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Symposium 'Hoe gaan we écht bijdragen' (Groningen, 15 november 2022)

The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.

O3® Regional Oximetry (Masimo Corporation, California, USA) is validated for cerebral oximetry. We aimed to assess agreement of somatic and renal near-infrared spectroscopy with reference blood samples.O3 sensors were placed bilaterally on the quadriceps and flank of 26 healthy volunteers. A stepped, controlled hypoxia sequence was performed by adding a mixture of nitrogen and room air to the breathing circuit. O3-derived oxygen saturation values were obtained at baseline and at six decremental saturation levels (5% steps). Blood samples (radial artery, iliac vein (somatic reference) and renal vein) were obtained at each step. Reference values were calculated as: 0.7 × venous saturation + 0.3 × arterial saturation. The agreement between O3-derived values with blood reference values was assessed by calculating root-mean-square error accuracy and Bland-Altman plots.The root-mean-square error accuracy was 6.0% between quadriceps oxygen saturation and somatic reference values. The mean bias was 0.8%, with limits of agreement from -7.7 to 9.3%. These were 5.1% and 0.6% (-8.3 to 9.5%) for flank oxygen saturation and somatic reference values, respectively, and 7.7% and -4.9% (-15.0 to 5.2%) for flank oxygen saturation and renal reference values. The kidney depth was 3.1 ± 0.9 cm below the skin.O3 regional oximetry can be used on the quadriceps and flank to monitor somatic saturation, yet has a saturation-level dependent bias. O3-derived values obtained at the flank underestimated renal reference values. Additionally, it is unlikely that the flank sensors did directly measure renal tissue.Clinicaltrials.gov (NCT04584788): registered October 6th, 2020.

Liver fibrosis is associated with poor patient-reported outcomes (PROs), but the impact of steatosis is unknown. We aimed to evaluate the impact of steatosis on PROs independent of liver fibrosis. We evaluated the impact of steatosis, measured by Controlled-Attenuation Parameter (CAP) on transient elastography, and PROs using the 2017–2018 National Health and Nutrition Examination Survey (NHANES) database. We used univariate and multivariate logistic and ordinal regression to evaluate categorical CAP score with PROs measuring physical disability, general health and depression. Of 4,509 participants included, 38% had severe steatosis (> 280 dB/m). Those with severe steatosis were older and more likely to be male (56% vs. 43% and 51%). On univariate analysis, severe steatosis was associated with more difficulty walking (P = 0.01), dressing (P = 0.005), lifting objects (P = 0.02), bending (P

The great potential gains in separation power and analysis time that can result from rigorously optimizing LC-MS and 2D-LC-MS methods for routine measurements has prompted many scientists to develop computer-aided method-development tools. The applicability of these has been proven in numerous applications, but their proliferation is still limited. Arguably, the majority of LC methods are still developed in a conventional manner, i.e. by analysts who rely on their knowledge and experience. In this work, a novel, open-source algorithm was developed for automated and interpretive method development of LC separations. A closed-loop workflow was constructed that interacted directly with the LC and ran unsupervised in an automated fashion. The algorithm was tested using two newly designed strategies. The first utilized retention modeling, whereas the second used the Bayesian-optimization machine-learning approach. In both cases, the algorithm could arrive within ten iterations at an optimum of the objective function, which included resolution and measurement time. The design of the algorithm was modular, so as to facilitate compatibility with previous works in literature and its performance thus hinged on each module (e.g., signal processing, choice of retention model, objective function). Key focus areas for further improvement were identified. Bayesian optimization did not require any peak tracking or retention modeling. Accurate prediction of elution profiles was found to be indispensable for the strategy using retention modeling. This is the first interpretive algorithm demonstrated with complex samples. Peak tracking was conducted using UV-Vis absorbance detection, but use of MS detection is expected to significantly broaden the applicability of the workflow.

Background: The rate or persistent perfusion defects after acute pulmonary embolism (PE) varies from 30 % to 50 % after 6 months of treatment. Moreover, PE patients may suffer from persistent dyspnea and decreased quality of life (QoL). However, it is unknown whether persistent dyspnea results from perfusion defects and if either may affect QoL on the very long term. This study assessed the rate of persistent dyspnea and perfusion defects after PE and their association with long-term QoL. Methods: This observational study included consecutive patients with acute PE. At 6 months, a perfusion scan (Q-scan) was performed, patient-reported dyspnea was assessed, and of both the cumulative incidence rates with 95 % confidence intervals (CI) were calculated. After five years, disease-specific QoL was assessed with the PEmb-QoL questionnaire. Differences in PEmb-QoL between patients with and without dyspnea and between patients with and without persisting perfusion defects were calculated with the Mann-Whitney U test. Results: In 179 PE patients, the rate of persistent dyspnea was 24 % (95 % CI:17–30 %). Of these patients, 57 % (95 % CI:40–72 %) had persistent perfusion defects at 6 months which was significantly related to the persistent dyspnea (OR: 2.3 (95 % CI:1.1–4.9); p = 0.027). Perfusion defects did not result a difference in PEmb-QoL at five years. However, patients with persistent dyspnea had significantly worse PEmb-QoL after 5 years (38 % [18–55 %] versus 11 % [4.2–25 %]; p < 0.001). Conclusion: Persistent dyspnea after acute PE was associated with a lower QoL on the long term, however no relation was found between persistent perfusion defects and a lower QoL.

The objective of the present work was to make a quantitative and critical comparison of a number of drift and noise-removal algorithms, which were proven useful by other researchers, but which had never been compared on an equal basis. To make a rigorous and fair comparison, a data generation tool is developed in this work, which utilizes a library of experimental backgrounds, as well as peak shapes obtained from curve fitting on experimental data. Several different distribution functions are used, such as the log-normal, bi-Gaussian, exponentially convoluted Gaussian, exponentially modified Gaussian and modified Pearson VII distributions. The tool was used to create a set of hybrid (part experimental, part simulated) data, in which the background and all peak profiles and areas are known. This large data set (500 chromatograms) was analysed using seven different drift-correction and five different noise-removal algorithms (35 combinations). Root-mean square errors and absolute errors in peak area were determined and it was shown that in most cases the combination of sparsity-assisted signal smoothing and asymmetrically reweighted penalized least-squares resulted in the smallest errors for relatively low-noise signals. However, for noisier signals the combination of sparsity-assisted signal smoothing and a local minimum value approach to background correction resulted in lower absolute errors in peak area. The performance of correction algorithms was studied as a function of the density and coverage of peaks in the chromatogram, shape of the background signal, and noise levels. The developed data-generation tool is published along with this article, so as to allow similar studies with other simulated data sets and possibly other algorithms. The rigorous assessment of correction algorithms in this work may facilitate further automation of data-analysis workflows.

Purpose: Non-invasive cerebral oxygen saturation (ScO2) monitoring is an established tool in the intraoperative phase of pediatric congenital cardiac surgery (CCS). This study investigated the association between ScO2 and postoperative outcome by investigating both baseline ScO2 values and intraoperative desaturations from baseline. Methods: All CCS procedures performed in the period 2010-2017 in our institution in which ScO2 was monitored were included in this historical cohort study. Baseline ScO2 was determined after tracheal intubation, before surgical incision. Subgroups were based on cardiac pathology and degree of intracardiac shunting. Poor outcome was defined based on length of stay (LOS) in the intensive care unit (ICU)/hospital, duration of mechanical ventilation (MV), and 30-day mortality. Intraoperatively, ScO2 total time below baseline (TBBL) and ScO2 time-weighted average (TWA) were calculated. Results: Data from 565 patients were analyzed. Baseline ScO2 was significantly associated with LOS in ICU (odds ratio [OR] per percentage decrease in baseline ScO2, 0.95; 95% confidence interval [CI], 0.93 to 0.97; P < 0.001), with LOS in hospital (OR, 0.93; 95% CI, 0.91 to 0.96; P < 0.001), with MV duration (OR, 0.92; 95% CI, 0.90 to 0.95; P < 0.001) and with 30-day mortality (OR, 0.94; 95% CI, 0.91 to 0.98; P = 0.007). Cerebral oxygen saturation TWA had no associations, while ScO2 TBBL had only a small association with LOS in ICU (OR, 1.02; 95% CI, 1.01 to 1.03; P < 0.001), MV duration (OR,1.02; 95% CI, 1.01 to 1.03; P = 0.002), and LOS in hospital (OR, 1.02; 95% CI, 1.01 to 1.04; P < 0.001). Conclusion: In pediatric patients undergoing cardiac surgery, low baseline ScO2 values measured after tracheal intubation were associated with several adverse postoperative outcomes. In contrast, the severity of actual intraoperative cerebral desaturation was not associated with postoperative outcomes. Baseline ScO2 measured after tracheal intubation may help identify patients at increased perioperative risk.

Purpose Metabolic syndrome in patients with morbid obesity causes a higher cardiovascular morbidity, eventually leading to left ventricular hypertrophy and decreased left ventricular ejection fraction (LVEF). Roux-en-Y gastric bypass (RYGB) is considered the gold standard modality for treatment of morbid obesity and might even lead to improved cardiac function. Our objective is to investigate whether cardiac function in patients with morbid obesity improves after RYGB. Materials and Methods In this single center pilot study, 15 patients with an uneventful cardiac history who underwent RYGB were included from May 2015 to March 2016. Cardiac function was measured by cardiac magnetic resonance imaging (CMRI), performed preoperatively and 3, 6, and 12 months postoperative. LVEF and myocardial mass and cardiac output were measured. Results A total of 13 patients without decreased LVEF preoperative completed follow-up (mean age 37, 48.0 ± 8.8). There was a significant decrease of cardiac output 12 months postoperative (8.3 ± 1.8 preoperative vs. 6.8 ± 1.8 after 12 months, P = 0.001). Average myocardial mass declined by 15.2% (P P = 0.36). There was a significant improvement of LVEF/BSA at 6 and 12 months postoperative (26.2 ± 4.1 preoperative vs. 28.4 ± 3.4 and 29.2 ± 3.6 respectively, both P = 0.002). Additionally, there was a significant improvement of stroke volume/BSA 12 months after surgery (45.8 ± 8.0 vs. 51.9 ± 10.7, P = 0.033). Conclusion RYGB in patients with morbid obesity with uneventful history of cardiac disease leads to improvement of cardiac function.

In the perioperative phase oxygen delivery and consumption can be influenced by different factors, i.e. type of surgery, anesthetic and cardiovascular drugs, or fluids. By combining near-infrared spectroscopy (NIRS) monitoring of regional tissue oxygen saturation (StO(2)) with an ischemic provocation test, the vascular occlusion test (VOT), local tissue oxygen consumption and vascular reactivity at the microcirculatory level can be assessed. This systematic review aims to give an overview of the clinical information that VOT-derived NIRS values can provide in the perioperative period. After performing a systematic literature search, we included 29 articles. It was not possible to perform a meta-analysis because of the lack of comparable data and the observational nature of the majority of the included articles. We have clustered the found articles in two groups: non-cardiac surgery and cardiac surgery. We found that VOT-derived NIRS values show a wide variability and are influenced by the effects of anesthetics, cardiovascular drugs, fluids, and by the type of surgery. Additionally, deviations in VOT-derived NIRS values are also associated with adverse patients' outcomes, such as postoperative complications, prolonged mechanical ventilation and prolonged hospital length of stay. However, given the variability in VOT-derived NIRS values, clinical applicability remains elusive. Future clinical interventional trials might provide additional insight into the potential of VOT associated with NIRS to optimize perioperative care by targeting specific interventions to optimize the function of the microvasculature.

A balanced incomplete block design is a set system in which all pairs of distinct elements occur with a constant frequency. By contrast, a Sarvate-Beam design induces an interval of distinct frequencies on pairs. In this paper, we settle the existence of a Sarvate-Beam variant of group divisible designs of uniform type with block size three.

Purpose: O3® Regional Oximetry (Masimo Corporation, California, USA) is validated for cerebral oximetry. We aimed to assess agreement of somatic and renal near-infrared spectroscopy with reference blood samples. Methods: O3 sensors were placed bilaterally on the quadriceps and flank of 26 healthy volunteers. A stepped, controlled hypoxia sequence was performed by adding a mixture of nitrogen and room air to the breathing circuit. O3-derived oxygen saturation values were obtained at baseline and at six decremental saturation levels (5% steps). Blood samples (radial artery, iliac vein (somatic reference) and renal vein) were obtained at each step. Reference values were calculated as: 0.7 × venous saturation + 0.3 × arterial saturation. The agreement between O3-derived values with blood reference values was assessed by calculating root-mean-square error accuracy and Bland-Altman plots. Results: The root-mean-square error accuracy was 6.0% between quadriceps oxygen saturation and somatic reference values. The mean bias was 0.8%, with limits of agreement from -7.7 to 9.3%. These were 5.1% and 0.6% (-8.3 to 9.5%) for flank oxygen saturation and somatic reference values, respectively, and 7.7% and -4.9% (-15.0 to 5.2%) for flank oxygen saturation and renal reference values. The kidney depth was 3.1 ± 0.9 cm below the skin. Conclusion: O3 regional oximetry can be used on the quadriceps and flank to monitor somatic saturation, yet has a saturation-level dependent bias. O3-derived values obtained at the flank underestimated renal reference values. Additionally, it is unlikely that the flank sensors did directly measure renal tissue. Trial registration: Clinicaltrials.gov (NCT04584788): registered October 6th, 2020.

Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies.