Objectives. This 5-yr study assessed urate-lowering and clinical efficacy and safety of long-term febuxostat therapy in subjects with gout. The primary efficacy end-point was reduction to and ...maintenance of serum urate (sUA) levels <6.0 mg/dl. Methods. Subjects who completed a previous 28-day study were entered into an open-label extension study and initially received febuxostat 80 mg daily. Between Weeks 4 and 24, dosing could be adjusted to febuxostat 40 or 120 mg. All subjects received gout flare prophylaxis during the first 4 weeks. Gout flares were recorded and treated throughout the study, and sUA, baseline tophi and safety were monitored. Results. Among 116 subjects initially enrolled, dose adjustments were made for 44 (38%) subjects. As a result, 8 subjects received febuxostat 40 mg, 79 received 80 mg, and 29 received 120 mg daily maintenance dose. At 5 yrs, 93% (54/58) of the remaining subjects had sUA <6.0 mg/dl. Fifty-eight subjects (50%) discontinued prematurely; 38 did so in the first year. Thirteen subjects withdrew due to an adverse event. Sustained reduction of sUA was associated with nearly complete elimination of gout flares. In 26 subjects with a tophus at baseline, resolution was achieved in 69% (18/26) by last visit on study drug at any point during the study (Final Visit). There were no deaths reported during the study. Conclusions. Long-term treatment with febuxostat resulted in durable maintenance of sUA <6.0 mg/dl for most subjects. There was nearly complete abolition of gout flares in patients completing the study. Baseline tophi resolved in a majority of subjects.
An event-related potential (ERP) component reliably associated with feedback processing and well studied in humans is the feedback-related negativity (FRN), which is assumed to indicate activation of ...midcingulate cortex (MCC) neurons. However, recent approaches have conceptualized this frontocentral ERP component as reflecting at least partially a reward positivity associated with activation in reward-related brain regions, in line with fMRI studies investigating feedback processing in the context of reward evaluation. To discover convergence of electrophysiological and BOLD responses elicited by performance feedback, we concurrently recorded EEG and fMRI during a time-estimation task. The ERP showed relatively more negative amplitudes to negative than to positive feedback. Conventional analyses of fMRI data revealed activation of a number of areas, including ventral striatum, anterior cingulate cortex, and medial prefrontal cortex to positive versus negative feedback. Most importantly, when using single-trial amplitudes of electrophysiological feedback signals to estimate hemodynamic responses, we found feedback-related BOLD-responses in ventral striatum, midcingulate, and midfrontal cortices to positive but not to negative feedback associated with feedback signals in the time range of the FRN. Specifically, activation in these areas increased as amplitudes became more positive. These findings suggest that, in the time-estimation task, a positivity elicited by reward is associated with brain activation in several reward-related brain regions and is driving differential ERP responses in the time range of the FRN.
Insulin glargine is processed in vivo into soluble 21A‐Gly‐human insulin (M1), the principal moiety responsible for metabolic effects, and subsequently into M2. This sub‐study compared metabolism and ...metabolite pharmacokinetic (PK) profiles of investigational new insulin glargine U300 (Gla‐300) with insulin glargine 100 U/ml (Gla‐100, Lantus®, Sanofi‐Aventis Deutschland GmbH, Frankfurt am Main, Germany) in people with type 1 diabetes. Participants received 0.4 (n = 18) or 0.6 U/kg Gla‐300 (n = 12), and 0.4 U/kg Gla‐100 (n = 30) once daily in randomized order for 8 days prior to a 36‐h euglycaemic clamp. Metabolites were quantified using immunoaffinity enrichment and liquid chromatography tandem mass spectrometry (LC‐MS/MS). Glargine metabolism was the same regardless of Gla‐100 or Gla‐300 administration; M1 was confirmed as the principal active moiety circulating in blood. Steady state concentrations of M1 were achieved after 2 days for Gla‐100, and 4 days for Gla‐300. Steady state M1 values defined prolonged and even flatter PK profiles after Gla‐300 administration compared with M1 profiles after Gla‐100.
The biocatalytic transformations used by chemists are often restricted to simple functional-group interconversions. In contrast, nature has developed complexity-generating biocatalytic reactions ...within natural product pathways. These sophisticated catalysts are rarely employed by chemists, because the substrate scope, selectivity and robustness of these catalysts are unknown. Our strategy to bridge the gap between the biosynthesis and synthetic chemistry communities leverages the diversity of catalysts available within natural product pathways. Here we show that, starting from a suite of biosynthetic enzymes, catalysts with complementary substrate scope as well as selectivity can be identified. This strategy has been applied to the oxidative dearomatization of phenols, a chemical transformation that rapidly builds molecular complexity from simple starting materials and cannot be accomplished with high selectivity using existing catalytic methods. Using enzymes from biosynthetic pathways, we have successfully developed a method to produce ortho-quinol products with controlled site- and stereoselectivity. Furthermore, we have capitalized on the scalability and robustness of this method in gram-scale reactions as well as multi-enzyme and chemoenzymatic cascades.
