Search

BACKGROUND: Brain-derived neurotrophic factor (BDNF) promotes activity-dependent neuroplasticity and is released following aerobic-exercise. OBJECTIVE: Feasibility and efficacy of 1.Moderate-Intensity Cycle-Ergometer-Training (MI-ET) and 2.Low-Intensity Circuit-Training (LI-CT) on BDNF-serum-concentration in chronic-stroke and consequently efficacy of motor-learning in varying BDNF-concentrations (neuroplasticity being the substrate for motor-learning) via upper-limb robotic-training (RT) in both groups. METHODS: Randomised-control feasibility-study. 12-week, 3x/week intervention, 17 chronic-stroke-survivors randomized into: (1) MI-ET&RT or (2) LI-CT&RT. Both groups completed 40 mins MI-ET or LI-CT followed by 40 mins RT. Feasibility outcomes: (1) screening and enrollment-rates, (2) retention-rates, (3) adherence: (i) attendance-rates, (ii) training-duration, (4) adverse events. Primary clinical outcomes: 1. serum-BDNF changes pre-post training (immediate) and pre-training basal-levels over 12-weeks (long-term). 2.upper-limb performance with Action-Research-Arm-Test (ARAT). Additionally, feasibility of an embedded health economic evaluation (HEE) to evaluate health-costs and cost-effectiveness. Outcomes: cost-questionnaire return-rates, cost-of-illness (COI) and Health-Utitility-Index (HUI). RESULTS: 21.5% of eligible and contactable enrolled. 10 randomized to MI-ET and 7 to LI-CT. 85% of training-sessions were completed in MI-ET (306/360) and 76.3% in LI-CT-group (165/216). 12-weeks: Drop-outs MI-ET-10%, LI-CT-43%. Clinical outcomes: No significant changes in immediate or long-term serum-BDNF in either group. Moderate-intensity aerobic-training did not increase serum-BDNF post-stroke. Individual but no group clinically-relevant changes in ARAT-scores. HEE outcomes at 12-weeks: 100% cost-questionnaires returned. Group-costs baseline and after treatment, consistently favouring MI-ET group. COI: (1-year-time-frame): MI-ET 67382 SD (43107) Swiss-Francs and LI-CT 95701(29473) Swiss-Francs. CONCLUSION: The study is feasible with modifications. Future studies should compare high-intensity versus moderate-intensity aerobic-exercise combined with higher dosage arm-training.

In Haus- und Gebäudeinstallationen werden Kompensatoren und Wellschläuche als flexibles Verbindungsstück zwischen Rohrleitungen eingesetzt. Ihre Hauptaufgabe besteht in der Ableitung auftretender Kräfte, die beispielsweise durch thermische Ausdehnung und Versatz hervorgerufen werden. Somit besitzen sie eine sicherheits- und funktionsrelevante Bedeutung. Für einen effizienten und sicheren Anlagenbetrieb sind zur Umsetzung einer zustandsabhängigen Instandhaltungsstrategie Kenntnisse über das Degradationsverhalten eines Kompensators notwendig, um frühzeitig mögliche Schadensereignisse zu erkennen. Innerhalb eines Forschungsprojekts wurden messtechnische Charakteristiken hypothetischer Degradationszustände mit dem Ziel untersucht, ein Konzept für eine Systemdiagnose zu entwickeln.

To evaluate whether same-day discharge increased the incidence of 30-day readmission (30dR) after conventional transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) at a single institution.In this retrospective study, 253 patients with HCC underwent 521 transarterial chemoembolization procedures between 2013 and 2020. TACE was performed with 50-mg doxorubicin/10-mg mitomycin C/5-10-mL ethiodized oil/particles. Patients not requiring intravenous pain medications were discharged after a 3-hour observation, and 30dR was tracked. The primary objective was to determine the incidence of 30dR in same-day discharge patients versus patients admitted for observation using the chi-square test. Secondary objectives assessed factors associated with overnight admission and factors predictive of 30dR using generalized estimated equation calculations and logistic regression.In the cohort, 24 readmissions occurred within 30 days (4.6%). Same-day discharge was completed after 331 TACE procedures with sixteen 30dRs (4.8%). Patients admitted overnight were readmitted 8 times after 190 TACE procedures (4.2%). This difference was not statistically significant (P = .4). Factors predicting overnight admission included female sex (58/190 [30.5%] vs 58/331 [17.5%], P.001) and tumor size of ≥3.8 cm (104/190 [55%] vs 85/190 [45%]). Factors predicting 30dR included female sex (10/116 [8.6%] vs 14/405 [0.2%]) and younger age (median [interquartile range], 63 years [55-65 years] vs 65 years [59-71 years]). At regression, factors predictive of 30dR were Child-Pugh Class B/C (odds ratio [OR], 2.1; P = .04) and female sex (OR, 2.9; P = .004).Same-day discharge after conventional TACE is a safe and effective strategy with 30dR rate of5%, similar to overnight observation.

Preeclampsia (PE) is characterized by placental and maternal endothelial dysfunction, and associated with fetal growth restriction (FGR), placental abruption, preterm delivery and stillbirth. The angiogenic factors soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by placental-related disorders. In this review, we summarize existing literature examining the performance of maternal PlGF, sFlt-1 and sFlt-1/PlGF ratio for a) screening and diagnosing PE, b) predicting PE development in the short term, c) monitoring established PE and d) predicting other placental-related disorders. We also discuss the performance of PlGF and the sFlt-1/PlGF ratio for predicting PE in twin pregnancies. For first trimester screening, a more accurate way of identifying high-risk women than current practices is to combine PlGF levels with clinical risk factors and ultrasound markers. To support diagnosis of PE later in pregnancy, the sFlt-1/PlGF ratio has advantages over PlGF because it has a higher pooled sensitivity and specificity for diagnosing and monitoring PE. The sFlt-1/PlGF ratio has clinical value because it can rule out the development of PE in the subsequent 1-4 weeks after the test. Once diagnosis of PE is established, repeated measurement of sFlt-1 and PlGF can help monitor progression of the condition and may inform clinical decision-making around optimal time for delivery. The sFlt-1/PlGF ratio is useful for predicting FGR and preterm delivery, but the association between stillbirth and the angiogenic factors remains unclear. The sFlt-1/PlGF ratio can also be used to predict PE in twin pregnancies, although different sFlt-1/PlGF ratio cut-offs to those of singleton pregnancies should be applied for optimal performance. In summary, PlGF, sFlt-1 and the sFlt-1/PlGF ratio are useful for screening, diagnosing, predicting, and monitoring placental-related disorders in singleton and twin pregnancies; we propose further integration of these angiogenic factor tests in clinical practice. This article is protected by copyright. All rights reserved.

The concept of a “speciation continuum” has gained popularity in recent decades. It emphasizes speciation as a continuous process that may be studied by comparing contemporary population pairs that show differing levels of divergence. In their recent perspective article in Evolution, Stankowski and Ravinet provided a valuable service by formally defining the speciation continuum as a continuum of reproductive isolation, based on opinions gathered from a survey of speciation researchers. While we agree that the speciation continuum has been a useful concept to advance the understanding of the speciation process, some intrinsic limitations exist. Here, we advocate for a multivariate extension, the speciation hypercube, first proposed by Dieckmann et al. in 2004, but rarely used since. We extend the idea of the speciation cube and suggest it has strong conceptual and practical advantages over a one-dimensional model. We illustrate how the speciation hypercube can be used to visualize and compare different speciation trajectories, providing new insights into the processes and mechanisms of speciation. A key strength of the speciation hypercube is that it provides a unifying framework for speciation research, as it allows questions from apparently disparate subfields to be addressed in a single conceptual model.

The first transcriptional pathway regulating βIV-spectrin expression, a key angiogenic regulator of sprouting angiogenesis, is identified.

Availability and accessibility are important preconditions for using real-world patient data across organizations. To facilitate and enable the analysis of data collected at a large number of independent healthcare providers, syntactic- and semantic uniformity need to be achieved and verified. With this paper, we present a data transfer process implemented using the Data Sharing Framework to ensure only valid and pseudonymized data is transferred to a central research repository and feedback on success or failure is provided. Our implementation is used within the CODEX project of the German Network University Medicine to validate COVID-19 datasets at patient enrolling organizations and securely transfer them as FHIR resources to a central repository.

AimsOncological patients suspected to have the risk for cardiotoxicity, are recommended to be under intensified cardiological surveillance. We aimed to investigate the value of cardiac biomarker and patient-related risk factors (age, cardiovascular risk factors (CRF), cardiac function) for the prediction of all-cause mortality (ACM) and development of cardiotoxicity.MethodsBetween 01/2016 to 12/2020, patients with oncological diseases, admitted to the cardio-oncology unit at the University Hospital Heidelberg were included. They were examined by medical history, physical examination, 12-lead-ECG, 2D-echocardiography and cardiac biomarkers (high sensitive Troponin T (hs-cTnT); N-terminal brain natriuretic peptide (NT-proBNP)). Primary endpoint was defined as ACM, secondary endpoint was defined as cardiotoxicity as defined by the European Society of Cardiology.ResultsFrom 1971 included patients, primary endpoint was reached by 490 patients (25.7%) with a median of 363.5 [IQR 121.8, 522.5] days after presentation. Hs-cTnT of ≥7 ng/L (OR 1.82, p < 0.001) and NT-proBNP (OR 1.98, p < 0.001) were independent predictors of ACM, while reduced LVEF was not associated with increased ACM (p=0.85). Secondary endpoint was reached by 182 patients (9.2%) within a median of 793.5 days [IQR 411.2, 1165.0]. Patients with multiple CRF (defined as high-risk, n=886) had an increased risk for cardiotoxicity (n=100/886, 11.3%; HR 1.57, p=0.004). They showed increased baseline values of hs-cTnT (OR 1.60; p=0.006) and NT-proBNP (OR 4.00, pConclusionsIn cancer patients, accumulation of CRF predetermines cardiotoxicity while increased hs-cTnT levels and NT-proBNP associate with ACM. Therefore, less intense surveillance protocols might be justified in patients with low values of cardiac biomarker and absence of CRF.

Objectives: To determine the cardiovascular risk burden rehabilitation discharge, and explore the association between recovery during rehabilitation and CVD-risk profile. Methods: We included adults without CVD history admitted for rehabilitation. We evaluated rehabilitation outcomes on admission and discharge. CVD-risk was assessed by Framingham risk score (FRS), high-density lipoprotein (HDL), and fasting glucose level. Results: We analyzed data from 706 participants (69.55% men) with median age of 53.5 years. The median time-since-injury was 14 days and the admission length was 5.2 months. Majority had paraplegia (53.26%), and motor incomplete injury (53.68%). One-third of the cohort had high cardiovascular risk profile pre-discharge. At discharge, poorer anthropometric measures were associated with higher FRS and lower HDL levels. Individuals with higher forced vital capacity (>2.72 L) and peak expiratory flow (>3.4 L/min) had 0.16 mmol/L and 0.14 mmol/L higher HDL compared to those with lower respiratory function, respectively. Individuals with higher mobility score (>12.5) and functional independence score (>74) had 0.21 mmol/L and 0.18 mmol/L higher HDL compared to those with lower scores. Conclusion: There is high cardiometabolic syndrome burden and CVD-risk upon rehabilitation discharge. Higher respiratory function, mobility, and overall independence were associated with better CVD profile, although with study design limitations and short follow-up. Future studies should explore whether rehabilitation outcomes could be used to prioritize screening., + ID der Publikation: unilu_68449 + Sprache: Englisch + Letzte Aktualisierung: 2023-06-30 11:55:35

Maintenance of sufficient healthy green leaf area after anthesis is key to ensuring an adequate assimilate supply for grain filling. Tightly regulated age-related physiological senescence and various biotic and abiotic stressors drive overall greenness decay dynamics under field conditions. Besides direct effects on green leaf area in terms of leaf damage, stressors often anticipate or accelerate physiological senescence, which may multiply their negative impact on grain filling. Here, we present an image processing methodology that enables the monitoring of chlorosis and necrosis separately for ears and shoots (stems + leaves) based on deep learning models for semantic segmentation and color properties of vegetation. A vegetation segmentation model was trained using semi-synthetic training data generated using image composition and generative adversarial neural networks, which greatly reduced the risk of annotation uncertainties and annotation effort. Application of the models to image time-series revealed temporal patterns of greenness decay as well as the relative contributions of chlorosis and necrosis. Image-based estimation of greenness decay dynamics was highly correlated with scoring-based estimations (r ≈ 0.9). Contrasting patterns were observed for plots with different levels of foliar diseases, particularly septoria tritici blotch. Our results suggest that tracking the chlorotic and necrotic fractions separately may enable (i) a separate quantification of the contribution of biotic stress and physiological senescence on overall green leaf area dynamics and (ii) investigation of the elusive interaction between biotic stress and physiological senescence. The potentially high-throughput nature of our methodology paves the way to conducting genetic studies of disease resistance and tolerance.

The availability of high-throughput molecular diagnostics builds the foundation for Molecular Tumor Boards (MTBs). Although more fine-grained data is expected to support decision making of oncologists, assessment of data is complex and time-consuming slowing down the implementation of MTBs, e.g., due to retrieval of the latest medical publications, assessment of clinical evidence, or linkage to the latest clinical guidelines. We share our findings from analysis of existing tumor board processes and defininion of clinical processes for the adoption of MTBs. Building on our findings, we have developed a real-world software prototype together with oncologists and medical professionals, which supports the preparation and conduct of MTBs and enables collaboration between medical experts by sharing medical knowledge even across the hospital locations. We worked in interdisciplinary teams of clinicians, oncologists, medical experts, medical informaticians, and software engineers using design thinking methodology. With their input, we identified challenges and limitations of the current MTB approaches, derived clinical process models using Business Process and Modeling Notation (BMPN), and defined personas, functional and non-functional requirements for software tool support. Based on it, we developed software prototypes and evaluated them with clinical experts from major university hospitals across Germany. We extended the Kanban methodology enabling holistic tracking of patient cases from “backlog” to “follow-up” in our app. The feedback from interviewed medical professionals showed that our clinical process models and software prototype provide suitable process support for the preparation and conduction of molecular tumor boards. The combination of oncology knowledge across hospitals and the documentation of treatment decision can be used to form a unique medical knowledge base by oncologists for oncologists. Due to the high heterogeneity of tumor diseases and the spread of the latest medical knowledge, a cooperative decision-making process including insights from similar patient cases was considered as a very valuable feature. The ability to transform prepared case data into a screen presentation was recognized as an essential feature speeding up the preparation process. Oncologists require special software tool support to incorporate and assess molecular data for the decision-making process. In particular, the need for linkage to the latest medical knowledge, clinical evidence, and collaborative tools to discuss individual cases were named to be of importance. With the experiences from the COVID-19 pandemic, the acceptance of online tools and collaborative working is expected to grow. Our virtual multi-site approach proved to allow a collaborative decision-making process for the first time, which we consider to have a positive impact on the overall treatment quality.

Switzerland is a global hotspot in dairy production and has above-average values of per-capita meat consumption. Its livestock production causes high environmental costs and is highly depending on concentrated feed imports. At the same time, the local grain legume production is negligible and diets of Swiss population become more and more plant-based. The consumption of legume protein has two main advantages over meat protein: legume-based protein has a lower environmental footprint due to biological nitrogen fixation and it has a healthy composition. This study evaluates the potential of grain legumes to diversify agricultural products while increasing sustainable food production and self-sufficiency. Especially peas and faba beans show potential for the Swiss agriculture but require adaptions in policy, pricing and breeding based on a qualitative assessment of expert opinions. A quantitative analysis using Geographic Information system (GIS) showed that when only suitable arable land (Scenario I) is used for grain legume production, more than 100% of Switzerland's meat protein consumption could be covered by legume-based proteins. Converting suitable meadows into additional arable land for legume production (Scenario II) would further increase this potential: 180% of the currently consumed meat protein could be generated. The increase in legume area could be compensated by forage area, i.e., leys and silage maize. Replacing 632,500 t of concentrated feed import additionally, the current monogastric and ruminant production would decrase by 31 and 39%, respectively. The ramped up production of legume protein (175,630 t) could replace the decrease in animal-based proteins (from milk and meat) and substantially increase self-sufficiency of Swiss agriculture. Increasing legume production is one promising path for Swiss agriculture toward more sustainability allowing to decrease environmental costs, such as greenhouse gas (GHG) emissions, nitrogen pollution, and pressure on deforestation through soybean import. To stimulate legume production, not only policy needs to increase support, but also the supply chain of the agricultural and food industry are to be built up in parallel. Besides that, the agricultural management of legume production needs to be improved and new varieties adapted to current and future requirements are to be developed.

