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1. Bortezomib, C1-Inhibitor and Plasma Exchange Do Not Prolong the Survival of Multi-Transgenic GalT-KO Pig Kidney Xenografts in Baboons

Author

Le Bas-Bernardet, S., Tillou, X., Branchereau, J., Dilek, N., Poirier, N., Châtelais, M., Charreau, B., Minault, D., Hervouet, J., Renaudin, K., Crossan, C., Scobie, L., Takeuchi, Y., Diswall, M., Breimer, M.E., Klar, N., Daha, M.R., Simioni, P., Robson, S.C., Nottle, M.B., Salvaris, E.J., Cowan, P.J., d’Apice, A.J.F., Sachs, D.H., Yamada, K., Lagutina, I., Duchi, R., Perota, A., Lazzari, G., Galli, C., Cozzi, E., Soulillou, J.-P., Vanhove, B., and Blancho, G.

Published
2015
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2. POS0531 FACTORS ASSOCIATED WITH BASELINE HYPERTENSION IN EARLY RHEUMATOID ARTHRITIS: DATA FROM A REAL-WORLD LARGE INCIDENT COHORT

Author

Hadwen, B., primary, Stranges, S., additional, Klar, N., additional, Bindee, K., additional, Pope, J., additional, Bartlett, S. J., additional, Boire, G., additional, Bessette, L., additional, Hitchon, C., additional, Hazlewood, G., additional, Keystone, E., additional, Schieir, O., additional, Thorne, C., additional, Tin, D., additional, Valois, M. F., additional, Bykerk, V., additional, and Barra, L., additional

Published
2021
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7. A Restricted Role for FcgammaR in the Regulation of Adaptive Immunity

Author

Fransen, M. F., Benonisson, H., van Maren, W. W., Sow, H. S., Breukel, C., Linssen, M. M., Claassens, J. W. C., Brouwers, C., van der Kaa, J., Camps, M., Kleinovink, J. W., Vonk, K. K., van Heiningen, S., Klar, N., van Beek, L., van Harmelen, V., Daxinger, L., Nandakumar, Kutty Selva, Holmdahl, R., Coward, C., Lin, Q., Hirose, S., Salvatori, D., van Hall, T., van Kooten, C., Mastroeni, P., Ossendorp, F., Verbeek, J. S., Fransen, M. F., Benonisson, H., van Maren, W. W., Sow, H. S., Breukel, C., Linssen, M. M., Claassens, J. W. C., Brouwers, C., van der Kaa, J., Camps, M., Kleinovink, J. W., Vonk, K. K., van Heiningen, S., Klar, N., van Beek, L., van Harmelen, V., Daxinger, L., Nandakumar, Kutty Selva, Holmdahl, R., Coward, C., Lin, Q., Hirose, S., Salvatori, D., van Hall, T., van Kooten, C., Mastroeni, P., Ossendorp, F., and Verbeek, J. S.

Abstract

By their interaction with IgG immune complexes, FcgammaR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcgammaR-knockout mice, it has been concluded that FcgammaRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcgammaRs (FcgammaRI/II/III/IV(-/-) mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcgammaRIIb-deficient mice, FcgammaRI/II/III/IV(-/-) mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcgammaRs in the modulation of the adaptive immune response in vivo. We conclude that FcgammaRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.

Published
2018
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9. Enhanced Ig production by human peripheral lymphocytes induced by aggregated C1q

Author

Daha, M. R., Klar, N., Hoekzema, R., van Es, L. A., and Other departments

Subjects
fluids and secretions, immune system diseases, Immunology, Immunology and Allergy, chemical and pharmacologic phenomena, urologic and male genital diseases, skin and connective tissue diseases
Abstract

Because B cells express receptors for C1q, we have investigated the role of C1q in the stimulation of B cells. When B cells were cultured in the presence of C1q that had been frozen, T cells, and suboptimal concentrations of PWM, there was a dose-dependent enhancement of IgM, IgG, and IgA by the B cells. No significant enhancement of Ig production by B cells was seen in the absence of T cells or PWM. The contribution of T cells or PWM could be replaced by supernatants of PMA and Con A-activated PBMC (T cell growth factor). C1q that had been frozen, in contrast with freshly isolated C1q, was at least 3 times more active in enhancement of the production of Ig by B cells in culture in the presence of suboptimal concentrations of T cell growth factor. The capability of C1q to stimulate B cells could be ascribed to aggregates of C1q. Monomeric C1q was only marginally active to stimulate B cell Ig production, whereas dimeric and tetrameric C1q were able to enhance Ig production by B cells in relation to their size. Furthermore, aggregation of C1q on soluble aggregates of rabbit IgM also increased its potential to enhance B cell Ig production. The interaction of C1q with the B cells occurs via the collagenous tail of C1q, as suggested by inhibition experiments with purified collagenous tails and globular heads of C1q. These results indicate that triggering of C1qR on B cells positively regulates Ig production in vitro.

Published
1990
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10. The Rauischholzhausen agenda for road ecology

Author

Roedenbeck, I. A., Fahrig, L., Findlay, C. S., Houlahan, J. E., Jaeger, J. A. G., Klar, N., Stephanie Kramer-Schadt, and Grift, E. A.

Subjects
density, precautionary principle, swareflex reflectors, conservation, Alterra - Centrum Landschap, habitat, breeding bird populations, environmental impacts, Landscape Centre, deer, sampling design, Wageningen Environmental Research, biodiversity
Abstract

Despite the documented negative effects of roads on wildlife, ecological research on road effects has had comparatively little influence on road planning decisions. We argue that road research would have a larger impact if researchers carefully considered the relevance of the research questions addressed and the inferential strength of the studies undertaken. At a workshop at the German castle of Rauischholzhausen we identified five particularly relevant questions, which we suggest provide the framework for a research agenda for road ecology: (1) Under what circumstances do roads affect population persistence? (2) What is the relative importance of road effects vs. other effects on population persistence? (3) Under what circumstances can road effects be mitigated? (4) What is the relative importance of the different mechanisms by which roads affect population persistence? (5) Under what circumstances do road networks affect population persistence at the landscape scale? We recommend experimental designs that maximize inferential strength, given existing constraints, and we provide hypothetical examples of such experiments for each of the five research questions. In general, manipulative experiments have higher inferential strength than do nonmanipulative experiments, and full before-after-control-impact designs are preferable to before-after or control-impact designs. Finally, we argue that both scientists and planners must be aware of the limits to inferential strength that exist for a given research question in a given situation. In particular, when the maximum inferential strength of any feasible design is low, decision makers must not demand stronger evidence before incorporating research results into the planning process, even though the level of uncertainty may be high

Published
2007

11. Evaluating the effectiveness of road mitigation measures

Author

van der Grift, E.A. (Edgar A.), van der Ree, R. (Rodney), Fahrig, L. (Lenore), Findlay, S. (Scott), Houlahan, J. (Jeff), Jaeger, J.A.G. (Jochen A.G.), Klar, N. (Nina), Madriñan, L.F. (L. Francisco), Olson, L. (Leif), van der Grift, E.A. (Edgar A.), van der Ree, R. (Rodney), Fahrig, L. (Lenore), Findlay, S. (Scott), Houlahan, J. (Jeff), Jaeger, J.A.G. (Jochen A.G.), Klar, N. (Nina), Madriñan, L.F. (L. Francisco), and Olson, L. (Leif)

Published
2013
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12. Evaluating the effectiveness of road mitigation measures

Author

van der Grift, E.A., van Ree, R., Fahrig, L., Houlahan, J.E., Jaeger, J.A.G., Klar, N., Francisco Madriñan, L., Olson, L., van der Grift, E.A., van Ree, R., Fahrig, L., Houlahan, J.E., Jaeger, J.A.G., Klar, N., Francisco Madriñan, L., and Olson, L.

Abstract

The last 20 years have seen a dramatic increase in efforts to mitigate the negative effects of roads and traffic on wildlife, including fencing to prevent wildlife-vehicle collisions and wildlife crossing structures to facilitate landscape connectivity. While not necessarily explicitly articulated, the fundamental drivers behind road mitigation are human safety, animal welfare, and/or wildlife conservation. Concomitant with the increased effort to mitigate has been a focus on evaluating road mitigation. So far, research has mainly focussed on assessing the use of wildlife crossing structures, demonstrating that a broad range of species use them. However, this research has done little to address the question of the effectiveness of crossing structures, because use of a wildlife crossing structure does not necessarily equate to its effectiveness. The paucity of studies directly examining the effectiveness of crossing structures is exacerbated by the fact that such studies are often poorly designed, which limits the level of inference that can be made. Without well performed evaluations of the effectiveness of road mitigation measures, we may endanger the viability of wildlife populations and inefficiently use financial resources by installing structures that are not as effective as we think they are. In this paper we outline the essential elements of a good experimental design for such assessments and prioritize the parameters to be measured. The framework we propose will facilitate collaboration between road agencies and scientists to undertake research programs that fully evaluate effectiveness of road mitigation measures. We discuss the added value of road mitigation evaluations for policy makers and transportation agencies and provide recommendations on how to incorporate such evaluations in road planning practices.

Published
2013

13. Habitat selection models for European wildcat conservation

Author

Klar, N., Fernández, Néstor, Kramer-Schadt, Stephanie, Herrmann, M., Trizen, M., Büttner, I., Niemitz, C., Klar, N., Fernández, Néstor, Kramer-Schadt, Stephanie, Herrmann, M., Trizen, M., Büttner, I., and Niemitz, C.

