Acremonium sp. diglycosidase-aid chemical diversification: valorization of industry by-products.

The fungal diglycosidase α-rhamnosyl-ß-glucosidase I (αRßG I) from Acremonium sp. DSM 24697 catalyzes the glycosylation of various OH-acceptors using the citrus flavanone hesperidin. We successfully applied a one-pot biocatalysis process to synthesize 4-methylumbellipheryl rutinoside (4-MUR) and glyceryl rutinoside using a citrus peel residue as sugar donor. This residue, which contained 3.5 % [w/w] hesperidin, is the remaining of citrus processing after producing orange juice, essential oil, and peel-juice. The low-cost compound glycerol was utilized in the synthesis of glyceryl rutinoside. We implemented a simple method for the obtention of glyceryl rutinoside with 99 % yield, and its purification involving activated charcoal, which also facilitated the recovery of the by-product hesperetin through liquid-liquid extraction. This process presents a promising alternative for biorefinery operations, highlighting the valuable role of αRßG I in valorizing glycerol and agricultural by-products. KEYPOINTS: • αRßG I catalyzed the synthesis of rutinosides using a suspension of OPW as sugar donor. • The glycosylation of aliphatic polyalcohols by the αRßG I resulted in products bearing a single rutinose moiety. • αRßG I catalyzed the synthesis of glyceryl rutinoside with high glycosylation/hydrolysis selectivity (99 % yield).

Participation in Competitive Sports by Patients With Congenital Heart Disease: AHA/ACC and EAPC/ESC/AEPC Guidelines Comparison.

Sports participation in patients with congenital heart disease is an evolving subject. The American Heart Association/American College of Cardiology released a set of guidelines that advise the type and level of sports participation based primarily on anatomical defects with secondary consideration given to hemodynamic effects. Recently, the European Association of Preventive Cardiology/European Society of Cardiology/Association for European Paediatric and Congenital Cardiology offered a contrasting approach to sports participation that is based on hemodynamic and electrophysiological profiles of each patient, regardless of anatomical consideration. These guidelines are drastically different in their approaches but do have some similarities. In this review, we compare both documents, focusing on the aim, population, classification of sports, and the methodology of making recommendations. This review aims to assist practicing cardiologists in integrating the available published data and recommendations when counseling patients for sports participation.

Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy.

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.

Prognostic Impact and Spatial Interplay of Immune Cells in Urothelial Cancer.

BACKGROUND: Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. OBJECTIVE: To characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Spatial immune parameters were compared with histopathological parameters and overall survival data. RESULTS AND LIMITATIONS: The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8+ cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8+ T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells. CONCLUSIONS: The density of intraepithelial CD8+ T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8+ cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8+ T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index. PATIENT SUMMARY: Quantification of intraepithelial CD8+ T cells, the strongest prognostic feature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.

High-sensitive troponin T and N-terminal pro-B-type natriuretic peptide independently predict survival and cardiac-related events in adults with congenital heart disease.

AIMS: High-sensitive troponin T (hs-TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) are established prognostic biomarkers for cardiovascular (CV) morbidity and mortality and frequently used in symptomatic and/or hospitalized adults with congenital heart disease (ACHD). Their prognostic value in clinically stable ACHD has not yet been well established. This study investigates the predictive value of hs-TnT, NT-proBNP, and CRP for survival and CV events in stable ACHD. METHODS AND RESULTS: In this prospective cohort study, 495 outpatient ACHD (43.9 ± 10.0 years, 49.1% female) underwent venous blood sampling including hs-TnT, NT-proBNP, and CRP. Patients were followed up for survival status and the occurrence of CV events. Survival analyses were performed with Cox proportional hazards regression analysis and Kaplan-Meier curves. During a mean follow-up of 2.8 ± 1.0 years, 53 patients (10.7%) died or reached a cardiac-related endpoint including sustained ventricular tachycardia, hospitalization with cardiac decompensation, ablation, interventional catheterization, pacer implantation, or cardiac surgery. Multivariable Cox regression revealed hs-TnT (P = 0.005) and NT-proBNP (P = 0.018) as independent predictors of death or cardiac-related events in stable ACHD, whilst the prognostic value of CRP vanished after multivariable adjustment (P = 0.057). Receiver-operator characteristic curve analysis identified cut-off values for event-free survival of hs-TnT ≤9 ng/L and NT-proBNP ≤200 ng/L. Patients with both increased biomarkers had a 7.7-fold (confidence interval 3.57-16.40, P < 0.001) higher risk for death and cardiac-related events compared with patients without elevated blood values. CONCLUSION: Subclinical values of hs-TnT and NT-proBNP are a useful, simple, and independent prognostic tool for adverse cardiac events and survival in stable outpatient ACHD. REGISTRATION: German Clinical Trial Registry DRKS00015248.

