bluuebunny/crossref_metadata_2025 huggingface dataset:
HPOFiller: identifying missing protein–phenotype associations by graph convolutional network
Authors: Liu Lizhi , Mamitsuka Hiroshi , Zhu Shanfeng
Published: April 2021

Motivation

Exploring the relationship between human proteins and abnormal phenotypes is of great importance in the prevention, diagnosis and treatment of diseases. The human phenotype ontology (HPO) is a standardized vocabulary that describes the phenotype abnormalities encountered in human diseases. However, the current HPO annotations of proteins are not complete. Thus, it is important to identify missing protein–phenotype associations.

Results

We propose HPOFiller, a graph convolutional network (GCN)-based approach, for predicting missing HPO annotations. HPOFiller has two key GCN components for capturing embeddings from complex network structures: (i) S-GCN for both protein–protein interaction network and HPO semantic similarity network to utilize network weights; (ii) Bi-GCN for the protein–phenotype bipartite graph to conduct message passing between proteins and phenotypes. The core idea of HPOFiller is to repeat run these two GCN modules consecutively over the three networks, to refine the embeddings. Empirical results of extremely stringent evaluation avoiding potential information leakage including cross-validation and temporal validation demonstrates that HPOFiller significantly outperforms all other state-of-the-art methods. In particular, the ablation study shows that batch normalization contributes the most to the performance. The further examination offers literature evidence for highly ranked predictions. Finally using known disease-HPO term associations, HPOFiller could suggest promising, unknown disease–gene associations, presenting possible genetic causes of human disorders.

Availabilityand implementation

https://github.com/liulizhi1996/HPOFiller.

Supplementary information

Supplementary data are available at Bioinformatics online.
Increased facial asymmetry in focal epilepsies associated with unilateral lesions
Authors: Balestrini Simona , Lopez Seymour M , Chinthapalli Krishna , Sargsyan Narek , Demurtas Rita , Vos Sjoerd , Altmann Andre , Suttie Michael , Hammond Peter , Sisodiya Sanjay M
Published: April 2021

The epilepsies are now conceptualized as network disruptions: focal epilepsies are considered to have network alterations in the hemisphere of seizure onset, whilst generalized epilepsies are considered to have bi-hemispheric network changes. Increasingly, many epilepsies are also considered to be neurodevelopmental disorders, with early changes in the brain underpinning seizure biology. The development of the structure of the face is influenced by complex molecular interactions between surface ectoderm and underlying developing forebrain and neural crest cells. This influence is likely to continue postnatally, given the evidence of facial growth changes over time in humans until at least 18 years of age. In this case–control study, we hypothesized that people with lateralized focal epilepsies (i.e. unilateral network changes) have an increased degree of facial asymmetry, compared with people with generalized epilepsies or controls without epilepsy. We applied three-dimensional stereophotogrammetry and dense surface models to evaluate facial asymmetry in people with epilepsy, aiming to generate new tools to explore pathophysiological mechanisms in epilepsy. We analysed neuroimaging data to explore the correlation between face and brain asymmetry. We consecutively recruited 859 people with epilepsy attending the epilepsy clinics at a tertiary referral centre. We used dense surface modelling of the full face and signature analyses of three-dimensional facial photographs to analyse facial differences between 378 cases and 205 healthy controls. Neuroimaging around the time of the facial photograph was available for 234 cases. We computed the brain asymmetry index between contralateral regions. Cases with focal symptomatic epilepsy associated with unilateral lesions showed greater facial asymmetry compared to controls (P = 0.0001, two-sample t-test). This finding was confirmed by linear regression analysis after controlling for age and gender. We also found a significant correlation between duration of illness and the brain asymmetry index of total average cortical thickness (r = −0.19, P = 0.0075) but not for total average surface area (r = 0.06, P = 0.3968). There was no significant correlation between facial asymmetry and asymmetry of regional cortical thickness or surface area. We propose that the greater facial asymmetry in cases with focal epilepsy caused by unilateral abnormality might be explained by early unilateral network disruption, and that this is independent of underlying brain asymmetry. Three-dimensional stereophotogrammetry and dense surface modelling are a novel powerful phenotyping tool in epilepsy that may permit greater understanding of pathophysiology in epilepsy, and generate further insights into the development of cerebral networks underlying epilepsy, and the genetics of facial and neural development.
A Sensitive UPLC-MS/MS Method for the Determination of Flurbiprofen in Rat Plasma: Application to Real Sample
Authors: Yaman Mehmet Emrah , Atila Alptug , Akman Tugrul Cagri , Albayrak Mevlut , Kadioglu Yucel , Halici Zekai
Published: April 2021

For the quantification of flurbiprofen in rat plasma, a simple UPLC-MS/MS method with high sensitivity and short retention time for flurbiprofen was developed and validated using specific parameters. Etodolac was used as internal standard. The transitions (precursor to the product) of flurbiprofen and internal standard were obtained using the electrospray ionization in the negative ion multiple reaction monitoring mode, 243.2 → 199.2, 286.2 → 212.1, respectively. For chromatographic separation, C18 column was used for the stationary phase and gradient elution was used for the mobile phase. This mobile phase consisted of a methanol (A) and a 5 mM ammonium formate solution (B), which varied at a flow rate of 0.4 mL/min. For flurbiprofen, LLOQ was determined as 5 ng/mL. Quantification of flurbiprofen in the rat plasma with a linear calibration curve of 5–5000 ng/mL (r > 0.9991 for plasma) is possible with a retention time of 1.89 min. The total analysis time of the method was 3 min. The proposed method was validated. The intraday and inter-day precision (RSD%) and accuracy (RE%) were within 10% in all cases for flurbiprofen. The stability of flurbiprofen was evaluated under conditions such as short-term, long-term, autosampler and freeze/thaw. After method validation, flurbiprofen was succesfully quantified in real rat plasma samples.
Agency and Autonomy in the Maritime Silk Road Initiative: An Examination of Djibouti’s Doraleh Container Terminal Disputes
Authors: Barton Benjamin
Published: April 2021

Touted as the second coming of the Hambantota debt-for-equity swap deal, the ongoing legal dispute pitting Dubai Ports (DP) World (United Arab Emirates) and China Merchants Port (CMP) over the Doraleh Container Terminal (DCT) (Djibouti) in front of the Hong Kong High Courts has been hastily interpreted as yet another act of Chinese economic statecraft. Yet, when looking more closely at the specifics of this dispute, it would appear that the evidence does not lend itself favourably to those who advocate the power of Chinese political leverage in return for “debt traps”. This article debunks the myth of Chinese grand strategy as the driving force behind the legal dispute over the DCT, by instead placing the combination of Djiboutian elite agency and CMP’s entrepreneurial autonomy as the primary causal variables. It does so by predominantly drawing on unexplored publicly available data obtained from the various legal disputes pertaining to the DCT.
Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression
Authors: Pathak Gita A , Wendt Frank R , Levey Daniel F , Mecca Adam P , van Dyck Christopher H , Gelernter Joel , Polimanti Renato
Published: April 2021

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume.

We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for ‘fourth ventricle’, ‘gray matter’ and ‘cerebellar vermal lobules I–IV’ volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10−6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10−7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes—GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B—show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug–gene interactions, we identified process ‘transmission across chemical synapses’ (P < 2.78 × 10−4).

This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.
Short Shrift to International Non-Refoulement Obligations? Australia’s Approach to Criminal Deportation
Authors: Bostock Chantal , Cabarrús Jason
Published: April 2021

Australia’s Migration Act 1958 (Cth) provides for visas that honour Australia’s international non-refoulement obligations; it also provides for visas to be refused or cancelled on criminal grounds, resulting in removal from Australia. In 2014, Australia introduced mandatory visa cancellation for certain criminal non-citizens sentenced to 12 months or more in prison. Coinciding with these changes was the codification of aspects of refugee and human rights law, the severing of references to the 1951 Convention relating to the Status of Refugees, and the introduction of section 197C in the Migration Act, which provides that non-refoulement obligations are irrelevant when considering the power to remove non-citizens. This article focuses on the interaction between these changes in the law, analysing the application of the complex legal provisions which govern the legal position of those seeking protection or owed international non-refoulement obligations.

This analysis identifies a number of unintended consequences that appear to have resulted from these changes. These include risks that Australia’s international non-refoulement obligations may not be adequately considered or safeguarded, resulting in serious consequences for the individual concerned, including the possibility of indefinite detention or refoulement. They also include implications for the rule of law, and uncertainty, delay, and cost in aspects of the system for decision making and review.
T-Cell Homeostatic Imbalance in Placentas From Women With Human Immunodeficiency Virus in the Absence of Vertical Transmission
Authors: Ikumi Nadia M , Pillay Komala , Tilburgs Tamara , Malaba Thokozile R , Dzanibe Sonwabile , Enninga Elizabeth Ann L , Chakraborty Rana , Lamorde Mohammed , Myer Landon , Khoo Saye , Jaspan Heather B , Gray Clive M
Published: April 2021

Background

Implementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of human immunodeficiency virus (HIV)–exposed uninfected children, who remain vulnerable to morbid effects. In the current study, we investigated whether T-cell alterations in the placenta contribute to altered immune status in HIV-exposed uninfected.

Methods

We analyzed T cells from term placenta decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWH) who initiated ART late in pregnancy (n = 21) with pregnant women not living with HIV (PWNH) (n = 9).

Results

Placentas from PWH showed inverted CD4/CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentas. CD8+ T cells in the fetal capillaries, which were of fetal origin, were positively correlated with maternal plasma viremia before ART initiation, implying that imbalanced T cells persisted throughout pregnancy. In addition, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua.

