Bayesian hierarchical modeling of longitudinal glaucomatous visual fields using a two-stage approach

The Bayesian approach has become increasingly popular because it allows to fit quite complex models to data via Markov chain Monte Carlo sampling. However, it is also recognized nowadays that Markov chain Monte Carlo sampling can become computationally prohibitive when applied to a large data set. We encountered serious computational difficulties when fitting an hierarchical model to longitudinal glaucoma data of patients who participate in an ongoing Dutch study. To overcome this problem, we applied and extended a recently proposed two-stage approach to model these data. Glaucoma is one of the leading causes of blindness in the world. In order to detect deterioration at an early stage, a model for predicting visual fields (VFs) in time is needed. Hence, the true underlying VF progression can be determined, and treatment strategies can then be optimized to prevent further VF loss. Because we were unable to fit these data with the classical one-stage approach upon which the current popular Bayesian software is based, we made use of the two-stage Bayesian approach. The considered hierarchical longitudinal model involves estimating a large number of random effects and deals with censoring and high measurement variability. In addition, we extended the approach with tools for model evaluation. Copyrigh

Role of Medium- and Short-Chain L-3-Hydroxyacyl-CoA Dehydrogenase in the Regulation of Body Weight and Thermogenesis

Dysregulation of fatty acid oxidation plays a pivotal role in the pathophysiology of obesity and insulin resistance. Medium- and short-chain-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (SCHAD) (gene name, hadh) catalyze the third reaction of the mitochondrial β-oxidation cascade, the oxidation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA, for medium- and short-chain fatty acids. We identified hadh as a putative obesity gene by comparison of two genome-wide scans, a quantitative trait locus analysis previously performed in the polygenic obese New Zealand obese mouse and an earlier described small interfering RNA-mediated mutagenesis in Caenorhabditis elegans. In the present study, we show that mice lacking SCHAD (hadh(−/−)) displayed a lower body weight and a reduced fat mass in comparison with hadh(+/+) mice under high-fat diet conditions, presumably due to an impaired fuel efficiency, the loss of acylcarnitines via the urine, and increased body temperature. Food intake, total energy expenditure, and locomotor activity were not altered in knockout mice. Hadh(−/−) mice exhibited normal fat tolerance at 20 C. However, during cold exposure, knockout mice were unable to clear triglycerides from the plasma and to maintain their normal body temperature, indicating that SCHAD plays an important role in adaptive thermogenesis. Blood glucose concentrations in the fasted and postprandial state were significantly lower in hadh(−/−) mice, whereas insulin levels were elevated. Accordingly, insulin secretion in response to glucose and glucose plus palmitate was elevated in isolated islets of knockout mice. Therefore, our data indicate that SCHAD is involved in thermogenesis, in the maintenance of body weight, and in the regulation of nutrient-stimulated insulin secretion

Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses:A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients

Vascular complications with a plug-based vascular closure device after transcatheter aortic valve replacement: Predictors and bail-outs

Background: The MANTA vascular closure device (VCD) is dedicated to large bore access closure and associated with favorable results in selected study populations. Anatomical predictors for access site complications are lacking. Aim: To evaluate MANTA in a real-world population and identify predictors for vascular complications. Methods: All patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) between January 2016 and May 2020 with MANTA closure were included. Baseline characteristics were collected, pre-procedural computed tomography and post-deployment femoral angiograms were analyzed for anatomical differences. The primary endpoint was a composite of access site related major and minor vascular complications at 30 days follow-up according to the VARC-2 definitions. Secondary endpoints included bleeding, time to hemostasis, procedural length and incomplete arteriotomy closure or arterial occlusion by angiography. A Cox proportional hazards model was used to compare all-cause mortality for patients with and without an access site complication. Results: The 512 patients underwent TAVR with MANTA access closure. Median age was 80 (IQR 75–85), 53% was male, median BMI was 26.4 kg/m2 (IQR 23.4–29.7). Access site related major- or minor vascular complication occurred in 20 (4%) and 23 (4%) of patients respectively. Median time to hemostasis was 42 s (IQR 28–98). Post deployment angiogram showed an occlusion in 24 patients (5%), incomplete closure in 60 patients (12%) or both in three patients (1%). Of these 87 patients, 36 (41%) had a vascular complication. Femoral artery diameter (OR 0.70 [0.53–0.93]), low- (OR 3.47 [1.21–10.00]) and high (OR 2.43 [1.16–5.10]) arteriotomies were independent predictors for vascular complications. Conclusion: In this contemporary TAVR population, access-site related complications occurred in 8% of patients and were mainly due to percutaneous closure device failure. Small artery diameter and off-target punctures were independent predictors

Impact of baseline and newly acquired conduction disorders on need for permanent pacemakers with 3 consecutive generations of self-expanding transcatheter aortic heart valves

