[Pre-randomisation in study designs: getting past the taboo]. / Prerandomisatie bij wetenschappelijk onderzoek: een taboe doorbroken.

In October 2006 the Dutch Ministry of Health, Welfare and Sport announced that the use of pre-randomisation in study designs is admissible and not in conflict with the Dutch Medical Research in Human Subjects Act. With pre-randomisation, the conventional sequence of obtaining informed consent followed by randomisation is reversed. According to the original pre-randomisation design (Zelen design), participants are randomised before they are asked to consent; after randomisation, only participants in the experimental group are asked to consent to treatment and effect measurement. In the past, pre-randomisation has seldom been used, and when it was, it was often under the wrong circumstances. Awareness regarding the ethical, legal and methodological objections to pre-randomisation is increasing. About a decade ago, we illustrated the applicability and acceptability of pre-randomisation by means of a fictitious heroin provision trial. In general, pre-randomisation is justified if valid evaluation of the effects of an intervention is impossible using a conventional randomised design, e.g., if knowledge of the intervention may lead to non-compliance or drop-out in the control group, or when the intervention is an educational programme. Other requirements for pre-randomisation include the following: the study has a clinically relevant objective, it is likely that the study will lead to important new insights, the informed consent procedure bears no potential harm to participants, at least standard care is offered to participants in the control group, and the approval of an independent research ethics committee is obtained.

WITHDRAWN: Injection therapy for subacute and chronic benign low-back pain.

BACKGROUND: Injection with anaesthetics and/or steroids is one of the treatment modalities used in patients with chronic low back pain which needs evaluation with respect to the effectiveness on short and long term pain relief. OBJECTIVES: To evaluate the effectiveness of injection therapy in patients with low back pain lasting longer than one month. We distinguished between three injection sites: facet joint, epidural or local injections. SEARCH STRATEGY: We searched the Medline and Embase databases up to 1996 and other search methods as advocated by the Back Review Group search strategy. Abstracts and unpublished studies were not included. SELECTION CRITERIA: Randomized controlled trials of injection therapy for pain relief (although additional treatments were allowed) in patients with benign low back pain lasting longer than one month and not originating from cancer. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials for methodological quality. Subgroup analyses were made between trials with different control groups (placebo and active injections), with different injection site (facet joint, epidural and local injection), and timing of outcome measurement (short and long term). Within the resulting 12 subcategories of studies (2*3*2), the overall relative risks and corresponding 95% confidence intervals were estimated, using a random effects model (DerSimonian and Laird). In the case of trials in which control groups were active injections, we refrained from pooling the results. MAIN RESULTS: Twenty-one randomized trials were included in this review. All studies involved patients with low back pain lasting longer than one month. Only 11 studies compared injection therapy with placebo injections (explanatory trials). The methodologic quality of many studies was low: only 8 studies had a methodologic score of 50 or more points. There were only three well designed explanatory clinical trials: one on injections into the facet joints with a short-term RR of 0.89 (95% CI: 0.65-1.21) and a long-term RR of 0.90 (95% CI: 0.69-1.17); one on epidural injections with a short-term RR of 0.94 (95% CI: 0.76-1.15) and a long-term RR of 1.00 (95% CI: 0.71-1.41); and one on local injections with a long-term RR of 0.79 (95% CI: 0.65-0.96). Within the 6 subcategories of explanatory studies the pooled RRs with 95% confidence intervals were: facet joint, short-term: RR=0.89 (0.65-1.21); facet joint, long-term: RR=0.90 (0.69-1.17); epidural, short-term: RR=0.93 (0.79-1.09); epidural, long-term: RR=0.92 (0.76-1.11); local, short-term: RR=0.80 (0.40-1.59); local, long-term: RR=0.79 (0.65-0.96). AUTHORS' CONCLUSIONS: Convincing evidence is lacking on the effects of injection therapies for low back pain. There is a need for more, well designed explanatory trials in this field.

