Combined hormonal contraceptive use in Europe before and after the European Commission mandated changes in product information

Objectives: We investigated combined hormonal contraceptives (CHC) prescribing patterns (focusing on combined oral contraceptives; COC) in three countries (Netherlands, Denmark, United Kingdom) in a time period preceding and in a time period following the European Commission's decision to update product information, and we estimated changes in incidence of venous thromboembolism (VTE) between the two periods. / Study design: We conducted a drug utilization analysis and a cohort study using routinely collected data. We calculated number, proportion and incidence rate of new users, switchers, and stoppers of COC in both time periods. VTE incidence was calculated in new users of COC and in all women aged 18–49 years. / Results: In all countries, the largest proportion (> 75%) of new users used COC containing levonorgestrel, norethisterone, or norgestimate, (i.e., indicated by European Medicines Agency (EMA) as the safest preparations) in both time periods. Switching did not demonstrate a clear pattern towards these types of COC and distribution of stoppers was similar in both time periods. While the proportion of new users initiating COC containing levonorgestrel, norethisterone, or norgestimate increased slightly, this did not translate to a decrease in the overall VTE incidence. / Conclusion: All three countries had the greatest proportion of women initiating a COC containing levonorgestrel, norethisterone, or norgestimate, and this proportion increased in the period after the European Commission decision albeit the increase was small due to the high percentage of use before the decision. This did not translate into a measureable change in the incidence of VTE. / Implications: Both before and after the European Commission's decision, the largest proportion of new users started with combined oral contraceptives containing levonorgestrel, norethisterone, or norgestimate. Earlier studies had already indicated an increased risk of VTE associated with COC containing other progestogens compared with these preparations, so it is possible that physicians were already preferentially prescribing COC containing levonorgestrel, norethisterone, or norgestimate to new users

The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study

Objective To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands

Understanding mode of action can drive the translational pipeline towards more reliable health benefits for probiotics

The different levels of knowledge described in a translational pipeline (the connection of molecular mechanisms with pre-clinical physiological and human health effects) are not complete for many probiotics. At present, we are not in a position to fully understand the mechanistic basis of many well established probiotic health benefits which, in turn, limits our ability to use mechanisms to predict which probiotics are likely to be effective in any given population. Here we suggest that this concept of a translation pipeline connecting mechanistic insights to probiotic efficacy can support the selection and production of improved probiotic products. Such a conceptual pipeline would also provide a framework for the design of clinical trials to convincingly demonstrate the benefit of probiotics to human health in well-defined subpopulations.Peer reviewe

Recurrent Cerebral Venous Thrombosis Associated with Elevated Factor VIII

Cerebral venous thrombosis (CVT) rarely recurs, and the factors associated with a recurrence remain unclear. Recently, however, elevated plasma coagulation factor VIII has been considered a factor related to recurrent venous thromboembolism. Here we report a patient who had recurrent CVT associated with significantly elevated levels of factor VIII despite the chronic use of an antiplatelet agent. Factor IX was also elevated in this patient. These findings suggest that elevated factor VIII is a factor underlying the recurrence of CVT, and that prolonged anticoagulation therapy may have to be considered in patients with elevated coagulation factor levels

Appropriate medication use in Dutch terminal care:study protocol of a multicentre stepped-wedge cluster randomized controlled trial (the AMUSE study)

Background: Polypharmacy is common among patients with a limited life expectancy, even shortly before death. This is partly inevitable, because these patients often have multiple symptoms which need to be alleviated. However, the use of potentially inappropriate medications (PIMs) in these patients is also common. Although patients and relatives are often willing to deprescribe medication, physicians are sometimes reluctant due to the lack of evidence on appropriate medication management for patients in the last phase of life. The aim of the AMUSE study is to investigate whether the use of CDSS-OPTIMED, a software program that gives weekly personalized medication recommendations to attending physicians of patients with a limited life expectancy, improves patients’ quality of life. Methods: A multicentre stepped-wedge cluster randomized controlled trial will be conducted among patients with a life expectancy of three months or less. The stepped-wedge cluster design, where the clusters are the different study sites, involves sequential crossover of clusters from control to intervention until all clusters are exposed. In total, seven sites (4 hospitals, 2 general practices and 1 hospice from the Netherlands) will participate in this study. During the control period, patients will receive ‘care as usual’. During the intervention period, CDSS-OPTIMED will be activated. CDSS-OPTIMED is a validated software program that analyses the use of medication based on a specific set of clinical rules for patients with a limited life expectancy. The software program will provide the attending physicians with weekly personalized medication recommendations. The primary outcome of this study is patients’ quality of life two weeks after baseline assessment as measured by the EORTC QLQ-C15-PAL questionnaire, quality of life question.Discussion: This will be the first study investigating the effect of weekly personalized medication recommendations to attending physicians on the quality of life of patients with a limited life expectancy. We hypothesize that the CDSS-OPTIMED intervention could lead to improved quality of life in patients with a life expectancy of three months or less. Trial registration: This trial is registered at ClinicalTrials.gov (NCT05351281, Registration Date: April 11, 2022).</p

Synthetic glycans control gut microbiome structure and mitigate colitis in mice

Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. Here, we study the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures results in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome

Appropriate medication use in Dutch terminal care:study protocol of a multicentre stepped-wedge cluster randomized controlled trial (the AMUSE study)

