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Objectives. We evaluated the relationship between smoking and adenocarcinoma of the prostate. Methods. We pooled data from 24 cohort studies enrolling 21 579 prostate cancer case participants for a general variance-based meta-analysis. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated separately for mortality and incidence studies. We tested the robustness of effect measures and evaluated statistical heterogeneity with sensitivity analyses. Results. In the pooled data, current smokers had no increased risk of incident prostate cancer (RR = 1.04; 95% CI = 0.87, 1.24), but in data stratified by amount smoked they had statistically significant elevated risk (cigarettes per day or years: RR = 1.22; 95% CI = 1.01, 1.46; pack years of smoking: RR = 1.11; 95% CI = 1.01, 1.22). Former smokers had an increased risk (RR = 1.09; 95% CI = 1.02, 1.16). Current smokers had an increased risk of fatal prostate cancer (RR = 1.14; 95% CI = 1.06, 1.19). The heaviest smokers had a 24% to 30% greater risk of death from prostate cancer than did nonsmokers. Conclusions. Observational cohort studies show an association of smoking with prostate cancer incidence and mortality. Ill-defined exposure categories in many cohort studies suggest that pooled data underestimate risk.

Immigrant mothers in developed countries often experience worse pregnancy outcomes than native women. Several epidemiological studies have described the pregnancy outcome of immigrant women in European receiving countries, with conflicting results. The present systematic review makes a quantitative synthesis of available evidence on the association between pregnancy outcomes and integration policies. We reviewed all epidemiological studies comparing the pregnancy outcome of native versus immigrant women in European countries from 1966 to 2004 and retained 65 for analysis, from 12 host countries. Overall, as compared to native women, immigrant women showed a clear disadvantage for all the outcomes considered: 43% higher risk of low birth weight, 24% of pre-term delivery, 50% of perinatal mortality, and 61% of congenital malformations. The risks were clearly and significantly reduced in countries with a strong integration policy. This trend was maintained even after adjustment for age at delivery and parity. On the basis of an analysis of naturalisation rates, five countries in our sample could be categorised as having a strong policies promoting the integration of immigrant communities. The mechanisms through which integration policies may be protective include the increased participation of immigrant communities in the life of the receiving society, and the decreased stress and discrimination they may face. The results of this study highlight a serious problem of equity in perinatal health across European countries. Immigrant women clearly need targeted attention to improve the health of their newborn, but a deep societal change is also necessary to integrate and respect immigrant communities in receiving societies.

Objective Although calcium is essential for maintaining bone health in children, the optimum dietary intake of calcium in this age group, particularly in the form of dairy foods, is not well defined. A meta-analysis was conducted to examine the impact of dietary calcium/dairy supplementation on bone mineral content in this age group. Methods Data were pooled from randomized controlled intervention trials and observational studies using previously described methods. The outcome of interest was a summary mean difference bone mineral content. Sensitivity analyses were employed to evaluate any observed statistical heterogeneity and to examine the influence of specific study characteristics on the summary estimate of effect. Results Initially combining data from twenty-one randomized controlled trials (RCTs) using total body bone mineral content (TB-BMC) as the outcome of interest, yielded a non-statistically significant increase in TB-BMC of 2 g (supplemented versus controls). These data demonstrated substantial statistical heterogeneity with sensitivity analyses revealing that among study subjects with normal or near normal baseline dietary calcium/dairy intakes, supplemental dairy/calcium showed little impact on bone mineral content. Sensitivity analyses suggested that baseline calcium intake could potentially account for the statistical heterogeneity. Pooling the three reports utilizing low intake subjects yielded a statistically significant summary mean BMC of 49 g (24.0–76–6). Pooling two RCTs using calcium/dairy supplement plus vitamin D was also associated with an increase in lumbar spine BMC of, on average, 35 g (− 6.8–41.8). The lack of data using BMC measurements at other anatomic sites as well as sparse data from non-randomized studies, precluded further statistical pooling. Conclusion Increased dietary calcium/dairy products, with and without vitamin D, significantly increases total body and lumbar spine BMC in children with low base-line intakes.

In this study, we examined the available evidence and sources of heterogeneity for studies of dairy products, calcium, and vitamin D intake and the risk of prostate cancer. We pooled data from 45 observational studies using a general variance-based, meta-analytic method employing CIs. Summary relative risks (RRs) were calculated for specific dairy products such as milk and dairy micronutrients. Sensitivity analyses were performed to test the robustness of these summary measures of effect. Cohort studies showed no evidence of an association between dairy [RR = 1.06; 95% confidence interval (CI) = 0.92-1.22] or milk intake (RR = 1.06; 95% CI = 0.91-1.23) and risk of prostate cancer. This was supported by pooled results of case-control analyses (RR = 1.14; 95% CI = 1.00-1.29), although studies using milk as the exposure of interest were heterogeneous and could not be combined. Calcium data from cohort studies were heterogeneous. Case-control analyses using calcium as the exposure of interest demonstrated no association with increased risk of prostate cancer (RR = 1.04; 95% CI = 0.90-1.15). Dietary intake of vitamin D also was not related to prostate cancer risk (RR = 1.16; 95% CI = 0.98-1.38). The data from observational studies do not support an association between dairy product use and an increased risk of prostate cancer.

Prior work suggests an association between perineal use of cosmetic talc and increased ovarian cancer risk. A meta-analysis was performed to examine this hypothesis by evaluating ovarian cancer risk associated with direct exposure of the female genital tract to talc via dusting of contraceptive diaphragms. Data were pooled from epidemiological studies using a general variance-based meta-analytic method that employs confidence intervals. The outcome of interest was a summary relative risk reflecting the risk of ovarian cancer development associated with the use of cosmetic talc on contraceptive diaphragms. Sensitivity analyses were performed to explain any observed statistical heterogeneity and to explore the influence of specific study characteristics on the summary estimate of effect. Initially, combining homogeneous data from nine case-control studies yielded a non-statistically significant summary relative risk of 1.03 (0.80-1.37), suggesting no association between talc-dusted diaphragms and ovarian cancer development. Sensitivity analyses were performed to evaluate the robustness of this finding. All resultant summary relative risks were not statistically significant. The available epidemiological data do not support a causal association between the use of cosmetic talc-dusted diaphragms and ovarian cancer development.

Background and objective: Narrative reviews represent a popular source of information for clinicians, especially where the evidence on a given subject is sparse and analogies from other fields of medicine may help in filling the information gap. Unfortunately, narrative reviews often follow less stringent criteria for information selection and appraisal than systematic reviews, potentially leading to incomplete or biased recommendations. The objective of the present study was to examine the quality of the recommendations provided by narrative reviews on how to improve patient adherence to pharmacological treatment of unipolar depressive disorders. Method: We sought to locate all narrative review papers addressing adherence to treatment in unipolar depressive disorders. In order to do so, we searched Medline and PsychInfo from 1980 to December 2003, using the following keywords: review, depressive disorders, treatment, dropout, patient compliance and adherence. We inspected the title and the abstract, whenever available to identify the relevant reviews and obtained a full copy of the publications in this subset, and read the articles to identify further relevant reviews. These were in turn copied and reviewed, until no further references were found. Results and discussion: We identified 23 reviews, providing a total of 87 recommendations. The most common recommendation was for patient education (19 times), patient-physician empathy/ alliance (14 times), and education of family (nine Received 20 October 2005, Accepted 31 October 2005 Correspondence: Dr Carmelo Munizza, Centro Studi e Ricerche in Psichiatria, Piazza del Donatore di Sangue, 3, 10154 Torino, Italy. Tel./fax: +39 011 852936; e-mail: cmunizza@tin.it times). Reviewers' recommendations were based on the literature on depression 54 times, and on other medical conditions 17 times. A critical appraisal of the evidence base of the recommendations showed that randomized controlled trials or meta-analyses were quoted to support the recommendations only 23% of the times, while important interventions of proven efficacy in the field of depression or in other chronic conditions (e.g. medication clinics, training of nurses, psychological treatment, and telephone follow-up) were not mentioned. Conclusions: Narrative reviews on adherence to pharmacological treatment of depressive disorders suffer not only from the limited availability of good quality evidence, but also from an incomplete critical appraisal of available evidence on interventions both for depression and for other chronic disorders.

Objective. This study examined the methodology of observational studies that explored an association between personal use of hair dye products and the risk of bladder cancer. Methods. Data were pooled from epidemiological studies using a general variance-based meta-analytic method that employed confidence intervals. The outcome of interest was a summary relative risk (RRs) reflecting the risk of bladder cancer development associated with use of hair dye products vs. non-use. Sensitivity analyses were performed to explain any observed statistical heterogeneity and to explore the influence of specific study characteristics of the summary estimate of effect. Results. Initially combining homogenous data from six case-control and one cohort study yielded a non-significant RR of 1.01 (0.92, 1.11), suggesting no association between hair dye use and bladder cancer development. Sensitivity analyses examining the influence of hair dye type, color, and study design on this suspected association showed that uncontrolled confounding and design limitations contributed to a spurious non-significant summary RR. The sensitivity analyses yielded statistically significant RRs ranging from 1.22 (1.11, 1.51) to 1.50 (1.30, 1.98), indicating that personal use of hair dye products increases bladder cancer risk by 22% to 50% vs. non-use. Conclusion. The available epidemiological data suggest an association between personal use of hair dye products and increased risk of bladder cancer.

PURPOSE: Statins reduce cardiovascular events by more than can be explained by their effects on lipids. We conducted a systematic review of how statins affect vascular structure and function, differences among statins, and correlations between the effects of statins on vascular outcomes and either lipid levels or cardiovascular outcomes. METHODS: We primarily searched MEDLINE (1980 to March 2004) to identify all studies with at least 10 subjects that reported the effects of currently available statins on coronary artery stenosis, carotid intima-media thickness, and endothelial function (excluding studies of drug combinations and subjects with organ transplants). Meta-analyses were performed when feasible. RESULTS: Statins decrease the progression and increase the regression of coronary artery lesions and luminal narrowing. Compared with placebo, statins decrease the likelihood of coronary artery restenosis (summary risk ratio = 0.85; 95% confidence interval: 0.77 to 0.95). Statins appear to slow the progression of carotid artery intima-media thickness. Although the effect of statins on coronary endothelial function is uncertain, statins appear to improve peripheral endothelial function. There is no conclusive evidence to suggest that individual statins differ in their effects on these outcomes. Studies generally found weak or no correlation between the effects of statins on vascular outcomes and lipid levels. No study showed a correlation between vascular effect and clinical outcome. CONCLUSION: Statins slow the progression of, and may reverse, atherosclerosis. The magnitude of these effects, however, is small compared with the effects of statins on cardiovascular events. Statins also improve measures of vascular function, which may contribute to their clinical benefits. There is insufficient evidence to suggest that individual statins differ in their vascular effects.

Currently, the true impact of intravesical chemotherapy or immunotherapy (bacilli Calmette-Guerin [BCG]) on the rate of progression of superficial transitional cell carcinoma of the bladder to muscle invasive disease is unclear. A metaanalysis was performed to statistically compare the efficacy of these treatments in preventing tumor progression in this disease setting.A prospective protocol outlining the metaanalysis noted here was developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eight randomized, controlled trials were found that met protocol specifications. These reports contained data on 2427 patients who were statistically pooled using a fixed-effects model (Peto). The outcome of interest was the proportion of patients progressing to muscle invasive or metastatic disease expressed as a summary odds ratio (ORp). An ORp greater than unity favored BCG versus chemotherapy.Initial pooling of these 8 trials gave a nonstatistically significant summary odds ratio of 1.24 (0.95-1.61) without evidence of statistical heterogeneity. Analysis by drug type showed significant attenuation of the ORp when the effects of mitomycin C were compared with BCG, ie, 1.04 (0.76-1.42) suggesting that: 1) mitomycin is probably more active than the other chemotherapeutics used in the available trials and 2) BCG is not clearly superior to mitomycin C. Sensitivity analyses also demonstrated that failure to control for prior intravesical drug treatment in all but 2 of the analyzed studies produces a spurious result favoring BCG over intravesical chemotherapy.The available data fail to support a clear superiority of intravesical BCG over intravesical chemotherapy in preventing progression of superficial transitional cell carcinoma of the bladder. Mitomycin C appears more effective than the other commonly used drugs, and failure to control for prior intravesical chemotherapy in most of available studies results in a spurious finding of greater clinic effect of BCG over chemotherapy.

To determine the occurrence of cancer-related fatigue, the methods used to assess it, and the efficacy of the available treatments, we performed literature searches that identified English-language publications on these topics. Twenty-seven studies were identified in which the quantitative estimation of the occurrence of cancer-related fatigue was an end point. Fifty-six were judged to be relevant to the assessment of fatigue, and 10 randomized controlled clinical trials of treatments of cancer-related fatigue were retrieved. The occurrence of cancer-related fatigue was found to range from 4% to 91%, depending on the population studied and the methods of assessment. Few population-based studies and no longitudinal studies of cancer-related fatigue have been performed. The methods of fatigue assessment were highly variable. Exercise programs show promise to prevent or treat fatigue in some subsets of cancer patients, and the use of epoetin alfa for correction of anemia has been shown to ameliorate fatigue. The number of subjects in the treatment trials was small and their methodologic quality was inconsistent.

Bacille Calmette-Guérin (BCG) immunotherapy is currently considered the most effective agent in the management of superficial bladder cancer. Prior work suggests that the efficacy of intravesical chemotherapy in preventing tumor recurrence may be greater than previously suggested. This latter finding, therefore, brings into question the currently perceived superiority of BCG treatment for this disease. A metaanalysis was performed to rigorously examine existing data relevant to this relationship and to quantify the relative efficacy of both treatment modalities on tumor recurrence. A prospective protocol outlining the above-noted metaanalysis was initially developed followed by a thorough search of the existing published literature using strict eligibility criteria. Nine randomized trials were found that met protocol specifications. These reports contained data on 2,261 patients that were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients with recurrence at 1, 2, and 3 years following intravesical therapy (i.e., a summary odds ratio, ORp). Combining all nine trials using 1-year recurrence as the endpoint demonstrated significant statistical heterogeneity, although the ORp favored BCG over intravesical chemotherapy (0.89 [0.74-1.07]). This precluded statistical pooling of the data and sensitivity analyses were performed to determine the source of heterogeneity. These tests showed that the prior chemotherapy treatment in a large number of the randomized trials biased study results in favor of the BCG arms. Once the data were stratified on presence or absence of prior drug treatment, intravesical chemotherapy reduced 1-, 2-, and 3-year recurrence by 21% to 82% versus BCG, depending on the endpoint of interest. The available data suggest that clinical trials directly comparing intravesical BCG to intravesical chemotherapy must stratify on the presence or absence of prior chemotherapy. Recurrences following prior intravesical chemotherapy appear less responsive to drug therapy than those in chemotherapy-naive patients. The currently perceived superiority of BCG therapy may therefore be an artifact of this phenomenon, since most randomized trials include chemotherapy failures in their chemotherapy treatment arms.

Objectives. This study examined the methodology of epidemiological studies that suggest use of topical sunscreen preparations is associated with increased risk of malignant melanoma. Methods. We pooled data from observational studies using a general variance–based meta-analytic method that employed confidence intervals (previously described). The outcome of interest was a summary relative risk (RR) reflecting the risk of melanoma associated with sunscreen use versus nonuse. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. Results. Combining studies that used nonheterogeneous data yielded a summary RR of 1.01, indicating no association between sunscreen use and development of malignant melanoma. Conclusions. The available epidemiological data do not support the existence of a relationship between topical sunscreen use and an increased risk of cutaneous malignant melanoma. (Am J Public Health. 2002;92:1173–1177)

Objective: Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood brain tumors. A meta-analysis was performed statistically pooling all available observational studies on this topic in order to evaluate this suspected association. Methods: Using previously described methods, a protocol was developed for a meta-analysis examining the association between maternal smoking during pregnancy and subsequent development of primary brain tumors in their offspring. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of childhood brain tumor development associated with mother's smoking during the index pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity and/or to evaluate the impact of demographic or study characteristics on the summary estimate of effect. Results: Twelve observational studies meeting protocol specified inclusion criteria were obtained via a comprehensive literature search. These studies enrolled a total of 6566 patients. Analysis for homogeneity demonstrated that the data were homogeneous (P>0.50) and could be statistically combined. Pooling all twelve reports yielded an RRs of 1.05 (0.90–1.21), a non-statistically significant result suggesting no clear association between maternal smoking during pregnancy and risk of childhood brain tumor development. Numerous sensitivity analyses examining the possible effect of study design and various patient characteristics failed to show any influence on the RRs further supporting the observed lack of association. Conclusion: The available epidemiological data do not support a clear association between maternal smoking during pregnancy and pediatric brain tumor development. Although it appears likely that no association exists, limitations in study designs limit definitive conclusions based on available data.

The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary fat intake is associated with an increased risk of this tumor, although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. Using previously described methods, a protocol was developed for a meta-analysis examining the association between high vs. low dietary fat intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance-based meta-analytic method employing confidence intervals (CI) previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high vs. low dietary fat intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. The literature search yielded 8 observational studies enrolling 6,689 subjects. Data were stratified into three dietary fat intake categories: total fat, animal fat, and saturated fat. Initial tests for statistical homogeneity demonstrated that hospital-based studies accounted for observed heterogeneity possibly because of selection bias. Accounting for this, an RRs was calculated for high vs. low total fat intake, yielding a value of 1.24 (95% CI = 1.07-1.43), a statistically significant result. That is, high total fat intake is associated with a 24% increased risk of ovarian cancer development. The RRs for high saturated fat intake was 1.20 (95% CI = 1.04-1.39), suggesting a 20% increased risk of ovarian cancer among subjects with these dietary habits. High vs. low animal fat diet gave an RRs of 1.70 (95% CI = 1.43-2.03), consistent with a statistically significant 70% increased ovarian cancer risk. High dietary fat intake appears to represent a significant risk factor for the development of ovarian cancer. The magnitude of this risk associated with total fat and saturated fat is rather modest. Ovarian cancer risk associated with high animal fat intake appears significantly greater than that associated with the other types of fat intake studied, although this requires confirmation via larger analyses. Further work is needed to clarify factors that may modify the effects of dietary fat in vivo.

The authors wanted to determine whether adding interferon-alpha (IFN-alpha) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-alpha (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-alpha therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-alpha had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-alpha in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-alpha treatment. Although questions remain about its optimal use. IFN-alpha appears to prolong survival time in patients with follicular NHL.

Mutation of the p53 tumor suppressor gene is considered a possible marker of poor survival among patients with non-small cell lung cancer (NSCLC). This report presents the results of a meta-analysis of the available data addressing this issue. Using previously described methods, a protocol was developed for a meta-analysis examining the prognostic significance of p53 mutations in NSCLC. Two-year survival data derived from 829 patients in eight published studies were analyzed using a general variance-based method employing confidence intervals described by Greenland (Epidemiol. Rev. 9 (1986) 1-30). The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 2 years associated with p53 mutation positive versus p53 negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 22.3. With 8 degrees of freedom, this yielded a P value corresponding to P

BackgroundAntidepressant drugs are usually prescribed at low doses, possibly to avoid adverse reactions. No comprehensive review has addressed the issue of dose, clinical response and tolerability in a quantitative way.AimsTo determine whether high doses of antidepressants are more effective than lowdoses, and how safety is affected by dose.MethodTrials comparing two or more doses of the same antidepressant were located, and all antidepressants administered were converted to the equivalent dose of imipramine. Generalised estimating equations were used to analyse percentage improvement and adverse event rate according to dose level.ResultsThirty-three studies were identified. The dose level 100-200 mg imipramine equivalents showed an average improvement of 53% by ‘intention-to-treat’. Higher doses were not accompanied by increased efficacy, while lower doses showed reduction in efficacy. Adverse events significantly increased with dose.ConclusionsWith a low dose of antidepressants, clinicians trade off a slightly reduced chance of improvement for a higher chance of avoiding adverse reactions.

A meta-analysis was performed to compare the risk of serious adverse events associated with the use of all formulations of isradipine, when used as monotherapy in hypertension, to active drug or placebo controls. Eligible studies totalled 65 published and unpublished randomised controlled trials involving 9903 subjects and 10,675 treatment exposures: 4492 to isradipine, 1473 to isradipine sustained release, 2768 to other active drugs, and 1942 to placebo. Mortality, cardiovascular outcomes, other serious incident illnesses, such as cancer, and withdrawals were sought. Seventy-five per cent of the isradipine exposures were to standard-release formulations and 25% were to sustained-release formulations. Overall, isradipine therapy shows no difference in risk of major adverse events or withdrawals compared to other active controls or placebo (odds ratios [OR] 0.9; 95% CI 0.7-1.46 and 0.5; 95% CI 0.2-1.3). These major adverse events included angina, fatal and non-fatal myocardial infarction, stroke and overall mortality. Isradipine sustained release could be compared only to placebo, based on available data, and shows a lower risk of withdrawals (OR 0.5; 95% CI 0.3-0.9), and a similar trend was observed for major adverse events, (OR 0.8; 95% CI 0.3-2.5). Published and unpublished randomised controlled trials were analysed in separate meta-analyses and later combined when this sensitivity analysis of risk showed no differences between the groups. In conclusion, we find no evidence for increased risk of serious adverse events in patients receiving isradipine as monotherapy for hypertension.

OBJECTIVE: To illustrate the current meta-analytic approach to extracting clinically useful information from the glut of randomized controlled trials (RCTs) of the treatment of acute attacks of Crohn's disease.PROCEDURE: Acceptable RCTs were classified in a matrical format so that the feasibility of a meta-analysis of each treatment could be quickly determined. Each potential inclusion was then photocopied after blinding the source and outcome to minimize bias by the investigators.RESULTS AND CONCLUSIONS: The search was started in 1990, when a previous meta-analysis was completed. Over 100 citations in MEDLINE contained 21 RCTs of the treatment of acute attacks of Crohn's disease, and 11 more were culled from the references of recent papers. The meta-analysis most indicated by the matrix was a comparison of several different immunosuppressive regimens with a placebo. The previously demonstrated statistical significance was confirmed and the point made that it is no longer justified to compare any new treatments with a placebo. Cumulative meta-analysis, the process of performing a new analysis every time a new trial is published, revealed the importance of employing both random and fixed effect models when heterogeneity of treatment results is appreciable, as in this case.

Background Physical activity and exercise appear to improve psychological health. However, the quantitative effects of Tai Chi on psychological well-being have rarely been examined. We systematically reviewed the effects of Tai Chi on stress, anxiety, depression and mood disturbance in eastern and western populations. Methods Eight English and 3 Chinese databases were searched through March 2009. Randomized controlled trials, non-randomized controlled studies and observational studies reporting at least 1 psychological health outcome were examined. Data were extracted and verified by 2 reviewers. The randomized trials in each subcategory of health outcomes were meta-analyzed using a random-effects model. The quality of each study was assessed. Results Forty studies totaling 3817 subjects were identified. Approximately 29 psychological measurements were assessed. Twenty-one of 33 randomized and nonrandomized trials reported that 1 hour to 1 year of regular Tai Chi significantly increased psychological well-being including reduction of stress (effect size [ES], 0.66; 95% confidence interval [CI], 0.23 to 1.09), anxiety (ES, 0.66; 95% CI, 0.29 to 1.03), and depression (ES, 0.56; 95% CI, 0.31 to 0.80), and enhanced mood (ES, 0.45; 95% CI, 0.20 to 0.69) in community-dwelling healthy participants and in patients with chronic conditions. Seven observational studies with relatively large sample sizes reinforced the beneficial association between Tai Chi practice and psychological health. Conclusions Tai Chi appears to be associated with improvements in psychological well-being including reduced stress, anxiety, depression and mood disturbance, and increased self-esteem. Definitive conclusions were limited due to variation in designs, comparisons, heterogeneous outcomes and inadequate controls. High-quality, well-controlled, longer randomized trials are needed to better inform clinical decisions.

The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction.We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction.An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratios, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction.Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy.

In vivo and in vitro studies suggest that dairy products, calcium, and dietary vitamin D inhibits the development of colorectal cancer (CRC). A meta-analysis was performed to evaluate this relationship in observational studies. Data from 60 epidemiological studies enrolling 26,335 CRC cases were pooled using a general variance-based meta-analytic method. Summary relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated for the highest vs. the lowest intake categories. Sensitivity analyses tested the robustness of these summary effect measures and the statistical heterogeneity. The summary RR for high milk and dairy product intake, respectively, on colon cancer risk was 0.78 (95% CI = 0.67-0.92) and 0.84 (95% CI = 0.75-0.95). Milk intake was unrelated to rectal cancer risk. High calcium intake had a greater protective effect against tumors of the distal colon and rectal cancer vs. proximal colon. The risk reduction associated with calcium was similar for dietary and supplemental sources. Vitamin D was associated with a nonsignificant 6% reduction in CRC risk. Higher consumption of milk/dairy products reduces the risk of colon cancer, and high calcium intake reduces the risk of CRC. Low vitamin D intake in the study populations may limit the ability to detect a protective effect if one exists.

Objective Although calcium is essential for maintaining bone health in children, the optimum dietary intake of calcium in this age group, particularly in the form of dairy foods, is not well defined. A meta-analysis was conducted to examine the impact of dietary calcium/dairy supplementation on bone mineral content in this age group. Methods Data were pooled from randomized controlled intervention trials and observational studies using previously described methods. The outcome of interest was a summary mean difference bone mineral content. Sensitivity analyses were employed to evaluate any observed statistical heterogeneity and to examine the influence of specific study characteristics on the summary estimate of effect. Results Initially combining data from twenty-one randomized controlled trials (RCTs) using total body bone mineral content (TB-BMC) as the outcome of interest, yielded a non-statistically significant increase in TB-BMC of 2 g (supplemented versus controls). These data demonstrated substantial statistical heterogeneity with sensitivity analyses revealing that among study subjects with normal or near normal baseline dietary calcium/dairy intakes, supplemental dairy/calcium showed little impact on bone mineral content. Sensitivity analyses suggested that baseline calcium intake could potentially account for the statistical heterogeneity. Pooling the three reports utilizing low intake subjects yielded a statistically significant summary mean BMC of 49 g (24.0–76–6). Pooling two RCTs using calcium/dairy supplement plus vitamin D was also associated with an increase in lumbar spine BMC of, on average, 35 g (− 6.8–41.8). The lack of data using BMC measurements at other anatomic sites as well as sparse data from non-randomized studies, precluded further statistical pooling. Conclusion Increased dietary calcium/dairy products, with and without vitamin D, significantly increases total body and lumbar spine BMC in children with low base-line intakes.

Studies on the relation between dietary n-3 fatty acids (FAs) and cardiovascular disease vary in quality, and the results are inconsistent. A systematic review of the literature on the effects of n-3 FAs (consumed as fish or fish oils rich in eicosapentaenoic acid and docosahexaenoic acid or as alpha-linolenic acid) on cardiovascular disease outcomes and adverse events was conducted. Studies from MEDLINE and other sources that were of > or =1 y in duration and that reported estimates of fish or n-3 FA intakes and cardiovascular disease outcomes were included. Secondary prevention was addressed in 14 randomized controlled trials (RCTs) of fish-oil supplements or of diets high in n-3 FAs and in 1 prospective cohort study. Most trials reported that fish oil significantly reduced all-cause mortality, myocardial infarction, cardiac and sudden death, or stroke. Primary prevention of cardiovascular disease was reported in 1 RCT, in 25 prospective cohort studies, and in 7 case-control studies. No significant effect on overall deaths was reported in 3 RCTs that evaluated the effects of fish oil in patients with implantable cardioverter defibrillators. Most cohort studies reported that fish consumption was associated with lower rates of all-cause mortality and adverse cardiac outcomes. The effects on stroke were inconsistent. Evidence suggests that increased consumption of n-3 FAs from fish or fish-oil supplements, but not of alpha-linolenic acid, reduces the rates of all-cause mortality, cardiac and sudden death, and possibly stroke. The evidence for the benefits of fish oil is stronger in secondary- than in primary-prevention settings. Adverse effects appear to be minor.

Greater fish oil consumption has been associated with reduced CVD risk, although the mechanisms are unclear. Plant-source oil omega-3 fatty acids (ALA) have also been studied regarding their cardiovascular effect. We conducted a systematic review of randomized controlled trials that evaluated the effect of consumption of fish oil and ALA on commonly measured serum CVD risk factors, performing meta-analyses when appropriate. Combining 21 trials evaluating lipid outcomes, fish oil consumption resulted in a summary net change in triglycerides of -27 (95% CI -33, -20)mg/dL, in HDL cholesterol of +1.6 (95% CI +0.8, +2.3)mg/dL, and in LDL cholesterol of +6 (95% CI +3, +8)mg/dL. There was no effect of fish oil on total cholesterol. Across studies, higher fish oil dose and higher baseline levels were associated with greater reductions in serum triglycerides. Overall, the 27 fish oil trials evaluating Hgb A(1c) or FBS found small non-significant net increases compared to control oils. Five studies of ALA were inconsistent in their effects on lipids, Hgb A(1c) or FBS. Four studies investigating the effects of omega-3 fatty acids on hs-CRP were also inconsistent and non-significant. The evidence supports a dose-dependent beneficial effect of fish oil on serum triglycerides, particularly among people with more elevated levels. Fish oil consumption also modestly improves HDL cholesterol, increases LDL cholesterol levels, but does not appear to adversely affect glucose homeostasis. The evidence regarding the effects of omega-3 fatty acids on hs-CRP is inconclusive, as are data on ALA.

The objective of this study was to assess the effects of omega-3 fatty acid supplementation on various kidney transplant-related outcomes. A systematic review and meta-analysis was performed of published randomized, controlled trials (RCT). There were 16 kidney transplant RCT with a total of 812 patients. All trials evaluated fish oil with dosages that ranged from 1.2 to 5.4 g/d. No consistent benefits were observed for any outcome with the exception of a modest benefit on triglycerides. A meta-analysis of rejection episodes found no significant benefit on either early (

Greater omega-3 fatty acid consumption is associated with reduced cardiovascular disease risk. Though the mechanisms of their effect are unclear, they may involve lesion formation and heart function. We conducted a systematic review of the clinical literature on the effect of omega-3 fatty acids on measures of vascular structure and function. We included studies that assessed fish and plant sources of omega-3 fatty acids on coronary artery restenosis after angioplasty, carotid IMT, and exercise capacity. Compared to placebo, the summary risk ratio of coronary artery restenosis with fish oil is 0.87 (95% CI 0.73, 1.05) across 12 randomized controlled trials. Two prospective studies reported increased carotid IMT, whereas two cross-sectional studies reported a reduction of IMT, with fish, fish oil or ALA consumption. Three randomized trials and three uncontrolled studies reported small non-significant improvements in exercise capacity with fish oil. Overall, little or no effect of fish oil was found for a variety of markers of cardiovascular disease risk. There are insufficient studies to draw conclusions about the effect of ALA. The dearth of long term data on fish consumption or omega-3 fatty acid supplementation on measures of cardiovascular disease risk severely limits our ability to draw definitive conclusions at this time.

Background and Relevance: Intracranial atherosclerosis is responsible for 70,000 ischemic strokes each year in the USA. Noninvasive testingsuch as transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) to identify intracranial atherosclerosis is in widespread use, but has not been rigorously validated against the gold standard, catheter angiography. The recently NIH-funded Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial will compare warfarin with aspirin for stroke prevention in patients with intracranial atherosclerosis. WASID requires performance of angiography along with TCD and MRA, providing an opportunity to critically evaluate these noninvasive tests. Main Objective: The purpose of the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) study is to develop the noninvasive diagnosis of intracranial atherosclerosis. The primary aim of SONIA is to define velocity values on TCD and anatomic abnormalities on MRA that identify severe (50–99%) intracranial stenosis of large, proximal arteries seen on catheter angiography. SONIA will define the criteria, or ‘cutpoints’, for an abnormal TCD or MRA and show that they perform with a reliable positive predictive value (PPV). Study Design: SONIA will be conducted in collaboration with WASID. Study-wide cutpoints defining positive TCD and MRA have been developed and reviewed by the site investigators of WASID. Hard copy angiography, TCD and MRA generated in WASID will be centrally read in SONIA. TCD and MRA cutpoints seek to achieve a target PPV of 80% for the identification of severe intracranial stenosis on angiography. Conclusions: Central readings will be used to validate the cutpoints and to develop measures of negative predictive value, and inter- and intra-observer variability. Sensitivity and specificity will be determined after adjustment for verification bias and employed in receiver-operator characteristic analyses. SONIA will use these techniques to develop TCD and MRA cutpoints that minimize the clinical consequences of test errors occurring in the noninvasive evaluation of patients with suspected intracranial atherosclerosis.

Objective: N-Nitroso compounds (NOCs) are recognized neural carcinogens in animal models and are suspected human carcinogens. A meta-analysis was performed examining the possible association of maternal intake of cured meat (an important source of dietary NOCs) during pregnancy and the risk of pediatric brain tumors. Methods: Data from epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals described by Greenland in 1986. The outcome of interest was a summary relative risk (RR) reflecting the risk of childhood brain tumor (CBT) development associated with maternal intake of cured meats during pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. Results: Seven observational studies were found that met the protocol-specified inclusion criteria. Analysis for heterogeneity demonstrated a lack of statistical heterogeneity (p = 0.59), indicating that the data could be statistically combined. Pooling data from the 6 reports containing data on maternal cured meat intake of all types yielded an RR of 1.68 (1.30– 2.17), being a statistically significant result. Analyzing CBT risk by type of cured meat ingested showed that hot dog consumption increased CBT risk by 33% (1.08–1.66), with a similar increase shown by frequent ingestion of sausage, i.e. 44%. Conclusion: The data provide support for the suspected causal association between ingestion of NOCs from cured meats during pregnancy and subsequent CBT in offspring. Limitations in study design preclude definitive conclusions, but the relationship warrants exploration via additional observational and laboratory-based studies.

