Systematic Review of Medicine-Related Problems in Adult Patients with Atrial Fibrillation on Direct Oral Anticoagulants

New oral anticoagulant agents continue to emerge on the market and their safety requires assessment to provide evidence of their suitability for clinical use. There-fore, we searched standard databases to summarize the English language literature on medicine-related problems (MRPs) of direct oral anticoagulants DOACs (dabigtran, rivaroxban, apixban, and edoxban) in the treatment of adults with atri-al fibrillation. Electronic databases including Medline, Embase, International Pharmaceutical Abstract (IPA), Scopus, CINAHL, the Web of Science and Cochrane were searched from 2008 through 2016 for original articles. Studies pub-lished in English reporting MRPs of DOACs in adult patients with AF were in-cluded. Seventeen studies were identified using standardized protocols, and two reviewers serially abstracted data from each article. Most articles were inconclusive on major safety end points including major bleeding. Data on major safety end points were combined with efficacy. Most studies inconsistently reported adverse drug reactions and not adverse events or medication error, and no definitions were consistent across studies. Some harmful drug effects were not assessed in studies and may have been overlooked. Little evidence is provided on MRPs of DOACs in patients with AF and, therefore, further studies are needed to establish the safety of DOACs in real-life clinical practice

Risk-induced hatching timing showslow heritability and evolves independently of spontaneous hatching in red-eyed treefrogs

Plasticity in the timing of transitions between stages of complex life cycles allows organisms to adjust their growth and development to local environ- mental conditions. Genetic variation in such plasticity is common, but the evolution of context-dependent transition timing may be constrained by information reliability, lag-time and developmental constraints. We studied the genetic architecture of hatching plasticity in embryos of the red-eyed treefrog (Agalychnis callidryas) in response to simulated predator attacks using a series of paternal and maternal half-sibs from a captive breeding colony of wild-collected animals. We compared the developmental timing of induced early hatching across sibships and estimated cross-environment genetic correlations between induced and spontaneous hatching traits. Additive genetic variance for induced early hatching was very low, indicating a constraint on the short-term evolution of earlier hatching timing. This con- straint is likely related to the maturation of the hatching mechanism. The most plastic genotypes produced the most extreme spontaneous hatching phenotypes, indicating that developmental range, per se, is not constrained. Cross-environment genetic correlation in hatching timing was negligible, so the evolution of spontaneous hatching in this species has not depended on the evolution of risk-induced hatching and vice versa.Peer reviewe

Evolution of adaptive plasticity: Risk-sensitive hatching in neotropical leaf-breeding treefrogs

Adaptive plasticity at switch points in complex life cycles (e.g., hatching, metamorphosis) is well known, but the evolutionary history of such plasticity is not. Particularly unclear is how a single plastic response (e.g., shifts in hatching timing) evolves to respond to different threats and cues (e.g., abiotic and biotic). We conducted a comparative phylogenetic study of hatching plasticity in a group of frogs with arboreal embryos to determine when risk-accelerated hatching evolved in the clade, whether responses to two common egg-stage risks (snake predation and flooding) evolved independently, and whether the overall capacity for hatching plasticity was evolutionarily more conservative than responses to specific cues. Red-eyed treefrogs (Agalychnis callidryas) hatch early to escape from several egg-stage risks but otherwise hatch later, improving larval survival with predators. We reconstructed a phylogeny for Agalychnis and related genera based on three mitochondrial and four nuclear genes. We quantified onset of hatching competence, spontaneous hatching timing, responses to egg-stage risks, and costs of premature hatching in Agalychnis and Pachymedusa. We also assessed hatching plasticity in a basal phyllomedusine, Crttziohyla calcarifer. The capacity to hatch ∼30% before the spontaneous hatching age appears ancestral for phyllomedusines, with little change over ∼34-50 million years among the species examined. A strong hatching response to flooding, with no mortality of hatching-competent eggs, is similarly ancient and conserved. Premature hatchlings of Agalychnis and Pachymedusa are more vulnerable to fish predation than are full-term hatchlings, indicating a conserved risk trade-off across hatching that would make plasticity advantageous. In contrast, the hatching response to snake attack has undergone major changes at least twice in the Agalychnis-Pachymedusa clade, with two species showing substantially lower escape success than the others. Responses to different threats have thus evolved independently. The capacity for switch point plasticity may be evolutionarily more stable than the response to individual stage-specific threats. © 2008 by the Ecological Socity of America.Peer Reviewe

Genetic variation in pathogen-induced early hatching of toad embryos

Accelerated hatching is one of few defences available to embryos, and is effective against many egg-stage risks. We present the first analysis of genetic variation in hatching plasticity, examining premature hatching of American toad embryos in response to pathogenic water moulds. We reared eggs from half- and full-sib families in the presence and absence of water mould. Hatching age and hatchling size showed low cross-environment genetic correlations, suggesting that early-induced hatching can evolve largely independently of spontaneous hatching. We found less phenotypic and additive genetic variation for early-induced hatching than spontaneous hatching, and a stronger correlation between egg and induced hatchling sizes. Directional selection by the pathogen may have eroded variation in early-induced hatching, pushing it against the constraint of hatching gland development. Later hatching has a second, muscular component. This pattern of variation may characterize defences based on developmental transitions, although other inducible defences show more variation in induced phenotypes. © 2008 The Authors.Peer Reviewe

The shape of things to come: linking developmental plasticity to post-metamorphic morphology in anurans

Development consists of growth and differentiation, which can be partially decoupled and can be affected by environmental factors to different extents. In amphibians, variation in the larval environment influences development and causes changes in post-metamorphic shape. We examined post-metamorphic consequences, both morphological and locomotory, of alterations in growth and development. We reared tadpoles of two phylogenetically and ecologically distant frog species (the red-eyed treefrog Agalychnis callidryas and the African clawed frog Xenopus laevis) under different temperatures with ad libitum food supply and under different food levels at a constant temperature. Low temperature and low food levels both resulted in similarly extended larval periods. However, low temperature yielded relatively long-legged frogs with a lower degree of ossification than warm temperature, whereas low food yielded relatively short-legged frogs with a higher degree of ossification than high food levels. Such allometric differences had no effect on locomotor performance of juveniles. Our results provide a basis for understanding the relationship between growth, differentiation and post-metamorphic shape in anurans and help explain many of the discrepancies reported in previous studies. © 2010 The Authors. Journal Compilation © 2010 European Society For Evolutionary Biology.Peer Reviewe

Quantitative genetic analyses of risk-induced hatching reveal limits to plasticity of inducible defenses

Peer Reviewe