Bone tumor-targeted delivery of theranostic 195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells.

Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (195mPt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, 195mPt-based radiopharmaceuticals should be targeted toward â€‹tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity. Herein, we show that systemically administered radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The 195mPt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to 195mPt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, 195mPt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to 195mPt-cisplatin. We show that systemically administered 195mPt-BP is radiotherapeutically active, as evidenced by an 11-fold increased DNA damage in metastatic tumor cells compared to non-radioactive Pt-BP controls. Moreover, apoptosis in metastatic tumor cells is enhanced more than 3.4-fold upon systemic administration of 195mPt-BP vs. radioactive 195mPt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of 195mPt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons.

Development and evaluation of a blended educational programme for general practitioners' trainers to stimulate proactive HIV testing.

BACKGROUND: In the Netherlands, a substantial proportion of newly diagnosed HIV patients present late for care, therefore, we investigated the effectiveness of a blended educational programme for trainers of GPs designed to stimulate proactive HIV testing. METHODS: GP trainers at the Academic Medical Center in Amsterdam were invited to participate in a two days training programme incorporating evidence-based practice guidelines and multiple teaching strategies, including interactive lectures, discussion groups, e-learning and quality improvement targets. The GP trainers completed questionnaires before and after the programme to evaluate the effect of the programme. We also used six-monthly cumulative laboratory data from 2010 to 2015 to compare the participating GPs' HIV tests to the general trend in testing among non-participating GPs. RESULTS: 150 GP trainers attended the first session, and 74 completed the questionnaires for both sessions. GPs median score on achieving their quality improvement targets was high and the quality of the programme highly appreciated. Between 2010 and 2013, the mean annual number of laboratory-documented HIV tests decreased by 9.1% in the 624 GPs in the control group, and by 13.0% for 11 GPs in the intervention group. After the programme, the annual decreases were 2.3% and 1.8%, respectively. Before the programme, the GPs in the intervention group had 50% more laboratory-documented HIV tests than GPs in the control group. After the programme, GPs in the intervention group had twice as many laboratory-documented HIV tests as the controls. CONCLUSIONS: We provided a detailed description of a programme based on educational and clinical evidence. We could not retrieve laboratory-documented HIV testing data for the majority of GPs in both the intervention and control groups. Therefore, the limited results should be interpreted with caution as our findings may not be representative of all participants. The blended educational programme appears to have stabilized - at a higher level - the initially stronger downward trend in testing for 11 GPs undergoing the intervention, indicating that the programme may have had an impact on their HIV testing behaviour.

Modelling the formation and self-healing of creep damage in iron-based alloys.

A self-consistent model is applied to predict the creep cavity growth and strain rates in metals from the perspective of self-healing. In this model, the creep cavity growth rate is intricately linked to the strain rate. The self-healing process causes precipitates to grow inside creep cavities. Due to the Kirkendall effect, a diffusional flux of vacancies is induced in the direction away from the creep cavity during this selective self-healing precipitation. This process impedes the creep cavity growth. The critical stress for self-healing can be derived, and an analysis is made of the efficiency of self-healing elements in binary Fe-Cu, Fe-Au, Fe-Mo, and Fe-W alloys. Fe-Au is found to be the most efficient self-healing alloy. Fe-Mo and Fe-W alloys provide good alternatives that have the potential to be employed at high temperatures.

[Driving status of syncope patients is not part of standard advice]. / Rijgeschiktheid bij syncope niet standaard besproken.

OBJECTIVE: Some medical problems, such as syncope, have direct consequences for fitness to drive. Our objective was to discover if patients had been informed about their driving status after a syncopal episode by their physician, and if this advice was in line with current legislation. DESIGN: Cross-sectional study. METHOD: By means of a structured questionnaire, 150 patients referred to the syncope clinic at the Academic Medical Centre, Amsterdam, were asked about the advice they had received concerning their driving status during previous consultations with their general practitioner or specialists. A syncope expert then assessed the driving status of all patients in the light of the existing and new ruling. RESULTS: In 121 of the 150 patients (81%), a certain or highly-likely cause for their loss of consciousness was determined: 68 patients had reflex syncope, 25 patients orthostatic hypotension, 20 patients psychogenic pseudosyncope, three patients cardiac syncope, three patients had epilepsy and two patients another diagnosis. Seven patients had experienced an episode while driving. Only 26/150 patients (17%) reported that the consequences of their episodes for their driving status had been discussed with them at earlier consultations. If driving was discussed, in only 31% had the current Dutch legislation on driving been followed. Over a third (38%) of the patients felt they should no longer drive. CONCLUSION: Fewer than one in five patients reported that driving status was discussed by a physician after a syncope episode. If advice had been given, it was often not in line with current legislation.

Blended learning in CME: the perception of GP trainers.

INTRODUCTION: Blended learning (the combination of electronic methods with traditional teaching methods) has the potential to combine the best of traditional education with the best of computer-mediated training. We chose to develop such an intervention for GP trainers who were undertaking a Continuing Medical Education (CME) course in evidence-based medicine (EBM). This study reports on our experience and investigated the factors influencing the perception on usefulness and logistics of blended learning for learners in CME. METHODS: In total, 170 GP trainers participated in the intervention. We used questionnaires, observations during the four face-to-face meetings and evaluations in the e-course over one year. Additionally we organised focus groups to gain insight in some of the outcomes of the questionnaires and interpretations of the observations. RESULTS: The GP trainers found the design and the educational method (e-course in combination with meetings) attractive, instructive and complementary. Factors influencing their learning were (1) educational design, (2) educational method, (3) topic of the intervention, (4) time (planning), (5) time (intervention), (6) learning style, (7) technical issues, (8) preconditions and (9) level of difficulty. A close link between daily practice and the educational intervention was considered an important precondition for the success of the intervention in this group of learners. CONCLUSION: GP trainers were positive about blended learning: they found e-learning a useful way to gain knowledge and the meetings a pleasant way of transferring the knowledge into practice. Although some preconditions should be taken into consideration during its development and implementation, they would participate in similarly designed learning in the future.

Teaching evidence-based practice (EBP) to speech-language therapy students: are students competent and confident EBP users?

BACKGROUND: The importance and value of the principles of evidence-based practice (EBP) in the decision-making process is recognized by speech-language therapists (SLTs) worldwide and as a result curricula for speech-language therapy students incorporated EBP principles. However, the willingness actually to use EBP principles in their future profession not only depends on EBP knowledge and skills, but also on self-efficacy and task value students perceive towards EBP. AIMS: To investigate the relation between EBP knowledge and skills, and EBP self-efficacy and task value in different year groups of Dutch SLT students. METHODS & PROCEDURES: Students from three year groups filled in a tool that measured EBP knowledge and skills: the Dutch Modified Fresno (DMF). EBP self-efficacy and task value were assessed by using a 20-item questionnaire. Both tools were validated for this population. Mean scores for the three year groups were calculated and tested for group differences using a one-way analysis of variance (ANOVA) with a post-hoc Games-Howell procedure. With a multiple linear regression technique it was assessed whether EBP self-efficacy and task value predict learning achievement scores on the DMF. Other possible predictors included in the model were: level of prior education, standard of English, having had mathematics in prior education and the SLT study year. OUTCOME & RESULTS: A total of 149 students filled in both measurement tools. Mean scores on EBP knowledge and skills were significantly different for the three year groups, with students who were further along their studies scoring higher on the DMF. Mean scores on the EBP self-efficacy and task value questionnaire were the same for the three year groups: all students valued EBP positive but self-efficacy was low in all groups. Of the possible predictors, only the year in which students study and EBP self-efficacy were significant predictors for learning achievements in EBP. CONCLUSIONS & IMPLICATIONS: Despite a significant increase in EBP knowledge and skills over the years as assessed by the DMF, the integrated EBP curriculum did not raise levels of EBP self-efficacy and task value. This lack of feeling competent might have an impact on students' willingness actually to use EBP. In curricula, therefore, there should be a focus on how to raise EBP self-efficacy in SLT students. This goes even beyond the educational department because a professional culture in which professionals are competent and confident EBP users would have a positive effect on EBP self-efficacy in students.

Competent in evidence-based practice (EBP): validation of a measurement tool that measures EBP self-efficacy and task value in speech-language therapy students.

BACKGROUND: Worldwide speech-language therapy (SLT) students are educated in evidence-based practice (EBP). For students to use EBP in their future day-to-day clinical practice, they must value EBP as positive and must feel confident in using it. For curricula developers it is therefore important to know the impact their teaching has on these aspects of students' motivational beliefs. AIMS: To develop and validate a measurement tool to assess EBP task value and self-efficacy in SLT students. METHODS & PROCEDURES: A 20-item questionnaire was developed based on a review of the literature and an additional group interview with speech-language therapists. Face validity of the questionnaire was established using a Delphi panel consisting of six EBP lecturers. Dutch bachelor SLT students (n = 149) with a different level of EBP knowledge and skills filled in the newly developed questionnaire. Reliability (internal consistency) was assessed using Cronbach's alpha and internal validity using a principal component analysis (PCA). Construct validity was assessed by comparing the bachelor SLT student scores with a group of m students (n = 15) who were highly experienced in EBP. OUTCOMES & RESULTS: The PCA showed that the questionnaire consists of two components, representing EBP task value and self-efficacy, both with good reliability (Cronbach's α = 0.83 and 0.79, respectively). The hypothesis that master's students would score significantly higher on both components than bachelor SLT students was met. CONCLUSIONS & IMPLICATIONS: The study provides evidence on the internal consistency and construct validity of this questionnaire to evaluate EBP task value and self-efficacy in SLT students. As is common with new measures, more research is needed to evaluate further its psychometric properties.

At the heart of the arterial baroreflex: a physiological basis for a new classification of carotid sinus hypersensitivity.

The aim of this review is to provide an update of the current knowledge of the physiological mechanisms underlying reflex syncope. Carotid sinus syncope will be used as the classical example of an autonomic reflex with relatively well-established afferent, central and efferent pathways. These pathways, as well as the pathophysiology of carotid sinus hypersensitivity (CSH) and the haemodynamic effects of cardiac standstill and vasodilatation will be discussed. We will demonstrate that continuous recordings of arterial pressure provide a better understanding of the cardiovascular mechanisms mediating arterial hypotension and cerebral hypoperfusion in patients with reflex syncope. Finally we will demonstrate that the current criteria to diagnose CSH are too lenient and that the conventional classification of carotid sinus syncope as cardioinhibitory, mixed and vasodepressor subtypes should be revised because isolated cardioinhibitory CSH (asystole without a fall in arterial pressure) does not occur. Instead, we suggest that all patients with CSH should be thought of as being 'mixed', between cardioinhibition and vasodepression. The proposed stricter set of criteria for CSH should be evaluated in future studies.

Factors influencing the EBM behaviour of GP trainers: a mixed method study.

BACKGROUND: General practitioner (GP) trainees state that their trainers are not consistent in using evidence-based medicine (EBM) or are even dismissive of it. As trainers are important role models in the Dutch GP training system this could have a large influence on the EBM training of GP trainees. AIM: To establish the motivations and barriers of Dutch GP trainers in using EBM. METHODS: A questionnaire on personal characteristics, knowledge, skills (Berlin, score 0-15) and attitude (McColl, VAS score 0-100), and statements about EBM barriers were presented to 106 GP trainers. Additionally, three focus group sessions with trainers (n = 30) were held. RESULTS: Knowledge and skills were less than half correct (mean 6.1, standard deviation (SD) 2.9); the overall score on attitude was 58.8 (SD 9.4). Factor analysis showed four categories of barriers: EBM competence (mean 3.5 (SD 0.8)), search activities (mean 3.5 (SD 0.8)), motivation (mean 3.8 (SD 0.7)) and time (mean 2.5 (SD 0.9)). After analysis of the focus group sessions, five categories of motivations and barriers predominated: EBM competence, attitude and behaviour, sources, time and logistics. CONCLUSION: GP trainers experience motivations in EBM; however, these motivations can also be barriers, depending on the trainer's level of knowledge and attitude.

Development and validation of an assessment instrument for teaching evidence-based practice to students in allied health care: the Dutch Modified Fresno.

