bluuebunny/crossref_metadata_2025 huggingface dataset:
pCRM1exportome: database of predicted CRM1-dependent Nuclear Export Signal (NES) motifs in cancer-related genes
Authors: Lee Yoonji , Baumhardt Jordan M , Pei Jimin , Chook Yuh Min , Grishin Nick V
Published: August 2019

Motivation

The consensus pattern of Nuclear Export Signal (NES) is a short sequence motif that is commonly identified in protein sequences, whether the motif acts as an NES (true positive) or not (false positive). Finding more plausible NES functioning regions among the vast array of consensus-matching segments would provide an interesting resource for further experimental validation. Better defined NES should also allow meaningful mapping of cancer-related mutation positions, leading to plausible explanations for the relationship between nuclear export and disease.

Results

Possible NES candidate regions are extracted from the cancer-related human reference proteome. Extracted NES are scored for reliability by combining sequence-based and structure-based approaches. The confidently identified NES candidate motifs were checked for overlap with cancer-related mutation positions annotated in the COSMIC database. Among the ∼700 cancer-related sequences in the COSMIC Cancer Gene Census, 178 sequences are predicted to have possible NES motifs containing cancer-related mutations at their key positions. These lists are organized into our database (pCRM1exportome), and other protein sequences in the human reference proteome can also be retrieved by their UniProt IDs.

Availability and implementation

The database is freely available at http://prodata.swmed.edu/pCRM1exportome.

Supplementary information

Supplementary data are available at Bioinformatics online.
Improved representation of sequence bloom trees
Authors: Harris Robert S , Medvedev Paul
Published: August 2019

Motivation

Algorithmic solutions to index and search biological databases are a fundamental part of bioinformatics, providing underlying components to many end-user tools. Inexpensive next generation sequencing has filled publicly available databases such as the Sequence Read Archive beyond the capacity of traditional indexing methods. Recently, the Sequence Bloom Tree (SBT) and its derivatives were proposed as a way to efficiently index such data for queries about transcript presence.

Results

We build on the SBT framework to construct the HowDe-SBT data structure, which uses a novel partitioning of information to reduce the construction and query time as well as the size of the index. Compared to previous SBT methods, on real RNA-seq data, HowDe-SBT can construct the index in less than 36% of the time and with 39% less space and can answer small-batch queries at least five times faster. We also develop a theoretical framework in which we can analyze and bound the space and query performance of HowDe-SBT compared to other SBT methods.

Availability and implementation

HowDe-SBT is available as a free open source program on https://github.com/medvedevgroup/HowDeSBT.

Supplementary information

Supplementary data are available at Bioinformatics online.
miComplete: weighted quality evaluation of assembled microbial genomes
Authors: Hugoson Eric , Lam Wai Tin , Guy Lionel
Published: August 2019

Metagenomics and single-cell genomics have revolutionized the study of microorganisms, increasing our knowledge of microbial genomic diversity by orders of magnitude. A major issue pertaining to metagenome-assembled genomes (MAGs) and single-cell amplified genomes (SAGs) is to estimate their completeness and redundancy. Most approaches rely on counting conserved gene markers. In miComplete, we introduce a weighting strategy, where we normalize the presence/absence of markers by their median distance to the next marker in a set of complete reference genomes. This approach alleviates biases introduced by the presence/absence of shorter DNA pieces containing many markers, e.g. ribosomal protein operons.

Availability and implementation

miComplete is written in Python 3 and released under GPLv3. Source code and documentation are available at https://bitbucket.org/evolegiolab/micomplete.

Supplementary information

Supplementary data are available at Bioinformatics online.
Gut Microbiome Signatures Are Predictive of Infectious Risk Following Induction Therapy for Acute Myeloid Leukemia
Authors: Galloway-Peña Jessica R , Shi Yushu , Peterson Christine B , Sahasrabhojane Pranoti , Gopalakrishnan Vancheswaran , Brumlow Chelcy E , Daver Naval G , Alfayez Mansour , Boddu Prajwal C , Khan Md Abdul Wadud , Wargo Jennifer A , Do Kim-Anh , Jenq Robert R , Kontoyiannis Dimitrios P , Shelburne Samuel A
Published: August 2019

Background

The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML).

Methods

16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion.

Results

At the start of IC, higher stool Shannon diversity (hazard ratio [HR], 0.36; 95% confidence interval [CI], .18–.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18–.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum β-lactamase–producing organism. Patients who received carbapenems for >72 hours had significantly lower α-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73–11.93).

Conclusions

Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.

Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.
Impact of a Multidisciplinary eBoard on the Management of Patients With Complex Inflammatory Bowel Disease
Authors: Quinn Kevin P , Prothero Breanne L , Russell Jennifer M , Hegge Ryan J , von Bormann Alexander G , Larson Putchalee A , Christofferson Sara N , Smyrk Thomas C , Mathis Kellie L , Goenka Ajit H , Sheedy Shannon P , Bruining David H , Fletcher Joel G , Loftus Edward V , Raffals Laura E
Published: August 2019

Background

We aim to assess the impact of a multidisciplinary inflammatory bowel disease (IBD) conference on the management of patients with complex IBD.

Methods

Data were collected during each conference from February 2017 through October 2018 with chart review performed at 6 months to determine if conference recommendations were successfully implemented.

Results

Eighty-five patients were discussed. The presenting diagnosis was changed by 11.8%. Recommendations for further testing, medical therapy, and surgery were successfully implemented in 77.1%, 98.1%, and 88.4%, respectively.

Conclusions

This study supports the role of IBD multidisciplinary conferences in the management of patients with complex IBD.
Diagnosis and management of left atrial appendage thrombus in patients with atrial fibrillation undergoing cardioversion or percutaneous left atrial procedures: results of the European Heart Rhythm Association survey
Authors: Farkowski Michal M , Jubele Kristine , Marín Francisco , Gandjbakhch Estelle , Ptaszynski Pawel , Merino Jose L , Lenarczyk Radoslaw , Potpara Tatjana S
Published: August 2019

Practices regarding indications and timing for transoesophageal echocardiography (TOE) before cardioversion (CV) of atrial fibrillation (AF) or left atrial (LA) interventional procedures, and preferred imaging techniques and pharmacotherapy, in cases of thrombus resistant to chronic oral anticoagulation (OAC) treatment, are largely unknown. The European Heart Rhythm Association (EHRA) conducted a survey to capture contemporary clinical practice in those areas of AF care. A 22-item online questionnaire was developed and distributed among the EHRA electrophysiology research network centres. The survey contained questions regarding indications, type and timing of imaging before CV or LA procedures and management of LA appendage (LAA) thrombus with special emphasis on thrombus resistant to OAC. Of 54 responding centres 63% were university hospitals. Most commonly, TOE would be performed in cases of inadequate or unclear pre-procedural anticoagulation, even in AF lasting <48 h (52% and 50%, respectively), and 15% of centres would perform TOE before AF ablation in all patients. If thrombus was diagnosed despite chronic OAC, the prevalent strategy was to change current OAC to another with different mechanism of action; 51% of centres would wait 3–4 weeks after changing the OAC before using another imaging test, and 60% of centres reported two attempts to dissolve the thrombus. Our survey showed a significant utilization of TOE before CV or AF ablation in European centres, extending beyond AF guidelines-suggested indications. When thrombus was diagnosed despite chronic pre-procedural OAC, most centres would use another anticoagulant drug with different mode of action.
Vision-Based Assessment of Gait Features Associated With Falls in People With Dementia
Authors: Mehdizadeh Sina , Dolatabadi Elham , Ng Kimberley-Dale , Mansfield Avril , Flint Alastair , Taati Babak , Iaboni Andrea
Published: August 2019

Background

Gait impairments contribute to falls in people with dementia. In this study, we used a vision-based system to record episodes of walking over a 2-week period as participants moved naturally around their environment, and from these calculated spatiotemporal, stability, symmetry, and acceleration gait features. The aim of this study was to determine whether features of gait extracted from a vision-based system are associated with falls, and which of these features are most strongly associated with falling.

Methods

Fifty-two people with dementia admitted to a specialized dementia unit participated in this study. Thirty different features describing baseline gait were extracted from Kinect recordings of natural gait over a 2-week period. Baseline clinical and demographic measures were collected, and falls were tracked throughout the participants’ admission.

Results

A total of 1,744 gait episodes were recorded (mean 33.5 ± 23.0 per participant) over a 2-week baseline period. There were a total of 78 falls during the study period (range 0–10). In single variable analyses, the estimated lateral margin of stability, step width, and step time variability were significantly associated with the number of falls during admission. In a multivariate model controlling for clinical and demographic variables, the estimated lateral margin of stability (p = .01) was remained associated with number of falls.

Conclusions

Information about gait can be extracted from vision-based recordings of natural walking. In particular, the lateral margin of stability, a measure of lateral gait stability, is an important marker of short-term falls risk.
Prevalence of American Heart Association defined ideal cardiovascular health metrics in Nepal: findings from a nationally representative cross-sectional study
Authors: Ghimire Umesh , Shrestha Nipun , Gyawali Bishal , Pradhan Pranil Man Singh , Mishra Shiva Raj
Published: August 2019

Background

The ever-increasing burden of non-communicable diseases (NCDs) is posing a serious health challenge for Nepal. This study examines the status of ideal cardiovascular health (ICH) and its associated determinants in Nepal using the American Heart Association (AHA) definition of ICH metrics.

Methods

The AHA has defined ICH as having five to seven of the ideal health metrics. A representative sample from the NCD risk factors STEPS survey 2013 were drawn to analyse the prevalence and sociodemographic determinants of ideal, intermediate and poor cardiovascular health in Nepal. Multivariable logistic regression was used to measure the determinants of ICH.