Introductions: We aimed to compare conduction dynamics and need for permanent pacemaker implantation (PPI) after CoreValve, Evolut R and PRO (transcatheter aortic valve replacement (TAVR)). Methods: Patients were stratified based on conduction at baseline; Cohort A had normal conduction, Cohort B had conduction abnormalities including atrioventricular (AV)-block, fascicular block or complete bundle branch block. Three different dynamic QRS-patterns were defined: stable QRS-duration, transient QRS-prolongation and persistent QRS-prolongation. We performed multivariable regression analysis to estimate the effect of the three separate transcatheter heart valves (THV's) on need for PPI at 30 days. Results: TAVR was performed with CoreValve (N = 113), Evolut R (N = 157) or Evolut PRO (N = 92). Conduction dynamics were similar between the different THVs. Overall, Evolut R and PRO showed a tendency towards less PPI compared to CoreValve (17% vs. 19% vs. 27%, P = 0.08), which was driven by a lower PPI rate in Cohort A (6% vs. 11% vs. 25%, P = 0.002). Need for PPI was restricted to patients with persistent QRS-prolongation in Cohort A (26/106) but did not correlate with conduction dynamics in Cohort B. In multivariable logistic regression analysis the use of Evolut R (OR 0.38, 95% CI 0.19–0.78, P = 0.008) and PRO (OR 0.41, 95% CI 0.19–0.91, P-value = 0.028) were independently associated with less need for PPI. Conclusion: The newer generations Evolut R and PRO were associated with less PPI compared to CoreValve. Acquired persistent conduction abnormalities predicted PPI after TAVR only in patients with normal conduction at baseline. Our findings may help identify eligible patients for early discharge after Evolut R/PRO TAVR

Impact of Valvulo-Arterial Impedance on Long-Term Quality of Life and Exercise Performance After Transcatheter Aortic Valve Replacement

BACKGROUND: In aortic stenosis, valvulo-arterial impedance (Zva) estimates the overall left ventricular afterload (valve and arterial component). We investigated the association of Zva (≥5 versus <5 mm Hg mL-1 m-2) on quality of life (QOL) and exercise performance (EP) ≥1 year after transcatheter aortic valve replacement (TAVR). METHODS: The study population consists of 250 TAVR patients in whom baseline Zva and follow-up QOL was prospectively assessed using EuroQOL-5-dimensions instruments; EP was assessed in 192 patients who survived ≥1 year after TAVR using questionnaires related to daily activities. In 124 patients, Zva at 1-year was also available and was used to study the change in Zva (baseline to 1 year) on QOL/EP. RESULTS: Elevated baseline Zva was present in 125 patients (50%). At a median of 28 (IQR, 17-40) months, patients with elevated baseline Zva were more limited in mobility (88% versus 71%; P=0.004), self-care (40% versus 25%; P=0.019), and independent daily activities (taking a shower: 53% versus 38%, P=0.030; walking 100 meter: 76% versus 54%, P=0.001; and walking stairs: 74% versus 54%, P=0.011). By multivariable analysis, elevated Zva predicted unfavorable QOL (lower EuroQOL-5-dimensions-Utility Index, odds ratio, 1.98; CI, 1.15-3.41) and unfavorable EP (any limitation in ≥3 daily activities, odds ratio, 2.55; CI, 1.41-4.62). After TAVR, the proportion of patients with elevated Zva fell from 50% to 21% and remained 21% at 1 year and was found to be associated with more limitations in mobility, self-care, and daily activities compared with patients with Zva <5 mm Hg mL-1 m-2. CONCLUSIONS: Elevated Zva was seen in half of patients and predicted unfavorable long-term QOL and EP. At 1 year after TAVR, the prevalence of elevated Zva was 21% but remained associated with poor QOL/EP

Dedicated plug based closure for large bore access –The MARVEL prospective registry

Objectives: To study safety and performance of the MANTA Vascular closure device (VCD) under real world conditions in 10 centers. Background: The MANTA is a novel plug-based devic

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review).

During the last 2 years, several novel genes that encode glucose transporter-like proteins have been identified and characterized. Because of their sequence similarity with GLUT1, these genes appear to belong to the family of solute carriers 2A (SLC2A, protein symbol GLUT). Sequence comparisons of all 13 family members allow the definition of characteristic sugar/polyol transporter signatures: (1) the presence of 12 membrane-spanning helices, (2) seven conserved glycine residues in the helices, (3) several basic and acidic residues at the intracellular surface of the proteins, (4) two conserved tryptophan residues, and (5) two conserved tyrosine residues. On the basis of sequence similarities and characteristic elements, the extended GLUT family can be divided into three subfamilies, namely class I (the previously known glucose transporters GLUT1-4), class II (the previously known fructose transporter GLUT5, the GLUT7, GLUT9 and GLUT11), and class III (GLUT6, 8, 10, 12, and the myo-inositol transporter HMIT1). Functional characteristics have been reported for some of the novel GLUTs. Like GLUT1-4, they exhibit a tissue/cell-specific expression (GLUT6, leukocytes, brain; GLUT8, testis, blastocysts, brain, muscle, adipocytes; GLUT9, liver, kidney; GLUT10, liver, pancreas; GLUT11, heart, skeletal muscle). GLUT6 and GLUT8 appear to be regulated by sub-cellular redistribution, because they are targeted to intra-cellular compartments by dileucine motifs in a dynamin dependent manner. Sugar transport has been reported for GLUT6, 8, and 11; HMIT1 has been shown to be a H+/myo-inositol co-transporter. Thus, the members of the extended GLUT family exhibit a surprisingly diverse substrate specificity, and the definition of sequence elements determining this substrate specificity will require a full functional characterization of all members