Impact of pharmaceutical policy interventions on utilization of antipsychotic medicines in Finland and Portugal in times of economic recession: interrupted time series analyses

Objectives: To analyze the impacts of pharmaceutical sector policies implemented to contain country spending during the economic recession – a reference price system in Finland and a mix of policies including changes in reimbursement rates, a generic promotion campaign and discounts granted to the public payer in Portugal – on utilization of, as a proxy for access to, antipsychotic medicines. Methodology We obtained monthly IMS Health sales data in standard units of antipsychotic medicines in Portugal and Finland for the period January 2007 to December 2011. We used an interrupted time series design to estimate changes in overall use and generic market shares by comparing pre-policy and post-policy levels and trends. Results: Both countries’ policy approaches were associated with slight, likely unintended, decreases in overall use of antipsychotic medicines and with increases in generic market shares of major antipsychotic products. In Finland, quetiapine and risperidone generic market shares increased substantially (estimates one year post-policy compared to before, quetiapine: 6.80% [3.92%, 9.68%]; risperidone: 11.13% [6.79%, 15.48%]. The policy interventions in Portugal resulted in a substantially increased generic market share for amisulpride (estimate one year post-policy compared to before: 22.95% [21.01%, 24.90%]; generic risperidone already dominated the market prior to the policy interventions. Conclusions: Different policy approaches to contain pharmaceutical expenditures in times of the economic recession in Finland and Portugal had intended – increased use of generics – and likely unintended – slightly decreased overall sales, possibly consistent with decreased access to needed medicines – impacts. These findings highlight the importance of monitoring and evaluating the effects of pharmaceutical policy interventions on use of medicines and health outcomes

Effect of the economic recession on pharmaceutical policy and medicine sales in eight European countries

Abstract Objective: To identify pharmaceutical policy changes during the economic recession in eight European countries and to determine whether policy measures resulted in lower sales of, and less expenditure on, pharmaceuticals. Methods: Information on pharmaceutical policy changes between 2008 and 2011 in eight European countries was obtained from publications and pharmaceutical policy databases. Data on the volume and value of the quarterly sales of products between 2006 and 2011 in the 10 highest-selling therapeutic classes in each country were obtained from a pharmaceutical market research database. We compared these indicators in economically stable countries; Austria, Estonia and Finland, to those in economically less stable countries, Greece, Ireland, Portugal, Slovakia and Spain. Findings: Economically stable countries implemented two to seven policy changes each, whereas less stable countries implemented 10 to 22 each. Of the 88 policy changes identified, 33 occurred in 2010 and 40 in 2011. They involved changing out-of-pocket payments for patients in 16 cases, price mark-up schemes in 13 and price cuts in 11. Sales volumes increased moderately in all countries except Greece and Portugal, which experienced slight declines after 2009. Sales values decreased in both groups of countries, but fell more in less stable countries. Conclusion: Less economically stable countries implemented more pharmaceutical policy changes during the recession than economically stable countries. Unexpectedly, pharmaceutical sales volumes increased in almost all countries, whereas sales values declined, especially in less stable countries

Methylation of H2AR29 is a novel repressive PRMT6 target

<p>Abstract</p> <p>Background</p> <p>Covalent histone modifications are central to all DNA-dependent processes. Modifications of histones H3 and H4 are becoming well characterised, but knowledge of how H2A modifications regulate chromatin dynamics and gene expression is still very limited.</p> <p>Results</p> <p>To understand the function of H2A modifications, we performed a systematic analysis of the histone H2A methylation status. We identified and functionally characterised two new methylation sites in H2A: R11 (H2AR11) and R29 (H2AR29). Using an unbiased biochemical approach in combination with candidate assays we showed that protein arginine methyltransferase (PRMT) 1 and PRMT6 are unique in their ability to catalyse these modifications. Importantly we found that H2AR29me2 is specifically enriched at genes repressed by PRMT6, implicating H2AR29me2 in transcriptional repression.</p> <p>Conclusions</p> <p>Our data establishes R11 and R29 as new arginine methylation sites in H2A. We identified the specific modifying enzymes involved, and uncovered a novel functional role of H2AR29me2 in gene silencing <it>in vivo</it>. Thus this work reveals novel insights into the function of H2A methylation and in the mechanisms of PRMT6-mediated transcriptional repression.</p

Yersinia pestis Evolution on a Small Timescale: Comparison of Whole Genome Sequences from North America

Yersinia pestis, the etiologic agent of plague, was responsible for several devastating epidemics throughout history and is currently of global importance to current public heath and biodefense efforts. Y. pestis is widespread in the Western United States. Because Y. pestis was first introduced to this region just over 100 years ago, there has been little time for genetic diversity to accumulate. Recent studies based upon single nucleotide polymorphisms have begun to quantify the genetic diversity of Y. pestis in North America.To examine the evolution of Y. pestis in North America, a gapped genome sequence of CA88-4125 was generated. Sequence comparison with another North American Y. pestis strain, CO92, identified seven regions of difference (six inversions, one rearrangement), differing IS element copy numbers, and several SNPs.The relatively large number of inverted/rearranged segments suggests that North American Y. pestis strains may be undergoing inversion fixation at high rates over a short time span, contributing to higher-than-expected diversity in this region. These findings will hopefully encourage the scientific community to sequence additional Y. pestis strains from North America and abroad, leading to a greater understanding of the evolutionary history of this pathogen

Host Factors Required for Modulation of Phagosome Biogenesis and Proliferation of Francisella tularensis within the Cytosol

Francisella tularensis is a highly infectious facultative intracellular bacterium that can be transmitted between mammals by arthropod vectors. Similar to many other intracellular bacteria that replicate within the cytosol, such as Listeria, Shigella, Burkholderia, and Rickettsia, the virulence of F. tularensis depends on its ability to modulate biogenesis of its phagosome and to escape into the host cell cytosol where it proliferates. Recent studies have identified the F. tularensis genes required for modulation of phagosome biogenesis and escape into the host cell cytosol within human and arthropod-derived cells. However, the arthropod and mammalian host factors required for intracellular proliferation of F. tularensis are not known. We have utilized a forward genetic approach employing genome-wide RNAi screen in Drosophila melanogaster-derived cells. Screening a library of ∼21,300 RNAi, we have identified at least 186 host factors required for intracellular bacterial proliferation. We silenced twelve mammalian homologues by RNAi in HEK293T cells and identified three conserved factors, the PI4 kinase PI4KCA, the ubiquitin hydrolase USP22, and the ubiquitin ligase CDC27, which are also required for replication in human cells. The PI4KCA and USP22 mammalian factors are not required for modulation of phagosome biogenesis or phagosomal escape but are required for proliferation within the cytosol. In contrast, the CDC27 ubiquitin ligase is required for evading lysosomal fusion and for phagosomal escape into the cytosol. Although F. tularensis interacts with the autophagy pathway during late stages of proliferation in mouse macrophages, this does not occur in human cells. Our data suggest that F. tularensis utilizes host ubiquitin turnover in distinct mechanisms during the phagosomal and cytosolic phases and phosphoinositide metabolism is essential for cytosolic proliferation of F. tularensis. Our data will facilitate deciphering molecular ecology, patho-adaptation of F. tularensis to the arthropod vector and its role in bacterial ecology and patho-evolution to infect mammals

Complete Genome Sequence of Francisella tularensis Subspecies holarctica FTNF002-00