Prior epidemiological studies suggest an association between perineal cosmetic talc use and increased risk of epithelial ovarian cancer. A meta-analysis was performed to evaluate this suspected association.Using previously described methods, a protocol was developed for a meta-analysis examining the association between perineal talc use versus non-use and the development of invasive epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer development associated with perineal talc use versus non-use. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity.Sixteen observational studies meeting protocol specified inclusion criteria were located via a comprehensive literature search. These studies enrolled a total of 11,933 subjects. Analysis for heterogeneity demonstrated that the data were homogenous (p = 0.17) and could be combined in a meta-analysis. Pooling all sixteen studies yielded a RRs of 1.33 (CI = 1.16-1.45), a statistically significant result suggesting a 33% increased risk of ovarian cancer with perineal talc use. Despite this finding, the data showed a lack of a clear dose-response relationship making the RRs of questionable validity. Further sensitivity analyses showed that hospital-based studies showed no relationship between talc use and ovarian cancer risk, i.e. RRs 1.19 (0.99-1.41) versus population-based studies (RRs = 1.38, CI = 1.25-1.52). This suggests that selection bias and/or uncontrolled confouding may result in a spurious positive association between talc use and ovarian cancer risk in population-based studies.The available observational data do not support the existence of a causal relationship between perineal talc exposure and an increased risk of epithelial ovarian cancer. Selection bias and uncontrolled confouding may account for the positive associations seen in prior epidemiological studies.

Prior epidemiological studies suggest a possible association between maternal smoking during pregnancy and risk of childhood brain tumors. A meta-analysis was performed statistically pooling all available observational studies on this topic in order to evaluate this suspected association.Using previously described methods, a protocol was developed for a meta-analysis examining the association between maternal smoking during pregnancy and subsequent development of primary brain tumors in their offspring. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of childhood brain tumor development associated with mother's smoking during the index pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity and/or to evaluate the impact of demographic or study characteristics on the summary estimate of effect.Twelve observational studies meeting protocol specified inclusion criteria were obtained via a comprehensive literature search. These studies enrolled a total of 6566 patients. Analysis for homogeneity demonstrated that the data were homogeneous (P0.50) and could be statistically combined. Pooling all twelve reports yielded an RRs of 1.05 (0.90-1.21), a non-statistically significant result suggesting no clear association between maternal smoking during pregnancy and risk of childhood brain tumor development. Numerous sensitivity analyses examining the possible effect of study design and various patient characteristics failed to show any influence on the RRs further supporting the observed lack of association.The available epidemiological data do not support a clear association between maternal smoking during pregnancy and pediatric brain tumor development. Although it appears likely that no association exists, limitations in study designs limit definitive conclusions based on available data.

It is currently unclear whether the addition of chemotherapy to standard radiation therapy improves clinical outcome in patients with locoregionally advanced nasopharyngeal cancer. A meta-analysis was performed to evaluate the impact of integrating chemotherapy with external beam radiation therapy in this clinical setting. Using previously described methods, a protocol was developed outlining a meta-analysis examining the influence of chemoradiation versus radiation alone (control arm) in locoregionally advanced nasopharyngeal carcinoma. The outcomes of interest were disease-free/progression-free and overall survival. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from all available randomized controlled trials was pooled using a fixed effects model (Peto). Results were expressed as summary relative risks. Statistical tests for heterogeneity were performed. If statistical heterogeneity was demonstrated, sensitivity analyses were performed to evaluate possible sources of heterogeneity across the included studies. The literature search identified six randomized controlled trials enrolling more than 1,500 patients. All trials compared standard radical external beam radiation therapy (control arm) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. Pooling all six studies using disease-free/progression-free survival as the endpoint demonstrated that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the summary relative risk for overall survival at 2 years after treatment with the addition of chemotherapy to the treatment regimen was 0.80 (0.63-1.02), reflecting a 20% increase in 2-year survival. This finding was marginally non-statistically significant. Three- and 4-year survival was increased by 19% and 21%, respectively, with the data for 4-year survival being statistically significant. The addition of chemotherapy to standard radical radiation therapy for locoregionally advanced nasopharyngeal cancer increases both disease-free/progression-free and overall survival by 19 to 40% at 2 to 4 years after treatment, depending on the endpoint of interest. Future trials are needed to confirm these results and determine the most effective regimen for integrating chemotherapy with radiation therapy in this setting.

BackgroundNon-adherence with antidepressant treatment is very common. Increasing adherence to pharmacological treatment may affect response rate.AimsTo review and summarise quantitative evidence on factors associated with adherence and of adherence-enhancing interventions.MethodA systematic review of computerised databases was carried out to identify quantitative studies of adherence in depression. Papers retained addressed unipolar depression and considered adherence as the primary end-point.ResultsOf studies published between 1973 and 1999, 32 met the review criteria: epidemiological descriptive studies (n=14): non-random comparisons of control and intervention groups (n=3); randomised interventions (n=14); and meta-analysis (n=1). Patient education and medication clinics were the interventions most commonly tested, combined with a variety of other interventions.ConclusionsThe studies did not give consistent indications of which interventions may be effective. Carefully designed clinical trials are needed to clarify the effect of single and combined interventions.

Amplification of the epidermal growth factor receptor (EGFR) gene occurs in approximately 40% of cases of glioblastoma multiforme (GBM) and is considered a possible marker of poor prognosis. This report presents the results of a meta-analysis of the available data addressing this issue. Using a prospective protocol, a meta-analysis was designed to assess the possible prognostic importance of EGFR gene amplification in GBM. One-year survival data derived from seven published studies were analyzed using a general variance based method employing confidence intervals described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of death at 1 year from diagnosis associated with EGFR amplification-positive versus -negative disease. Prior to calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 9.21. With 6 df this yielded a P value of 0.12, indicating that the data were homogenous and could be combined in a meta-analysis. Pooling all available studies gave a RRs of 1.13 with a 95% confidence interval of 0.71-1.80, a nonstatistically significant result. The data suggest that the available studies are insufficient for determining whether EGFR gene amplification is of prognostic value in GBM. Important potential confounding factors are the influence of underlying EFGR gene mutation on patient survival and lack of control for important known clinical prognostic indicators in many studies. Future work must incorporate these parameters in multivariate analyses to determine whether EGFR gene alterations are truly associated with poor clinical outcome.

