Exosome mimetics: a novel class of drug delivery systems

The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics

The Applied Data Analytics in Medicine Program: Lessons Learned From Four Years' Experience With Personalizing Health Care in an Academic Teaching Hospital

The University Medical Center (UMC) Utrecht piloted a hospital-wide innovation data analytics program over the past 4 years. The goal was, based on available data and innovative data analytics methodologies, to answer clinical questions to improve patient care. In this viewpoint, we aimed to support and inspire others pursuing similar efforts by sharing the three principles of the program: the data analytics value chain (data, insight, action, value), the innovation funnel (structured innovation approach with phases and gates), and the multidisciplinary team (patients, clinicians, and data scientists). We also discussed our most important lessons learned: the importance of a clinical question, collaboration challenges between health care professionals and different types of data scientists, the win-win result of our collaboration with external partners, the prerequisite of available meaningful data, the (legal) complexity of implementation, organizational power, and the embedding of collaborative efforts in the health care system as a whole

Testing bias in clinical databases: methodological considerations

<p>Abstract</p> <p>Background</p> <p>Laboratory testing in clinical practice is never a random process. In this study we evaluated testing bias for neutrophil counts in clinical practice by using results from requested and non-requested hematological blood tests.</p> <p>Methods</p> <p>This study was conducted using data from the Utrecht Patient Oriented Database. This clinical database is unique, as it contains physician requested data, but also data that are not requested by the physician, but measured as result of requesting other hematological parameters. We identified adult patients, hospitalized in 2005 with at least two blood tests during admission, where requests for general blood profiles and specifically for neutrophil counts were contrasted in scenario analyses. Possible effect modifiers were diagnosis and glucocorticoid use.</p> <p>Results</p> <p>A total of 567 patients with requested neutrophil counts and 1,439 patients with non-requested neutrophil counts were analyzed. The absolute neutrophil count at admission differed with a mean of 7.4 × 10⁹/l for requested counts and 8.3 × 10⁹/l for non-requested counts (p-value < 0.001). This difference could be explained for 83.2% by the occurrence of cardiovascular disease as underlying disease and for 4.5% by glucocorticoid use.</p> <p>Conclusion</p> <p>Requests for neutrophil counts in clinical databases are associated with underlying disease and with cardiovascular disease in particular. The results from our study show the importance of evaluating testing bias in epidemiological studies obtaining data from clinical databases.</p

Redundant laboratory testing on referral from general practice to the outpatient clinic: a post-hoc analysis

BACKGROUND: Inappropriately repeated laboratory testing is a commonly occurring problem. However, this has not been studied extensively in the outpatient clinic after referral by GPs. AIM: The aim of this study was to investigate how often laboratory tests ordered by the GP were repeated on referral to the outpatient clinic, and how many of the normal test results remained normal on repetition. DESIGN & SETTING: This is a post-hoc analysis of a study on laboratory testing strategies in patients newly referred to the outpatient clinic between April 2015 and April 2017. METHOD: All patients who had a referral letter including laboratory test results ordered by the GP were included. These results were compared with the laboratory test results ordered in the outpatient clinic. RESULTS: Data were available for 295 patients, 191 of which had post-visit testing done. In this group, 56% of tests ordered by the GP were repeated. Tests with abnormal results were repeated more frequently than tests with normal results (65% versus 53%; P<0.001). A longer test interval was associated with slightly smaller odds of tests being repeated (odds ratio [OR] 0.97, 95% confidence interval [CI] = 0.95 to 0.99; P = 0.003). Of the tests with normal test results that were repeated, 90% remained normal. This was independent of testing interval or testing strategy. CONCLUSION: Laboratory tests ordered by the GP are commonly repeated on referral to the outpatient clinic. The number of test results remaining normal on repetition suggests a high level of redundancy in laboratory test repetition

Финансовое обеспечение деятельности туристического предприятия

Целью статьи является разработка рекомендаций по повышению эффективности финансового обеспечения деятельности туристического предприятия, определение приоритетных путей совершенствования финансовых показателей его деятельности

The interplay between drivers of erythropoiesis and iron homeostasis in rare hereditary anemias: Tipping the balance

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA

Thirty Days of Home Blood Pressure Monitoring in Patients Following Carotid Endarterectomy: A Feasibility Study

