Cadmium-Related Mortality and Long-Term Secular Trends in the Cadmium Body Burden of an Environmentally Exposed Population

BACKGROUND: Few population studies have reported on the long-term changes in the internal cadmium dose and simultaneously occurring mortality. OBJECTIVE: We monitored blood cadmium (BCd), 24-hr urinary cadmium (UCd), and mortality in an environmentally exposed population. METHODS: Starting from 1985, we followed BCd (until 2003), UCd (until 1996), and mortality (until 2007) among 476 and 480 subjects, randomly recruited from low- exposure areas (LEA) and high-exposure areas (HEA). The last cadmium-producing plant in the HEA closed in 2002. RESULTS: From 1985-1989 to 1991-1996, BCd decreased by 40.3% and 18.9% in the LEA and HEA, respectively (p < 0.0001 for between-area difference). From 1991-1996 until 2001-2003, BCd remained unchanged in the HEA (+ 1.8%) and increased by 19.7% in the LEA (p < 0.0001). Over the entire follow-up period, the annual decrease in BCd averaged 2.7% in the LEA (n = 258) and 1.8% in the HEA (n = 203). From 1985-1989 to 1991-1996, UCd fell by 12.9% in the LEA and by 16.6% in the HEA (p = 0.22), with mean annual decreases of 2.7% (n = 366) and 3.4% (n = 364). Over 20.3 years (median), 206 deaths (21.5%) occurred. At baseline, BCd (14.6 vs. 10.2 nmol/L) and UCd (14.1 vs. 8.6 nmol/24-hr) were higher in deaths than in survivors. The risks (p <= 0.04) associated with a doubling of baseline UCd were 20% and 44% for total and noncardiovascular mortality, and 25% and 33% for a doubling of BCd. CONCLUSIONS: Even if zinc-cadmium smelters close, historical environmental contamination remains a persistent source of exposure. Environmental exposure to cadmium increases total and noncardiovascular mortality in a continuous fashion without threshold

Individual participant data meta-analysis to examine interactions between treatment effect and participant-level covariates: statistical recommendations for conduct and planning

Precision medicine research often searches for treatment‐covariate interactions, which refers to when a treatment effect (eg, measured as a mean difference, odds ratio, hazard ratio) changes across values of a participant‐level covariate (eg, age, gender, biomarker). Single trials do not usually have sufficient power to detect genuine treatment‐covariate interactions, which motivate the sharing of individual participant data (IPD) from multiple trials for meta‐analysis. Here, we provide statistical recommendations for conducting and planning an IPD meta‐analysis of randomized trials to examine treatment‐covariate interactions. For conduct, two‐stage and one‐stage statistical models are described, and we recommend: (i) interactions should be estimated directly, and not by calculating differences in meta‐analysis results for subgroups; (ii) interaction estimates should be based solely on within‐study information; (iii) continuous covariates and outcomes should be analyzed on their continuous scale; (iv) nonlinear relationships should be examined for continuous covariates, using a multivariate meta‐analysis of the trend (eg, using restricted cubic spline functions); and (v) translation of interactions into clinical practice is nontrivial, requiring individualized treatment effect prediction. For planning, we describe first why the decision to initiate an IPD meta‐analysis project should not be based on between‐study heterogeneity in the overall treatment effect; and second, how to calculate the power of a potential IPD meta‐analysis project in advance of IPD collection, conditional on characteristics (eg, number of participants, standard deviation of covariates) of the trials (potentially) promising their IPD. Real IPD meta‐analysis projects are used for illustration throughout

Bone Resorption and Environmental Exposure to Cadmium in Women: A Population Study

BACKGROUND: Environmental exposure to cadmium decreases bone density indirectly through hypercalciuria resulting from renal tubular dysfunction. OBJECTIVE: We sought evidence for a direct osteotoxic effect of cadmium in women. METHODS: We randomly recruited 294 women (mean age, 49.2 years) from a Flemish population with environmental cadmium exposure. We measured 24-hr urinary cadmium and blood cadmium as indexes of lifetime and recent exposure, respectively. We assessed the multivariate-adjusted association of exposure with specific markers of bone resorption, urinary hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), as well as with calcium excretion, various calciotropic hormones, and forearm bone density. RESULTS: In all women, the effect sizes associated with a doubling of lifetime exposure were 8.4% (p = 0.009) for HP, 6.9% (p = 0.10) for LP, 0.77 mmol/day (p = 0.003) for urinary calcium, -0.009 g/cm(2) (p = 0.055) for proximal forearm bone density, and -16.8% (p = 0.065) for serum parathyroid hormone. In 144 postmenopausal women, the corresponding effect sizes were -0.01223 g/cm(2) (p = 0.008) for distal forearm bone density, 4.7% (p = 0.064) for serum calcitonin, and 10.2% for bone-specific alkaline phosphatase. In all women, the effect sizes associated with a doubling of recent exposure were 7.2% (p = 0.001) for urinary HP, 7.2% (p = 0.021) for urinary LP, -9.0% (p = 0.097) for serum parathyroid hormone, and 5.5% (p = 0.008) for serum calcitonin. Only one woman had renal tubular dysfunction (urinary retinol-binding protein > 338 mu g/day). CONCLUSIONS: In the absence of renal tubular dysfunction, environmental exposure to cadmium increases bone resorption in women, suggesting a direct osteotoxic effect with increased calciuria and reactive changes in calciotropic hormones

Sodium intake in men and potassium intake in women determine the prevalence of metabolic syndrome in Japanese hypertensive patients: OMEGA Study

Dietary intake affects hypertension and metabolic syndrome (MS) and their management. In Japanese hypertensive patients, little evidence exists regarding the relation between diet and MS. A self-administered lifestyle questionnaire was completed by each patient at the baseline. Three dietary scores were calculated for each patient: sodium intake, potassium intake and soybean/fish intake. The relationships between dietary scores and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed by multiple regression analysis. The relation between dietary intake of sodium, potassium and soybean/fish, and the presence of MS was evaluated by the Mantel–Haenszel test. A total of 9585 hypertensive patients (mean age, 64.9 years; women, 51.4%) were included in this sub-analysis. High sodium intake was significantly related to increased SBP (P=0.0003) and DBP (P=0.0130). Low potassium intake was significantly related to increased SBP (P=0.0057) and DBP (P=0.0005). Low soybean/fish intake was significantly related to increased SBP (P=0.0133). A significantly higher prevalence of MS was found in men in the highest quartile of sodium intake compared with the lower quartiles (P=0.0026) and in women in the lowest quartile of potassium intake compared with the higher quartiles (P=0.0038). A clear relation between dietary habits and blood pressure was found in Japanese hypertensive patients using a patient-administered questionnaire. Sodium and potassium intake affect MS prevalence. Dietary changes are warranted within hypertension treatment strategies

Fracture risk and the use of a diuretic (indapamide sr) ± perindopril: a substudy of the Hypertension in the Very Elderly Trial (HYVET)

BACKGROUND: The Hypertension in the Very Elderly Trial (HYVET) is a placebo controlled double blind trial of treating hypertension with indapamide Slow Release (SR) ± perindopril in subjects over the age of 80 years. The primary endpoints are stroke (fatal and non fatal). In view of the fact that thiazide diuretics and indapamide reduce urinary calcium and may increase bone mineral density, a fracture sub study was designed to investigate whether or not the trial anti-hypertensive treatment will reduce the fracture rate in very elderly hypertensive subjects. METHODS: In the trial considerable care is taken to ascertain any fractures and to identify risk factors for fracture, such as falls, co-morbidity, drug treatment, smoking and drinking habits, levels of activity, biochemical abnormalities, cardiac irregularities, impaired cognitive function and symptoms of orthostatic hypotension. POTENTIAL RESULTS: The trial is expected to provide 10,500 patient years of follow-up. Given a fracture rate of 40/1000 patient years and a 20% difference in fracture rate, the power of the sub study is 58% to detect this difference at the 5% level of significance. The corresponding power for a reduction of 25% is 78%. CONCLUSION: The trial is well under way, expected to complete in 2009, and on target to detect, if present, the above differences in fracture rate

Favorable patient acceptance of ambulatory blood pressure monitoring in a primary care setting in the United States: a cross-sectional survey

BACKGROUND: The use of ambulatory blood pressure monitoring (ABPM) in the diagnosis and management of hypertension in primary care settings in the United States is increasing. Insufficient information is available describing patients' experiences and acceptance of this technology in the United States, where medical insurance coverage of the procedure is often limited. The objective of this study was to describe patient satisfaction with ABPM performed in a primary care office in the United States, using modern ABPM technology. METHODS: Cross-sectional survey performed on consecutive patients referred to the ABPM service of the Family Care Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa from January 2001 to July 2003. Measures of patient satisfaction and acceptance with the device, comfort, and overall session were assessed via a 9-question, Likert-scale response survey. RESULTS: Since its inception two and a half years ago, 245 total ABPM sessions have been conducted in 235 unique patients. Of the 235 eligible respondents, 177 returned completed surveys, yielding a 75% response rate. Three-fourths (75%) of patients believed that undergoing the test was worthwhile considering the time and monetary cost involved, while most (90%) reported they thought the information provided by the test would be helpful to their physician in making treatment decisions. Patients reporting that their physician had clearly explained the benefit of undergoing the testing were more likely to report that they thought the results of the test would be more helpful in making treatment decisions. Few patients (20%) found that wearing the monitor was uncomfortable. CONCLUSIONS: When clinically indicated, clinicians should not hesitate to order ABPM testing for fear of subjecting patients to an uncomfortable test, or an uncovered insurance benefit. When ordering ABPM, they should be sure to educate the patient about the potential benefits of undergoing the testing. Most patients believe the test will provide useful information in making treatment decisions, despite probable lack of insurance coverage, and appear willing to experience some discomfort for the overall gain of the results obtained from undergoing the session

Blood pressure changes after renal denervation at 10 European expert centers

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P0.08). Normalization was a systolic BP of &#60;140 mm Hg on office measurement or &#60;130 mm Hg on 24-h monitoring and improvement was a fall of 10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-μmol l(-1) increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment

Blood pressure and urinary sodium excretion in relation to the A-1984G adrenomedullin polymorphism in a Chinese population

Adrenomedullin (ADM) is a vasodilator and inhibits salt appetite. An A-to-G substitution at position -1984 in the promoter region of the ADM gene likely increases transcription. We therefore investigated this polymorphism in relation to blood pressure and urinary sodium in a Chinese population. We genotyped 427 Chinese enrolled in a family-based population study. We measured blood pressure by conventional sphygmomanometry and ambulatory monitoring. The frequencies of the ADM AA, AG, and GG genotypes were 50.6, 38.2, and 11.2%, respectively. In adjusted analyses, G allele carriers, compared to AA homozygotes, had significantly lower conventional (45.3 versus 48.5 mm Hg, P=0.004) and 24-h (42.6 versus 44.3 mm Hg, P=0.03) pulse pressures and urinary sodium excretion (143.8 versus 159.4 mmol/day, P=0.03). In parents, but not offspring, both systolic pressure and pulse pressure were significantly (P<0.01) lower in G allele carriers. The genotypic difference in sodium excretion was consistent across the age range. In 68 informative offspring, transmission of the G allele was associated with lower urinary sodium excretion (effect size, 40.1 mmol/day, P=0.01). In 81 healthy volunteers, the plasma ADM concentration was 15.2% higher in GG homozygotes than in sex- and age-matched AA subjects (11.4 versus 9.9 pmol/l, P=0.10). In conclusion, in Chinese, the ADM -1984G allele is associated with lower sodium excretion and in older subjects also with lower systolic pressure and narrower pulse pressure

Does self-monitoring reduce blood pressure? Meta-analysis with meta-regression of randomized controlled trials

Introduction. Self-monitoring of blood pressure (BP) is an increasingly common part of hypertension management. The objectives of this systematic review were to evaluate the systolic and diastolic BP reduction, and achievement of target BP, associated with self-monitoring. Methods. MEDLINE, Embase, Cochrane database of systematic reviews, database of abstracts of clinical effectiveness, the health technology assessment database, the NHS economic evaluation database, and the TRIP database were searched for studies where the intervention included self-monitoring of BP and the outcome was change in office/ambulatory BP or proportion with controlled BP. Two reviewers independently extracted data. Meta-analysis using a random effects model was combined with meta-regression to investigate heterogeneity in effect sizes. Results. A total of 25 eligible randomized controlled trials (RCTs) (27 comparisons) were identified. Office systolic BP (20 RCTs, 21 comparisons, 5,898 patients) and diastolic BP (23 RCTs, 25 comparisons, 6,038 patients) were significantly reduced in those who self-monitored compared to usual care (weighted mean difference (WMD) systolic −3.82 mmHg (95% confidence interval −5.61 to −2.03), diastolic −1.45 mmHg (−1.95 to −0.94)). Self-monitoring increased the chance of meeting office BP targets (12 RCTs, 13 comparisons, 2,260 patients, relative risk = 1.09 (1.02 to 1.16)). There was significant heterogeneity between studies for all three comparisons, which could be partially accounted for by the use of additional co-interventions. Conclusion. Self-monitoring reduces blood pressure by a small but significant amount. Meta-regression could only account for part of the observed heterogeneity