Background: Polypharmacy is common among patients with a limited life expectancy, even shortly before death. This is partly inevitable, because these patients often have multiple symptoms which need to be alleviated. However, the use of potentially inappropriate medications (PIMs) in these patients is also common. Although patients and relatives are often willing to deprescribe medication, physicians are sometimes reluctant due to the lack of evidence on appropriate medication management for patients in the last phase of life. The aim of the AMUSE study is to investigate whether the use of CDSS-OPTIMED, a software program that gives weekly personalized medication recommendations to attending physicians of patients with a limited life expectancy, improves patients’ quality of life. Methods: A multicentre stepped-wedge cluster randomized controlled trial will be conducted among patients with a life expectancy of three months or less. The stepped-wedge cluster design, where the clusters are the different study sites, involves sequential crossover of clusters from control to intervention until all clusters are exposed. In total, seven sites (4 hospitals, 2 general practices and 1 hospice from the Netherlands) will participate in this study. During the control period, patients will receive ‘care as usual’. During the intervention period, CDSS-OPTIMED will be activated. CDSS-OPTIMED is a validated software program that analyses the use of medication based on a specific set of clinical rules for patients with a limited life expectancy. The software program will provide the attending physicians with weekly personalized medication recommendations. The primary outcome of this study is patients’ quality of life two weeks after baseline assessment as measured by the EORTC QLQ-C15-PAL questionnaire, quality of life question.Discussion: This will be the first study investigating the effect of weekly personalized medication recommendations to attending physicians on the quality of life of patients with a limited life expectancy. We hypothesize that the CDSS-OPTIMED intervention could lead to improved quality of life in patients with a life expectancy of three months or less. Trial registration: This trial is registered at ClinicalTrials.gov (NCT05351281, Registration Date: April 11, 2022).</p

Gene probing reveals the widespread distribution, diversity and abundance of isoprene-degrading bacteria in the environment

Background: Approximately 500 Tg of isoprene are emitted to the atmosphere annually, an amount similar to that of methane, and despite its significant effects on the climate, very little is known about the biological degradation of isoprene in the environment. Isolation and characterisation of isoprene degraders at the molecular level has allowed the development of probes targeting isoA encoding the α-subunit of the isoprene monooxygenase. This enzyme belongs to the soluble diiron centre monooxygenase family and catalyses the first step in the isoprene degradation pathway. The use of probes targeting key metabolic genes is a successful approach in molecular ecology to study specific groups of bacteria in complex environments. Here, we developed and tested a novel isoA PCR primer set to study the distribution, abundance, and diversity of isoprene degraders in a wide range of environments. Results: The new isoA probes specifically amplified isoA genes from taxonomically diverse isoprene-degrading bacteria including members of the genera Rhodococcus, Variovorax, and Sphingopyxis. There was no cross-reactivity with genes encoding related oxygenases from non-isoprene degraders. Sequencing of isoA amplicons from DNA extracted from environmental samples enriched with isoprene revealed that most environments tested harboured a considerable variety of isoA sequences, with poplar leaf enrichments containing more phylogenetically diverse isoA genes. Quantification by qPCR using these isoA probes revealed that isoprene degraders are widespread in the phyllosphere, terrestrial, freshwater and marine environments. Specifically, soils in the vicinity of high isoprene-emitting trees contained the highest number of isoprene-degrading bacteria. Conclusion: This study provides the molecular ecology tools to broaden our knowledge of the distribution, abundance and diversity of isoprene degraders in the environment, which is a fundamental step necessary to assess the impact that microbes have in mitigating the effects of this important climate-active gas

Microbial cycling of isoprene, the most abundantly produced biological volatile organic compound on Earth

Isoprene (2-methyl-1,3-butadiene), the most abundantly produced biogenic volatile organic compound (BVOC) on Earth, is highly reactive and can have diverse and often detrimental atmospheric effects, which impact on climate and health. Most isoprene is produced by terrestrial plants, but (micro)algal production is important in aquatic environments, and the relative bacterial contribution remains unknown. Soils are a sink for isoprene, and bacteria that can use isoprene as a carbon and energy source have been cultivated and also identified using cultivation-independent methods from soils, leaves and coastal/marine environments. Bacteria belonging to the Actinobacteria are most frequently isolated and identified, and Proteobacteria have also been shown to degrade isoprene. In the freshwater-sediment isolate, Rhodococcus strain AD45, initial oxidation of isoprene to 1,2-epoxy-isoprene is catalyzed by a multicomponent isoprene monooxygenase encoded by the genes isoABCDEF. The resultant epoxide is converted to a glutathione conjugate by a glutathione S-transferase encoded by isoI, and further degraded by enzymes encoded by isoGHJ. Genome sequence analysis of actinobacterial isolates belonging to the genera Rhodococcus, Mycobacterium and Gordonia has revealed that isoABCDEF and isoGHIJ are linked in an operon, either on a plasmid or the chromosome. In Rhodococcus strain AD45 both isoprene and epoxy-isoprene induce a high level of transcription of 22 contiguous genes, including isoABCDEF and isoGHIJ. Sequence analysis of the isoA gene, encoding the large subunit of the oxygenase component of isoprene monooxygenase, from isolates has facilitated the development of PCR primers that are proving valuable in investigating the ecology of uncultivated isoprene-degrading bacteria