Mathematical Modelling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development

<p><b>Left:</b> Typical development in stem cells (top panel A) and mature cells (bottom panel B). Healthy hematopoietic cells (full blue curves) dominate in the early phase where the number of malignant cells (stipulated red curves) are few. The total number of cells is also shown (dotted green curves). When a stem cell mutates without repairing mechanisms, a slowly increasing exponential growth starts. At a certain stage, the malignant cells become dominant, and the healthy hematopoietic cells begin to show a visible decline. Finally, the composition between the cell types results in a takeover by the malignant cells, leading to an exponential decline in hematopoietic cells and ultimately their extinction. The development is driven by an approximately exponential increase in the MPN stem cells, and the development is closely followed by the mature MPN cells. <b>Right:</b> B)The corresponding allele burden (7%, 33% and 67% corresponding to ET, PV, and PMF, respectively) defined as the ratio of MPN mature cells to the total number of mature cells.</p

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Standardized data to support conservation prioritization for sharks and batoids (Elasmobranchii)

We collated and synthesized information on 1,226 Elasmobranch species (i.e., sharks, rays, and skates) globally from a wide range of sources. We obtained curated and standardized data from online databases, legal documents, press releases, and websites. All data were standardized according to the taxonomic nomenclature described in the Catalogue of Life. We grouped data into five categories: 1) biological information, 2) conservation status, 3) management opportunities, 4) use, and 5) inclusion in international conventions and treaties. For species biological information, we included migration, habitat, species characteristics such as length & body weight, their threat to humans, life-history trait data availability from FishBase, whether the species was listed on the Global Register of Migratory Species, the presence of occurrence data from the Global Biodiversity Information Facility (GBIF), information on genomics from GenBank, and species evolutionary distinctiveness scores. For conservation status, we recorded threat status from the International Union for Conservation of Nature Red List of Threatened Species™ and inclusion in the Alliance for Zero Extinction (AZE). For management opportunities, we identified species under human care in zoos and aquariums in the Species360 network, species under management in studbooks from the European Association of Zoos and Aquaria (EAZA), the American Association for Zoos and Aquariums (AZA), and the Zoo and Aquarium Association Australasia (ZAA), as well as data on recovery, management, and action plans at the class, family, and species levels. For use, we collated species-level data on international trade levels from the CITES (the Convention on International Trade in Endangered Species of Wild Fauna and Flora) Trade Database, as used in aquaculture, as bait, and as gamefish, recording the purpose of the trade according to the IUCN Red List and the global catches reported to the FAO (Food and Agriculture Organization of the United Nations). Finally, we collated information from seven international conventions and treaties: CITES, UNCLOS (the United Nations Convention for the Law of the Sea), CMS (the Convention on the Conservation of Migratory Species of Wild Animals), Shark MoU (the Memorandum of Understanding on the Conservation of Migratory Sharks), BERN (the Convention on the Conservation of European Wildlife and Natural Habitats), OSPAR (Protecting and conserving the North-East Atlantic and its resources), and the Barcelona Convention for the Protection of the Marine Environment and the Coastal Region of the Mediterranean. Our data are comparable across databases and will assist further research on in-situ and ex-situ population management for sharks and batoids. Our data can be of use to international policy makers, aquarium curators, management authorities, conservation practitioners, and scientists interested in prioritizing Elasmobranchs for conservation.publishe