Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Prevalence and causes of failure of receiving thrombolytic therapy in patients with acute ST-segment elevation myocardial infarction

AbstractBackgroundMissing thrombolytic therapy in patients with acute ST-elevation myocardial infarction (STEMI) can have dire consequences. We studied the prevalence and causes of failure of receiving thrombolytic therapy in patients with STEMI and its impact on the clinical outcome during hospitalization.Patients and methodsThis was an observational, analytic, cross sectional study carried out in the CCU and emergency departments of three public hospitals in Port Said, Egypt. We interrogated all patients admitted within 72h of possible acute coronary syndrome and only patients proved to have STEMI as defined by the updated ACC criteria were analyzed for receiving thrombolytic therapy or not. All STEMI patients were subjected to: medical history taking, thorough clinical examination, 12-leads surface electrocardiography, cardiac biomarkers (troponin I), and predischarge trans-thoracic echocardiography.ResultsOf 6522 patients screened, only 288 patients had STEMI. The prevalence of missed thrombolysis in these patients was 45%. Delayed presentation after the onset of symptoms represented the most common cause for failure to receive thrombolysis (54% of the cases), while misdiagnosis at the emergency department represented 35% of the cases. Female gender, diabetes mellitus and inferior location of myocardial infarction were independent predictors of missed thrombolytic therapy. Cardiac death, clinical heart failure and significant cardiac dysrhythmias were higher in patients who missed thrombolysis than in those who received it.ConclusionIn this study, up to 45% of patients with STEMI missed the opportunity to receive thrombolysis, most likely due to delayed presentation or misdiagnosis at the emergency department. Patients with missed thrombolysis were at higher risk of cardiac death, clinical heart failure, and hemodynamically significant cardiac dysrhythmias

The ``Outside-In'' Outburst of HT Cassiopeiae

We present results from photometric observations of the dwarf nova system HT Cas during the eruption of November 1995. The data include the first two--colour observations of an eclipse on the rise to outburst. They show that during the rise to outburst the disc deviates significantly from steady state models, but the inclusion of an inner-disc truncation radius of about 4 $R_{wd}$ and a ``flared'' disc of semi-opening angle of $10^{\circ}$ produces acceptable fits. The disc is found to have expanded at the start of the outburst to about $0.41R_{L1}$, as compared to quiescent measurements. The accretion disc then gradually decreases in radius reaching $<0.32R_{L1}$ during the last stages of the eruption. Quiescent eclipses were also observed prior to and after the eruption and a revised ephemeris is calculated.Comment: 9 pages, 11 figures, to appear in MNRA

Prediction of uncomplicated pregnancies in obese women: a prospective multicentre study.

BACKGROUND: All obese pregnant women are considered at equal high risk with respect to complications in pregnancy and birth, and are commonly managed through resource-intensive care pathways. However, the identification of maternal characteristics associated with normal pregnancy outcomes could assist in the management of these pregnancies. The present study aims to identify the factors associated with uncomplicated pregnancy and birth in obese women, and to assess their predictive performance. METHODS: Data form obese women (BMI ≥ 30 kg/m2) with singleton pregnancies included in the UPBEAT trial were used in this analysis. Multivariable logistic regression was used to identify sociodemographic, clinical and biochemical factors at 15+0 to 18+6 weeks' gestation associated with uncomplicated pregnancy and birth, defined as delivery of a term live-born infant without antenatal or labour complications. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC). Internal validation and calibration were also performed. Women were divided into fifths of risk and pregnancy outcomes were compared between groups. Sensitivity, specificity, and positive and negative predictive values were calculated using the upper fifth as the positive screening group. RESULTS: Amongst 1409 participants (BMI 36.4, SD 4.8 kg/m2), the prevalence of uncomplicated pregnancy and birth was 36% (505/1409). Multiparity and increased plasma adiponectin, maternal age, systolic blood pressure and HbA1c were independently associated with uncomplicated pregnancy and birth. These factors achieved an AUROC of 0.72 (0.68-0.76) and the model was well calibrated. Prevalence of gestational diabetes, preeclampsia and other hypertensive disorders, preterm birth, and postpartum haemorrhage decreased whereas spontaneous vaginal delivery increased across the fifths of increasing predicted risk of uncomplicated pregnancy and birth. Sensitivity, specificity, and positive and negative predictive values were 38%, 89%, 63% and 74%, respectively. A simpler model including clinical factors only (no biomarkers) achieved an AUROC of 0.68 (0.65-0.71), with sensitivity, specificity, and positive and negative predictive values of 31%, 86%, 56% and 69%, respectively. CONCLUSION: Clinical factors and biomarkers can be used to help stratify pregnancy and delivery risk amongst obese pregnant women. Further studies are needed to explore alternative pathways of care for obese women demonstrating different risk profiles for uncomplicated pregnancy and birth

Decomposition, Reformulation, and Diving in University Course Timetabling

In many real-life optimisation problems, there are multiple interacting components in a solution. For example, different components might specify assignments to different kinds of resource. Often, each component is associated with different sets of soft constraints, and so with different measures of soft constraint violation. The goal is then to minimise a linear combination of such measures. This paper studies an approach to such problems, which can be thought of as multiphase exploitation of multiple objective-/value-restricted submodels. In this approach, only one computationally difficult component of a problem and the associated subset of objectives is considered at first. This produces partial solutions, which define interesting neighbourhoods in the search space of the complete problem. Often, it is possible to pick the initial component so that variable aggregation can be performed at the first stage, and the neighbourhoods to be explored next are guaranteed to contain feasible solutions. Using integer programming, it is then easy to implement heuristics producing solutions with bounds on their quality. Our study is performed on a university course timetabling problem used in the 2007 International Timetabling Competition, also known as the Udine Course Timetabling Problem. In the proposed heuristic, an objective-restricted neighbourhood generator produces assignments of periods to events, with decreasing numbers of violations of two period-related soft constraints. Those are relaxed into assignments of events to days, which define neighbourhoods that are easier to search with respect to all four soft constraints. Integer programming formulations for all subproblems are given and evaluated using ILOG CPLEX 11. The wider applicability of this approach is analysed and discussed.Comment: 45 pages, 7 figures. Improved typesetting of figures and table

Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention.

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

Background: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. Methods: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. Results: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. Conclusion: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money

Optometrists show rudimentary understanding of evidence-based practice but are ready to embrace it: can barriers be overcome?

Evidence-based practice (EBP) involves integration of the best available evidence from research, the patient's preferences or circumstances, the clinical environment and the health practitioner's expertise. There have been several qualitative studies of EBP in health-care but none has focused on the profession of optometry. Therefore, the aim of the present study was to assess optometrists' perceptions of EBP in optometry

Acute Ethanol Effects on Focal Cerebral Ischemia in Nonfasted Rats

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66417/1/j.1530-0277.1997.tb03832.x.pd

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib