[Determinants of hypercholesterolemia in Geneva: should the focus be on genes or environment?]. / Déterminants de l'hypercholestérolémie a Genève: doit-on se concentrer sur res gènes ou l'environnement?

Do genetic (G), or environmental (E), factors primarily determine blood lipid concentrations in the Geneva population? On-going research on the causes of hypercholesterolemia in populations based on data collected by the Bus Santé Survey is summarized. About 2/3 of the HDL-cholesterol variance could not be explained by the most important 5 of 10 environmental factors and 9 of 275 common genetic variants identified in the analyses. The remaining 1/3 of the variance was explained mainly by obesity, smoking, alcohol intake, age, and gender. The common polymorphisms played a much smaller role. GxG, GxE, and ExE interactions were the weakest determinants. Environmental factors appear to be the main determinants of hypercholesterolemia in populations. Measurement of genetic traits for clinical or public health purposes is currently not useful.

Transcranial Doppler versus angiography in patients with vasospasm due to a ruptured cerebral aneurysm: A systematic review.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) is used for diagnosis of vasospasm in patients with subarachnoid hemorrhage due to a ruptured aneurysm. Our aim was to evaluate both the accuracy of TCD compared with angiography and its usefulness as a screening method in this setting. METHODS: A search (MEDLINE, EMBASE, Cochrane Library, bibliographies, hand searching, any language, through January 31, 2001) was performed for studies comparing TCD with angiography. Data were critically appraised using a modified published 10-point score and were combined using a random-effects model. RESULTS: Twenty-six reports compared TCD with angiography. Median validity score was 4.5 (range 1 to 8). Meta-analyses could be performed with data from 7 trials. For the middle cerebral artery (5 trials, 317 tests), sensitivity was 67% (95% CI 48% to 87%), specificity was 99% (98% to 100%), positive predictive value (PPV) was 97% (95% to 98%), and negative predictive value (NPV) was 78% (65% to 91%). For the anterior cerebral artery (3 trials, 171 tests), sensitivity was 42% (11% to 72%), specificity was 76% (53% to 100%), PPV was 56% (27% to 84%), and NPV was 69% (43% to 95%). Three of these 7 studies reported on the same patients, each on another artery, and for 4, data recycling could not be disproved. Other arteries were tested in only 1 trial each. CONCLUSIONS: For the middle cerebral artery, TCD is not likely to indicate a spasm when angiography does not show one (high specificity), and TCD may be used to identify patients with a spasm (high PPV). For all other situations and arteries, there is either lack of evidence of accuracy or of any usefulness of TCD. Most of these data are of low methodological quality, bias cannot not be ruled out, and data reporting is often uncritical.

Breast cancer and earlier detection efforts. Realized and unrealized impact on stage.

OBJECTIVE: To test our hypotheses that increased public and professional education in breast cancer detection (screening mammography, clinical breast examination, and breast self-examination) would lead to detection at earlier stages of disease with each of the three methods. DESIGN AND SETTING: A survey study of all pathologically diagnosed breast cancers in a defined geographic area (all nonfederal general hospitals in the state of Vermont) before (1975-1984, n = 1652) and after (1989-1990, n = 683) screening mammography became more commonly used. MAIN OUTCOME MEASURES: Method of detection of breast cancer and stage at detection. RESULTS: The age-adjusted annual incidence rate of breast cancer among adult women was 99 per 100,000 during the years 1975 to 1984 compared with 169 per 100,000 during 1989-1990 (P < .001). Mammography as the method of detection increased in use from 2% to 36% (P < .001). In the later era, invasive breast cancers were detected at more favorable TNM stage (P < .001); mean maximum tumor diameter was smaller (2.2 cm vs 2.7 cm; P < .001); percentage of histologically positive nodes was lower (37% vs 47%; P < .001). When mammographically detected cancers were excluded from the analysis of invasive cancers, the mean maximum tumor diameter and percentage of negative nodes in the two eras were similar even though there was an apparent shift to detection at an earlier clinical stage. CONCLUSION: The earlier stages of detection and the sudden increase in incidence could almost entirely be credited to screening mammography. Mammographic screening had a much greater impact on stage at detection in women aged 50 years and older than in those younger than 50 years.

Blood transfusions and survival after surgery for breast cancer.

Numerous reports have demonstrated that blood transfusions given prior to renal allografting have an immunomodulating effect that leads to increased graft survival. To determine if blood transfusions would adversely affect the outcome for patients with breast cancer, we examined 226 patients with invasive breast cancer who had a mastectomy and found 65 (29%) had received transfusions. The patients who had transfusions and those who did not were similar in age, clinical tumor-node-metastasis stage, and number of histologic nodal metastases. At a median follow-up of 52 months for surviving patients, 48 (21%) of the patients were dead. Log-rank and Cox regression analyses that compared patients who had transfusions v those who did not showed no excess of either overall deaths or deaths due to cancer in the group that received transfusions. The hypothesis that blood transfusions might have an adverse effect on survival was not supported by this study. Additional studies involving other groups of patients with malignant neoplasms and other blood donor populations are needed.

Blood transfusions and survival after lung cancer resection.

The immunosuppressive effects of blood transfusions in renal transplantation patients are now well documented. The question arises as to whether the possible immunosuppressive effects of blood transfusions in cancer patients cause a more favorable host environment for tumor growth. One hundred fifty-five patients undergoing resection for lung carcinoma were analyzed retrospectively, and it was shown that the use of blood transfusions was associated with a significant decrease in survival time in patients undergoing curative resection of lung carcinoma despite multivariate adjustments for age, sex, cell type, right lung versus left lung location, type of operation, and stage. This association supports, but does not prove, the hypothesis that blood transfusions, possibly through an immunosuppressive mechanism, are responsible for a poorer prognosis in patients who undergo resection for carcinoma of the lung.

Impact of 'Mad Cow Disease' publicity on trends in meat and total vitamin A consumption in Geneva between 1993 and 2000.

BACKGROUND: In March 1996, revelations about the possible risk for humans of the 'mad cow disease' epidemic had a sudden impact on the diets of European populations. OBJECTIVE: To assess changes in meat and nutrient intakes in adults living in Geneva, Switzerland from 1993 to 2000. DESIGN: Independent annual cross-sectional surveys (4047 women and 4092 men total). MAIN OUTCOME MEASURE: Dietary habits assessed and compared to baseline (January 1993-April 1996) via validated semi-quantitative food-frequency questionnaire. RESULTS: Women beef abstainers increased from 8.9 to 14.9% in late 1996 (P<0.001) and 13.3% in 1997 (P<0.05); among meat consumers, in late 1996 meat/beef intakes declined -10/-12% (both P<0.05). From 1997 to 2000 most intake levels drifted back toward those at baseline, but chicken intakes were significantly (all P<0.05) greater each year (+19% in 2000 (P<0.001). Consistent but less dramatic changes were observed among men. From late 1996 until 2000, liver abstention was significantly (all P<0.05) greater (women from 60 to 78%; men from 61 to 73% in 2000; (both P<0.001). The only nutrient intakes that decreased significantly (all P<0.05) each year from 1997 through 2000 were retinol and total vitamin A women: -22% (P<0.001); -11% (P<0.05) respectively; men: -16% (P<0.001); -10% (P<0.05) respectively, in 2000). Total vitamin A intakes exceeded the dietary reference intake (DRI) for liver eaters (women 185%, men 153%), but were below the DRI for liver abstainers (women 83%; men 66%) in 2000. CONCLUSION: The decreases in beef and liver consumption since late 1996 led to the discovery of a long-term disparity in the retinol and total vitamin A intakes of liver eaters vs abstainers.

Epidemiologic studies of low-back pain.

The records of 3920 patients (2068 females, 1852 males) entering a model family practice unit between 1975 and 1978 have been analyzed. Eleven percent of males and 9.5% of females reported an episode of low-back pain during that 3-year interval. The complaint of medically reported low-back pain was significantly related to occupational factors such as truck driving (p < 0.001), lifting, carrying, pulling, pushing, and twisting (P < 0.001 for all variables) as well as nondriving vibrational exposure (P < 0.001). Patients reporting low-back pain also reported more episodes of anxiety (P < 0.001) and depression (P < 0.001) and had more emotionally stressful occupations (P < 0.001). The mean number of pregnancies was greater in women with low-back pain (2.6) than in those without (1.6) (P < 0.001). The low-back pain sufferers were more likely to be cigarette smokers (P < 0.001), particularly when smoking was accompanied by a chronic cough (P < 0.001). This population is currently under prospective study to define the relevance of each of these risk factors to the complaint of low-back pain.

The assessment of appropriate indications for laminectomy.

We have developed criteria to determine the appropriate indications for lumbar laminectomy, using the standard procedure developed at the RAND corporation and the University of California at Los Angeles (RAND-UCLA). A panel of five surgeons and four physicians individually assessed 1000 hypothetical cases of sciatica, back pain only, symptoms of spinal stenosis, spondylolisthesis, miscellaneous indications or the need for repeat laminectomy. For the first round each member of the panel used a scale ranging from 1 (extremely inappropriate) to 9 (extremely appropriate). After discussion and condensation of the results into three categories laminectomy was considered appropriate in 11% of the 1000 theoretical scenarios, equivocal in 26% and inappropriate in 63%. There was some variation between the six categories of malalignment, but full agreement in 64% of the hypothetical cases. We applied these criteria retrospectively to the records of 196 patients who had had surgical treatment for herniated discs in one Swiss University hospital. We found that 48% of the operations were for appropriate indications, 29% for equivocal reasons and that 23% were inappropriate. The RAND-UCLA method is a feasible, useful and coherent approach to the study of the indications for laminectomy and related procedures, providing a number of important insights. Our conclusions now require validation by carefully designed prospective clinical trials, such as those which are used for new medical techniques.

Reproductive factors and incidence of breast cancer: an international ecological study.

Ecological studies can help in understanding the relation of reproductive history of breast cancer. We analyzed data from 9416 women, comprising the control groups of seven countries (Australia, People's Republic of China, Colombia, (former) German Democratic Republic, Israel, Philippines, and Thailand) from the WHO international, multi-center case-control study of female cancers. Positive correlations with country-specific breast cancer incidence were observed for (median) duration of reproductive life (r > or = 0.95, p < 0.005), age at menopause (r > or = 0.84, p < 0.025) and delay to first birth (r > or = 0.59, p < 0.22) (when People's Republic of China was omitted, r > or = 0.85, p < 0.07). The association of age at first birth with breast cancer incidence was weakly positive in the whole sample (age-adjusted r = 0.18, p = 0.73), but weakly negative in the age groups 15-29 and 30-39 years and weakly positive in the age groups 40-49 and 50-64 years. A strong inverse correlation was observed between age at menarche and breast cancer incidence (r < or = -0.84, p < 0.03). These international ecological correlations agree with the associations previously reported for single populations, between higher incidence of breast cancer and younger age at menarche, older age at menopause, longer duration of reproductive life, and (possibly) longer delay to first birth. In contrast, age at first birth is only weakly related to breast cancer incidence across populations, indicating that this variable represents different constructs when measured ecologically versus individually.

Physical activity of urban adults: a general population survey in Geneva.

