Publications by authors named "E A Klasen"

65 Publications

Prevalence of symptomatic urinary incontinence and pelvic organ prolapse among women in rural Nepal.

Int Urogynecol J 2020 09 7;31(9):1851-1858. Epub 2019 Dec 7.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Introduction And Hypothesis: Although pelvic floor disorders (PFDs) are a significant public health issue in higher income countries, less is known about these disorders and associated risk factors in low income countries. We aimed to determine prevalence and associated risk factors for stress urinary incontinence (SUI), urge urinary incontinence (UUI), and pelvic organ prolapse (POP) in reproductive age women in Sarlahi District in rural Nepal.

Methods: We conducted a community-based cross-sectional survey of parous, reproductive age women in rural Nepal and screened for pelvic floor disorders using validated screening questions for PFDs. Overall frequency of self-reported symptoms for SUI, UUI, and POP was estimated and compared across demographic and pregnancy history information.

Results: Of 14,469 women available for analysis, the mean (SD, range) age was 33.5 (8.2, 13-52) years, and median (range) number of pregnancies was 4 (1-15). The prevalence of SUI was 24.1% (95% CI: 23.3-24.8), of UUI was 13.5% (95% CI: 13.0-14.1), and of POP was 8.0% (95% CI: 7.5-8.4). Bivariate analysis identified the risk of PFD increased incrementally with age and number of vaginal deliveries; these covariates were highly correlated. Multivariable logistic regression revealed age, vaginal deliveries, and previous pelvic surgeries were independently associated with PFD.

Conclusions: PFDs are common in a community of parous, reproductive age women in rural Nepal. Risk factors for these conditions are similar to risk factors found in higher income countries.
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http://dx.doi.org/10.1007/s00192-019-04129-yDOI Listing
September 2020

Validation of an obstetric fistula screening questionnaire in rural Nepal: a community-based cross-sectional and nested case-control study with clinical examination.

BJOG 2017 May 27;124(6):955-964. Epub 2016 Jul 27.

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objective: To validate a symptom-based fistula screening questionnaire and estimate obstetric fistula (OF) prevalence in rural Nepal.

Design: Cross-sectional and nested case-control study.

Setting: Sarlahi District, Nepal.

Population: Parous, reproductive age women.

Methods: The questionnaire assessed symptoms of vesicovaginal and rectovaginal fistula (VVF and RVF, respectively), stress and urge urinary incontinence (SUI and UUI, respectively), fecal incontinence (FI), and included interviewer observations on the smell and presence of urine and/or stool. All women who screened positive for OF and a randomly selected group of women who screened negative for OF were included in a nested case-control study (one case, four normal controls, and four incontinent controls) and underwent confirmatory clinical examinations.

Main Outcome Measures: Clinically confirmed OF, and questionnaire sensitivity (Se) and specificity (Sp).

Results: Of the 16 893 women who completed cross-sectional screening, 68 were screened-positive cases. Fifty-five (82%) screened-positive cases, 203 screened-negative normal controls, and 203 screened-incontinent controls participated in the case-control study, which confirmed one case of VVF and one case of both VVF and RVF without any false-negative cases. For VVF, the screening tool demonstrated Se 100% (95% CI 34.2-100.0%), Sp 86.9% (95% CI 83.3-89.9%), and estimated VVF prevalence as 12 per 100 000 (95% CI 3-43); for RVF, it demonstrated Se 100% (95% CI 20.7-100.0), Sp 99.8% (95% CI 98.6-100.0), and estimated RVF prevalence as 6 per 100 000 (95% CI 1-34).

Conclusions: The OF screening questionnaire demonstrated high sensitivity and specificity in this low-prevalence setting.

Tweetable Abstract: Community-based obstetric fistula screening tool validation study, Nepal, n = 16 893: High Se, Sp & feasibility.
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http://dx.doi.org/10.1111/1471-0528.14202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272910PMC
May 2017

Association of Roadway Proximity with Indoor Air Pollution in a Peri-Urban Community in Lima, Peru.

Int J Environ Res Public Health 2015 Oct 26;12(10):13466-81. Epub 2015 Oct 26.

Division of Pulmonary and Critical Care, School of Medicine, John Hopkins University, Baltimore, MD 21224, USA.

The influence of traffic-related air pollution on indoor residential exposure is not well characterized in homes with high natural ventilation in low-income countries. Additionally, domestic allergen exposure is unknown in such populations. We conducted a pilot study of 25 homes in peri-urban Lima, Peru to estimate the effects of roadway proximity and season on residential concentrations. Indoor and outdoor concentrations of particulate matter (PM₂.₅), nitrogen dioxide (NO₂), and black carbon (BC) were measured during two seasons, and allergens were measured in bedroom dust. Allergen levels were highest for dust mite and mouse allergens, with concentrations above clinically relevant thresholds in over a quarter and half of all homes, respectively. Mean indoor and outdoor pollutant concentrations were similar (PM₂.₅: 20.0 vs. 16.9 μg/m³, BC: 7.6 vs. 8.1 μg/m³, NO₂: 7.3 vs. 7.5 ppb), and tended to be higher in the summer compared to the winter. Road proximity was significantly correlated with overall concentrations of outdoor PM₂.₅ (rs = -0.42, p = 0.01) and NO₂ (rs = -0.36, p = 0.03), and outdoor BC concentrations in the winter (rs = -0.51, p = 0.03). Our results suggest that outdoor-sourced pollutants significantly influence indoor air quality in peri-urban Peruvian communities, and homes closer to roadways are particularly vulnerable.
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http://dx.doi.org/10.3390/ijerph121013466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627043PMC
October 2015

Low correlation between household carbon monoxide and particulate matter concentrations from biomass-related pollution in three resource-poor settings.

Environ Res 2015 Oct 31;142:424-31. Epub 2015 Jul 31.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA; Program in Global Disease Epidemiology and Control, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA; CRONICAS Center of Excellence in Chronic Diseases, Universidad Peruana Cayetano Heredia, Lima, Peru. Electronic address:

Household air pollution from the burning of biomass fuels is recognized as the third greatest contributor to the global burden of disease. Incomplete combustion of biomass fuels releases a complex mixture of carbon monoxide (CO), particulate matter (PM) and other toxins into the household environment. Some investigators have used indoor CO concentrations as a reliable surrogate of indoor PM concentrations; however, the assumption that indoor CO concentration is a reasonable proxy of indoor PM concentration has been a subject of controversy. We sought to describe the relationship between indoor PM2.5 and CO concentrations in 128 households across three resource-poor settings in Peru, Nepal, and Kenya. We simultaneously collected minute-to-minute PM2.5 and CO concentrations within a meter of the open-fire stove for approximately 24h using the EasyLog-USB-CO data logger (Lascar Electronics, Erie, PA) and the personal DataRAM-1000AN (Thermo Fisher Scientific Inc., Waltham, MA), respectively. We also collected information regarding household construction characteristics, and cooking practices of the primary cook. Average 24h indoor PM2.5 and CO concentrations ranged between 615 and 1440 μg/m(3), and between 9.1 and 35.1 ppm, respectively. Minute-to-minute indoor PM2.5 concentrations were in a safe range (<25 μg/m(3)) between 17% and 65% of the time, and exceeded 1000 μg/m(3) between 8% and 21% of the time, whereas indoor CO concentrations were in a safe range (<7 ppm) between 46% and 79% of the time and exceeded 50 ppm between 4%, and 20% of the time. Overall correlations between indoor PM2.5 and CO concentrations were low to moderate (Spearman ρ between 0.59 and 0.83). There was also poor agreement and evidence of proportional bias between observed indoor PM2.5 concentrations vs. those estimated based on indoor CO concentrations, with greater discordance at lower concentrations. Our analysis does not support the notion that indoor CO concentration is a surrogate marker for indoor PM2.5 concentration across all settings. Both are important markers of household air pollution with different health and environmental implications and should therefore be independently measured.
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http://dx.doi.org/10.1016/j.envres.2015.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932836PMC
October 2015

Behavioral attitudes and preferences in cooking practices with traditional open-fire stoves in Peru, Nepal, and Kenya: implications for improved cookstove interventions.

Int J Environ Res Public Health 2014 Oct 3;11(10):10310-26. Epub 2014 Oct 3.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

Global efforts are underway to develop and promote improved cookstoves which may reduce the negative health and environmental effects of burning solid fuels on health and the environment. Behavioral studies have considered cookstove user practices, needs and preferences in the design and implementation of cookstove projects; however, these studies have not examined the implications of the traditional stove use and design across multiple resource-poor settings in the implementation and promotion of improved cookstove projects that utilize a single, standardized stove design. We conducted in-depth interviews and direct observations of meal preparation and traditional, open-fire stove use of 137 women aged 20-49 years in Kenya, Peru and Nepal prior in the four-month period preceding installation of an improved cookstove as part of a field intervention trial. Despite general similarities in cooking practices across sites, we identified locally distinct practices and norms regarding traditional stove use and desired stove improvements. Traditional stoves are designed to accommodate specific cooking styles, types of fuel, and available resources for maintenance and renovation. The tailored stoves allow users to cook and repair their stoves easily. Women in each setting expressed their desire for a new stove, but they articulated distinct specific alterations that would meet their needs and preferences. Improved cookstove designs need to consider the diversity of values and needs held by potential users, presenting a significant challenge in identifying a "one size fits all" improved cookstove design. Our data show that a single stove design for use with locally available biomass fuels will not meet the cooking demands and resources available across the three sites. Moreover, locally produced or adapted improved cookstoves may be needed to meet the cooking needs of diverse populations while addressing health and environmental concerns of traditional stoves.
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http://dx.doi.org/10.3390/ijerph111010310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210980PMC
October 2014

Feasibility intervention trial of two types of improved cookstoves in three resource-limited settings: study protocol for a randomized controlled trial.

