bluuebunny/crossref_metadata_2025 huggingface dataset:
Convergent evolution of bird-mammal shared characteristics for adapting to nocturnality
Authors: Wu Yonghua , Wang Haifeng
Published: February 2019

The diapsid lineage (birds) and synapsid lineage (mammals), share a suite of functionally similar characteristics (e.g. endothermy) that are considered to be a result of their convergent evolution, but the candidate selections leading to this convergent evolution are still under debate. Here, we used a newly developed molecular phyloecological approach to reconstruct the diel activity pattern of the common ancestors of living birds. Our results strongly suggest that they had adaptations to nocturnality during their early evolution, which is remarkably similar to that of ancestral mammals. Given their similar adaptation to nocturnality, we propose that the shared traits in birds and mammals may have partly evolved as a result of the convergent evolution of their early ancestors adapting to ecological factors (e.g. low ambient temperature) associated with nocturnality. Finally, a conceptually unifying ecological model on the evolution of endothermy in diverse organisms with an emphasis on low ambient temperature is proposed. We reason that endothermy may evolve as an adaptive strategy to enable organisms to effectively implement various life-cycle activities under relatively low-temperature environments. In particular, a habitat shift from high-temperature to relatively low-temperature environments is identified as a common factor underlying the evolution of endothermy.
A global meta-analysis of the ecological impacts of alien species on native amphibians
Authors: Nunes Ana L. , Fill Jennifer M. , Davies Sarah J. , Louw Marike , Rebelo Alexander D. , Thorp Corey J. , Vimercati Giovanni , Measey John
Published: February 2019

The exponential increase in species introductions during the Anthropocene has brought about a major loss of biodiversity. Amphibians have suffered large declines, with more than 16% considered to be threatened by invasive species. We conducted a global meta-analysis of the impacts of alien species on native amphibians to determine which aspects of amphibian ecology are most affected by plant, invertebrate, fish, amphibian, reptile, or mammal introductions. Measures of fitness were most strongly affected; amphibian performance was consistently lower in the presence of alien species. While exposure to alien species caused a significant decrease in amphibian behavioural activity when compared with a no species control, this response was stronger towards a control of native impacting species. This indicates a high degree of prey naiveté towards alien species and highlights the importance of using different types of controls in empirical studies. Alien invertebrates had the greatest overall impact on amphibians. This study sets a new agenda for research on biological invasions, highlighting the lack of studies investigating the impacts of alien species on amphibian terrestrial life-history stages. It also emphasizes the strong ecological impacts that alien species have on amphibian fitness and suggests that future introductions or global spread of alien invertebrates could strongly exacerbate current amphibian declines.
Invasive species and postglacial colonization: their effects on the genetic diversity of a Patagonian fish
Authors: Vera-Escalona Iván , Habit Evelyn , Ruzzante Daniel E.
Published: February 2019

The present distribution of Patagonian species is the result of a complex history involving Quaternary refugial populations, Holocene range expansions and demographic changes occurring during the Anthropocene. Invasive salmonids were introduced in Patagonia during the last century, occupying most rivers and lakes, preying on and competing with native species, including the fishGalaxias platei. Here, we usedG. plateias a case study to understand how long-term (i.e. population differentiation during the Holocene) and short-term historical processes (salmonid introductions) affect genetic diversity. Using a suite of microsatellite markers, we found that the number of alleles is negatively correlated with the presence of salmonids (short-term processes), withG. plateipopulations from lakes with salmonids exhibiting significantly lower genetic diversity than populations from lakes without salmonids. Simulations (100 years backwards) showed that this difference in genetic diversity can be explained by a 99% reduction in population size. Allelic richness and observed heterozygosities were also negatively correlated with the presence of salmonids, but also positively correlated with long-term processes linked to Quaternary glaciations. Our results show how different genetic parameters can help identify processes taking place at different scales and their importance in terms of conservation.
Early-life social environment predicts social network position in wild zebra finches
Authors: Brandl Hanja B. , Farine Damien R. , Funghi Caterina , Schuett Wiebke , Griffith Simon C.
Published: February 2019

