Low extracellular vesicle concentrations predict survival in patients with heart failure

BackgroundHeart disease is of worldwide importance due to high morbidity and mortality. Extracellular vesicle (EV) concentration and size represent novel diagnostic and prognostic biomarkers, e.g. in patients with liver cancer, but data on their prognostic relevance in heart disease are lacking. Here, we investigated the role of EV concentration, size and zeta potential in patients with heart disease.MethodsVesicle size distribution, concentration and zeta potential were measured by nanoparticle tracking analysis (NTA) in 28 intensive care unit (ICU) and 20 standard care (SC) patients and 20 healthy controls.ResultsPatients with any disease had a lower zeta potential compared to the healthy controls. Vesicle size (X50) was significantly higher in ICU patients (245 nm) with heart disease as compared to those patients with heart disease receiving standard care (195 nm), or healthy controls (215 nm) (p = 0.001). Notably, EV concentration was lower in ICU patients with heart disease (4.68 × 1010 particles/ml) compared to SC patients with heart disease (7,62 × 1010 particles/ml) and healthy controls (1.50 × 1011 particles/ml) (p = 0.002). Extracellular vesicle concentration is prognostic for overall survival in patients with heart disease. Overall survival is significantly reduced when the vesicle concentration is below 5.55 × 1010 particles/ml. Median overall survival was only 140 days in patients with vesicle concentrations below 5.55 × 1010 particles/ml compared to 211 days in patients with vesicle concentrations above 5.55 × 1010 particles/ml (p = 0.032).SummaryConcentration of EVs is a novel prognostic marker in ICU and SC patients with heart disease

Lysine-based surfactants in nanovesicle formulations: the role of cationic charge position and hydrophobicity in in vitro cytotoxicity and intracellular delivery

Understanding nanomaterial interactions within cells is of increasing importance for assessing their toxicity and cellular transport. Here, we developed nanovesicles containing bioactive cationic lysine-based amphiphiles, and assessed whether these cationic compounds increase the likelihood of intracellular delivery and modulate toxicity. We found different cytotoxic responses among the formulations, depending on surfactant, cell line and endpoint assayed. The induction of mitochondrial dysfunction, oxidative stress and apoptosis were the general mechanisms underlying cytotoxicity. Fluorescence microscopy analysis demonstrated that nanovesicles were internalized by HeLa cells, and evidenced that their ability to release endocytosed materials into cell cytoplasm depends on the structural parameters of amphiphiles. The cationic charge position and hydrophobicity of surfactants determine the nanovesicle interactions within the cell and, thus, the resulting toxicity and intracellular behavior after cell uptake of the nanomaterial. The insights into some toxicity mechanisms of these new nanomaterials contribute to reducing the uncertainty surrounding their potential health hazards

A non-enzymatic function of 17 beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival

Deficiency of the mitochondrial enzyme 2-methyl-3-hydroxybutyryl-CoA dehydrogenase involved in isoleucine metabolism causes an organic aciduria with atypical neurodegenerative course. The disease-causing gene is HSD17B10 and encodes 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), a protein also implicated in the pathogenesis of Alzheimer's disease. Here we show that clinical symptoms in patients are not correlated with residual enzymatic activity of mutated HSD10. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10(-/-) mice demonstrate that a property of HSD10 independent of its enzymatic activity is essential for structural and functional integrity of mitochondria. Impairment of this function in neural cells causes apoptotic cell death whilst the enzymatic activity of HSD10 is not required for cell survival. This finding indicates that the symptoms in patients with mutations in the HSD17B10 gene are unrelated to accumulation of toxic metabolites in the isoleucine pathway and, rather, related to defects in general mitochondrial function. Therefore alternative therapeutic approaches to an isoleucine-restricted diet are required

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Machine Learning Can Predict the Probability of Biologic Therapy in Patients with Inflammatory Bowel Disease

Background: Inflammatory bowel disease (IBD) is of high medical and socioeconomic relevance. Moderate and severe disease courses often require treatment with biologics. The aim of this study was to evaluate machine learning (ML)-based methods for the prediction of biologic therapy in IBD patients using a large prescription database. Methods: The present retrospective cohort study utilized a longitudinal prescription database (LRx). Patients with at least one prescription for an intestinal anti-inflammatory agent from a gastroenterologist between January 2015 and July 2021 were included. Patients who had received an initial biologic therapy prescription (infliximab, adalimumab, golimumab, vedolizumab, or ustekinumab) were categorized as the “biologic group”. The potential predictors included in the machine learning-based models were age, sex, and the 100 most frequently prescribed drugs within 12 months prior to the index date. Six machine learning-based methods were used for the prediction of biologic therapy. Results: A total of 122,089 patients were included in this study. Of these, 15,824 (13.0%) received at least one prescription for a biologic drug. The Light Gradient Boosting Machine had the best performance (accuracy = 74%) and was able to correctly identify 78.5% of the biologics patients and 72.6% of the non-biologics patients in the testing dataset. The most important variable was prednisolone, followed by lower age, mesalazine, budesonide, and ferric iron. Conclusions: In summary, this study reveals the advantages of ML-based models in predicting biologic therapy in IBD patients based on pre-treatment and demographic variables. There is a need for further studies in this regard that take into account individual patient characteristics, i.e., genetics and gut microbiota, to adequately address the challenges of finding optimal treatment strategies for patients with IBD

An Elevated FIB-4 Score Is Associated with an Increased Incidence of Depression among Outpatients in Germany

Background: Liver disease and depression are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. However, the predictive value of an elevated FIB-4 score regarding the development of depression and/or anxiety disorders among the general population is unknown. Methods: By using the Disease Analyzer database (IQVIA), which compiles diagnoses and laboratory values as well as basic medical and demographic data of patients followed in general practices in Germany, we identified 370,756 patients with available lab values for FIB-4 score calculation between 2005 and 2019. Patients with an FIB-4 score < 2 were matched 1:1 to patients with an FIB-4 index ≥ 2 by age, sex and yearly consultation frequency. Results: In regression analysis, the incidence rate ratio (IRR) of depression was significantly higher among patients with an FIB-4 score ≥ 2.0 compared to patients with a lower FIB-4 score <2.0 (IRR: 1.12, p < 0.001). This association was significant for both female (IRR: 1.10, p = 0.004) and male (IRR: 1.15, p < 0.001) patients and strongest in the age groups ≤50 years (IRR: 1.42, p < 0.001) and 51-60 years (IRR: 1.34, p < 0.001). There was no significant association between an elevated FIB-4 score ≥ 2.0 and the incidence of depression among patients aged 60 years and older. There was no significant increase in the IRR of anxiety disorders for patients with high or low FIB-4 scores. Conclusion: Our study suggests a previously unknown association between an elevated FIB-4 score and an increased incidence of depression. This finding suggests that the FIB-4 score is not only a valuable tool for the prediction of liver-specific endpoints but also may be of relevance for the prediction of extrahepatic comorbidities, which in turn may argue for clinical screening programs in patients with an elevated FIB-4

Antihypertensive Therapy and Incidence of Cancer

Background: Antihypertensive pharmacological therapy includes diuretics, beta-blockers, ACE inhibitors, calcium channel blockers and angiotensin II receptor blockers. Besides their use in arterial hypertension, these drugs also play a major role in the therapy of portal hypertension, heart failure and coronary artery disease. Systematic analyses on the possible influence of these medications on cancer incidence are lacking. Methods: By utilizing the Disease Analyzer database (IQVIA), 349,210 patients with antihypertensive drug prescriptions between 2010 and 2020 without a diagnosis of cancer prior to or at the date of initial drug prescription were included. Propensity score matching was carried out by 1:1:1:1:1 according to the five antihypertensive treatments. Cox regression analyses were performed to investigate an association between antihypertensive drugs and the incidence of cancer. Results: Patients who were diagnosed with cancer were treated with diuretics in 19.9% of cases, calcium channel blockers in 16.9% of cases, and angiotensin II receptor blockers, ACE inhibitors, or beta-blockers in 13.9%, 13.2% and 12.8% of cases, respectively. Cox regression models revealed that diuretic use positively correlated with liver cancer incidence (HR: 1.31, 95%CI: 1.12–2.63) and lymphoid/haematopoietic tissue cancer incidence (HR: 1.27, 95%CI: 1.10–1.46). Use of diuretics negatively correlated with the incidence of prostate (HR: 0.64, 95%CI: 0.53–0.78) and skin cancer (HR: 0.81, 95%CI: 0.72–0.92). Finally, a positive association was found between angiotensin II receptor inhibitors and prostate cancer incidence (HR: 1.50, 95%CI: 1.28–1.65). Conclusions: These data suggest that diuretic use might be associated with liver cancer and lymphoid/haematopoetic tissue cancer development

The Spectrum of Co-Diagnoses in Patients with Colorectal Cancer: A Retrospective Cohort Study of 17,824 Outpatients in Germany

Background: The prognosis of colorectal cancer (CRC) patients is determined to a decisive extent by comorbidities. On the other hand, anti-cancer treatments for CRC are associated with relevant toxicities and may therefore cause additional comorbidities. Methods: This retrospective cohort study assessed the prevalence of various diseases in patients 12 months before and 12 months after an initial diagnosis of colorectal cancer (ICD-10: C18, C20) in 1274 general practices in Germany between January 2000 and December 2018. The study is based on the Disease Analyzer database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data. Patients with and without CRC were matched by sex, age, and index year. Results: We identified several diagnoses with a significantly higher prevalence among CRC patients 12 months prior to the index date compared to controls. These diagnoses included gastrointestinal hemorrhage, hemorrhoids, perianal venous thrombosis, and abdominal and pelvic pain, as well as functional intestinal disorders. In contrast, the prevalence of lipid metabolism disorder, depression, hypertension, coronary heart disease, or acute bronchitis was significantly lower in CRC cases. After diagnosis of CRC, we found a significantly higher prevalence of anemia, polyneuropathies, functional intestinal disorders, and chronic kidney disease among CRC patients compared to the control group, while the prevalence of acute upper respiratory infections of multiple and unspecified sites and acute bronchitis was significantly lower in CRC patients compared to non-CRC patients. Conclusions: In the present study, we identified a variety of diseases occurring at higher or lower frequencies in CRC patients compared to matched controls without CRC. This might help to select patients for early CRC screening and improve the clinical management of CRC patients

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile