bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential role of lava lizards as pollinators across the Galápagos Islands
Authors: HERVÍAS‐PAREJO Sandra , NOGALES Manuel , GUZMÁN Beatriz , TRIGO María del Mar , OLESEN Jens M. , VARGAS Pablo , HELENO Ruben , TRAVESET Anna
Published: February 2019

Lizards have been reported as important pollinators on several oceanic islands. Here we evaluate the potential role of Galápagos lava lizards (Microlophus spp.) as pollinators across their radiation. Over 3 years, we sampled pollen transport by 9 lava lizard species on the 10 islands where they are present, including 7 single‐island endemics. Overall, only 25 of 296 individuals sampled (8.4%) transported pollen of 10 plant species, the most common being Prosopis juliflora, Exodeconus miersii, Sesuvium sp. and Cordia leucophlyctis. At least 8 of these plant species were native, and none were confirmed as introduced to the archipelago. Despite the low overall proportion of individuals carrying pollen, this was observed in 7 of the nine lizard species, and on 8 of the ten main islands (Española, Fernandina, Floreana, Isabela, Marchena, Pinta, Santa Cruz and Santiago), suggesting that this is a widespread interaction. The results reported here support the potential role of lava lizards as pollinators across their radiation, although they may represent a relatively modest contribution when compared with birds and insects. However, we cannot discard that lizards may be ecologically significant for particular plant species and ecosystems given the specific climatic condition and functional diversity of each island.
Voles and weasels in the boreal Fennoscandian small mammal community: what happens if the least weasel disappears due to climate change?
Authors: YLÖNEN Hannu , HAAPAKOSKI Marko , SIEVERT Thorbjörn , SUNDELL Janne
Published: February 2019

Climate change, habitat loss and fragmentation are major threats for populations and a challenge for individual behavior, interactions and survival. Predator–prey interactions are modified by climate processes. In the northern latitudes, strong seasonality is changing and the main predicted feature is shortening and instability of winter. Vole populations in the boreal Fennoscandia exhibit multiannual cycles. High amplitude peak numbers of voles and dramatic population lows alternate in 3–5‐year cycles shortening from North to South. One key factor, or driver, promoting the population crash and causing extreme extended lows, is suggested to be predation by the least weasel. We review the arms race between prey voles and weasels through the multiannual density fluctuation, affected by climate change, and especially the changes in the duration and stability of snow cover. For ground‐dwelling small mammals, snow provides thermoregulation and shelter for nest sites, and helps them hide from predators. Predicted increases in the instability of winter forms a major challenge for species with coat color change between brown summer camouflage and white winter coat. One of these is the least weasel, Mustela nivalis nivalis. Increased vulnerability of wrong‐colored weasels to predation affects vole populations and may have dramatic effects on vole dynamics. It may have cascading effects on other small rodent–predator interactions and even on plant–animal interactions and forest dynamics.
Unconventional Natural Gas Accumulations in Stacked Deposits: A Discussion of Upper Paleozoic Coal‐Bearing Strata in the East Margin of the Ordos Basin, China
Authors: LI Yong , YANG Jianghao , PAN Zhejun , MENG Shangzhi , WANG Kai , NIU Xinlei
Published: February 2019

The Upper Paleozoic (Carboniferous to Permian) succession in the east margin of the Ordos Basin in the North China Craton has a potential to contain significant hydrocarbon resources, though attention have been mainly attracted for its successful development of coalbed methane (CBM). To improve the previous resource estimates and evaluate the hydrocarbon play possibilities, this study incorporated new discoveries of hydrocarbon units and their stratigraphic relation with source rocks, hydrocarbon migration and trapping configurations. Continuous hydrocarbon accumulation units were identified within the Upper Paleozoic, including the Taiyuan, Shanxi and Xiashihezi formations with great tight gas potential, and the Taiyuan and Shanxi formations also containing shale gas and CBM. Different strata combinations are identified with coal deposition and favour for continuous gas accumulations, including the tidal flat, deltaic and fluvial systems distributed in most of the study areas. Methane was not only generated from the thick coal seams in the Taiyuan and Shanxi formations, but also from shale and dark mudstones. The coal, shale and tight sandstones are proved of remarkable gas content and hydrocarbon indications, and the gas saturation of tight sandstones decreases upward. The stacked deposit combinations vary isochronally in different areas, while the coal seams were developed stably showing good gas sources. Two key stages control the hydrocarbon enrichment, the continuous subsidence from coal forming to Late Triassic and the anomalous paleo‐geothermal event happened in Early Cretaceous, as indicated by the fluid inclusions evidence. Extensive areas show good hydrocarbon development potential presently, and more works should be focused on the evaluation and selection of good reservoir combinations.
Numerical Taxonomy and Bayes Discriminant Analysis on 42 Fossil Species in Dicksoniaceae from China
Authors: XIN Cunlin , WANG Jingjing , WANG Luhan , ZHANG Yamei
Published: February 2019

As the basal group of Polypodiales, the specific taxonomy of Dicksoniaceae is still being debated. As a quantitative analysis method, numerical taxonomy has been applied to the taxonomic study of many plant families and genera in recent years due to its simplicity and high accuracy. However, the numerical analysis of the Dicksoniaceae fossils has not been reported at present. In the present study, the pinnule morphological data of 42 Mesozoic fossil species of the Dicksoniaceae were analyzed using cluster analysis, principal component analysis and correlation analysis. The results revealed that 42 taxonomic units could be divided into six representative groups, which are consistent with the traditional taxonomy. After screening, an identification key on 28 fossil species of four genera with a definite taxonomic position was established. According to the quantitative analysis, a Bayes discriminant model was established for the selected species. Lastly, the model was tested using the morphological data of the fossil pinnules in Dicksoniaceae from the Yaojie Formation, suggesting that the discriminant model is accurate to a certain extent. As a result, the numerical taxonomy can be applied to the classification of the Dicksoniaceae fossils.
Heavy Oils and Oil Sands: Global Distribution and Resource Assessment
Authors: LIU Zuodong , WANG Hongjun , BLACKBOURN Graham , MA Feng , HE Zhengjun , WEN Zhixing , WANG Zhaoming , YANG Zi , LUAN Tiansi , WU Zhenzhen
Published: February 2019

Global recoverable resources of heavy oil and oil sands have been assessed by CNPC using a geology‐based assessment method combined with the traditional volumetric method, spatial interpolation method, parametric‐probability method etc. The most favourable areas for exploration have been selected in accordance with a comprehensive scoring system. The results show: (1) For geological resources, CNPC estimate 991.18 billion tonnes of heavy oil and 501.26 billion tonnes of oil sands globally, of which technically recoverable resources of heavy oil and oil sands comprise 126.74 billion tonnes and 64.13 billion tonnes respectively. More than 80% of the resources occur within Tertiary and Cretaceous reservoirs distributed across 69 heavy‐oil basins and 32 oil‐sands basins. 99% of recoverable resources of heavy oil and oil sands occur within foreland basins, passive continental‐margin basins and cratonic basins. (2) Since residual hydrocarbon resources remain following large‐scale hydrocarbon migration and destruction, heavy oil and oil sands are characterized most commonly by late hydrocarbon accumulation, the same basin types and source‐reservoir conditions as for conventional hydrocarbon resources, shallow burial depth and stratabound reservoirs. (3) Three accumulation models are recognised, depending on basin type: degradation along slope; destruction by uplift; and migration along faults. (4) In addition to mature exploration regions such as Canada and Venezuela, the Volga‐Ural Basin and the Pre‐Caspian Basin are less well‐explored and have good potential for oil‐sand discoveries, and it is predicted that the Middle East will be an important region for heavy‐oil development.
The Paradoxical Perception of Contemporary Democracy, and the Question of its Future
Authors: Coicaud Jean‐Marc
Published: February 2019

This article explores the perception of democracy today, at the national and international levels. This perception is rather paradoxical. On the one hand, democracy is celebrated. As such it functions as a benchmark of political legitimacy. On the other hand, it is criticized. The article provides explanations for this state of affairs. Among the explanations put forward in order to account for the criticisms of democracy the article stresses the deepening of economic inequalities and a sense of social alienation that has been growing in recent years among the people that globalization and its associated policies are affecting negatively. For the way forward the article offers suggestions in order to improve the reputation and reality of democracy. In this regard it argues that the possibility to improve democracy, both at the national and international levels, is to a large extent based on making it more inclusive (especially economically speaking) and reflective.
On the Future of Public Policy Schools: What Can Be Done to ‘Take Back Control’?
Authors: Offe Claus
Published: February 2019

Anheier's five recommendations suggest valuable steps in the right direction. Yet let me add a sixth one – the comparative institutional analysis of what I have termed ‘agency gaps’, or structural governance deficiencies and ‘hindrances’.
Theorizing Democracy between National and International Politics: A Snapshot from East Asia Introduction
Authors: Chen Chia‐Ming , Coicaud Jean‐Marc
Published: February 2019

There is now a reality on which most people agree: democracy is in trouble in the West. The fact that in election after election, mainstream and established political parties and politicians, whatever their political affiliation, are being challenged and more often than not defeated by political forces presenting themselves as populist is a case in point.
Conflict of Interest, Disclosure and Vertical Relationships: An Experimental Analysis
Authors: Chen Paul , Richardson Martin
Published: February 2019

Vertical integration in providing financial products and advice is not uncommon. We conduct an experiment in which a financial advisor recommends to a client one of two potential assets to purchase and an asset purchase price. In one setting, the players’ incentives are aligned. In another, a conflict of interest exists with the advisor's remuneration favouring one particular asset. We find that conflict influences the advisor's asset recommendation away from the asset that would better serve the client. Disclosure of that conflict, however, influences neither the advisor's asset recommendation nor, more surprisingly, the client's likelihood of rejecting that recommendation.
Longitudinal Findings from a Randomized Clinical Trial of Varenicline for Alcohol Use Disorder with Comorbid Cigarette Smoking
Authors: Bold Krysten W. , Zweben Allen , Fucito Lisa M. , Piepmeier Mary E. , Muvvala Srinivas , Wu Ran , Gueorguieva Ralitza , O'Malley Stephanie S.
Published: February 2019

Background

This study is the first to examine longitudinal posttreatment outcomes of a placebo‐controlled trial of varenicline for alcohol use disorder (AUD) with comorbid cigarette smoking.

Methods

Participants were 131 adults (n = 39 female) seeking alcohol treatment in a randomized, double‐blind, parallel group, placebo‐controlled, 16‐week multisite trial of varenicline combined with medical management (MM). Timeline follow‐back assessments of alcohol and smoking behavior were conducted at the end of treatment (4 months), with follow‐ups at 6, 9, and 12 months. Outcomes were percentage of heavy drinking days (PHDD), percent of participants with no heavy drinking days (NHDD), cotinine‐confirmed prolonged smoking abstinence (PA), and good clinical outcome on either NHDD or PA.

Results

Treatment improvements were maintained posttreatment. For the sample overall, PHDD or NHDD did not differ significantly by treatment condition (ps > 0.13), but varenicline produced higher rates of PA versus placebo at 4, 9, and 12 months (p < 0.05). Significant differences were observed by sex: Males had higher rates of NHDD with varenicline (28.9%) versus placebo (6.4%) at the end of treatment (p = 0.004), and these effects were maintained at 12 months (varenicline: 40.0% vs. placebo: 19.2%, p = 0.03). Higher rates of PA were seen for varenicline in both males (8.9%) and females (21.1%) versus placebo (males/females: 0%) at the end of treatment (p = 0.05), and this effect was maintained at 12 months for females (varenicline: 21.1% vs. placebo, 0.0%, p = 0.05).

Conclusions

Varenicline treatment combined with MM appears to have enduring benefits for patients with co‐occurring AUD and cigarette smoking, and these effects may differ by sex.
Incorporating Writing into a Personalized Normative Feedback Intervention to Reduce Problem Drinking Among College Students
Authors: Young Chelsie M. , Neighbors Clayton
Published: February 2019

Background

Personalized normative feedback (PNF) interventions have repeatedly been found to reduce drinking among undergraduates. However, effects tend to be small, potentially due to inattention to and inadequate processing of the information. Adding a writing component to PNF interventions may allow for greater cognitive processing of the feedback, thereby boosting intervention efficacy. Additionally, expressive writing (EW) has been shown to reduce drinking intentions; however, studies have not examined whether it can reduce drinking behavior. The present experiment evaluated whether including a writing task would improve the efficacy of PNF and whether EW alone can be used to reduce drinking and alcohol‐related problems.

Methods

Heavy drinking undergraduates (N = 250) were randomized to receive either: (i) PNF about their alcohol use; (ii) EW about a negative, heavy drinking occasion; (iii) PNFplus writing about the norms feedback; or (iv) attention control feedback about their technology use in an online brief intervention. Participants (N = 169) then completed a 1‐month follow‐up survey about their past month alcohol use and alcohol‐related problems online.

Results

PNFplus writing reduced alcohol‐related problems compared to all other conditions. No significant reductions were found for EW. Both PNF and PNFplus writing reduced perceived norms and perceived norms mediated intervention effects for both feedback conditions.

Conclusions

The current findings suggest that adding a writing component to traditional norms‐based feedback approaches might be an efficacious strategy, particularly for reducing alcohol‐related consequences.
Willing to Work But Not to Wait: Individuals with Greater Alcohol Use Disorder Show Increased Delay Discounting Across Commodities and Less Effort Discounting for Alcohol
Authors: Phung Quan H. , Snider Sarah E. , Tegge Allison N. , Bickel Warren K.
Published: February 2019

Background

Delay discounting refers to the devaluation of a reward given increasing delays to delivery. Similarly, effort discounting refers to the devaluation of a reward given increasing effort required to obtain it. Individuals with substance use disorder show higher rates of delay discounting, exacerbating short‐term positive reinforcement at the expense of long‐term consequences. This study explores how effort discounting compares to delay discounting behavior among alcohol users as well as how these preferences change between monetary and alcohol rewards.

Methods

A total of 100 participants completed an online survey through Amazon Mechanical Turk. Participant alcohol use was evaluated using DSM‐5 and the Alcohol Use Disorders Identification Test criteria. All participants completed 4 randomized discounting tasks involving delay or effort discounting, in which the reward was money or alcohol. A follow‐up experiment (n = 423) added the alcohol purchase task to assess alcohol valuation.

Results

Individuals with greater alcohol use disorder (AUD) severity discounted future money and alcohol significantly more than those with less AUD. However, individuals meeting more DSM‐5 criteria were only willing to perform more effort for alcohol. The follow‐up experiment replicated these findings and demonstrated that individuals with greater AUD also showed an increased valuation of alcohol and alcohol value‐mediated effort discounting.

Conclusions

These results suggest that individuals with greater AUD were less willing to wait for money or alcohol. While all participants were willing to work for money regardless of AUD severity, individuals with greater AUD showed increased valuation of alcohol drinks and were willing to exert more effort to obtain alcohol. Together, these results paint a picture of individuals with increased AUD as both more impulsive and willing to work to obtain alcohol, contributing to our understanding of decision making among individuals who abuse substances.
Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity
Authors: El‐Boraie Ahmed , Taghavi Taraneh , Chenoweth Meghan J. , Fukunaga Koya , Mushiroda Taisei , Kubo Michiaki , Lerman Caryn , Nollen Nicole L. , Benowitz Neal L. , Tyndale Rachel F.
Published: February 2019

The nicotine metabolite ratio (NMR; 3‐hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome‐wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European‐ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine‐d2/(nicotine‐d2 + cotinine‐d2)). CYP2A6 genotypes and the NMR were assessed in European‐ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory‐based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR‐stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.
Molecular cloning of WIF1 and HMGA2 reveals ear‐preferential expression while uncovering a missense mutation associated with porcine ear size in WIF1
Authors: Liang J. , Zhang Y. , Wang L. , Liu X. , Yan H. , Wang L. , Zhang L.
Published: February 2019

Considerable diversity exists in porcine ear size, which is an important morphological feature of pig breeds. Previously, we localized four crucial candidate genes—high mobility group AT‐hook 2 (HMGA2), LEM domain‐containing 3 (LEMD3), methionine sulfoxide reductase B3 (MSRB3) and Wnt inhibitory factor 1 (WIF1)—on Sus Scrofa chromosome 5 affecting porcine ear size, then cloned LEMD3 and MSBR3. In this study, we performed rapid amplification of cDNA ends to obtain full‐length cDNA sequences of 2338‐bp WIF1 and 2998‐bp HMGA2. Using quantitative real‐time PCR, we revealed that WIF1 expression was highest in ear cartilage of 60‐day‐old pigs and that this is therefore a better candidate gene for ear size than HMGA2. We further screened coding sequence variants in both genes and identified only one missense mutation (WIF1:c.1167C>G) in a conserved epidermal growth factor‐like domain from the mammalian WIF1 protein. The protein‐altering mutation was significantly associated with ear size across the Large White × Minzhu hybrid and Beijing Black pig populations. When WIF1:c.1167C>G was included as fixed effect in the model to re‐run a genome‐wide association study in the Large White × Minzhu intercross population the P‐value of the peak SNP on SSC5 from re‐running the genome‐wide association study dropped from 2.45E‐12 to 7.33E‐05. Taken together, the WIF1:c.1167C>G could be an important mutation associated with ear size. Our findings provide helpful information for further studies of the molecular mechanisms controlling porcine ear size.
Primary lymphangioma circumscriptum of the vulva presenting as warty plaques
Authors: Gude Geethanjali , Gupta Parikshaa , Sharma Ramesh Kumar , Rajwanshi Arvind
Published: February 2019

Lymphangioma circumscriptum is a benign hamartomatous malformation involving the lymphatic system of skin and subcutaneous tissue. It can involve any part of the body with maximum predilection for proximal parts of limbs. Vulvar involvement is quite infrequent. Based on the aetiopathogenesis, it can be either primary or secondary, with the secondary form being relatively more common in vulva. We report an exceedingly rare case of primary lymphangioma circumscriptum in a post‐menopausal female presenting with multiple warty, papulo‐nodular lesions on both labia majora. The patient was diagnosed histopathologically and managed surgically by wide local excision with primary closure.
Political Finance Regulation and Reform in New South Wales: Towards a Fairer System?
Authors: Nwokora Zim , Anderson Malcolm , Tham Joo‐Cheong , Gauja Anika , Mills Stephen , Miragliotta Narelle
Published: February 2019