Early-life experience can fundamentally shape individual life-history trajectories. Previous research has suggested that exposure to stress during development causes differences in social behaviour later in life. In captivity, juvenile zebra finches exposed to elevated corticosterone levels were less socially choosy and more central in their social networks when compared to untreated siblings. These differences extended to other aspects of social life, with ‘stress-exposed’ juveniles switching social learning strategies and juvenile males less faithfully learning their father's song. However, while this body of research suggests that the impacts of early-life stress could be profound, it remains unknown whether such effects are strong enough to be expressed under natural conditions. Here, we collected data on social associations of zebra finches in the Australian desert after experimentally manipulating brood sizes. Juveniles from enlarged broods experienced heightened sibling competition, and we predicted that they would express similar patterns of social associations to stress-treated birds in the captive study by having more, but less differentiated, relationships. We show striking support for the suggested consequences of developmental stress on social network positions, with our data from the wild replicating the same results in 9 out of 10 predictions previously tested in captivity. Chicks raised in enlarged broods foraged with greater numbers of conspecifics but were less ‘choosy’ and more central in the social network. Our results confirm that the natural range of variation in early-life experience can be sufficient to predict individuals' social trajectories and support theory highlighting the potential importance of developmental conditions on behaviour.
The evolution of traits and functions in herbivorous coral reef fishes through space and time
Authors: Siqueira Alexandre C. , Bellwood David R. , Cowman Peter F.
Published: February 2019

Herbivory by fishes has been identified as a key ecological process shaping coral reefs through time. Although taxonomically limited, herbivorous reef fishes display a wide range of traits, which results in varied ecosystem functions on reefs around the world. Yet, we understand little about how these trait combinations and functions in ecosystems changed through time and across biogeographic realms. Here, we used fossils and phylogenies in a functional ecological framework to reveal temporal changes in nominally herbivorous fish assemblages among oceanic basins in both trait space and lineage richness among functions. We show that the trait space occupied by extant herbivorous fishes in the Indo-Pacific resulted from an expansion of traits from the ancestral Tethyan assemblages. By contrast, trait space in the Atlantic is the result of lineage turnover, with relatively recent colonization by lineages that arose in the east Tethys/Indo-Pacific. From an ecosystem function perspective, the Atlantic supports a depauperate fauna, with few extant herbivorous reef fish lineages performing each function. Indo-Pacific fishes support both more functions and more lineages within each function, with a marked Miocene to Pleistocene expansion. These disparities highlight the importance of history in explaining global variation in fish functional composition on coral reefs.
Diurnal variation in the production of vocal information about food supports a model of social adjustment in wild songbirds
Authors: Hillemann F. , Cole E. F. , Keen S. C. , Sheldon B. C. , Farine D. R.
Published: February 2019

Wintering songbirds have been widely shown to make economic foraging decisions to manage the changing balance of risks from predation and starvation over the course of the day. In this study, we ask whether the communication and use of information about food availability differ throughout the day. First, we assessed temporal variation in food-related vocal information produced in foraging flocks of tits (
Paridae
) using audio recordings at radio-frequency identification-equipped feeding stations. Vocal activity was highest in the morning and decreased into the afternoon. This pattern was not explained by there being fewer birds present, as we found that group sizes increased over the course of the day. Next, we experimentally tested the underlying causes for this diurnal calling pattern. We set up bird feeders with or without playback of calls from tits, either in the morning or in the afternoon, and compared latency to feeder discovery, accumulation of flock members, and total number of birds visiting the feeder. Irrespective of time of day, playbacks had a strong effect on all three response measures when compared to silent control trials, demonstrating that tits will readily use vocal information to improve food detection throughout the day. Thus, the diurnal pattern of foraging behaviour did not appear to affect use and production of food-related vocalizations. Instead, we suggest that, as the day progresses and foraging group sizes increase, the costs of producing calls at the food source (e.g. competition and attraction of predators) outweigh the benefits of recruiting group members (i.e. adding individuals to large groups only marginally increases safety in numbers), causing the observed decrease in vocal activity into the afternoon. Our findings imply that individuals make economic social adjustments based on conditions of their social environment when deciding to vocally recruit group members.
Ancestral and offspring nutrition interact to affect life-history traits inDrosophila melanogaster
Authors: Deas Joseph B. , Blondel Leo , Extavour Cassandra G.
Published: February 2019

Ancestral environmental conditions can impact descendant phenotypes through a variety of epigenetic mechanisms. Previous studies on transgenerational effects inDrosophila melanogastersuggest that parental nutrition may affect the body size, developmental duration and egg size of the next generation. However, it is unknown whether these effects on phenotype remain stable across generations, or if specific generations have general responses to ancestral diet. In the current study, we examined the effect on multiple life-history phenotypes of changing diet quality across three generations. Our analysis revealed unforeseen patterns in how phenotypes respond to dietary restriction. Our generalized linear model showed that when considering only two generations, offspring phenotypes were primarily affected by their own diet, and to a lesser extent by the diet of their parents or the interaction between the two generations. Surprisingly, however, when considering three generations, offspring phenotypes were primarily impacted by their grandparents' diet and their own diet. Interactions among different generations’ diets affected development time, egg volume and pupal mass more than ovariole number or wing length. Furthermore, pairwise comparisons of diet groups from the same generation revealed commonalities in strong responses to rich versus poor diet: ovariole number, pupal mass and wing length responded more strongly to poor diet than to rich diet, while development time responded strongly to both rich and poor diets. To improve investigations into the mechanisms and consequences of transgenerational, epigenetic inheritance, future studies should closely examine how phenotypes change across a higher number of generations, and consider responses to broader variability in diet treatments.
Sexual selection and ageing: interplay between pre- and post-copulatory traits senescence in the guppy
Authors: Gasparini Clelia , Devigili Alessandro , Pilastro Andrea
Published: February 2019

Traits associated with mating and fertilization success are expected to senesce with age, but limited information is available on their relative rates of senescence. In polyandrous species, male reproductive fitness depends on both mating and fertilization success. Because successful mating is a prerequisite for post-copulatory sexual selection, ejaculate traits are expected to senesce faster than pre-copulatory traits, as pre-copulatory sexual selection is often deemed to be stronger than post-copulatory sexual selection. This pattern has generally been found in the few empirical studies conducted so far. We tested this prediction in the guppy (
Poecilia reticulata
), a livebearing fish characterized by intense sperm competition, by comparing the expression of male sexual traits at two ages (four and nine months). Contrary to prediction, we found that post-copulatory traits senesced at a significantly slower rate than pre-copulatory traits. We also looked at whether early investment in those sexual traits affects longevity, and the interaction between sperm age (duration of sperm storage inside the male) and male age. Our results suggest that the relative senescence rate of pre- and post-copulatory sexual traits may vary among species with different mating systems and ecology.
Genomic signatures of G-protein-coupled receptor expansions reveal functional transitions in the evolution of cephalopod signal transduction
Authors: Ritschard Elena A. , Fitak Robert R. , Simakov Oleg , Johnsen Sönke
Published: February 2019

Coleoid cephalopods show unique morphological and neural novelties, such as arms with tactile and chemosensory suckers and a large complex nervous system. The evolution of such cephalopod novelties has been attributed at a genomic level to independent gene family expansions, yet the exact association and the evolutionary timing remain unclear. In the octopus genome, one such expansion occurred in the G-protein-coupled receptors (GPCRs) repertoire, a superfamily of proteins that mediate signal transduction. Here, we assessed the evolutionary history of this expansion and its relationship with cephalopod novelties. Using phylogenetic analyses, at least two cephalopod- and two octopus-specific GPCR expansions were identified. Signatures of positive selection were analysed within the four groups, and the locations of these sequences in the
Octopus bimaculoides
genome were inspected. Additionally, the expression profiles of cephalopod GPCRs across various tissues were extracted from available transcriptomic data. Our results reveal the evolutionary history of cephalopod GPCRs. Unexpanded cephalopod GPCRs shared with other bilaterians were found to be mainly nervous tissue specific. By contrast, duplications that are shared between octopus and the bobtail squid or specific to the octopus' lineage generated copies with divergent expression patterns devoted to tissues outside of the brain. The acquisition of novel expression domains was accompanied by gene order rearrangement through either translocation or duplication and gene loss. Lastly, expansions showed signs of positive selection and some were found to form tandem clusters with shared conserved expression profiles in cephalopod innovations such as the axial nerve cord. Altogether, our results contribute to the understanding of the molecular and evolutionary history of signal transduction and provide insights into the role of this expansion during the emergence of cephalopod novelties and/or adaptations.
Does exceptional preservation distort our view of disparity in the fossil record?
Authors: Flannery Sutherland Joseph T. , Moon Benjamin C. , Stubbs Thomas L. , Benton Michael J.
Published: February 2019

