183 research outputs found
Potential limits of AAV-based gene therapy with the use of new transgenes expressing factor IX fusion proteins
Introduction: The variety of treatment for haemophilia B (HB) has recently improved with the emergence of both AAVâbased gene therapy and bioengineered human factor IX (hFIX) molecules with prolonged halfâlife due to fusion to either albumin (Alb) or immunoglobulin Fc fragment (Fc). /
Aim: Adenoâassociated viral vectors (AAV) mediating expression of hFIXâAlb and hFIXâFc fusion proteins was investigated for gene therapy of HB to explore if their extended halfâlife translates to higher plasma levels of FIX. /
Methods: Singleâstranded crossâpackaged AAV2/8 vectors expressing hFIXâAlb, hFIXâFc and hFIX were evaluated in vitro, and in mice. /
Results: Both hFIXâAlb and hFIXâFc fusion proteins were synthesized and expressed as single chains of expected size following AAVâmediated gene transfer in vitro and in vivo. The procoagulant properties of these hFIXâfusion proteins were comparable to wildâtype hFIX. However, their expression levels were threefold lower than wildâtype hFIX in vivo most likely due to inefficient secretion. /
Conclusion: This, the first, evaluation of hFIXâfusion proteins in the context of AAV gene transfer suggests that the hFIXâfusion proteins are secreted inefficiently from the liver, thus preventing their optimal use in gene therapy approaches
Fusion Techniques in Biomedical Information Retrieval
For difficult cases clinicians usually use their experience and also the information found in textbooks to determine a diagnosis. Computer tools can help them supply the relevant information now that much medical knowledge is available in digital form. A biomedical search system such as developed in the Khresmoi project (that this chapter partially reuses) has the goal to fulfil information needs of physicians. This chapter concentrates on information needs for medical cases that contain a large variety of data, from free text, structured data to images. Fusion techniques will be compared to combine the various information sources to supply cases similar to an example case given. This can supply physicians with answers to problems similar to the one they are analyzing and can help in diagnosis and treatment planning
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Combining macula clinical signs and patient characteristics for age-related macular degeneration diagnosis: a machine learning approach
Background: To investigate machine learning methods, ranging from simpler interpretable techniques to complex (non-linear) âblack-boxâ approaches, for automated diagnosis of Age-related Macular Degeneration (AMD).
Methods: Data from healthy subjects and patients diagnosed with AMD or other retinal diseases were collected during routine visits via an Electronic Health Record (EHR) system. Patientsâ attributes included demographics and, for each eye, presence/absence of major AMD-related clinical signs (soft drusen, retinal pigment epitelium, defects/ pigment mottling, depigmentation area, subretinal haemorrhage, subretinal fluid, macula thickness, macular scar, subretinal fibrosis). Interpretable techniques known as white box methods including logistic regression and decision trees as well as less interpreitable techniques known as black box methods, such as support vector machines (SVM), random forests and AdaBoost, were used to develop models (trained and validated on unseen data) to diagnose AMD. The gold standard was confirmed diagnosis of AMD by physicians. Sensitivity, specificity and area under the receiver operating characteristic (AUC) were used to assess performance.
Results: Study population included 487 patients (912 eyes). In terms of AUC, random forests, logistic regression and adaboost showed a mean performance of (0.92), followed by SVM and decision trees (0.90). All machine learning models identified soft drusen and age as the most discriminating variables in cliniciansâ decision pathways to diagnose AMD. C
Conclusions: Both black-box and white box methods performed well in identifying diagnoses of AMD and their decision pathways. Machine learning models developed through the proposed approach, relying on clinical signs identified by retinal specialists, could be embedded into EHR to provide physicians with real time (interpretable) support
The impact range for smooth wallâliquid interactions in nanoconfined liquids
Bulk and nanoconfined liquids have initially very different physics; for
instance, nanoconfined liquids show stratification and position-dependent
relaxation processes. A number of similarities between bulk and nanoconfined
liquids have nevertheless been reported in computer simulations during the last
decade. Inspired by these observations, we present results from molecular
dynamics computer simulations of three nanoconfined liquids (i.e.,
single-component Lennard-Jones (LJ) liquid, Kob-Andersen binary LJ mixture, and
an asymmetric dumbbell model) demonstrating also a microscopic similarity
between bulk and nanoconfined liquids. The results show that the interaction
range for the wall-liquid and liquid-liquid interactions of the nanoconfined
liquid are identical to the bulk liquid as long as the liquid remains "Roskilde
simple" in nanoconfinement, i.e., the liquid has strong correlations between
virial and potential energy equilibrium fluctuations in the NVT ensemble.Comment: 8 page
Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain EntryâA Study in Rats Subjected to Status Epilepticus by Kainate
This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20Â mg/kg quinidine over 30 min or 4Â h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7Â h after the start of the infusion. Effect of pretreatment with tariquidar (15Â mg/kg, administered 30Â min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the bloodâbrain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the bloodâbrain barrier is altered at 1Â week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level
Functional impairment of systemic scleroderma patients with digital ulcerations: Results from the DUO registry
A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.
PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.
METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.
RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (nâ=â19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (pâ=â0.04).
CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode
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