Abstract

Populations of the European wildcat (Felis silvestris) are only slowly recovering in Central Europe after a severe decline in the last centuries and require specific conservation plans in many areas. However, detailed information on wildcat occurrence and habitat require- ments is still scarce and controversial. We present a fine-scale habitat selection model for wildcats based on detailed species and land use information and evaluate its accu- racy to predict habitat distribution in new areas. We analysed habitat use within home ranges using single locations of 12 radio-tracked individuals from south western Germany. Several competing models were fitted and compared using generalised linear mixed models (GLMM) and information-theoretic approaches. Radio-tracking data of 9 and 10 wildcats from two distant areas were used to evaluate the models. The selected model predicted habitat associated to close distance to forest, watercourses and mead- ows and a critical distance to villages, single houses and roads. To predict area suitable for home ranges we superimposed rules derived from home range attributes at a higher level of selection. Predictions from the combination of the fine-scale habitat model and home range rules matched well with more than 2000 wildcat observations of south- western Germany. We discuss the application of the model in wildcat conservation for finding potential reintroduction sites, identifying small isolated populations and aiding in the evaluation of the needs of mitigation and compensation within the scope of the European Habitats Directive.

Published
2008

14. The Rauischholzhausen agenda for road ecology

Author

Roedenbeck, I.A. (Inga A.), Fahrig, L. (Lenore), Findlay, C.S. (C. Scott), Houlahan, J.E. (Jeff E.), Jaeger, J.A.G. (Jochen A.G.), Klar, N. (Nina), Kramer-Schadt, S. (Stephanie), van der Grift, E.A. (Edgar A.), Roedenbeck, I.A. (Inga A.), Fahrig, L. (Lenore), Findlay, C.S. (C. Scott), Houlahan, J.E. (Jeff E.), Jaeger, J.A.G. (Jochen A.G.), Klar, N. (Nina), Kramer-Schadt, S. (Stephanie), and van der Grift, E.A. (Edgar A.)

Abstract

Despite the documented negative effects of roads on wildlife, ecological research on road effects has had comparatively little influence on road planning decisions. We argue that road research would have a larger impact if researchers carefully considered the relevance of the research questions addressed and the inferential strength of the studies undertaken. At a workshop at the German castle of Rauischholzhausen we identified five particularly relevant questions, which we suggest provide the framework for a research agenda for road ecology: (1) Under what circumstances do roads affect population persistence? (2) What is the relative importance of road effects vs. other effects on population persistence? (3) Under what circumstances can road effects be mitigated? (4) What is the relative importance of the different mechanisms by which roads affect population persistence? (5) Under what circumstances do road networks affect population persistence at the landscape scale? We recommend experimental designs that maximize inferential strength, given existing constraints, and we provide hypothetical examples of such experiments for each of the five research questions. In general, manipulative experiments have higher inferential strength than do nonmanipulative experiments, and full before-after-control-impact designs are preferable to before-after or control-impact designs. Finally, we argue that both scientists and planners must be aware of the limits to inferential strength that exist for a given research question in a given situation. In particular, when the maximum inferential strength of any feasible design is low, decision makers must not demand stronger evidence before incorporating research results into the planning process, even though the level of uncertainty may be high. Copyright

Published
2007

15. The Rauischholzhausen agenda for road ecology

Author

Roedenbeck, I.A., Fahrig, L., Findlay, C.S., Houlahan, J.E., Jaeger, J.A.G., Klar, N., Kramer-Schadt, S., van der Grift, E.A., Roedenbeck, I.A., Fahrig, L., Findlay, C.S., Houlahan, J.E., Jaeger, J.A.G., Klar, N., Kramer-Schadt, S., and van der Grift, E.A.

Abstract

Despite the documented negative effects of roads on wildlife, ecological research on road effects has had comparatively little influence on road planning decisions. We argue that road research would have a larger impact if researchers carefully considered the relevance of the research questions addressed and the inferential strength of the studies undertaken. At a workshop at the German castle of Rauischholzhausen we identified five particularly relevant questions, which we suggest provide the framework for a research agenda for road ecology: (1) Under what circumstances do roads affect population persistence? (2) What is the relative importance of road effects vs. other effects on population persistence? (3) Under what circumstances can road effects be mitigated? (4) What is the relative importance of the different mechanisms by which roads affect population persistence? (5) Under what circumstances do road networks affect population persistence at the landscape scale? We recommend experimental designs that maximize inferential strength, given existing constraints, and we provide hypothetical examples of such experiments for each of the five research questions. In general, manipulative experiments have higher inferential strength than do nonmanipulative experiments, and full before-after-control-impact designs are preferable to before-after or control-impact designs. Finally, we argue that both scientists and planners must be aware of the limits to inferential strength that exist for a given research question in a given situation. In particular, when the maximum inferential strength of any feasible design is low, decision makers must not demand stronger evidence before incorporating research results into the planning process, even though the level of uncertainty may be high

Published
2007

16. Understanding of prognosis among parents of children who died of cancer: impact on treatment goals and integration of palliative care.

