Prospective multicenter non-interventional real-world study to assess the patterns of use, effectiveness and safety of follitropin delta in routine clinical practice (the PROFILE study)

Objective: To observe the real-world utilization patterns, effectiveness and safety profile of follitropin delta in women ≥18 years naïve to ovarian stimulation undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Design: Prospective, multinational, multicenter, observational study. All IVF/ICSI treatment protocols were conducted according to routine clinical practice, including undertaking fresh/frozen transfers. Outcomes included use of dosing algorithm, follitropin delta dosing patterns, ovarian response, pregnancy rates and adverse drug reactions (ADRs). Results: The first ovarian stimulation cycle using follitropin delta was initiated in 944 women. Mean baseline demographics were: age, 33.5 ± 4.7 years; bodyweight, 67.1 ± 13.6 kg; anti-Müllerian hormone, 20.3 ± 16.1 pmol/L (2.84 ± 2.25 ng/mL). The dosing algorithm was used to calculate the follitropin delta daily starting dose in 893/944 women (94.5%). The mean difference between the calculated and prescribed daily dose was small (0.2 ± 1.40 µg). The mean daily starting follitropin delta dose was 10.4 ± 2.72 µg and the mean total dose administered was 104 µg. Follitropin delta dose adjustments were reported for 57/944 (6.0%) women. The mean number of retrieved oocytes was 10.1 ± 7.03. Ongoing pregnancy at 10–11 weeks was reported for 255 women (27.0% per initiated cycle and 43.1% per fresh transfer [n=592]). Cumulative ongoing pregnancy rate after fresh and/or frozen transfer was 36.4% (344/944). Four women discontinued follitropin delta due to ADRs. Ovarian hyperstimulation syndrome (OHSS) was the most frequently reported ADR (n=37 [3.9%]); most cases of OHSS were of mild or moderate intensity (n=30 [3.2%]). Conclusions: This large real-world study of follitropin delta utilization patterns confirms its good pregnancy rates while minimizing OHSS risk during first ovarian stimulation cycle

Budesonide with multi-matrix technology as second-line treatment for ulcerative colitis: evaluation of long-term cost-effectiveness in the Netherlands

<p><b>Aims:</b> Budesonide with multi-matrix technology (MMX) is an oral corticosteroid, shown to have high topical activity against ulcerative colitis (UC) while maintaining low systemic bioavailability with few adverse events. The aim of this study was to evaluate the cost-effectiveness of budesonide MMX versus commonly used corticosteroids, in the second-line treatment of active mild-to-moderate UC in the Netherlands.</p> <p><b>Materials and methods:</b> An eight-state Markov model with an 8 week cycle length captured remission, four distinct therapy stages, hospitalization, possible colectomy and mortality. Remission probability for budesonide MMX was based on the CORE-II study. Population characteristics were derived from the Dutch Inflammatory Bowel Disease South Limburg cohort (<i>n</i> = 598) and included patients with proctitis (39%), left-sided (42%) and extensive disease (19%). Comparators (topical budesonide foam and enema, oral budesonide and prednisolone) were selected based on current Dutch clinical practice. Treatment effects were evaluated by network meta-analysis using a Bayesian framework. Cost-effectiveness analysis was performed over a 5 year time horizon from a societal perspective, with costs, health-state and adverse event utilities derived from published sources. Outcomes were weighted by disease extent distribution and corresponding comparators.</p> <p><b>Results:</b> Budesonide MMX was associated with comparable quality-adjusted life year (QALY) gain versus foam and oral formulations (+0.01 QALYs) in the total UC population, whilst being cost-saving (EUR 366 per patient). Probabilistic sensitivity analysis evaluated an 86.6% probability of budesonide MMX being dominant (cost-saving with QALY gain) versus these comparators. Exploratory analysis showed similar findings versus prednisolone.</p> <p><b>Limitations:</b> Differing definitions of trial end-points and remission across trials meant indirect comparison was not ideal. However, in the absence of head-to-head clinical data, these comparisons are reasonable alternatives and currently offer the only comparison of second-line UC treatments.</p> <p><b>Conclusions:</b> In the present analysis, budesonide MMX was shown to be cost-effective versus comparators in the total UC population, for the second-line treatment of active mild-to-moderate UC in the Netherlands.</p

The Swiss-Prot variant page and the ModSNP database: a resource for sequence and structure information on human protein variants

Missense mutation leading to single amino acid polymorphism (SAP) is the type of mutation most frequently related to human diseases. The Swiss-Prot protein knowledgebase records information on such mutations in various sections of a protein entry, namely in the "feature," "comment," and "reference" fields. To facilitate users in obtaining the most relevant information about each human SAP recorded in the knowledgebase, the Swiss-Prot Variant web pages were created to provide a summary of available sequence information, as well as additional structural information on each variant. In particular, the ModSNP database was set up to store information related to SAPs and to manage the modeling of SAPs onto protein structures via an automatic homology modeling pipeline. Currently, among the 16,566 human SAPs recorded in the Swiss-Prot knowledgebase (release 42.5, 21 November 2003), more than 25% have corresponding 3D-models. Of these variants, 47% are related to disease, 26% are polymorphisms, and 27% are not yet clearly classified. The ModSNP database is updated and the subsequent model construction pipeline is launched with each weekly Swiss-Prot release. Thus, the ModSNP database represents a valuable resource for the structural analysis of protein variation. The Swiss-Prot variant pages are accessible from the NiceProt view of a Swiss-Prot entry on the ExPASy server (www.expasy.org/), via a hyperlink created for the stable and unique identifier FTId of each human SAP

Annotating single amino acid polymorphisms in the UniProt/Swiss-Prot knowledgebase

UniProtKB/Swiss-Prot (http://beta.uniprot.org/uniprot; last accessed: 19 October 2007) is a manually curated knowledgebase providing information on protein sequences and functional annotation. It is part of the Universal Protein Resource (UniProt). The knowledgebase currently records a total of 32,282 single amino acid polymorphisms (SAPs) touching 6,086 human proteins (Release 53.2, 26 June 2007). Nearly all SAPs are derived from literature reports using strict inclusion criteria. For each SAP, the knowledgebase provides, apart from the position of the mutation and the resulting change in amino acid, information on the effects of SAPs on protein structure and function, as well as their potential involvement in diseases. Presently, there are 16,043 disease-related SAPs, 14,266 polymorphisms, and 1,973 unclassified variants recorded in UniProtKB/Swiss-Prot. Relevant information on SAPs can be found in various sections of a UniProtKB/Swiss-Prot entry. In addition to these, cross-references to human disease databases as well as other gene-specific databases, are being added regularly. In 2003, the Swiss-Prot variant pages were created to provide a concise view of the information related to the SAPs recorded in the knowledgebase. When compared to the information on missense variants listed in other mutation databases, UniProtKB/Swiss-Prot further records information on direct protein sequencing and characterization including posttranslational modifications (PTMs). The direct links to the Online Mendelian Inheritance in Man (OMIM) database entries further enhance the integration of phenotype information with data at protein level. In this regard, SAP information in UniProtKB/Swiss-Prot complements nicely those existing in genomic and phenotypic databases, and is valuable for the understanding of SAPs and diseases