How much of evolutionary history is lost because of the unevenness of the fossil record? Lagerstätten, sites which have historically yielded exceptionally preserved fossils, provide remarkable, yet distorting insights into past life. When examining macroevolutionary trends in the fossil record, they can generate an uneven sampling signal for taxonomic diversity; by comparison, their effect on morphological variety (disparity) is poorly understood. We show here that lagerstätten impact the disparity of ichthyosaurs, Mesozoic marine reptiles, by preserving higher diversity and more complete specimens. Elsewhere in the fossil record, undersampled diversity and more fragmentary specimens produce spurious results. We identify a novel effect, that a taxon moves towards the centroid of a Generalized Euclidean dataset as its proportion of missing data increases. We term this effect ‘centroid slippage’, as a disparity-based analogue of phylogenetic stemward slippage. Our results suggest that uneven sampling presents issues for our view of disparity in the fossil record, but that this is also dependent on the methodology used, especially true with widely used Generalized Euclidean distances. Mitigation of missing cladistic data is possible by phylogenetic gap filling, and heterogeneous effects of lagerstätten on disparity may be accounted for by understanding the factors affecting their spatio-temporal distribution.
AutoCryoPicker: An Unsupervised Learning Approach for Fully Automated Single Particle Picking in Cryo-EM Images
Authors: Al-Azzawi Adil , Ouadou Anes , Tanner John J. , Cheng Jianlin
Published: February 2019

Background

An important task of macromolecular structure determination by cryo-electron microscopy (cryo-EM) is the identification of single particles in micrographs (particle picking). Currently, particle picking is laborious, time consuming, and potentially biased due to the need of human intervention to initialize the particle picking. The results typically include many false positives and negatives. Adjusting the parameters to eliminate false positives often excludes true particles in certain orientations. The supervised machine learning (e.g. deep learning) methods for particle picking often need a large training dataset, which requires extensive manual annotation. Other reference-dependent methods rely on low-resolution templates for particle detection, matching and picking, and therefore, are not fully automated. These issues motivate us to develop a fully automated, unbiased framework for particle picking.

Results

We design a fully automated, unsupervised approach for single particle picking in cryo-EM micrographs. Our approach consists of three stages: image preprocessing, particle clustering, and particle picking. The image preprocessing is based on image averaging, normalization, cryo-EM image contrast enhancement correction (CEC), histogram equalization, restoration, adaptive histogram equalization, guided image filtering, and morphological operations significantly improves the quality of original cryo-EM images. Our particle clustering method is based on an intensity distribution model which is much faster and more accurate than traditional K-means and Fuzzy C-Means (FCM) algorithms for single particle clustering. Our particle picking method, based on image cleaning and shape detection with a modified Circular Hough Transform algorithm, effectively detects the shape and the center of each particle and creates a bounding box encapsulating the particles.

Conclusions

AutoCryoPicker can automatically and effectively recognizes particle-like objects from in noisy cryo-EM micrographs without the need of labeled training data and human intervention and therefore is a useful tool for cryo-EM protein structure determination.
Instability of the pseudoautosomal boundary in house mice
Authors: Morgan Andrew P , Bell Timothy A , Crowley James J , de Villena Fernando Pardo-Manuel
Published: February 2019

Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here we estimate the genetic map in a previously-documented expansion of the PAR in the Mus musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the Mus musculus musculus subspecies and show that it involves a complex rearrangement but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus and M. m. castaneus. Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance in the population of unusual levels of polymorphism of unknown functional significance.
fragilityindex: An R Package for Statistical Fragility Estimates in Biomedicine
Authors: Johnson Kipp W. , Rappaport Eli , Shameer Khader , Glicksberg Benjamin S. , Dudley Joel T.
Published: February 2019

Poor reproducibility is a growing crisis in biomedical research. The fragility index was introduced as a convenient measure to estimate how fragile statistical results in clinical trials are to small perturbations in event outcome counts. There is currently no freely available R package to produce this calculation. Furthermore, the original definition of the method is applicable only to 2x2 contingency tables.

As such, we developed an R package to calculate fragility index. We have also extended the concept of a statistical fragility index to two of the most commonly used methods in clinical research, survival analysis via weighted log-rank tests and logistic regression, and implemented these technique sin this R package. We describe example applications of these methods to existing publically available datasets. This R package is freely available under the AGPL license on CRAN (https://cran.r-project.org/web/packages/fragilityindex/index.html). The most recent versions may be downloaded and installed via Github (https://github.com/kippjohnson/fragilityindex).
RanGTP regulates cilium formation and ciliary trafficking of a kinesin-II subunit independent of its nuclear functions
Authors: Huang Shengping , Avasthi Prachee
Published: February 2019