Biomechanical comparison of two different compression screws for the treatment of odontoid fractures in human dens axis specimen.

BACKGROUND: Lag screw osteosynthesis for odontoid fractures has a high rate of pseudoarthrosis, especially in elderly patients. Besides biomechanical properties of the different screw types, insufficient fragment compression or unnoticed screw stripping may be the main causing factors for this adverse event. The aim of the study was to compare two screws in clinical use with different design principles in terms of compression force and stability against screw stripping. METHODS: Twelve human cadaveric C2 vertebral bodies were considered. Bone density was determined. The specimens were matched according to bone density and randomly assigned to two experimental groups. An odontoid fracture was induced, which were fixed either with a 3.5 mm standard compression screw or with a 5 mm sleeve nut screw. Both screws are certified for the treatment of odontoid fractures. The bone samples were fixed in a measuring device. The screwdriver was driven mechanically. The tests were analyzed for peak interfragmentary compression and screw-in torque with a frequency of 20 Hz. FINDINGS: The maximum fragment compression was significantly higher with screw with sleeve nut at 346.13(SD ±72.35) N compared with classic compression screw at 162.68(SD ±114.13) N (p = 0.025). Screw stripping occurred significantly earlier in classic compression screw at 255.5(SD ±192.0)° rotation after reaching maximum compression than in screw with sleeve nut at 1005.2(SD ±341.1)° (p = 0.0039). INTERPRETATION: Screw with sleeve nut achieves greater fragment compression and is more robust to screw stripping compared to classic compression screw. Whether the better biomechanical properties lead to a reduction of pseudoarthrosis has to be proven in clinical studies.

Longitudinal development of central SBP in children with congenital heart disease.

AIMS: Central SBP (cSBP) was shown to be increased already in children with congenital heart disease (CHD). However, its development over time has not yet been investigated. The aim of this study was to evaluate the natural course of cSBP over time from longitudinal assessment in children with CHD. METHODS: In this longitudinal study, 306 children and adolescents (11.3 ±â€Š2.9 years, 34% girls) with various CHD were prospectively examined from July 2014 to May 2022. Over a mean follow-up length of 30.1 ±â€Š18.9 months, 467 follow-up assessments have been conducted. cSBP was noninvasively assessed by oscillometric measurement via Mobil-O-Graph. A linear mixed effect model was performed to examine the course of cSBP. RESULTS: cSBP increased significantly over time by 1.22 mmHg per year of age (P < 0.001). The longitudinal increase in cSBP over time remained significant when including sex (b = 0.68, P < 0.001), BMI (b = 1.12, P < 0.001), hypertensive medication (b = 1.13, P < 0.001), disease severity (b = 1.04, P < 0.001), and CHD type (b = 3.74, P = 0.03) in the model. Patients with transposition of the great arteries (TGA) after arterial switch had a significantly higher cSBP increase over time (b = 1.78, P < 0.001). The longitudinal cSBP increase was significantly higher in obese CHD children (b = 2.52, P = 0.005) and in boys (b = 0.85, P < 0.001). CONCLUSION: This study shows a longitudinal increase in cSBP in children with CHD. Whether observed trajectories of cSBP are normal or abnormal needs to be investigated in further studies. Monitoring of the vascular function with a special focus on patients with TGA and obese CHD children seems indicated.

Automated Prognosis Marker Assessment in Breast Cancers Using BLEACH&STAIN Multiplexed Immunohistochemistry.