Trials 2013 Oct 10;14:327. Epub 2013 Oct 10.

Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, 1800 Orleans Ave, Suite 9121, Baltimore, MD 21205, USA.

Background: Exposure to biomass fuel smoke is one of the leading risk factors for disease burden worldwide. International campaigns are currently promoting the widespread adoption of improved cookstoves in resource-limited settings, yet little is known about the cultural and social barriers to successful improved cookstove adoption and how these barriers affect environmental exposures and health outcomes.

Design: We plan to conduct a one-year crossover, feasibility intervention trial in three resource-limited settings (Kenya, Nepal and Peru). We will enroll 40 to 46 female primary cooks aged 20 to 49 years in each site (total 120 to 138).

Methods: At baseline, we will collect information on sociodemographic characteristics and cooking practices, and measure respiratory health and blood pressure for all participating women. An initial observational period of four months while households use their traditional, open-fire design cookstoves will take place prior to randomization. All participants will then be randomized to receive one of two types of improved, ventilated cookstoves with a chimney: a commercially-constructed cookstove (Envirofit G3300/G3355) or a locally-constructed cookstove. After four months of observation, participants will crossover and receive the other improved cookstove design and be followed for another four months. During each of the three four-month study periods, we will collect monthly information on self-reported respiratory symptoms, cooking practices, compliance with cookstove use (intervention periods only), and measure peak expiratory flow, forced expiratory volume at 1 second, exhaled carbon monoxide and blood pressure. We will also measure pulmonary function testing in the women participants and 24-hour kitchen particulate matter and carbon monoxide levels at least once per period.

Discussion: Findings from this study will help us better understand the behavioral, biological, and environmental changes that occur with a cookstove intervention. If this trial indicates that reducing indoor air pollution is feasible and effective in resource-limited settings like Peru, Kenya and Nepal, trials and programs to modify the open burning of biomass fuels by installation of low-cost ventilated cookstoves could significantly reduce the burden of illness and death worldwide.

Trial Registration: ClinicalTrials.gov NCT01686867.
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http://dx.doi.org/10.1186/1745-6215-14-327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852602PMC
October 2013

Societal output and use of research performed by health research groups.

Health Res Policy Syst 2010 Oct 12;8:30. Epub 2010 Oct 12.

Technopolis Group the Netherlands, Herengracht 141, 1015 BH Amsterdam, the Netherlands.

The last decade has seen the evaluation of health research pay more and more attention to societal use and benefits of research in addition to scientific quality, both in qualitative and quantitative ways. This paper elaborates primarily on a quantitative approach to assess societal output and use of research performed by health research groups (societal quality of research). For this reason, one of the Dutch university medical centres (i.e. the Leiden University Medical Center (LUMC)) was chosen as the subject of a pilot study, because of its mission to integrate top patient care with medical, biomedical and healthcare research and education. All research departments were used as units of evaluation within this university medical centre.The method consisted of a four-step process to reach a societal quality score per department, based on its (research) outreach to relevant societal stakeholders (the general public, healthcare professionals and the private sector). For each of these three types of stakeholders, indicators within four modes of communication were defined (knowledge production, knowledge exchange, knowledge use and earning capacity). These indicators were measured by a bottom-up approach in a qualitative way (i.e. all departments of the LUMC were asked to list all activities they would consider to be of societal relevance), after which they were converted into quantitative scores. These quantitative scores could then be compared to standardised scientific quality scores that are based on scientific publications and citations of peer-reviewed articles.Based on the LUMC pilot study, only a weak correlation was found between societal and scientific quality. This suggests that societal quality needs additional activities to be performed by health research groups and is not simply the consequence of high scientific quality. Therefore we conclude that scientific and societal evaluation should be considered to be synergistic in terms of learning for the future, accountability and advocacy.This quantitative approach to assess societal quality in a quantitative sense is based on indicators that function as proxies for society quality on different levels, based on the communication of researchers with their societal stakeholders (i.e. knowledge production, knowledge exchange and knowledge use). The methodology presented is just a first attempt to compare scientific quality scores (publication and citation scores) with societal quality scores in a quantitative way. This comparison can be used by organisations (e.g. university medical centres) in their planning and control cycle.
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http://dx.doi.org/10.1186/1478-4505-8-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964714PMC
October 2010

[Physicians and scientific research: slight decline of the numbers of physicians with a doctoral degree].

Ned Tijdschr Geneeskd 2006 Jul;150(27):1509-12

Koninklijke Nederlandse Akademie van Wetenschappen, Postbus 19.121, 1000 GC Amsterdam.

Objective: To establish whether the number of physicians interested in a career in academia (i.e. research) is declining.

Design: Descriptive.

Method: The researchers analysed the pre- and post-doctoral careers of PhD students at 3 university medical centres (VU Amsterdam, Nijmegen and Maastricht) in 4 separate reference years (1989, 1994, 1999 and 2003), using information from doctoral dissertations and the Dutch medical address book. The researchers recorded the gender of the students and the timing of the doctorate in relation to specialist training, university education and employment, as applicable.

Results: The total number of dissertations produced at the 3 medical faculties in the 4 reference years increased gradually by nearly a factor of 2 (1989: 112; 1994: 152; 1999: 198; 2003: 213). In terms of absolute numbers, the number of dissertations authored by physicians increased from 1989 to 1994 and again in 1999 (64, 90 and 105), but decreased slightly in 2003 (96). The percentage of female physicians obtaining a doctorate doubled during this period (1989: 9/64 (14); 2003: 28/96 (29)). Increasingly, physicians prepared their dissertation before or during their training as specialists or general practitioners (1989: 15/64 (23%); 2003: 51/96 (53%)). Ofthe clinical specialists who had received their doctorate, approximately half continued to work in an academic setting after obtaining their degree. This percentage remained approximately the same in all reference years (1989: 13/26 (50); 1994:19/35 (54); 1999: 21/45 (47); 2003: 21/40 (53)).

Conclusion: Although the number of physicians performing scientific research as part of their doctoral degree project declined slightly in 2003 following an initial rise, our data indicate no cause for major concern. One reason may be increased interest in Clinical Research Fellow programmes. However, the future of medical research would look brighter if young physicians with doctorates had better career prospects within academic centres. To follow the academic careers of clinicians in The Netherlands, a national registry is needed to collect the type of data analysed in this study continually.
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July 2006

[Dutch medical specialists as authors of scientific publications in English on clinical drug research (1997/'03)].

Ned Tijdschr Geneeskd 2005 Sep;149(36):1994-2000

Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Sociale Geneeskunde, Meibergdreef 15, 1105 AZ Amsterdam.

Objective: To determine the number and type of medical specialists in Dutch hospitals that were authors of scientific papers published in English in the field of clinical drug research in the period 1997/'03.

Design: Descriptive.

Method: PubMed was searched for articles on clinical drug research published in February 1997-January 2003. (Co)authors were included if they were registered in the Geneeskundig Adresboek 2002-2003 (Medical Address Book 2002-2003) as a medical specialist working in a hospital. Hospitals were categorized as academic, non-academic teaching, general or non-affiliated. Journals were categorized by the type of published research: fundamental or biomedical, disease-specific, or specialty-specific.

Results: A total of 1776 articles in 426 journals were retrieved with at least 1 medical specialist listed as a (co)author. 1728 medical specialists were identified as authors, which represents 11% of the 16.065 registered medical specialists in The Netherlands. Most authors were involved in the nonsurgical specialties, primarily internist subspecialties, followed by paediatrics, cardiology, and neurology. The authors were employed in nearly all Dutch hospitals. The 1728 specialists had a total of 4952 authorships; 57% of the authors and 70% of the authorships came from academic hospitals. The average impact factor, the number of articles and the number ofauthorships were greatest in the disease-specific journal category. In the period 1997/'03 the number of authorships from non-academic teaching hospitals and general hospitals decreased, while the number of authorships from academic hospitals increased, particularly with regard to the number of co-authorships.
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September 2005

[A case of fraud in a neurological pharmaceutical clinical trial].

Ned Tijdschr Geneeskd 2003 Jul;147(28):1372-7

Universiteit Maastricht, ZonMw, Postbus 93.245, 2509 AE Den Haag.

This paper describes the laborious and lengthy path to clarification and disclosure in a case of fraud in a neurological pharmaceutical clinical trial in the Netherlands. A Dutch neurologist was suspected of irregularities within the context of the 'European stroke prevention study 2' (ESPS-2), a multicentre study into medicinal prophylaxis in patients who had suffered a stroke. The Netherlands Society of Neurology (NVN) established an independent inquiry committee for further investigation of the case. The identity of 425 of the 438 patients (97%) included in the trial by the neurologist could be retrieved. The majority of these patients were known to the neurologist with cerebral infarct. For a sample of 115 patients, the general practitioners (GPs) were contacted by means of a questionnaire. Ninety percent of the responding GPs were unaware of their patients' participation in the pharmaceutical clinical trial. A total of forty patients were asked by their GP about participation: 36 (90%; 95%-CI: 76-97) indicated that they had not participated in the trial, and 4 could not remember. The committee concluded that the neurologist had committed fraud, in the sense that he had used the names of existing patients without these patients actually being enrolled in the study. The report of the independent committee was not made public; the committee and the NVN board differed in opinion on the interpretation and implications of the agreements regarding this subject. Following prolonged legal action, the regional Disciplinary Board suspended the neurologist from practice for one year and the court of law sentenced him to 180 days imprisonment or a fee of 130,000 Euro. Based on the experience gained from this case, recommendations in case of suspicion of fraud are discussed, such as the timely appointment of an independent inquiry committee and the establishment of unambiguous agreements regarding the disclosure of the results of the investigation. Possible legal implications should be considered in advance by the organisations involved; statutes should provide regulations for procedural rules. In the Netherlands there now exists a National Body for Scientific Integrity and a committee for the Scientific Integrity of Healthcare Research to prevent scientific misconduct and to stimulate reporting and appropriate handling of this problem.
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July 2003

[Reporting of scientific misconduct in health care research].

Ned Tijdschr Geneeskd 2002 Aug;146(35):1622-4

Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Den Haag.

The incidence of scientific dishonesty in the Netherlands is not known, yet experiences at both the NWO (the Netherlands Organization for Scientific Research) and Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) indicate that there must be several cases per year. For scientific fraud to be prevented students and researchers should receive thorough teaching, and in research laboratories an emphasis should be placed upon integrity. The Academic Medical Centre in Amsterdam has published a research protocol which is perfect for internal use. The Royal Netherlands Academy of Arts and Sciences publishes brochures on good research practice for researchers, teachers and students. The NWO and the Vereniging van Universiteiten (Dutch Association of Universities) have set up a committee for scientific integrity to function as a fallback mechanism and to assess the institutional procedures or to repeat the inquiries. As healthcare research institutions other than universities are involved since authorities are not always objective, an independent committee has been established to assess complaints about scientific dishonesty, the Scientific Integrity Health Research. Like the Committee on Publication Ethics it will publish its cases anonymously on an annual basis. Its judgments will be communicated to the people involved and the proper authorities.
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August 2002

[A comparative study of the expenditures on health research in 7 western countries in 1997 places the Netherlands at the bottom of the list].

Ned Tijdschr Geneeskd 2002 Jul;146(29):1369-74

Leids Universitair Medisch Centrum, Vakgroep Metamedica, Leiden.

Objective: To compare the expenditures on health research in the Netherlands with those in other Western countries.

Design: Descriptive.

Method: The expenditures on health research in 1997 were determined for the Netherlands, the United Kingdom, Germany, Norway, Denmark, Sweden and the USA and subsequently classified into: governmental funding for research in medical faculties or clusters; grants from MHRCs and other bodies; and private funding from industry and charities. The sources of information were the total research budgets 2002 of the Dutch Ministry of Education, Culture and Science, annual reports from charities, the Dutch Central Statistical Bureau and, for foreign countries, MHRCs or comparable institutions.

Results: In 1997, the Netherlands spent the equivalent of 855 million US dollars on health research (extremes of the investigated countries: 382 (Norway)-32,283 (USA)). This was less than in the other countries, whether calculated per capita, in US dollars (55 (Netherlands)-159 (Sweden)), as a promillage of the gross national product (2.27 (Netherlands)-5.84 (Sweden)), or as a percentage of the total expenditures for health care (2.62 (Netherlands)-7.54 (UK)). Especially the industrial expenditures on health research in the Netherlands were low, but the governmental expenditures were also lower than in the other countries.
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July 2002

[Research proposals submitted to the Dutch Investigative Medicine Fund; evaluation of the scientific quality by the Council for Scientific Research (NWO)].

Ned Tijdschr Geneeskd 2001 Jan;145(1):37-40

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), gebied Medische Wetenschappen (MW), Postbus 93.138, 2509 AC Den Haag.

The Council for Medical and Health Research (MW-NWO) assessed the scientific quality of research proposals submitted to the Dutch Investigative Medicine Fund, and analysed if there had been changes over time in the proportion of proposals which the MW-NWO advised to reject, the role of reports of external reviewers and the most important methodological flaws. In the period 1995-1999 'reject' had been advised for an average of 50% of the proposals, with a tendency to a smaller proportion in recent years. In nearly half of the proposals the judgements of external reviewers were not in agreement with each other. There was only a weak correlation between the judgements of the reviewers and the final advice of NWO. Among the most important flaws mentioned in the NWO advice were: efficacy not proven (a prerequisite for the Fund), proposed study not needed to solve the policy problem and methodological flaws, e.g. design and power calculation not adequate, deficiencies of inclusion and exclusion criteria.
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January 2001

[The SGO Health Research Promotion Program. XIV. Final evaluation].

Ned Tijdschr Geneeskd 1999 Jan;143(1):41-5

Nederlandse Organisatie voor Wetenschappelijk Onderzock, Gebied Medische Wetenschappen, Den Haag.

