bluuebunny/crossref_metadata_2025 huggingface dataset:
End-to-end validation of the geometric dose delivery performance of MR linac adaptive radiotherapy
Authors: Bernchou Uffe , Christiansen Rasmus L , Bertelsen Anders , Tilly David , Riis Hans L , Jensen Henrik R , Mahmood Faisal , Hansen Christian R , Hansen Vibeke N , Schytte Tine , Brink Carsten
Published: December 2020

The clinical introduction of hybrid magnetic resonance (MR) guided radiotherapy (RT) delivery systems has led to the need to validate the end-to-end dose delivery performance on such machines. In the current study, an MR visible phantom was developed and used to test the spatial deviation between planned and delivered dose at two 1.5 T MR linear accelerator (MR linac) systems, including pre-treatment imaging, dose planning, online imaging, image registration, plan adaptation, and dose delivery. The phantom consisted of 3D printed plastic and MR visible silicone rubber. It was designed to minimise air gaps close to the radiochromic film used as a dosimeter. Furthermore, the phantom was designed to allow submillimetre, reproducible positioning of the film in the phantom. At both MR linac systems, 54 complete adaptive, MR guided RT workflow sessions were performed. To test the dose delivery performance of the MR linac systems in various adaptive RT (ART) scenarios, the sessions comprised a range of systematic positional shifts of the phantom and imaging or plan adaptation conditions. In each workflow session, the positional translation between the film and the adaptive planned dose was determined. The results showed that the accuracy of the MR linac systems was between 0.1 and 0.9 mm depending on direction. The highest mean deviance observed was in the posterior–anterior direction, and the direction of the error was consistent between centres. The precision of the systems was related to whether the workflow utilized the internal image registration algorithm of the MR linac. Workflows using the internal registration algorithm led to a worse precision (0.2–0.7 mm) compared to workflows where the algorithm was decoupled (0.2 mm). In summary, the spatial deviation between planned and delivered dose of MR-guided ART at the two MR linac systems was well below 1 mm and thus acceptable for clinical use.
Effect of microdistribution of alpha and beta-emitters in targeted radionuclide therapies on delivered absorbed dose in a GATE model of bone marrow
Authors: Tranel Jonathan , Feng Felix Y , James Sara St , Hope Thomas A
Published: December 2020

Acute hematologic toxicity is a frequent adverse effect of beta-emitter targeted radionuclide therapies (TRTs). Alpha emitters have the potential of delivering high linear energy transfer (LET) radiation to the tumor attributed to its shorter range. Antibody-based TRTs have increased blood-pool half-lives, and therefore increased marrow toxicity, which is a particular concern with alpha emitters. Accurate 3D absorbed dose calculations focusing on the interface region of blood vessels and bone can elucidate energy deposition patterns. Firstly, a cylindrical geometry model with a central blood vessel embedded in the trabecular tissue was modeled. Monte Carlo simulations in GATE were performed considering beta (177Lu, 90Y) and alpha emitters (211At, 225Ac) as sources restricted to the blood pool. Subsequently, the radioactive sources were added in the trabecular bone compartment in order to model bone marrow metastases infiltration (BMMI). Radial profiles, dose-volume histograms and voxel relative differences were used to evaluate the absorbed dose results. We demonstrated that alpha emitters have a higher localized energy deposition compared to beta emitters. In the cylindrical geometry model, when the sources are confined to the blood pool, the dose to the trabecular bone is greater for beta emitting radionuclides, as alpha emitters deposit the majority of their energy within 70 μm of the vessel wall. In the BMMI model, alpha emitters have a lower dose to untargeted trabecular bone. Our results suggest that when alpha emitters are restricted to the blood pool, as when labeled to antibodies, hematologic toxicities may be lower than expected due to differences in the microdistribution of delivered absorbed dose.
EDGE2D-EIRENE modeling of the impact of wall materials on core edge, scrape-off layer and divertor parameters
Authors: Chankin A V , Corrigan G
Published: December 2020

A series of EDGE2D-EIRENE cases was run in different wall materials of JET L-mode plasma with the input power close to the H-mode power threshold in ITER-like wall (ILW), with tungsten (W) covering the divertor, and beryllium (Be)—main chamber surfaces. Cases with all carbon (C) and all W walls were run at the same input power as in ILW cases. Contrary to expectations based on the idea that deeper penetration of neutrals re-emitted from surfaces with higher atomic mass into the plasma core raises core density, EDGE2D-EIRENE cases had the highest density in the C wall case. This is explained via the effect of the ‘power deficit’ in the divertor, as recycling neutrals deposit a fraction of their power into walls, thereby cooling the divertor plasma. This effect is stronger in C compared to W divertor surfaces. The plasma cooling in the divertor increases plasma density and neutral recycling, with more neutrals penetrating into the core. Metal wall (ILW and W wall) EDGE2D-EIRENE cases were found to have larger radial electric field (E
r) both inside and outside of the separatrix, in line with the mechanism of the E × B shear turbulence suppression and experimental observations of lower H-mode power threshold in metal wall machines. The originally expected trend for higher core densities in metal wall machines, based on the effect of deeper penetration of neutrals re-emitted from higher atomic mass surfaces, was recovered in much lower density EDGE2D-EIRENE cases, where the effect of the power deficit in the divertor was less important. Subtle effects of interplay among mechanisms involving neutral circulation in the divertor and in the main chamber wall are considered to explain differences between ILW and W wall cases.
Analysis of nonclassical features in a coupled macroscopic binary system
Authors: Ham Byoung S
Published: December 2020

Nonclassical phenomena of quantum mechanics such as anticorrelation and photonic de Broglie waves (PBWs) have been recently understood as a special case of coherence optics with a particular phase relation between orthogonal bases composing a classical system. Such a macroscopic understanding of nonclassical features has also been confirmed experimentally for a coherence version of PBWs in a doubly-coupled Mach–Zehnder interferometer (MZI). Here, a multi-coupled MZI system is analyzed and discussed to obtain a general understanding of the nonclassical feature using tensor products of binary bases of a classical system. This analysis should intrigue a fundamental question on quantumness or nonclassicality limited to a microscopic world of a single photon or a single particle.
Bright-dark solitons and interaction phenomenon for p-gBKP equation by using bilinear neural network method
Authors: Zhang Run-Fa , Bilige Sudao , Liu Jian-Guo , Li Mingchu
Published: December 2020

In the present paper, we focus on the bright-dark solitons and interaction behavior associated with a dimensionally reduced p-gBKP equation. New test functions are constructed by using the Bilinear Neural Network Method (BNNM). These test functions are composed of arbitrary functions in ‘3-2-2-2’ neural network model or specific activation functions in single-layer model. The bright-dark solitons and interaction solutions between lump and double exponential function or hyperbolic tangent function are obtained by choosing appropriate values and activation functions. Via various three-dimensional plots, 2D plots, contour plots and density plots, the evolution characteristics of these waves are exhibited well.
A novel high accuracy micrometer for the measurement of diameter
Authors: Stoup John , Doiron Ted
Published: December 2020

The dimensional metrology group at the National Institute of Standards and Technology (NIST) has developed an ultra-high accuracy laser micrometer capable of external diameter measurements with a targeted expanded uncertainty, U(k = 2), of less than 20 nm. This instrument is an advanced iteration of a design developed at NIST in the 1990s and has been continuously improved since its inception. This newest approach takes advantage of the lessons learned through two decades of operation, process control measurement data, and performance analysis. This approach advances the state of the art for diameter measurements within an artifact diameter range of 0.02 mm to 55 mm. The instrument makes use of low thermal expansion materials, a stable structural design, environmental control, and remote manipulation of the artifacts to address the most significant uncertainty sources identified in previous versions of the instrument. A review of the instrument development and components will be presented. We will outline the significant contributions to the operational measurement uncertainty budget for this instrument along with identifying the high accuracy applications that will benefit from this effort.
Impact of dose heterogeneity in target on TCP and NTCP for various radiobiological models in liver SBRT: different isodose prescription strategy
Authors: Thaper Deepak , Singh Gaganpreet , Kamal Rose , Oinam Arun S. , Yadav Hanuman P , Kumar Rishabh , Kumar Vivek
Published: December 2020

Introduction: The impact of dose heterogeneity within the tumor on TCP and NTCP was studied using various radiobiological models. The effect of the degree of heterogeneity index (HI) on TCP was also analyzed. Materials and Methods: Thirty-seven pre-treated liver SBRT cases were included in this study. Two different kinds of treatment techniques were employed. In both arms, the prescribed dose was received by 95% of the PTV. Initially, the inhomogeneous treatment plans (IHTP) were made in which the spatial change of dose within the PTV was high and the maximum dose within the PTV can go up to 160%. Subsequently, in another arm, homogeneous treatment plans (HTP) were generated in which PTV was covered with the same prescription isodose and the maximum dose can go up to 120%. As per RTOG 1112, all organs at risk (OAR’s) were considered while optimization of the treatment plans. TCP was calculated using the Niemierko and Poisson model. NTCP was calculated using the Niemierko and LKB fractionated model. Results: For the IHTP, TCP was decreasing as ‘a’ value decreased in the Niemierko model whereas, for HTP, TCP was found to be the same. NTCP of the normal liver was less in IHTP as compared to HTP, and the Niemierko model overestimates the NTCP as compared to LKB fractionated model. NTCP for all other OAR’s was <1% in both kinds of treatment plans. Conclusion: IHTP is found to be clinically better than HTP because NTCP of the normal liver was significantly less and TCP was more for certain ‘a’ values of the Niemierko model and the Poisson model. There is not any effect of HI on TCP was observed. Advances in knowledge: IHTP could be used clinically because of the dose-escalation and subsequently, leads to an increase in the TCP.
Share the details of your experimental methods
Authors: Siegel Vivian
Published: December 2020

Incomplete methods sections have made it difficult for researchers to replicate and build on the work of others, contributing to problems in reproducibility. It is important to increase the level of detail in our methods sections and to share step-by-step protocols in protocol repositories or journals. Request a Protocol is a new feature in Molecular Biology of the Cell that allows readers to request detailed protocols directly from the methods section of the research article, with links between the protocols and the research articles, and has the potential to improve research reproducibility and help everyone design and execute robust life science experiments.
Fifty years of cycling
Authors: Biggins Sue , Hartwell Lee , Toczyski David
Published: December 2020

Fifty years ago, the first isolation of conditional budding yeast mutants that were defective in cell division was reported. Looking back, we now know that the analysis of these mutants revealed the molecular mechanisms and logic of the cell cycle, identified key regulatory enzymes that drive the cell cycle, elucidated structural components that underly essential cell cycle processes, and influenced our thinking about cancer and other diseases. Here, we briefly summarize what was concluded about the coordination of the cell cycle 50 years ago and how that relates to our current understanding of the molecular events that have since been elucidated.
Fission yeast cell cycle mutants and the logic of eukaryotic cell cycle control
Authors: Nurse Paul
Published: December 2020

Cell cycle mutants in the budding and fission yeasts have played critical roles in working out how the eukaryotic cell cycle operates and is controlled. The starting point was Lee Hartwell’s 1970s landmark papers describing the first cell division cycle (CDC) mutants in budding yeast. These mutants were blocked at different cell cycle stages and so were unable to complete the cell cycle, thus defining genes necessary for successful cell division. Inspired by Hartwell’s work, I isolated CDC mutants in the very distantly related fission yeast. This started a program of searches for mutants in fission yeast that revealed a range of phenotypes informative about eukaryotic cell cycle control. These included mutants defining genes that were rate-limiting for the onset of mitosis and of the S-phase, that were responsible for there being only one S-phase in each cell cycle, and that ensured that mitosis only took place when S-phase was properly completed. This is a brief account of the discovery of these mutants and how they led to the identification of cyclin-dependent kinases as core to these cell cycle controls.
Perilipin2 is an Earlier Marker Than Perilipin1 for Identifying Adipocyte Regeneration in Fat Grafts
Authors: Zhang Kaili , Chen Xi , Zhang Peng , Liu Guangpeng
Published: December 2020

Background

Both perilipin1 (Plin1) and perilipin2 (Plin2) play a crucial role in regulating lipid droplet (LD) formation in fat cells. Plin2 is expressed early in the adipocyte differentiation process but is replaced by Plin1 after cell maturation. In free fat grafts, only a small number of adipocytes remain alive or are replaced by newly regenerated fat cells. It is known that Plin1-positive adipocytes participate in regeneration, but the characteristics of Plin2 expression during this process are still poorly understood.

Objectives

The aim of this study was to investigate whether Plin2 is a more precise early marker for detecting adipocyte regeneration in fat grafts than Plin1.

Methods

Autologous fat tissue (120 mg) harvested from inguinal fat pads was injected under the scalps of C57 mice. Samples were explanted at days 3, 7, 15, and 30 after transplantation. Changes in sample size and weight were evaluated. Hematoxylin-eosin staining, real-time polymerase chain reaction, and immunostaining of Plin1 and Plin2 expression were performed.

Results

Plin1, but not Plin2, expression was detected in the freshly harvested fat, but the latter was activated after grafting. Newly regenerated Plin2-positive adipocytes increased from day 3 to day 7 and then declined, whereas the number of Plin1-positive fat cells decreased first and began to increase after day 15. The expression levels of Plin1 and Plin2 mRNA demonstrated similar changes over time. At day 30, adipocytes lost Plin2 expression and were positive for Plin1 again.

Conclusions

Our experiments showed convincing evidence that Plin2 expression could be used to detect early adipocyte regeneration in grafted fat tissue.
The Aging Parotid Gland: A Longitudinal Volumetric Study and Implications for Treatment
Authors: Tower Jacob I , Sawan Tareq , Gordon Neil A , Paskhover Boris
Published: December 2020

Background

The parotid gland accounts for significant soft tissue volume in the face and is therefore of central relevance to facial and neck rejuvenation.

Objectives

The aim of this study was to determine how parotid gland volume is predicted by age and other factors.

Methods

We conducted a retrospective longitudinal study of patients with multiple computed tomography (CT) scans of the neck performed at least 7 years apart. Parotid gland volumes were measured and multiple linear regression analysis was performed to model the relations between age, body mass index (BMI), and parotid volume.

Results

The study cohort comprised 70 patients. The mean [standard deviation] ages at initial and final imaging time points were 47.5 [12.6] and 58.8 [12.2] years, respectively, with an average of 11.3 years elapsed between CT scans. The mean parotid gland volume increased from 28.7 [10.0] to 32.2 [10.7] mL over the average 11.3-year period (P = 0.03). However, the results of the multiple linear regression analysis show that when controlling for BMI and sex, age alone does not predict parotid volume (P = 0.29). BMI was directly correlated with gland volume (P < 0.01). An increase of 1.0 kg/m2 in BMI predicted an increase in parotid volume by 1.1 mL. Male sex was also associated with significantly greater parotid volume.

