dot probes have been used.

A Fast Ion Deuterium Alpha (FIDA) spectrometer was installed on MAST to measure radially resolved information about the fast ion density and its distribution in energy and pitch angle. Toroidally and vertically-directed collection lenses are employed, to detect both passing and trapped particle dynamics, and reference views are installed to subtract the background. This background is found to contain a substantial amount of passive FIDA emission driven by edge neutrals, and to depend delicately on viewing geometry. Results are compared with theoretical expectations based on the codes NUBEAM (for fast ion distributions) and FIDASIM. Calibrating via the measured beam emission peaks, the toroidal FIDA signal profile agrees with classical simulations in MHD quiescent discharges where the neutron rate is also classical. Long-lived modes (LLM) and chirping modes decrease the core FIDA signal significantly, and the profile can be matched closely to simulations using anomalous diffusive transport; a spatially uniform diffusion coefficient is sufficient for chirping modes, while a core localized diffusion is better for a LLM. Analysis of a discharge with chirping mode activity shows a dramatic drop in the core FIDA signal and rapid increase in the edge passive signal at the onset of the burst indicating a very rapid redistribution towards the edge. Vertical viewing measurements show a discrepancy with simulations at higher Doppler shifts when the neutron rate is classical, which, combined with the fact that the toroidal signals agree, means that the difference must be occurring for pitch angles near the trapped-passing boundary. Further evidence of an anomalous transport mechanism for these particles is provided by the fact that an increase of beam power does not increase the higher energy vertical FIDA signals, while the toroidal signals do increase., submitted to PPCF

Using the recently-installed Fast-Ion Deuterium Alpha (FIDA) spectrometer, the effects of low-frequency (20-50 kHz) chirping energetic particle modes with toroidal mode number n \geq 1 on the fast-ion population in MAST plasmas are considered. Results from the FIDA diagnostic are presented and discussed in the light of the present theoretical understanding of these modes, known as fishbones, in plasmas with reversed shear. Measurements of the fast-ion population reveal strong redistribution of fast ions in both real and velocity space as a result of the fishbones. Time-resolved measurements throughout the evolution of a fishbone show radial redistribution of fast ions with energies up to 95% of the primary beam injection energy. Correlations between changes in the FIDA signal and the peak time derivative of the magnetic field perturbation are observed in a limited range of operating scenarios. The transient reduction in signal caused by a fishbone may in some cases reach 50% of the signal intensity before mode onset., Comment: 19 pages, 12 figures. Submitted to Plasma Phys. Control. Fusion

A first-ever demonstration of controlling power and torque injection through time evolution of neutral beam energy has been achieved in recent experiments at the DIII-D tokamak (Luxon 2002 Nucl. Fusion 42 614). Pre-programmed waveforms for the neutral beam energy produce power and torque inputs that can be separately and continuously controlled. Previously, these inputs were tailored using on/off modulation of neutral beams resulting in large perturbations (e.g. power swings of over 1 MW). The new method includes, importantly for experiments, the ability to maintain a fixed injected power while varying the torque. In another case, different beam energy waveforms (in the same plasma conditions) produce significant changes in the observed spectrum of beam ion-driven instabilities. Measurements of beam ion loss show that one energy waveform results in the complete avoidance of coherent losses due to Alfvénic instabilities. This new method of neutral beam operation is intended for further application in a variety of DIII-D experiments including those concerned with high-performance steady state scenarios, fast particle effects, and transport in the low torque regime. Developing this capability would provide similar benefits and improved plasma control for other magnetic confinement fusion facilities.

The addition of stoichiometric amounts of CuCl efficiently improves the coupling of aryl chlorides and of polyhalo or hindered arylboronates to give higher yields in a shorter time.

The total synthesis of (V) is achieved with the construction of the intermediate (IV) with complete diastereoselectivity as a key step.

An appropriately constructed 2-substituted derivative of L-tryptophane undergoes conversion, in a single step, to a prephalarine structure. The reaction occurs in a diastereoselective fashion, leading shortly thereafter to the naturally occurring version of the alkaloid, phalarine.

A series of methyl ether derivatives of the vancomycin, teicoplanin, and ristocetin aglycon methyl esters was synthesized and their antimicrobial activity was established. These derivatives exhibit increased activity against VanB resistant strains of bacteria equipotent with that observed with sensitive bacteria.