Results

More than half of the participants had ICH metrics (51.6%), with the 45–69 y age group having the lowest prevalence of ICH (28%) and females having better cardiovascular health compared with their male counterparts (60.6% vs 41.7%). The prevalence of low intake of fruit and vegetables, tobacco smoking and elevated blood pressure were quite high (99%, 18.8% and 31.4%, respectively). The status of ICH declined with age: individuals 15–29 y of age had 6 times (95% confidence interval [CI] 4.80–8.60) higher odds of having ICH compared with those who were 45–69 y, and it was low among urban residents (referent: rural; adjusted odds ratio 0.77 [95% CI 0.58–1.01]).

Conclusions

Nearly half of the participants had ICH, which declined with ageing. Further, urban residents had poor cardiovascular health. This highlights the need for a comprehensive population-based intervention targeting elderly and urban residents to improve overall cardiovascular health.
Variability of the HIV-1 3′ polypurine tract (3′PPT) region and implication in integrase inhibitor resistance
Authors: Malet Isabelle , Delelis Olivier , Nguyen Thuy , Leducq Valentin , Abdi Besma , Morand-Joubert Laurence , Calvez Vincent , Marcelin Anne-Geneviève
Published: August 2019

Background

Integrase strand-transfer inhibitors (INSTIs) are efficient at impairing retroviral integration, which is a critical step in HIV-1 replication. To date, resistance to these compounds has been explained by mutations in the viral protein integrase, which catalyses the integration step. Recently, it has been shown that selected mutations in the 3′ polypurine tract (3′PPT), a sequence involved in the reverse transcription mechanism, result in high-level resistance to these compounds. This observation was reinforced by the description of a patient who failed INSTI treatment by selecting mutations in the 3′PPT sequence.

Methods

Sequences of the 3′PPT region were analysed in 30706 treatment-naive patients from the public Los Alamos database belonging to six different subtypes and, in parallel, in 107 patients failing INSTI treatment.

Results

The analysis showed that the sequences of patients failing INSTI treatment, in the same way as those of treatment-naive patients, are very well conserved regardless of the presence or absence of resistance mutations in the integrase gene.

Conclusions

This study confirms that the selection of a mutation in the 3′PPT region conferring high-level resistance to INSTIs is a rare event. It would require a particular in vivo context and especially a long enough time to be selected, this exposure time being generally reduced by the rapid change of treatment in the case of virological failure. Larger-scale studies in patients with INSTI treatment failure are needed to determine whether the 3′PPT region can play an important role in vivo in INSTI resistance.
The corresponding relationship between the change of goaf pressure and the key stratum breaking
Authors: Xie Jianlin , Xu Jialin
Published: August 2019

Existing studies mostly focus on the stress change of coal in front of a goaf, but rarely conduct field monitoring on the internal pressure of a goaf, primarily due to the complex environment and other restrictive conditions of goafs. This paper first used physical simulation to monitor and analyze the internal pressure of goaf and found that goaf pressure presented a stepwise growth with the key stratum breaking. In addition, field measurements were conducted to monitor the goaf pressures of two different working faces. Goaf pressures both presented linear growth with the advance of the working face. According to comparative analysis, there were some differences between the two monitoring methods in terms of the corresponding relationship. This reflects that in the actual rock mass, after the breaking of a key stratum, the loads of the strata under its control are not transferred to the goaf instantaneously and load transfer characteristics are probably related to roof separation distribution characteristics of overlying strata, the bulking characteristics of caved rock mass, lateral stress limitation and other factors. The results of this study will offer some guidance for studies on the movement laws of overlying strata and the load transfer of overlying strata above goafs.
A parallel electric field penetration technique for identifying hazardous water sources beneath coal seam mining face floors
Authors: Hu Xiongwu , Meng Dangdang , Luo Bin , Zhang Pingsong , Wu Rongxin
Published: August 2019

In this work, a highly applicable multi-channel parallel electric field penetration technique is proposed to facilitate identification of hazardous water sources beneath coal seam mining face floors. The effects of various parameters on the characteristics of the apparent resistivity curves of a spherical model were analyzed through numerical simulation. It was determined that the proposed technique was sensitive to several model parameters (resistivity, size and spatial location). In addition, physical model experiments were also performed. Resistivity was determined from a three-dimensional inversion of the measurements. The results showed that the proposed technique was highly effective in determining the electrical characteristics and spatial distribution range of the anomalous bodies in the physical model. An engineering application of the proposed technique further demonstrated its effectiveness and reliability. The proposed technique can provide a basis for formulating water disaster prevention and control measures for mining faces.
The mechanical behaviour of rock specimens with specific edge crack distributions under triaxial loading conditions
Authors: Duan Guoyong , Li Jianlin , Zhang Jingyu , Luo Zuosen , Wan Liangpeng , Li Bing
Published: August 2019