Francisella tularensis subspecies holarctica FTNF002-00 strain was originally obtained from the first known clinical case of bacteremic F. tularensis pneumonia in Southern Europe isolated from an immunocompetent individual. The FTNF002-00 complete genome contains the RD23 deletion and represents a type strain for a clonal population from the first epidemic tularemia outbreak in Spain between 1997–1998. Here, we present the complete sequence analysis of the FTNF002-00 genome. The complete genome sequence of FTNF002-00 revealed several large as well as small genomic differences with respect to two other published complete genome sequences of F. tularensis subsp. holarctica strains, LVS and OSU18. The FTNF002-00 genome shares >99.9% sequence similarity with LVS and OSU18, and is also ∼5 MB smaller by comparison. The overall organization of the FTNF002-00 genome is remarkably identical to those of LVS and OSU18, except for a single 3.9 kb inversion in FTNF002-00. Twelve regions of difference ranging from 0.1–1.5 kb and forty-two small insertions and deletions were identified in a comparative analysis of FTNF002-00, LVS, and OSU18 genomes. Two small deletions appear to inactivate two genes in FTNF002-00 causing them to become pseudogenes; the intact genes encode a protein of unknown function and a drug:H+ antiporter. In addition, we identified ninety-nine proteins in FTNF002-00 containing amino acid mutations compared to LVS and OSU18. Several non-conserved amino acid replacements were identified, one of which occurs in the virulence-associated intracellular growth locus subunit D protein. Many of these changes in FTNF002-00 are likely the consequence of direct selection that increases the fitness of this subsp. holarctica clone within its endemic population. Our complete genome sequence analyses lay the foundation for experimental testing of these possibilities

Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage ؊ /CD34 ؉ /CD38 ؊ /CD90 ؉ ) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS i

Effectiveness of an intensive care telehealth programme to improve process quality (ERIC): a multicentre stepped wedge cluster randomised controlled trial

Purpose!#!Supporting the provision of intensive care medicine through telehealth potentially improves process quality. This may improve patient recovery and long-term outcomes. We investigated the effectiveness of a multifaceted telemedical programme on the adherence to German quality indicators (QIs) in a regional network of intensive care units (ICUs) in Germany.!##!Methods!#!We conducted an investigator-initiated, large-scale, open-label, stepped-wedge cluster randomised controlled trial enrolling adult ICU patients with an expected ICU stay of ≥ 24 h. Twelve ICU clusters in Berlin and Brandenburg were randomly assigned to three sequence groups to transition from control (standard care) to the intervention condition (telemedicine). The quality improvement intervention consisted of daily telemedical rounds guided by eight German acute ICU care QIs and expert consultations. Co-primary effectiveness outcomes were patient-specific daily adherence (fulfilled yes/no) to QIs, assessed by a central end point adjudication committee. Analyses used mixed-effects logistic modelling adjusted for time. This study is completed and registered with ClinicalTrials.gov (NCT03671447).!##!Results!#!Between September 4, 2018, and March 31, 2020, 1463 patients (414 treated on control, 1049 on intervention condition) were enrolled at ten clusters, resulting in 14,783 evaluated days. Two randomised clusters recruited no patients (one withdrew informed consent; one dropped out). The intervention, as implemented, significantly increased QI performance for 'sedation, analgesia and delirium' (adjusted odds ratio (99.375% confidence interval [CI]) 5.328, 3.395-8.358), 'ventilation' (OR 2.248, 1.198-4.217), 'weaning from ventilation' (OR 9.049, 2.707-30.247), 'infection management' (OR 4.397, 1.482-13.037), 'enteral nutrition' (OR 1.579, 1.032-2.416), 'patient and family communication' (OR 6.787, 3.976-11.589), and 'early mobilisation' (OR 3.161, 2.160-4.624). No evidence for a difference in adherence to 'daily multi-professional and interdisciplinary clinical visits' between both conditions was found (OR 1.606, 0.780-3.309). Temporal trends related and unrelated to the intervention were detected. 149 patients died during their index ICU stay (45 treated on control, 104 on intervention condition).!##!Conclusion!#!A telemedical quality improvement program increased adherence to seven evidence-based German performance indicators in acute ICU care. These results need further confirmation in a broader setting of regional, non-academic community hospitals and other healthcare systems