Objectives: Hemodynamic disturbances are the causative mechanism in half the perioperative strokes following Carotid Endarterectomy (CEA). Nevertheless, insight into individual hemodynamics after discharge is lacking. We assessed the feasibility of daily post-discharge Blood Pressure (BP) self-measurements at home following CEA and analyzed BP-trend patterns as well as patient experiences. Methods: Thirty CEA-patients (age 68 ± 8 years; 87% male) measured BP at home twice daily for 30 days with an ambulatory BP-monitor. Exclusion criteria: Modified Rankin Scale score >2 or no access to Wi-Fi. BP-values were transmitted to an online dashboard on a web application. If individually determined systolic target BP exceeded by ≥ 15% an alert was generated, and patients were requested to visit the outpatient clinic after 4 consecutive alerts. After 30 days, patients completed a survey regarding their experiences and perceived feasibility of home BP-monitoring. Adherence to the monitoring protocol, BP time-series, and any interventions were scored. Results: Post-discharge, four adverse events occurred; bleeding requiring surgery (n=1), TIA (n=1), myocardial infarction (n=1), readmission due to stress-related hypertension (n=1). None of the patients had four consecutive BP-measurements exceeding the BP threshold. Patient adherence was high; 24 patients provided ≥ 90% of the expected BP-measurements. Eight patients visited their general practitioner with concerns regarding their observed BP-values, in two leading to changes in anti-hypertensive therapy. Over 90% of patients experienced home BP-monitoring as positive and all except one recommended adding home BP-monitoring to standard care. Median intra-individual variability of systolic and diastolic BP of all patients was 12.7 mmHg and 7.4 mmHg, respectively. No significant differences in systolic BP variability or absolute values were found between patients with a post-discharge event and those without. Conclusion: Postoperative home BP-monitoring was feasible and well-accepted by CEA-patients. Future studies need to address the clinical gain of home BP-monitoring in early detection of patients at risk for postoperative hemodynamic complications

Association of low testosterone with changes in non-cardiovascular biomarkers in adult men

Testosterone has effects on many organs and systems. The purpose of this study was to test the hypothesis that low testosterone is associated with changes in various non-cardiovascular biomarkers in men older than 40 who were tested for possible hypogonadism. We extracted data from 9939 outpatient men who were over 40 years old (median age 56) and who also had concurrent laboratory measurements of total testosterone and one or more biomarkers of interest: estradiol, uric acid, prostate-specific antigen (PSA), sex-hormone binding globulin (SHBG), luteinizing hormone, creatinine, bone alkaline phosphatase (BAP), creatine kinase, hemoglobin A1c, and 25-hydroxy-vitamin D, and body mass index (BMI). In a smaller exploratory study of 19 otherwise healthy men presenting for evaluation of possible hypogonadism, pre-albumin (a.k.a.transthyretin, a marker of anabolism) and testosterone were measured. Men with lower levels of testosterone had significantly (p < 0.001) lower mean levels of PSA, SHBG, luteinizing hormone, and estradiol. Overall, men with low levels of testosterone also had significantly (p < 0.001) higher mean levels of LDH and BAP, but these associations varied between men who were younger or older than 56 years. There was a moderate but statistically significant positive correlation (r = 0.63, p < 0.05) between testosterone levels and pre-albumin. These results confirm our hypothesis that testosterone deficiency is associated with a broad range of systemic changes demonstrable in hormonal and non-hormonal serum assays in men over 40 years old being tested for possible hypogonadism

Improving acute kidney injury alerts in tertiary care by linking primary care data: An observational cohort using routine care data

OBJECTIVE: Acute kidney injury (AKI) is easily missed and underdiagnosed in routine clinical care. Timely AKI management is important to decrease morbidity and mortality risks. We recently implemented an AKI e-alert at the University Medical Center Utrecht, comparing plasma creatinine concentrations with historical creatinine baselines, thereby identifying patients with AKI. This alert is limited to data from tertiary care, and primary care data can increase diagnostic accuracy for AKI. We assessed the added value of linking primary care data to tertiary care data, in terms of timely diagnosis or excluding AKI. METHODS: With plasma creatinine tests for 84,984 emergency department (ED) visits, we applied the Kidney Disease Improving Global Outcome guidelines in both tertiary care-only data and linked data and compared AKI cases. RESULTS: Using linked data, the presence of AKI could be evaluated in an additional 7886 ED visits. Sex- and age-stratified analyses identified the largest added value for women (an increase of 4095 possible diagnoses) and patients ≥60 years (an increase of 5190 possible diagnoses). We observed 398 additional visits where AKI was diagnosed, as well as 185 cases where AKI could be excluded. We observed no overall decrease in time between baseline and AKI diagnosis (28.4 days vs. 28.0 days). For cases where AKI was diagnosed in both data sets, we observed a decrease of 2.8 days after linkage, indicating a timelier diagnosis of AKI. CONCLUSIONS: Combining primary and tertiary care data improves AKI diagnostic accuracy in routine clinical care and enables timelier AKI diagnosis