Lipid-lowering therapy with PCSK9-inhibitors in the management of cardiovascular high-risk patients: Effectiveness, therapy adherence and safety in a real world cohort

  Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitors have shown great po­tential in efficient lipid lowering to achieve low-density lipoprotein-cholesterol (LDL-C) treatment goals. The aim of the study was too describe the clinical use of PCSK9-inhibitors and to investigate therapy adherence and safety outside of clinical trials. Methods: Thirty-eight patients were treated with PSCK9-inhibitors. Patients were eligible for this therapy based on their individual cardiovascular risk and when all other available lipid-lowering regi­men had failed. Every patient answered a questionnaire concerning medical history and relevant side effects and therapy adherence. Results: Conventional therapy reduced patient LDL-C levels by about 38%. However, in 26 of the 38 patients, LDL-C treatment goals were not fulfilled because patients did not tolerate further dose es­calation due to side effects. Using a PCSK9 inhibitor, LDL-C levels were reduced by another 54% and 42% of patients reaching treatment goals. The results show that most patients still require concomitant therapy to reach LDL-C target levels. Three patients required dose reduction or change of the PCSK9 inhibitor. 16% did not inject the PCSK9 inhibitor regularly. Conclusions: Only a minority of patients reached the recommended LDL-C goals. PCSK9-inhibitors were generally well tolerated. Despite low rates of reported side effects, therapy adherence was incom­plete, with 6 patients not injecting PCSK9-inhibitors on a regular basis. In-depth information about the medication and close supervision is advisable. PCSK9 inhibitors have shown great potential in aggressive lipid lowering therapy, but basic therapy is still required in most cases. Close supervision is recommended to improve therapy adherence. (Cardiol J 2018; 25, 1: 32–41

Genetic mouse models as in vivo tools for cholangiocarcinoma research

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system

Methylomonas albis sp. nov. and Methylomonas fluvii sp. nov.: Two cold-adapted methanotrophs from the river Elbe and emended description of the species Methylovulum psychrotolerans

Three strains of methanotrophic bacteria (EbAT, EbBT and Eb1) were isolated from the River Elbe, Germany. These Gram-negative, rod-shaped or coccoid cells contain intracytoplasmic membranes perpendicular to the cell surface. Colonies and liquid cultures appeared bright-pink. The major cellular fatty acids were 12:0 and 14:0, in addition in Eb1 the FA 16:1ω5t was also dominant. Methane and methanol were utilized as sole carbon sources by EbBT and Eb1, while EbAT could not use methanol. All strains oxidize methane using the particulate methane monooxygenase. Both strains contain an additional soluble methane monooxygenase. The strains grew optimally at 15–25 °C and at pH 6 and 8. Based on 16S rRNA gene analysis recovered from the full genome, the phylogenetic position of EbAT is robustly outside any species clade with its closest relatives being Methylomonas sp. MK1 (98.24%) and Methylomonas sp. 11b (98.11%). Its closest type strain is Methylomonas methanica NCIMB11130 (97.91%). The 16S rRNA genes of EbBT are highly similar to Methylomonas methanica strains with Methylomonas methanica R-45371 as the closest relative (99.87% sequence identity). However, average nucleotide identity (ANI) and digital DNA-DNA-hybridization (dDDH) values reveal it as distinct species. The DNA G + C contents were 51.07 mol% and 51.5 mol% for EbAT and EbBT, and 50.7 mol% for Eb1, respectively. Strains EbAT and EbBT are representing two novel species within the genus Methylomonas. For strain EbAT we propose the name Methylomonas albis sp. nov (LMG 29958, JCM 32282) and for EbBT, we propose the name Methylomonas fluvii sp. nov (LMG 29959, JCM 32283). Eco-physiological descriptions for both strains are provided. Strain Eb1 (LMG 30323, JCM 32281) is a member of the species Methylovulum psychrotolerans. This genus is so far only represented by two isolates but Eb1 is the first isolate from a temperate environment; so, an emended description of the species is given

Exploring larval phenology as predictor for range expansion in an invasive species

Predicting range expansion of invasive species is one of the key challenges in ecology. We modelled the phenological window for successful larval release and development (WLR) in order to predict poleward expansion of the invasive crab Hemigrapsus sanguineus along the Atlantic coast of North America and north Europe. WLR quantifies the number of opportunities (in days) when larval release leads to a successful completion of the larval phase; WLR depends on the effects of temperature on the duration of larval development and survival. Successful larval development is a necessary requirement for the establishment of self‐persistent local populations. WLR was computed from a mechanistic model, based on in situ temperature time series and a laboratory–calibrated curve predicting duration of larval development from temperature. As a validation step, we checked that model predictions of the time of larval settlement matched observations from the field for our local population (Helgoland, North Sea). We then applied our model to the North American shores because larvae from our European population showed, in the laboratory, similar responses to temperature to those of a North American population. WLR correctly predicted the northern distribution limit in North American shores, where the poleward expansion of H. sanguineus appear to have stalled (as of 2015). For north Europe, where H. sanguineus is a recent invader, WLR predicted ample room for poleward expansion towards NE England and S Norway. We also explored the importance of year‐to‐year variation in temperature for WLR and potential expansion: variations in WLR highlighted the role of heat waves as likely promoters of recruitment subsidising sink populations located at the distribution limits. Overall, phenological windows may be used as a part of a warning system enabling more targeted programs for monitoring

Expert consensus document:Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted

Bank of England interest rate announcements and the foreign exchange market

Since 1997, the Bank of England Monetary Policy Committee (MPC) has met monthly to set the UK policy interest rate. Using a Markov-switching framework that incorporates endogenous transition probabilities, we examine intraday, five-minute return data for evidence of systematic patterns in exchange rate movements on MPC policy announcement days. We find evidence for non-linear regime switching between a high-volatility, informed trading state and a low-volatility, liquidity trading state. MPC surprise announcements are shown to significantly affect the probability that the market enters and remains within the informed trading regime, with some limited evidence of market positioning just prior to the announcement

Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system