Objectives To describe the concept, establishment and the operationalization of the biobank of the Swiss Spinal Cord Injury Cohort Study (SwiSCI), the available biosamples, and demographic and clinical characteristics of study participants. Setting: The SwiSCI biobank is a platform for research within SwiSCI. It collects and processes serum, plasma, PBMCs, RNA, DNA, and urine from three rehabilitation centers. Samples are collected at admission to first rehabilitation and at discharge. Additionly, the biobank provides services to projects nested in SwiSCI or otherclinical trials among Spinal Cord Injury population. Methods Descriptive statistics were used for an overview of available biosamples, study participant characteristics, and comparison of the participating centers. Results Since the biobank establishment 232 (49.5%) individuals agreed to provide biosamples. As of 22nd March 2022, 217 SCI individuals went through first inpatient rehabilitation. Among these, the mean age of study participants was 50.74 (± 17.1) years old, the majority were male (78.34%) with traumatic injury (65.44%) and paraplegic (56.22%), 47.93% with motor-complete injury. The median SCIM score was 29 (IQR 19–49). The percentage of individuals with paired samples at both time points (beginning and end of rehabilitation) ranged from 63.59% (for RNA) to 68.66% (for urine and urine sediment). Conclusions The SwiSCI Biobank is a unique platform designed to serve as a basis for collaborative SCI research, including multi-omics approaches. Longitudinality of biosamples collection and cryopreservation of multiple aliquots per individual are key for studying temporality of associations, assuring reproducibility of research and acheiving adequate sample size.

Background Comorbidities are expected to impact pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model multiple comorbidities to help to improve our understanding of HFpEF. Methods We retrospectively explored 569 comorbidities documented in 29,074 HF patients, including 8,062 HFpEF and 6,585 heart failure with reduced ejection fraction (HFrEF) patients from a German university hospital. To analyze comorbidity profiles, first we assessed differences between comorbidity profiles by HF subtype. We fit machine learning classifiers to discriminate between HFpEF and HFrEF patients to interpret important comorbidities. Then we built a network to represent comorbid relationships in HF patients (HFnet) and identified main disease clusters. Lastly, we performed novel gene candidate prediction for HFpEF by linking the HFnet to a multi-layer gene network by integrating multiple databases (HFhetnet). To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature. Results We found that comorbidity profiles vary more in association with HFpEF/HFrEF status than with age or sex. The comorbidities present in HFpEF patients were more diverse than those in HFrEF, and included neoplastic, osteologic and rheumatoid disorders, among others. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups and sex. Within the HFhetnet, we predicted novel gene candidates, including genes involved in fibrosis (COL3A1, MMP1, LOX), oxidative stress (NOS1, GSST1, XDH) and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature. Conclusion We applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data will provide insights that may be leveraged to improve diagnosis and treatment for HFpEF patients.

Der Informationsfluss in der Medizin wächst ebenso rasant wie Erkenntnisse aus neuesten wissenschaftlichen Publikationen. Neben den klassischen Informationsquellen stehen elektronische Ressourcen zur Verfügung, die allerorts schnellen Zugriff auf neuestes Wissen erlauben. Offen bleiben folgende Fragen: Wie bringen Fachleute aus Gesundheitsprofessionen sich auf den neuesten Wissensstand? Wie gelangt relevantes Wissen in die Praxis? Die vorliegende Befragung untersucht, welche Informationsquellen medizinische Fachpersonen hauptsächlich nutzen, um sich auf dem aktuellen Forschungsstand zu halten.

Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.

Background Thyroid dysfunction has a strong association with cardiac arrhythmias. However, subclinical hypothyroidism (SH) is often neglected in studies. SH is characterized by increased values of TSH and normal values of T3/T4. Recent studies indicate that high TSH levels are related to an increased incidence of cardiac electrical abnormalities, especially atrial fibrillation (AF). Purpose The present work aims to investigate direct effects of TSH on ion channel remodelling in cardiomyocytes and a possible causative role in the increased occurrence of arrhythmia in SH. Methods A retrospective monocentric study analysed medical records, ECGs and echocardiographies of 3134 patients between 2007 to 2020. Inclusion criteria comprised patient age ≥18 years, normal fT4, TSH values 4–75 mU/l and available ECGs. The patient cohort was divided into two groups based on current treatment recommendations for SH (TSH level 4–9.9 mU/l; 10–75 mU/l). Direct effects on ion channel remodelling were analysed in HL-1 and neonatal cardiomyocytes with confirmed expression of TSH receptors. TSH concentrations of 15, 30, and 60 mU/l simulated different degrees of hypothyroidism. RT-qPCR analyses, western blots and immunofluorescence stainings were performed after incubation with respective TSH concentrations for 24h. In vitro video analyses of automatism in NRCM before and after TSH incubation were performed. Statistical comparisons were calculated using student's t-tests and the chi-square test. In addition, a multivariate analysis of factors affecting the occurrence of AF in patients with SH was carried out. Results Elevated TSH levels were associated with higher prevalence of AF. In the group of patients with a TSH value of 10–75 mU/l, AF was observed in 42.8% of cases compared to 31.7% in patients with lower TSH levels (p Conclusion The prevalence of atrial fibrillation is significantly increased in patients with SH. Our findings further reveal a direct effect of TSH on ion channel expression in cardiomyocytes as potential proarrhythmic mechanism. TSH induced changes in the expression of ion channels that determine action potential duration. Subclinical hypothyroidism contributes to the development of atrial fibrillation. Underlying mechanisms and therapeutic implications require further research. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Heidelberg University Medical School - Olympia Morata

Background Mechanical arterial recanalization is increasingly used to treat acute ischemic stroke. Known to inflict vascular injury, it might affect pro-thrombotic character and healing patterns. Stent-retriever thrombectomy (SR) and direct aspiration (DA) are both used for acute recanalization and not only lead to endothelial denudation, but also to platelet activation and local formation of microthrombi, potentially adding to the risk of distal embolization. Purpose We aimed to quantify and characterize endovascular damage, microthrombus formation, and vascular healing following SR and DA in a swine model of arterial thrombo-embolic occlusion. Methods Aged autologous thrombi, created under flow, were used to occlude swine extracranial arteries for two hours to mimic a thrombo-embolic occlusion. Arteries were randomized to SR, DA, or control (C). Injury was assessed acutely (SR n=8; DA n=7; C n=4), and at 3 days follow-up (SR n=8; DA n=7; C n=4) using Evans Blue (EB) dye-exclusion-testing to quantify injury, expressed as %EB-area in the treated area. Scanning electron microscopy (SEM) was used to characterize vascular injury and presence of microthrombi ( Results Regression analysis for EB-area (ANOVA p Conclusions Stent-retrievers induce more endothelial damage than direct aspiration. Both treatments yield microthrombi, platelet activation and leukocyte adhesion. After three days, the endothelium is significantly, but only partially recovered. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): We acknowledge the support of the Netherlands Cardiovascular Research Initiative which is supported by the Dutch Heart Foundation (CVON2015-01: CONTRAST), the support of the Brain Foundation Netherlands (HA2015.01.06), and the support of Health∼Holland, Top Sector Life Sciences & Health (LSHM17016), Stryker, Medtronic and Cerenovus. The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships.

Objective To evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI). Methods A prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding. Results Infants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89). Conclusions Use of SRIs among pregnant women on MOUD might be associated with more severe NOWS. Impact A potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders.

Our earlier in vitro and in vivo studies have revealed that the phytosterol, pentalinonsterol (cholest-4,20,24-trien-3-one) (PEN), isolated from the roots of Pentalinon andrieuxii, possesss immunomodulatory properties in macrophages and dendritic cells. Leishmaniasis, caused by the infection of Leishmania spp. (a protozoan parasite), is emerging as the second-leading cause of mortality among the tropical diseases and there is an unmet need for a pharmacological intervention of leishmaniasis. Given the beneficial immunomodulatory actions and lipophilic properties of PEN, the objective of this study was to elucidate the mechanism(s) of action of the immunomodulatory action(s) of PEN in macrophages through the modulation of phospholipase A2 (PLA2) activity that might be crucial in the antileishmanial action of PEN. Therefore, in this study, we investigated whether PEN would modulate the activity of PLA2 in RAW 264.7 macrophages and mouse bone marrow-derived primary macrophages (BMDMs) in vitro and further determined how the upstream PLA2 activation would regulate the downstream cytokine release in the macrophages. Our current results demonstrated that (i) PEN induced PLA2 activation (arachidonic acid release) in a dose- and time-dependent manner that was regulated upstream by the mitogen-activated protein kinases (MAPKs); (ii) the PEN-induced activation of PLA2 was attenuated by the cPLA2-specific pharmacological inhibitors; and (iii) the cPLA2-specific pharmacological inhibitors attenuated the release of inflammatory cytokines from the macrophages. For the first time, our current study demonstrated that PEN exhibited its immunomodulatory actions through the activation of cPLA2 in the macrophages, which potentially could be used in the development of a pharmacological intervention against leishmaniasis.

Asthma is a heterogeneous pulmonary disease that has constantly increased in prevalence over the past several decades. Primary symptoms include airway constriction, airway hyperresponsiveness, and airway remodeling with additional symptoms such as shortness of breath, wheezing, and difficulty breathing. Allergic asthma involves chronic inflammation of the lungs, and the rise in its yearly diagnosis is potentially associated with the increased global consumption of foods similar to the western diet. Thus, there is growing interest into the link between diet and asthma symptoms, with mounting evidence for an important modulatory role for dietary lipids. Lipids can act as biological mediators in both a proinflammatory and proresolution capacity. Fatty acids play key roles in signaling and in the production of mediators in the allergic and inflammatory pathways. The western diet leads to a disproportionate ω-6:ω-3 ratio, with drastically increased ω-6 levels. To counteract this, consumption of fish and fish oil and the use of dietary oils with anti-inflammatory properties such as olive and sesame oil can increase ω-3 and decrease ω-6 levels. Increasing vitamin intake, lowering LDL cholesterol levels, and limiting consumption of oxidized lipids can help reduce the risk of asthma and the exacerbation of asthmatic symptoms. These dietary changes can be achieved by increasing intake of fruits, vegetables, nuts, oily fish, seeds, animal-related foods (eggs, liver), cheeses, grains, oats, and seeds, and decreasing consumption of fried foods (especially fried in reused oils), fast foods, and heavily processed foods.

Rationale: Coronary artery disease (CAD) is a pervasive and critical health care problem. Elevated high-density lipoprotein-associated cholesterol (HDL-C) is associated with improved atherosclerotic cardiovascular disease outcomes on a population level, but clinical trials aimed at HDL-C elevation have not succeeded in improving atherosclerotic cardiovascular disease event risk. Nevertheless, human variants in the HDL receptor, encoded by SCARB1 , are associated with dyslipidemia, suggesting that HDL metabolism, not HDL-C, is a suitable target for therapy. However, variants in SCARB1 have never been directly attributed to CAD by Mendelian inheritance. Objective: To determine if compound heterozygous variants in SCARB1 cause disease in 2 brothers with severe, early-onset CAD. Methods and Results: Using whole exome sequencing, we have identified rare, compound heterozygous variants in SCARB1 that segregate with severe, premature CAD, following patterns of Mendelian inheritance. Using induced pluripotent stem cell–derived hepatocyte-like cells from the proband, we discovered the maternal variant (c.754_755delinsC) to be the first identified SCARB1 null allele, characterized by the absence of RNA and protein expression. Further, we demonstrate that the variant on the paternal allele (c.956G>T [p.G319V]) results in decreased cholesterol uptake, decreased SR-BI:HDL binding, and increased affinity for SR-BI dimerization. Finally, we generated a p.G319V knock-in mouse model that displays nearly 100% homozygous lethality and elevated plasma cholesterol in heterozygous animals, confirming pathogenicity of this variant. Conclusions: In summary, our data provide the first molecular mechanism to show the Mendelian inheritance of CAD as a result of human SCARB1 variants. The rarity of these variants supports pathogenicity in this family. Furthermore, SR-BI p.G319V, which has previously been reported benign in the context of heterozygosity, was uniquely presented alongside a null allele, demonstrating the disease-contributing capability of loss-of-function SCARB1 variants within the population.

The integration of routine medical care data into research endeavors promises great value. However, access to this extra-domain data is constrained by numerous technical and legal requirements. The German Medical Informatics Initiative (MII) - initiated by the Federal Ministry of Research and Education (BMBF) - is making progress in setting up Medical Data Integration Centers to consolidate data stored in clinical primary information systems. Unfortunately, for many research questions cross-organizational data sources are required, as one organization's data is insufficient, especially in rare disease research. A first step, for research projects exploring possible multi-centric study designs, is to perform a feasibility query, i.e., a cohort size calculation transcending organizational boundaries. Existing solutions for this problem, like the previously introduced feasibility process for the MII's HiGHmed consortium, perform well for most use cases. However, there exist use cases where neither centralized data repositories, nor Trusted Third Parties are acceptable for data aggregation. Based on open standards, such as BPMN 2.0 and HL7 FHIR R4, as well as the cryptographic techniques of secure Multi-Party Computation, we introduce a fully automated, decentral feasibility query process without any central component or Trusted Third Party. The open source implementation of the proposed solution is intended as a plugin process to the HiGHmed Data Sharing Framework. The process's concept and underlying algorithms can also be used independently.

Crop breeders increasingly need to mitigate the effects of climate change. Ideally, their selection strategies are based on an understanding of crop responses to environmental covariates such as temperature. In this study, the height of 352 varieties (European and Swiss) was repeatedly measured in multiple years. P-splines were used to model plant height as a function of time, from which the phenology parameters jointing (start) and end of stem elongation were derived. An asymptotic model was used to estimate the base-temperature of growth (Tmin), the steepness of the response (lrc), and the growth at optimum temperature (rmax). Parameter rmax had the largest effect on final height, whereas the temperature-response parameters in the narrow sense (Tmin, lrc) were closely connected to phenology. Final height and rmax decreased from the more continental, eastern European countries towards the more maritime, western countries. For genotypes registered in Great Bitain, Tmin was distinctly lower compared to most other regions. Integrating such analysis of in-season responsiveness to fluctuating environmental conditions in breeding will help to improve the genetic gain for climate adaptation. It can only be achieved based on high-throughput assessment of phenotypes in the field throughout the season.HighlightWheat phenology and environmental responses have been affected by breeders’ selections since 1970. High throughput field phenotyping methods reveal these developments, allowing to better adapt future varieties to climate change.

Background The Federal Ministry of Education and Research (BMBF) funds a network of university medicines (NUM) to support COVID-19 and pandemic research at national level. The “COVID-19 Data Exchange Platform” (CODEX) as part of NUM establishes a harmonised infrastructure that supports decentral but standardised provision as well as federated combination and research use of COVID-19 datasets. The broad consent (BC) of the Medical Informatics Initiative (MII) is agreed by all German federal states and forms the legal base for such data processing. All 34 participating university hospitals (NUM sites) work upon a harmonised infrastructural as well as legal basis for their data protection-compliant collection and transfer of their research dataset to the central CODEX platform. Each NUM site ensures that the exchanged consent information conforms to the already-balloted HL7® FHIR® consent profiles and the interoperability concept of the MII Task Force “Consent Implementation” (TFCI). The Independent Trusted Third-Party (TTP) of the University Medicine Greifswald successfully supports data protection-compliant data processing in various research projects since 2014 and provides the consent management solutions gICS®, which supports fully digital and paper-based consent management. Results A “TTP-FHIR Gateway” for the HL7® FHIR®-compliant exchange of consent information using gICS® throughout NUM-CODEX was implemented and provided to all NUM sites in June 2021 as a separate software component. The gateway relies on the gICS® application logic. All FHIR® functionalities comply with the already-balloted FHIR® consent profiles of the HL7® Working Group Consent Management. A pre-configured consent template for the BC is provided to all NUM sites, thereby simplifying the technical BC rollout and the corresponding implementation of the TFCI interoperability concept at the NUM sites. Conclusions This article proves that a HL7® FHIR®-compliant and interoperable nationwide exchange of consent information could be built using of the consent management software gICS® and the provided TTP-FHIR Gateway. The initial functional scope of the solution covers the requirements identified in the NUM-CODEX setting. The semantic correctness of these functionalities was validated by project-partners from the Ludwig-Maximilian University in Munich. The production rollout of the solution package to all NUM sites has started successfully.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (

One goal of this study was to test the role of emotion knowledge and teacher-child closeness and conflict in predicting academic readiness for kindergarten over and above demographic factors and executive functioning skills (especially inhibitory control) known to predict readiness. Another goal was to test teacher-child closeness as a moderator of the association between emotion knowledge or executive functioning and academic readiness. A total of 141 4- and 5-year-old children completed emotion knowledge, academic readiness, and inhibitory control measures. Preschool teachers reported their perceived relationship closeness and conflict with individual students. Accounting for child age in months, family income, and inhibitory control, emotion knowledge and teacher-child closeness were positively associated with academic readiness. Teacher-child closeness moderated the relationship between emotion knowledge and academic readiness, suggesting that teacher-child closeness may be especially important in promoting academic readiness for preschool students with low emotion knowledge.

Avian incubation is a highly complex, adjustable behavior essential to embryo development and survival. When incubating, parents face a tradeoff between investing in incubation to maintain optimal temperatures for egg development or in self-maintenance behaviors to ensure their own survival and future reproduction. Because nest ectoparasites are costly and can reduce nestling quality and survival, infections could shift parental investment in current vs. future offspring. However, it is not well understood whether birds change investment in incubation in response to nest ectoparasitism, particularly in the context of other factors that are known to influence incubation behavior, such as ambient temperature, clutch size, and embryo development. We hypothesized that parents could respond to nest parasites by 1) investing more in incubation to promote the development of high-quality offspring to help offset the cost of parasites, 2) investing less in incubation or even abandoning their nest during incubation to save resources for future reproduction, or 3) being unresponsive to parasite infections, as incubation is more constrained by other factors. We tested these hypotheses by experimentally removing and adding mites in barn swallow nests at the start of incubation and deploying thermocouple eggs to measure egg temperatures at one-minute intervals until hatching. We found that while ambient temperature, clutch initiation date, embryo age, and clutch size were the main factors driving variation in egg conditions and parental incubation behavior, parasitized nests had higher mean egg temperatures, which could aid in nestling immune development. However, despite more optimal developmental temperatures, eggs in parasitized nests also had lower hatching success. Our results indicate that incubation is a dynamic behavior that is largely driven by the constraints of maintaining appropriate egg temperatures for development. Although quite costly upon hatching, ectoparasites appear to play a relatively minor role in driving variation in parental incubation investment.LAY SUMMARYIncubation is a complex behavior shaped by both internal and external factors.Ectoparasites often decrease quality and survival of nestlings and could influence investment in incubation because of tradeoffs in how parents spend energy.We manipulated parasites in barn swallow nests and used fake eggs with temperature sensors to collect data on egg temperatures and parental behavior throughout incubation.We found that other factors were the main drivers of variation in incubation behavior, but that eggs in parasite nests were warmer on average, which could help nestlings better cope with parasites upon hatching.Despite more optimal developmental temperatures, eggs in parasitized nests had lower hatching success.Although quite costly to nestlings, ectoparasites played a minor role in shaping parental incubation behavior.

BackgroundThere are a growing number of evidence-based interventions (EBIs) for autistic individuals, but few are successfully implemented with fidelity in under-resourced communities and with families from traditionally disenfranchised groups. Implementation science offers tools to increase EBI use in communities, but most implementation strategies are designed specific to a single EBI. It is not feasible to develop a new implementation strategy each time a new EBI is introduced in the community. Therefore, to test the effectiveness and generalizability of implementation strategies we are developing and testing a multifaceted implementation strategy with three EBIs concurrently. The goal of this protocol paper is to describe the randomized field trial of an implementation strategy for use across autism EBIs, diverse settings and participants, with the goal of increasing rapid uptake of effective practices to reach our most vulnerable children.MethodsWe developed a multifaceted implementation strategy called Using Novel Implementation Tools for Evidence-based intervention Delivery (UNITED) to facilitate the implementation and sustainment of three EBIs in under-resourced settings. We will compare fidelity to, and effectiveness of, each intervention [Mind the Gap (MTG), Remaking Recess (RR), Self-Determined Learning Model of Instruction (SDLMI)] with and without UNITED in a randomized field trial. Randomization will be stratified using a minimization allocation method. We will train community practitioners using remote delivery of modules specific to the intervention, and active coaching via Zoom for at least 6 sessions and up to 12 as dictated by each EBI. Our primary outcome is fidelity to each EBI, and our secondary outcome is at the child or family level (family empowerment for MTG, child peer social engagement for RR, and adolescent self-determination for SDLMI, respectively). We will measure progress through the implementation phases using the Stages of Implementation Completion and cost-effectiveness of UNITED.DiscussionThe results of this study will provide rigorous data on the effectiveness and generalizability of one relatively light-touch implementation strategy in increasing use of autism EBIs and associated outcomes in diverse under resourced public service settings for underrepresented autistic youth.Trial registrationMind the Gap: Clinicaltrials.gov Identifier: NCT04972825 (Date registered July 22, 2021); Remaking Recess:Clinicaltrials.gov Identifier: NCT04972838 (Date registered July 22, 2021); Self-Determined Learning Model of Instruction:Clinicaltrials.gov Identifier: NCT04972851 (Date registered July 22, 2021).

There are currently few suitable test systems for the chronic toxicity testing of aquatic macroinvertebrates under stream conditions. Therefore, a new test system mimicking running water conditions was developed for testing with lotic insects. This system uses small test cages, with 10 of these suspended inside each 25-L container and rotating at 0.1 m/s, to create a water flow for the individual organism inside each cage. To test the performance of the new exposure system, chronic effects (21 d) of the neonicotinoid imidacloprid were investigated with field-collected larvae of the stonefly Protonemura sp. Endpoints were survival, growth, and/or emergence (depending on the developmental stage of the larvae at the start of the exposure). Two experiments conducted 1 yr apart showed good reproducibility: growth 10% effect concentration (EC10) values were 15.3 and 18.5 mg/L and no-observed-effect concentration (NOEC) values were 30.3 and 21.5 mg/L. A third experiment, performed with further-developed larval instars, showed a significant effect of imidacloprid on emergence (with EC10 of 5.97 mg/L and NOEC of 2.89 mg/L) and a significant effect on survival (with median lethal concentration of 44.7 µg/L). The results of the present study show that the newly developed test system provides a suitable approach for toxicity testing with stonefly larvae and potentially for other lotic macroinvertebrate species. Environ Toxicol Chem 2021;40:2229-2239. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

We investigate the effects of opioid abuse on municipal finance. We employ instrumental variables, border discontinuity difference-in-differences regressions, and coarsened exact matching to identify consistent causal effects, while controlling for variation in economic conditions and demographics. Opioid abuse lowers credit ratings, increases new offer yields, and reduces bond issuance. Reversal of these effects following effective antiopioid legislation further supports causality. Differential effects due to investor heterogeneity suggest that opioid abuse affects municipal finance through a capital supply channel. Overall, we conclude that local opioid abuse impedes municipalities’ access to capital and thus hurts their ability to provide public services and infrastructure.

