Extracellular histone release by renal cells after warm and cold ischemic kidney injury: Studies in an ex-vivo porcine kidney perfusion model.

Extracellular histones are cytotoxic molecules involved in experimental acute kidney injury. In patients receiving a renal transplant from donors after circulatory death, who suffer from additional warm ischemia, worse graft outcome is associated with higher machine perfusate extracellular histone H3 concentrations. We now investigated temperature-dependent extracellular histone release in an ex vivo porcine renal perfusion model, and subsequently studied histone release in the absence and presence of non-anticoagulant heparin. Seven pairs of ischemically damaged porcine kidneys were machine perfused at 4°C (cold ischemia) or 28°C (warm ischemia). Perfusate histone H3 concentration was higher after warm as compared to cold ischemia (median (IQR) = 0.48 (0.20-0.83) µg/mL vs. 0.02 (0.00-0.06) µg/mL; p = .045, respectively). Employing immune-electron microscopy (EM), histone containing cytoplasmic protrusions of tubular and endothelial cells were found after warm ischemic injury. Furthermore, abundant histone localization was detected in debris surrounding severely damaged glomerular cells, in a "buck shot" pattern. In vitro, histones were cytotoxic to endothelial and kidney epithelial cells in a temperature-dependent manner. In a separate ex vivo experiment, addition of heparin did not change the total histone H3 levels observed in the perfusate but revealed a continuous increase in the level of a lower molecular weight histone H3 variant. Our findings show that ischemically damaged kidneys release more extracellular histones in warm ischemia, which by EM was due to histone release by renal cells. Blocking of histone-mediated damage during transplantation may be beneficial in prevention of renal injury.

Identifying genes targeted by disease-associated non-coding SNPs with a protein knowledge graph.

Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) that play important roles in the genetic heritability of traits and diseases. With most of these SNPs located on the non-coding part of the genome, it is currently assumed that these SNPs influence the expression of nearby genes on the genome. However, identifying which genes are targeted by these disease-associated SNPs remains challenging. In the past, protein knowledge graphs have often been used to identify genes that are associated with disease, also referred to as "disease genes". Here, we explore whether protein knowledge graphs can be used to identify genes that are targeted by disease-associated non-coding SNPs by testing and comparing the performance of six existing methods for a protein knowledge graph, four of which were developed for disease gene identification. We compare our performance against two baselines: (1) an existing state-of-the-art method that is based on guilt-by-association, and (2) the leading assumption that SNPs target the nearest gene on the genome. We test these methods with four reference sets, three of which were obtained by different means. Furthermore, we combine methods to investigate whether their combination improves performance. We find that protein knowledge graphs that include predicate information perform comparable to the current state of the art, achieving an area under the receiver operating characteristic curve (AUC) of 79.6% on average across all four reference sets. Protein knowledge graphs that lack predicate information perform comparable to our other baseline (genetic distance) which achieved an AUC of 75.7% across all four reference sets. Combining multiple methods improved performance to 84.9% AUC. We conclude that methods for a protein knowledge graph can be used to identify which genes are targeted by disease-associated non-coding SNPs.

Fifteen-year trajectories of multimorbidity and polypharmacy in Dutch primary care-A longitudinal analysis of age and sex patterns.

OBJECTIVE: After stratifying for age, sex and multimorbidity at baseline, our aim is to analyse time trends in incident multimorbidity and polypharmacy in the 15-year clinical trajectories of individual patients in a family medicine setting. METHODS: This study was carried out using data from the Registration Network Family Medicine in the South of the Netherlands. The clinical trajectories of 10037 subjects during the 15-year period (2000-2014) were analyzed in a repeated measurement of using a generalized estimating equations model as well as a multilevel random intercept model with repeated measurements to determine patterns of incident multimorbidity and polypharmacy. Hierarchical age-period-cohort models were used to generate age and cohort trajectories for comparison with prevalence trends in multimorbidity literature. RESULTS: Multimorbidity was more common in females than in males throughout the duration of the 15-year trajectory (females: 39.6%; males: 33.5%). With respective ratios of 11.7 and 5.9 between the end and the beginning of the 15-year period, the youngest female and male groups showed a substantial increase in multimorbidity prevalence. Ratios in the oldest female and male groups were 2.2 and 1.9 respectively. Females had higher levels of multimorbidity than males in the 0-24-year and 25-44-year age groups, but the levels converged to a prevalence of 92.2% in the oldest male and 90.7% in the oldest female group. Similar, albeit, moderate differences were found in polypharmacy patterns. CONCLUSIONS: We sought to specify the progression of multimorbidity from an early age. As a result, our study adds to the multimorbidity literature by specifying changes in chronic disease accumulation with relation to polypharmacy, and by tracking differences in patient trajectories according to age and sex. Multimorbidity and polypharmacy are common and their prevalence is accelerating, with a relatively rapid increase in younger groups. From the point of view of family medicine, this underlines the need for a longitudinal approach and a life course perspective in patient care.

Patient-reported quality of life after stand-alone and concomitant arrhythmia surgery: a systematic review and meta-analysis.

OBJECTIVES: Patient-reported quality of life (QOL) has become an important endpoint for arrhythmia surgery for atrial fibrillation (AF). While studies specifically evaluating the effect of arrhythmia surgery on QOL are scarce, we aimed to summarize current evidence of QOL following concomitant and stand-alone arrhythmia surgery for AF. METHODS: All studies reporting on QOL using questionnaires from patients undergoing arrhythmia surgery for AF, both stand-alone and concomitant, were included in this systematic review. A meta-analysis was performed on inter-study heterogeneity of changes in QOL on 9 of 12 included studies that used the Short-Form 36 tool and meta-regression based on rhythm outcome after 1 year was executed. Finally, differences in QOL following stand-alone arrhythmia surgery and concomitant procedures were evaluated. RESULTS: Overall, QOL scores improved 1 year after surgical ablation for AF evaluated by several questionnaires. In stand-alone arrhythmia procedures, meta-regression showed significant improvements in those who were in sinus rhythm compared to those in AF after 1 year. This association between an improved QOL and the procedural effectiveness was also suggested in concomitant procedures. However, when comparing QOL of patients undergoing cardiac surgery with and without add-on surgical ablation for AF, only the variable 'physical role' demonstrated a significant improvement. CONCLUSIONS: In patients with AF, QOL improves after both stand-alone and concomitant arrhythmia surgery. In the concomitant group, this improvement can be attributed to both the cardiac procedure itself as well as the add-on arrhythmia surgery. However, both in stand-alone and concomitant procedures, the improvement in QOL seems to be related to the effectiveness of the procedure to maintain sinus rhythm after 12 months.

Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study.

BACKGROUND: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). METHODS: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. RESULTS: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). CONCLUSION: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. CLINICAL TRIAL REGISTRATION: NTR3093 in the Dutch trial register ( www.trialregister.nl ).

Prediction of Microscopic Metastases in Patients with Metachronous Oligo-Metastases after Curative Treatment of Non-Small Cell Lung Cancer: A Microsimulation Study.

Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and the 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with a high versus low risk of undetected metastases can be separated. Because there is no clinical data on undetected metastases available, a microsimulation model of the development and detection of metastases in 100,000 hypothetical stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for the unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with a different risk of undetectable metastases. We identified the size and number of detected oligo-metastases, as well as the presence of symptoms that are the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group, having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively. Currently, the model is based on a synthesis of the literature data and individual patient-level data that were not collected for the purpose of this study. Optimization and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such a validation study.

Bicycle-related injuries in the emergency department: a comparison between E-bikes and conventional bicycles: a prospective observational study.

PURPOSE: To investigate the mechanisms and severity of injuries of e-bikers compared with conventional bicycle (CB) users at the emergency department (ED) of a level 2 trauma center in the Netherlands. METHODS: We performed a prospective observational study. All patients ≥ 16 years who presented at the ED with an e-bike or conventional bicycle accident were eligible for inclusion. Primary outcomes were mechanisms and severity of injury. Injury severity was defined by the abbreviated injury score and the injury severity score (ISS). Data were analyzed using SPSS (IBM version 24). RESULTS: A total of 78 e-bikers and 91 CB, were included. The mean age of the e-bikers was 66.9 ± 13.6 years (CB 45.2 ± 20.5 years, P < 0.001). The Charlson comorbidity index was higher in e-bikers (3.1 vs. 1.2, P < 0.001). Mechanism of injury and ISS did not differ between the groups (median ISS 4.0), even though two e-bikers were severely injured (ISS ≥ 16). Alcohol was consumed twice as frequently in CB-related injuries (40% vs. 19.2%, P < 0.01). CONCLUSION: In this cohort of bicycle injuries in the ED of a level 2 trauma center, e-bikers were older and had more comorbidities than CB users. Except for a higher rate of thoracic and soft-tissue trauma in e-bikers, no differences were found in the mechanism and severity of injury. While it is important to note that helmet use and alcohol avoidance have demonstrable health benefits for bicyclists, further studies to quantify these benefits are recommended.

Development of Multimorbidity Over Time: An Analysis of Belgium Primary Care Data Using Markov Chains and Weighted Association Rule Mining.

BACKGROUND: The prevalence of multimorbidity is increasing in recent years, and patients with multimorbidity often have a decrease in quality of life and require more health care. The aim of this study was to explore the evolution of multimorbidity taking the sequence of diseases into consideration. METHODS: We used a Belgian database collected by extracting coded parameters and more than 100 chronic conditions from the Electronic Health Records of general practitioners to study patients older than 40 years with multiple diagnoses between 1991 and 2015 (N = 65 939). We applied Markov chains to estimate the probability of developing another condition in the next state after a diagnosis. The results of Weighted Association Rule Mining (WARM) allow us to show strong associations among multiple conditions. RESULTS: About 66.9% of the selected patients had multimorbidity. Conditions with high prevalence, such as hypertension and depressive disorder, were likely to occur after the diagnosis of most conditions. Patterns in several disease groups were apparent based on the results of both Markov chain and WARM, such as musculoskeletal diseases and psychological diseases. Psychological diseases were frequently followed by irritable bowel syndrome. CONCLUSIONS: Our study used Markov chains and WARM for the first time to provide a comprehensive view of the relations among 103 chronic conditions, taking sequential chronology into consideration. Some strong associations among specific conditions were detected and the results were consistent with current knowledge in literature, meaning the approaches were valid to be used on larger data sets, such as National Health care Systems or private insurers.

What is the minimum response rate on patient-reported outcome measures needed to adequately evaluate total hip arthroplasties?

BACKGROUND: Unknown is which response rate on patient-reported outcome measures (PROMs) is needed to both obtain an accurate outcome and ensure generalizability in evaluating total hip arthroplasty (THA) procedures. Without an evidence based minimum response rate (MRR) on THA PROMs, it is possible that hospitals report invalid patient-reported outcomes (PROs) due to a too low response rate. Alternatively, hospitals may invest too much in achieving an unnecessary high response rate. The aim of this study is to gain an insight into the MRR on PROMs needed to adequately evaluate THA procedures from a clinical perspective. METHODS: Retrospective study on prospective collected data of primary, elective THA procedures was performed. MRR was investigated for each PROM (NRS pain at rest, NRS pain during activity, EQ-5D-3L, HOOS-PS, anchor function, OHS, anchor pain and NRS satisfaction) separately to calculate the primary outcome: MRR for the THA PROMs set. MRR on a PROM needed to have (condition 1.) similar PRO change score (3 month score minus preoperative score) including confidence interval, (condition 2.) maintaining the influence of each change score predictor and (condition 3.) equal distribution of each predictor, as those of a 100% PROM response rate group. Per PROM, a 100%-group was identified with all patients having the PRO change score. Randomly assessed groups of 90% till 10% response rate (in total 90 groups) were compared with the 100%-group. Linear mixed model analyses and linear regressions were executed. RESULTS: The MRR for the THA PROMs set was 100% (range: 70-100% per PROM). The first condition resulted in a MRR of 60%, the second condition in a MRR of 100% and the third condition in a MRR of 10%. CONCLUSIONS: A 100% response rate on PROMs is needed in order to adequately evaluate THA procedures from a clinical perspective. All stakeholders using THA PROs should be aware that 100% of the THA patients should respond on both preoperative and 3 month postoperative PROMs. For now, taking the first step in improving evaluation of THA for quality control by achieving at least two of the three conditions of MRR, advised is to require a response rate on PROMs of 60% as the lower limit.