[A gastroenteritis epidemic caused by a Norwalk-like virus after 2 weddings in a restaurant; a plea for integral microbiological investigation]. / Een epidemie van gastro-enteritis door een Norwalk-achtig virus na twee bruiloften in een restaurant; een pleidooi voor integraal microbiologisch onderzoek.

OBJECTIVE: To elucidate the cause of an epidemic of gastroenteritis amongst the guests and waiting staff of two weddings celebrated on the same day in the same restaurant. DESIGN: Retrospective and descriptive. METHOD: Following an outbreak of gastroenteritis amongst 215 wedding guests and restaurant staff in 1999, the Public Health Institute Midden-Limburg, the Netherlands, inventoried the demographic and clinical variables and consumed foods by means of a structured written interview. Faecal samples and remaining food products were bacteriologically examined, and later on faeces were virologically examined for the presence of the Norwalk-like virus (NLV). The attack rates and the incidence rates of NLV-positive faecal specimens amongst consumers and non-consumers of specific food products were calculated, as well as the corresponding relative risks with 95% confidence intervals. RESULTS: The overall attack rate was 66%. An NLV with the same genotype was found statistically significantly more frequently in faecal specimens of ill persons compared with non-ill individuals. Of the 61 different dishes served, two showed a statistically significant relation with being ill. These food products were eaten by 26% of the ill persons. No statistically significant association was found between NLV-positive faeces and consumption of a specific dish. The index case began having symptoms of gastroenteritis at the morning of the wedding party, before food was served. The guests of the two wedding parties used the same entrance and toilets. CONCLUSION: The epidemic was caused by a single NLV strain. No association could be found between the consumption of certain food products and being ill. The NLV epidemic was probably caused through direct or indirect contact between wedding guests and restaurant personnel. In the case of such reports of gastroenteritis epidemics, it is strongly recommended to test faecal, food product and environment samples for both bacteria and viruses, with an emphasis on NLV, to ensure early diagnosis.

Vegetable and fruit consumption and risks of colon and rectal cancer in a prospective cohort study: The Netherlands Cohort Study on Diet and Cancer.

The relation between vegetable and fruit consumption and colorectal cancer risk was comprehensively assessed in the Netherlands Cohort Study on Diet and Cancer using a validated 150-item food frequency questionnaire. After 6.3 years of follow-up (1986-1992), over 1,000 incident cases of colorectal cancer were registered. Using case-cohort analysis, the authors calculated rate ratios and 95% confidence intervals adjusted for age, alcohol intake, and family history of colorectal cancer. For colon cancer, no statistically significant associations with total vegetable intake or total fruit intake were found. However, among women, an inverse association was observed with vegetables and fruits combined (for the highest quintile vs. the lowest, the rate ratio was 0.66 (95% confidence interval: 0.44, 1.01)). Brassica vegetables and cooked leafy vegetables showed inverse associations for both men and women. Among women and, to a lesser extent, among men, inverse associations were stronger for distal colonic tumors than for proximal colonic tumors. For rectal cancer, no statistically significant associations were found for vegetable consumption or fruit consumption or for specific groups of vegetables and fruits; only Brassica vegetables showed a positive association in women. As in other cohort studies, the observed inverse relation between vegetable and fruit consumption and occurrence of colorectal cancer was less strong than relations reported in case-control studies.

Injection therapy for subacute and chronic benign low back pain.