In order to study the galaxy population of galaxy clusters with photometric data, one must be able to accurately discriminate between cluster members and non-members. The redMaPPer cluster finding ...algorithm treats this problem probabilistically, focusing exclusively on the red galaxy population. Here, we utilize Sloan Digital Sky Survey (SDSS) and Galaxy And Mass Assembly spectroscopic membership rates to validate the redMaPPer membership probability estimates for clusters with z ∈ 0.1, 0.3. We find small – but correctable – biases, sourced by three different systematics. The first two were expected a priori, namely blue cluster galaxies and correlated structure along the line of sight. The third systematic is new: the redMaPPer template fitting exhibits a non-trivial dependence on photometric noise, which biases the original redMaPPer probabilities when utilizing noisy data. After correcting for these effects, we find exquisite agreement (≈1 per cent) between the photometric probability estimates and the spectroscopic membership rates, demonstrating that we can robustly recover cluster membership estimates from photometric data alone. As a byproduct of our analysis we find that on average unavoidable projection effects from correlated structure contribute ≈6 per cent of the richness of a redMaPPer galaxy cluster. This work also marks the second public release of the SDSS redMaPPer cluster catalogue.
Aims
To characterize the variability in exposure and metabolic effect of insulin glargine 300 U/ml (Gla‐300) at steady state in people with type 1 diabetes (T1DM).
Methods
A total of 50 participants ...with T1DM underwent two 24‐h euglycaemic clamps in steady‐state conditions after six once‐daily administrations of 0.4 U/kg Gla‐300 in a double‐blind, randomized, two‐treatment, two‐period, crossover clamp study. Participants were randomized to receive Gla‐300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate‐20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within‐ and between‐day variability.
Results
The cumulative exposure and effect of Gla‐300 developed linearly over 24 h, and were evenly distributed across 6‐ and 12‐h intervals. Diurnal fluctuation in exposure (within‐day variability) was low; the peak‐to‐trough ratio of insulin concentration profiles was <2, and both the swing and peak‐to‐trough fluctuation were <1. Day‐to‐day reproducibility of exposure was high: the between‐day within‐subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24 h after dosing) and maximum insulin concentration were 17.4% 95% confidence interval (CI) 15–21 and 33.4% (95% CI 28–41), respectively. Reproducibility of the metabolic effect was lower than that of exposure.
Conclusions
Gla‐300 provides predictable, evenly distributed 24‐h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.
Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct ...a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10
) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Infection of implanted medical devices has catastrophic consequences. For cardiac rhythm devices, pre-procedural cefazolin is standard prophylaxis but does not protect against methicillin-resistant ...gram-positive organisms, which are common pathogens in device infections.
This study tested the clinical effectiveness of incremental perioperative antibiotics to reduce device infection.
The authors performed a cluster randomized crossover trial with 4 randomly assigned 6-month periods, during which centers used either conventional or incremental periprocedural antibiotics for all cardiac implantable electronic device procedures as standard procedure. Conventional treatment was pre-procedural cefazolin infusion. Incremental treatment was pre-procedural cefazolin plus vancomycin, intraprocedural bacitracin pocket wash, and 2-day post-procedural oral cephalexin. The primary outcome was 1-year hospitalization for device infection in the high-risk group, analyzed by hierarchical logistic regression modeling, adjusting for random cluster and cluster-period effects.
Device procedures were performed in 28 centers in 19,603 patients, of whom 12,842 were high risk. Infection occurred in 99 patients (1.03%) receiving conventional treatment, and in 78 (0.78%) receiving incremental treatment (odds ratio: 0.77; 95% confidence interval: 0.56 to 1.05; p = 0.10). In high-risk patients, hospitalization for infection occurred in 77 patients (1.23%) receiving conventional antibiotics and in 66 (1.01%) receiving incremental antibiotics (odds ratio: 0.82; 95% confidence interval: 0.59 to 1.15; p = 0.26). Subgroup analysis did not identify relevant patient or site characteristics with significant benefit from incremental therapy.
The cluster crossover design efficiently tested clinical effectiveness of incremental antibiotics to reduce device infection. Device infection rates were low. The observed difference in infection rates was not statistically significant. (Prevention of Arrhythmia Device Infection Trial PADIT Pilot PADIT; NCT01002911).
In our second paper on long-term quasar variability, we employ a much larger database of quasars than in de Vries, Becker & White. This expanded sample, containing 35,165 quasars from the Sloan ...Digital Sky Survey (SDSS) Data Release 2 and 6413 additional quasars in the same area of the sky taken from the Two Degree Field (2dF) QSO Redshift Survey, allows us to significantly improve on our earlier conclusions. As before, all the historic quasar photometry has been calibrated onto the SDSS scale by using large numbers of calibration stars around each quasar position. We find the following: (1) The outbursts have an asymmetric light-curve profile, with a fast-rise, slow-decline shape; this argues against a scenario in which microlensing events along the line of sight to the quasars are dominating the long-term variations in quasars. (2) There is no turnover in the structure function of the quasars up to timescales of ~40 yr, and the increase in variability with increasing time lags is monotonic and constant. (3) Consequently, there is not a single preferred characteristic outburst timescale for the quasars, but most likely a continuum of outburst timescales. (4) The magnitude of the quasar variability is a function of wavelength: variability increases toward the blue part of the spectrum. (5) High-luminosity quasars vary less than low-luminosity quasars, consistent with a scenario in which variations have limited absolute magnitude. On this basis, we conclude that quasar variability is intrinsic to the active galactic nucleus and is caused by chromatic outbursts or flares that have limited luminosity range, varying timescales, and an overall asymmetric light-curve shape. Currently, the model that has the most promise of fitting the observations is based on accretion disk instabilities.
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