Long-term safety of Mometasone Furoate administered via a dry powder inhaler in children: Results of an open-label study comparing Mometasone Furoate with Beclomethasone Dipropionate in children with persistent asthma

<p>Abstract</p> <p>Background</p> <p>To assess the long-term pediatric safety of 2 doses of mometasone furoate administered via a dry powder inhaler (MF-DPI) for mild-to-moderate persistent asthma and compare them with that of beclomethasone dipropionate administered via a metered dose inhaler (BDP-MDI) in the treatment of persistent asthma. Both MF-DPI doses tested are twice the approved pediatric dosage of 100 μg once-daily (QD) for children aged 4–11 years.</p> <p>Methods</p> <p>Children (N = 233) aged 4–11 years were randomized to 52 weeks of treatment with MF-DPI 200 μg QD AM, MF-DPI 100 μg twice daily (BID), or BDP-MDI 168 μg BID. Patients had used inhaled corticosteroids (ICSs) daily for ≥ 30 days before the screening visit and were on stable ICS doses for ≥ 2 weeks before screening. The primary safety variable was the incidence of adverse events. Secondary safety variables were laboratory tests (including cortisol concentrations), vital signs, and physical examination.</p> <p>Results</p> <p>The incidence of adverse events was similar in all 3 treatment groups. The most frequently reported adverse event was upper respiratory tract infection, reported by 47%–49% of the MF-DPI-treated patients and 51% of the BPD-treated patients. Most adverse events were considered unrelated to study drug. The most frequently reported related adverse events were headache (MF-DPI 200 μg QD AM, 8%; MF-DPI 100 μg BID, 4%; BDP-MDI 168 μg BID, 2%) and oral candidiasis (4% in each treatment group). No clinically relevant changes in laboratory values, including plasma cortisol, vital signs, or physical examinations were noted in any treatment group.</p> <p>Conclusion</p> <p>Both MF-DPI doses were well tolerated, with no unusual or unexpected adverse events or safety concerns, and had a similar adverse event profile to that of BDP-MDI 168 μg BID.</p

Improved adherence with once-daily versus twice-daily dosing of mometasone furoate administered via a dry powder inhaler: a randomized open-label study

Background Poor adherence with prescribed asthma medication is a major barrier to positive treatment outcomes. This study was designed to determine the effect of a once-daily administration of mometasone furoate administered via a dry powder inhaler (MF-DPI) on treatment adherence compared with a twice-daily administration. Methods This was a 12-week open-label study designed to mimic an actual clinical setting in patients ≥12 years old with mild-to-moderate persistent asthma. Patients were randomized to receive MF-DPI 400 μg once-daily in the evening or MF-DPI 200 μg twice-daily. Adherence was assessed primarily using the number of actual administered doses reported from the device counter divided by the number of scheduled doses. Self-reports were also used to determine adherence. Health-related quality of life, healthcare resource utilization, and days missed from work or school were also reported. Results 1233 patients were randomized. The mean adherence rates, as measured by the automatic dose counter, were significantly better (P < 0.001) with MF-DPI 400 μg once-daily in the evening (93.3%) than with MF-DPI 200 μg twice-daily (89.5%). Mean adherence rates based on self-reports were also significantly better (P < 0.001) with MF-DPI 400 μg QD PM (97.2%) than with MF-DPI 200 μg twice-daily (95.3%). Adherence rates were lower in adolescents (12-17 years old). Health-related quality of life improved by 20% in patients using MF-DPI once-daily in the evening and by 14% in patients using MF-DPI twice-daily. Very few (<8%) patients missed work/school. Conclusion Mean adherence rates were greater with a once-daily dosing regimen of MF-DPI than with a twice-daily dosing regimen. This trial was completed prior to the ISMJE requirements for trial registration

Genetic Variations and Haplotype Diversity of the UGT1 Gene Cluster in the Chinese Population

Vertebrates require tremendous molecular diversity to defend against numerous small hydrophobic chemicals. UDP-glucuronosyltransferases (UGTs) are a large family of detoxification enzymes that glucuronidate xenobiotics and endobiotics, facilitating their excretion from the body. The UGT1 gene cluster contains a tandem array of variable first exons, each preceded by a specific promoter, and a common set of downstream constant exons, similar to the genomic organization of the protocadherin (Pcdh), immunoglobulin, and T-cell receptor gene clusters. To assist pharmacogenomics studies in Chinese, we sequenced nine first exons, promoter and intronic regions, and five common exons of the UGT1 gene cluster in a population sample of 253 unrelated Chinese individuals. We identified 101 polymorphisms and found 15 novel SNPs. We then computed allele frequencies for each polymorphism and reconstructed their linkage disequilibrium (LD) map. The UGT1 cluster can be divided into five linkage blocks: Block 9 (UGT1A9), Block 9/7/6 (UGT1A9, UGT1A7, and UGT1A6), Block 5 (UGT1A5), Block 4/3 (UGT1A4 and UGT1A3), and Block 3′ UTR. Furthermore, we inferred haplotypes and selected their tagSNPs. Finally, comparing our data with those of three other populations of the HapMap project revealed ethnic specificity of the UGT1 genetic diversity in Chinese. These findings have important implications for future molecular genetic studies of the UGT1 gene cluster as well as for personalized medical therapies in Chinese

One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing

Temporal Patterns of Nucleotide Misincorporations and DNA Fragmentation in Ancient DNA

