Fetal Tachyarrhythmia - Part I: Diagnosis

Fetal tachycardia, first recognized in 1930 by Hyman et al1, is a condition occurring in approximately 0.4-0.6% of all pregnancies2. A subset of these cases with more sustained periods of tachycardia is clinically relevant. The necessity of therapeutic intervention in this condition is still a matter of discussion focused on the natural history of the disease. The spectrum of opinions varies from non-intervention3,4,5 based on a number of cases in which the tachycardia subsided spontaneously6, to aggressive pharmacotherapeutic intervention7,8 based on reports of deterioration of the fetal condition ultimately ending in significant neurological morbidity9,10,11, or fetal demise12,13,14. Prenatal treatment through indirect, maternally administered drug therapy seems to be the preference of most centers15,16,17,18,19,20,21. This matter will be discussed further in Fetal Tachyarrhythmia, Part II, Treatment

Fetal Tachyarrhythmia - Part II: Treatment

The decision to initiate pharmacological intervention in case of fetal tachycardia depends on several factors and must be weighed against possible maternal and/or fetal adverse effects inherent to the use of antiarrhythmics. First, the seriousness of the fetal condition must be recognized. Many studies have shown that in case of fetal tachycardia, there is a significant predisposition to congestive heart failure and subsequent development of fetal hydrops and even sudden cardiac death1,2,3 Secondly, predictors of congestive heart failure have been suggested in several studies, such as the percentage of time that the tachycardia is present, the gestational age at which the tachycardia occurs4, the ventricular rate5 and the site of origin of the tachycardia6. However, the sensitivity of these predictors is low and they are therefore clinically not very useful. In addition, hemodynamic compromise may occur in less than 24 - 48 hours as has been shown in the fetal lamb7 and in tachycardic fetuses8,9. On the other hand, spontaneous resolution of the tachycardia has also been described10. Thirdly, transplacental management of fetuses with tricuspid regurgitation11, congestive heart failure or fetal hydrops is difficult12,13, probably as a result of limited transplacental transfer of the antiarrhythmic drug14,15. In case of fetal hydrops, conversion rates are decreased and time to conversion is increased13. Treatment of sustained fetal tachycardia is therefore to be preferred above expectant management, although some centers oppose this regimen and suggest that in cases with (intermittent) fetal SVT not complicated by congestive heart failure or fetal hydrops, conservative management and close surveillance might be a reasonable alternative16,17,18

4π4\pi periodic Andreev bound states in a Dirac semimetal

Electrons in a Dirac semimetals possess linear dispersion in all three spatial dimensions, and form part of a developing platform of novel quantum materials. Bi$_{1-x}$Sb$_x$ supports a three-dimensional Dirac cone at the Sb-induced band inversion point. Nanoscale phase-sensitive junction technology is used to induce superconductivity in this Dirac semimetal. Radio frequency irradiation experiments reveal a significant contribution of 4$\pi$-periodic Andreev bound states to the supercurrent in Nb-Bi$_{0.97}$Sb$_{0.03}$-Nb Josephson junctions. The conditions for a substantial $4\pi$ contribution to the supercurrent are favourable because of the Dirac cone's topological protection against backscattering, providing very broad transmission resonances. The large g-factor of the Zeeman effect from a magnetic field applied in the plane of the junction, allows tuning of the Josephson junctions from 0 to $\pi$ regimes.Comment: Supplementary information is include

Diaphragm-Based Position Verification to Improve Daily Target Dose Coverage in Proton and Photon Radiation Therapy Treatment of Distal Esophageal Cancer

Purpose: In modern conformal radiation therapy of distal esophageal cancer, target coverage can be affected by variations in the diaphragm position. We investigated if daily position verification (PV) extended by a diaphragm position correction would optimize target dose coverage for esophageal cancer treatment. Methods and Materials: For 15 esophageal cancer patients, intensity modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans were computed. Displacements of the target volume were correlated with diaphragm displacements using repeated 4-dimensional computed tomography images to determine the correction needed to account for diaphragm variations. Afterwards, target coverage was evaluated for 3 PV approaches based on: (1) bony anatomy (PV_B), (2) bony anatomy corrected for the diaphragm position (PV_BD) and (3) target volume (PV_T). Results: The cranial-caudal mean target displacement was congruent with almost half of the diaphragm displacement (y = 0.459x), which was used for the diaphragm correction in PV_BD. Target dose coverage using PV_B was adequate for most patients with diaphragm displacements up till 10 mm (>= 94% of the dose in 98% of the volume [D-98%]). For larger displacements, the target coverage was better maintained by PV_T and PV_BD. Overall, PV_BD accounted best for target displacements, especially in combination with tissue density variations (D-98%: IMPT 94% +/- 5%, VMAT 96% +/- 5%). Diaphragm displacements of more than 10 mm were observed in 22% of the cases. Conclusions: PV_B was sufficient to achieve adequate target dose coverage in case of small deviations in diaphragm position. However, large deviations of the diaphragm were best mitigated by PV_BD. To detect the cases where target dose coverage could be compromised due to diaphragm position variations, we recommend monitoring of the diaphragm position before treatment through online imaging. (C) 2021 Elsevier Inc. All rights reserved

The transcriptome of Pinus pinaster under Fusarium circinatum challenge

Additional file 1 Symptoms at the shoot tip of inoculated (left side) and mock-inoculated (right side) Pinus pinaster seedlings by the end of the experiment (33 dpi).Additional file 2. Statistics for each TransABySS and Trinity assembly. N seq: number of transcripts; N bases: number of bases; Mean length: mean length of the transcripts; N50: N50 value; Ns: number of unknown bases; % GC: guanine and cytosine content; trinity-N: in silico normalized trinity assembly; trinity-nN: non-normalized trinity assemblies. * Best quality preliminary assemblies selected to generate the final assembly.Additional file 3. Comparative statistics between normalized (Norm) and non-normalized (N-norm) Trinity preliminary assemblies. Kmer value; % of mapped fragments; % of good mapping; AS: assembly score; OP: optimal score; OC: optimal cutoff; Number of good contigs; % good contigs.Additional file 4. BUSCO analysis against the embryophyta lineage database comparing the last Pinus de novo transcriptomes published. P. patula v1.0 [110]; P. patula v2.0 and P. tecunumanii [108].Additional file 5. Pinus pinaster de novo transcriptome annotation.Additional file 6. Pinus pinaster de novo transcriptome annotation by Mercator tool.Additional file 7. mapped reads for each species. Number of differential expressed (DE) genes for Pinus pinaster and DE genes for Fusarium circinatum at each time point in inoculated samples (FDR 0.5). Ppin: P. pinaster; Fcir: F. circinatum;HC: high confident.Additional file 8. Principal component analyses (PCA) for Pinus pinaster (above) and Fusarium circinatum (below) rlog data of the differential expression gene analysis (DESeq2). In red: mock-inoculated samples; in blue: inoculated samples at 3 dpi; in green: inoculated samples at 5 dpi; in yellow: inoculated samples at 10 dpi.Additional file 9. Clustering of Pinus pinaster and Fusarium circinatum differential expressed (DE) genes. For each cluster with gene ontology (GO) enriched terms, number of genes and percentage for genes are indicated.Additional file 10. Significantly enriched GO terms identified from Pinus pinaster genes in each cluster.Additional file 11: Phytohormone related differentially expressed (DE) genes in Pinus pinaster.Additional file 12: Pathogenesis related (PR) genes differentially expressed (DE) in Pinus pinaster.Additional file 13: Significantly enriched GO terms identified from high confidence expressed Fusarium circinatum genes.Additional file 14: Hormone related differential expressed (DE) genes in Fusarium circinatum.Additional file 15: Fusarium circinatum DE genes related to hormone production with hits in the Pathogen Host Interaction (PHI) database.Additional file 16:. RNA-seq data statistics for each sample at each time point, before and after filtering and trimming. Dpi: days post-inoculation; BR: biological replicate, RIN: RNA Integrity Number; Q 30: Phred quality score 30.BACKGROUND : Fusarium circinatum, the causal agent of pitch canker disease, poses a serious threat to several Pinus species affecting plantations and nurseries. Although Pinus pinaster has shown moderate resistance to F. circinatum, the molecular mechanisms of defense in this host are still unknown. Phytohormones produced by the plant and by the pathogen are known to play a crucial role in determining the outcome of plant-pathogen interactions. Therefore, the aim of this study was to determine the role of phytohormones in F. circinatum virulence, that compromise host resistance. RESULTS : A high quality P. pinaster de novo transcriptome assembly was generated, represented by 24,375 sequences from which 17,593 were full length genes, and utilized to determine the expression profiles of both organisms during the infection process at 3, 5 and 10 days post-inoculation using a dual RNA-sequencing approach. The moderate resistance shown by Pinus pinaster at the early time points may be explained by the expression profiles pertaining to early recognition of the pathogen, the induction of pathogenesis-related proteins and the activation of complex phytohormone signaling pathways that involves crosstalk between salicylic acid, jasmonic acid, ethylene and possibly auxins. Moreover, the expression of F. circinatum genes related to hormone biosynthesis suggests manipulation of the host phytohormone balance to its own benefit. CONCLUSIONS : We hypothesize three key steps of host manipulation: perturbing ethylene homeostasis by fungal expression of genes related to ethylene biosynthesis, blocking jasmonic acid signaling by coronatine insensitive 1 (COI1) suppression, and preventing salicylic acid biosynthesis from the chorismate pathway by the synthesis of isochorismatase family hydrolase (ICSH) genes. These results warrant further testing in F. circinatum mutants to confirm the mechanism behind perturbing host phytohormone homeostasis.Laura Hernández was supported by a fellowship from INIA (FPI-INIA) and additional funding for a Short-Term Scientific Mission in the Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa, was provided by Pinestrength Cost Action (FP1406). Financial support for this research was provided by project RTA 2017–00063-C04–01 (Programa Estatal I + D + i, INIA, Spain). EAV was supported through the Technology Innovation Agency (TIA) South Africa, Forest Molecular Genetics Cluster Program. SN was supported by the National Research Foundation (NRF) of South Africa, Y-rated grant program.https://bmcgenomics.biomedcentral.comam2020BiochemistryForestry and Agricultural Biotechnology Institute (FABI)GeneticsMicrobiology and Plant Patholog

High-sensitive Troponin T assay for the diagnosis of acute myocardial infarction: An economic evaluation

__Abstract__ Background: Delayed diagnosis and treatment of Acute Myocardial Infarction (AMI) has a major adverse impact on prognosis in terms of both morbidity and mortality. Since conventional cardiac Troponin assays have a low sensitivity for diagnosing AMI in the first hours after myocardial necrosis, high-sensitive assays have been developed. The aim of this study was to assess the cost effectiveness of a high-sensitive Troponin T assay (hsTnT), alone or combined with the heart-type fatty acid-binding protein (H-FABP) assay in comparison with the conventional cardiac Troponin (cTnT) assay for the diagnosis of AMI in patients presenting to the hospital with chest pain.Methods: We performed a cost-utility analysis (quality adjusted life years-QALYs) and a cost effectiveness analysis (life years gained-LYGs) based on a decision analytic model, using a health care perspective in the Dutch context and a life time time-horizon. The robustness of model predictions was explored using one-way and probabilistic sensitivity analyses.Results: For a life time incremental cost of 30.70 Euros, use of hsTnT over conventional cTnT results in gain of 0.006 Life Years and 0.004 QALY. It should be noted here that hsTnT is a diagnostic intervention which costs only 4.39 Euros/test more than the cTnT test. The ICER generated with the use of hsTnT based diagnostic strategy comparing with the use of a cTnT-based strategy, is 4945 Euros per LYG and 7370 Euros per QALY. The hsTnT strategy has the highest probability of being cost effective at thresholds between 8000 and 20000 Euros per QALY. The combination of hsTnT and h-FABP strategy's probability of being cost effective remains lower than hsTnT at all willingness to pay thresholds.Conclusion: Our analysis suggests that hsTnT assay is a very cost effective diagnostic tool relative to conventional TnT assay. Combination of hsTnT and H-FABP does not offer any additional economic and health benefit over hsTnT test alone

Dual RNA-Seq analysis of the pine-Fusarium circinatum interaction in resistant (Pinus tecunumanii) and susceptible (Pinus patula) hosts

Fusarium circinatum poses a serious threat to many pine species in both commercial and natural pine forests. Knowledge regarding the molecular basis of pine-F. circinatum host-pathogen interactions could assist efforts to produce more resistant planting stock. This study aimed to identify molecular responses underlying resistance against F. circinatum. A dual RNA-seq approach was used to investigate host and pathogen expression in F. circinatum challenged Pinus tecunumanii (resistant) and Pinus patula (susceptible), at three- and seven-days post inoculation. RNA-seq reads were mapped to combined host-pathogen references for both pine species to identify differentially expressed genes (DEGs). F. circinatum genes expressed during infection showed decreased ergosterol biosynthesis in P. tecunumanii relative to P. patula. For P. tecunumanii, enriched gene ontologies and DEGs indicated roles for auxin-, ethylene-, jasmonate- and salicylate-mediated phytohormone signalling. Correspondingly, key phytohormone signaling components were down-regulated in P. patula. Key F. circinatum ergosterol biosynthesis genes were expressed at lower levels during infection of the resistant relative to the susceptible host. This study further suggests that coordination of phytohormone signaling is required for F. circinatum resistance in P. tecunumanii, while a comparatively delayed response and impaired phytohormone signaling contributes to susceptibility in P. patula.The National Research Foundation (NRF) of South Africa Scarce Skills Doctoral Scholarship Programme (Grant ID: 97892), the NRF Bioinformatics and Functional Genomics Programme (Grant IDs: 86936, 97911) and a strategic grant from the Department of Science and Technology (DST) for the Tree Genomics Platform at the University of Pretoria. Further support was provided by Sappi, Mondi, York Timbers and Hans Merensky Foundation though the Forest Molecular Genetics (FMG) Programme with co-funding from the Technology and Human Resources for Industry Programme (THRIP, Grant ID: 96413).http://www.mdpi.com/journal/microorganismsam2020BiochemistryForestry and Agricultural Biotechnology Institute (FABI)GeneticsMicrobiology and Plant Patholog

Combined de novo and genome guided assembly and annotation of the Pinus patula juvenile shoot transcriptome

BACKGROUND : Pines are the most important tree species to the international forestry industry, covering 42 % of the global industrial forest plantation area. One of the most pressing threats to cultivation of some pine species is the pitch canker fungus, Fusarium circinatum, which can have devastating effects in both the field and nursery. Investigation of the Pinus-F. circinatum host-pathogen interaction is crucial for development of effective disease management strategies. As with many non-model organisms, investigation of host-pathogen interactions in pine species is hampered by limited genomic resources. This was partially alleviated through release of the 22 Gbp Pinus taeda v1.01 genome sequence (http://pinegenome.org/pinerefseq/) in 2014. Despite the fact that the fragmented state of the genome may hamper comprehensive transcriptome analysis, it is possible to leverage the inherent redundancy resulting from deep RNA sequencing with Illumina short reads to assemble transcripts in the absence of a completed reference sequence. These data can then be integrated with available genomic data to produce a comprehensive transcriptome resource. The aim of this study was to provide a foundation for gene expression analysis of disease response mechanisms in Pinus patula through transcriptome assembly. RESULTS : Eighteen de novo and two reference based assemblies were produced for P. patula shoot tissue. For this purpose three transcriptome assemblers, Trinity, Velvet/OASES and SOAPdenovo-Trans, were used to maximise diversity and completeness of assembled transcripts. Redundancy in the assembly was reduced using the EvidentialGene pipeline. The resulting 52 Mb P. patula v1.0 shoot transcriptome consists of 52 112 unigenes, 60 % of which could be functionally annotated. CONCLUSIONS : The assembled transcriptome will serve as a major genomic resource for future investigation of P. patula and represents the largest gene catalogue produced to date for this species. Furthermore, this assembly can help detect gene-based genetic markers for P. patula and the comparative assembly workflow could be applied to generate similar resources for other non-model species.Additional file 1: Table S1. EvidentialGene tr2aacds pipeline output summary.Additional file 2: Table S2. Assembly statistics for EvidentialGene tr2aacds pipeline merged assembly compared to average statistics for each assembler.Additional file 3: Table S3. Predicted species distribution for non-pine origin sequences removed from the Pinus patula v1.0 transcriptome.Additional file 4: Figure S1. Molecular function gene ontology distribution for the Pinus patula v1.0 transcriptome.Additional file 5: Table S4. Tribe-MCL gene families and annotations for all 15 species used.Additional file 6: Table S5. Conditional reciprocal best BLAST alignment results between full-length Sanger sequenced Pinus taeda cDNA and representative Pinus patula transcripts for each cDNA.Additional file 7: Figure S2. Summary statistics for alignment of Pinus taeda complete CDS sequences to assembled Pinus patula transcripts. Pita = P. taeda. The x-axis represents the query P. taeda cDNA sequence. The solid y-axis (left) illustrates: cDNA query sequence length (pink circle), P. patula subject sequence length (blue square), conditional reciprocal best BLAST alignment length (gold triangle). The dashed y-axis (right) depicts the: percentage identity between sequences (black line), percentage coverage of the P. taeda cDNA by the corresponding P. patula transcript (green cross) and vice versa (purple plus).Additional file 8: Table S6. EBSeq differential expression analysis results comparing expression between inoculated and mock-inoculated data.Additional file 9: Table S7. Summarized list of differentially expressed genes between inoculated and mock-inoculated data with annotations.Forestry South Africa (for seed funding), the Genomics Research Institute (GRI) and the National Research Foundation’s (NRF) Bioinformatics and Functional Genomics Programme (NBFG, UID:71255) as well as Innovation, Thuthuka and THRIP grants (Grant numbers: 84951, 86936, 87912).http://www.biomedcentral.com/bmcgenomicsam201

Assessment of a diaphragm override strategy for robustly optimized proton therapy planning for esophageal cancer patients

PURPOSE: To ensure target coverage in the treatment of esophageal cancer, a density override to the region of diaphragm motion can be applied in the optimization process. Here, we evaluate the benefit of this approach during robust optimization for intensity modulated proton therapy (IMPT) planning.MATERIALS AND METHODS: For ten esophageal cancer patients, two robustly optimized IMPT plans were created either using (WDO) or not using (NDO) a diaphragm density override of 1.05 g/cm3 during plan optimization. The override was applied to the excursion of the diaphragm between exhale and inhale. Initial robustness evaluation was performed for plan acceptance (setup errors of 8 mm, range errors of ±3%), and subsequently, on all weekly repeated 4DCTs (setup errors of 2 mm, range errors of ±3%). Target coverage and hotspots were analyzed on the resulting voxel-wise minimum (Vwmin ) and voxel-wise maximum (Vwmax ) dose distributions.RESULTS: The nominal dose distributions were similar for both WDO and NDO plans. However, visual inspection of the Vwmax of the WDO plans showed hotspots behind the right diaphragm override region. For one patient, target coverage and hotspots improved by applying the diaphragm override. We found no differences in target coverage in the weekly evaluations between the two approaches.CONCLUSION: The diaphragm override approach did not result in a clinical benefit in terms of planning and interfractional robustness. Therefore, we don't see added value in employing this approach as a default option during robust optimization for IMPT planning in esophageal cancer.</p

Assessment of a diaphragm override strategy for robustly optimized proton therapy planning for esophageal cancer patients

PURPOSE: To ensure target coverage in the treatment of esophageal cancer, a density override to the region of diaphragm motion can be applied in the optimization process. Here, we evaluate the benefit of this approach during robust optimization for intensity modulated proton therapy (IMPT) planning. MATERIALS AND METHODS: For ten esophageal cancer patients, two robustly optimized IMPT plans were created either using (WDO) or not using (NDO) a diaphragm density override of 1.05 g/cm3 during plan optimization. The override was applied to the excursion of the diaphragm between exhale and inhale. Initial robustness evaluation was performed for plan acceptance (setup errors of 8 mm, range errors of ±3%), and subsequently, on all weekly repeated 4DCTs (setup errors of 2 mm, range errors of ±3%). Target coverage and hotspots were analyzed on the resulting voxel-wise minimum (Vwmin ) and voxel-wise maximum (Vwmax ) dose distributions. RESULTS: The nominal dose distributions were similar for both WDO and NDO plans. However, visual inspection of the Vwmax of the WDO plans showed hotspots behind the right diaphragm override region. For one patient, target coverage and hotspots improved by applying the diaphragm override. We found no differences in target coverage in the weekly evaluations between the two approaches. CONCLUSION: The diaphragm override approach did not result in a clinical benefit in terms of planning and interfractional robustness. Therefore, we don't see added value in employing this approach as a default option during robust optimization for IMPT planning in esophageal cancer