In the Netherlands, the SGO Health Research Promotion Programme was carried out from 1986 until 1997. The aim of the programme was to strengthen patient-oriented clinical research in specific fields of medicine. Some of the programme sections certainly produced a number of good publications in established national and international journals, but the programme advisory committee's main objective was to bring about a cultural change in the field of health care investigation: awareness of the principle that scientific and notably patient-centred investigation has a place in its own right in research, education and care. This resulted in a large diversity of methods of stimulation ranging from stimulation of co-operation between researchers, training of physician researchers, support of methodology development, stimulation of education and postgraduate training, to establishment of actual institutes for clinical scientific research. Patient-oriented research is the necessary link within the continuum of health research, medical education and care. Changing social and demographic developments ask for continuous innovation of this type of research. Top-down steering, as practised by the SGO, can be necessary and effective to reach this innovation.
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January 1999

Partnership between south and north crystallizes around malaria.

Science 1998 Jan;279(5350):498-9

Netherlands Organisation for Scientific Research, The Hague, Netherlands.

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http://dx.doi.org/10.1126/science.279.5350.498DOI Listing
January 1998

[AGIKO (Clinical Research Fellow); a training model aimed at enhancement of clinical scientific research].

Ned Tijdschr Geneeskd 1997 Jun;141(25):1247-51

Nederlandse Organisatie voor Wetenschappelijk Onderzoek, gebied Medische Wetenschappen, Den Haag.

The enhancement of clinical scientific research in the Netherlands is being stimulated to a substantial extent by the introduction and stimulation of a training model aimed at the combined training of physicians to both a general practitioner or specialist and a clinical researcher, the AGIKO (Clinical Research Fellow). The model has been recognized by the Central College for Recognition and Registration of Medical Specialists. Extra stimulation by the section Medical Sciences of the Netherlands Organization for Scientific Research (MW-NWO) makes it possible to appoint AGIKOs on second or third flows of funds but also within the first flow of funds. During the last two years, 25 AGIKO applications from ten medical specialisms have been approved. The AGIKO model may help to meet (expected) needs for future clinical-medical research workers in specific research areas.
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June 1997

[Peer review when applying for a subsidy].

Authors:
E C Klasen

Ned Tijdschr Geneeskd 1997 Jun;141(23):1161-2

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June 1997

Different characteristics of ferrochelatase in cultured fibroblasts of erythropoietic protoporphyria patients and normal controls.

Biochim Biophys Acta 1990 Jul;1039(3):339-42

Sylvius Laboratories, Department of Medical Biochemistry, Leiden, The Netherlands.

Ferrochelatase activity was measured in crude extracts of fibroblasts, obtained from erythropoietic protoporphyria patients and healthy controls. The enzyme activity in erythropoietic protoporphyria fibroblasts was about 50% lower, compared to the controls. The sulfhydryl-oxidising reagent diamide inhibited the normal enzyme by about 50%, whereas ferrochelatase from erythropoietic protoporphyria fibroblasts was completely insensitive to the reagent. Pb2+ inhibits ferrochelatase activity by reacting with essential sulfhydryl groups. Low concentrations of Pb2+ inhibited the normal enzyme by 56%, but the mutant enzyme by only 8%. The photodynamic activity of bound mesoporphyrin substrate caused a biphasic inactivation of the normal enzyme. During the first 5 min of illumination a fast decrease of enzyme activity occurred to about 60% of the initial value. Experimental evidence indicates that this first phase of inactivation is caused by photooxidation of sulfhydryl groups. During further illumination inactivation continued at a much slower rate. With ferrochelatase from erythropoietic protoporphyria fibroblasts only the second, slow phase of photodynamic inactivation was observed. These observations suggest a mutation of ferrochelatase in erythropoietic protoporphyria, affecting the reactivity of sulfhydryl groups, involved in the catalytic activity of the enzyme.
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http://dx.doi.org/10.1016/0167-4838(90)90268-kDOI Listing
July 1990

Use of bispecific hybrid antibodies for the development of a homogeneous enzyme immunoassay.

J Immunol Methods 1989 Sep;123(1):131-40

Cattedra di Immunologia dell'Università di Genova, Italy.

Hybrid bispecific monoclonal antibodies reacting with carcinoembryonal antigen (CEA) and with the E. coli enzyme beta-galactosidase (GZ) were produced by fusion of hybridomas or chemical linkage of half-antibodies. Since the original anti-GZ antibody used in these experiments was capable of protecting GZ from thermal denaturation, it was possible, by hybridizing it with two different non-competitive anti-CEA antibodies, to design a homogeneous enzyme immunoassay for quantitation of CEA. In fact, a mathematical analysis of the reaction indicates that, under appropriate concentrations of the reactants, circular complexes can be formed which contain the two hybrid antibodies, the GZ enzyme and the CEA antigen. The stability of these complexes can be expected to be substantially greater than that of the more labile CEA-free GZ-antibody complexes, prompting a significant increase in the amount of enzyme molecules which are bound to antibody and are consequently protected from thermal denaturation. These expectations were supported by experimental results: under appropriate conditions, heat-resistant enzyme activity was indeed proportional to concentration of CEA in the range up to 75 ng/ml. As predicted by theory, however, in the presence of excess CEA - in fact at CEA concentrations which are higher than those of possible clinical relevance - circular complexes tended to open up, leading to a marked prozone effect.
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http://dx.doi.org/10.1016/0022-1759(89)90037-9DOI Listing
September 1989

Exclusion of the dysplastic nevus syndrome (DNS) locus from the short arm of chromosome 1 by linkage studies in Dutch families.

Genomics 1989 Jul;5(1):61-4

Department of Human Genetics, State University, Leiden, The Netherlands.

Familial dysplastic nevus syndrome (DNS) is an autosomal dominant premalignant condition characterized by multiple large moles of variable size and color and a strongly increased risk for cutaneous malignant melanoma. In order to determine the chromosomal localization of the DNS gene, linkage studies were initiated in six large Dutch families. No support was obtained for linkage between the loci for DNS and the rhesus blood group on chromosome 1. Data from additional markers (DNF15S1, D1Z2, FUCA1, D1S17, D1S57, and PGM1) make it possible to exclude the DNS gene from the short arm of chromosome 1 in these Dutch families.
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http://dx.doi.org/10.1016/0888-7543(89)90086-4DOI Listing
July 1989

A Pro----Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen.

Hum Genet 1989 Feb;81(3):264-8

Department of Human Genetics, Sylvius Laboratories, State University of Leiden, The Netherlands.

The molecular defect has been elucidated in the alpha-1-antitrypsin (PI) gene of a patient with a serum level of only 5 mg/100 ml and a PI M-like phenotype, designated PI MHeerlen. The restriction fragment patterns obtained by probes covering the whole gene and flanking sequences were normal, suggesting no major rearrangements. The nucleotide sequence of the exons, intron/exon junctions, and a part of the promoter region is similar to that of a PI M1(Ala213) gene except for an C----T mutation in codon 369, causing a Pro----Leu substitution. Haplotype analysis and oligonucleotide hybridization studies demonstrated the homozygous state of the mutation in the index case. It is most likely that the Pro369----Leu substitution is responsible for the low serum alpha-1-antitrypsin concentration of the patient because this mutation is solely confined to the PI MHeerlen allele and no other relevant mutations could be revealed. As proline is important for the secondary and tertiary structure of proteins, the mutation may cause an abnormal processing of the nascent polypeptide. The same mutation was observed in two unrelated subjects known to carry a PI allele giving a low serum alpha-1-antitrypsin level.
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http://dx.doi.org/10.1007/BF00279001DOI Listing
February 1989

Apolipoprotein E polymorphism in The Netherlands and its effect on plasma lipid and apolipoprotein levels.

Hum Genet 1988 Nov;80(3):287-92

Department of Human Genetics, State University Leiden, The Netherlands.

By isoelectric focusing of delipidated sera followed by immunoblotting we studied the apolipoprotein (apo) E polymorphism in 2018 randomly selected 35-years-old males from three different areas in the Netherlands. Comparison of the APOE allele (E*2, E*3, and E*4) frequencies estimated in this study with those reported for several other population samples showed that there are marked differences between the Dutch population and the populations of Japan, New Zealand, Finland, and the United States. These differences in APOE allele frequencies appeared to be mainly due to differences in frequencies of the E*2 allele (decreased in Japan and Finland; increased in New Zealand) and the E*4 allele (increased in Finland; decreased in Japan and the United States). No difference in APOE allele frequencies was found between the Dutch population and the populations of West Germany and Scotland. Measurements of plasma cholesterol and apo B and E concentrations showed that the E*4 allele is associated with elevated plasma cholesterol and apo B levels and with decreased apo E concentrations, whereas the opposite is true for the E*2 allele. In the Dutch population, the sum of average allelic effects of the common APOE alleles on plasma cholesterol and apo B levels is 6.8% and 14.2%, respectively, of the total population mean. The total average allelic effect on plasma apo E concentrations was more pronounced (50.1%), suggesting that the APOE alleles primarily affect apo E concentrations rather than plasma cholesterol and apo B levels. This hypothesis is sustained by the observation that for plasma apo E levels the genetic variance associated with the APOE gene locus contributed about 18% to the total phenotypic variance. For plasma cholesterol and apo B this contribution was only 1.4% and 2.3% and is relatively low as compared with that reported for other population samples.
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http://dx.doi.org/10.1007/BF01790099DOI Listing
November 1988

Cloning and characterization of an alpha 1-antitrypsin like gene 12 KB downstream of the genuine alpha 1-antitrypsin gene.

Biochem Biophys Res Commun 1988 Sep;155(2):634-42

Department of Human Genetics, Sylvius Laboratories, State University, Leiden, The Netherlands.