DNA that survives in museum specimens, bones and other tissues recovered by archaeologists is invariably fragmented and chemically modified. The extent to which such modifications accumulate over time is largely unknown but could potentially be used to differentiate between endogenous old DNA and present-day DNA contaminating specimens and experiments. Here we examine mitochondrial DNA sequences from tissue remains that vary in age between 18 and 60,000 years with respect to three molecular features: fragment length, base composition at strand breaks, and apparent C to T substitutions. We find that fragment length does not decrease consistently over time and that strand breaks occur preferentially before purine residues by what may be at least two different molecular mechanisms that are not yet understood. In contrast, the frequency of apparent C to T substitutions towards the 5′-ends of molecules tends to increase over time. These nucleotide misincorporations are thus a useful tool to distinguish recent from ancient DNA sources in specimens that have not been subjected to unusual or harsh treatments

Biomechanical testing of fixed and adjustable femoral cortical suspension devices for ACL reconstruction under high loads and extended cyclic loading

Purpose: To compare loop elongation after 5000 cycles, loop-elongation at failure, and load at failure of the fixed-loop G-Lok device and three adjustable-loop devices (UltraButton, RigidLoop Adjustable and ProCinch RT), during testing over extended cycles under high loading. Methods: Five devices of each type were tested on a custom-built rig fixed to an Instron machine. The testing protocol had four stages: preloading, cyclic preconditioning, incremental cyclic loading and pull-to-failure. Outcome measures were loop elongation after 5000 cycles, loop-elongation at failure, and load at failure. Results: The loop elongation after 5000 cycles for G-Lok was 1.46 ± 0.25 mm, which was comparable to that of RigidLoop (1.51 ± 0.16 mm, p = 1.000) and ProCinch (1.60 ± 0.09 mm, p = 1.000). In comparison, the loop elongation for UltraButton was 2.66 ± 0.28 mm, which was significantly larger than all other devices (p = 0.048). The failure load for all devices ranged between 1455 and 2178 N. G-Lok was significantly stronger than all adjustable-loop devices (p = 0.048). The elongation at failure was largest for UltraButton (4.20 ± 0.33 mm), which was significantly greater than G-Lok (3.17 ± 0.33 mm, p = 0.048), RigidLoop (2.88 ± 0.20 mm, p = 0.048) and ProCinch (2.78 ± 0.08 mm, p = 0.048). There was no significant difference in elongation at failure for the rest of the devices. Conclusions: Our study has shown that the G-Lok fixed-loop device and the three adjustable-loop devices (UltraButton, RigidLoop Adjustable and ProCinch RT) all elongated less than 3 mm during testing over an extended number of cycles at high loads, nonetheless, the fixed loop device performed best in terms of least elongation and highest load at failure.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted versio

Erroneous attribution of relevant transcription factor binding sites despite successful prediction of cis-regulatory modules

<p>Abstract</p> <p>Background</p> <p><it>Cis</it>-regulatory modules are bound by transcription factors to regulate gene expression. Characterizing these DNA sequences is central to understanding gene regulatory networks and gaining insight into mechanisms of transcriptional regulation, but genome-scale regulatory module discovery remains a challenge. One popular approach is to scan the genome for clusters of transcription factor binding sites, especially those conserved in related species. When such approaches are successful, it is typically assumed that the activity of the modules is mediated by the identified binding sites and their cognate transcription factors. However, the validity of this assumption is often not assessed.</p> <p>Results</p> <p>We successfully predicted five new <it>cis</it>-regulatory modules by combining binding site identification with sequence conservation and compared these to unsuccessful predictions from a related approach not utilizing sequence conservation. Despite greatly improved predictive success, the positive set had similar degrees of sequence and binding site conservation as the negative set. We explored the reasons for this by mutagenizing putative binding sites in three <it>cis</it>-regulatory modules. A large proportion of the tested sites had little or no demonstrable role in mediating regulatory element activity. Examination of loss-of-function mutants also showed that some transcription factors supposedly binding to the modules are not required for their function.</p> <p>Conclusions</p> <p>Our results raise important questions about interpreting regulatory module predictions obtained by finding clusters of conserved binding sites. Attribution of function to these sites and their cognate transcription factors may be incorrect even when modules are successfully identified. Our study underscores the importance of empirical validation of computational results even when these results are in line with expectation.</p

Fragmentation of Contaminant and Endogenous DNA in Ancient Samples Determined by Shotgun Sequencing; Prospects for Human Palaeogenomics

Despite the successful retrieval of genomes from past remains, the prospects for human palaeogenomics remain unclear because of the difficulty of distinguishing contaminant from endogenous DNA sequences. Previous sequence data generated on high-throughput sequencing platforms indicate that fragmentation of ancient DNA sequences is a characteristic trait primarily arising due to depurination processes that create abasic sites leading to DNA breaks

Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay

We reconstruct the rare decays $B^+ \to K^+\mu^+\mu^-$, $B^0 \to K^{*}(892)^0\mu^+\mu^-$, and $B^0_s \to \phi(1020)\mu^+\mu^-$ in a data sample corresponding to $4.4 {\rm fb^{-1}}$ collected in $p\bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ by the CDF II detector at the Fermilab Tevatron Collider. Using $121 \pm 16$ $B^+ \to K^+\mu^+\mu^-$ and $101 \pm 12$ $B^0 \to K^{*0}\mu^+\mu^-$ decays we report the branching ratios. In addition, we report the measurement of the differential branching ratio and the muon forward-backward asymmetry in the $B^+$ and $B^0$ decay modes, and the $K^{*0}$ longitudinal polarization in the $B^0$ decay mode with respect to the squared dimuon mass. These are consistent with the theoretical prediction from the standard model, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the $B^0_s \to \phi\mu^+\mu^- decay and measure its branching ratio${\mathcal{B}}(B^0_s \to \phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}$using$27 \pm 6$signal events. This is currently the most rare$B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let