Michiel R. de Boer

Birth weight and prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): A meta-analysis within 12 European birth cohorts

Objectives: Exposure to high concentrations of persistent organochlorines may cause fetal toxicity, but the evidence at low exposure levels is limited. Large studies with substantial exposure contrasts and appropriate exposure assessment are warranted. Within the framework of the EU (European Union) ENRIECO (ENvironmental Health RIsks in European Birth Cohorts) and EU OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life) projects, we examined the hypothesis that the combination of polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) adversely affects birth weight. Methods: We used maternal and cord blood and breast milk samples of 7,990 women enrolled in 15 study populations from 12 European birth cohorts from 1990 through 2008. Using identical variable definitions, we performed for each cohort linear regression of birth weight on estimates of cord serum concentration of PCB-153 and p,p´-DDE adjusted for gestational age and a priori selected covariates. We obtained summary estimates by meta-analysis and performed analyses of interactions. Results: The median concentration of cord serum PCB-153 was 140 ng/L (range of cohort medians 20–484 ng/L) and that of p,p´-DDE was 528 ng/L (range of cohort medians 50–1,208 ng/L). Birth weight decreased with increasing cord serum concentration of PCB-153 after adjustment for potential confounders in 12 of 15 study populations. The meta-analysis including all cohorts indicated a birth weight decline of 150 g [95% confidence interval (CI): –250, –50 g] per 1-µg/L increase in PCB-153, an exposure contrast that is close to the range of exposures across the cohorts. A 1-µg/L increase in p,p´-DDE was associated with a 7-g decrease in birth weight (95% CI: –18, 4 g). Conclusions: The findings suggest that low-level exposure to PCB (or correlated exposures) impairs fetal growth, but that exposure to p,p´-DDE does not. The study adds to mounting evidence that low-level exposure to PCBs is inversely associated with fetal growth.

Risk of Second Malignancies in Survivors of Retinoblastoma: More Than 40 Years of Follow-up

BACKGROUND Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce. METHODS Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided. RESULTS After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease. CONCLUSION Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.

Spinal manipulative therapy for chronic low-back pain: an update of a Cochrane review

Study Design. Systematic review of interventions. Objective. To assess the effects of spinal manipulative therapy (SMT) for chronic low-back pain. Summary of Background Data. SMT is one of the many therapies for the treatment of low-back pain, which is a worldwide, extensively practiced intervention. Methods. Search methods. An experienced librarian searched for randomized controlled trials (RCTs) in multiple databases up to June 2009. Selection criteria. RCTs that examined manipulation or mobilization in adults with chronic low-back pain were included. The primary outcomes were pain, functional status, and perceived recovery. Secondary outcomes were return-to-work and quality of life. Data collection and analysis. Two authors independently conducted the study selection, risk of bias assessment, and data extraction. GRADE was used to assess the quality of the evidence. Results. We included 26 RCTs (total participants = 6070), 9 of which had a low risk of bias. Approximately two-thirds of the included studies (N = 18) were not evaluated in the previous review. There is a high-quality evidence that SMT has a small, significant, but not clinically relevant, short-term effect on pain relief (mean difference −4.16, 95% confidence interval −6.97 to −1.36) and functional status (standardized mean difference −0.22, 95% confidence interval −0.36 to −0.07) in comparison with other interventions. There is varying quality of evidence that SMT has a significant short-term effect on pain relief and functional status when added to another intervention. There is a very low-quality evidence that SMT is not more effective than inert interventions or sham SMT for short-term pain relief or functional status. Data were particularly sparse for recovery, return-to-work, quality of life, and costs of care. No serious complications were observed with SMT. Conclusions. High-quality evidence suggests that there is no clinically relevant difference between SMT and other interventions for reducing pain and improving function in patients with chronic low-back pain. Determining cost-effectiveness of care has high priority.

Prenatal Exposure to Perfluoroalkyl Substances and Behavioral Development in Children

Background: In recent years, prevalence rates of behavioral disorders in children have increased. One factor possibly implied in the etiology of behavioral disorders is exposure to perfluoroalkyl substances (PFASs). The use of PFASs is highly integrated into everyday life, and exposure is ubiquitous. Exposure to PFASs during early life may be particularly harmful, as it represents a critical time window for brain development. However, research in the area is limited, especially among preschool children. The objective of the current study was to explore the relationship between prenatal exposure to several PFASs and behavioral development at the age of 18 months. Methods: Data from the Dutch cohort LINC (Linking Maternal Nutrition to Child Health) were used. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord plasma. The total exposure of PFASs was also calculated (ΣPFASs). Behavioral development was assessed with the Child Behavior Checklist 1.5–5 (CBCL 1.5–5). The CBCL scales “Attention Deficit Hyperactivity Disorder” (ADHD) and “Externalizing problems” were used for further analysis. Separate regression models were composed for each combination, in which exposure levels were classified in tertiles. Both whole population and sex-stratified analyses were performed. A family history of ADHD, the educational level, smoking or using alcohol or illicit drugs during pregnancy were considered as confounders. In total, data from 76 mother-child pairs was included. Results: No significant associations were found between prenatal PFAS exposure and ADHD scores in the whole population and in the sex-stratified analyses. With regard to externalizing behavior, a significant negative association was found between the highest levels of ΣPFAS exposure and externalizing problem behavior in the whole population, but only in the crude model. After stratifying for sex, boys in the second and third tertile of exposure to PFOA presented significantly lower scores on the Externalizing Problem Scale than boys with the lowest exposure levels in the adjusted model. Girls exposed to higher levels of ΣPFAS exposure (T2) showed significantly lower scores on the Externalizing Problem Scale, in both crude and adjusted models. No significant associations with PFOS were found. Conclusions: Results from the current study show that prenatal exposure to PFOA was negatively related to externalizing behavior in boys. Results were different for boys and girls, emphasizing that mechanisms at work might be sex-dependent. However, results should be interpreted with caution as the sample size was small.

Multiple imputation of missing values was not necessary before performing a longitudinal mixed-model analysis

BACKGROUND AND OBJECTIVES As a result of the development of sophisticated techniques, such as multiple imputation, the interest in handling missing data in longitudinal studies has increased enormously in past years. Within the field of longitudinal data analysis, there is a current debate on whether it is necessary to use multiple imputations before performing a mixed-model analysis to analyze the longitudinal data. In the current study this necessity is evaluated. STUDY DESIGN AND SETTING The results of mixed-model analyses with and without multiple imputation were compared with each other. Four data sets with missing values were created-one data set with missing completely at random, two data sets with missing at random, and one data set with missing not at random). In all data sets, the relationship between a continuous outcome variable and two different covariates were analyzed: a time-independent dichotomous covariate and a time-dependent continuous covariate. RESULTS Although for all types of missing data, the results of the mixed-model analysis with or without multiple imputations were slightly different, they were not in favor of one of the two approaches. In addition, repeating the multiple imputations 100 times showed that the results of the mixed-model analysis with multiple imputation were quite unstable. CONCLUSION It is not necessary to handle missing data using multiple imputations before performing a mixed-model analysis on longitudinal data.

Price discounts significantly enhance fruit and vegetable purchases when combined with nutrition education: a randomized controlled supermarket trial

BACKGROUND Reducing fruit and vegetable (F&V) prices is a frequently considered policy to improve dietary habits in the context of health promotion. However, evidence on the effectiveness of this intervention is limited. OBJECTIVE The objective was to examine the effects of a 50% price discount on F&Vs or nutrition education or a combination of both on supermarket purchases. DESIGN A 6-mo randomized controlled trial within Dutch supermarkets was conducted. Regular supermarket shoppers were randomly assigned to 1 of 4 conditions: 50% price discounts on F&Vs, nutrition education, 50% price discounts plus nutrition education, or no intervention. A total of 199 participants provided baseline data; 151 (76%) were included in the final analysis. F&V purchases were measured by using supermarket register receipts at baseline, at 1 mo after the start of the intervention, at 3 mo, at 6 mo (end of the intervention period), and 3 mo after the intervention ended (9 mo). RESULTS Adjusted multilevel models showed significantly higher F&V purchases (per household/2 wk) as a result of the price discount (+3.9 kg; 95% CI: 1.5, 6.3 kg) and the discount plus education intervention (+5.6 kg; 95% CI: 3.2, 7.9 kg) at 6 mo compared with control. Moreover, the percentage of participants who consumed recommended amounts of F&Vs (≥400 g/d) increased from 42.5% at baseline to 61.3% at 6 mo in both discount groups (P = 0.03). Education alone had no significant effect. CONCLUSIONS Discounting F&Vs is a promising intervention strategy because it resulted in substantially higher F&V purchases, and no adverse effects were observed. Therefore, pricing strategies form an important focus for future interventions or policy. However, the long-term effects and the ultimate health outcomes require further investigation. This trial was registered at the ISRCTN Trial Register as number ISRCTN56596945 and at the Dutch Trial Register (http://www.trialregister.nl/trialreg/index.asp) as number NL22568.029.08.

A systematic review on the effectiveness of complementary and alternative medicine for chronic non-specific low-back pain.

The purpose of this systematic review was to assess the effects of spinal manipulative therapy (SMT), acupuncture and herbal medicine for chronic non-specific LBP. A comprehensive search was conducted by an experienced librarian from the Cochrane Back Review Group (CBRG) in multiple databases up to December 22, 2008. Randomised controlled trials (RCTs) of adults with chronic non-specific LBP, which evaluated at least one clinically relevant, patient-centred outcome measure were included. Two authors working independently from one another assessed the risk of bias using the criteria recommended by the CBRG and extracted the data. The data were pooled when clinically homogeneous and statistically possible or were otherwise qualitatively described. GRADE was used to determine the quality of the evidence. In total, 35 RCTs (8 SMT, 20 acupuncture, 7 herbal medicine), which examined 8,298 patients, fulfilled the inclusion criteria. Approximately half of these (2 SMT, 8 acupuncture, 7 herbal medicine) were thought to have a low risk of bias. In general, the pooled effects for the studied interventions demonstrated short-term relief or improvement only. The lack of studies with a low-risk of bias, especially in regard to SMT precludes any strong conclusions; however, the principal findings, which are based upon low- to very-low-quality evidence, suggest that SMT does not provide a more clinically beneficial effect compared with sham, passive modalities or any other intervention for treatment of chronic low-back pain. There is evidence, however, that acupuncture provides a short-term clinically relevant effect when compared with a waiting list control or when acupuncture is added to another intervention. Although there are some good results for individual herbal medicines in short-term individual trials, the lack of homogeneity across studies did not allow for a pooled estimate of the effect. In general, these results are in agreement with other recent systematic reviews on SMT, but in contrast with others. These results are also in agreement with recent reviews on acupuncture and herbal medicine. Randomized trials with a low risk of bias and adequate sample sizes are direly needed.

Endothelial Dysfunction and Low-Grade Inflammation Are Associated With Greater Arterial Stiffness Over a 6-Year Period

Endothelial dysfunction and low-grade inflammation are associated with cardiovascular disease. Arterial stiffening plays an important role in cardiovascular disease and, thus, may be a mechanism through which endothelial dysfunction and/or low-grade inflammation lead to cardiovascular disease. We investigated the associations between, on the one hand, biomarkers of endothelial dysfunction (soluble endothelial selectin, thrombomodulin, and both vascular and intercellular adhesion molecules 1 and von Willebrand factor) and of low-grade inflammation (C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumor necrosis factor-&agr; and, soluble intercellular adhesion molecule 1) and, on the other hand, arterial stiffness over a 6-year period, in 293 healthy adults (155 women). Biomarkers were combined into mean z scores. Carotid, femoral, and brachial arterial stiffness and carotid-femoral pulse wave velocity were determined by ultrasonography. Measurements were obtained when individuals were 36 and 42 years of age. Associations were analyzed with generalized estimating equation and adjusted for sex, height, and mean arterial pressure. The endothelial dysfunction z score was inversely associated with femoral distensibility (&bgr;: −0.51 [95% CI: −0.95 to −0.06]) and compliance coefficients (&bgr;: −0.041 [95% CI: −0.076 to −0.006]) but not with carotid or brachial stiffness or carotid-femoral pulse wave velocity. The low-grade inflammation z score was inversely associated with femoral distensibility (&bgr;: −0.51 [95% CI: −0.95 to −0.07]) and compliance coefficients (&bgr;: −0.050 [95% CI: −0.084 to −0.016]) and with carotid distensibility coefficient (&bgr;: −0.910 [95% CI: −1.810 to −0.008]) but not with brachial stiffness or carotid-femoral pulse wave velocity. Biomarkers of endothelial dysfunction and low-grade inflammation are associated with greater arterial stiffness. This provides evidence that arterial stiffening may be a mechanism through which endothelial dysfunction and low-grade inflammation lead to cardiovascular disease.

Spinal manipulative therapy for acute low back pain: an update of the cochrane review

Study Design. Systematic review of interventions. Objective. To assess the effects of spinal manipulative therapy (SMT) for acute low back pain. Summary of Background Data. SMT is one of many therapies for the treatment of low back pain, which is a worldwide, extensively practiced intervention. Methods. An experienced librarian searched for randomized controlled trials (RCTs) in multiple databases up to March 13, 2011. RCTs that examined manipulation or mobilization in adults with acute low back pain (<6-week duration) were included. The primary outcomes were pain, functional status and perceived recovery. Secondary outcomes were return-to-work and quality of life. Two authors independently conducted the study selection, risk of bias assessment and data extraction. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess the quality of the evidence. The effects were examined for SMT versus (1) inert interventions, (2) sham SMT, (3) other interventions, and (4) SMT as adjunct therapy. Results. We identified 20 RCTs (total participants = 2674), 12 (60%) of which were not included in the previous review. In total, 6 trials (30% of all included studies) had a low risk of bias. In general, for the outcomes of pain and functional status, there is low- to very low-quality evidence suggesting no difference in effect for SMT when compared with inert interventions, sham SMT or as adjunct therapy. There was varying quality of evidence (from very low to moderate) suggesting no difference in effect for SMT when compared with other interventions. Data were particularly sparse for recovery, return-to-work, quality of life, and costs of care. No serious complications were observed with SMT. Conclusion. SMT is no more effective for acute low back pain than inert interventions, sham SMT or as adjunct therapy. SMT also seems to be no better than other recommended therapies. Our evaluation is limited by the few numbers of studies; therefore, future research is likely to have an important impact on these estimates. Future RCTs should examine specific subgroups and include an economic evaluation.

Magnetic resonance imaging for diagnosing lumbar spinal pathology in adult patients with low back pain or sciatica: a diagnostic systematic review

PurposeIn about 5% of all cases LBP is associated with serious underlying pathology requiring diagnostic confirmation and directed treatment. Magnetic resonance imaging (MRI) is often used for this diagnostic purpose yet its role remains controversial. Consequently, this review aimed to summarize the available evidence on the diagnostic accuracy of MRI for identifying lumbar spinal pathology in adult low back pain (LPB) or sciatica patients.MethodsMEDLINE, EMBASE and CINAHL were searched (until December 2009) for observational studies assessing the diagnostic accuracy of MRI compared to a reference test for the identification of lumbar spinal pathology. Two reviewers independently selected studies for inclusion, extracted data and assessed methodological quality. Pooled summary estimates of sensitivity and specificity with 95% confidence intervals were calculated for homogenous subsets of studies.ResultsEight studies were included in this review. Strata were defined for separate pathologies i.e. lumbar disc herniation (HNP) and spinal stenosis. Five studies comparing MRI to findings at the surgery for identifying HNP were included in a meta-analysis. Pooled analysis resulted in a summary estimate of sensitivity of 75% (95% CI 65–83%) and specificity of 77% (95% CI 61–88%). For spinal stenosis pooling was not possible.ConclusionsThe results suggest that a considerable proportion of patients may be classified incorrectly by MRI for HNP and spinal stenosis. However, the evidence for the diagnostic accuracy of MRI found by this review is not conclusive, since the results could be distorted due to the limited number of studies and large heterogeneity.