Cosmid clones containing alpha 1-antitrypsin (alpha 1AT) gene sequences were observed to contain alpha 1AT-like sequences approximately 12 kb downstream of the authentic alpha 1AT gene. Restriction mapping suggested the alpha 1AT-like gene lacks promoter sequences. Cosmid clones from one library contained a truncated alpha 1AT-like gene with a deletion encompassing 1745 bp, including the whole exon IV and part of exon V. Sequencing of exon II of this truncated gene revealed a nucleotide homology of 76% but included critical mutations in the start codon (ATG - greater than ATA) and the 3' exon-intron junction. These results strongly suggest that the truncated alpha 1AT-like gene is a pseudogene, which is present at a frequency of 0.30 in the Dutch population.
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http://dx.doi.org/10.1016/s0006-291x(88)80542-4DOI Listing
September 1988

Linkage studies in facioscapulohumeral muscular dystrophy.

Muscle Nerve 1988 Aug;11(8):833-5

Department of Neurology, State University of Leiden, the Netherlands.

Possible linkage between the locus for autosomal dominant facioscapulo-humeral muscular dystrophy and the locus for the constant region of the heavy chains of the IgG immunoglobulins (Gm) was tested in 1 kindred (23 affected and 18 unaffected sibs) using the polymorphic DNA probe D14S1, which is known to be closely linked with Gm. No linkage between the loci for the disease and the probe was found, and the lod scores suggested that the locus for facioscapulohumeral muscular dystrophy is not situated on the distal part of the long arm of chromosome 14.
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http://dx.doi.org/10.1002/mus.880110806DOI Listing
August 1988

Interactions among stimulated human polymorphonuclear leucocytes, released elastase and bronchial antileucoprotease.

Clin Sci (Lond) 1988 Jul;75(1):53-62

Department of Pulmonology, University Hospital of Leiden, The Netherlands.

1. We investigated the effect of stimulated human polymorphonuclear leucocytes (PMN's) on both the antitrypsin and anti-elastase activity of bronchial antileucoprotease (ALP). 2. Incubation of ALP with stimulated human PMN's resulted in a rapid loss of anti-elastase activity which paralleled that of the antitrypsin activity, suggesting that both inhibitor activities are represented by the same active site. 3. The myeloperoxidase-oxidizing system was found to be responsible for the inactivation of ALP. 4. The oxidized inhibitor was unable to form stable complexes with PMN elastase but was resistant to breakdown by proteolytic enzymes from stimulated PMN's. 5. It was observed that stimulated cells are capable of releasing elastase which shows full activity in the presence of a large molar excess of ALP. 6. We conclude from this study that stimulated PMN's are able to inactivate ALP by which released elastase is able to express enzymatic activity in spite of the presence of this low-molecular-weight inhibitor. Thus, inactivation of ALP by triggered PMN's may contribute to destructive processes in which elastase is thought to be a mediator.
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http://dx.doi.org/10.1042/cs0750053DOI Listing
July 1988

The flaccid lung syndrome and alpha 1-protease inhibitor deficiency.

Chest 1988 Apr;93(4):831-5

St. Antonius Hospital, Nieuwegein, The Netherlands.

We examined breathing mechanics and alpha 1PI deficiency in 1,850 unrelated male subjects with various lung complaints. The loss in lung elasticity appeared to be significantly more pronounced in ZZ individuals as compared to MM, MS and also MZ individuals. The MZ group did not differ significantly in this respect from MM individuals. This implies that the excess risk of developing a flaccid lung (C greater than 1 kPa-1) due to the partial alpha 1-antitrypsin deficiency is negligible. PI MZ and PI ZZ frequencies are significantly higher in the population with flaccid lung compared to control subjects. Furthermore, it was found that the increase in residual volume in smokers is independent of the PI type.
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http://dx.doi.org/10.1378/chest.93.4.831DOI Listing
April 1988

Helping dyslexics-A task for sharing.

Authors:
E Klasen

Ann Dyslexia 1988 Jan;38(1):22-30

, Munich, West Germany.

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http://dx.doi.org/10.1007/BF02648246DOI Listing
January 1988

Alpha-1-antitrypsin phenotypes and serum concentrations in duodenal ulcer patients in The Netherlands.

Digestion 1988 ;39(1):20-5

Department of Gastroenterology and Hepatology, Leiden University Hospital, The Netherlands.

Hereditary alpha 1-antitrypsin (alpha 1-AT) deficiency has been suggested to be associated with peptic ulcer disease. Since the serum concentration of the enzyme is the result of both hereditary and nonhereditary factors, we have studied not only the serum levels but also the alpha 1-AT electrophoretic variants in 177 Dutch patients with duodenal ulcer disease and compared with 357 healthy blood donors. No relation was found between any of the alpha 1-antitrypsin phenotypes and duodenal ulcer disease. Serum levels of alpha 1-AT were significantly higher than in the controls in the patients. This study does not support an association between hereditary alpha 1-AT deficiency and duodenal ulcer disease, and makes therefore a possible role of such a deficiency in the etiology of peptic ulcer disease highly unlikely.
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http://dx.doi.org/10.1159/000199603DOI Listing
August 1988