UNLABELLED: To enable students to become competent evidence-based working professionals, teaching evidence-based practice (EBP) to students in allied health care has to be effective. Measuring effectiveness of EBP curricula, however, appears to be difficult due to the lack of valid instruments for this target population. The effort needed to develop and validate a new instrument is easily underestimated. This article details this process applied to an existing EBP measurement tool. AIMS: This study focuses on the development and validation of an instrument measuring the effectiveness of teaching EBP to Dutch students in allied health care. METHODS: The instrument was developed from a translated Fresno Test, using a Delphi panel where face validity was assessed. To determine reliability and construct validity, we used a cross-sectional design with four groups of students (n = 169 total) with different levels of education in EBP. RESULTS: Cronbach's alpha was 0.832, and inter-rater reliability ICC was 0.985 (95% CI 0.976-0.991). The content validity index was 0.92. Mean scores of all four groups were statistically different from each other on a p < 0.05 level. Responsiveness was 3.2 for more extreme groups and 0.9 for more similar groups. CONCLUSION: The Dutch Modified Fresno is a reliable and valid instrument to measure effects of teaching EBP in the domains knowledge and skills in the aforementioned population. The instrument is able to detect minimal important changes over time.

Attitudes towards obesity treatment in GP training practices: a focus group study.

BACKGROUND: Both patients and government expect the GP to treat obesity. Previous studies reported a negative attitude of GPs towards this task. Little is known about the attitude of GP trainees. OBJECTIVES: To assess the attitude and other factors that influence the willingness and ability of GP trainees to provide lifestyle interventions for overweight patients. METHODS: A qualitative study was performed using focus groups, consisting of first- and third-year trainees, GP trainers and teachers. Two researchers analysed the data independently. RESULTS: First-year trainees lack knowledge and a positive attitude. Third-year trainees, although trained in motivational interviewing techniques, lack specific knowledge and feel cheated when discussing eating habits. Trainers are despondent as they rarely observe long-lasting results. Teachers warn the trainees not to have high hopes. The trainers and trainees fear ruining the relationship with their patient, and all make a request for evidence-based multidisciplinary treatment programmes, joint responsibility and an image change in society to stop the epidemic. CONCLUSIONS: Trainees do not feel more competent in treating overweight patients successfully over the course of their GP specialty training and GP trainers are not convinced of the success of the treatment of overweight patients. Therefore, it could be equally important to reflect on the GP trainer as a role model as to concentrate on the education of the trainee. Both need a revived attitude and evidence-based treatment programmes, help from policy makers and an attitude change in society are desired.

Experimental field estimation of organic nitrogen formation in tree canopies.

The content of organic N has been shown in many studies to increase during the passage of rain water through forest canopies. The source of this organic N is unknown, but generally assumed to come from canopy processing of wet or dry-deposited inorganic N. There have been very few experimental studies in the field to address the canopy formation or loss of organic N. We report two studies: a Scots pine canopy exposed to ammonia gas, and a Sitka spruce canopy exposed to ammonium and nitrate as wet deposition. In both cases, organic N deposition in throughfall was increased, but only represented a small fraction (<10%) of the additional inorganic N supplied, suggesting a limited capacity for net organic N production, similar in both conifer canopies under Scottish summertime conditions, of less than 1.6 mmol N m(-2) mth(-1) (equivalent to 3 kg N ha(-1) y(-1)).

Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial.

OBJECTIVES: The primary objective was to compare a single, 6 ml, intra-articular injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis. The safety of a repeat injection of hylan G-F 20 was also assessed. METHODS: Patients with primary osteoarthritis knee pain were randomly assigned to arthrocentesis plus a 6 ml intra-articular injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/one blinded observer) study. RESULTS: were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index A pain. Secondary outcome measures included WOMAC A1 and C, patient global assessment (PGA) and clinical observer global assessment (COGA) and Outcome Measures in Rheumatology, Osteoarthritis Research Society International responder rates. A 4-week, open, repeat treatment phase evaluated safety only. Results: A total of 253 patients (Kellgren-Lawrence grade II or III) was randomly assigned. Patients receiving hylan G-F 20 experienced statistically significantly greater improvements in WOMAC A pain scores (-0.15, SE 0.076, p = 0.047), and several of the secondary outcome measures (WOMAC A1, PGA and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase. CONCLUSIONS: This placebo-controlled study demonstrated that, in patients with knee osteoarthritis, a single 6 ml intra-articular injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference versus placebo.