UNLABELLED META-ANALYSIS: A meta-analysis of published randomized control trials of nifedipine in hypertension and stable angina pectoris was performed. RESULTS The results suggest a formulation-dependent increased risk of mortality and adverse cardiovascular outcomes for monotherapy use in patients with stable angina pectoris. No increased risk was seen in the hypertension studies.

Objective: Our objective was to determine whether the use of preoperative antibiotics prevents serious infections associated with total abdominal hysterectomy. Study design: We identified 25 randomized controlled trials of antibiotic prophylaxis that used rigorous protocols. We performed meta-analyses and cumulative meta-analyses for all of the trials, and then we performed separate meta-analyses for cefazolin, metronidazole, and Imidazole. Results: Overall, 21.1% (373 of 1768) of the patients who did not receive antibiotic prophylaxis had serious infections after abdominal hysterectomy. Among patients who received any antibiotics, we found that 9.0% (166/1836) had serious postoperative infections; among those who received cefazolin, metronidazole, or tinidazole, 11.4% (70 of 615), 6.3% (17 of 269), and 5.0% (5 of 101), respectively, had serious postoperative morbidity. The differences in the prevalence of infection between women who received prophylaxis and women who did not receive prophylaxis were statistically significant (any antibiotics, p = 0.00001; cefazolin, p = 0.00021; metronidazole, p = 0.015; and tinidazole, p = 0.034). Conclusion: Because preoperative antibiotics are highly effective in the prevention of serious infections associated with total abdominal hysterectomy, we believe they should be used routinely. In addition, we believe that the use of controls who receive no treatment is no longer justified in trials of antibiotic prophylaxis for total abdominal hysterectomy.

ContextThe minimum standard of care required for participants in clinical trials conducted in resource-poor settings is a matter of controversy; international documents offer contradictory guidance.ObjectiveTo determine whether recently published trials conducted in sub-Saharan Africa met standards of care consistent with best current clinical standards for human immunodeficiency virus (HIV) treatment, tuberculosis treatment, and malaria prevention.Data SourcesTrials published during or after January 1998 that were indexed at the time of the MEDLINE and Cochrane Controlled Trials Register Search (November 20, 2003).Study SelectionAll randomized clinical trials that were conducted in sub-Saharan Africa in 3 clinical domains: HIV disease, tuberculosis treatment, and malaria prophylaxis.Data ExtractionTo establish criteria for best current standards of care, evidence from the literature and published guidelines accepted for well-resourced settings were analyzed; the actual care offered in the trial was then compared with these standards.Data SynthesisA total of 128 eligible articles described data from 73 different randomized clinical trials. Only 12 trials (16%) provided care that met guidelines to both intervention and control patients. Only 1 of the 34 trials that enrolled patients with HIV disease provided antiretroviral treatment that conformed to guidelines. Conversely, all tuberculosis treatment trials (n = 13, including 3 for HIV-infected patients) provided tuberculosis therapy that conformed to guidelines. Twenty-one (72%) of 29 malaria prophylaxis trials tested interventions that met guidelines, but only 3 (10%) used any active prophylactic intervention in the control group. Of the 59 trials (81%) that reported on the process of ethical review, all were reviewed by a host African institution and 64% were additionally reviewed by an institution in a developed country.ConclusionsRates of adherence to established clinical guidelines of care in randomized clinical trials of HIV treatment, tuberculosis treatment, and malaria prophylaxis varied considerably between disease categories. In determining clinical standards for trials in sub-Saharan Africa, researchers and ethics committees appear to take the local level of care into account.

Background Adherence to antidepressant medication use is a problem in clinical practice. Some authors have posited that combined psychological treatment facilitates adherence to pharmacotherapy. Objectives To study the relationship between adherence to use of and efficacy of antidepressant drugs plus psychological treatment vs drug treatment alone in depressive disorders. Data Sources MEDLINE, Current Contents, PsychInfo, Cochrane Library, and reference lists were searched, from January 1980 to November 2002. Study Selection Randomized clinical trials comparing antidepressant treatment alone with antidepressant treatment in combination with a psychological intervention in depressive disorders were considered. The decision to include studies in the meta-analysis was performed by 2 reviewers. Data Extraction Three independent reviewers extracted the data, using a precoded form. Methodological quality of the studies was evaluated in terms of allocation concealment and independence of evaluators. Data Synthesis Sixteen trials met the inclusion criteria, with 932 patients randomized to pharmacotherapy alone and 910 to combined treatment. Overall, patients receiving combined treatment improved significantly compared with those receiving drug treatment alone (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.38-2.52), but dropouts and nonresponders did not differ in distribution between the 2 treatment modalities (OR, 0.86; 95% CI, 0.60-1.24). Studies longer than 12 weeks showed a significant advantage of combined treatment over drug treatment alone (OR, 2.21; 95% CI, 1.22-4.03), with a significant reduction in dropouts compared with nonresponders (OR, 0.59; 95% CI, 0.39-0.88). These estimates were not affected by study quality. Conclusions Psychological treatment combined with antidepressant therapy is associated with a higher improvement rate than drug treatment alone. In longer therapies, the addition of psychotherapy helps to keep patients in treatment. Further studies are needed to investigate whether the improvement in response attributable to the combination of drug treatment and psychotherapy can be achieved by a combination of pharmacotherapy and a compliance-enhancing intervention.

Background Statins reduce cardiovascular events to a greater extent than can be explained by their effect on lipids. Several studies have attempted to elucidate mechanisms by which statins reduce cardiovascular risk. Purpose To summarize the effects of statins on nonlipid serum markers and to correlate statins' effect on serum markers with lipid levels and cardiovascular outcomes. Data sources MEDLINE (1980 to 2003) search limited to English-language articles. Study selection Studies reporting original data in at least 10 participants on the effect of statins on outcomes of interest, excluding studies of cerivastatin, drug combinations, and patients with organ transplants. Data extraction Study design, sample size, treatment, and outcome data extracted on the basis of preestablished criteria. When appropriate, meta-analysis was performed by using a random-effects model. Data synthesis All statins are effective at lowering C-reactive protein levels, and the effect is not dose-dependent. Studies do not demonstrate a correlation between statins' effects on C-reactive protein levels and on lipids or cardiovascular outcomes. Statins do not affect fibrinogen levels, and limited data suggest little effect on lipid oxidation, tissue plasminogen activator, or plasminogen activator inhibitor. Platelet aggregation data are inconclusive. Conclusions Among nonlipid serum markers examined, only C-reactive protein levels are statistically significantly affected by statins. These findings suggest that statin-mediated anti-inflammatory effects may contribute to the ability of statins to reduce risk for cardiovascular disease. Overall, however, available data are insufficient to support recommendations for using nonlipid serum markers in decisions regarding statin therapy for individual patients.

We agree with all of the points raised by Marshall et al. Our meta-analysis was designed to address the issue of whether the available epidemiological data support the contention that sunscreen use is associated with an increased risk of melanoma (as suggested by some in the existing literature). Marshall et al. are correct in suggesting that the lack of statistical heterogeneity indicated by the Q statistic for the studies using population controls does not completely rule out confounding. The tests for statistical heterogeneity suffer from limited statistical power, particularly in the context of meta-analyses pooling small numbers of studies.1 Although we cannot rule out residual confounding among those reports using population controls, the analysis for heterogeneity serves as a method for demonstrating and exploring sources of variation across the available studies, despite its recognized limitations. Our finding of statistical heterogeneity was followed by a number of sensitivity analyses designed to further characterize and explain its existence and implications. This is one of the most important features of any meta-analysis. We also agree that “the potential for . . . upward confounding to obscure a protective sunscreen effect” is entirely possible, and this potential points out an important limitation of studies to date. (Our original manuscript briefly addressed this issue but was subsequently edited.) Since sunscreen users may in fact tend to stay in the sun longer than nonusers, our data indirectly suggest a protective effect.2 Further work is needed on the behavioral aspects of sunscreen use and their impact on disease risk. Finally, the issue of SPF is an important one. With the limited literature cited in our analysis, it was not possible to formally address this topic. Again, additional studies are needed to better understand the interplay of host factors and behavioral issues related to type and method of sunscreen use, with SPF being one of many variables of interest.

Objective N-nitroso compounds (NOCs) are recognized neural carcinogens in animal models and are suspected human carcinogens. A meta-analysis was performed examining the possible association of dietary N-nitroso intake from cured meats and the risk of gliomas in adults. Methods A prospective protocol was developed outlining the intent, methods, and statistical analysis of the meta-analysis. Data from nine epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals as described by Greenland. The outcome of interest was a summary relative risk (SRR) reflecting the risk of brain tumor (glioma) development associated with high dietary intake of cured meats (as defined by individual study investigators). Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. Results Nine observational studies met protocol-specified inclusion criteria. Analysis for heterogeneity demonstrated a lack of statistical heterogeneity (p = 0.58). Pooling the data on dietary cured meat intake of all types yielded an RR of 1.48 (1.20-1.83), suggesting a 48% increased risk of glioma development among adults ingesting high levels of cured meat. Analyzing brain tumor risk by meat type yielded an RR of 0.90 (0.63-1.25) for hotdogs (a nonstatistically significant result), 1.31 (1.00-1.71) for bacon, and 1.64 (1.27-2.14) for ham. Sensitivity analyses showed that the failure of most studies to adjust for total energy intake might lead to a spurious positive association between cured meat intake and brain tumor risk. Insufficient data were available for analyzing dose-response relationships, although a few individual studies showed evidence of increasing risk with increasing cured meat intake. Conclusion The available data do not provide clear support for the suspected causal association between ingestion of NOCs from cured meat in adults and subsequent brain tumor risk. Uncontrolled confounding may account for the previously noted positive association seen in some epidemiological studies.

In Reply. —We appreciate the interest of Drs Borzak and Rosman in our recent article comparing the results of cumulative meta-analyses of randomized controlled trials for acute myocardial infarction and the recommendations of clinical experts. We agree that meta-analysis can permit more expeditious identification of the effectiveness of individual interventions. Furthermore, as suggested by some authorities, 1 cumulative meta-analysis may aid investigators in determining whether continued study of a particular clinical problem is warranted. Borzak and Rosman rightly point out that the complexities of clinical medicine, as exemplified by the treatment of a patient with acute myocardial infarction, necessitate skilled clinical judgment. This requires a synthesis not only of the emerging data in the medical literature but also of the particular clinical features of the patient in question with respect to whether he or she is representative of the individuals enrolled in the randomized controlled trials reported in the literature.

Objective. —To examine the temporal relationship between accumulating data from randomized control trials of treatments for myocardial infarction and the recommendations of clinical experts writing review articles and textbook chapters. Data Sources. —(1) MEDLINE search from 1966 to present; search terms used were myocardial infarction, clinical trials, multicenter studies, double-blind method, meta-analysis , and the text word "random:"; (2) references from pertinent articles and books; and (3) all editions of English-language general medical texts and manuals and review articles on treatment of myocardial infarction. Study Selection. —Randomized control trials of therapies for reducing the risk of total mortality in myocardial infarction (acute and secondary prevention). Review articles and textbook chapters dealing with the general clinical management of patients with myocardial infarction. Data Extraction. —Two authors read the material and recorded the results; disagreements were resolved by conference. Data Synthesis. —We used the technique of cumulative meta-analysis (performing a new meta-analysis when the results of a new clinical trial are published) and compared the results with the recommendations of the experts for various treatments for myocardial infarction. Discrepancies were detected between the meta-analytic patterns of effectiveness in the randomized trials and the recommendations of reviewers. Review articles often failed to mention important advances or exhibited delays in recommending effective preventive measures. In some cases, treatments that have no effect on mortality or are potentially harmful continued to be recommended by several clinical experts. Conclusions. —Finding and analyzing all therapeutic trials in a given field has become such a difficult and specialized task that the clinical experts called on to summarize the evidence in a timely fashion need access to better databases and new statistical techniques to assist them in this important task. ( JAMA . 1992;268:240-248)

INTRODUCTION: CHRONIC KIDNEY disease (CKD) is a worldwide public health issue. In the United States, there is a rising incidence and prevalence of kidney failure (Fig 1), with poor outcomes and high cost. The prevalence of earlier stages of CKD is approximately 100 times greater than the prevalence of kidney failure, affecting almost 11% of adults in the United States. There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by preventive measures, early detection, and treatment. Hypertension is a cause and complication of CKD. Hypertension in CKD increases the risk of important adverse outcomes, including loss of kidney function and kidney failure, early development and accelerated progression of cardiovascular disease (CVD), and premature death. In the ongoing effort to improve outcomes of CKD, the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) appointed a Work Group and an Evidence Review Team in 2001 to develop clinical practice guidelines on hypertension and use of antihypertensive agents in CKD. During this same time, clinical practice guidelines on this topic relevant to CKD were also under development by other organizations, including the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2003 report of the American Diabetes Association (ADA) on the Treatment of Hypertension in Adults with Diabetes. The Work Group maintained contact with these organizations during development of these guidelines. The purpose of the Executive Summary is to provide a "stand-alone" summary of the background, scope, methods, and key recommendations, as well as the complete text of the guideline statements. Most tables and figures in the Executive Summary are taken from other sections of the document. BACKGROUND: Chronic Kidney Disease: Figure 2 is a conceptual model of CKD, which defines stages of CKD, as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes. CKD is defined as kidney damage, as confirmed by kidney biopsy or markers of damage, or glomerular filtration rate (GFR)