100 research outputs found
Assessment of immunogenicity of romiplostim in clinical studies with ITP subjects
Romiplostim is an Fc-peptide fusion protein that activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor leading to increased platelet production. Romiplostim has been engineered to have no amino acid sequence homology to endogenous TPO. Recombinant protein therapeutics can be at a risk of development of an antibody response that can impact efficacy and safety. Hence, a strategy to detect potential antibody formation to the drug and to related endogenous molecules can be useful. The immunogenicity assessment strategy involved both the detection and characterization of binding and neutralizing antibodies. The method for detection was based on a surface plasmon resonance biosensor platform using the Biacore 3000. Samples that tested positive for binding antibodies in the Biacore immunoassay were then tested in a neutralization assay. Serum samples from 225 subjects with immune thrombocytopenic purpura (ITP) dosed with romiplostim and 45 ITP subjects dosed with placebo were tested for romiplostim and TPO antibodies. Prior to romiplostim treatment, 17 subjects (7%) tested romiplostim antibody positive and 12 subjects (5%) tested TPO antibody positive for pre-existing binding antibodies. After romiplostim exposure, 11% of the subjects exhibited binding antibodies against romiplostim and 5% of the subjects with ITP showed binding antibodies against TPO. The antibodies against romiplostim did not cross-react with TPO and vice versa. No cases of anti-TPO neutralizing antibodies were detected in romiplostim-treated subjects. The incidence of anti-romiplostim neutralizing antibodies to romiplostim was 0.4% (one subject); this subject tested negative at the time of follow-up 4Β months later. No impact on platelet profiles were apparent in subjects that had antibodies to romiplostim to date. In summary, administration of romiplostim in ITP subjects resulted in the development of a binding antibody response against romiplostim and TPO ligand. One subject developed a neutralizing antibody response to romiplostim that impacted the platelet counts of this subject. No neutralizing antibodies to endogenous TPO were observed
No effect of epoprostenol on right ventricular diameter in patients with acute pulmonary embolism: a randomized controlled trial
<p>Abstract</p> <p>Background</p> <p>Right ventricular dilatation in the setting of acute pulmonary embolism is associated with an adverse prognosis. Treatment with a pulmonary vasodilator has never been studied systematically. We evaluated the effect of epoprostenol on right ventricular diameter and function in patients with acute pulmonary embolism and right ventricular dilatation.</p> <p>Methods</p> <p>In a randomized, single-blind study, 14 patients with acute pulmonary embolism received epoprostenol or placebo infusion for 24 hours on top of conventional treatment. Effects on right ventricular end-diastolic diameter, systolic pulmonary artery pressure, right ventricle fractional area changeand tricuspid annular plane systolic excursion were assessed by serial echocardiography. Furthermore Troponin T and NT-proBNP were measured serially.</p> <p>Results</p> <p>Compared to placebo, epoprostenol was associated with a relative change from baseline in right ventricular end-diastolic diameter of +2% after 2.5 hours and -8% after 24 hours. Epoprostenol did not have a significant effect on systolic pulmonary artery pressure, right ventricular fractional area change and tricuspid annular plane systolic excursion, nor on biochemical parameters.</p> <p>Conclusion</p> <p>In patients with acute pulmonary embolism and right ventricular overload, treatment with epoprostenol did not improve right ventricular dilatation or any other measured variables of right ventricular overload.</p> <p>Trial Registration</p> <p><it>Registration</it>: URL: NCT01014156</p> <p><it>Medical ethical committee</it>: Medisch-ethische toetsingscommissie (METc) from the VUmc (free university medical centre)</p
Systematic Review of Mucosal Immunity Induced by Oral and Inactivated Poliovirus Vaccines against Virus Shedding following Oral Poliovirus Challenge
Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5β30 days after a βchallengeβ dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08β0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59β1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82β1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV
Harmonizing and improving European education in prescribing: An overview of digital educational resources used in clinical pharmacology and therapeutics
Aim: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose. Methods: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials
HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads
There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS) β only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (pβ=β0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log10 lower (compared to 0.59 log10 lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (pβ=β0.0001)and BMS ADCC activity (pβ=β0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (pβ=β0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk
2021 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Neonatal Life Support; Education, Implementation, and Teams; First Aid Task Forces; and the COVID-19 Working Group
The International Liaison Committee on Resuscitation initiated a continuous review of new, peer-reviewed published cardiopulmonary resuscitation science. This is the fifth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; a more comprehensive review was done in 2020. This latest summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation task force science experts. Topics covered by systematic reviews in this summary include resuscitation topics of video-based dispatch systems; head-up cardiopulmonary resuscitation; early coronary angiography after return of spontaneous circulation; cardiopulmonary resuscitation in the prone patient; cord management at birth for preterm and term infants; devices for administering positive-pressure ventilation at birth; family presence during neonatal resuscitation; self-directed, digitally based basic life support education and training in adults and children; coronavirus disease 2019 infection risk to rescuers from patients in cardiac arrest; and first aid topics, including cooling with water for thermal burns, oral rehydration for exertional dehydration, pediatric tourniquet use, and methods of tick removal. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, according to the Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations or good practice statements. Insights into the deliberations of the task forces are provided in Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces listed priority knowledge gaps for further research
CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4 beta-hydroxycholesterol levels
Objective and methods A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4 beta-hydroxycholesterol. We studied plasma 4 beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4 beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A. Results In patients treated with efavirenz, the median plasma 4 beta-hydroxycholesterol level increased by 46 ng/mL (p=0.004; n=11). In contast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4 beta-hydroxycholesterol of -9.4 ng/mL (p=0.0003; n=22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p=0.38; n=19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4 beta-hydroxycholesterol levels (p < 0.0001). Conclusion Changes in plasma 4 beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4 beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction
Thermoelectric transport properties of highly oriented FeSb2 thin films
Highly textured FeSb2 films were produced on quartz wafers by a sputtering method. Their resistivity and Seebeck coefficient (S) were measured and a maximum absolute value of S similar to 160 mu V K-1 at 50 K was obtained. Hall measurements were employed to study the charge carrier concentrations and Hall mobilities of the FeSb2 films. By comparing with the transport properties of FeSb2 single crystals and an extrinsically doped FeSb1.98Te0.02 single crystal, the thermoelectric properties of the FeSb2 films are demonstrated to be dominated by the intrinsic properties of FeSb2 at a high charge carrier concentration.Original Publication:Y Sun, S Johnsen, Per Eklund, M Sillassen, J Bottiger, N Oeschler, P Sun, F Steglich and B B Iversen, Thermoelectric transport properties of highly oriented FeSb2 thin films, 2009, JOURNAL OF APPLIED PHYSICS, (106), 3, 033710.http://dx.doi.org/10.1063/1.3155800Copyright: American Institute of Physicshttp://www.aip.org
Direct Measurement of Interface Strength between Copper Submicron-Dot and Silicon Dioxide Substrate
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