Symptoms and signs of syncope: a review of the link between physiology and clinical clues.

Detailed history taking is of paramount importance to establish a reliable diagnosis in patients with transient loss of consciousness. In this article the clinical symptoms and signs of the successive phases of a syncopal episode are reviewed. A failure of the systemic circulation to perfuse the brain sufficiently results in a stereotyped progression of neurological symptoms and signs culminating in loss of consciousness; when transient, this is syncope. Prior to loss of consciousness the affected individual tends to exhibit unclear thinking, followed by fixation of the eyes in the midline and a 'frozen' appearance. Narrowing of the field of vision with loss of colour vision ('greying' out) and finally a complete loss of vision (hence 'blacking' out) occurs. Hearing loss may occur following loss of vision. This process may take as little as approximately 7 s in cases of sudden complete circulatory arrest (e.g. abrupt asystole), but in other circumstances it may take longer depending on the rate and depth of cerebral hypoperfusion. Complete loss of consciousness occurs with the 'turning up' of the eyeballs. Profound cerebral hypoperfusion may be accompanied by myoclonic jerks.

Self-healing behaviour in man-made engineering materials: bioinspired but taking into account their intrinsic character.

Man-made engineering materials generally demonstrate excellent mechanical properties, which often far exceed those of natural materials. However, all such engineering materials lack the ability of self-healing, i.e. the ability to remove or neutralize microcracks without (much) intentional human interaction. This inability is the unintentional consequence of the damage prevention paradigm underlying all current engineering material optimization strategies. The damage management paradigm observed in nature can be reproduced successfully in man-made engineering materials, provided the intrinsic character of the various types of engineering materials is taken into account.

The influence of nitrogen in stemflow and precipitation on epiphytic bryophytes, Isothecium myosuroides Brid., Dicranum scoparium Hewd. and Thuidium tamariscinum (Hewd.) Schimp of Atlantic oakwoods.

The spatial relationship between the concentration and deposition of the major ions in precipitation and stemflow and their influence on the tissue nitrogen concentration of three epiphytic bryophytes on Quercus petraea (Matt) Liebl. and Q. robur L. was investigated at seven UK Atlantic oak woodland sites with a range of total N deposition of 55-250 mmol m(-2). The main driver of change in tissue N concentrations of three epiphytic bryophytes (Isothecium myosuroides Brid. (Eurhynchium myosuroides (Brid.) Schp.), Dicranum scoparium Hewd. and Thuidium tamariscinum (Hewd.) Schimp.) was total N deposition in stemflow, dominated by ammonium deposition. The three epiphytic species also showed strong relationships between tissue N concentration and total N deposition in rainfall but a poor correlation with total N ion concentration in rainfall. This study shows that epiphytic bryophytes utilise stemflow N and thus increase their risk from inputs of total N deposition compared to terricolous species at the same site.

Stress responses of Calluna vulgaris to reduced and oxidised N applied under 'real world conditions'.

Effects and implications of reduced and oxidised N, applied under 'real world' conditions, since May 2002, are reported for Calluna growing on an ombrotrophic bog. Ammonia has been released from a 10 m line source generating monthly concentrations of 180-6 microg m(-3), while ammonium chloride and sodium nitrate are applied in rainwater at nitrate and ammonium concentrations below 4mM and providing up to 56 kg N ha(-1) year(-1) above a background deposition of 10 kg N ha(-1) year(-1). Ammonia concentrations, >8 microg m(-3) have significantly enhanced foliar N concentrations, increased sensitivity to drought, frost and winter desiccation, spring frost damage and increased the incidence of pathogen outbreaks. The mature Calluna bushes nearest the NH3 source have turned bleached and moribund. By comparison the Calluna receiving reduced and oxidised N in rain has shown no significant visible or stress related effects with no significant increase in N status.