Prognostic markers in routine clinical management of breast cancer are often assessed using RNA-based multi-gene panels that depend on fluctuating tumor purity. Multiplex fluorescence immunohistochemistry (mfIHC) holds the potential for an improved risk assessment. To enable automated prognosis marker detection (i.e., progesterone receptor [PR], estrogen receptor [ER], androgen receptor [AR], GATA3, TROP2, HER2, PD-L1, Ki67, TOP2A), a framework for automated breast cancer identification was developed and validated involving thirteen different artificial intelligence analysis steps and an algorithm for cell distance analysis using 11+1-marker-BLEACH&STAIN-mfIHC staining in 1404 invasive breast cancers of no special type (NST). The framework for automated breast cancer detection discriminated normal glands from malignant glands with an accuracy of 98.4%. This approach identified that five (PR, ER, AR, GATA3, PD-L1) of nine biomarkers were associated with prolonged overall survival (p ≤ 0.0095 each) and two of these (PR, AR) were found to be independent risk factors in multivariate analysis (p ≤ 0.0151 each). The combined assessment of PR-ER-AR-GATA3-PD-L1 as a five-marker prognosis score showed strong prognostic relevance (p < 0.0001) and was an independent risk factor in multivariate analysis (p = 0.0034). Automated breast cancer detection in combination with an artificial intelligence-based analysis of mfIHC enables a rapid and reliable analysis of multiple prognostic parameters. The strict limitation of the analysis to malignant cells excludes the impact of fluctuating tumor purity on assay precision.

Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU.

BACKGROUND: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency. METHODS: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome. RESULTS: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control. CONCLUSIONS: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).

Enabling strain imaging in realistic Eulerian ultrasound simulation methods.

Cardiovascular strain imaging is continually improving due to ongoing advances in ultrasound acquisition and data processing techniques. The phantoms used for validation of new methods are often burdensome to make and lack flexibility to vary mechanical and acoustic properties. Simulations of US imaging provide an alternative with the required flexibility and ground truth strain data. However, the current Lagrangian US strain imaging models cannot simulate heterogeneous speed of sound distributions and higher-order scattering, which limits the realism of the simulations. More realistic Eulerian modelling techniques exist but have so far not been used for strain imaging. In this research, a novel sampling scheme was developed based on a band-limited interpolation of the medium, which enables accurate strain simulation in Eulerian methods. The scheme was validated in k-Wave using various numerical phantoms and by a comparison with Field II. The method allows for simulations with a large range in strain values and was accurate with errors smaller than -60 dB. Furthermore, an excellent agreement with the Fourier theory of US scattering was found. The ability to perform simulations with heterogeneous speed of sound distributions was demonstrated using a pulsating artery model. The developed sampling scheme contributes to more realistic strain imaging simulations, in which the effect of heterogenous acoustic properties can be taken into account.

Resilience in children with congenital heart disease: a comparative study with health counterparts.

OBJECTIVE: Resilience is a complex, yet rather unexplored topic in patients with congenital heart disease (CHD). The goal of this study was to assess and compare resilience in children with CHD with healthy controls during the COVID-19 pandemic. DESIGN AND PATIENTS: From June 2020 to June 2021, 124 children with various CHDs (14.6±2.1 years, 49 girls) and 124 matched healthy controls (14.8±2.0 years, 49 girls) completed the Resilience Scale-11 short version. RESULTS: Resilience was significantly reduced in children with CHD compared with healthy controls (CHD: 59.0±10.0 vs healthy controls: 64.4±6.5, p<0.001). That reduction was prominent in all CHD subgroups except those with left heart obstruction (aortic stenosis and coarctation of the aorta) and patients with transposition of the great arteries. Complex CHD had the lowest resilience of 57.6±8.4 (p<0.001) after adjusting for age and sex according to group differences. There was no difference between native CHD and CHD with open-heart surgery (native: 59.5±12.2 vs surgery: 58.8±9.3, p=0.758). CONCLUSIONS: Resilience was reduced in children and adolescents with CHD compared with healthy peers during the COVID-19 pandemic. Children with complex severity appeared to be particularly affected. These findings emphasise continued efforts to provide a holistic and multidisciplinary approach in medical aftercare of these patients and their families.

IL-3 orchestrates ulcerative colitis pathogenesis by controlling the development and the recruitment of splenic reservoir neutrophils.

Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoiesis. During acute colitis, Il-3-/- show, however, increased resistance to the disease as well as reduced intestinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein ß (S100ß), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1ß, and S100ß levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.

Human lung virtual histology by multi-scale x-ray phase-contrast computed tomography.