Author

Wolfe J, Klar N, Grier HE, Duncan J, Salem-Schatz S, Emanuel EJ, Weeks JC, Wolfe, J, Klar, N, Grier, H E, Duncan, J, Salem-Schatz, S, Emanuel, E J, and Weeks, J C

Abstract

Context: Parents' understanding of prognosis or decision making about palliative care for children who die of cancer is largely unknown. However, a more accurate understanding of prognosis could alter treatment goals and expectations and lead to more effective care.Objectives: To evaluate parental understanding of prognosis in children who die of cancer and to assess the association of this factor with treatment goals and the palliative care received by children.Design, Setting, and Participants: Survey, conducted between September 1997 and August 1998, of 103 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital, Boston, Mass, and who died of cancer between 1990 and 1997 (72% of those eligible and those located) and 42 pediatric oncologists.Main Outcome Measure: Timing of parental understanding that the child had no realistic chance for cure compared with the timing of physician understanding of this prognosis, as documented in the medical record.Results: Parents first recognized that the child had no realistic chance for cure a mean (SD) of 106 (150) days before the child's death, while physician recognition occurred earlier at 206 (330) days before death. Among children who died of progressive disease, the group characterized by earlier recognition of this prognosis by both parents and physicians had earlier discussions of hospice care (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.06; P =.01), better parental ratings of the quality of home care (OR, 3.31; 95% CI, 1.15-9.54; P =.03), earlier institution of a do-not-resuscitate order (OR, 1.03; 95% CI, 1.00-1.06; P =.02), less use of cancer-directed therapy during the last month of life (OR, 2.80; 95% CI, 1.05-7.50; P =.04), and higher likelihood that the goal of cancer-directed therapy identified by both physician and parent was to lessen suffering (OR, 5.17; 95% CI, 1.86-14.4; P =.002 for physician and OR, 6.56; 95% CI, 1.54-27.86; P =.01 for parents).Conclusion: Considerable delay exists in parental recognition that children have no realistic chance for cure, but earlier recognition of this prognosis by both physicians and parents is associated with a stronger emphasis on treatment directed at lessening suffering and greater integration of palliative care. JAMA. 2000;284:2469-2475. [ABSTRACT FROM AUTHOR]

Published
2000
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18. Analysis of dichotomous outcome data for community intervention studies

Author

Bellamy, SL, Gibberd, R, Hancock, L, Howley, P, Kennedy, B, Klar, N, Lipsitz, S, Ryan, L, Bellamy, SL, Gibberd, R, Hancock, L, Howley, P, Kennedy, B, Klar, N, Lipsitz, S, and Ryan, L

Abstract

Community intervention trials are becoming increasingly popular as a tool for evaluating the effectiveness of health education and intervention strategies. Typically, units such as households, schools, towns, counties, are randomized to receive either intervention or control, then outcomes are measured on individuals within each of the units of randomization. It is well recognized that the design and analysis of such studies must account for the clustering of subjects within the units of randomization. Furthermore, there are usually both subject level and cluster level covariates that must be considered in the modelling process. While suitable methods are available for continuous outcomes, data analysis is more complicated when dichotomous outcomes are measured on each subject. This paper will compare and contrast several of the available methods that can be applied in such settings, including random effects models, generalized estimating equations and methods based on the calculation of 'design effects', as implemented in the computer package SUDAAN. For completeness, the paper will also compare these methods of analysis with more simplistic approaches based on the summary statistics. All the methods will be applied to a case study based on adolescent anti-smoking intervention in Australia. The paper concludes with some general discussion and recommendations for routine design and analysis.

Published
2000

28. Developments in cluster randomized trials and Statistics in Medicine.

Author

Campbell, M. J., Donner, A., and Klar, N.

Abstract

The design and analysis of cluster randomized trials has been a recurrent theme in Statistics in Medicine since the early volumes. In celebration of 25 years of Statistics in Medicine, this paper reviews recent developments, particularly those that featured in the journal. Issues in design such as sample size calculations, matched paired designs, cohort versus cross-sectional designs, and practical design problems are covered. Developments in analysis include modification of robust methods to cope with small numbers of clusters, generalized estimation equations, population averaged and cluster specific models. Finally, issues on presenting data, some other clustering issues and the general problem of evaluating complex interventions are briefly mentioned. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2007
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29. Antidepressant medication use and non-Hodgkin's lymphoma risk: no association.

Author

Bahl S, Cotterchio M, Kreiger N, and Klar N

Abstract

Animal and human studies have suggested that antidepressant medications may be associated with several cancers. The authors evaluated the association between antidepressant medication use and the risk of non-Hodgkin's lymphoma using a Canadian population-based case-control study, the National Enhanced Cancer Surveillance Study. Non-Hodgkin's lymphoma cases (n=638) diagnosed in 1995-1996 were identified using the Ontario Cancer Registry, and controls (n=1,930) were identified from the Ontario Ministry of Finance Property Assessment Database. Antidepressant medication use was ascertained using a self-administered questionnaire. Multivariate logistic regression was used to estimate odds ratios. 'Ever' use of antidepressant medications was not associated with non-Hodgkin's lymphoma risk. The odds ratio for non-Hodgkin's lymphoma with 25 or more months of tricyclic antidepressant medication use was 1.6; however, this was nonsignificant. Duration or history of use or individual types of antidepressant medications were not associated with non-Hodgkin's lymphoma risk. These findings do not support an increased risk of non-Hodgkin's lymphoma with antidepressant medication use. [ABSTRACT FROM AUTHOR]

Published
2004
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32. Binding and catabolism of aggregated immunoglobulins bearing C3b or iC3b by U937 cells.

Author

Daha, M. R., Gorter, A., Leijh, P. J. C., Klar, N., and Van Es, L. A.

Subjects
IMMUNOGLOBULINS, METABOLISM, PLASMA cells, ANTIGENS, CELL culture, CELL lines
Abstract

Mononuclear cells play an important role in the elimination of immune complexes (IC). In the presence of complement (C) the binding and degradation of IC by mononuclear cells is enhanced at least two-fold. The enhancement of binding is caused by a synergistic interaction of the IC with cellular Fc and complement receptors (R). In the present study we have investigated the contribution of the complement receptors CRI and CR3 of human monocyte cell line U937 on the complement- mediated binding and degradation of immune complexes and soluble aggregates of IgG (AIgG) bearing C3b or iC3b. It was found that deposition of C3b on AIgG enhanced the binding of AIgO to U937 cells at least two-fold. The C3b-mediated enhancement of binding was abolished by anti-CR1. iC3b-bound to AIgG also enhanced the binding of AIgO to the cells. This binding was only partially reduced by anti-CR3 antibodies, but the combination of anti-CR1 and anti-CR3 fully abolished the iC3b-mediated enhancement of binding. These results suggest that both CR1 and CR3 contribute to the complement-mediated binding and degradation of soluble IC by mononuclear phagocytes. [ABSTRACT FROM AUTHOR]

Published
1988

35. Methods for comparing event rates in intervention studies when the unit of allocation is a cluster.

Author

Donner, A and Klar, N

Abstract

The aim of many research investigations is to compare the proportion of individuals in each of several groups that have a certain characteristic. The unit of allocation for such investigations is often an intact social unit, as in randomizing families, medical practices, schools, or entire communities, to different intervention groups. Standard statistical methods are not appropriate for these designs, since they do not take into account the dependencies among individuals within the same cluster. The authors review the strengths and weaknesses of several approaches for dealing with this problem, using data from a school-based smoking cessation trial. A principal conclusion is that the choice of method should depend on whether or not random allocation is used in the assignment of interventions.

Published
1994
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38. Binding and catabolism of aggregated immunoglobulins bearing C3b or iC3b by U937 cells

Author

Daha, M R, Gorter, A, Leijh, P J, Klar, N, and van Es, L A

Subjects
Protein Denaturation, Immunoglobulin G, parasitic diseases, Receptors, Complement 3b, Humans, chemical and pharmacologic phenomena, Antigen-Antibody Complex, Complement System Proteins, Monocytes, Research Article, Cell Line, Receptors, Complement
Abstract

Mononuclear cells play an important role in the elimination of immune complexes (IC). In the presence of complement (C) the binding and degradation of IC by mononuclear cells is enhanced at least two-fold. The enhancement of binding is caused by a synergistic interaction of the IC with cellular Fc and complement receptors (R). In the present study we have investigated the contribution of the complement receptors CR1 and CR3 of human monocyte cell line U937 on the complement-mediated binding and degradation of immune complexes and soluble aggregates of IgG (AIgG) bearing C3b or iC3b. It was found that deposition of C3b on AIgG enhanced the binding of AIgG to U937 cells at least two-fold. The C3b-mediated enhancement of binding was abolished by anti-CR1. iC3b-bound to AIgG also enhanced the binding of AIgG to the cells. This binding was only partially reduced by anti-CR3 antibodies, but the combination of anti-CR1 and anti-CR3 fully abolished the iC3b-mediated enhancement of binding. These results suggest that both CR1 and CR3 contribute to the complement-mediated binding and degradation of soluble IC by mononuclear phagocytes.

Published
1988

39. A blended knowledge translation initiative to improve colorectal cancer staging [ISRCTN56824239]

Author

Ryan David P, Klar Neil, Last Linda D, Law Calvin HL, Wright Frances C, and Smith Andrew J

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Background A significant gap has been documented between best practice and the actual practice of surgery. Our group identified that colorectal cancer staging in Ontario was suboptimal and subsequently developed a knowledge translation strategy using the principles of social marketing and the influence of expert and local opinion leaders for colorectal cancer. Methods/Design Opinion leaders were identified using the Hiss methodology. Hospitals in Ontario were cluster-randomized to one of two intervention arms. Both groups were exposed to a formal continuing medical education session given by the expert opinion leader for colorectal cancer. In the treatment group the local Opinion Leader for colorectal cancer was detailed by the expert opinion leader for colorectal cancer and received a toolkit. Forty-two centres agreed to have the expert opinion leader for colorectal cancer come and give a formal continuing medical education session that lasted between 50 minutes and 4 hours. No centres refused the intervention. These sessions were generally well attended by most surgeons, pathologists and other health care professionals at each centre. In addition all but one of the local opinion leaders for colorectal cancer met with the expert opinion leader for colorectal cancer for the academic detailing session that lasted between 15 and 30 minutes. Discussion We have enacted a unique study that has attempted to induce practice change among surgeons and pathologists using an adapted social marketing model that utilized the influence of both expert and local opinion leaders for colorectal cancer in a large geographic area with diverse practice settings.

Published
2006
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44. Disclosure of familial genetic information: perceptions of the duty to inform.

Author

Lehmann, Lisa Soleymani, Weeks, Jane C., Lehmann, L S, Weeks, J C, Klar, N, Biener, L, and Garber, J E

Subjects
*MEDICAL communication, *MEDICAL ethics
Abstract

Background: The familial implications of genetic information can lead to a conflict between a physician's duties to maintain patient confidentiality and to inform at-risk relatives about susceptibility to genetic diseases. As genes are discovered that can identify patients at risk of adverse outcomes, this conflict has become the subject of discussion and debate.Methods: We performed a one-time telephone survey of a population-based sample of 200 Jewish women to assess knowledge and attitudes about genetic testing. Attitudes toward sharing genetic test results with family members were evaluated using three hypothetical scenarios that described an easily preventable disease, a disease (breast cancer) in which the only option for prevention was prophylactic mastectomies, and a nonpreventable disease.Results: Nearly all respondents believed that a patient should inform at-risk family members when the disease was preventable (100% and 97% in the relevant scenarios), compared with only 85% who felt a duty to inform at-risk family members about a nonpreventable disease (P <0.001). The proportions of respondents who believed that physicians should seek out and inform at-risk family members against a patient's wishes was much lower: only 18% of respondents to the easily preventable disease scenario, 22% of respondents to the breast cancer scenario, and 16% of respondents to the nonpreventable disease scenario.Conclusions: Most women surveyed believed that genetic information should be shared within families, unless it violated a patient's wishes. These sorts of opinions should be considered in the debate over the confidentiality of genetic information. [ABSTRACT FROM AUTHOR]

Published
2000
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45. Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons

Author

Andrea Perota, Simon C. Robson, David H. Sachs, Cesare Galli, Gilles Blancho, Mark B. Nottle, Emanuele Cozzi, Paolo Simioni, Béatrice Charreau, S. Le Bas-Bernardet, N. Klar, Giovanna Lazzari, Nahzli Dilek, Anthony J. F. D'apice, Evelyn J Salvaris, Irina Lagutina, Nicolas Poirier, Kazuhiko Yamada, Jeremy Hervouet, J. P. Soulillou, Julien Branchereau, Linda Scobie, Claire Crossan, Xavier Tillou, Karine Renaudin, Michael E. Breimer, Bernard Vanhove, M. Châtelais, Y Takeuchi, Peter J. Cowan, M. Diswall, Roberto Duchi, David Minault, Mohamed R. Daha, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Transplant Immunology Unit [Padua, Italy], Padua General Hospital [Padua, Italy], Consorzio per la Ricerca sul Trapianto d'Organ = Consortium for Research in Organ Transplantation (CORIT), Effimune SAS [Nantes], Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Biological & Biomedical Sciences [Glasgow, UK], Glasgow Caledonian University (GCU), University College of London [London] (UCL), Department of Surgery [Gothenburg, Sweden] (Institute of Clinical Sciences), Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Nephrology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Department of Cardiologic, Thoracic and Vascular Sciences [Padua, Italy], Università degli Studi di Padova = University of Padua (Unipd), Department of Medicine [Boston, MA, USA], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), School of Paediatrics and Reproductive Health [Adelaide, Australia], University of Adelaide-Robinson Research Institute, University of Adelaide, Immunology Research Centre [Melbourne, VIC, Australia], St Vincent's Hospital Melbourne [Australia], Transplantation Biology Research Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Avantea [Cremona, Italy], Department of Veterinary Medical Science [Ozzano Emilia, Italy], University of Bologna/Università di Bologna, This work was supported by the European Commission’s Sixth Framework Programme, under the priority thematic area Life Sciences, Genomics and Biotechnology for Health, contract N°. LSHB-CT- 2006- 037377, XENOME and by NIH Grant #5P01AI45897., Le Bihan, Sylvie, Consortium for Research in Organ Transplantation [Padua, Italy] (CORIT), University of Padua [Italy], University of Bologna, Le Bas-Bernardet, S., Tillou, X., Branchereau, J., Dilek, N., Poirier, N., Chatelais, M., Charreau, B., Minault, D., Hervouet, J., Renaudin, K., Crossan, C., Scobie, L., Takeuchi, Y., Diswall, M., Breimer, M.E., Klar, N., Daha, M.R., Simioni, P., Robson, S.C., Nottle, M.B., Salvaris, E.J., Cowan, P.J., D'Apice, A.J.F., Sachs, D.H., Yamada, K., Lagutina, I., Duchi, R., Perota, A., Lazzari, G., Galli, C., Cozzi, E., Soulillou, J.-P., Vanhove, B., and Blancho, G.