BACKGROUND: Injection with anaesthetics and/or steroids is one of the treatment modalities used in patients with chronic low back pain which needs evaluation with respect to the effectiveness on short and long term pain relief. OBJECTIVES: To evaluate the effectiveness of injection therapy in patients with low back pain lasting longer than one month. We distinguished between three injection sites: facet joint, epidural or local injections. SEARCH STRATEGY: We searched the Medline and Embase databases up to 1996 and other search methods as advocated by the Back Review Group search strategy. Abstracts and unpublished studies were not included. SELECTION CRITERIA: Randomized controlled trials of injection therapy for pain relief (although additional treatments were allowed) in patients with benign low back pain lasting longer than one month and not originating from cancer. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trials for methodological quality. Subgroup analyses were made between trials with different control groups (placebo and active injections), with different injection site (facet joint, epidural and local injection), and timing of outcome measurement (short and long term). Within the resulting 12 subcategories of studies (2*3*2), the overall relative risks and corresponding 95% confidence intervals were estimated, using a random effects model (DerSimonian and Laird). In the case of trials in which control groups were active injections, we refrained from pooling the results. MAIN RESULTS: Twenty-one randomized trials were included in this review. All studies involved patients with low back pain lasting longer than one month. Only 11 studies compared injection therapy with placebo injections (explanatory trials). The methodologic quality of many studies was low: only 8 studies had a methodologic score of 50 or more points. There were only three well designed explanatory clinical trials: one on injections into the facet joints with a short-term RR of 0.89 (95% CI: 0.65-1.21) and a long-term RR of 0.90 (95% CI: 0.69-1.17); one on epidural injections with a short-term RR of 0.94 (95% CI: 0.76-1.15) and a long-term RR of 1.00 (95% CI: 0.71-1.41); and one on local injections with a long-term RR of 0.79 (95% CI: 0.65-0.96). Within the 6 subcategories of explanatory studies the pooled RRs with 95% confidence intervals were: facet joint, short-term: RR=0.89 (0.65-1.21); facet joint, long-term: RR=0.90 (0.69-1.17); epidural, short-term: RR=0.93 (0. 79-1.09); epidural, long-term: RR=0.92 (0.76-1.11); local, short-term: RR=0.80 (0.40-1.59); local, long-term: RR=0.79 (0.65-0. 96). REVIEWER'S CONCLUSIONS: Convincing evidence is lacking on the effects of injection therapies for low back pain. There is a need for more, well designed explanatory trials in this field.

A prospective cohort study on antioxidant and folate intake and male lung cancer risk.

Many studies have reported inverse associations between vegetable and fruit consumption and lung cancer risk. The aim of the present study was to elucidate the role of several antioxidants and folate in this relationship. In the Netherlands Cohort Study on Diet and Cancer, 58,279 men of ages 55-69 years at baseline in 1986 returned a questionnaire including a 150-item food frequency questionnaire. After 6.3 years of follow-up, 939 male lung cancer cases were registered. A new Dutch carotenoid database was used to estimate intake of alpha-carotene, beta-carotene, lutein + zeaxanthin, beta-cryptoxanthin, and lycopene, completed with the antioxidant vitamins C and E and folate. Using case-cohort analysis, rate ratios were calculated, adjusted for age, smoking, educational level, and family history of lung cancer. Protective effects on lung cancer incidence were found for lutein + zeaxanthin, beta-cryptoxanthin, folate, and vitamin C. Other carotenoids (alpha-carotene, beta-carotene, and lycopene) and vitamin E did not show significant associations. After adjustment for vitamin C, only folate remained inversely associated, and after adjustment for folate, only beta-cryptoxanthin and vitamin C remained significantly associated. Inverse associations were strongest among current smokers and weaker for former smokers at baseline. Inverse associations with carotenes, lutein + zeaxanthin, and beta-cryptoxanthin seemed to be limited to small cell and squamous cell carcinomas. Only folate and vitamin C intake appeared to be inversely related to small cell and squamous cell carcinomas and adenocarcinomas. Folate, vitamin C, and beta-cryptoxanthin might be better protective agents against lung cancer in smokers than alpha-carotene, beta-carotene, lutein + zeaxanthin, and lycopene.

Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on diet and cancer.

