Neuroprotection after cardiac arrest with 2-iminobiotin: a single center phase IIa study on safety, tolerability, and pharmacokinetics

BackgroundBrain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic–ischemic reperfusion injury. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase.MethodsSingle-center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC0-24h of 600–1,200 ng*h/m in cohort A, of 2,100–3,300 ng*h/mL in cohort B, and 7,200–8,400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 min after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed. Brain biomarkers and patient outcomes were collected 30 days after OHCA.ResultsA total of 21 patients was included, eight in cohort A and B and five in cohort C. No changes in vital signs were observed, and no adverse events related to 2-IB were reported. A two-compartment PK model described data the best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC0-24h 2,398 ng*h/mL). Renal function was an important covariate; therefore, in cohort B, dosing was performed on eGFR on admission. In cohort B and C, the targeted exposure was met (median AUC0-24h 2,917 and 7,323 ng*h/mL, respectively).ConclusionThe administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed

Auxin distribution in Lotus japonicus during root nodule development

Microbial Biotechnolog

Moving Beyond the Research-practice Gap: Impact of Teacher Research on Professional Development and Knowledge Utilization in Schools

In various policy actions of the Dutch government, an assumption is made that teachers who had carried out a master thesis are able to generate knowledge and stimulate knowledge utilization in schools (Ministerie van OCW, 2013). Yet evidence of positive effects of teacher research, either as part of a master’s program or carried out by inservice teachers is minimal and somewhat ambiguous. The current study aims to answer the following research questions: How is teacher research evaluated with respect to the professional development as teacher?How is teacher research evaluated with respect to knowledge utilization in schools?Teaching and Teacher Learning (ICLON

Voorbij de kloof tussen onderwijsonderzoek en de onderwijspraktijk

Teaching and Teacher Learning (ICLON

Optimal anatomical location for needle chest decompression for tension pneumothorax:A multicenter prospective cohort study

Objective: Tension Pneumothorax (TP) can occur as a potentially life threatening complication of chest trauma. Both the 2nd intercostal space in the midclavicular line (ICS2-MCL) and the 4th/5th intercostal space in the anterior axillary line (ICS 4/5-AAL) have been proposed as preferred locations for needle decompression (ND) of a TP. In the present study we aim to determine chest wall thickness (CWT) at ICS2-MCL and ICS4/5-AAL in normal weight-, overweight- and obese patients, and to calculate theoretical success rates of ND for these locations based on standard catheter length. Methods: We performed a prospective multicenter study of a convenience sample of adult patients presenting in Emergency Departments (ED) of 2 university hospitals and 6 teaching hospitals participating in the XXX consortium. CWT was measured bilaterally in ISC2-MCL and ISC4/5-AAL with point of care ultrasound (POCUS) and hypothetical success rates of ND were calculated for both locations based on standard equipment used for ND. Results: A total of 392 patients was included during a 2 week period. Mean age was 51 years (range 18-89), 52% was male and mean BMI was 25.5 (range 16.3-45.0). Median CWT was 26 [IQR 21-32] (range 9-52) mm in ISC2-MCL, and 26 [21-33] (range 10-78) mm in ICS4/5-AAL (p30, p=0.016 subjects, but not in subjects with a normal BMI. Hypothetical failure rates for 45mm Venflon and 50mm Angiocatheter were 2.5% and 0.8% for ICS2-MCL and 6.2% and 2.5% for ISC4/5-AAL (p=0.016 and p=0.052 respectively). Conclusion: In overweight- and obese subjects, the chest wall is thicker in ICS 4/5-AAL than in ICS2-MCL and theoretical chances of successful needle decompression of a tension pneumothorax are significantly higher in ICS2-MCL compared to ICS 4/5-AAL. (C) 2020 The Author(s). Published by Elsevier Ltd

From master student to master teacher: The meaning of teacher research for school practice