Identifying disease trajectories with predicate information from a knowledge graph.

BACKGROUND: Knowledge graphs can represent the contents of biomedical literature and databases as subject-predicate-object triples, thereby enabling comprehensive analyses that identify e.g. relationships between diseases. Some diseases are often diagnosed in patients in specific temporal sequences, which are referred to as disease trajectories. Here, we determine whether a sequence of two diseases forms a trajectory by leveraging the predicate information from paths between (disease) proteins in a knowledge graph. Furthermore, we determine the added value of directional information of predicates for this task. To do so, we create four feature sets, based on two methods for representing indirect paths, and both with and without directional information of predicates (i.e., which protein is considered subject and which object). The added value of the directional information of predicates is quantified by comparing the classification performance of the feature sets that include or exclude it. RESULTS: Our method achieved a maximum area under the ROC curve of 89.8% and 74.5% when evaluated with two different reference sets. Use of directional information of predicates significantly improved performance by 6.5 and 2.0 percentage points respectively. CONCLUSIONS: Our work demonstrates that predicates between proteins can be used to identify disease trajectories. Using the directional information of predicates significantly improved performance over not using this information.

Risk of bias in studies investigating novel diagnostic biomarkers for heart failure with preserved ejection fraction. A systematic review.

AIM: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). METHODS AND RESULTS: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. CONCLUSION: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.

Nucleotide sugar profiles throughout development in wildtype and galt knockout zebrafish.

Nucleotide sugars (NS) are fundamental molecules in life and play a key role in glycosylation reactions and signal conduction. Several pathways are involved in the synthesis of NS. The Leloir pathway, the main pathway for galactose metabolism, is crucial for production of uridine diphosphate (UDP)-glucose and UDP-galactose. The most common metabolic disease affecting this pathway is galactose-1-phosphate uridylyltransferase (GALT) deficiency, that despite a lifelong galactose-restricted diet, often results in chronically debilitating complications. Alterations in the levels of UDP-sugars leading to galactosylation abnormalities have been hypothesized as a key pathogenic factor. However, UDP-sugar levels measured in patient cell lines have shown contradictory results. Other NS that might be affected, differences throughout development, as well as tissue specific profiles have not been investigated. Using recently established UHPLC-MS/MS technology, we studied the complete NS profiles in wildtype and galt knockout zebrafish (Danio rerio). Analyses of UDP-hexoses, UDP-hexosamines, CMP-sialic acids, GDP-fucose, UDP-glucuronic acid, UDP-xylose, CDP-ribitol, and ADP-ribose profiles at four developmental stages and in tissues (brain and gonads) in wildtype zebrafish revealed variation in NS levels throughout development and differences between examined tissues. More specifically, we found higher levels of CMP-N-acetylneuraminic acid, GDP-fucose, UDP-glucuronic acid, and UDP-xylose in brain and of CMP-N-glycolylneuraminic acid in gonads. Analysis of the same NS profiles in galt knockout zebrafish revealed no significant differences from wildtype. Our findings in galt knockout zebrafish, even when challenged with galactose, do not support a role for abnormalities in UDP-glucose or UDP-galactose as a key pathogenic factor in GALT deficiency, under the tested conditions.

Comparable clinical outcome and implant longevity after CT- or MRI-based patient-specific instruments for total knee arthroplasty: a 2-year follow-up of a RCT.

PURPOSE: Patient-specific instruments (PSI) are already widespread used in total knee arthroplasty (TKA). Either computed tomography (CT) scans or magnetic resonance imaging (MRI) scans are used pre-operatively to create jigs to guide resection during surgery. This study is a sequel of previous work that showed significantly more radiological outliers for posterior slope when CT-based guides were used. The aim of this study was to assess differences in revision rate and clinical outcome between the two groups at 2-year follow-up. METHODS: At the 2-year follow-up, 124 patients were analysed in this prospective, randomised single-blind study. A survival analysis with revision of the TKA as endpoint was performed. Patients fulfilled four patient-reported outcome measurements (PROMs). Scores on the questionnaires were compared between both groups at the different follow-up visits. RESULTS: At final follow-up, there was no significant difference in the survival rates of the CT- and MRI-based PSI surgery. Postoperatively, the PROMs significantly improved within each group compared with the pre-operative values. There were no significant differences for the PROMs between both groups at the 2-years follow-up. CONCLUSIONS: Although previous results showed more outliers regarding posterior slope for CT-based PSIs, no difference in revision rate or the outcome of PROMs was found at 2-year follow-up. Further research to determine what the influence is of radiological outliers on implant survival and clinical outcomes is necessary. LEVEL OF EVIDENCE: I.

Drug prioritization using the semantic properties of a knowledge graph.

Compounds that are candidates for drug repurposing can be ranked by leveraging knowledge available in the biomedical literature and databases. This knowledge, spread across a variety of sources, can be integrated within a knowledge graph, which thereby comprehensively describes known relationships between biomedical concepts, such as drugs, diseases, genes, etc. Our work uses the semantic information between drug and disease concepts as features, which are extracted from an existing knowledge graph that integrates 200 different biological knowledge sources. RepoDB, a standard drug repurposing database which describes drug-disease combinations that were approved or that failed in clinical trials, is used to train a random forest classifier. The 10-times repeated 10-fold cross-validation performance of the classifier achieves a mean area under the receiver operating characteristic curve (AUC) of 92.2%. We apply the classifier to prioritize 21 preclinical drug repurposing candidates that have been suggested for Autosomal Dominant Polycystic Kidney Disease (ADPKD). Mozavaptan, a vasopressin V2 receptor antagonist is predicted to be the drug most likely to be approved after a clinical trial, and belongs to the same drug class as tolvaptan, the only treatment for ADPKD that is currently approved. We conclude that semantic properties of concepts in a knowledge graph can be exploited to prioritize drug repurposing candidates for testing in clinical trials.

It is safe to use minimal restrictions following posterior approach total hip arthroplasty: results from a large cohort study.

BACKGROUND: To prevent early postoperative dislocation following a total hip arthroplasty (THA) procedure, patients must adhere to restrictions. Restrictive protocols are common if THA surgery is performed using the posterior approach, but scientific evidence form larger studies that supports these restrictions are scarce. In this large cohort study we compare the <90-days dislocation rate between patients receiving posterior approach THA managed with minimal versus extensive restrictions. METHODS: Prospective cohort (n = 1049) of consecutive elective primary hip replacement surgery procedures (September 2014-July 2017) managed with minimal postoperative restrictions. Hospital charts were prospectively reviewed for patient demographics, risk factors and any hip dislocation. Control (n = 1102) consecutive primary elective THAs (January 2011-August 2014) managed with a traditional restrictive protocol. A posterior surgical approach was used in all procedures. RESULTS: Minimal restrictions group: 17 dislocations <90 days (1.6%); Restricted group: 28 (2.5%), chi-square p = 0.1. Testing the hypothesis of inferiority by a minimum of 1% increase in ⩽90 days dislocation risk: p = 0.14 (test for difference) and p < 0.001 (non-inferiority test), allowing us to discard the null hypothesis (absolute increase in risk of ⩾1% with minimal restrictions). The proportion of surgeries performed with a femoral head size ⩾32 mm was higher in the minimal restrictions group. CONCLUSIONS: Patients can be managed safely with minimal restrictions following posterior approach THA if combined with frequent use of larger femoral heads.

Hybrid versus catheter ablation in patients with persistent and longstanding persistent atrial fibrillation: a systematic review and meta-analysis†.

As the mechanisms underlying persistent atrial fibrillation (AF) are still incompletely understood, a 'gold standard' strategy for ablation is lacking. The results of catheter ablation, independent of the ablation strategy applied, are disappointing. Hybrid ablation, combining a thoracoscopic epicardial and transvenous endocardial approach, has shown more favourable outcomes. To date, studies comparing both techniques are lacking. Therefore, we conducted a systematic review and meta-analysis of hybrid versus catheter ablation in patients with persistent or longstanding persistent AF. A systematic literature search of studies reporting on catheter and hybrid ablation of persistent or longstanding persistent AF was performed in the PubMed database. All identified articles were screened and checked for eligibility. A meta-analysis was performed on inter-study heterogeneity and pooled correlation between baseline characteristics, primary and secondary outcomes of hybrid and catheter studies. From the 520 articles identified by the search, 34 articles could be included in the analysis. Hybrid ablation resulted in higher freedom of atrial arrhythmias in patients with persistent and longstanding-persistent AF than catheter ablation (70.7% vs 49.9%, P < 0.001). Although hybrid ablation had a slightly higher complication rate than catheter ablation, overall morbidity and mortality were low. In conclusion, hybrid ablation is more effective than catheter ablation in maintaining the sinus rhythm in patients with persistent or longstanding persistent AF. However, data directly comparing both techniques are lacking, and small, heterogenic, single-arm studies in a random-effects model prevent definite conclusions from being drawn. Therefore, larger randomized controlled trials directly comparing both techniques are needed.

Using predicate and provenance information from a knowledge graph for drug efficacy screening.

BACKGROUND: Biomedical knowledge graphs have become important tools to computationally analyse the comprehensive body of biomedical knowledge. They represent knowledge as subject-predicate-object triples, in which the predicate indicates the relationship between subject and object. A triple can also contain provenance information, which consists of references to the sources of the triple (e.g. scientific publications or database entries). Knowledge graphs have been used to classify drug-disease pairs for drug efficacy screening, but existing computational methods have often ignored predicate and provenance information. Using this information, we aimed to develop a supervised machine learning classifier and determine the added value of predicate and provenance information for drug efficacy screening. To ensure the biological plausibility of our method we performed our research on the protein level, where drugs are represented by their drug target proteins, and diseases by their disease proteins. RESULTS: Using random forests with repeated 10-fold cross-validation, our method achieved an area under the ROC curve (AUC) of 78.1% and 74.3% for two reference sets. We benchmarked against a state-of-the-art knowledge-graph technique that does not use predicate and provenance information, obtaining AUCs of 65.6% and 64.6%, respectively. Classifiers that only used predicate information performed superior to classifiers that only used provenance information, but using both performed best. CONCLUSION: We conclude that both predicate and provenance information provide added value for drug efficacy screening.

Aortic elongation part I: the normal aortic ageing process.