Conclusions

Mean parotid volume increased over time but these gains were driven by increases in BMI and not age alone. These findings are highly relevant to the treatment of the aging face and neck.
A Systematic Review on Extracellular Vesicles-Enriched Fat Grafting: A Shifting Paradigm
Authors: Ghiasloo Mohammad , De Wilde Laura , Singh Kashika , Tonnard Patrick , Verpaele Alexis , De Wever Olivier , Blondeel Phillip
Published: December 2020

Background

Recent evidence confirms that mesenchymal stem cells (MSCs) facilitate angiogenesis mainly through paracrine function. Extracellular vesicles (EVs) are regarded as key components of the cell secretome, possessing functional properties of their source cells. Subsequently, MSC-EVs have emerged as a novel cell-free approach to improve fat graft retention rate.

Objectives

The authors sought to provide a systematic review of all studies reporting the utilization of MSC-EVs to improve graft retention rate.

Methods

A systematic search was undertaken employing the Embase, PubMed, and Cochrane Central Register of Controlled Trials databases. Outcome measures included donor/receptor organism of the fat graft, study model, intervention groups, evaluation intervals, EV research data, and in vitro and in vivo results.

Results

Of the total 1717 articles, 62 full texts were screened. Seven studies reporting on 294 mice were included. Overall, EV-treated groups showed higher graft retention rates compared with untreated groups. Notably, retention rate was similar following EV and MSC treatment. In addition to reduced inflammation, graft enrichment with EVs resulted in early revascularization and better graft integrity. Interestingly, hypoxic preconditioning of MSCs improved their beneficial paracrine effects and led to a more proangiogenic EV population, as observed by both in vitro and in vivo results.

Conclusions

MSC-EVs appear to offer an interesting cell-free alternative to improve fat graft survival. Although their clinical relevance remains to be determined, it is clear that not the cells but rather their secretome is essential for graft survival. Thus, a paradigm shift from cell-assisted lipotransfer towards “secretome-assisted lipotransfer” is well on its way.

Level of Evidence: 4
Computational resources for identifying and describing proteins driving liquid–liquid phase separation
Authors: Pancsa Rita , Vranken Wim , Mészáros Bálint
Published: December 2020

One of the most intriguing fields emerging in current molecular biology is the study of membraneless organelles formed via liquid–liquid phase separation (LLPS). These organelles perform crucial functions in cell regulation and signalling, and recent years have also brought about the understanding of the molecular mechanism of their formation. The LLPS field is continuously developing and optimizing dedicated in vitro and in vivo methods to identify and characterize these non-stoichiometric molecular condensates and the proteins able to drive or contribute to LLPS. Building on these observations, several computational tools and resources have emerged in parallel to serve as platforms for the collection, annotation and prediction of membraneless organelle-linked proteins. In this survey, we showcase recent advancements in LLPS bioinformatics, focusing on (i) available databases and ontologies that are necessary to describe the studied phenomena and the experimental results in an unambiguous way and (ii) prediction methods to assess the potential LLPS involvement of proteins. Through hands-on application of these resources on example proteins and representative datasets, we give a practical guide to show how they can be used in conjunction to provide in silico information on LLPS.
Hypergraph-based persistent cohomology (HPC) for molecular representations in drug design
Authors: Liu Xiang , Wang Xiangjun , Wu Jie , Xia Kelin
Published: December 2020

Artificial intelligence (AI) based drug design has demonstrated great potential to fundamentally change the pharmaceutical industries. Currently, a key issue in AI-based drug design is efficient transferable molecular descriptors or fingerprints. Here, we present hypergraph-based molecular topological representation, hypergraph-based (weighted) persistent cohomology (HPC/HWPC) and HPC/HWPC-based molecular fingerprints for machine learning models in drug design. Molecular structures and their atomic interactions are highly complicated and pose great challenges for efficient mathematical representations. We develop the first hypergraph-based topological framework to characterize detailed molecular structures and interactions at atomic level. Inspired by the elegant path complex model, hypergraph-based embedded homology and persistent homology have been proposed recently. Based on them, we construct HPC/HWPC, and use them to generate molecular descriptors for learning models in protein–ligand binding affinity prediction, one of the key step in drug design. Our models are tested on three most commonly-used databases, including PDBbind-v2007, PDBbind-v2013 and PDBbind-v2016, and outperform all existing machine learning models with traditional molecular descriptors. Our HPC/HWPC models have demonstrated great potential in AI-based drug design.
Assessment and Simplification of Treatment Eligibility Among Patients With Chronic Hepatitis B Infection in Vietnam
Authors: Vu Hai Vinh , Shimakawa Yusuke , Kim Jin , Do Ngoc Hai , Le Minh Quang , Laureillard Didier , Lemoine Maud
Published: December 2020

Background

Treatment eligibility and the accuracy of its simplified criteria have been poorly documented in patients with chronic hepatitis B virus (HBV) infection worldwide, especially in low- and middle-income countries.

Methods

From a cohort of HBV-infected patients in Vietnam, we assessed the proportion of patients eligible for treatment using the national guidelines based on reference tests (HBV DNA quantification and FibroScan); and the accuracy of simplified treatment criteria free from HBV DNA and FibroScan (Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score and simplified World Health Organization [WHO] criteria) to select patients for antiviral therapy using the national guidelines as a reference.