OBJECTIVES: Describing the distribution of physical activity in populations is of major importance for developing public health campaigns to prevent sedentarism. METHODS: A population-based survey conducted during 1997-1999 in Geneva, Switzerland, included 3410 randomly selected men (n = 1707) and women (n = 1703), aged 35 to 74 years. Percentiles P10, P50, and P90 summarised the distributions of the total energy expenditure and of the percents used in moderate intensity activities (3 to 3.9 times the basal metabolism rate (BMR), e.g., normal walking, household chores), and in high and very high intensity activities (> or = 4 BMR, e.g., brisk walking, sports). RESULTS: The total energy expenditure (median 2929 kcal/day in men, 2212 kcal/day in women) decreased with age. Prevalence of sedentarism, defined as less than 10% of total energy expended in > or = 4 BMR activities, was 57% in men and 70% in women. Men expended 12% (median) of their total energy in 3 to 3.9 BMR and 8% in > or = 4 BMR activities. Corresponding percentages in women were 11% and 5%. The highest prevalence of sedentarism was in older age, women, and lower socio-economic status persons. CONCLUSION: Most of Geneva population is sedentary. Promoting physical activity should target children, adults and elderly, and physical activities which would be both attractive and financially affordable by most people.

[Nutritional balance of the diet of the adult residents of Geneva]. / Equilibre nutritionnel de l'alimentation de la population adulte résidant à Genève.

Diet of the Swiss population has probably changed over the last 10 years, but these changes have not been recorded yet by nutritional studies. In the present study, 3 registered dieticians interviewed over the telephone 626 adults, resident of Canton Geneva, using a 24 hour recall. Interviews were performed during the 7 days of the week. Participants were randomly selected according to their age, sex and nationality. Participation was 80%. The following caloric (C) and nutritional intakes in proteins (P), lipids (L), carbohydrates (CH) and alcohol (A) were recorded: In non Swiss men: C = 2464 kcal/j., P = 16.2%, L = 32.4%, CH = 44.4%, A = 7.0%; in Swiss men: C = 2752 kcal/j., P = 15.3%, L = 34.0%, CH = 43.5%, A = 7.1%; in non Swiss women: C = 1897 kcal/j., P = 16.4%, L = 35.1%, CH = 46.5%, A = 2.4%; in Swiss women: C = 1865 kcal/j., P = 15.0%, L = 35.3%, CH = 46.0%, A = 3.2%. Total caloric intake and iron intake decreased with age. Older women ate less calcium than younger. In summary, the most important determinants of diet are age and sex. Proportion of lipids is relatively low in both men and women. Small differences related to nationality were observed in men.

Undocumented migrants in Switzerland: geographical origin versus legal status as risk factor for tuberculosis.

Undocumented migrants, meaning migrants without a legal residency permit, come to Geneva from countries with high tuberculosis (TB) incidence. We estimate here whether being undocumented is a determinant of TB, independently of origin. Cross-sectional study including undocumented migrants in a TB screening program in 2002; results were compared to 12,904 age and frequency matched participants in a general TB screening program conducted at various workplaces in Geneva, Switzerland from 1992 to 2002. A total of 206 undocumented migrants (36% male, 64% female, mean age 37.8 years (SD 11.8), 82.5% from Latin America) participated in the TB screening program. Compared to legal residents, undocumented migrants had an adjusted OR for TB-related fibrotic signs of 1.7 (95% CI 0.8;3.7). The OR of TB-related fibrotic signs for Latin American (vs. other) origin was 2.7 (95% CI 1.6;4.7) among legal residents and 5.5 (95% CI 2.8;10.8) among undocumented migrants. Chest X-ray screening identified a higher proportion of TB-related fibrotic signs among Latin Americans, independently of their residency status.

Twelve-year trends and correlates of dietary salt intakes for the general adult population of Geneva, Switzerland.