Conclusions

T-cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.
Broad Severe Acute Respiratory Syndrome Coronavirus 2 Cell Tropism and Immunopathology in Lung Tissues From Fatal Coronavirus Disease 2019
Authors: Ramos da Silva Suzane , Ju Enguo , Meng Wen , Paniz Mondolfi Alberto E , Dacic Sanja , Green Anthony , Bryce Clare , Grimes Zachary , Fowkes Mary , Sordillo Emilia M , Cordon-Cardo Carlos , Guo Haitao , Gao Shou-Jiang
Published: April 2021

Background

Coronavirus disease 2019 (COVID-19) patients manifest with pulmonary symptoms reflected by diffuse alveolar damage (DAD), excessive inflammation, and thromboembolism. The mechanisms mediating these processes remain unclear.

Methods

We performed multicolor staining for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and lineage markers to define viral tropism and lung pathobiology in 5 autopsy cases.

Results

Lung parenchyma showed severe DAD with thromboemboli. Viral infection was found in an extensive range of cells including pneumocyte type II, ciliated, goblet, club-like, and endothelial cells. More than 90% of infiltrating immune cells were positive for viral proteins including macrophages, monocytes, neutrophils, natural killer (NK) cells, B cells, and T cells. Most but not all infected cells were angiotensin-converting enzyme 2 (ACE2) positive. The numbers of infected and ACE2-positive cells are associated with extensive tissue damage. Infected tissues exhibited high levels of inflammatory cells including macrophages, monocytes, neutrophils, and NK cells, and low levels of B cells but abundant T cells consisting of mainly T helper cells, few cytotoxic T cells, and no regulatory T cells. Robust interleukin-6 expression was present in most cells, with or without infection.

Conclusions

In fatal COVID-19 lungs, there are broad SARS-CoV-2 cell tropisms, extensive infiltrated innate immune cells, and activation and depletion of adaptive immune cells, contributing to severe tissue damage, thromboemboli, excess inflammation, and compromised immune responses.
Does Experiencing International Research Collaboration Permanently Affect the Impact of Scientific Production? Evidence from Africa
Authors: Mirnezami Seyed Reza , Beaudry Catherine
Published: April 2021

This paper examines the effect of experiencing a research collaboration between African scientists and their international partners on the African scientists’ research impact, measured by scores based on the number of citations and journal impact factor. Using a difference-in-difference regression analysis on publication data of African scientists, the results show that international research collaboration in a given year has a positive and significant effect on research impact, which lasts in the subsequent years. The presence of such permanent effect suggests a sort of ‘permanent learning by international collaboration’. The positive effect of international collaboration on research impact, however, does not necessarily imply that the scientists with only local research collaboration are lesser scientists.
Stability and Validation of a High-Throughput LC-MS/MS Method for the Quantification of Cefepime, Meropenem, and Piperacillin and Tazobactam in Serum
Authors: Bjergum Matthew W , Barreto Erin F , Scheetz Marc H , Rule Andrew D , Jannetto Paul J
Published: April 2021

Background

The class of antibiotics known as β-lactams are a commonly used due to their effectiveness and safety. Therapeutic drug monitoring has been proposed but requires an accurate assay along with well-characterized preanalytic stability, as β-lactams are known to be relatively unstable.

Methods

A high-throughput LC-MS/MS assay validation and stability study was performed for cefepime, meropenem, and piperacillin and tazobactam in serum. Patient samples, standards, and QCs were crashed with acetonitrile containing internal standard. Following centrifugation, an aliquot of the supernatant was diluted with clinical laboratory reagent water and analyzed by LC-MS/MS.

Results

The assay showed linearity between 0.5 and 60 µg/mL for each analyte. The intra- and interassay reproducibility at 3 different concentrations (approximately 2, 25, and 40 µg/mL) was <5% for each analyte. Accuracy studies for each analyte were compared using linear regression and demonstrated: slope = 1.0 ± 0.1; r2 ≥ 0.980; and y intercept 95% CI that included zero. Minimal ion suppression or enhancement was observed, and no significant carryover was observed up to 500 µg/mL of each analyte. Stability studies demonstrated significant loss in serum for each analyte at ambient and refrigerated temperatures (2–8 °C) and at −20 °C over days or weeks. In contrast, when stored at −80 °C, no significant loss was observed.

Conclusions

The LC-MS/MS assay showed acceptable performance characteristics for quantitation of β-lactams. With well-characterized stability, this assay can be used with residual specimens for pharmacokinetic modeling, which may lead to individualized dosing and improved patient care.
Life History of Bedellia somnulentella (Lepidoptera: Bedelliidae) Feeding on Ipomoea batatas (Solanales: Convolvulaceae) Leaves and Survey of Parasitoids in Brazil
Authors: dos Santos Marinalva Martins , Soares Marcus Alvarenga , da Silva Isabel Moreira , Caldeira Zaira Vieira , de Abreu Caique Menezes , Rocha de Souza Michael Willian , da Silva Antônio Alberto , Zanuncio José Cola , de Castro e Castro Bárbara Monteiro
Published: April 2021

The microlepidoptera, Bedellia somnulentella (Zeller), is an important pest of sweetpotato, Ipomoea batatas (L.) Lam. Damage by B. somnulentella occurs in the larval stage and when consuming the foliar mesophyll of I. batatas make the leaves brown, wrinkled, and reducing the photosynthetic area and the yield. The detection and management of this pest depends on knowing its biological cycle and identifying its natural enemies. The objectives of this study were to determine the life history of B. somnulentella feeding on I. batatas leaves and to survey parasitoids of this pest in the field. The duration and viability of B. somnulentella egg, larva, prepupa, pupa, and adult stages were evaluated under laboratory conditions. Cephalic capsule width was measured to determine the number of B. somnulentella instars, based on the Dyar rule and analyzed by the Akaike statistical model (AIC). The developmental period of B. somnulentella was 32.5 ± 0. 21 d with a viability of 75, 84, 100, and 84% for the egg, larva, prepupa, and pupa stages, respectively. The identification of this pest on the plants is possible from the third instar and in the pupal and adult stages. The parasitoid Conura sp. (Hymenoptera: Chalcididae) was identified parasitizing pupae of B. somnulentella and could be considered a potential natural enemy for the integrated management of this pest.
Guiding or Following the Crowd? Strategic Communication as Reputational and Regulatory Strategy
Authors: Müller Moritz , Braun Caelesta
Published: April 2021

A recently emerging literature demonstrates that reputational concerns explain why regulatory agencies strategically communicate and engage with their manifold audience. We complement this literature by examining the potential of strategic communication as a reputational and regulatory strategy. Based on a reputational approach to public agencies, we assume agencies to strategically diversify between proactively or reactively engaging with public concerns raised by their audiences, depending on whether a core or evolving competency is at stake. We test these assumptions empirically by examining frame alignment between formal communication of the European Central Bank (ECB) and public concerns raised by ECB audiences. Our analysis yields two key findings. First, our findings indicate external frame alignment signaling a strategic reactive strategy by the ECB to diversify its timing in responding to concerns raised by its audiences. Second, we find a pattern of internal frame alignment between the ECB’s core competencies and evolving competencies, indicating strategic linkage of attention to various competencies. Our study demonstrates how analyzing an agency’s formal communication in tandem with public concerns of its audiences via machine learning techniques can significantly improve our understanding of agency responsiveness and yields significant insights into the democratic legitimacy of regulatory agencies.
Patterns of Antimicrobial Use in Hospitalized Children: A Repeated Point Prevalence Survey From Pakistan
Authors: Arif Sara , Sadeeqa Saleha , Saleem Zikria
Published: April 2021

Three repeated point prevalence surveys (PPSs) were conducted in pediatric wards of 5 hospitals using the methodology developed by Global-PPS to identify key targets for interventions and antibiotic stewardship programs. Out of the 916 hospitalized patients, 865 (94.6%) were treated with at least 1 antibiotic.
BALRoGO: Bayesian Astrometric Likelihood Recovery of Galactic Objects – Global properties of over one hundred globular clusters with Gaia EDR3
Authors: Vitral Eduardo
Published: April 2021

We present BALRoGO: Bayesian Astrometric Likelihood Recovery of Galactic Objects, a public code to measure the centres, effective radii, and bulk proper motions of Milky Way (MW) globular clusters and Local Group dwarf spheroidals, whose data are mixed with MW field stars. Our approach presents innovative methods such as surface density fits allowing for strong interloper contamination and proper motion fits using a Pearson VII distribution for interlopers, instead of classic Gaussian-mixture recipes. We also use non-parametric approaches to represent the colour–magnitude diagram of such stellar systems based in their membership probabilities, previously derived from surface density and proper motion fits. The robustness of our method is verified by comparing its results with previous estimates from the literature as well as by testing it on mock data from N-body simulations. We applied BALRoGO to Gaia EDR3 data for over 100 MW globular clusters and nine Local Group dwarf spheroidals, and we provide positions, effective radii, and bulk proper motions. Finally, we make our algorithm available as an open source software.
Cardiopulmonary exercise testing in patients with end-stage kidney disease: principles, methodology and clinical applications of the optimal tool for exercise tolerance evaluation
Authors: Pella Eva , Boutou Afroditi , Boulmpou Aristi , Papadopoulos Christodoulos E , Papagianni Aikaterini , Sarafidis Pantelis
Published: April 2021

Chronic kidney disease (CKD), especially end-stage kidney disease (ESKD), is associated with an increased risk for cardiovascular events and all-cause mortality. Exercise intolerance as well as reduced cardiovascular reserve is extremely common in patients with CKD. Cardiopulmonary exercise testing (CPET) is a non-invasive, dynamic technique that provides an integrative evaluation of cardiovascular, pulmonary, neuropsychological and metabolic function during maximal or submaximal exercise, allowing the evaluation of functional reserves of these systems. This assessment is based on the principle that system failure typically occurs when the system is under stress and thus CPET is currently considered to be the gold standard for identifying exercise limitation and differentiating its causes. It has been widely used in several medical fields for risk stratification, clinical evaluation and other applications, but its use in everyday practice for CKD patients is scarce. This article describes the basic principles and methodology of CPET and provides an overview of important studies that utilized CPET in patients with ESKD, in an effort to increase awareness of CPET capabilities among practicing nephrologists.
The Comparative Effectiveness of Varenicline and Nicotine Patches for Smoking Abstinence During Pregnancy: Evidence From a Population-based Cohort Study
Authors: Choi Stephanie K Y , Tran Duong T , Kemp-Casey Anna , Preen David B , Randall Deborah , Einarsdottir Kristjana , Jorm Louisa R , Havard Alys
Published: April 2021

Introduction

In the general population, varenicline is consistently shown to be more efficacious for smoking cessation than nicotine replacement therapy (NRT). Current clinical guidelines for the management of smoking during pregnancy recommend against the use of varenicline, whilst supporting the use of NRT. However, little is known about the comparative effectiveness of these smoking cessation therapies among pregnant women.

Aims and Methods

Routinely-collected records of all births in two Australian States during 2011 and 2012 were used to create a population-based cohort of women who smoked during the first half of pregnancy. Pharmaceutical dispensing data were used to identify varenicline and nicotine patch dispensings in the first half of pregnancy. Propensity score matching was used to account for the potentially different distribution of confounding factors between the treatment groups. The outcome was defined as smoking abstinence during the second half of pregnancy.

Results

After propensity score-matching, our cohort comprised 60 women who used varenicline and 60 who used nicotine patches during the first half of pregnancy. More varenicline users (33.3%, 95% CI: 21.7%–46.7%) quit smoking than nicotine patch users (13.3%, 95% CI: 5.9%–24.6%). The adjusted rate difference was 24.2% (95% CI: 10.2%–38.2%) and the adjusted relative risk was 2.8 (95% CI: 1.4–5.7).

Conclusions

Varenicline was almost three times more effective than nicotine patches in assisting pregnant women to quit smoking. Further studies are needed to corroborate our results. Together with data on the safety of varenicline during pregnancy, evidence regarding the relative benefit of varenicline and NRT during pregnancy important for informing clinical decisions for pregnant smokers.

Implications

This study is the first to measure the comparative effectiveness of varenicline and nicotine patches during pregnancy – women using varenicline were almost three times as likely to quit smoking than those using nicotine patches. This study addressed a clinically important question using an observational study, noting that there is an absence of evidence from randomized controlled trials because of the ethical issues associated with including pregnant women in clinical trials of medicines of unknown safety.
Harm Reduction Associated with Dual Use of Cigarettes and e-Cigarettes in Black and Latino Smokers: Secondary Analyses from a Randomized Controlled e-Cigarette Switching Trial
Authors: Arnold Michael J , Nollen Nicole L , Mayo Matthew S , Ahluwalia Jasjit S , Leavens Eleanor L , Zhang Guanlin , Rice Myra , Pulvers Kim
Published: April 2021

Introduction

Most adult cigarette smokers who use e-cigarettes are dual cigarette and e-cigarette (CC-EC) users, yet little is known about relative consumption of cigarettes to e-cigarettes and any associated harm reduction.

Methods

Rate of substitution from cigarettes to e-cigarettes at week 6 and change in biomarkers of exposure and potential harm were examined among dual dual cigarette and e-cigarette users [64/114 (56%); 35 Black, 29 Latino] in an e-cigarette switching randomized trial.

Results

Dual users averaged 79% substitution of cigarettes for e-cigarettes at week 6, resulting in a reduction from baseline of 70.0 ± 54.1 cigarettes per week (p < .001). Total nicotine consumption remained stable (baseline: 1160.5 ± 1042.1 pg/mL of cotinine, week 6: 1312.5 ± 1725.9 pg/mL of cotinine, p = .47), while significant reductions were seen in the potent lung carcinogen 4-(methylnitrosamino)-1-(3-pyridul)-1-butanol (NNAL) (-55.9 ± 88.6 ng/ml, p < .001), carbon monoxide (-6.3 ± 8.6 ppm, p < .001), and self-reported respiratory symptoms (−3.3 ± 8.0, p = .002). No significant changes were found in blood pressure or spirometry. Greater substitution from cigarettes to e-cigarettes was associated with larger reductions in NNAL (r = −.29, p = .02).

Conclusions

The predominant dual-use pattern was characterized by regular e-cigarette and intermittent cigarette use. Findings demonstrate the short-term harm reduction potential of this dual-use pattern in Black and Latino smokers and suggest that the greatest benefit, aside from cessation of both products, is achieved by higher substitution of e-cigarettes for cigarettes. Findings need confirmation in a larger sample with longer follow-up in dual users with greater variability in the rate of substitution.

ClinicalTrials.gov Identifier

NCT03511001

Implications

Findings suggest short-term harm reduction potential of dual cigarette-e-cigarette use for Black and Latino smokers. Results also demonstrate the heterogeneity of dual-use, with the greatest harm reduction seen in dual users with higher rates of substitution from cigarettes to e-cigarettes. Study results should be confirmed in a full clinical trial with long-term follow-up to evaluate maintenance of dual-use patterns and associated harm reduction potential over time.
Sensing stress responses in potato with whole-plant redox imaging
Authors: Hipsch Matanel , Lampl Nardy , Zelinger Einat , Barda Orel , Waiger Daniel , Rosenwasser Shilo
Published: April 2021

Environmental stresses are among the major factors that limit crop productivity and plant growth. Various nondestructive approaches for monitoring plant stress states have been developed. However, early sensing of the initial biochemical events during stress responses remains a significant challenge. In this work, we established whole-plant redox imaging using potato (Solanum tuberosum) plants expressing a chloroplast-targeted redox-sensitive green fluorescence protein 2 (roGFP2), which reports the glutathione redox potential (EGSH). Ratiometric imaging analysis demonstrated the probe response to redox perturbations induced by H2O2, DTT, or a GSH biosynthesis inhibitor. We mapped alterations in the chloroplast EGSH under several stress conditions including, high-light (HL), cold, and drought. An extremely high increase in chloroplast EGSH was observed under the combination of HL and low temperatures, conditions that specifically induce PSI photoinhibition. Intriguingly, we noted a higher reduced state in newly developed compared with mature leaves under steady-state and stress conditions, suggesting a graded stress sensitivity as part of the plant strategies for coping with stress. The presented observations suggest that whole-plant redox imaging can serve as a powerful tool for the basic understanding of plant stress responses and applied agricultural research, such as toward improving phenotyping capabilities in breeding programs and early detection of stress responses in the field.
TWAS results are complementary to and less affected by linkage disequilibrium than GWAS
Authors: Li Delin , Liu Qiang , Schnable Patrick S
Published: April 2021

A genome-wide association study (GWAS) is used to identify genetic markers associated with phenotypic variation. In contrast, a transcriptome-wide association study (TWAS) detects associations between gene expression levels and phenotypic variation. It has previously been shown that in the cross-pollinated species, maize (Zea mays), GWAS, and TWAS identify complementary sets of trait-associated genes, many of which exhibit characteristics of true positives. Here, we extend this conclusion to the self-pollinated species, Arabidopsis thaliana and soybean (Glycine max). Linkage disequilibrium (LD) can result in the identification, via GWAS, of false-positive associations. In all three analyzed plant species, most trait-associated genes identified via TWAS are well separated physically from other candidate genes. Hence, TWAS is less affected by LD than is GWAS, demonstrating that TWAS is particularly well suited for association studies in genomes with slow rates of LD decay, such as soybean. TWAS is reasonably robust to the plant organs/tissues used to determine expression levels. In summary, this study confirms that TWAS is a promising approach for accurate gene-level association mapping in plants that is complementary to GWAS, and established that TWAS can exhibit substantial advantages relative to GWAS in species with slow rates of LD decay.
Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies
Authors: McGonagle Dennis , McInnes Iain B , Deodhar Atul , Schett Georg , Shawi May , Kafka Shelly , Karyekar Chetan S , Kollmeier Alexa P , Hsia Elizabeth C , Xu Xie L , Sheng Shihong , Agarwal Prasheen , Zhou Bei , Ritchlin Christopher T , Rahman Proton , Mease Philip J
Published: April 2021

Objective

To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes.

Methods

Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0–6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data.

Results

Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70–75%), moderate (LEI = 2; 69–73%) or severe (LEI = 3–6; 42–44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis.

Conclusion

Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes.

Clinical trial registration

DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285)
Genome Sequence Resource for the Plant Pathogen Sclerotinia sclerotiorum WH6 Isolated in China
Authors: Zhang Xiong , Cheng Xiaohui , Liu Lijiang , Liu Shengyi
Published: April 2021

Sclerotinia sclerotiorum is a notorious fungal pathogen that causes sclerotinia stem rot (SSR) on many important crops in China and worldwide. Here, we present a high-quality genome assembly of S. sclerotiorum strain WH6 using the PacBio SMRT cell platform. The assembled genome has a total size of 38.96 Mbp, with a contig N50 length of 1.90 Mbp, and encodes 10,512 predicted coding genes, including 685 secreted proteins and 65 effector candidates. This is the first report of a S. sclerotiorum genome sequence from China. The WH6 genome sequence provides a valuable resource for facilitating our understanding of S. sclerotiorum-host interactions and SSR control in China and the world.
Verticillium klebahnii and V. isaacii Isolates Exhibit Host-Dependent Biological Control of Verticillium Wilt Caused by V. dahliae
Authors: Puri Krishna D. , Hu Xiaoping , Gurung Suraj , Short Dylan P. G. , Sandoya German V. , Schild Marion , Zhang Yuanyuan , Zhao Jun , Anchieta Amy G. , Klosterman Steven J. , Subbarao Krishna V.
Published: April 2021

Verticillium dahliae, the soilborne fungal pathogen, causes vascular wilt on many economically important crops, resulting in significant yield losses. V. klebahnii (isolate PD659) and V. isaacii (isolate PD660), two related species that cause few or no symptoms in some hosts, were evaluated as potential biocontrol agents (BCAs) in eggplant, lettuce, and tomato by pre-, post-, and coinoculation with a virulent race 1 isolate of V. dahliae (VdLs16). Initial studies demonstrated that the biocontrol efficacy of both BCAs was similar to reference BCA Talaromyces flavus (NRRL15936) across all hosts (α = 0.05). Subsequent experiments with PD659 against V. dahliae isolate Sm113 from eggplant, VdLs16 and VdLs17 isolates from lettuce, and Le1811 isolate from tomato demonstrated a significant biocontrol efficacy in eggplant and tomato but not in lettuce (at 95% confidence interval), suggesting host-dependent effectiveness of V. klebahnii. Confocal microscopy using green fluorescent protein-tagged tomato V. dahliae isolate Le1811 indicated delayed xylem colonization or lack of pathogen progression into the vascular system in a host-dependent manner on BCA-treated plants. Quantitative analyses of the expression of defense-related genes PR1a, PR5, acidic extracellular β-1,3-glucanase (GlucA), basic intracellular β-1,3-glucanase (GlucB), acidic extracellular chitinase (Chi3), basic intracellular chitinase (Chi9), and cysteine proteases (cysProteases) in tomato in the presence or absence of PD659 suggested an elevated expression of defense-related genes in compatible interaction of V. dahliae–tomato cultivar Early Pak. V. klebahnii (PD659) may delay the entry of V. dahliae by competing for space or nutrients during the initial stages of root colonization.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
When Feedback Backfires: Influences of Negative Discrepancies Between Physicians' Self and Assessors' Scores on Their Subsequent Multisource Feedback Ratings
Authors: van der Meulen Mirja W. , Arah Onyebuchi A. , Heeneman Sylvia , oude Egbrink Mirjam G. A. , van der Vleuten Cees P. M. , Lombarts Kiki M. J. M. H.
Published: April 2021

Introduction:

With multisource feedback (MSF) physicians might overrate their own performance compared with scores received from assessors. However, there is limited insight into how perceived divergent feedback affects physicians' subsequent performance scores.

Methods:

During 2012 to 2018, 103 physicians were evaluated twice by 684 peers, 242 residents, 999 coworkers, and themselves in three MSF performance domains. Mixed-effect models quantified associations between the outcome variable “score changes” between first and second MSF evaluations, and the explanatory variable “negative discrepancy score” (number of items that physicians rated themselves higher compared with their assessors' scores) at the first MSF evaluation. Whether associations differed across assessor groups and across a physician's years of experience as a doctor was analyzed too.

Results:

Forty-nine percent of physicians improved their total MSF score at the second evaluation, as assessed by others. Number of negative discrepancies was negatively associated with score changes in domains “organization and (self)management” (b = −0.02; 95% confidence interval [CI], −0.03 to −0.02; SE = 0.004) and “patient-centeredness” (b = −0.03; 95% CI, −0.03 to −0.02; SE = 0.004). For “professional attitude,” only negative associations between score changes and negative discrepancies existed for physicians with more than 6-year experience (b6–10yearsofexperience = −0.03; 95% CI, −0.05 to −0.003; SE = 0.01; b16–20yearsofexperience = −0.03; 95% CI, −0.06 to −0.004; SE = 0.01).

Discussion:

The extent of performance improvement was less for physicians confronted with negative discrepancies. Performance scores actually declined when physicians overrated themselves on more than half of the feedback items. PA score changes of more experienced physicians confronted with negative discrepancies and were affected more adversely. These physicians might have discounted feedback due to having more confidence in own performance. Future work should investigate how MSF could improve physicians' performance taking into account physicians' confidence.
Evaluation of a Nanoparticle-Based Busulfan Immunoassay for Rapid Analysis on Routine Clinical Analyzers
Authors: Hilaire Mary Rose , Gill Regina V. , Courtney Jodi B. , Baburina Irina , Gardiner JoAnn , Milone Michael C. , Shaw Leslie M. , Meng Qing H. , Salamone Salvatore J.
Published: April 2021

Background:

Busulfan is an alkylating agent used in allogeneic hematopoietic stem cell transplantation for various malignant and nonmalignant disorders. Therapeutic drug monitoring of busulfan is common because busulfan exposure has been linked to veno-occlusive disease, disease relapse, and failed engraftment. The authors developed an automated immunoassay, along with stable calibrators and controls, and quantified busulfan in sodium heparin plasma.

Methods:

The authors evaluated a homogenous nanoparticle immunoassay, the MyCare Oncology Busulfan Assay Kit (Saladax Biomedical, Inc), for precision, sensitivity, accuracy, and linearity on an open channel clinical chemistry analyzer; they compared the method with 2 mass spectrometry methods (liquid chromatography–tandem mass spectrometry and gas chromatography/mass spectrometry), using anonymized, remnant patient samples.

Results:

The coefficients of variation for repeatability and within-laboratory precision were ≤9.0%. The linear range was 150–2000 ng/mL; samples up to 6000 ng/mL can be measured with sample dilution. Measured values deviated by ≤14% from assigned values. Comparison between validated mass spectrometry methods resulted in a correlation coefficient R ≥ 0.995.

Conclusions:

The MyCare Busulfan Assay Kit shows the precision, accuracy, linearity, and test range for performing busulfan concentration measurements in sodium heparin plasma on routine clinical chemistry analyzers.
Impact of a Bayesian Individualization of Cyclosporine Dosage Regimen for Children Undergoing Allogeneic Hematopoietic Cell Transplantation: A Cost-Effectiveness Analysis
Authors: Beyron C. , Ceraulo A. , Bertrand Y. , Bleyzac N. , Philippe M.
Published: April 2021

Background:

Cyclosporine A (CsA) is the main drug used to prevent graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). CsA therapeutic drug monitoring (TDM) has been performed for ages, with studies revealing clinical benefits, but failing to examine its economic impact. In this article, the main objective was to evaluate the economic impact of the CsA TDM strategy, based on a Bayesian approach, by assessing costs related to its clinical impact. Furthermore, TDM effectiveness was analyzed for pharmacokinetics and clinical outcomes.

Methods:

A cost-effective, nonrandomized, retrospective, single-center study compared 2 CsA monitoring and dose adaptation strategies in pediatric patients undergoing HSCT. From 2014 to 2016, CsA TDM was performed using a population pharmacokinetics model-coupled Bayesian approach by a pharmacist [“pharmacist-assisted individualization” (PAI)]. From 2017 to 2018, CsA TDM was performed by the clinician without a Bayesian approach (non-PAI group). HSCT costs were evaluated from the French National Insurance perspective. Economic and clinical outcomes were assessed by measuring incremental cost-effectiveness ratios.

Results:

The study included 144 patients: 90 and 54 patients in PAI and non-PAI groups, respectively. Both groups were comparable for sociodemographic and clinical characteristics. The mean total cost per patient was significantly lower (P < 0.01) in the PAI group (€85,947) than in the non-PAI group (€100,435). Multivariate analysis revealed that TDM based on the Bayesian approach was a protective factor (odds ratio = 0.86) for severe acute graft-versus-host disease. We noted that pharmacist-based TDM was the dominant strategy. Bayesian method–based TDM allowed an increase in the percentage of target attainment at any period post-HSCT.

Conclusions:

CsA TDM with a Bayesian approach is a cost-effective procedure, and highlighted clinical benefits encourage the development of new TDM strategies for HSCT.
CAUSES AND CLINICAL MANIFESTATIONS OF MASQUERADE SYNDROMES IN INTRAOCULAR INFLAMMATORY DISEASES
Authors: Rothova Aniki , Groen Fahriye , ten Berge Josianne C. E. M. , Lubbers Susanne M. , Vingerling Johannes R. , Thiadens Alberta A. H. J.
Published: April 2021

Objective:

To identify the clinical characteristics and prevalence of neoplastic and nonneoplastic inflammatory masquerade syndromes (IMSs) in a tertiary center and determine the useful diagnostic tests.

Methods:

A retrospective cohort study of consecutive 1906 patients diagnosed with intraocular inflammatory disease.

Results:

Of all patients initially diagnosed with intraocular inflammatory disease, we identified 116 (6%) patients with noninflammatory causes (neoplastic IMSs in 36/116; 31% and nonneoplastic IMSs in 52/116; 45%). In addition, 26 patients (22%, 1.4% of all) had drug-induced uveitis and 2 (2%, 0.1% of all) had paraneoplastic uveitis. The large B-cell lymphoma was the most common neoplastic IMS (78%), and the major clinical features were presence of cells and floaters in the vitreous (69%) and chorioretinal lesions (33%). The causes of nonneoplastic IMSs included retinal vascular disorders (38%), hereditary retinal diseases (31%), and degenerative ocular disorders (19%). The common clinical manifestations consisted of chorioretinal scars (27%), small white–yellow retinal lesions (17%), and leaking vessels on fluorescein angiography (14%).

Conclusion:

Noninflammatory causes were determined in 6% of a large population with initial diagnosis of intraocular inflammatory disease. Although neoplastic IMS was commonly characterized by vitreous cells and opacities, most common definitive diagnoses in nonneoplastic IMS encompassed diverse retinal disorders.