Teachers generally seem to have limited knowledge of, access to and interest in insights from academic educational research. A possible way to bridge the gap between research and practice might be research by teachers. This line of thinking has found its way to policy actions of the Dutch government, in which master programs for teachers are promoted. Yet evidence of positive effects of teacher research is minimal and somewhat ambiguous. The current study aims to answer the following research question: ‘How is teacher research evaluated with respect to the professional development of teachers and knowledge utilization in schools?’ First, a biographical study has been conducted with 36 teachers (primary education, secondary education and vocational education). Second, a Q-sort questionnaire was administered with a small group of teachers from each educational sector, which measures beliefs about teacher research as a professional development strategy. The preliminary conclusions indicate that a master program contributes to teachers’ professional development, among others, in terms of their ability to conduct teacher research.  However, for knowledge utilization in schools to take place, teachers with a master degree are a helpful but not a sufficient condition. Teaching and Teacher Learning (ICLON

HDAC3 Mediates the Inflammatory Response and LPS Tolerance in Human Monocytes and Macrophages

Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or HDAC3 siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or HDAC3 siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages

Catalytic Mechanism of Bacteriophage T4 Rad50 ATP Hydrolysis

Spontaneous double-strand breaks (DSBs) are one of the most deleterious forms of DNA damage, and their improper repair can lead to cellular dysfunction. The Mre11 and Rad50 proteins, a nuclease and an ATPase, respectively, form a well-conserved complex that is involved in the initial processing of DSBs. Here we examine the kinetic and catalytic mechanism of ATP hydrolysis by T4 Rad50 (gp46) in the presence and absence of Mre11 (gp47) and DNA. Single-turnover and pre-steady state kinetics on the wild-type protein indicate that the rate-limiting step for Rad50, the MR complex, and the MR-DNA complex is either chemistry or a conformational change prior to catalysis. Pre-steady state product release kinetics, coupled with viscosity steady state kinetics, also supports that the binding of DNA to the MR complex does not alter the rate-limiting step. The lack of a positive deuterium solvent isotope effect for the wild type and several active site mutants, combined with pH–rate profiles, implies that chemistry is rate-limiting and the ATPase mechanism proceeds via an asymmetric, dissociative-like transition state. Mutation of the Walker A/B and H-loop residues also affects the allosteric communication between Rad50 active sites, suggesting possible routes for cooperativity between the ATP active sites

Structured feedback on students’ concept maps: the proverbial path to learning?

Good conceptual knowledge is an essential requirement for health professions students, in that they are required to apply concepts learned in the classroom to a variety of different contexts. However, the use of traditional methods of assessment limits the educator’s ability to correct students’ conceptual knowledge prior to altering the educational context. Concept mapping (CM) is an educational tool for evaluating conceptual knowledge, but little is known about its use in facilitating the development of richer knowledge frameworks. In addition, structured feedback has the potential to develop good conceptual knowledge. The purpose of this study was to use Kinchin’s criteria to assess the impact of structured feedback on the graphical complexity of CM’s by observing the development of richer knowledge frameworks. Fifty-eight physiotherapy students created CM’s targeting the integration of two knowledge domains within a case-based teaching paradigm. Each student received one round of structured feedback that addressed correction, reinforcement, forensic diagnosis, benchmarking, and longitudinal development on their CM’s prior to the final submission. The concept maps were categorized according to Kinchin’s criteria as either Spoke, Chain or Net representations, and then evaluated against defined traits of meaningful learning. The inter-rater reliability of categorizing CM’s was good. Pre-feedback CM’s were predominantly Chain structures (57%), with Net structures appearing least often. There was a significant reduction of the basic Spoke- structured CMs (P = 0.002) and a significant increase of Net-structured maps (P < 0.001) at the final evaluation (post-feedback). Changes in structural complexity of CMs appeared to be indicative of broader knowledge frameworks as assessed against the meaningful learning traits. Feedback on CM’s seemed to have contributed towards improving conceptual knowledge and correcting naive conceptions of related knowledge. Educators in medical education could therefore consider using CM’s to target individual student development