BACKGROUND/OBJECTIVES: Investigate dietary salt intake trends by gender, and their associations with risk factors for cardiovascular diseases in Geneva, Switzerland. SUBJECTS/METHODS: Continuous surveillance of the Geneva general adult (35-74 years) population for 12 years (1993-2004) using a validated, semi-quantitative food frequency questionnaire (FFQ) in random, cross-sectional, representative samples (6688 men, 6647 women). Dietary salt intake assessment by FFQ excluded discretionary salt, but was calibrated on total salt intake using an independent validation substudy of 100 volunteers who additionally provided 24-h urine collections. RESULTS: Quartiles (mean) of calibrated dietary salt intake (g per day) were 9.9, 10.5, 11.2 (10.6) in men, and 7.0, 7.8, 8.9 (8.1) in women and were above current recommendations. Quartiles (mean) of salt density (g MJ(-1)) were 0.99, 1.16, 1.39 (1.23) in men, and 0.98, 1.12, 1.30 (1.17) in women. Both measures were stable during the 12-year surveillance period, regardless of hypertension treatment. Salt-density differences between cardiovascular disease risk factor subgroups were moderate. Salt density increased with age and body mass index. The main dietary non-discretionary salt food sources (men/women: 47/48%) were breads (17/17%), cheeses (11/10%), meat and meat products (8/7%), soups (6/9%) and ready-to-eat foods (5/5%). CONCLUSIONS: Salt intakes from all sources for the Geneva, and perhaps the Swiss adult population are above current recommendations. The quantitative and qualitative data provided in this paper could be used to develop and implement strategies for salt-intake reduction in Switzerland.

Cancer risks in LKB1 germline mutation carriers.

BACKGROUND AND AIMS: Germline mutations in the LKB1 gene are known to cause Peutz-Jeghers syndrome, which is an autosomal dominant disorder characterised by hamartomatous polyposis and mucocutaneous pigmentation. This syndrome is associated with an increased risk of malignancies in different organs but there is a lack of data on cancer range and risk in LKB1 germline mutation carriers. PATIENTS AND METHODS: The cumulative incidence of cancer in 149 Peutz-Jeghers syndrome patients with germline mutation(s) in LKB1 was estimated using Kaplan-Meier time to cancer onset analyses and compared between relevant subgroups with log rank tests. RESULTS: Thirty two cancers were found in LKB1 mutation carriers. Overall cancer risks at ages 30, 40, 50, 60, and 70 years were 6%, 18%, 31%, 41%, and 67%, respectively. There were similar overall cancer risks between male and female carriers. However, there were overall cancer risk differences for exon 6 mutation carriers versus non-exon 6 mutation carriers (log rank p=0.022 overall, 0.56 in males, 0.0000084 in females). Most (22/32) of the cancers occurred in the gastrointestinal tract, and the overall gastrointestinal cancer risks at ages 40, 50, 60, and 70 years were 12%, 24%, 34%, and 63%, respectively. In females, the risks for developing gynaecologic cancer at ages 40 and 50 years were 13% and 18%, respectively. CONCLUSIONS: Mutations in exon 6 of LKB1 are associated with a higher cancer risk than mutations within other regions of the gene. Moreover, this study provides age related cumulative risks of developing cancer in LKB1 mutation carriers that should be useful for developing a tailor made cancer surveillance protocol for Peutz-Jeghers syndrome patients.

Matching.

Matching is an intuitively appealing design strategy for ensuring balance on one or more potential confounding variables, usually either among subjects who were exposed or unexposed to a suspected risk factor for disease in a cohort study or between diseased and nondiseased subjects in a case-control study. But does matching always automatically "control" confounding and is it always as good a strategy as it seems? It is the intention of this review to shed light on these questions primarily through illustrative examples of the effects of matching on the validity of point estimates of the odds ratio between exposure and disease status in both types of study designs. It is seen that the results of matching are more or less in line with expectations in cohort studies, but that matching can lead to unexpected results in case-control studies. In a case-control study, confounding is not automatically controlled by matching per se; rather, matching and a statistical analysis that properly accounts for the matching are needed to obtain a valid estimate of effect in a case-control study design.

International variability in ages at menarche, first livebirth, and menopause. World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives.