In recent years the regulation of political finance in Australia has moved from systems of laissez‐faire to systems of enhanced regulation, which aim to curb the scale and influence of donations. This article examines political finance regulation in New South Wales — the jurisdiction that has seen the most significant transformation of its regulatory setup — to assess whether and how the new regulations have affected donations to political parties in the state. We find, based on analysis of the pattern of donations before and after the reforms, that the regulations have made the financing system fairer and thus improved the quality of democracy in the state.
Anti‐Conservatism: Paul Hasluck and Liberal Development in Papua New Guinea
Authors: MacWilliam Scott
Published: February 2019

In the continuing debates about the relative importance of conservatism and liberalism in the history of the Australian Liberal Party, one important dimension remains absent. Liberal developmentalism as an important anti‐conservative strand of thought was critical to the party's formative years after the Second World War as a party of government. The importance of this facet of liberalism is illustrated here by reference to the role of long‐serving Minister for Territories Paul Hasluck in overseeing development in Papua and New Guinea (PNG). Hasluck and the Australian Administration formulated policy intended to secure the indigenous population on rural smallholdings at higher standards of living before industrialisation's anticipated effects of proletarianisation could take effect.
Development and validation of a multiple‐choice questionnaire‐based theoretical test in direct ophthalmoscopy
Authors: Jørgensen Morten , Savran Mona Meral , Christakopoulos Christos , Bek Toke , Grauslund Jakob , Toft Peter Bjerre , Ziemssen Focke , Konge Lars , Sørensen Torben Lykke , Subhi Yousif
Published: February 2019

Purpose

Direct ophthalmoscopy can reveal systemic, neurologic and ophthalmic conditions, but is poorly mastered among young physicians. A theoretical test is needed to measure effect of educational interventions. We developed and gathered validity evidence for a multiple‐choice questionnaire (MCQ)‐based theoretical test in direct ophthalmoscopy.

Methods

The MCQ was developed by interviewing experts. Then, validity evidence was evaluated using Messick's validity framework. Content was ensured by inviting the experts to contribute in a Delphi‐like process. Response process was ensured by piloting and by streamlining all instructions. Then, the test was taken by ophthalmologists and by medical students without experience in direct ophthalmoscopy. Results were used to evaluate internal structure (item quality analysis and internal consistency), relations to other variables (correlation of test scores to experience level) and consequences (establishment of pass–fail score and the consequences of its use).

Results

The first phase of the study yielded 100 MCQs. In second phase, we identified that 60 items fulfilled predefined relevance and item quality requirements. These items demonstrated very high internal consistency (Cronbach's alpha = 0.95), significantly discriminated medical students from specialists (p < 0.001, independent samples t‐test) and the established pass–fail score of 50 (83%) correct answers resulted in no false positives (students passing) and no false negatives (specialists failing). A Decision study identified that sampling 15 items suffice for certification.

Conclusion

We developed and validated an MCQ‐based theoretical test in direct ophthalmoscopy that enables an evidence‐based approach to measuring, evaluating and certifying the theoretical knowledge necessary for direct ophthalmoscopy.
Correlation between skeletal muscle fiber type and free amino acid levels in Japanese Black steers
Authors: Mashima Daisuke , Oka Yoshiaki , Gotoh Takafumi , Tomonaga Shozo , Sawano Shoko , Nakamura Mako , Tatsumi Ryuichi , Mizunoya Wataru
Published: February 2019

Free amino acids are important components of tastants and flavor precursors in meat. To clarify the correlation between muscle fiber type and free amino acids, we determined the concentrations of various free amino acids and dipeptides in samples of different muscle tissues (n = 21), collected from 26‐month‐old Japanese Black steers (n = 3) at 2 days postmortem. The proportions of the myosin heavy chain (MyHC), slow (MyHC1) and fast (MyHC2) isoforms were determined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE). The contents of free amino acids and dipeptides were measured by high performance liquid chromatography (HPLC). The MyHC isoform composition varied among the tissue samples. The MyHC1 proportion ranged from 6.9% ± 3.9% to 83.3% ± 16.7%. We confirmed that there was a strong positive correlation between MyHC1 composition and total free amino acid concentrations, including those for two dipeptides. Among the 31 measured free amino acids and dipeptides, 11 showed significant positive correlations and five showed significant negative correlations with MyHC1 composition. These results suggest that a high MyHC1 content induces high free amino acid contents in bovine muscles possibly because of greater oxidative metabolism. This high level of free amino acids could contribute to the intense flavor of meat that is rich in slow‐twitch fibers.
Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues
Authors: Ittner Lars M. , Klugmann Matthias , Ke Yazi D.
Published: February 2019