Objectives.As the central organ of the respiratory system, the human lung is responsible for supplying oxygen to the blood, which reaches the erythrocytes by diffusion through the alveolar walls and is then distributed throughout the body. By exploiting the difference in electron density detected by a phase shift in soft tissue, high-resolution x-ray phase-contrast computed tomography (XPCT) can resolve biological structures in a sub-µm range, shedding new light on the three-dimensional structure of the lungs, physiological functions and pathological mechanisms.Approach.This work presents both synchrotron and laboratory XPCT results of postmortem tissue from autopsies and biopsies embedded with various preparation protocols such as precision-cut lung slices, cryogenically fixed lung tissue, as well as paraffin and alcohol fixed tissue. The selection of pathological abnormalities includes channel of Lambert, bronchus-associated lymphoid tissue and alveolar capillary dysplasia with misalignment of pulmonary veins. Subsequently, quantification and visualization approaches are presented.Main results.The overall high image quality even of in-house XPCT scans for the case of FFPE biopsies can be exploited for a wide range of pulmonary pathologies and translated to dedicated and optimized instrumentation which could be operated in clinical setting. By using synchrotron radiation, contrast can be further increased to resolve sub-µm sized features down to the sub-cellular level. The results demonstrate that a wide range of preparation protocols including sample mounting in liquids can be used.Significance.With XPCT, poorly understood 3D structures can be identified in larger volume overview and subsequently studied in more detail at higher resolution. With the full 3D structure, the respective physiological functions of airways or vascular networks, and the different pathophysiologic mechanisms can be elucidated or at least underpinned with structural data. Moreover, synchrotron data can be used to validate laboratory protocols and provide ground truth for standardizing the method.

Duration of Surgery and Intraoperative Blood Pressure Management Are Modifiable Risk Factors for Postoperative Neurocognitive Disorders After Spine Surgery: Results of the Prospective CONFESS Study.

STUDY DESIGN: Prospective quasi-experimental observational study. OBJECTIVE: The objective of this study was to evaluate whether duration of surgery is a modifiable risk factor for postoperative delirium (POD) after spine surgery and explore further modifiable risk factors. In addition, we sought to investigate the association between POD and postoperative cognitive dysfunction and persistent neurocognitive disorders. SUMMARY OF BACKGROUND DATA: Advances in spine surgery enable technically safe interventions in elderly patients with disabling spine disease. The occurrence of POD and delayed neurocognitive complications ( e.g. postoperative cognitive dysfunction/persistent neurocognitive disorder) remain a concern since these contribute to inferior functional outcomes and long-term care dependency after spine surgery. MATERIALS AND METHODS: This prospective single-center study recruited patients aged 60 years or above and scheduled for elective spine surgery between February 2018 and March 2020. Functional (Barthel Index, BI) and cognitive outcomes [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery; telephone Montréal Cognitive Assessment] were assessed at baseline, three (V3), and 12 months postoperatively. The primary hypothesis was that the duration of surgery predicts POD. Multivariable predictive models of POD included surgical and anesthesiological parameters. RESULTS: Twenty-two percent of patients developed POD (n=22/99). In a multivariable model, duration of surgery [OR adj =1.61/h (95% CI, 1.20-2.30)], age [OR adj =1.22/yr (95% CI, 1.10-1.36)], and baseline deviations of intraoperative systolic blood pressure [25th percentile: OR adj =0.94/mm Hg (95% CI, 0.89-0.99); 90th percentile: OR adj =1.07/mm Hg (95% CI, 1.01-1.14)] were significantly associated with POD. Postoperative cognitive scores generally improved (V3, ΔCERAD total z -score: 0.22±0.63). However, this positive group effect was counteracted by POD [beta: -0.87 (95% CI, -1.31 to 0.42)], older age [beta: -0.03/yr (95% CI, -0.05 to 0.01)], and lack of functional improvement [ΔBI; beta: -0.04/point (95% CI, -0.06 to 0.02)]. Cognitive scores at twelve months remained inferior in the POD group, adjusted for baseline cognition/age. CONCLUSIONS: This study identified distinct neurocognitive effects after spine surgery, which are influenced by perioperative risk factors. Potential cognitive benefits are counteracted by POD, rendering its prevention critical in an aging population.

Digital Health Nudging to increase physical activity in pediatric patients with congenital heart disease: A randomized controlled trial.