Kinesin is part of the microtubule (MT)-binding motor protein superfamily, which exerts crucial functions in cell division and intracellular transport in different organelles. The heterotrimeric kinesin-II, consisting of the kinesin like protein KIF3A/3B heterodimer and kinesin-associated protein KAP3, is highly conserved across species between the green algaChlamydomonasand humans. It plays diverse roles in cargo transport including anterograde (base to tip) trafficking in cilium. However, the molecular determinants mediating trafficking of heterotrimeric kinesin-II itself is poorly understood. Using the unicellular eukaryoteChlamydomonasand mammalian cells, we show that RanGTP regulates ciliary trafficking of KAP3. We found the armadillo repeat region 6-9 (ARM6-9) of KAP3, required for its nuclear translocation, is sufficient for its targeting to the ciliary base. Given that KAP3 is essential for cilia formation and the emerging roles of RanGTP/importin β in ciliary protein targeting, we further investigate the effect of RanGTP in cilium length regulation in these two different systems. We demonstrate that precise control of RanGTP levels, revealed by different Ran mutants, is crucial for cilium formation and maintenance. Most importantly, we were able to segregate RanGTP regulation of ciliary protein incorporation from of its nuclear roles. Our work provides important support for the model that nuclear import mechanisms have been coopted for independent roles in ciliary import.
Postpartum trend in blood pressure and renal function in women with severe preeclampsia and eclampsia: A prospective cohort-study at Mulago hospital, Kampala, Uganda
Authors: Muteke Kasereka , Beyeza Jolly , Musaba Milton W , Wandabwa Julius , Kiondo Paul
Published: February 2019

Background

Preeclampsia/Eclampsia is a multisystem disorder of pregnancy with kidney involvement. Our objective was to assess the postpartum trend in blood pressure, renal function and proteinuria and, to investigate their predictors in Ugandan women with severe preeclampsia and eclampsia.

Methods

This was a prospective cohort study that involved 97 women with severe preeclampsia and Eclampsia, conducted at Mulago National referral hospital from August 2017 to April 2018. The clinical and laboratory variables were collected from the women on day1, 7, 21 and day 42 after delivery. Kaplan-Meier Survival analysis, Cox-proportional Regression and Log-Rank tests were used to compare the baseline and the follow-up variables with changes in blood pressure, renal function and urine protein.

Results

Most women (93.8%) recovered from hypertension within 6 weeks of childbirth with the mean time to resolution of 2.49 weeks (95% CI: 2.13-2.82). About 81% of the women recovered their renal function and the mean time to recovery was 24.54 days (95% CI: 20.14-28.95). Proteinuria resolved in approximately 84% of the women and the mean time resolution of urine protein of 32.85 days (95% CI: 30.31-35.39). Having multiple pregnancy versus a singleton pregnancy was associated with persistence of hypertension six weeks after child birth (P-value = 0.013).

Conclusion

In this study, the blood pressure and renal function of most women with severe preeclampsia and eclampsia normalized within six weeks after childbirth. A special interdisciplinary follow up for patients with preeclampsia/eclampsia by an obstetrician and physician is needed in the postpartum period to reduce the maternal morbidity and mortality associated with this condition in our community.
Reading “Canadian” management in context: development of English and French education
Authors: Arseneault Rene , Deal Nicholous M. , Mills Albert J.
Published: February 2019

Purpose

The purpose of this paper is to explore the pluralist contours of Canadian management “knowledge” using the discourse “official” bilingualism – the English and French languages – to understand the impact of socio-historical-political differences on the development of management knowledge production.

Design/methodology/approach

Drawing upon an archival collection of management textbooks as historical data, the authors critically explore and analyze the development of Canadian “schools” and management theory. Using narrative analysis and critical hermeneutics, the paper considers the socio-historical-political context of the various “Canadian” scholars that sought to establish a unique business academy distinct but paradoxically akin to the management schools in the USA.

Findings

Mirroring the struggle of Francophones in a dominant English imperative, French management textbooks appeared decades later than English titles. When French texts began to disseminate, it remained in the shadows of American management ideologies.

Research limitations/implications

As only Canadian organizational behavior texts published within the previous 50 years were used as data in this study, it may be incautious to draw broader conclusions. The empirical element of this research relied upon convenience sampling of textbooks.

Practical implications

Management educators weld a considered level of socio-political power that they may or may not knowingly possess, especially in terms of selecting a textbook and other course materials. Regardless of background, management students are somewhat a “tabula rasa;” open to learning new content to make sense of the world. This “open state” places a great deal of responsibility on the professorate in shaping management students’ theoretical understanding of everyday life in organizations. The authors suggest practitioners be reflexive, aware of how textbooks serve as an important vehicle in education that in times past, have promoted or reified mono-cultural agendas.

Originality/value

The research in this paper builds on recent research that considers the role of socio-historical-political context in how management knowledge and theory is performed, as well as contributes to understanding textbooks in how they may shape a pluralist account of Canadian management “knowledge”.
Breaking the Mould? Roy Jenkins’ ‘Radical Centre’ and British Social Democracy in the ‘New Hard Times’
Authors: Diamond Patrick
Published: February 2019

Social democratic politics in Britain requires compelling answers to three animating questions that Roy Jenkins posed in his landmark 1979 Dimbleby lecture. Firstly, how can the British system of democracy be reformed to develop a culture of political participation and pluralism that leads to more equitable economic and social policies? Secondly, how can the centre‐left and left unite to forestall long periods of Tory dominance in electoral politics, thereby avoiding calamities such as the 2016 referendum on EU membership? And, thirdly, how can a flourishing intellectual ecosystem be cultivated on the progressive left that generates radical ideas for economic and social reform, recognising the importance of concerted dialogue between political traditions? This article revisits Jenkins’ 1979 lecture by considering the prospects for ‘breaking the mould’ of British politics in the ‘new hard times’ of Brexit and ‘permanent austerity’.
Government Companies as Regulators
Authors: Daintith Terence
Published: February 2019

In 2016 the government established a new sectoral regulator, with power to grant and withdraw licences, set performance standards, and impose sanctions, not as a statutory authority but in the form of a company wholly owned by the Secretary of State: the Oil and Gas Authority.  This article critically examines this and other uses in the UK of government‐owned or ‐ controlled companies to discharge public regulatory functions, against the background of current government practice regarding arm's length public bodies in general and government companies in particular. It assesses the acceptability of the company form by reference to criteria of democratic control, independence and accountability of regulatory institutions.
Improved efficacy of ramucirumab plus docetaxel after nivolumab failure in previously treated non‐small cell lung cancer patients
Authors: Shiono Ayako , Kaira Kyoichi , Mouri Atsuto , Yamaguchi Ou , Hashimoto Kosuke , Uchida Takahiro , Miura Yu , Nishihara Fuyumi , Murayama Yoshitake , Kobayashi Kunihiko , Kagamu Hiroshi
Published: February 2019

Background

It is unclear whether the chemotherapy response improves after exposure to immunotherapy. Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects that stimulate tumor shrinkage. We conducted a retrospective study to evaluate improvement of the efficacy of ramucirumab plus docetaxel after the failure of nivolumab as a PD‐1 inhibitor.

Methods

From February 2016 to December 2017, 152 patients with non‐small cell lung cancer (NSCLC) administered nivolumab in our institution were identified. We reviewed the records of 20 NSCLC patients administered ramucirumab plus docetaxel after nivolumab failure. The overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were investigated. Pegylated granulocyte colony‐stimulating factor was prophylactically administered to 18 patients (90%) after the administration of ramucirumab plus docetaxel.

Results

The median age of the patients was 70 (range: 55–77) years. Twelve patients were male and eight were female. The histology was adenocarcinoma in 16 patients, squamous cell carcinoma in three, and other in one. The ORR of ramucirumab plus docetaxel was 60%, and the PFS and OS were 169 and 343 days, respectively. Among the 20 patients, 12 achieved a partial response, giving an ORR of 60.0%. Six patients had stable disease and two had progressive disease. The disease control rate was 90%. Gastrointestinal adverse events were frequently observed in 19 patients.

Conclusions

Ramucirumab plus docetaxel achieved a higher response rate when administered immediately after nivolumab failure compared to regimens without prior nivolumab administration.
Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models
Authors: Trujillo‐Estrada Laura , Nguyen Cassidy , da Cunha Celia , Cai Lena , Forner Stefania , Martini Alessandra C. , Ager Rahasson R. , Prieto Gilberto Aleph , Cotman Carl W. , Baglietto‐Vargas David , LaFerla Frank M.
Published: February 2019

Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule‐associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain‐of‐function and loss‐of‐function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild‐type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.
HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex
Authors: González Betina , Bernardi Alejandra , Torres Oscar V. , Jayanthi Subramaniam , Gomez Natalia , Sosa Máximo H. , García‐Rill Edgar , Urbano Francisco J. , Cadet Jean‐Lud , Bisagno Verónica
Published: February 2019

Dysregulation of histone deacetylases (HDAC) has been proposed as a potential contributor to aberrant transcriptional profiles that can lead to changes in cognitive functions. It is known that METH negatively impacts the prefrontal cortex (PFC) leading to cognitive decline and addiction whereas modafinil enhances cognition and has a low abuse liability. We investigated if modafinil (90 mg/kg) and methamphetmine (METH) (1 mg/kg) may differentially influence the acetylation status of histones 3 and 4 (H3ac and H4ac) at proximal promoters of class I, II, III, and IV HDACs. We found that METH produced broader acetylation effects in comparison with modafinil in the medial PFC. For single dose, METH affected H4ac by increasing its acetylation at class I Hdac1 and class IIb Hdac10, decreasing it at class IIa Hdac4 and Hdac5. Modafinil increased H3ac and decreased H4ac of Hdac7. For mRNA, single‐dose METH increased Hdac4 and modafinil increased Hdac7 expression. For repeated treatments (4 d after daily injections over 7 d), we found specific effects only for METH. We found that METH increased H4ac in class IIa Hdac4 and Hdac5 and decreased H3/H4ac at class I Hdac1, Hdac2, and Hdac8. At the mRNA level, repeated METH increased Hdac4 and decreased Hdac2. Class III and IV HDACs were only responsive to repeated treatments, where METH affected the H3/H4ac status of Sirt2, Sirt3, Sirt7, and Hdac11. Our results suggest that HDAC targets linked to the effects of modafinil and METH may be related to the cognitive‐enhancing vs cognitive‐impairing effects of these psychostimulants.
Single versus multi‐drug antimicrobial surgical infection prophylaxis for left ventricular assist devices: A systematic review and meta‐analysis
Authors: Patel Sinal , Choi Jae Hwan , Moncho Escrivá Ester , Rizvi Syed Saif Abbas , Maynes Elizabeth J. , Samuels Louis E. , Luc Jessica G. Y. , Morris Rohinton J. , Massey Howard T. , Tchantchaleishvili Vakhtang , Aburjania Nana
Published: February 2019

Infection remains the Achilles heel of left ventricular assist device (LVAD) therapy. However, an optimal antimicrobial surgical infection prophylaxis (SIP) regimen has not been established. This study evaluated the efficacy of a single‐drug SIP compared to a multi‐drug SIP on clinical outcomes in patients undergoing continuous‐flow LVAD (CF‐LVAD) and pulsatile LVAD (P‐LVAD) implantation. An electronic search was performed to identify studies in the English literature on SIP regimens in patients undergoing LVAD implantation. Identified articles were assessed for inclusion and exclusion criteria. Fourteen articles with 1,311 (CF‐LVAD: 888; P‐LVAD: 423) patients were analyzed. Overall, 501 (38.0%) patients received single‐drug SIP, whereas 810 (62.0%) received multi‐drug SIP. Time to infection was comparable between groups. There was no significant difference in overall incidence of LVAD‐specific infections [single‐drug: 18.7% vs. multi‐drug: 24.8%, P = 0.49] including driveline infections [single‐drug: 14.1% vs. multi‐drug: 20.8%, P = 0.37]. Compared to single‐drug SIP, patients who received multi‐drug SIP had a significantly lower survival rate [single‐drug: 90.0% vs. multi‐drug: 76.0%, P = 0.01] and infection‐free survival rate [single‐drug: 88.4% vs. multi‐drug: 77.3%, P = 0.04] at 90 days. However, there were no significant differences in 1‐year survival and 1‐year infection‐free survival between groups. No survival differences were observed in the CF‐LVAD subset as well. This study demonstrated no additional advantage of a multi‐drug compared to a single‐drug regimen for SIP. Although there was a modest advantage in early survival among CF‐LVAD and P‐LVAD patients who received single‐drug SIP, there were no significant differences in the 1‐year survival and 1‐year infection‐free survival.
Evaluation of selective laser trabeculoplasty as an intraocular pressure lowering option
Authors: Belitsky Yuri , Škiljić Dragana , Zetterberg Madeleine , Kalaboukhova Lada
Published: February 2019

Purpose

Selective laser trabeculoplasty (SLT) is one of the many treatment options for lowering intraocular pressure (IOP) in patients with glaucoma. This study aimed to evaluate the effect of SLT.

Methods

Data were collected from medical records of 289 patients who underwent SLT treatment (180° of trabecular meshwork) during 2014 and 2015 at the Department of Ophthalmology, Sahlgrenska University Hospital, Mölndal, Sweden. Baseline characteristics and information from a follow‐up within 100 days were also recorded. The study analysed different subtypes of glaucoma with regard to SLT, with a particular focus on exfoliative glaucoma, a common subtype in Sweden. Successful treatment was defined as an IOP lowering effect of >20% with no further changes in treatment. The impact of surgeon's experience on treatment outcome was also analysed.