The occurrences and timing of reproduction-related events, such as menarche, first birth, and menopause, play major roles in a woman's life. There is a lack of comparative information on the overall patterns of the ages at and the timing between these events among different populations of the world. This study describes the variability in reproductive factors across populations in Europe, the Americas, Asia, Australia, and Africa. The study sample consisted of 18,997 women from 13 centers in 11 countries interviewed between 1979 and 1988 who comprised the control group in a World Health Organization international, multicenter case-control study of female cancers. All were surveyed with the same questionnaire and methodology. Overall, a typical woman in this study reached menarche at age 14 years and delivered her first live child 8 years later, at age 22. She was 50 years old at natural menopause and had had 36 years of reproductive life. The median ages at menarche varied across centers from 13 to 16 years. For all centers, the median age at first livebirth was 20 or more years, with the largest observed median (25 years) occurring in China. The median delay from menarche to first livebirth ranged from 5 to 11 years. Among the centers, the median age at natural menopause ranged between 49 and 52 years. In most populations, younger women had a first birth at a later age than did older women. This tendency was more accentuated in some populations. These results reveal, perhaps for the first time, the variability of reproductive histories across different populations in a large variety of geographic and cultural settings. Except for menopause, international variability is substantial for both biologically related variables (age at menarche) and culturally related variables (age at first birth). There is a generational effect, characterized by more variability of age at first birth and delay to first birth in the younger than in the older generations.

Breast self-examination practices and breast cancer survival.

To determine the relation between breast self-examination and survival of breast cancer patients, the authors studied 1004 newly diagnosed invasive breast cancer patients in Vermont general hospitals from 1 July 1975 to 31 December 1982. More frequent breast self-examination was associated with a greater likelihood of the patient's detecting her own cancer, less delay from first symptom to histologic diagnosis, earlier clinical stage, smaller pathologic tumor size, and fewer axillary node metastases. At a median follow-up time of 52 months (maximum follow-up, 92 months), 14% of the breast self-examination performers had died of breast cancer versus 26% of the nonperformers (P less than 0.001 based on chi-square). The product limit survival curve for breast self-examination performers (N = 424) was significantly better (P less than 0.001 by log-rank test) than for breast self-examination nonperformers (N = 411). Survival at 5 years was 75% for breast self-examination performers versus 57% for the nonperformers. The significant survival differences persisted after adjusting for any combination of the covariates age, method of detection, family history of breast cancer, and delay in treatment (P less than 0.002). Lead-time would have to be at least 3 years to negate the apparent beneficial effects of breast self-examination on survival. The authors conclude that in this population of breast cancer patients, breast self-examination was related to earlier detection and improved survival.

Relationship between breast self-examination and death from breast cancer by age groups.

To quantitate the relationship between breast self-examination and survival from breast cancer, we have studied 1,003 newly diagnosed patients with invasive breast cancer in Vermont general hospitals since July 1, 1975. Death certificates, autopsy reports, and hospital records were reviewed to determine the cause of death. Examination of product limit survival curves by three age groups demonstrated that death due to breast cancer was less likely in breast cancer patients who had performed breast self-examination than in nonperformers in each of the three age groups. The associated lead-time would have to exceed 36 months to negate the apparent beneficial effects of breast self-examination in decreasing the likelihood of death from breast cancer. We conclude that in this population of breast cancer patients, breast self-examination probably contributed to earlier detection and thereby improved survival.

Estimation of the design effect in community intervention studies.

This paper considers the estimation of the variance of a mortality rate in community intervention studies with little or no replication of intervention regimens. Our approach in estimation of this cluster sampling variance is to determine the variance for simple random sampling and multiply it by a design effect which we calculate with use of information obtained from other sources. When the county is the unit of randomization and the outcome is mortality, we calculate the design effect as the ratio of the age adjusted mortality rates for single stage cluster sampling relative to simple random sampling; we use information from all counties in a state in the calculations. We apply this approach empirically for breast cancer mortality. We found that these design effects were dependent on length of time for accumulation of deaths (1.1 for one year up to 3.5 for eight years) and were quite consistent for the three states and nine years considered in the investigation. We present a model that accounts for the time dependence of the design effect and we show it provides a good representation of the observed relationship.