OBJECTIVE: The purpose was to study the association between vegetable and fruit consumption and lung cancer incidence using 1074 cases after 6.3 years of follow-up in the Netherlands Cohort Study. METHODS: Dietary intake was assessed using a 150-item food-frequency questionnaire. Multivariate models were used including age, sex, family history of lung cancer, highest educational level attained, and smoking history. RESULTS: Statistically significant inverse associations were found with total vegetables and most vegetable groups. Rate ratios (RRs) based on consumption frequency showed the strongest effect of vegetables from the Brassica group (RR 0.5, 95% confidence interval (95% CI) 0.3-0.9, for consumption > or = 3 times per week versus < or = once a month). RR of highest versus lowest quintile of total vegetable consumption was 0.7 (95% CI 0.5-1.0, p-trend 0.001). Statistically significant inverse associations were found for all fruits listed in the questionnaire. RRs for quintiles of total fruit intake were 1.0, 0.7, 0.6, 0.6 and 0.8 respectively (p-trend < 0.0001). Protective effects of fruits and vegetables were stronger in current than in former smokers, and weaker for adenocarcinomas than for other types of tumors. CONCLUSIONS: Inverse associations with lung cancer are found for both vegetable and fruit intake, but no specific type of vegetable or fruit seems to be particularly responsible.

The Zelen design may be the best choice for a heroin-provision experiment.

Recently, the Dutch Parliament agreed upon the conduct of a randomized clinical trial on the effects on heroin provision on general health and psychosocial and criminal behavior in long-term addicts. Previous studies failed to establish the effects beyond reasonable doubt. The main reasons why previous trials failed are massive dropout or noncompliance in the control group. Designing a new heroin-provision trial, we concluded that the Zelen design provides the best guarantee for obtaining valid study results. Compared with the traditional design, the Zelen design probably reduces noncompliance and dropout considerably, thus increasing validity. Depending on the study population, the Zelen design may reduce study precision. However, in a trial aimed at badly integrated addicts, the Zelen design can be conducted without loss of precision because baseline measurements will only weakly correlate with effect measurements. The arguments favoring the Zelen design may be generalized to trials in which the experimental treatment is highly attractive to the study participants. However, the use of the Zelen design precludes blinding of participants who receive the experimental treatment. We argue that the conduct of studies that predictably tend to produce invalid results is ethically dubious. The ethical problem of studying participants without their consent can be solved by a slight modification of the Zelen design in which the sampling of a control group is postponed. Both the traditional and the Zelen design can imply ethical problems. Both designs can be ethically justifiable and should not be rejected on a priori grounds.

[Informed well-considered consent ('informed consent'): an end or a means?]. / Geïnformeerde weloverwogen toestemming ('informed consent'): doel of middel?

Since World War II, all sorts of protective measures have been taken for people who receive medical care or who are involved in scientific research. More and more, informed consent has become the standard. In the field of experimental therapeutical research, informed consent is still a controversial subject; the individual person's interests versus general interests. But informed consent appears to have become such an absolute prerequisite for all types of observational research that the future of epidemiological research based on existing data is threatened. According to both the Declaration of Helsinki and the Dutch Law for Protection of Persons, it is possible to omit asking individual informed consent under certain circumstances. Permission for research could then be given by a supervisory board or a medical-ethical commission. After all, informed consent was never meant to be a goal of its own, but a means for self-protection and securing the right to autonomy. In situations where this right is curbed for other reasons, it appears that insisting on informed consent misses its target completely.

[An epidemic of Salmonella typhimurium associated with traditional salted, smoked, and dried ham]. / Een Salmonella-typhimurium-epidemie in verband gebracht met ambachtelijk gezouten, gerookte en gedroogde varkensham.