Research on the mechanical behaviour of rock masses with multiple joints has become a popular topic and has practical applications in natural slope stability. This paper aims to clarify the influence of joint geometry, joint orientation and joint connectivity ratio on the mechanical behaviour of rock specimens containing two pre-existing joints. Triaxial compression tests were conducted under various confining pressures to simulate the variation in external conditions. An exponential criterion was used to describe the relationship between the axial stress and confining pressure. The experimental crack propagation was explored by varying the joint orientation, joint connectivity ratio and confining pressure. The structural plane with a greater angle of inclination controlled the failure of the rock sample. Two failure patterns were observed under the loading conditions: shear failure and mixed failure. The failure surface trajectory presented similar deviations with the increase in joint inclination angle, joint connectivity ratio and confining pressure, which also accelerates the transition from mixed failure to shear failure. The experimental results highlight the significance of elucidating the influence of structural planes in practical engineering to predict the stability of natural slopes.
Cross-Cumulation Arrangement as FTA Under GATT Article XXIV
Authors: Kim Jong Bum
Published: August 2019

A cross-cumulation arrangement helps manufacturers meet the demands of the global value chain economy by facilitating the sourcing of intermediate products within the territories of participants in the arrangement. It is a de facto free-trade area formed by a network of bilateral free-trade areas underpinning the arrangement. However, a cross-cumulation clause provided in a bilateral free-trade area that underpins a cross-cumulation arrangement is inconsistent with General Agreement on Tariffs and Trade (GATT) Articles I and III because the intermediate products from the participants in the arrangement are more favorably treated than products from non-participants in the arrangement. The GATT inconsistencies of a cross-cumulation clause cannot be justified by the GATT Article XXIV exception, because a cross-cumulation clause of a bilateral free-trade area derogates from the free-trade area’s aim by facilitating trade in intermediate products between the free-trade area parties and non-parties to the free-trade area that are participants in the arrangement. In contrast, a cumulation clause provided in a free-trade area contributes to the free-trade area’s aim by facilitating trade in intermediate products between the parties to the free-trade area. To bring a cross-cumulation arrangement such as the Regional Convention on Pan-Euro-Med Preferential Rules of Origin into conformity with World Trade Organization law, the arrangement and its underlying free-trade areas should be recognized as a de jure free-trade area under GATT Article XXIV and notified to the World Trade Organization as such. A large cross-cumulation arrangement as a mega-free-trade area is likely to contribute to the world trading system by harmonizing divergent free-trade area rules of origin and providing an efficient mechanism for the formation of a mega-free-trade area.
Gastric necrosis late after a Collis-Nissen procedure
Authors: Misheva Bojana , Hajjar Roy , Schwenter Frank , Martin Jocelyne , Sebajang Herawaty
Published: August 2019

A Nissen procedure is an efficient surgical approach to treat gastroesophageal reflux disease. It is sometimes combined with a Collis gastroplasty to lengthen the functional distal esophagus to allow a 360° Nissen fundoplication without tension. We present the case of a 76-year-old female patient, with a history of a Collis-Nissen procedure, who developed extensive gastric necrosis after ingesting a significant quantity of maize. She underwent an urgent total gastrectomy with Roux-en-Y esophagojejunostomy. The cause of ischemia and necrosis in this case is believed to be an insufficient blood supply due to excessive intraluminal pressure. Necrosis of the gastric cavity is usually more likely to be due to venous insufficiency as veins’ walls are less resistant to compression than arterial vessels. Gastric necrosis after a Collis-Nissen procedure is exceedingly rare, and symptoms of such a complication are usually vague and not pathognomonic, which might delay surgical care and increase morbidity.
Temporal and angular variations of 3D core-collapse supernova emissions and their physical correlations
Authors: Vartanyan David , Burrows Adam , Radice David
Published: August 2019

We provide the time series and angular distributions of the neutrino and gravitational wave emissions of 11 state-of-the-art 3D non-rotating core-collapse supernova models and explore correlations between these signatures and the real-time dynamics of the shock and the proto-neutron star (PNS) core. The neutrino emissions are roughly isotropic on average, with instantaneous excursions about the mean inferred luminosity of as much as ±20 per cent. The deviation from isotropy is least for the ‘νμ’-type neutrinos and the lowest mass progenitors. Instantaneous temporal luminosity variations along a given direction for exploding models average ∼2–4 per cent, but can be as high as ∼10 per cent. For non-exploding models, they can achieve ∼25 per cent. The temporal variations in the neutrino emissions correlate with the temporal and angular variations in the mass accretion rate. We witness the lepton-number emission self-sustained asymmetry (LESA) phenomenon in all our models and find that the vector direction of the LESA dipole and that of the inner Ye distribution are highly correlated. For our entire set of 3D models, we find strong connections between the cumulative neutrino energy losses, the radius of the proto-neutron star, and the f-mode frequency of the gravitational wave emissions. When physically normalized, the progenitor-to-progenitor variation in any of these quantities is no more than ∼10 per cent. Moreover, the reduced f-mode frequency is independent of time after bounce to better than ∼10 per cent. Therefore, simultaneous measurement of gravitational waves and neutrinos from a given supernova event can be used synergistically to extract real physical quantities of the supernova core.
A stellar relic filament in the Orion star-forming region
Authors: Jerabkova Tereza , Boffin Henri M J , Beccari Giacomo , Anderson Richard I
Published: August 2019

We report the discovery of the oldest stellar substructure in the Orion star-forming region (OSFR), the Orion relic filament. The relic filament is physically associated with the OSFR, as demonstrated by Gaia DR2 photometry and astrometry, as well as by targeted radial velocity follow-up observations of a bright subsample of proper motion-selected candidate members. Gaia DR2 parallaxes place the Orion relic filament in the more distant part of the OSFR, ∼430 pc from the Sun. Given its age, velocity dispersion, spatial extent, and shape, it is not possible for the Orion relic filament to have formed as a single stellar cluster, even taking into account residual gas expulsion. The relic filament is also too young to be a tidal stream, because Galactic tides act on much longer time-scales, of the order of 100 Myr. It therefore appears likely that the structure formed from a molecular cloud filament similar to Orion A in the OSFR and retained its morphology despite decoupling from its natal gas. Hence, the Orion relic filament bears witness to the short-lived evolutionary phase between gas removal and dispersion owing to shears and tides, and provides crucial new insights into how stars are formed in molecular clouds.
Sensory Evaluation of E-Liquid Flavors by Smelling and Vaping Yields Similar Results
Authors: Krüsemann Erna J Z , Wenng Franziska M , Pennings Jeroen L A , de Graaf Kees , Talhout Reinskje , Boesveldt Sanne
Published: August 2019

Introduction

Sensory research on e-liquid flavors can be performed by means of smelling and vaping. However, data comparing smelling versus vaping e-liquid flavors are lacking. This study aims to investigate if smelling could be an alternative to vaping experiments by determining the correlation for hedonic flavor assessment between orthonasal smelling and vaping of e-liquids, for smokers and nonsmokers.

Methods

Twenty-four young adult smokers (mean age 24.8 ± 9.3) and 24 nonsmokers (mean age 24.9 ± 7.7) smelled and vaped 25 e-liquids in various flavors. Participants rated liking, intensity, familiarity, and irritation on a 100-mm Visual Analog Scale. Pearson correlations within and between smelling and vaping were calculated. Differences between user groups were calculated using t tests.

Results

Correlation coefficients between smelling and vaping based on mean group ratings were 0.84 for liking, 0.82 for intensity, 0.84 for familiarity, and 0.73 for irritation. Means of the within-subjects correlation coefficients were, respectively, 0.51, 0.37, 0.47, and 0.25. Correlations between smelling and vaping varied across individuals (ranging from −0.27 to 0.87) and flavors (−0.33 to 0.81). Correlations and mean liking ratings did not differ between smokers and nonsmokers.

Conclusions

The strong group-level correlations between orthonasal smelling and vaping e-liquid flavors justify the use of smelling instead of vaping in future research. For example, smelling could be used to investigate differences in e-liquid flavor liking between (potential) user groups such as nicotine-naïve adolescents. The more modest within-subject correlations and variation across individuals and flavors merit caution in using smelling instead of vaping in other types of experiments.

Implications

This study supports the use of orthonasal smelling (instead of vaping) e-liquids to measure hedonic flavor perception in some studies where vaping would be inappropriate or not feasible. Examples of research situations where smelling e-liquids may be sufficient are (1) investigating nicotine-naïve individuals (ie, nonusers), (2) investigating individuals under legal age for e-cigarette use (ie, youth and adolescents), (3) investigating brain responses to exposure of e-liquid flavors using functional magnetic resonance imaging or electroencephalogram, and (4) comparing hedonic flavor assessment between adolescent nonusers and current smokers to provide support for future regulations on e-liquid flavors.
Patients with inflammatory rheumatic diseases: quality of self-reported medical information in a prospective cohort event monitoring system
Authors: Kosse Leanne J , Jessurun Naomi T , Hebing Renske C F , Huiskes Victor J B , Spijkers Karin M , van den Bemt Bart J F , Nurmohamed Mike T
Published: August 2019

Objectives

Assessment of the quality of patient-reported medical information in the Dutch Biologic Monitor and evaluation of the representativeness of the sampled participants.

Methods

Consecutive adult patients using a biologic DMARD (bDMARD) for an immune-mediated inflammatory disease were included in eight Dutch centres. For this substudy, data of 550 patients with inflammatory rheumatic diseases were used. Patient-reported bDMARD prescription, indication and combination therapy were verified for patients that permitted access to their electronic health record using percentage agreement and/or Cohen’s kappa (n = 483). Conservative post hoc sensitivity analysis was performed to account for missing data. Population representativeness was tested for the entire substudy population by comparing age, gender and prescribed bDMARD to the centres’ reference populations using Mann–Whitney U-test, χ2 goodness-of-fit or Fisher’s exact test with Monte Carlo simulation (n = 550).

Results

The correct bDMARD was reported by 95.8% of the participants. Agreement between patients and electronic health record was almost perfect for indications (κ = 0.832) and substantial for combination therapies (κ = 0.725). Agreement on combination therapies remained substantial after post hoc sensitivity analysis (κ = 0.640). Gender distribution (P > 0.05) and bDMARD use (P > 0.05) were similar to the reference populations. Median age was different (58.0 vs 56.0 years, P = 0.04), but considered clinically irrelevant.