Subjects
basic (laboratory) research/science, translational research/science, medicine.medical_treatment, Sus scrofa, Cytomegalovirus, kidney transplantation/nephrology, immunosuppression/immune modulation, 030230 surgery, Pharmacology, Kidney, Virus Replication, xenoantibody, Animals, Genetically Modified, Bortezomib, Gene Knockout Techniques, 0302 clinical medicine, Models, xenotransplantation, Innate, Immunology and Allergy, genetics, Pharmacology (medical), 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Plasma Exchange, Medicine (all), Graft Survival, Immunosuppression, Galactosyltransferases, Boronic Acids, Papio anubis, 3. Good health, Pyrazines, Models, Animal, Heterografts, Complement C1 Inhibitor Protein, Immunosuppressive Agents, medicine.drug, plasmapheresis/plasma exchange, Xenotransplantation, Genetically Modified, Animal models: nonhuman primate, immunosuppressive regimens, Animals, Autoimmune Diseases, Immunity, Innate, Kidney Transplantation, Transplantation, Article, 03 medical and health sciences, Classical complement pathway, biology.animal, medicine, 030304 developmental biology, business.industry, Animal, Immunity, Complement system, immunosuppressive regimen, Immunology, Alternative complement pathway, genetic, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Baboon
Abstract

Galactosyl-transferase KO (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 inhibitor combined with cyclophosphamide or bortezomib with or without 2-3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n = 2) that lost their grafts on days 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (PCMV) replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection.

Published
2015
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46. Tumor-Infiltrating Lymphocytes in Patients With Stage I Triple-Negative Breast Cancer Untreated With Chemotherapy.

Author

Geurts VCM, Balduzzi S, Steenbruggen TG, Linn SC, Siesling S, Badve SS, DeMichele A, Ignatiadis M, Leon-Ferre RA, Goetz MP, Wolff AC, Klar N, Michiels S, Loi S, Adams S, Horlings HM, Sonke GS, Salgado R, and Kok M

Subjects
Humans, Female, Middle Aged, Aged, Adult, Netherlands, Neoadjuvant Therapy, Chemotherapy, Adjuvant, Cohort Studies, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms immunology, Triple Negative Breast Neoplasms mortality, Lymphocytes, Tumor-Infiltrating immunology, Neoplasm Staging
Abstract

Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking., Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs., Design, Setting, and Participants: This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023., Main Outcomes and Measures: The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients., Results: Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater., Conclusions and Relevance: Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.

Published
2024
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47. Severe (level 3) hypoglycaemia occurrence in a real-world cohort of adults with type 1 or 2 diabetes mellitus (iNPHORM, United States).

Author

Ratzki-Leewing A, Black JE, Kahkoska AR, Ryan BL, Zou G, Klar N, Timcevska K, and Harris SB

Subjects
Humans, Adult, Male, United States epidemiology, Middle Aged, Hypoglycemic Agents adverse effects, Prospective Studies, Secretagogues, Insulin adverse effects, Insulin, Regular, Human, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 epidemiology, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 epidemiology, Hypoglycemia chemically induced, Hypoglycemia epidemiology, Hypoglycemia therapy
Abstract

Aims: Among adults with insulin- and/or secretagogue-treated diabetes in the United States, very little is known about the real-world descriptive epidemiology of iatrogenic severe (level 3) hypoglycaemia. Addressing this gap, we collected primary, longitudinal data to quantify the absolute frequency of events as well as incidence rates and proportions., Materials and Methods: iNPHORM is a US-wide, 12-month ambidirectional panel survey (2020-2021). Adults with type 1 diabetes mellitus (T1DM) or insulin- and/or secretagogue-treated type 2 diabetes mellitus (T2DM) were recruited from a probability-based internet panel. Participants completing ≥1 follow-up questionnaire(s) were analysed., Results: Among 978 respondents [T1DM 17%; mean age 51 (SD 14.3) years; male: 49.6%], 63% of level 3 events were treated outside the health care system (e.g. by family/friend/colleague), and <5% required hospitalization. Following the 12-month prospective period, one-third of individuals reported ≥1 event(s) [T1DM 44.2% (95% CI 36.8%-51.8%); T2DM 30.8% (95% CI 28.7%-35.1%), p = .0404, α = 0.0007]; and the incidence rate was 5.01 (95% CI 4.15-6.05) events per person-year (EPPY) [T1DM 3.57 (95% CI 2.49-5.11) EPPY; T2DM 5.29 (95% CI 4.26-6.57) EPPY, p = .1352, α = 0.0007]. Level 3 hypoglycaemia requiring non-transport emergency medical services was more common in T2DM than T1DM (p < .0001, α = 0.0016). In total, >90% of events were experienced by <15% of participants., Conclusions: iNPHORM is one of the first long-term, prospective US-based investigations on level 3 hypoglycaemia epidemiology. Our results underscore the importance of participant-reported data to ascertain its burden. Events were alarmingly frequent, irrespective of diabetes type, and concentrated in a small subsample., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Published
2023
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48. Development and validation of a real-world model to predict 1-year Level 3 (severe) hypoglycaemia risk in adults with diabetes (the iNPHORM study, United States).

Author

Ratzki-Leewing AA, Black JE, Ryan BL, Zou G, Klar N, Webster-Bogaert S, Timcevska K, and Harris SB

Subjects
Male, Adult, Humans, United States epidemiology, Middle Aged, Adolescent, Young Adult, Aged, Aged, 80 and over, Hypoglycemic Agents adverse effects, Glycated Hemoglobin, Blood Glucose Self-Monitoring, Blood Glucose, Insulin therapeutic use, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 epidemiology, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemia etiology
Abstract

Aims: We aimed to develop and internally validate a real-world prognostic model for Level 3 hypoglycaemia risk compatible with outpatient care in the United States., Materials and Methods: iNPHORM is a 12-month, US-based panel survey. Adults (18-90 years old) with type 1 diabetes mellitus or insulin- and/or secretagogue-treated type 2 diabetes mellitus were recruited from a nationwide, probability-based internet panel. Among participants completing ≥ 1 follow-up questionnaire(s), we modelled 1-year Level 3 hypoglycaemia risk using Andersen and Gill's Cox survival and penalized regression with multiple imputation. Candidate variables were selected for their clinical relevance and ease of capture at point-of-care., Results: In total, 986 participants [type 1 diabetes mellitus: 17%; men: 49.6%; mean age: 51 (SD: 14.3) years] were analysed. Across follow-up, 035.1 (95% CI: 32.2-38.1)% reported ≥1 Level 3 event(s), and the rate was 5.0 (95% CI: 4.1-6.0) events per person-year. Our final model showed strong discriminative validity and parsimony (optimism corrected c-statistic: 0.77). Numerous variables were selected: age; sex; body mass index; marital status; level of education; insurance coverage; race; ethnicity; food insecurity; diabetes type; glycated haemoglobin value; glycated haemoglobin variability; number, type and dose of various medications; number of SH events requiring hospital care (past year and over follow-up); type and number of comorbidities and complications; number of diabetes-related health care visits (past year); use of continuous/flash glucose monitoring; and general health status., Conclusions: iNPHORM is the first US-based primary prognostic study on Level 3 hypoglycaemia. Future model implementation could potentiate risk-tailored strategies that reduce real-world event occurrence and overall diabetes burden., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Published
2023
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49. Does Shiftwork Impact Cognitive Performance? Findings from the Canadian Longitudinal Study on Aging (CLSA).

Author

Alonzo R, Anderson KK, Rodrigues R, Klar N, Chiodini P, Montero-Odasso M, and Stranges S

Subjects
Adult, Canada epidemiology, Cognition, Humans, Longitudinal Studies, Male, Aging psychology, Executive Function
Abstract

Few large nationwide studies have investigated the relationship between shiftwork and cognitive performance, and little is known about whether and how psychological distress may impact this relationship. This study aimed to examine: (1) the cross-sectional relationship between shiftwork (yes/no) and some aspects of cognitive performance (declarative memory and executive functioning) and (2) the potential moderating effect of psychological distress among 20,610 community-dwelling adults from the comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA). Differences by sex and retirement status were also explored. Shiftwork was significantly associated with poorer performance for executive functioning (interference condition: ß = 0.47, 95% CI: 0.31 to 0.63; MAT: ß = -0.85, 95% CI: -1.21 to -0.50) but not for declarative memory. Completely and not/partly retired males showed poorer cognitive performance on executive functioning. However, no evidence of a moderating effect by psychological distress was found. Our findings confirm the association between shiftwork and cognitive performance and highlight important health correlates of shiftwork.

Published
2022
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