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that presents with cognitive decline. The current understanding of underlying disease mechanisms remains incomplete. Genetically modified mouse models have been instrumental in deciphering pathomechanisms in AD. While these models were typically generated by classical transgenesis and genome editing, the use of adeno‐associated viruses (AAVs) to model and investigate AD in mice, as well as to develop novel gene‐therapy approaches, is emerging. Here, we reviewed literature that used AAVs to study and model AD and discuss potential gene therapy strategies.

Linked Articles

This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
Integrative molecular profiling identifies a novel cluster of estrogen receptor‐positive breast cancer in very young women
Authors: Park Charny , Yoon Kyong‐Ah , Kim Jihyun , Park In Hae , Park Soo Jin , Kim Min Kyeong , Jang Wooyeong , Cho Soo Young , Park Boyoung , Kong Sun‐Young , Lee Eun Sook
Published: February 2019

Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER)‐positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. TP53, PIK3CA and GATA3 were highly recurrent somatic mutation genes. APOBEC‐associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A‐like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin‐mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial‐mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.
Phase I study of tirabrutinib (ONO‐4059/GS‐4059) in patients with relapsed or refractory B‐cell malignancies in Japan
Authors: Munakata Wataru , Ando Kiyoshi , Hatake Kiyohiko , Fukuhara Noriko , Kinoshita Tomohiro , Fukuhara Suguru , Shirasugi Yukari , Yokoyama Masahiro , Ichikawa Satoshi , Ohmachi Ken , Gion Naokazu , Aoi Arata , Tobinai Kensei
Published: February 2019

We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second‐generation, enhanced‐selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B‐cell non−Hodgkin lymphoma (B‐cell NHL) and chronic lymphocytic leukemia (CLL). This was an open‐label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose‐limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1‐4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B‐cell NHL/CLL.
Severe asthma—A population study perspective
Authors: Backman Helena , Jansson Sven‐Arne , Stridsman Caroline , Eriksson Berne , Hedman Linnea , Eklund Britt‐Marie , Sandström Thomas , Lindberg Anne , Lundbäck Bo , Rönmark Eva
Published: February 2019

Background

Severe asthma is a considerable challenge for patients, health‐care professionals and society. Few studies have estimated the prevalence of severe asthma according to modern definitions of which none based on a population study.

Objective

To describe characteristics and estimate the prevalence of severe asthma in a large adult population‐based asthma cohort followed for 10‐28 years.

Methods

N = 1006 subjects with asthma participated in a follow‐up during 2012‐14, when 830 (mean age 59 years, 56% women) still had current asthma. Severe asthma was defined according to three internationally well‐known criteria: the ATS workshop definition from 2000 used in the US Severe Asthma Research Programme (SARP), the 2014 ATS/ERS Task force definition and the GINA 2017. All subjects with severe asthma according to any of these criteria were undergoing respiratory specialist care and were also contacted by telephone to verify treatment adherence.

Results

The prevalence of severe asthma according to the three definitions was 3.6% (US SARP), 4.8% (ERS/ATS Taskforce), and 6.1% (GINA) among subjects with current asthma. Although all were using high ICS doses and other maintenance treatment, >90% did not have controlled asthma according to the asthma control test. Severe asthma was related to age >50 years, nasal polyposis, impaired lung function, sensitization to aspergillus, and tended to be more common in women. Further, neutrophils in blood significantly discriminated severe asthma from other asthma.

Conclusions and Clinical Relevance

Severe asthma differed significantly from other asthma in terms of demographic, clinical and inflammatory characteristics, results suggesting possibilities for improved treatment regimens of severe asthma. The prevalence of severe asthma in this asthma cohort was 4%‐6%, corresponding to approximately 0.5% of the general population.
Hyperuricemia and acute gout after laparoscopic sleeve gastrectomy
Authors: Katsogridaki Georgia , Tzovaras George , Sioka Eleni , Perivoliotis Konstantinos , Zachari Eleni , Magouliotis Dimitrios , Tasiopoulou Vassiliki , Zacharoulis Dimitrios
Published: February 2019

The aim of this study was to evaluate the prevalence of hyperuricemia and acute gout after laparoscopic sleeve gastrectomy (LSG). Risk factors for developing gout were also examined. Eighty‐five patients underwent LSG were enrolled in this prospective study. Serum uric acid levels, gout attacks and total water levels % derived by bioimpedance were examined pre‐operatively and 1 month post‐operatively. Hyperuricemia was identified in 30.6% pre‐operatively and in 18.82% of patients post‐operatively. From the patients’ group with pre‐operative hyperuricemia, 53.9% were normalized, 46.2% had increased uric acid post‐operatively while gout was observed in 11.5%. From the patients group without pre‐operative hyperuricemia, hyperuricemia and gout were observed in 6.8% and 5.1% post‐operatively, respectively. The relative risk for developing hyperuricemia was 6.2 (95% confidence interval [CI] 2.2‐17.8) and for developing gout was 2.3 (95% CI 2.2‐17.8). Statistical significant differences for gout among the groups with and without gout were indicated concerning pre‐operative use of medications (P < 0.001), age (P = 0.025), post‐operative uric acid levels (P < 0.001) and post‐operative total water levels % (P = 0.048). The prevalence of hyperuricemia was 18.8% and gout attack of 7.1% 1 month after LSG. From the cohort of patients with pre‐operative hyperuricemia, a significant proportion normalized uric acid, while 11.5% developed gout. Patients without hyperuricemia pre‐operatively developed hyperuricemia and gout in 6.8% and 5.1% post‐operatively, respectively. The patients who had gout were younger and had 37% water levels post‐operatively.
Patient perception of obesity versus physician documentation of obesity: A quality improvement study
Authors: Mawardi George , Kirkland Elizabeth B. , Zhang Jingwen , Blankinship Devin , Heincelman Marc E. , Schreiner Andrew D. , Moran William P. , Schumann Samuel O.
Published: February 2019

As the prevalence of obesity increases, the prevalence of associated comorbid diseases, obesity‐related mortality rates and healthcare costs rise concordantly. Two main factors that hinder efforts to treat obesity include a lack of recognition by patients and documentation by physicians. This study evaluates the relationship between patient perception of obese weight and physician documentation of obesity. This quality improvement observational study surveyed patients of an academic internal medicine clinic on their perception of obesity. Responses were compared to longitudinal physician documentation of obesity and body mass index (BMI). A total of 59.9% of patients with obesity perceived their weight as obese. While 33.7% of patients with a BMI of 30 to 34.9 kg/m2 perceived themselves as having obesity, 71.4% of patients with a BMI of 45 to 49.9 kg/m2 perceived themselves as having obesity. A total of 42.4% of patients with obesity had physician documentation of obesity in the last year. While 25% of patients with a BMI of 30 to 34.9 kg/m2 had physician documentation of obesity, 85.7% of patients with a BMI of 45 to 49.9 kg/m2 had physician documentation of obesity. For patients with a BMI ≥50 kg/m2, 52.9% perceived their weight to be obese and 76.5% had physician documentation of obesity in the last year. Both patient perception and physician documentation of obesity were significantly less than the prevalence of obesity. Patient perception of obesity and provider documentation of obesity increased as BMI increased until a BMI ≥50 kg/m2. Both patients and providers must improve recognition of this disease.
Experience of the implementation and outcomes of universal testing for Lynch syndrome in the United Kingdom
Authors: Cavazza A. , Radia C. , Harlow C. , Monahan K. J.
Published: February 2019

Aim

Colorectal cancer (CRC) is diagnosed in approximately 45 000 people annually in the UK, and it is estimated that Lynch syndrome (LS) accounts for 3.1% of these cases. In February 2017, National Institute for Health and Care Excellence (NICE guideline DG27 recommended universal testing of new cases of CRC for mismatch repair (MMR) status. The aim of this study was to implement universal testing for LS in CRC patients in a secondary care setting.

Method

We prospectively collected data on consecutive newly diagnosed CRC patients at our centre from November 2016 to August 2018, including evidence of MMR status determined by immunohistochemistry. We recorded clinicopathological data including age at diagnosis, stage, tumour site, reported histological findings and MMR tumour status. Statistical analysis was performed using the chi‐square test and the two‐tailed t‐test for binary and continuous variables, respectively.

Results

A cohort of 203 consecutive patients were diagnosed with CRC during this period. Universal MMR testing was performed for the 198 CRC patients in whom a diagnosis of adenocarcinoma was confirmed, with colonoscopic biopsy used as the source material in 68.6% of cases. Twenty‐three CRCs (11.6%) were MMR deficient (dMMR). Most dMMR CRCs (21/23) were early stage tumours (Dukes A or B, P = 0.002). In 39 Dukes B CRCs in patients under 70 years of age, the result of MMR testing influenced decision‐making about personalized treatment with 5‐fluorouracil based chemotherapy.

Conclusion

Our results demonstrate that universal testing of all new cases of CRC for features suggestive of LS is feasible and effective in the UK. Our data also indicate the importance of genetic testing and personalized oncological care.
Interactions between anti‐infective agents and immunosuppressants—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Sparkes Tracy , Lemonovich Tracy L. ,   the AST Infectious Diseases Community of Practice
Published: February 2019

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation provide an update on potential drug‐drug interactions between anti‐infectives and immunosuppressants, which are most notable with calcineurin and mTOR inhibitors. Drug‐drug interactions may occur through pharmacokinetic mechanisms leading to altered drug concentrations of either the anti‐infective or immunosuppressive drug, or by pharmacodynamic interactions increasing or decreasing the efficacy or toxicity of the medications. Many of the significant pharmacokinetic interactions occur through inhibition or induction of the cytochrome 3A4 system by anti‐infective agents leading to increased or decreased immunosuppressive agent levels, respectively. The membrane transporter P‐glycoprotein is also often involved in drug interactions. Since the last iteration of these guidelines, multiple new hepatitis C virus direct‐acting antivirals have become available for use in SOT recipients. Of these agents, some are substrates of cytochrome and drug transporter systems, while others inhibit these systems and may affect immunosuppressive agents. Due to the high risk for drug‐drug interactions in the solid organ transplant population, practitioners must be aware of potential interactions and be vigilant in monitoring and adjusting drug dosing when appropriate.
RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Manuel Oriol , Estabrook Michele ,   the American Society of Transplantation Infectious Diseases Community of Practice
Published: February 2019

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of RNA respiratory viral infections in the pre‐ and post‐transplant period. Viruses reviewed include influenza, respiratory syncytial virus (RSV), parainfluenza, rhinovirus, human metapneumovirus (hMPV), and coronavirus. Diagnosis is by nucleic acid testing due to improved sensitivity, specificity, broad range of detection of viral pathogens, automatization, and turnaround time. Respiratory viral infections may be associated with acute rejection and chronic lung allograft dysfunction in lung transplant recipients. The cornerstone of influenza prevention is annual vaccination and in some cases antiviral prophylaxis. Treatment with neuraminidase inhibitors and other antivirals is reviewed. Prevention of RSV is limited to prophylaxis with palivizumab in select children. Therapy of RSV upper or lower tract disease is controversial but may include oral or aerosolized ribavirin in some populations. There are no approved vaccines or licensed antivirals for parainfluenza, rhinovirus, hMPV, and coronavirus. Potential management strategies for these viruses are given. Future studies should include prospective trials using contemporary molecular diagnostics to understand the true epidemiology, clinical spectrum, and long‐term consequences of respiratory viruses as well as to define preventative and therapeutic measures.
Cytopreparation of duodenal biopsy fixative improves detection rate of giardia in clinically suspected cases
Authors: Garg Neha , Singh Jyoti , Anjum Hasib , Puri Amarender S. , Sakhuja Puja , Batra Vineeta V.
Published: February 2019

Introduction

Giardia intestinalis is a flagellated protozoan, frequently documented as an agent for enteric illness worldwide. Laboratory procedures for diagnosis include stool examination, antigenic detection assays and, at times, mucosal biopsy. We hypothesised that the formalin fixative used as a preservative for mucosal biopsy can be a good diagnostic sample for detecting surface mucosal and luminal infective agents such as giardia. The aim of the study was to find out the utility of processing the remaining formalin fixative as a complementary diagnostic method for detecting giardia.

Methods

This study included 200 cases of duodenal biopsies sampled over 6 months. The biopsies were picked up using clean forceps and the remaining fixative was processed using standard cytospin protocol. The cytospin preparation and formalin‐fixed paraffin‐embedded tissue sections were examined by two pathologists independently blinded to each others findings.

Results

On cytology, trophozoites of giardia were detected in 23 out of 200 cases (11.50%). The cytomorphology of pear‐shaped organism with paired flagella and nuclei is very diagnostic. One case also showed presence of cryptosporidium spores. No other intestinal parasite was seen. Out of the 23 positive cytology samples, only 12 (6%) corresponding formalin‐fixed paraffin‐embedded tissue sections showed presence of giardia.

Conclusion

Concurrent examination of duodenal biopsy and the formalin fixative cytopreparation in cases with high index of clinical suspicion of giardiasis proved to be a useful adjunct to biopsy diagnosis of giardiasis, which was statistically significant (P < .0001). This approach adds negligible cost and effort but with good diagnostic yield. We recommend that the formalin cytopreparation be used as a complementary technique to biopsy for cases suspected of intestinal parasitic infection.