OBJECTIVE: To discover the cause of an outbreak of gastroenteritis after a family party. DESIGN: Retrospective cohort study. METHODS: All 109 party-goers were asked to complete a written questionnaire about consumed food products and demographic and clinical variables and to hand in a faeces sample. The data were collected at the Public Health Institute Midden-Limburg, the Netherlands. Faeces and the remaining food products were examined microbiologically. The attack rates and the incidence rates of positive faeces culture among consumers and non-consumers of specific food products were calculated as well as the corresponding relative risks (RR) with 95% confidence intervals (95% CI). RESULTS: The overall attack rate was 35%. Salmonella typhimurium phage type 20 was found in 'Coburger ham' and statistically significantly more frequently in faeces of ill compared with non-ill party-goers (RR: 6.4; 95% CI: 2.5-16.1). Twenty-eight different food products were served. Consumption of 'Coburger ham' only, was statistically significantly related to a positive faeces culture (RR: 4.1; 95% CI: 2.0-8.5). Only consumption of 'Coburger ham' and of 'bone ham' was statistically significantly related to being ill (RR: 2.4; 95% CI: 1.5-4.0 and RR: 1.4; 95% CI: 1.1-1.9, respectively). 'Coburger ham' and 'bone ham' originated from the same batch of raw meat and were prepared in the same manner in the same salt bath. The shorter duration of salting and drying of 'Coburger ham' compared with 'bone ham' corresponded with a higher relative risk of becoming ill. CONCLUSION: Consumption of 'bone ham' and 'Coburger ham' infected with S. typhimurium phage type 20 caused the outbreak. Traditional salting, drying and smoking of raw pork meat was not antimicrobiologically effective against S. typhimurium. Investigation of the antimicrobiological effect of the traditional preparation of meat and the importance of Good Manufacturing Practices and quality control in all stages of production of pork meat, according to the principles of Hazard Analysis and Critical Control Points, is advised.

[Nursing home day-care: a growing function for a rather stable patient group]. / Verpleeghuisdagbehandeling: een groeiende functie voor een tamelijk vast omschreven doelgroep.

This article is a descriptive study of the characteristics of nursing home day-care patients in the Netherlands in 1995 at first admission and at discharge. Data were derived from the National Nursing Home Registration System (SIVIS), in which in 1995 over 85% of Dutch nursing homes participated. Newly admitted day-care patients are characterized by high age (89% older than 65 years), a distribution with (only!) 9% more women than men and a morbidity pattern of chronic somatic (cerebrovascular disease 45%) and psychogeriatric (dementia 80%) disorders. This morbidity pattern was associated with a considerable degree of disability, in particular regarding the activities of daily living and mobility. Most patients (78%) come from their own homes. The average length of stay from admittance to discharge, for both somatic and psychogeriatic day-care patients was nine months. For about 10% of the somatic patients and 40% of the psychogeriatic ones ambulatory day-care resulted in (subsequent) admission to the nursing home itself. In the last decade nursing home day-care capacity has increased rapidly and parallel to this also the number of day-care patients. Remarkably the average level of disability and the average period of treatment of nursing home day-care patients has remained approximately the same in this period.

Mortality update of workers exposed to acrylonitrile in The Netherlands.

A retrospective cohort study investigating the cause-specific mortality patterns of 2842 workers occupationally exposed to acrylonitrile for at least 6 months before 1 July 1979 was updated. The comparison group consisted of 3961 workers from a nitrogen fixation plant during the same time interval. Industrial hygiene assessments quantified past exposure to acrylonitrile, the use of personal protective equipment, and exposure to other potential carcinogenic agents. All 6803 workers were followed for mortality until 1 January 1996. The follow-up was almost complete (99.6%), and for 99.3% the cause of death was ascertained. Age distribution, follow-up period, and temporal changes in background mortality rates were adjusted for in calculations of standardized mortality ratios for separate causes of death. Cumulative dose-effect relations were determined for 3 exposure categories and 3 latency periods. The results showed that, although cancer mortality fluctuated slightly, no cancer excess seems related to exposure to acrylonitrile.

Low diagnostic value of respiratory impedance measurements in children.

The aim of this study was to determine whether impedance values in children with various chronic respiratory complaints differed from those observed in symptom-free children. Respiratory impedance was measured using the forced oscillation technique in 1,776 Dutch children aged 6-12 yrs. In addition to the commonly used parameters of resistance and reactance, further impedance parameters were obtained by using linear and quadratic regression to describe individual resistance and reactance curves as a function of frequency. Furthermore, the diagnostic value of the individual impedance parameters was evaluated by means of receiver operator characteristic (ROC) curves. Statistically significant differences in impedance values were found in girls with symptoms suggesting asthma compared to symptom-free girls, but not in boys. In children with chronic cough, impedance was not significantly different from the values of symptom-free children. The results obtained by the additional impedance parameters were comparable to those of the commonly used measures. We conclude that the diagnostic values of the impedance parameters appeared to be low, as no cut-off points were found to discriminate clearly between symptomatic and symptom-free children. These findings may reflect absence of functional abnormalities in symptomatic children at this age.

Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study.

Association between breast cancer risk and the intake of vitamins C and E, retinol, beta (beta)-carotene, dietary fibre, vegetables, fruit and potatoes was examined in The Netherlands Cohort Study, for 62,573 women aged 55-69 years. After 4.3 years of follow-up, 650 incident breast cancer cases were identified. After adjusting for traditional risk factors, breast cancer risk was not influenced by the intake of beta-carotene, vitamin E, dietary fibre, supplements with vitamin C, vegetables or potatoes. Fruit consumption showed a non-significant inverse association with breast cancer risk (RR highest/lowest quintile = 0.76, 95% CI 0.54-1.08). A small reduction in risk was also observed with increasing intake of dietary vitamin C (RR highest/lowest quintile = 0.77, 95% CI 0.55-1.08). For retinol, a weak positive association was observed (RR highest/lowest quintile = 1.24, 95% CI 0.83-1.83). Among subjects with a high intake of polyunsaturated fatty acids (PUFAs), both beta-carotene and vitamin C intake showed a non-significant inverse association with breast cancer risk (P-trend = 0.15 and 0.16 respectively). Our findings do not suggest a strong role, if any, for intake of vitamins C and E, beta-carotene, retinol, dietary fibre, vegetables, fruit and potatoes in the aetiology of breast cancer.

The rate of respiratory symptoms among primary school children in two Dutch regions.

UNLABELLED: A cross-sectional study was conducted to evaluate possible interregional differences in respiratory health in primary school children living in two different towns of the Netherlands, Melick/Herkenbosch Asenray (MHA) (n = 511) and Leek (LK) (n = 612). The prevalence of respiratory symptoms was determined by means of a questionnaire and respiratory impedance was measures using the forced oscillation technique (FOT). Respiratory symptoms were reported consistently more often in MHA than in LK; chronic cough (17% MHA vs 5% LK), shortness of breath (15% vs 8%), wheeze (16% vs 13%) and attacks of shortness of breath with wheeze (10% vs 7%). However, doctor-diagnosed asthma was reported as 7% in MHA and 6% in LK. The prevalence rates expressed as odds ratios of MHA versus LK were all > 1 even when adjusted for known indoor environmental factors. Living in MHA appeared to be a statistically significant determinant of the reported symptom prevalence. Furthermore, the child's age, maternal smoking (> 10 cigarettes/day), and having had domestic animals were positively associated with one or more respiratory symptoms. Calculating adjusted differences in respiratory impedance between the regions resulted in a small but statistically significant difference in resonant frequency, LK being slightly at a disadvantage. Measured outdoor air pollution levels of SO2, NO2, O3 and PM10 were in general higher in MHA. In both regions however, the average levels remained below the present WHO guidelines, except for NO2 in MHA where the guideline was slightly exceeded. CONCLUSION: In this study prevalence rates of key symptoms of asthma were found to be significantly higher in children living in one region of the Netherlands (MHA) compared to another (LK). Known (indoor) risk factors for respiratory disease could not explain the observed differences in symptom prevalence between the regions. However, statistically but not clinically significant interregional differences in respiratory impedance values were found between children living in MHA and children living in LK. Further research will have to incorporate techniques to evaluate the potential influence of information bias.

Self-rated health and mortality in a Lithuanian and a Dutch population.

The hypothesis that the evaluation of one's health as poor is associated with mortality, independent of the results of a standardized medical examination, was tested in the Kaunas-Rotterdam Follow-Up Study. In this study two cohorts, one consisting of 2452 Lithuanian males and one of 3365 Dutch males, aged 45-60, were screened for cardiovascular risk factors in 1973, using identical protocols, and were followed for about ten years. Self-rated health was assessed by two direct questions: 'How would you assess your own health?' and 'What do you think of your own health compared to that of other men of your age?' as well as by a Semantic Differential Test of 'My Health'. In both cohorts a negative evaluation of one's health was associated with mortality, controlling for past or present heart disease, cardiovascular risk factors, parental life span, socio-economic and marital status. Especially the data with regard to the comparative question indicate that self-rated health is associated with mortality in men living in two different socio-cultural systems. The date suggest that a weak sense of mastery may explain the association between health perception and mortality.

Consumption of onions and a reduced risk of stomach carcinoma.

BACKGROUND & AIMS: Results from case-control studies and laboratory tests indicate that consumption of allium vegetables may considerably reduce the risk of stomach cancer. The association between onion and leek consumption, garlic supplement use, and the incidence of stomach carcinoma was studied. METHODS: The association was investigated in the Netherlands Cohort Study on diet and cancer, which started in 1986 with 120,852 men and women ranging in age from 55 to 69 years. Dietary data were available for 139 stomach carcinoma cases diagnosed during 3.3 years of follow-up and for 3123 subjects of the randomly selected subcohort. RESULTS: The rate ratio for stomach carcinoma in the highest onion consumption category (> or = 0.5 onions/day) was 0.50 (95% confidence interval, 0.26-0.95) compared with the lowest category (0 onions/day) after adjustment for other risk factors. The reduction in risk was restricted to carcinoma in the noncardia part of the stomach (P = 0.002) and was also found among subjects without a history of stomach disorders (P = 0.01). The consumption of leeks and the use of garlic supplements were not associated with stomach carcinoma risk. CONCLUSIONS: The Netherlands Cohort Study provides evidence for a strong inverse association between onion consumption and stomach carcinoma incidence.

Current use of thiazide diuretics and prevention of femur fractures.

A case control study of a defined population from The Netherlands was performed to evaluate the risk of femur fractures associated with the use of thiazide diuretics. Included were 386 patients hospitalized for femur fractures between 1986 and 1990 who were residents and 45 years of age and older. Per case, one age-, sex-, pharmacy-, and general practitioner-matched control was chosen from the general population. Drug use was ascertained from computerized pharmacy records. The adjusted odds ratio of current use of thiazide diuretics was 0.5 (95% confidence interval, 0.3-0.9). The protective effect of thiazide diuretics was greatest for use of 1 year or longer at relatively high doses of thiazides (odds ratio, 0.3; 95% confidence interval, 0.1-0.9). We also found that patients who discontinued thiazide use longer than 2 months were not protected against femur fractures. These results support the hypothesis that use of thiazide diuretics protects against femur fractures.

Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life.

BACKGROUND: In the past decade, the use of benzodiazepines has been identified as a major independent risk factor for accidental falls. OBJECTIVE: To study the role of dosing, timing, elimination half-life, and type of benzodiazepine in relation to the occurrence of accidental falls leading to hospitalization for femur fractures. METHODS: A 1:3 age-, sex-, and pharmacy-matched case-control study was performed using data from a Dutch record linkage system (PHARMO) (N = 300,000). Cases included 493 patients (55 years and older), newly admitted to the hospital for a femur fracture resulting from an accidental fall (between 1986 and 1992). Relative risk estimates were calculated using conditional logistic regression analyses to control for the potential confounding effects of concomitant drug use and presence of a wide range of underlying diseases. RESULTS: Falls were significantly associated with current use of benzodiazepines (odds ratio, 1.6; 95% confidence interval, 1.2 to 2.1) and in particular with short half-life benzodiazepines (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.0), sudden dose increases (odds ratio, 3.4; 95% confidence interval, 1.0 to 11.5), and concomitant use of several benzodiazepines (odds ratio, 2.5; 95% confidence interval, 1.3 to 4.9). A strong dose-response relationship (P < .0001) and dose-response relations among users of either short or long half-life benzodiazepines suggests that these increased risks are explained primarily by dose. CONCLUSIONS: Benzodiazepines are a major, independent risk factor for falls leading to femur fractures, and the increased risk is probably explained by prescribing too-high doses to the elderly.