Tumor heterogeneity may impact immunohistochemical (IHC) interpretation, thus potentially affecting decision making by treating oncologists for cancer patient management. Programmed cell death ligand-1 (PD-L1) IHC 22C3 pharmDx is a companion diagnostic used as an aid in identifying patient eligibility for treatment with pembrolizumab (KEYTRUDA). This study aims to investigate tumor heterogeneity impact on IHC staining when evaluating PD-L1 expression using PD-L1 IHC 22C3 pharmDx. The effect of tumor heterogeneity was evaluated based on the PD-L1 diagnostic status of PD-L1 IHC 22C3 pharmDx stained tumor tissue sections at relevant diagnostic cutoffs for non-small cell lung carcinoma, gastric or gastroesophageal junction adenocarcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, esophageal cancer and triple negative breast cancer. Overall agreement for the PD-L1 diagnostic status was assessed for each tumor type within a given specimen block (Intra-Block), between specimen blocks from the same surgical resection (Intra-Case), and between intrapatient primary and metastatic specimens. Intrablock and intracase point estimates were above 75%, and primary versus metastatic point estimates were above 50%. The results suggest that PD-L1 expression is consistent across cut sections through a minimum of 150 µm within a tissue block and between blocks from the same surgical resection and is significantly maintained across primary and metastatic blocks from the same patient despite changes to the tissue microenvironment. These data provide confidence for histopathologists and oncologists that evaluation of PD-L1 expression at clinically relevant cutoffs is reproducible among different assessments (or samplings) of a single tumor specimen.

A common belief among students is that computing is a boring subject that lacks a connection to the real world. The first class (one 80-minute session) in an introductory computer science course may be an appropriate instance to combat such a belief. Previous studies have used coursewide interventions, e.g., games and physical/tangible devices to improve students’ motivation. However, although other approaches help motivate students, they may lack real-world context or have a high cost of deployment. This article proposes a novel real-world based approach to introduce programming concepts in the first class of the introductory computer science course. This approach, called Protobject based, is applicable to courses with over 100 students, has a low deployment entry barrier, requires low investment, and may be used creatively to implement different experiences. Furthermore, the Protobject-based approach has an equivalent motivational effect—at least in the short-term—to a Game-based approach even if it is entirely focused on the real world. The low requirements of the approach make it especially suitable for an 80-minute first class in an introductory computer science course. The Protobject-based approach has been preliminarily validated and compared to a pure game-based approach with a study with 376 participants, and we present the analysis of motivation questionnaires, a pre-test and post-test, and a homework assignment given to the students. We posit that more research into initiatives such as this one—that can show students how computer science can impact the real world around them—is warranted.

Sirtuins have been shown to regulate the aging process. We have previously demonstrated that Sirt6 blocks the pressure overload-induced cardiac hypertrophy in mice. Here, we show that Sirt6 can also mitigate aging-induced cardiomyocyte senescence and cardiac hypertrophy. We found that aging is associated with altered Sirt6 activity along with development of cardiac hypertrophy and fibrosis. Compared to young mice (4-months), the hearts of aged mice (24-months) showed increased levels of mitochondrial DNA damage, shortened telomere length, and increased accumulation of 8-oxo-dG adducts, which are hallmarks of aging. The aged hearts also showed reduced levels of NAD+ and altered levels of mitochondrial fusion-fission proteins. Similar characteristics were observed in the hearts of Sirt6 deficient mice. Additionally, we found that doxorubicin (Dox) induced cardiomyocyte senescence, as measured by expression of p16INK4a, p53, and β-galactosidase, was associated with loss of Sirt6. However, Sirt6 overexpression protected cardiomyocytes from developing Dox-induced senescence. Further, compared to wild-type mice, the hearts of Sirt6.Tg mice showed reduced expression of aging markers, and the development of aging-associated cardiac hypertrophy and fibrosis. Our data suggest that Sirt6 is a critical anti-aging molecule that regulates various cellular processes associated with aging and protects the heart from developing aging-induced cardiac hypertrophy and fibrosis.

Sex chromosomes often bear distinct patterns of genetic variation due to unique patterns of inheritance and demography. The processes of mutation, recombination, genetic drift and selection also influence rates of evolution on sex chromosomes differently than autosomes. Measuring such differences provides information about how these processes shape genomic variation and their roles in the origin of species. To test hypotheses and predictions about patterns of autosomal and sex-linked genomic diversity and differentiation, we measured population genetic statistics within and between populations and subspecies of the barn swallow (Hirundo rustica) and performed explicit comparisons between autosomal and Z-linked genomic regions. We first tested for evidence of low Z-linked genetic diversity and high Z-linked population differentiation relative to autosomes, then for evidence that the Z chromosome bears greater ancestry information due to faster lineage sorting. Finally, we investigated geographical clines across hybrid zones for evidence that the Z chromosome is resistant to introgression due to selection against hybrids. We found evidence that the barn swallow mating system, demographic history and linked selection each contribute to low Z-linked diversity and high Z-linked differentiation. While incomplete lineage sorting is rampant across the genome, our results indicate faster sorting of ancestral polymorphism on the Z. Finally, hybrid zone analyses indicate barriers to introgression on the Z chromosome, suggesting that sex-linked traits are important in reproductive isolation, especially in migratory divide regions. Our study highlights how selection, gene flow and demography shape sex-linked genetic diversity and underlines the relevance of the Z chromosome in speciation.