BACKGROUND: Digital nudging is a modern e-health approach to increase physical activity (PA) in younger age groups. As activity promotion is particularly important in adolescents with congenital heart disease (CHD) this randomized-controlled trail examines if Digital Health Nudging via daily smartphone messages increases PA, activity-related self-efficacy (ArSE) and health-related quality of life (HrQoL) in adolescents with CHD. METHODS: From May 2021 to April 2022, 97 patients (15.1 ± 2.0 years, 50% girls) with moderate or severe CHD were randomly allocated 1:1 to intervention (IG) or control group (CG). Daily PA was objectively assessed in minutes of moderate-to-vigorous PA (MVPA) by the wearable "Garmin Vivofit jr. 2" over the entire study period. The IG received daily smartphone messages based on Bandura's social cognitive theory on the subject of PA over a period of 12-weeks. RESULTS: According to the linear mixed model, the change of MVPA over the study period did not significantly differ between IG and CG when taking baseline MVPA into account (b = 0.136, 95%-CI [-0.355; 0.627], P = .587). Activity level was comparably high and showed only minor variability in both groups with 73.7 [62.3; 78.8] min/day in IG and 78.4 [66.6; 93.9] min/d in CG throughout the whole 12-weeks. Emotional well-being significantly increased over the study period in the IG (IG: Δ1.60 [-0.2; 6.3] vs CG: Δ0.0 [-12.5; 6.3], P = .043), but not total HrQoL (P = .518) and ArSE (P = .305). CONCLUSIONS: 12-weeks, of Digital Health Nudging did not increase PA, but improved feelings of emotional well-being in adolescents with CHD. TRIAL REGISTRATION: Clinical Trials Identifier NCT04933786.

Identification of two early blood biomarkers ACHE and CLEC12A for improved risk stratification of critically ill COVID-19 patients.

In order to identify biomarkers for earlier prediction of COVID-19 outcome, we collected blood samples from patients with fatal outcomes (non-survivors) and with positive clinical outcomes (survivors) at ICU admission and after seven days. COVID-19 survivors and non-survivors showed significantly different transcript levels for 93 genes in whole blood already at ICU admission as revealed by RNA-Seq. These differences became even more pronounced at day 7, resulting in 290 differentially expressed genes. Many identified genes play a role in the differentiation of hematopoietic cells. For validation, we designed an RT-qPCR assay for C-type lectin domain family 12 member A (CLEC12A) and acetylcholinesterase (ACHE), two transcripts that showed highest potential to discriminate between survivors and non-survivors at both time points. Using our combined RT-qPCR assay we examined 33 samples to accurately predict patient survival with an AUROC curve of 0.931 (95% CI = 0.814-1.000) already at ICU admission. CLEC12A and ACHE showed improved prediction of patient outcomes compared to standard clinical biomarkers including CRP and PCT in combination (AUROC = 0.403, 95% CI = 0.108-0.697) or SOFA score (AUROC = 0.701 95% CI = 0.451-0.951) at day 0. Therefore, analyzing CLEC12A and ACHE gene expression from blood may provide a promising approach for early risk stratification of severely ill COVID-19 patients.

Occurrence Rate and Outcomes of Weaning Groups According to a Refined Weaning Classification: A Retrospective Observational Study.

OBJECTIVES: The weaning according to a new definition (WIND) classification groups mechanically ventilated (MV) patients into "short weaning," "difficult weaning," "prolonged weaning," and "no weaning." The aims of the study were: 1) to describe the weaning group distribution, 2) to evaluate if "short weaning" patients can be divided into groups with distinct characteristics and outcomes depending on the MV duration, and 3) to study 1-year outcomes related to weaning groups. DESIGN: Retrospective observational study. SETTING: Tertiary center with a mixed, mainly surgical ICU population. PATIENTS: MV patients admitted between April 11, 2018, and April 10, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A refined WIND classification was used, dividing "short weaning" patients into patients MV less than or equal to 24 hours, "short weaning a," and those MV greater than 24 hours, "short weaning b." Data were collected from electronic medical records. Of 1,801 MV patients, 65% were categorized as "short weaning a," 13% "short weaning b," 8% "difficult weaning," 6% "prolonged weaning," and 8% "no weaning." "Short weaning a" patients were older, more frequently male, and had lower disease severity compared with "short weaning b." Weaning duration (days: 0 [0-0] to 14 [10-21]), weaning success rate (99-69%), ICU length of stay (days: 2 [1-4] to 28 [19-48]), ICU mortality (1-37%), and hospital length of stay (days: 10 [7-18] to 48 [27-89]) and hospital mortality (4-42%; all p < 0.01) increasingly worsened from "short weaning a" to "prolonged weaning." One-year mortality increased from "short weaning a" (9%) to "short weaning b" (27%), "difficult weaning" (39%), and "prolonged weaning" (49%). In adjusted analyses, weaning groups remained independently associated with 1-year mortality. CONCLUSIONS: The high proportion of "short weaning" patients in this mainly surgical ICU population could be divided into two groups with distinct characteristics. This refined WIND classification allowed to enhance prognostication, also beyond hospitalization, highlighting the need to further optimize the weaning process.

An aberration correction approach for single and dual aperture ultrasound imaging of the abdomen.

Abdominal ultrasound image quality is hampered by phase aberration, that is mainly caused by the large speed-of-sound (SoS) differences between fat and muscle tissue in the abdominal wall. The mismatch between the assumed and actual SoS distribution introduces general blurring of the ultrasound images, and acoustic refraction can lead to geometric distortion of the imaged features. Large aperture imaging or dual-transducer imaging can improve abdominal imaging at deep locations by providing increased contrast and resolution. However, aberration effects for large aperture imaging can be even more severe, which limits its full potential. In this study, a model-based aberration correction method for arbitrary acquisition schemes is introduced for delay-and-sum (DAS) beamforming and its performance was analyzed for both single- and dual-transducer ultrasound imaging. The method employs aberration corrected wavefront arrival times, using manually assigned local SoS values. Two wavefront models were compared. The first model is based on a straight ray approximation, and the second model on the Eikonal equation, which is solved by a multi-stencils fast marching method. Their accuracy for abdominal imaging was evaluated in acoustic simulations and phantom experiments involving tissue-mimicking and porcine material with large SoS contrast (∼100 m/s). The lateral resolution was improved by up to 90% in simulations and up to 65% in experiments compared to standard DAS, in which the use of Eikonal beamforming generally outperformed straight ray beamforming. Moreover, geometric distortions were mitigated in multi-aperture imaging, leading to a reduction in position error of around 80%. A study on the sensitivity of the aberration correction to shape and SoS of aberrating layers was performed, showing that even with imperfect segmentations or SoS values, aberration correction still outperforms standard DAS.

Comparing two types of loading during inspiratory muscle training in patients with weaning difficulties: An exploratory study.

BACKGROUND: Inspiratory muscle training improves respiratory muscle function and may improve weaning outcomes in patients with weaning difficulties. Compared to the commonly used pressure threshold loading, tapered flow resistive loading better accommodates pressure-volume relationships of the respiratory muscles, which might help to facilitate application of external loads and optimise training responses. OBJECTIVE: The objective of this study was to compare acute breathing pattern responses and perceived symptoms during an inspiratory muscle training session performed against identical external loading provided as pressure threshold loading or as tapered flow resistive loading. We hypothesised that for a given loading, tapered flow resistive loading would allow larger volume expansion and higher inspiratory flow responses and consequently higher external work of breathing and power than pressure threshold loading and that subsequently patients perceived fewer symptoms during tapered flow resistive loading than during pressure threshold loading. METHODS: In this exploratory study, 21 patients (maximal inspiratory pressure: 35 ± 14 cmH2O and vital capacity:0.85 L±0.37 L) performed two training sessions against external loads equalling 42 ± 15% of maximal inspiratory pressure provided either as pressure threshold loading or as tapered flow resistive loading. During these training sessions, breath-by-breath data of breathing parameters were collected, and patients rated their perceived breathing effort, dyspnoea, and unpleasantness. RESULTS: Compared to pressure threshold loading, tapered flow resistive loading allowed significantly larger volume expansion (0.53 ± 0.28 L versus 0.41 ± 0.20 L, p < 0.01) and inspiratory flow responses (0.43 ± 0.20 L/s versus 0.33 ± 0.16 L/s, p = 0.01). Tapered flow resistive loading was perceived as less unpleasant (3.1 ± 1.9 versus 3.8 ± 2.4, p = 0.048). No significant differences in breathing effort, dyspnoea, work of breathing, and power were observed. CONCLUSIONS: For a given loading, inspiratory muscle training with tapered flow resistive loading allowed larger volume expansion and higher inspiratory flow responses than pressure threshold loading, which led patients to perceive tapered flow resistive loading as less unpleasant. This might help us to facilitate early implementation of inspiratory muscle training in patients with weaning difficulties. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier: NCT03240263.