OBJECTIVES: Differentiation between normal and abnormal features of vascular ageing is crucial, as the latter is associated with adverse outcomes. The normal aortic ageing process is accompanied by gradual luminal dilatation and reduction of vessel compliance. However, the influence of age on longitudinal aortic dimensions and geometry has not been well studied. This study aims to describe the normal evolution of aortic length and shape throughout life. METHODS: A total of 210 consecutive patients were prospectively enrolled in this cross-sectional single-centre study. All subjects underwent CT on a third-generation dual-source CT scanner. Morphometric measurements, including measurements of segmental length and tortuosity, were performed on three-dimensional models of the thoracic aorta. RESULTS: The length of the thoracic aorta was significantly related to age (r=0.54) and increased by 59 mm (males) or 66 mm (females) between the ages of 20 and 80 years. Elongation was most pronounced in the proximal descending aorta, which showed an almost 2.5-fold length increase during life. The lengthening of the thoracic aorta was accompanied by a marked change of its geometry: whereas the aortic apex was located between the branch vessels in younger patients, it shifted to a more distalward position in the elderly. CONCLUSIONS: The normal ageing process is accompanied by gradual aortic elongation and a notable change of aortic geometry. Part II of this two-part article investigates the hypothesis that excessive elongation could play a role in the occurrence of acute aortic dissection.

Aortic elongation part II: the risk of acute type A aortic dissection.

OBJECTIVES: Prophylactic surgery for prevention of acute type A aortic dissection (ATAAD) is reserved for patients with an ascending aortic aneurysm ≥55 mm. Identification of additional risk predictors is warranted since over 70% of patients presenting with ATAAD have a non-dilated aorta or an aneurysm that would not have met the diameter criterion for preventative surgery. Aim of the study was to evaluate ascending aortic elongation as a risk factor for ATAAD and to compare aortic lengths between ATAAD patients and healthy controls. METHODS: Aortic lengths and diameters of ATAAD patients were measured on three-dimensional modelled computed tomography and adjusted to predissection dimensions in this cross-sectional single-centre study. Logistic regression was used to evaluate the relation between ATAAD and aortic dimensions. Lengths of different aortic segments were compared with a healthy control group using propensity score matching. RESULTS: Two-hundred and fifty patients were included in the study (ATAAD, n=40; controls, n=210). Ascending aortic length and diameter proved to be independent predictors for ATAAD (OR=5.3, CI 2.5 to 11.4, p<0.001 and OR=8.6, CI 2.4 to 31.0, p=0.001). Eighty patients were matched based on propensity scores (ATAAD n=40, controls n=40). The ascending aorta was longer and more dilated in ATAAD patients compared with healthy controls (78.6±8.8 mm vs 68.9±7.2 mm, p<0.001, 34.4 mm ±3.2. vs 39.4 mm ±5.7, p<0.001, respectively). No differences were found in lengths of the aortic arch and descending aorta. CONCLUSIONS: Ascending aortic length could serve as an independent predictor for ATAAD. Future studies addressing indications for prophylactic surgery should also investigate aortic length.

Impaired fertility and motor function in a zebrafish model for classic galactosemia.

Classic galactosemia is a genetic disorder of galactose metabolism, caused by severe deficiency of galactose-1-phosphate uridylyltransferase (GALT) enzyme activity due to mutations of the GALT gene. Its pathogenesis is still not fully elucidated, and a therapy that prevents chronic impairments is lacking. In order to move research forward, there is a high need for a novel animal model, which allows organ studies throughout development and high-throughput screening of pharmacologic compounds. Here, we describe the generation of a galt knockout zebrafish model and present its phenotypical characterization. Using a TALEN approach, a galt knockout line was successfully created. Accordingly, biochemical assays confirm essentially undetectable galt enzyme activity in homozygotes. Analogous to humans, galt knockout fish accumulate galactose-1-phosphate upon exposure to exogenous galactose. Furthermore, without prior exposure to exogenous galactose, they exhibit reduced motor activity and impaired fertility (lower egg quantity per mating, higher number of unsuccessful crossings), resembling the human phenotype(s) of neurological sequelae and subfertility. In conclusion, our galt knockout zebrafish model for classic galactosemia mimics the human phenotype(s) at biochemical and clinical levels. Future studies in our model will contribute to improved understanding and management of this disorder.