Conclusion

The Dutch Biologic Monitor seems to be a valid tool to obtain patient-reported medical information. Reported medical information generally corresponded to the electronic health records and the participants represented their reference populations regarding age, gender and prescribed bDMARD.
Differential long‐term regulation of TAS2R14 by structurally distinct agonists
Authors: Woo Jung A. , Castaño Maria , Goss Ashley , Kim Donghwa , Lewandowski Eric M. , Chen Yu , Liggett Stephen B.
Published: August 2019

Bitter taste receptor‐14 (TAS2R14) is a GPCR also expressed on human airway smooth muscle cells, which signals to intracellular [Ca2+], resulting in relaxation of the airway, and is a novel target for bronchodilators. Here, we examine long‐term, agonist‐promoted down‐regulation of TAS2R14 expression because tachyphylaxis would be an undesirable therapeutic characteristic. Five TAS2R structurally distinct full agonists were studied to ascertain biasing away from down‐regulation. Agonist exposure for 18 h caused minimal desensitization by diphenhydramine (DPD) compared with ~50% desensitization with all other agonists. Agonists evoked β‐arrestin recruitment to TAS2R14, which was not seen with a phosphoacceptor‐deficient mutant, TAS2R14‐10A. All agonists except for DPD also caused subsequent TAS2R14 internalization and trafficking via early and late endosomes to down‐regulation. TAS2R14‐10A failed to undergo these events with any agonist. Molecular docking showed that DPD has specific interactions deep within a binding pocket that are not observed with the other agonists, which may lock the receptor in a conformation that does not internalize and therefore does not undergo down‐regulation. Thus, TAS2R14 is subject to β‐arrestin‐mediated internalization and subsequent down‐regulation with chronic exposure to most agonists. However, by manipulating the agonist structure, biasing toward G‐protein coupling but away from long‐term down‐regulation can be achieved.—Woo, J. A., Castaño, M., Goss, A., Kim, D., Lewandowski, E. M., Chen, Y., Liggett, S. B. Differential long‐term regulation of TAS2R14 by structurally distinct agonists. FASEB J. 33, 12213‐12225 (2019). www.fasebj.org
Effects of perimenopausal transdermal estradiol on self-reported sleep, independent of its effect on vasomotor symptom bother and depressive symptoms
Authors: Geiger Paul J. , Eisenlohr-Moul Tory , Gordon Jennifer L. , Rubinow David R. , Girdler Susan S.
Published: August 2019

Objective:

The aim of this study was to determine the efficacy of transdermal estradiol (E2) plus intermittent progesterone (EPT) for improving self-reported sleep in perimenopausal women, after controlling for vasomotor symptoms (VMS) bother and depressive symptoms.

Methods:

Using a double-blind, placebo-controlled design, 172 healthy women meeting STRAW+10 criteria for being in the menopausal transition or early postmenopause were randomized to 12 months of transdermal E2 (0.1 mg/d) + 200 mg progesterone (12 d every 3 mo) or placebo. Using standard questionnaires, self-reported sleep, depression, and VMS bother were obtained at baseline and bimonthly postrandomization.

Results:

Controlling for baseline levels, EPT (vs placebo) led to reductions in minutes to fall asleep (estimate = −0.12, P = 0.002) and number of awakenings (estimate = −0.24, P = 0.04) over the 12 months. Controlling for changes in VMS bother and depressive symptoms, EPT still predicted reductions in minutes to fall asleep (estimate = −0.28, P = 0.02) and number of awakenings (estimate = −0.11, P = 0.02) over the 12 months.

Conclusions:

We extend existing research by demonstrating that hormone therapy (HT) in subjective sleep cannot be fully explained by improvements in VMS bother or depressive symptoms. Research to examine the mechanism (s) underlying HT's effects on sleep would have public health significance for perimenopausal women and also advance our general understanding of the pathophysiology of impaired sleep.
A review of application of base editing for the treatment of inner ear disorders
Authors: Zhao Xingle , Sun Zhuoer , Kang Wen , Tao Yong , Wu Hao
Published: August 2019

The development of applications for the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system has increased greatly in recent years, especially in the area of gene therapy by efficient in vivo genome editing. Although great success has been achieved in repairing and rewriting genomes through homology-directed repair coupled with Cas9 nuclease cleavage, its in vivo efficiency is insufficient for gene therapy. Base editing is a next-generation genome-editing tool that does not involve double-stranded DNA breaks and uses components of the CRISPR system together with other enzymes to make point mutations directly in cellular DNA or RNA. Base editors, composed of an engineered deaminase and a catalytically impaired CRISPR/Cas9 variant, are powerful tools for targeted base editing in cells and organisms. In non-dividing cells, base editors can directly transform one base or base pair into another, efficiently installing a point mutation. Undesired by-products of editing are seldom generated during this procedure. Herein we review the different base-editing platforms, including their deaminase recruitment strategies and editing outcomes, and the in vivo delivery of base editors. Additionally, we summarize therapeutic applications of base editing in disorders of the inner ear.
The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications
Authors: Qian Yuli , Gurley Bill J. , Markowitz John S.
Published: August 2019

Purpose

Increased cannabis use and recent drug approvals pose new challenges for avoiding drug interactions between cannabis products and conventional medications. This review aims to identify drug-metabolizing enzymes and drug transporters that are affected by concurrent cannabis use and, conversely, those co-prescribed medications that may alter the exposure to one or more cannabinoids.

Methods

A systematic literature search was conducted utilizing the Google Scholar search engine and MEDLINE (PubMed) database through March 2019. All articles describing in vitro or clinical studies of cannabis drug interaction potential were retrieved for review. Additional articles of interest were obtained through cross-referencing of published bibliographies.

Findings

After comparing the in vitro inhibition parameters to physiologically achievable cannabinoid concentrations, it was concluded that CYP2C9, CYP1A1/2, and CYP1B1 are likely to be inhibited by all 3 major cannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The isoforms CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD. Δ9-Tetrahydrocannabinol also activates CYP2C9 and induces CYP1A1. For non-CYP drug-metabolizing enzymes, UGT1A9 is inhibited by CBD and CBN, whereas UGT2B7 is inhibited by CBD but activated by CBN. Carboxylesterase 1 (CES1) is potentially inhibited by THC and CBD. Clinical studies suggest inhibition of CYP2C19 by CBD, inhibition of CYP2C9 by various cannabis products, and induction of CYP1A2 through cannabis smoking. Evidence of CBD inhibition of UGTs and CES1 has been shown in some studies, but the data are limited at present. We did not identify any clinical studies suggesting an influence of cannabinoids on drug transporters, and in vitro results suggest that a clinical interaction is unlikely.

Conclusions

Medications that are prominent substrates for CYP2C19, CYP2C9, and CYP1A2 may be particularly at risk of altered disposition by concomitant use of cannabis or 1 or more of its constituents. Caution should also be given when coadministered drugs are metabolized by UGT or CES1, on which subject the information remains limited and further investigation is warranted. Conversely, conventional drugs with strong inhibitory or inductive effects on CYP3A4 are expected to affect CBD disposition.
Physiology of cerebrospinal fluid circulation
Authors: Shapey Jonathan , Toma A. , Saeed S.R.
Published: August 2019

Purpose of review

This article describes the physiology of cerebrospinal fluid (CSF). We review current evidence and new concepts relating to CSF physiology with respect to CSF secretion, circulation and resorption and we highlight key pathophysiological associations including the relationship between CSF and intracranial pressure.

Recent findings

CSF secretion occurs primarily via the choroid plexus. Various transport mechanisms facilitate CSF secretion but the role Aquaporins play in this process is a recent discovery and an area of ongoing research. CSF circulation is a dynamic process but the importance of the perivascular ‘Glymphatic system’ and extraarachnoidal pathways of resorption are relatively new concepts.

CSF physiology is dependent on various interacting factors and is critical for normal brain development and function.
The Impact of Focused Cardiac Ultrasound Performed by Pediatric Intensivists
Authors: Rato João , Camilo Cristina , Boto Leonor , Rios Joana , Abecasis Francisco , Vieira Marisa
Published: August 2019

Objectives

Focused cardiac ultrasound is an echocardiographic method used by medical intensivists for fast and reliable hemodynamic assessment. Prospective studies and guidelines have defined its role in adult critical care. Data regarding its use in pediatric critical care are scarce. This is the first prospective study that aims to evaluate its impact in this setting.

Methods

This is a single-center prospective study performed in a tertiary referral hospital pediatric intensive care unit (PICU). For a period of 6 months, when performing an echocardiogram, pediatric intensivists filled out a questionnaire that included the patient's clinical data and indication for the examination. The intensivists had to record both the clinical impression regarding that indication and therapeutic plan before and after the echocardiogram. All the patients with an echocardiogram performed by the pediatric intensive care unit medical staff were included.

Results

There were 80 echocardiograms performed on 35 patients during the study period. The most common patient diagnostic groups were respiratory infections (38%, n = 30) and septic shock (21%, n = 17). The main indication for the examination was assessment of intravascular volume status and left ventricular systolic function. After the echocardiogram, the clinical impression was maintained in 49% (n = 39) and changed in 44% (n = 35). There were new findings unrelated to the initial evaluation in 7% (n = 6). The planned treatment was maintained in 55% (n = 44) and changed in 45% (n = 36).