A general method for the deglycosidation of glycopeptide antibiotics has been developed. Treatment of vancomycin, ristocetin, and ramoplanin with anhydrous HF results in efficient cleavage of the sugars to provide the corresponding aglycons in high yield.

As part of the upgrade to the JET neutral beam heating system a new positive ion neutral injector (PINI) design has been commissioned. The new PINI delivers 60A total beam current at 130kV, approximately doubling the neutral beam power delivered to JET. A programme of testing on the Neutral Beam Test Bed established the preferred geometry to maintain horizontal and vertical beam focal lengths of 10m and 14m respectively. The results of these tests and the characterisation of the beam using a number of diagnostic techniques are described, together with predictions for neutral power delivery to the JET plasma.

Primary cytomegalovirus (CMV) infection with marked constitutional symptoms is rare in immunocompetent individuals and in those with iatrogenic immunosuppression, except transplant recipients. Four patients admitted to hospital with clinical illnesses associated with primary CMV infection were identified over a 12-month period. Their medical records were reviewed with regard to clinical and laboratory data, and outcome. Primary CMV infection was defined by the concomitant presence of CMV IgM and low avidity CMV IgG antibody. Of two patients with no known underlying illness, one presented with thrombocytopenic purpura and the other with vasculitis. Two patients receiving immunosuppressants for underlying ulcerative colitis presented with CMV-induced pancytopenia and CMV colitis. Atypical lymphocytosis was a feature on blood film examination in three of the four cases. One patient with disseminated CMV infection died of progressive multiorgan failure despite antiviral treatment. CMV disease following primary CMV infection should be considered in otherwise immunocompetent individuals with atypical lymphocytosis on blood film analysis, and particularly in patients on immunosuppressants such as those with ulcerative colitis, since early diagnosis and treatment with antiviral drugs may improve outcome. J. Med. Virol. 68: 237–240, 2002. © 2002 Wiley-Liss, Inc.

In this article we present an experimental study of the electron electrodynamics in an inductively coupled argon discharge. The discharge is configured in a re-entrant geometry and operates in the stochastic heating regime at pressures below 10 mTorr. The radial distribution of the induced rf electric field E and current density J were determined for a wide range of plasma parameters in argon gas from the measurement of the radial distribution of the magnetic field components and its spatial derivatives. The results show an anomalous skin effect at low pressure and high plasma densities that is characterized by a nonmonotonic spatial decay of the electromagnetic field E and current density J along with phase reversal and bifurcation of E and J and negative power absorption regions. These features are interpreted to be a result of nonlocal electrodynamics due to the electron thermal motion (which causes spatial dispersion in the conductivity). The electron thermal motion in the inhomogeneous rf induced electric field induces a phase randomization that leads to collisionless heating. The relative ratio of ohmic collisional heating to collisionless heating is estimated by comparing the total and collisional (deduced from an estimation of the electron-neutral collision frequency) power fluxes absorbed by the plasma electrons. This shows that collisionless heating dominates ohmic heating for pressures below 5 m Torr. These results are compared with the previously published work of Godyak et al. [V. A. Godyak, R. B. Piejak, and B. M. Alexandrovich, Phys. Rev. Lett. 80, 3264 (1998)] and show a surprisingly good agreement (at constant gas pressure and plasma density) despite the differing chamber geometry.

The binding affinity of 4, which incorporates a methylene (CH2) in place of the key linking amide of Ac2-l-Lys-d-Ala-d-Ala, for vancomycin was compared with that of Ac2-l-Lys-d-Ala-d-Ala (3) and Ac2-l-Lys-d-Ala-d-Lac (5). The vancomycin affinity for 4 was approximately 10-fold less than that of 3, but 100-fold greater than that of 5. This suggests that the reduced binding affinity of 5 (4.1 kcal/mol) may be attributed to both the loss of a key H-bond (1.5 kcal/mol) and a destabilizing lone pair/lone pair electrostatic interaction introduced with the ester oxygen of 5 (2.6 kcal/mol) with the latter, not the H-bond, being responsible for the largest share of the 1000-fold reduction.