Changes in anticoagulant prescription in Dutch patients with recent-onset atrial fibrillation: observations from the GARFIELD-AF registry.

BACKGROUND: For the improvement of AF care, it is important to gain insight into current anticoagulation prescription practices and guideline adherence. This report focuses on the largest Dutch subset of AF-patients, derived from the GARFIELD-AF registry. METHODS: Across 35 countries worldwide, patients with newly diagnosed 'non-valvular' atrial fibrillation (AF) with at least one additional risk factor for stroke were included. Dutch patients were enrolled in five, independent, consecutive cohorts from 2010 until 2016. RESULTS: In the Netherlands, 1189 AF-patients were enrolled. The prescription of non-vitamin K antagonist oral anticoagulants (NOAC) has increased sharply, and as per 2016, more patients were initiated on NOACs instead of vitamin K antagonists (VKA). In patients with a class I recommendation for anticoagulation, only 7.5% compared to 30.0% globally received no anticoagulation. Reasons for withholding anticoagulation in these patients were unfortunately often unclear. CONCLUSIONS: The data from the GARFIELD-AF registry shows the rapidly changing anticoagulation preference of Dutch physicians in newly diagnosed AF. Adherence to European AF guidelines in terms of anticoagulant regimen would appear to be appropriate. In absence of structured follow up of AF patients on NOAC, the impact of these rapid practice changes in anticoagulation prescription in the Netherlands remains to be established.

A truncated form of CD9-partner 1 (CD9P-1), GS-168AT2, potently inhibits in vivo tumour-induced angiogenesis and tumour growth.

BACKGROUND: Tetraspanins are transmembrane proteins known to contribute to angiogenesis. CD9 partner-1 (CD9P-1/EWI-F), a glycosylated type 1 transmembrane immunoglobulin, is a member of the tetraspanin web, but its role in angiogenesis remains to be elucidated. METHODS: We measured the expression of CD9P-1 under angiogenic and angiostatic conditions, and the influence of its knockdown onto capillary structures formation by human endothelial cells (hECs). A truncated form of CDP-1, GS-168AT2, was produced and challenged vs hEC proliferation, migration and capillaries' formation. Its association with CD9P-1, CD9, CD81 and CD151 and the expressions of these later at hEC surface were analysed. Finally, its effects onto in vivo tumour-induced angiogenesis and tumour growth were investigated. RESULTS: Vascular endothelial growth factor (VEGF)-induced capillary tube-like formation was inhibited by tumour necrosis factor α and was associated with a rise in CD9P-1 mRNA expression (P<0.05); accordingly, knockdown of CD9P-1 inhibited VEGF-dependent in vitro angiogenesis. GS-168AT2 dose-dependently inhibited in vitro angiogenesis, hEC migration and proliferation (P<0.05). Co-precipitation experiments suggest that GS-168AT2 corresponds to the sequence by which CD9P-1 physiologically associates with CD81. GS-168AT2 induced the depletion of CD151, CD9 and CD9P-1 from hEC surface, correlating with GS-168AT2 degradation. Finally, in vivo injections of GS-168AT2 inhibited tumour-associated angiogenesis by 53.4±9.5% (P=0.03), and reduced tumour growth of Calu 6 tumour xenografts by 73.9±16.4% (P=0.007) without bodyweight loss. CONCLUSION: The truncated form of CD9P-1, GS-168AT2, potently inhibits angiogenesis and cell migration by at least the downregulation of CD151 and CD9, which provides the first evidences for the central role of CD9P-1 in tumour-associated angiogenesis and tumour growth.

CD9P-1 expression correlates with the metastatic status of lung cancer, and a truncated form of CD9P-1, GS-168AT2, inhibits in vivo tumour growth.

BACKGROUND: Loss of CD9 expression has been correlated with a higher motility and metastatic potential of tumour cells originating from different organs. However, the mechanism underlying this loss is not yet understood. METHODS: We produced a truncated form of partner 1 of CD9 (CD9P-1), GS-168AT2, and developed a new monoclonal antibody directed towards the latter. We measured the expression of CD9 and CD9P-1 in human lung tumours (hLTs), and monitored the level of CD9 in NCI-H460, in vitro and in vivo, in the presence and absence of GS-168AT2. RESULTS: Loss of CD9 is inversely related to the expression of CD9P-1, which correlates with the metastatic status of hLT (n=55). In vitro, GS-168AT2 is rapidly internalised and degraded at both the membrane and cytoplasm of NCI-H460, and this correlates with the association of GS-168AT2 with both CD9 and CD81. Intraperitoneal injections of GS-168AT2 in NCI-H460-xenografted Nude mice led to drastic inhibition of tumour growth, as well as to the downregulation of CD9, but not of CD81, in the tumour core. CONCLUSION: These findings show for the first time that CD9P-1 expression positively correlates with the metastatic status of hLT, and that the upregulation of CD9P-1 expression could be one of the mechanisms underlying the loss of CD9 in solid tumours. Our study also reveals that, under certain conditions, loss of CD9 could be a tumour growth-limiting phenomenon rather than a tumour growth-promoting one.

Role of the Bordetella pertussis minor fimbrial subunit, FimD, in colonization of the mouse respiratory tract.

Bordetella pertussis fimbriae are composed of a major subunit, Fim2 or Fim3, and the minor subunit FimD. Using immunoelectron microscopy, we provide evidence that FimD is located at the fimbrial tip. The role of FimD in colonization of the mouse respiratory tract was studied by using two fimbrial mutants: a mutant completely devoid of fimbriae (designated FimD-) and a mutant devoid of the major fimbrial subunits but still producing the minor subunit (designated FimD+). The ability of the two fimbrial mutants to colonize the nasopharynx, trachea, and lungs was compared with those of the wild type parental strain and a filamentous hemagglutinin (FHA) mutant. Of the three mutants studied, the FimD- mutant showed the greatest defect, colonizing less well in the nasopharynx, trachea, and lungs. The most pronounced defect in colonizing ability of the three mutants was observed in the trachea. However, the colonizing defect of the FHA and FimD+ mutants in the trachea was observed only during the first 3 days of infection. After 10 days, the colonization level was nearly restored to wild-type levels. The FHA and FimD+ mutants showed a slight colonization defect in the nasopharynx but no defect in the lungs. A maltose binding protein-FimD fusion protein and a peptide derived from FimD were able to bind to heparin, a member of a class of sulfated sugars which are ubiquitous in the respiratory tract. Recently it was shown (W. L. W. Hazenbos, C. A. W. Geuijen, B. M. van den Berg, F. R. Mooi, and R. van Furth, J. Infect. Dis. 171:924-929, 1995) that FimD also binds to the integrin VLA-5, and our results suggest that the binding of B. pertussis to these two molecules plays an important role in colonization of the respiratory tract of the mouse.

Measuring knowledge and clinical reasoning skills in a problem-based curriculum.

The purpose of this study was to investigate the validity of the Progress Test that was specially designed for measuring the growth of knowledge and clinical reasoning skills in a problem-based medical curriculum. Scores and subscores of students from the different categories of the Progress Test were compared with their scores on a Clinical Reasoning Tests. Both the Progress Test and the Clinical Reasoning Test revealed the same pattern of increasing scores over the years, and had a high intercorrelation. Further analyses revealed that the clinical sciences subscore in the progress test explained the variations in the clinical reasoning test scores. The knowledge of the behavioural sciences subscore made a small but independent contribution. The knowledge of the biomedical sciences subscore did not have this independent effect. These outcomes are discussed in this paper from the perspective of development of medical expertise research and theory. Some educational consequences are also discussed.

The development of diagnostic competence: comparison of a problem-based, an integrated, and a conventional medical curriculum.

PURPOSE: To compare the diagnostic performances of students in five curriculum years educated at schools with problem-based, integrative, or conventional medical curricula. METHOD: Data were analyzed in 1994 for 612 students in their second, third, or fourth (preclinical) or fifth or sixth (clinical) years at three Dutch medical schools with problem-based, integrative, or conventional curricula. The students gave differential diagnoses for 30 case histories that were epidemiologically representative of Dutch society and covered all organ systems. The numbers of accurate diagnostic hypotheses were tallied for each of the groups involved. The data were analyzed using analysis of variance and post-hoc Newman-Keuls tests. RESULTS: Overall, the students trained within the problem-based framework and the students trained within the integrated curriculum made more accurate diagnoses than the students trained within the conventional curriculum. No overall differences were found between the students in the problem-based and integrated curricula, although the second- and third-year students from the latter performed better than the second- and third-year students from both other schools. CONCLUSION: Integration between basic and clinical sciences and an emphasis on patient problems may be the critical factors that determine superior diagnostic performance rather than whether a curriculum is self- or teacher-directed. Problem-based learning seems to live up to its expectations, but so does the integrated approach to medical education. In addition, the procedure for measuring diagnostic performance appears to be valid and to provide a simple means of measuring curriculum effects. It remains to be seen whether the findings would be replicated when students are allowed to freely gather data in open interaction with patients rather than respond to written presentations of cases.

Influence of transdermal scopolamine on motion sickness during 7 days' exposure to heavy seas.

We conducted a double-blind, placebo-controlled study to evaluate the efficacy and tolerability of transdermal scopolamine in the prevention of motion sickness (MS) aboard a frigate during 7 days of continuously moderate or heavy seas. Forty-nine healthy sailors with a previous history of MS were randomly assigned to receive a transdermal therapeutic system of scopolamine (TTS-S) or transdermal placebo (TD-P). Patches were placed behind the ears at least 4 hours before departure and were removed 72 hours later. Subjects were observed on days 1 to 4 and 6. In the TTS-S group, both subjective feeling of MS and the incidence of nausea were reduced during the first 2 days. Because of adaptation, differences in signs and symptoms of MS between subjects receiving TTS-S and TD-P disappeared after the second day. During the first 3 days, vomiting occurred less often in the TTS-S group. On day 6, 3 days after removal of the patch, vomiting occurred in 23% of the TTS-S group, probably due to delay in adaptation, but none of the subjects in the TD-P group vomited. Concentration was not adversely influenced, since the ability to work increased in the TTS-S group. During prolonged continuous exposure to heavy and moderate seas, 2.5 cm2 TTS-S discs proved to be efficacious in preventing MS, with xerostomia as a tolerable side effect and no significant ocular side effects.