Conclusions

The echocardiogram changed the clinical impression and therapeutic plan in almost half of the patients. These data show the value of focused cardiac ultrasound as a diagnostic and hemodynamic monitoring tool in pediatric intensive care and emphasize the importance of a rigorous training program.
Familial relationships in electronic health records (EHR) v2
Authors: Liu Zhouzerui , Tatonetti Nicholas
Published: August 2019

Heritability is an important statistic for evaluating genetic contribution to phenotypes. Estimating heritability, however, requires a laborious recruitment of a large number of relatives. Electronic health records (EHR) contain massive relative information in emergency contact forms. Recently, we presented RIFTEHR, an algorithm for extracting relationships from EHR. Here, we present an updated version and reconstructed 4.2 million familial relationships from the latest New York-Presbyterian/Columbia University Irving Medical Center (CUIMC) EHR system. The number of updated relationships is 30 percent more than the last version. We present a new implementation of RIFTEHR, which runs in linear time, thus largely improves the speed of the algorithm. We also present a data encryption method, to protect patient privacy in running the algorithm. These resources can be used for generalized use of familial relationships from EHR in genetic studies.
Preliminary findings of single session of noninvansive brain stimulation over parietal lobe and performance on spatial memory task
Authors: Čolić V Marija , Konstantinović Uroš , Bjekić Jovana , Filipović R Saša
Published: August 2019

Spatial memory relies on efficient encoding, storage and retrieval of spatial information, which enables us to remember paths or locations of objects in everyday life. Moreover, this type of memory has been shown to decline with age and various neurodegenerative disorders. Parietal cortex has been shown to play an important role in the formation of short-term representations of spatial information. The aim of the current study was to test the possibility of immediate and long-term spatial memory enhancement, by increasing excitability of parietal posterior cortex. We used transcranial direct current stimulation (tDCS) over posterior parietal cortex in a placebo-controlled cross-over study. Participants received anodal (1.5 mA) or sham tDCS stimulation over P4 site (10-20 EEG system) for 20 minutes in two separate sessions. Immediately after stimulation, participants completed a spatial maze task, which consisted of learning block, 2D recall, and 3D recall. Spatial memory performance was tested 24 hours and 7 days after stimulation, to assess potential long-term effects. We found no significant effects of anodal stimulation on spatial memory performance either on immediate or delayed recall. This was the case with both, 2D and 3D spatial memory recall. Our results are in line with some studies that suggest that single brain stimulation sessions do not always produce effects on cognitive functions.
ATLAS: a Snakemake workflow for assembly, annotation, and genomic binning of metagenome sequence data
Authors: Kieser Silas , Brown Joseph , Zdobnov Evgeny M. , Trajkovski Mirko , McCue Lee Ann
Published: August 2019

Background

Metagenomics and metatranscriptomics studies provide valuable insight into the composition and function of microbial populations from diverse environments, however the data processing pipelines that rely on mapping reads to gene catalogs or genome databases for cultured strains yield results that underrepresent the genes and functional potential of uncultured microbes. Recent improvements in sequence assembly methods have eased the reliance on genome databases, thereby allowing the recovery of genomes from uncultured microbes. However, configuring these tools, linking them with advanced binning and annotation tools, and maintaining provenance of the processing continues to be challenging for researchers.

Results

Here we present ATLAS, a software package for customizable data processing from raw sequence reads to functional and taxonomic annotations using state-of-the-art tools to assemble, annotate, quantify, and bin metagenome and metatranscriptome data. Genome-centric resolution and abundance estimates are provided for each sample in a dataset. ATLAS is written in Python and the workflow implemented in Snakemake; it operates in a Linux environment, and is compatible with Python 3.5+ and Anaconda 3+ versions. The source code for ATLAS is freely available, distributed under a BSD-3 license.

Conclusion

ATLAS provides a user-friendly, modular and customizable Snakemake workflow for metagenome and metatranscriptome data processing; it is easily installable with conda and maintained as open-source on GitHub at https://github.com/metagenome-atlas/atlas.
Biological machine learning combined with bacterial population genomics reveals common and rare allelic variants of genes to cause disease
Authors: Bandoy DJ Darwin R. , Weimer Bart C.
Published: August 2019

Highly dimensional data generated from bacterial whole genome sequencing is providing unprecedented scale of information that requires appropriate statistical frameworks of analysis to infer biological function from bacterial genomic populations. Application of genome wide association study (GWAS) methods is an emerging approach with bacterial population genomics that yields a list of genes associated with a phenotype with an undefined importance among the candidates in the list. Here, we validate the combination of GWAS, machine learning, and pathogenic bacterial population genomics as a novel scheme to identify SNPs and rank allelic variants to determine associations for accurate estimation of disease phenotype. This approach parsed a dataset of 1.2 million SNPs that resulted in a ranked importance of associated alleles of Campylobacter jejuni porA using multiple spatial locations over a 30-year period. We validated this approach using previously proven laboratory experimental alleles from an in vivo guinea pig abortion model. This approach, termed BioML, defined intestinal and extraintestinal groups that have differential allelic variants that cause abortion. Divergent variants containing indels that defeated gene callers were rescued using biological context and knowledge that resulted in defining rare and divergent variants that were maintained in the population over two continents and 30 years. This study defines the capability of machine learning coupled to GWAS and population genomics to simultaneously identify and rank alleles to define their role in abortion, and more broadly infectious disease.