Results

We analyzed 400 consecutive treatment-naïve HBV-monoinfected patients: 49% males, median age 38 years (range, 18–86), 32% hepatitis B e antigen-positive, median HBV DNA 4.8 log10 IU/mL (undetectable −8.4), median FibroScan 5.3 kPa (3.0–67.8), and 25% having significant liver fibrosis including 12% with cirrhosis. Of these, 167 (42%) fulfilled treatment criteria according to national guidelines. Using the national criteria as a reference, the performance of TREAT-B to select patients for treatment was high (area under the receiver operating characteristic [AUROC], 0.89 [95% confidence interval 0.87-0.92]) with a sensitivity of 74.3% and a specificity of 88.4%. In a subset of patients with 2 alanine aminotransferase measurements over a 6-month period (n = 89), the AUROC of TREAT-B was significantly higher than that of the simplified WHO criteria (P < .001).

Conclusions

Our study suggests that a large proportion of patients with chronic HBV infection require antiviral therapy in Vietnam. Compared with the simplified WHO criteria free from HBV DNA quantification, TREAT-B is a better alternative to easily indicate treatment eligibility and might help scale up treatment intervention in Vietnam.
Evaluating the Efficacy of Coronavirus Disease 2019 Vaccines
Authors: Lin Dan-Yu , Zeng Donglin , Mehrotra Devan V , Corey Lawrence , Gilbert Peter B
Published: December 2020

A large number of studies are being conducted to evaluate the efficacy and safety of candidate vaccines against coronavirus disease 2019 (COVID-19). Most phase 3 trials have adopted virologically confirmed symptomatic COVID-19 as the primary efficacy end point, although laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also of interest. In addition, it is important to evaluate the effect of vaccination on disease severity. To provide a full picture of vaccine efficacy and make efficient use of available data, we propose using SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19 as dual or triple primary end points. We demonstrate the advantages of this strategy through realistic simulation studies. Finally, we show how this approach can provide rigorous interim monitoring of the trials and efficient assessment of the durability of vaccine efficacy.
Steroid hormones in Pacific walrus bones collected over three millennia indicate physiological responses to changes in estimated population size and the environment
Authors: Charapata Patrick , Horstmann Lara , Misarti Nicole
Published: December 2020

The Pacific walrus (Odobenus rosmarus divergens) is an iconic Arctic marine mammal and an important resource to many Alaska Natives. A decrease in sea ice habitat and unknown population numbers has led to concern of the long-term future health of the walrus population. There is currently no clear understanding of how walrus physiology might be affected by a changing Arctic ecosystem. In this study, steroid hormone concentrations (progesterone, testosterone, cortisol and estradiol) were analysed in walrus bones collected during archaeological [3585–200 calendar years before present (BP)], historical [1880–2006 common era (CE)] and modern (2014–2016 CE) time periods, representing ~ 3651 years, to track changes in reproductive activity and cortisol concentrations (biomarker of stress) over time. Our results show that modern walrus samples have similar cortisol concentrations (median = 43.97 ± standard deviation 904.38 ng/g lipid) to archaeological walruses (38.94 ± 296.17 ng/g lipid, P = 0.75). Cortisol concentrations were weakly correlated with a 15-year average September Chukchi Sea ice cover (P = 0.002, 0.02, r2 = 0.09, 0.04, for females and males, respectively), indicating a possible physiological resiliency to sea ice recession in the Arctic. All steroid hormones had significant negative correlations with mean walrus population estimates from 1960 to 2016 (P < 0.001). Progesterone in females and testosterone in males exhibited significant correlations with average September Chukchi Sea ice cover for years 1880–2016 (P < 0.001 for both, r2 = 0.34, 0.22, respectively). Modern walruses had significantly lower (P = < 0.001) reproductive hormone concentrations compared with historic walruses during times of rapid population increase, indicative of a population possibly at carrying capacity. This is the first study to apply bone as a tool to monitor long-term changes in hormones that may be associated with changes in walrus population size and sea ice cover.
The cardiovascular–dialysis nexus: the transition to dialysis is a treacherous time for the heart
Authors: Chan Kevin , Moe Sharon M , Saran Rajiv , Libby Peter
Published: December 2020

Chronic kidney disease (CKD) patients require dialysis to manage the progressive complications of uraemia. Yet, many physicians and patients do not recognize that dialysis initiation, although often necessary, subjects patients to substantial risk for cardiovascular (CV) death. While most recognize CV mortality risk approximately doubles with CKD the new data presented here show that this risk spikes to >20 times higher than the US population average at the initiation of chronic renal replacement therapy, and this elevated CV risk continues through the first 4 months of dialysis. Moreover, this peak reflects how dialysis itself changes the pathophysiology of CV disease and transforms its presentation, progression, and prognosis. This article reviews how dialysis initiation modifies the interpretation of circulating biomarkers, alters the accuracy of CV imaging, and worsens prognosis. We advocate a multidisciplinary approach and outline the issues practitioners should consider to optimize CV care for this unique and vulnerable population during a perilous passage.
Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia
Authors: Pérez de Isla Leopoldo , Watts Gerald F , Alonso Rodrigo , Díaz-Díaz José Luis , Muñiz-Grijalvo Ovidio , Zambón Daniel , Fuentes Francisco , de Andrés Raimundo , Padró Teresa , López-Miranda José , Mata Pedro
Published: December 2020

Aims

Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH.

Methods and results

SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR [odds ratio 5.71; 95% confidence interval (CI): 1.78–18.4; P = 0.003] after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20–12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event.

Conclusion

The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials.

ClinicalTrials.gov number NCT02693548.
Using machine learning to identify local cellular properties that support re-entrant activation in patient-specific models of atrial fibrillation
Authors: Corrado Cesare , Williams Steven , Roney Caroline , Plank Gernot , O’Neill Mark , Niederer Steven
Published: December 2020

Aims

Atrial fibrillation (AF) is sustained by re-entrant activation patterns. Ablation strategies have been proposed that target regions of tissue that may support re-entrant activation patterns. We aimed to characterize the tissue properties associated with regions that tether re-entrant activation patterns in a validated virtual patient cohort.

Methods and results

Atrial fibrillation patient-specific models (seven paroxysmal and three persistent) were generated and validated against local activation time (LAT) measurements during an S1–S2 pacing protocol from the coronary sinus and high right atrium, respectively. Atrial models were stimulated with burst pacing from three locations in the proximity of each pulmonary vein to initiate re-entrant activation patterns. Five atria exhibited sustained activation patterns for at least 80 s. Models with short maximum action potential durations (APDs) were associated with sustained activation. Phase singularities were mapped across the atria sustained activation patterns. Regions with a low maximum conduction velocity (CV) were associated with tethering of phase singularities. A support vector machine (SVM) was trained on maximum local conduction velocity and action potential duration to identify regions that tether phase singularities. The SVM identified regions of tissue that could support tethering with 91% accuracy. This accuracy increased to 95% when the SVM was also trained on surface area.

Conclusion

In a virtual patient cohort, local tissue properties, that can be measured (CV) or estimated (APD; using effective refractory period as a surrogate) clinically, identified regions of tissue that tether phase singularities. Combing CV and APD with atrial surface area further improved the accuracy in identifying regions that tether phase singularities.
Genetic and functional diversity of PsyI/PsyR quorum-sensing system in the Pseudomonas syringae complex
Authors: Morohoshi Tomohiro , Oshima Akinori , Xie Xiaonan , Someya Nobutaka
Published: December 2020

Strains belonging to the Pseudomonas syringae complex often possess quorum-sensing systems that comprise N-acyl-l-homoserine lactone (AHL) synthases (PsyI) and AHL receptors (PsyR). Here, we investigated the diversity of PsyI/PsyR quorum-sensing systems in 630 strains of the P. syringae complex. AHL production was observed in most strains of Pseudomonas amygdali and Pseudomonas meliae, and a few strains of Pseudomonas coronafaciens and P. syringae. The DNA sequences of psyIR and their upstream and downstream regions were categorized into eight types. P. amygdali pv. myricae, Pseudomonas savastanoi, and P. syringae pv. solidagae, maculicola, broussonetiae, and tomato encoded psyI, but did not produce detectable amounts of AHL. In P. savastanoi, an amino acid substitution (R27S) in PsyI caused defective AHL production. The psyI gene of P. syringae pv. tomato was converted to pseudogenes by frameshift mutations. Escherichia coli harboring psyI genes from P. amygdali pv. myricae, P. syringae pv. solidagae and broussonetiae showed high levels of AHL production. Forced expression of functional psyR restored AHL production in P. amygdali pv. myricae and P. syringae pv. solidagae. In conclusion, our study indicates that the PsyI/PsyR quorum-sensing systems in P. syringae strains are genetically and functionally diverse, with diversity being linked to phylogenetic and pathovar classifications.
Identification of a differentiation stall in epithelial mesenchymal transition in histone H3–mutant diffuse midline glioma
Authors: Sanders Lauren M , Cheney Allison , Seninge Lucas , van den Bout Anouk , Chen Marissa , Beale Holly C , Kephart Ellen Towle , Pfeil Jacob , Learned Katrina , Lyle A Geoffrey , Bjork Isabel , Haussler David , Salama Sofie R , Vaske Olena M
Published: December 2020

Background

Diffuse midline gliomas with histone H3 K27M (H3K27M) mutations occur in early childhood and are marked by an invasive phenotype and global decrease in H3K27me3, an epigenetic mark that regulates differentiation and development. H3K27M mutation timing and effect on early embryonic brain development are not fully characterized.

Results

We analyzed multiple publicly available RNA sequencing datasets to identify differentially expressed genes between H3K27M and non-K27M pediatric gliomas. We found that genes involved in the epithelial-mesenchymal transition (EMT) were significantly overrepresented among differentially expressed genes. Overall, the expression of pre-EMT genes was increased in the H3K27M tumors as compared to non-K27M tumors, while the expression of post-EMT genes was decreased. We hypothesized that H3K27M may contribute to gliomagenesis by stalling an EMT required for early brain development, and evaluated this hypothesis by using another publicly available dataset of single-cell and bulk RNA sequencing data from developing cerebral organoids. This analysis revealed similarities between H3K27M tumors and pre-EMT normal brain cells. Finally, a previously published single-cell RNA sequencing dataset of H3K27M and non-K27M gliomas revealed subgroups of cells at different stages of EMT. In particular, H3.1K27M tumors resemble a later EMT stage compared to H3.3K27M tumors.

Conclusions

Our data analyses indicate that this mutation may be associated with a differentiation stall evident from the failure to proceed through the EMT-like developmental processes, and that H3K27M cells preferentially exist in a pre-EMT cell phenotype. This study demonstrates how novel biological insights could be derived from combined analysis of several previously published datasets, highlighting the importance of making genomic data available to the community in a timely manner.
Long-read assembly of the Brassica napus reference genome Darmor-bzh
Authors: Rousseau-Gueutin Mathieu , Belser Caroline , Da Silva Corinne , Richard Gautier , Istace Benjamin , Cruaud Corinne , Falentin Cyril , Boideau Franz , Boutte Julien , Delourme Regine , Deniot Gwenaëlle , Engelen Stefan , de Carvalho Julie Ferreira , Lemainque Arnaud , Maillet Loeiz , Morice Jérôme , Wincker Patrick , Denoeud France , Chèvre Anne-Marie , Aury Jean-Marc
Published: December 2020

Background

The combination of long reads and long-range information to produce genome assemblies is now accepted as a common standard. This strategy not only allows access to the gene catalogue of a given species but also reveals the architecture and organization of chromosomes, including complex regions such as telomeres and centromeres. The Brassica genus is not exempt, and many assemblies based on long reads are now available. The reference genome for Brassica napus, Darmor-bzh, which was published in 2014, was produced using short reads and its contiguity was extremely low compared with current assemblies of the Brassica genus.

Findings

Herein, we report the new long-read assembly of Darmor-bzh genome (Brassica napus) generated by combining long-read sequencing data and optical and genetic maps. Using the PromethION device and 6 flowcells, we generated ∼16 million long reads representing 93× coverage and, more importantly, 6× with reads longer than 100 kb. This ultralong-read dataset allows us to generate one of the most contiguous and complete assemblies of a Brassica genome to date (contig N50 > 10 Mb). In addition, we exploited all the advantages of the nanopore technology to detect modified bases and sequence transcriptomic data using direct RNA to annotate the genome and focus on resistance genes.

Conclusion

Using these cutting-edge technologies, and in particular by relying on all the advantages of the nanopore technology, we provide the most contiguous Brassica napus assembly, a resource that will be valuable to the Brassica community for crop improvement and will facilitate the rapid selection of agronomically important traits.
Aortic remodelling effect of the frozen elephant trunk technique on Stanford type A acute aortic dissection
Authors: Kuroda Yoshinori , Uchida Tetsuro , Ohba Eiichi , Yamashita Atsushi , Nakai Shingo , Kobayashi Kimihiro , Ochiai Tomonori , Sadahiro Mitsuaki
Published: December 2020

Total arch replacement using the frozen elephant trunk procedure is performed for true lumen expansion of the descending aorta in patients with type A acute aortic dissection. However, the remodelling effect of the frozen elephant trunk on the dissected descending aorta is unclear. We aimed to evaluate the effect of the frozen elephant trunk on postoperative descending aortic remodelling after surgery. Between December 2012 and January 2020, we retrospectively investigated 24 patients who underwent total arch replacement using the frozen elephant trunk for type A acute aortic dissection. Remodelling of the descending aorta was evaluated using computed tomography. The aortic remodelling effect, based on aortic true lumen ratio, was determined for (i) DeBakey type (type I versus type III retrograde); (ii) thoracic endovascular aneurysm repair reintervention status (reintervention versus no reintervention); and (iii) stent length of the frozen elephant trunk (60 vs 90 mm). Postoperative true lumen ratio significantly increased in the type I dissection group. The true lumen ratio in the no-reintervention group, which had many patients with the type I dissection, significantly increased after the frozen elephant trunk. Aortic remodelling due to the frozen elephant trunk can be expected after type I acute aortic dissections.
Vaccine Effectiveness Against Influenza-Associated Hospitalizations Among Adults, 2018–2019, US Hospitalized Adult Influenza Vaccine Effectiveness Network
Authors: Ferdinands Jill M , Gaglani Manjusha , Ghamande Shekhar , Martin Emily T , Middleton Donald , Monto Arnold S , Silveira Fernanda , Talbot Helen K , Zimmerman Richard , Smith Emily R , Patel Manish ,   US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) Study Investigators, Le Shoshona , DaSilva Juliana , Keong Lisa M , Stark Thomas J , Petrie Joshua G , Lamerato Lois E , Malani Anurag , Lauring Adam , Malosh Ryan E , Wyatt Dayna , Zhu Yuwei , Liu Zhouwen , Longmire Stephanie , Graves Kellie , Sedillo Emily , Simion Alina , Speer Karen , Alicie Bethany , Krantz Briana , Carillo Donna , Adams Laura , Drennan Amelia , Orga Jan , Peterson Lynn , Halasa Natasha , McHenry Rendi , Pulido Claudia Guevara , Murthy Kempapura , Bounds Kelsey , Zunie Tnelda , Clipper Lydia , Ghamande Shekhar , White Heath , Raiyani Chandni , Chang Kevin , Rao Arundhati , Mutnal Manohar , Arroliga Alejandro , Nowalk Mary Patricia , Balasubramani G K , Eng Heather , Saul Sean G , Hughes Kailey , Wheeler Nicole , Stiefel Lori , Yassin Mohamed , Williams John V
Published: December 2020

We estimated vaccine effectiveness (VE) for prevention of influenza-associated hospitalizations among adults during the 2018–2019 influenza season. Adults admitted with acute respiratory illness to 14 hospitals of the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) and testing positive for influenza were cases; patients testing negative were controls. VE was estimated using logistic regression and inverse probability of treatment weighting. We analyzed data from 2863 patients with a mean age of 63 years. Adjusted VE against influenza A(H1N1)pdm09–associated hospitalization was 51% (95% confidence interval [CI], 25%–68%). Adjusted VE against influenza A(H3N2) virus–associated hospitalization was −2% (95% CI, −65% to 37%) and differed significantly by age, with VE of −130% (95% CI, −374% to −27%) among adults 18 to ≤56 years of age. Although vaccination halved the risk of influenza A(H1N1)pdm09–associated hospitalizations, it conferred no protection against influenza A(H3N2)–associated hospitalizations. We observed negative VE for young and middle-aged adults but cannot exclude residual confounding as a potential explanation.
IL-6 in inflammation, autoimmunity and cancer
Authors: Hirano Toshio
Published: December 2020

IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6–STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6–STAT3 axis is a critical target for treating diseases.
Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: a prospective observational study
Authors: Falcone Marco , Tiseo Giusy , Giordano Cesira , Leonildi Alessandro , Menichini Melissa , Vecchione Alessandra , Pistello Mauro , Guarracino Fabio , Ghiadoni Lorenzo , Forfori Francesco , Barnini Simona , Menichetti Francesco ,   the Pisa COVID-19 Study Group, O Degl’Innocenti Sabrina Agostini , Barbieri Greta , Biancalana Martina , Borselli Matteo , Nencini Elia , Spinelli Stefano , Antognoli Rachele , Calsolario Valeria , Monzani Fabio , Paterni Simone , Baldassarri Rubia , Bertini Pietro , Brizzi Giulia , Rocca Alessandra Della , Malacarne Paolo , Monfroni Marco , Piagnani Chiara , Carpenè Nicoletta , Carrozzi Laura , Celi Alessandro , Desideri Massimiliano , Gherardi Marco , Serradori Massimiliano , Cinotti Francesco , Cipriano Alessandro , Park Naria , Forotti Giovanna , Mengozzi Alessandro , Masi Stefano , Ruberti Francesca , Sciuto Maria , Virdis Agostino , Maggi Fabrizio , Galfo Valentina
Published: December 2020

Background

Bacterial and fungal superinfections may complicate the course of hospitalized patients with COVID-19.

Objectives

To identify predictors of superinfections in COVID-19.

Methods

Prospective, observational study including patients with COVID-19 consecutively admitted to the University Hospital of Pisa, Italy, between 4 March and 30 April 2020. Clinical data and outcomes were registered. Superinfection was defined as a bacterial or fungal infection that occurred ≥48 h after hospital admission. A multivariate analysis was performed to identify factors independently associated with superinfections.

Results

Overall, 315 patients with COVID-19 were hospitalized and 109 episodes of superinfections were documented in 69 (21.9%) patients. The median time from admission to superinfection was 19 days (range 11–29.75). Superinfections were caused by Enterobacterales (44.9%), non-fermenting Gram-negative bacilli (15.6%), Gram-positive bacteria (15.6%) and fungi (5.5%). Polymicrobial infections accounted for 18.3%. Predictors of superinfections were: intestinal colonization by carbapenem-resistant Enterobacterales (OR 16.03, 95% CI 6.5–39.5, P < 0.001); invasive mechanical ventilation (OR 5.6, 95% CI 2.4–13.1, P < 0.001); immunomodulatory agents (tocilizumab/baricitinib) (OR 5.09, 95% CI 2.2–11.8, P < 0.001); C-reactive protein on admission >7 mg/dl (OR 3.59, 95% CI 1.7–7.7, P = 0.001); and previous treatment with piperacillin/tazobactam (OR 2.85, 95% CI 1.1–7.2, P = 0.028). Length of hospital stay was longer in patients who developed superinfections ompared with those who did not (30 versus 11 days, P < 0.001), while mortality rates were similar (18.8% versus 23.2%, P = 0.445).

Conclusions

The risk of bacterial and fungal superinfections in COVID-19 is consistent. Patients who need empiric broad-spectrum antibiotics and immunomodulant drugs should be carefully selected. Infection control rules must be reinforced.