Results

Both patients with exfoliative glaucoma and those with primary open‐angle glaucoma showed a reduction in mean IOP; no significant difference was found between these two subtypes before treatment or at the first follow‐up. The success rate at follow‐up (within 100 days) was 52%. There was a significant difference in outcome between surgeons with different levels of experience, but this difference could likely be explained by differences in treatment strategies and total energy used.

Conclusion

For many patients with glaucoma, SLT was an effective treatment option for lowering IOP. It was also effective for several glaucoma subtypes. However, not all patients had a significant reduction in IOP after treatment with SLT, and some may require additional treatment.
Polymorphisms in the NFkB, TNF‐alpha, IL‐1beta, and IL‐18 pathways are associated with response to anti‐TNF therapy in Danish patients with inflammatory bowel disease
Authors: Bank Steffen , Julsgaard Mette , Abed Osama Karim , Burisch Johan , Broder Brodersen Jacob , Pedersen Natalia Konstantinovich , Gouliaev Anja , Ajan Rullah , Nytoft Rasmussen Ditlev , Honore Grauslund Camilla , Roug Stine , Galsgaard Julie , Sprogøe Høyer Finsen David , Lindby Karoline ,   The Danish IBD Genetics Working Group, Sørensen Jeanette , Larsen Lone , Rohr Andersen Malene , Brandslund Ivan , Thomassen Mads , Green Anders , Bo Bojesen Anders , Bek Sørensen Signe , Vogel Ulla , Andersen Vibeke
Published: February 2019

Background

Anti‐tumor necrosis factor‐α (TNF‐α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one‐third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti‐TNF therapy among patients with CD or UC.

Aim

A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti‐TNF response.

Methods

Fifty‐three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender).

Results

Ten SNPs were associated with anti‐TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95% CI: 1.02‐3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95% CI: 1.00‐1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95% CI: 1.02‐1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95% CI: 0.33‐0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95% CI: 1.24‐4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27‐0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95% CI: 1.06‐2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95% CI: 0.44‐0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95% CI: 1.01‐2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65‐0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95% CI: 1.01‐1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95% CI: 0.57‐0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95% CI: 0.66‐1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95% CI: 1.01‐1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95% CI: 1.01‐1.53, P = 0.04)).

Conclusions

The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF‐α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti‐TNF therapy. Our multi‐SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.
Worlding aspirations and resilient futures: Framings of risk and contemporary city‐making in Metro Cebu, the Philippines
Authors: Ramalho Jordana
Published: February 2019

In the Philippines, calls for creating ‘global’, ‘sustainable’ and ‘resilient’ cities are placing urban poor communities in increasingly precarious positions. These communities have long been the targets of urban development and ‘modernisation’ efforts; more recently the erasure of informal settlements from Philippine cities is being bolstered at the behest of climate change adaptation and disaster risk management (DRM) agendas. In Metro Cebu, flood management has been at the heart of DRM and broader urban development discussions, and is serving as justification for the demolition and displacement of informal settler communities in areas classed as ‘danger zones’. Using Kusno's (2010) interpretation of the ‘exemplary centre’ as a point of departure, this paper interrogates the relationship between DRM, worlding aspirations (Roy and Ong, 2011) and market‐oriented urbanisation in Cebu, and considers the socio‐spatial implications of these intersecting processes for urban poor communities. Through analysing the contradictions inherent in framings of certain bodies and spaces as being ‘of risk’ or ‘at risk’ over others, I argue that the epistemologies of modernity, disaster risk and resilience endorsed and propagated by the state are facilitating processes of displacement and dispossession that serve elite commercial interests under the auspices of disaster resilience and pro‐poor development.
Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients
Authors: Le Louedec Félicien , Alix‐Panabières Catherine , Lafont Thierry , Allal Ben C. , Garrel Renaud , Digue Laurence , Guigay Joël , Cupissol Didier , Delord Jean‐Pierre , Lallemant Benjamin , Alfonsi Marc , Aubry Karine , Mazel Martine , Becher François , Perriard Françoise , Chatelut Etienne , Thomas Fabienne
Published: February 2019

Aims

Cetuximab associated with cisplatin and 5‐fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment.

Methods

An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating‐tumour cells vs progression‐free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS.

Results

PK data (28 patients, 203 observations) were best described by a two‐compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1–65.6) for each 1‐point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis.

Conclusions

Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.