Jaakko Nevalainen

Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.

PURPOSE The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases. PATIENTS AND METHODS This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity. RESULTS During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P =.127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P =.016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P =.257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P =.047) during the total follow-up period. CONCLUSION Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.

Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5‐year‐old children

Background Vitamin D is known to have a number of immunological effects and it may play a role in preventing allergic diseases.

The effect of particulate air pollution on life expectancy

Two recent US cohort studies suggest that current levels of particulate pollution in urban air are associated not only with short-term, but also with long-term increases in cardiorespiratory morbidity and mortality. The aim of the present analyses was to evaluate the change in life expectancy assuming the long-term increase in mortality rates as suggested by these studies. The method of competing causes of death was used and the effect of particulate air pollution on life expectancy was found to be notable in countries with high cardiovascular mortality like the US.

Food consumption and advanced β cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested case-control design

BACKGROUND Evidence for the role of food consumption during childhood in the development of β cell autoimmunity is scarce and fragmentary. OBJECTIVE We set out to study the associations of longitudinal food consumption in children with the development of advanced β cell autoimmunity. DESIGN Children with advanced β cell autoimmunity (n = 232) (ie, with repeated positivity for antibodies against islet cells) together with positivity for at least one of the other 3 antibodies analyzed or clinical type 1 diabetes were identified from a prospective birth cohort of 6069 infants with HLA-DQB1-conferred susceptibility to type 1 diabetes who were born in 1996-2004, with the longest follow-up to the age of 11 y. Repeated 3-d food records were completed by the families and daycare personnel. Diabetes-associated autoantibodies and diets were measured at 3-12-mo intervals. Four control subjects, who were matched for birth date, sex, area, and genetic risk, were randomly selected for each case. RESULTS In the main food groups, only intakes of cow-milk products (OR: 1.05; 95% CI: 1.00, 1.10) and fruit and berry juices (OR: 1.09; 95% CI: 1.02, 1.12) were significantly, although marginally, associated with advanced β cell autoimmunity. The consumption of fresh milk products and cow milk-based infant formulas was related to the endpoint, whereas no evidence was shown for consumption of sour milk products and cheese. The intake of fat from all milk products and protein from fresh milk products was associated with risk of advanced β cell autoimmunity. CONCLUSION Intakes of cow milk and fruit and berry juices could be related to the development of advanced β cell autoimmunity. This trial was registered at clinicaltrials.gov as number NCT00223613.

Cumulative Effect of Psychosocial Factors in Youth on Ideal Cardiovascular Health in Adulthood The Cardiovascular Risk in Young Finns Study

Background— The American Heart Association has defined a new metric of ideal cardiovascular health as part of its 2020 Impact Goals. We examined whether psychosocial factors in youth predict ideal cardiovascular health in adulthood. Methods and Results— Participants were 477 men and 612 women from the nationwide Cardiovascular Risk in Young Finns Study. Psychosocial factors were measured from cohorts 3 to 18 years of age at the baseline of the study, and ideal cardiovascular health was examined 27 years later in adulthood. The summary measure of psychosocial factors in youth comprised socioeconomic factors, emotional factors, parental health behaviors, stressful events, self-regulation of the child, and social adjustment of the child. There was a positive association between a higher number of favorable psychosocial factors in youth and greater ideal cardiovascular health index in adulthood (&bgr;=0.16; P<0.001) that persisted after adjustment for age, sex, medication use, and cardiovascular risk factors in childhood (&bgr;=0.15; P<0.001). The association was monotonic, suggesting that each increment in favorable psychosocial factors was associated with improvement in cardiovascular health. Of the specific psychosocial factors, a favorable socioeconomic environment (&bgr;=0.12; P<0.001) and participants’ self-regulatory behavior (&bgr;=0.07; P=0.004) were the strongest predictors of ideal cardiovascular health in adulthood. Conclusions— The findings suggest a dose-response association between favorable psychosocial factors in youth and cardiovascular health in adulthood, as defined by the American Heart Association metrics. The effect seems to persist throughout the range of cardiovascular health, potentially shifting the population distribution of cardiovascular health rather than simply having effects in a high-risk population.

Extended Safety Profile of Oral Clodronate After Long-Term Use in Primary Breast Cancer Patients

AbstractIntroduction: Long-term safety and tolerance is paramount when treating women who are otherwise healthy after the primary adjuvant therapy of breast cancer. Efficacy and limited safety results of a large-scale clinical trial, using adjuvant oral clodronate to prevent bone metastases in primary breast cancer patients, have been reported previously, demonstrating a reduction in the rate of bone metastases during treatment. Here we present expanded safety and tolerability results for clodronate treatment from this trial (cut-off date extended from June 1997 to June 2000). Study Design and Methods: For this randomised, double-blind, placebocontrolled, multicentre study, patients were enrolled and randomised to receive oral clodronate (Bonefos®) 1600 mg/day or placebo for 2 years. The total median treatment period plus follow-up was 5.5 years. Adverse events (AEs) and laboratory parameters were followed up regularly for the total study period. The 9 5% CIs were estimated for the difference in the rate of AEs between the treatment groups. Patients: A total of 1079 women with primary operable breast cancer were enrolled to the study; 538 received clodronate and 541 received placebo. Results: Overall incidence of AEs (96.5% of the patients) was the same in both treatment groups, although gastrointestinal disorders were significantly more frequent in the clodronate group during the total study period (66% vs 56.2%; 95% CI 4.0-15.6; p < 0.05). This was mainly due to an increase in non-severe diarrhoea beginning 3–4 months after treatment start. Serious AEs (SAEs) were reported for 39.4% of the patients receiving clodronate and 44.5% of those receiving placebo; no drug-related (clodronate or placebo) SAEs were identified. Clodronate significantly lowered mortality (98 deaths vs 129 deaths; hazard ratio 0.77; 95% CI 0.59–1.00; p = 0.047) reducing the risk of death over the total study period by 23%. AEs caused 58 early discontinuations (five drug-related events) in the clodronate group and 43 discontinuations (three drug-related events) in the placebo group. Conclusion: These results indicate that in women with early breast cancer receiving adjuvant systemic therapy, oral clodronate for 2 years is generally well tolerated with no serious long-term sequelae, providing a safe, long-term therapy in the adjuvant setting.

Missing values in longitudinal dietary data: a multiple imputation approach based on a fully conditional specification.

Multiple imputation (MI) has increasingly received attention as a flexible tool to resolve missing data problems both in observational and controlled studies. Our goal has been to develop a valid and efficient MI procedure for the Diabetes Prediction and Prevention Nutrition Study, in which the diet of a cohort of newborn children with HLA-DQB1-conferred susceptibility to type 1 diabetes is repeatedly measured by 3-day food records over early childhood. The estimation of risk is based on a nested case-control design setup within the cohort. We have used an iterative procedure known as the fully conditional specification (FCS) to generate appropriate values for the missing dietary data, here playing the role of time-dependent covariates. Our method extends the standard FCS to repeated measurements settings with the possibility of non-monotone missingness patterns by being doubly iterative over the follow-up time of the individuals. In addition, our proposed procedure is nonparametric in the sense that the variables can have distributions deviating strongly from normality: it makes use of quantile normal scores to transform to normality, performs imputations, and transforms back to the original scale. By the use of a moving time window and stepwise regression procedures, the two-fold FCS method operates well with a great number of variables each measured repeatedly over time. Extensive simulation studies demonstrate that the procedure together with the proposed transformations and variable selection methods provides tools for valid and efficient statistical inference in the nested case-control setting, and its applications extend beyond that.

Early introduction of root vegetables in infancy associated with advanced ß-cell autoimmunity in young children with human leukocyte antigen-conferred susceptibility to Type 1 diabetes.

Diabet. Med. 28, 965–971 (2011)

Early introduction of root vegetables in infancy associated with advanced beta-cell autoimmunity in young children with human leukocyte antigen-conferred susceptibility to Type 1 diabetes

Diabet. Med. 28, 965–971 (2011)

Serum fatty acids and risk of advanced β-cell autoimmunity: a nested case–control study among children with HLA-conferred susceptibility to type I diabetes

Background/Objectives:N-3 (omega-3) fatty acids have been reported to decrease the risk for development of β-cell autoimmunity and clinical type I diabetes. We set out to examine whether different serum fatty acids are associated with the development of advanced β-cell autoimmunity in children carrying human leukocyte antigen DQ β-1 (HLA-DQB1)-conferred susceptibility to type I diabetes.Subjects/Methods:Within a cohort, serum total fatty acid composition of 108 children with advanced β-cell autoimmunity and of 216 matched persistently autoantibody-negative controls was analyzed using gas chromatography. Non-fasting serum samples were obtained annually at the ages of 1–6 years. Conditional logistic regression was applied to analyze the associations between advanced β-cell autoimmunity and serum fatty acids.Results:The serum fatty acid profile of myristic acid (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.09–2.00, P=0.011), pentadecanoic acid (OR 1.65, 95% CI 1.19–2.28, P=0.003), palmitoleic acid isomers 16:1 n-7 (omega-7) (OR 1.41, 95% CI 1.03–1.92, P=0.030) and 16:1 n-9 (omega-9) (OR 1.45, 95% CI 1.05–2.01, P=0.026) and conjugated linoleic acid (OR 1.67, 95% CI 1.16–2.41, P=0.006) closest to the time of the appearance of multiple autoantibodies were positively associated with the risk of advanced β-cell autoimmunity after adjustment for potential confounding factors. Serum linoleic acid showed inverse, marginal association with the end point.Conclusions:Serum biomarkers of milk and ruminant meat fat consumption are directly associated and linoleic acid is inversely associated with advanced β-cell autoimmunity in children with HLA-conferred susceptibility to type I diabetes.