17,390 research outputs found

    Template matching-based method to detect bridge components in point clouds

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    Monitoring and maintenance activities for bridges benefit from the use of digital twins. A digital twin can be defined as a numerical model of an existing structure enhanced with real-time data, representing the actual state of an asset. The manual preparation of the underlying numerical model is considered to be time-consuming, consequently automating the Scan-to-BIM process is of particular interest. One major challenge of automation is to segment the built asset by automatically detecting its components. This contribution proposes a methodology for bridge component detection based on a template-matching algorithm. Tests showed the accuracy of the proposed solution, even for incomplete point clouds, without requiring extensive input datasets. Compared to other solutions, this approach shows potential for adaptation to a variety of bridge designs

    Table1_Fractional flow reserve measurements and long-term mortality‚ÄĒresults from the FLORIDA study.docx

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    BackgroundRandomized evidence suggested improved outcomes in fractional flow reserve (FFR) guidance of coronary revascularization compared to medical therapy in well-defined patient cohorts. However, the impact of FFR-guided revascularization on long-term outcomes of unselected patients with chronic or acute coronary syndromes (ACS) is unknown.AimsThe FLORIDA (Fractional FLOw Reserve In cardiovascular DiseAses) study sought to investigate outcomes of FFR-guided vs. angiography-guided treatment strategies in a large, real-world cohort.MethodsThis study included patients enrolled into the German InGef Research Database. Patients undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Eligible patients had at least one inpatient coronary angiogram for suspected coronary artery disease between January 2014 and December 2015. Patients were stratified into FFR arm if a coronary angiography with adjunctive FFR measurement was performed, otherwise into the angiography-only arm. Matching was applied to ensure a balanced distribution of baseline characteristics in the study cohort. Patients were followed for 3 years after index date and primary endpoint was all-cause mortality.ResultsIn the matched population, mortality at 3 years was 9.6% in the FFR-assessed group and 12.6% in the angiography-only group (p‚ÄČ=‚ÄČ0.002), corresponding to a 24% relative risk reduction with use of FFR. This effect was most pronounced in patients in whom revascularization was deferred based on FFR (8.7% vs. 12.3%, p‚ÄČ=‚ÄČ0.04) and in high-risk subgroups including patients aged ‚Č•75 years (14.9% vs. 20.1%, p‚ÄČConclusionsFFR-based revascularization strategy was associated with reduced mortality at 3 years. These findings further support the use of FFR in everyday clinical practice.</p

    Table2_Fractional flow reserve measurements and long-term mortality‚ÄĒresults from the FLORIDA study.docx

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    BackgroundRandomized evidence suggested improved outcomes in fractional flow reserve (FFR) guidance of coronary revascularization compared to medical therapy in well-defined patient cohorts. However, the impact of FFR-guided revascularization on long-term outcomes of unselected patients with chronic or acute coronary syndromes (ACS) is unknown.AimsThe FLORIDA (Fractional FLOw Reserve In cardiovascular DiseAses) study sought to investigate outcomes of FFR-guided vs. angiography-guided treatment strategies in a large, real-world cohort.MethodsThis study included patients enrolled into the German InGef Research Database. Patients undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Eligible patients had at least one inpatient coronary angiogram for suspected coronary artery disease between January 2014 and December 2015. Patients were stratified into FFR arm if a coronary angiography with adjunctive FFR measurement was performed, otherwise into the angiography-only arm. Matching was applied to ensure a balanced distribution of baseline characteristics in the study cohort. Patients were followed for 3 years after index date and primary endpoint was all-cause mortality.ResultsIn the matched population, mortality at 3 years was 9.6% in the FFR-assessed group and 12.6% in the angiography-only group (p‚ÄČ=‚ÄČ0.002), corresponding to a 24% relative risk reduction with use of FFR. This effect was most pronounced in patients in whom revascularization was deferred based on FFR (8.7% vs. 12.3%, p‚ÄČ=‚ÄČ0.04) and in high-risk subgroups including patients aged ‚Č•75 years (14.9% vs. 20.1%, p‚ÄČConclusionsFFR-based revascularization strategy was associated with reduced mortality at 3 years. These findings further support the use of FFR in everyday clinical practice.</p

    DNA methylation-based assessment of cell composition in human pancreas and islets

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    Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example insulin as a marker of beta-cells. A major limitation of these methods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here we demonstrate the use of cell type-specific DNA methylation markers for determining the fraction of specific cell types in human islet and pancreas specimens. We identified genomic loci that are uniquely demethylated in specific pancreatic cell types and applied targeted PCR to assess the methylation status of these loci in tissue samples, enabling inference of cell type composition. In islet preparations, normalization of insulin secretion to beta-cell DNA revealed similar beta-cell function in pre-T1D, T1D and T2D , which was significantly lower than in non-diabetic donors. In histological pancreas specimens from recent-onset T1D this assay showed beta-cell fraction within the normal range, suggesting a significant contribution of beta-cell dysfunction. In T2D pancreata we observed increased alpha-cell fraction and normal beta-cell fraction. Methylation-based analysis provides an accurate molecular alternative to immune detection of cell types in the human pancreas, with utility in the interpretation of insulin secretion assays and the assessment of pancreas cell composition in health and disease.</p

    Development of target antigen-displaying virus-like particles (VLPs) for the generation of antibodies using hybridoma technology

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    Formaldehyde-fixed, paraffin-embedded (FFPE) cell and tissue samples are of great importance for immunohistochemical studies of histological specimens. However, antibodies for FFPE samples pose a challenge to antibody discovery as current immunization strategies rely predominantly on soluble proteins that cannot adequately reflect the changes in target antigens during the FFPE process. Enveloped virus-like particles (VLPs) allow for the presentation of membrane-anchored target antigens on the VLP surface and elicit a strong target antigen-specific antibody response after immunization. This proof-of-concept study presents a novel FFPE-like fixation methodology for VLP preparation aiming at the generation of FFPE-compatible monoclonal antibodies (mAbs). Human 293-F-derived VLP-producing suspension cell pools were established to produce human immunodeficiency virus (HIV)-like particles decorated with the truncated human low affinity nerve growth factor receptor (trNGFR) as model antigen. The trNGFR antigen was efficiently incorporated into VLPs with an average of 284 } 24 trNGFR molecules per VLP. To develop a fixation protocol applicable to VLPs, trNGFR-expressing cells were subjected to a variety of fixation treatments. Changes in epitopes introduced by fixation were monitored using two mAbs recognizing either an epitope present in native NGFR or an epitope present in native and FFPE NGFR. The novel simplified fixation procedure consisted of only formaldehyde and 90 ¬įC heat fixation (FF90). Transmission electron microscopic and dynamic light scattering analysis of FF90 VLPs revealed that the fixed VLPs withstood the FF90 treatment and showed no morphological changes, allowing for the FF90 trNGFR-VLPs to be used to immunize mice for hybridoma cell generation. Hybridoma clones were screened for mAbs specifically recognizing native, FF90 and FFPE trNGFR-expressing cells in a flow cytometric assay. The isolated hybridoma mAbs did not recognize native epitopes but were reactive with FF90 and FFPE epitopes. The use of FF90-trNGFR VLPs for immunization led to the discovery of nine FFPE-NGFR-specific mAbs. This proofof-concept study demonstrated that FF90-treated VLPs decorated with a membrane-anchored target antigen are suitable antigens to preferentially generate FFPE-compatible mAbs. The FF90-VLP platform should be useful for the future discovery of specific mAbs directed against a variety of FFPE cell surface antigens

    Systematic Evaluation of Pharmacokinetic Models for Model-Informed Precision Dosing of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

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    The altered pharmacokinetics of renally cleared drugs such as meropenem in critically ill patients receiving continuous renal replacement therapy (CRRT) might impact target attainment. Model-informed precision dosing (MIPD) is applied to individualize meropenem dosing. However, most population pharmacokinetic (PopPK) models developed to date have not yet been evaluated for MIPD. Eight PopPK models based on adult CRRT patients were identified in a systematic literature research and encoded in NONMEM 7.4. A data set of 73 CRRT patients from two different study centers was used to evaluate the predictive performance of the models using simulation and prediction-based diagnostics for i) a priori dosing based on patient characteristics only and ii) Bayesian dosing by including the first measured trough concentration. Median prediction error (MPE) for accuracy within |20%| (95% confidence intervals including zero) and median absolute prediction error (MAPE) for precision‚ÄȂȧ‚ÄČ30% were considered clinically acceptable. For a priori dosing, most models (n‚ÄČ=‚ÄČ5) showed accuracy and precision MPE within |20%| and MAPE‚ÄČ<35%. The integration of the first measured meropenem concentration improved the predictive performance of all models (median MAPE decreased from 35.4 to 25.0%; median MPE decreased from 21.8 to 4.6%). The best predictive performance for intermittent infusion was observed for the O‚ÄôJeanson model, including residual diuresis as covariate (a priori and Bayesian dosing MPE within |2%|, MAPE‚ÄČ<30%). Our study revealed the O‚Ä≤Jeanson model as the best-predicting model for intermittent infusion. However, most of the selected PopPK models are suitable for MIPD in CRRT patients when one therapeutic drug monitoring sample is available

    Impact of gender on left atrial low-voltage zones in patients with persistent atrial fibrillation: results of a voltage-guided ablation

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    BackgroundGender-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. We assessed in persistent AF the regional distribution of left atrial (LA) bipolar voltage and the extent of low-voltage zones (LVZ) according to gender as well as the results of a voltage-guided substrate ablation.MethodsConsecutive patients who underwent a voltage-guided AF ablation were enrolled. LA endocardial voltage maps were obtained using a 3D electro-anatomical mapping system in sinus rhythm. LVZ was defined as &lt;0.5‚ÄÖmV.ResultsA total of 115 patients were enrolled (74 men, 41 women). The LA bipolar voltage amplitude was twice lower in the whole LA (p‚ÄČ&lt;‚ÄČ0.01) and in each atrial region in women compared with men, whereas the LA indexed volume was similar. LVZ were found in 56.1% of women and 16.2% of men (p‚ÄČ&lt;‚ÄČ0.01). LVZ were also more extensive in women (p‚ÄČ=‚ÄČ0.01), especially in the anterior LA. Atrial voltage alteration occurred earlier in women than in men. In a multivariate analysis, the female sex (OR 12.99; 95% CI, 3.23‚Äď51.63, p‚ÄČ=‚ÄČ0.0001) and LA indexed volume (OR 1.09; 95% CI, 1.04‚Äď1.16, p‚ÄČ=‚ÄČ0.001) were predictive of LVZ. Atrial arrhythmia-free survival was similar in men and women 36 months after a single ablation procedure.ConclusionThe study reports a strong relationship between the female gender and atrial substrate remodeling. The female gender was significantly associated with higher incidence, earlier occurrence, and greater extent of LVZ compared with men. Despite the female-specific characteristics in atrial remodeling, LVZ-guided ablation may improve the AF ablation outcome in women

    The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

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    Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (‚ąľ30 tissues √ó ‚ąľ15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics

    Novel suspension retroviral packaging cells generated by transposition using transposase encoding mRNA advance vector yields and enable production in bioreactors

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    To date, the establishment of high-titer stable viral packaging cells (VPCs) at large scale for gene therapeutic applications is very time- and cost-intensive. Here we report the establishment of three human suspension 293-F-derived ecotropic MLV-based VPCs. The classic stable transfection of an EGFP-expressing transfer vector resulted in a polyclonal VPC pool that facilitated cultivation in shake flasks of 100 mL volumes and yielded high functional titers of more than 1 × 106 transducing units/mL (TU/mL). When the transfer vector was flanked by transposon terminal inverted repeats (TIRs) and upon co-transfection of a plasmid encoding for the transposase, productivities could be slightly elevated to more than 3 × 106 TU/mL. In contrast and using mRNA encoding for the transposase, as a proof of concept, productivities were drastically improved by more than ten-fold exceeding 5 × 107 TU/mL. In addition, these VPC pools were generated within only 3 weeks. The production volume was successfully scaled up to 500 mL employing a stirred-tank bioreactor (STR). We anticipate that the stable transposition of transfer vectors employing transposase transcripts will be of utility for the future establishment of high-yield VPCs producing pseudotype vector particles with a broader host tropism on a large scale
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