Standardized Weighted Mean Difference Research Articles

Prevention of contrast-associated acute kidney injury in critically-ill and high-risk preoperative patient: Protocol for a systematic review and network meta-analysis

Introduction: There is limited information of the contrast-associated acute kidney (CA-AKI) prevention in critically-ill patients. Applying the evidence for CA-AKI prevention from non-critically-ill to critically-ill patients could potentially invalidate the data. Therefore, we find it necessary to assess the benefits of preventive strategy by summarizing existing evidence from clinical trials in this systematic review and network meta‐analysis (NMA). Methods and analysis: We will search electronic databases, including PubMed, Embase, and Scopus from their inception dates with no language restrictions. Both randomized trials and non-randomized studies using validated measurement tools that investigated the benefits of pharmacological interventions among patients who undergo contrast enhanced computed tomography (CECT). The primary outcome is the incidence of CA-AKI in medical and surgical critically-ill patients who undergo CECT after receiving medication. The risk of bias assessment and analysis of the strength of the evidence will be performed independently by a pair of reviewers. A two-step approach of traditional pairwise and NMA will be performed. Based on a random-effects model, standardized weighted mean differences and ORs with corresponding 95% CIs will be pooled as effect estimates for the continuous and categorical endpoints, respectively. Statistical and methodological heterogeneities will be assessed. Preplanned subgroup analyses and univariate meta-regression will be conducted to quantify the potential sources of heterogeneity. Evidence-based synthesis will be based on the magnitudes of effect size, evidence certainty and the surface under the cumulative ranking curve values. Ethics: Ethical approval is not required because this study is based on existing published data. PROSPERO registration number: CRD42022328974

The Relationship between Serum Calcium Level and Risk Factor of Pregnancy-Induced Hypertension: A Meta-Analysis

Background: The relationship between serum calcium levels and pregnancy-induced hypertension is controversial. This work aimed to evaluate the relationship between serum calcium levels and the risk of pregnancy-induced hypertension. Methods: The following database: Chinese National Knowledge Infrastructure and PubMed, were searched to identify articles on the relationship between serum calcium levels and pregnancy-induced hypertension. The meta-analysis was conducted by using Review Manager (RevMan) [Computer program]. Results: A total of twenty one articles included in the present study. The meta-analysis revealed that patients with pregnancy-induced hypertension (PIH) had lower calcium levels (standardized weighted mean difference (SMD) = –0.68; 95% (–0.79, –0.56); p < 0.05). Conclusions: Our study suggests that serum calcium levels may be associated with the risk of pregnancy-induced hypertension.

Effect of exercise training on insulin-stimulated glucose disposal: a systematic review and meta-analysis of randomized controlled trials.

The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults. MEDLINE, EMBASE, and CENTRAL databases were searched until January 2021. Randomized controlled trials lasting ≥4 weeks, including adults, and evaluating the effect of exercise on insulin-stimulated glucose disposal measured using the hyperinsulinemic euglycemic clamp, were included. Three reviewers extracted summary data from published trials. The primary outcome was insulin-stimulated glucose disposal. Standardized weighted mean differences (SMD) in glucose disposal between intervention and control were compared. The PEDro scale was used to assess risk of bias. We included 25 trials (36 interventions, N = 851). Exercise increased insulin-stimulated glucose disposal relative to control, SMD = 0.52 (95% confidence interval [CI]: 0.39, 0.65; p < 0.001; I2 = 47%) without significantly suppressing hepatic glucose production. In trials without isotopic tracers, exercise increased glucose disposal (SMD = 0.63; 95% CI: 0.48, 0.77; p < 0.001, I2 = 55%). In trials with isotopic tracers, exercise increased glucose disposal only when tracers were added to the exogenous glucose used for clamping (SMD = 0.34; 95% CI: 0.03, 0.66, p = 0.034. I2 = 0%). In a meta-regression model including aerobic exercise, weight change, and tracer technique, only percent weight change explained between trial heterogeneity (β = 0.069; 95% CI: 0.005, 0.013). The PEDro rating indicated relatively low risk of bias (5.8 ± 0.22). Exercise training for at least four weeks significantly increases insulin-stimulated glucose disposal. Weight loss maximizes the effect and may be needed to improve hepatic insulin sensitivity. Differences in tracer methodology contribute to divergent outcomes and should be considered when assessing conclusions from research examining the effect of exercise on insulin action. PROSPERO (CRD42019124381).

The effect of statin therapy in combination with ezetimibe on circulating C-reactive protein levels: a systematic review and meta-analysis of randomized controlled trials.

Previous studies have reported that statin or ezetimibe therapy has an anti-inflammatory effect. However, the results of individual studies on the effect of statin therapy in combination with ezetimibe on C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) levels have not been clear. Therefore, the present systematic review and meta-analysis were conducted on randomized clinical trials (RCTs) to evaluate the effect of statin therapy in combination with ezetimibe on CRP and hs-CRP levels. A literature search was carried out on the MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases up to February 2022 to find eligible studies. The pooled effect sizes were considered for weighted mean difference (WMD) and 95% confidence intervals (CI) for CRP and hs-CRP, and it was also determined as standardized weighted mean difference (SMD) for overall CRP. For all variables, a random-effects model was used. Of the 57 studies included in the systematic review, 53 were used for meta-analysis. Statin therapy in combination with ezetimibe significantly reduced the serum levels of hs-CRP (WMD - 0.2mg/l; 95% CI - 0.4, - 0.1, P ˂ 0.001) and overall CRP (SMD - 0.16mg/l; 95% CI - 0.2, - 0.07, P ˂ 0.001). Nevertheless, CRP levels were not significantly changed by combination therapy. A significant association was observed between the serum low-density lipoprotein cholesterol (LDL-C) changes and hs-CRP levels, which can justify the source of heterogeneity. The current study showed that statin therapy in combination with ezetimibe could be effective in reducing the levels of hs-CRP and overall CRP.

Difference in Pain, Complication Rates, and Clinical Outcomes After Suprapatellar Versus Infrapatellar Nailing for Tibia Fractures? A Systematic Review of 1447 Patients.

To assess the effectiveness of suprapatellar (SP)-nailing versus infrapatellar (IP)-nailing of tibia fractures in anterior knee pain, complications (retropatellar chondropathy, infection, and malalignment) and physical functioning and quality of life. A clinical question-driven and thorough systematic review of current literature is provided. PubMed and Embase databases were searched for studies published between 2010 and 2020 relating to SP and IP-nailing of tibia fractures. The study is performed in concordance with PRISMA-guidelines. Studies eligible for inclusion were randomized controlled trials, prospective and retrospective observational studies reporting on outcomes of interest. Data extraction was performed independently by 2 assessors. Methodological quality and risk of bias was assessed according to the guidelines of the McMaster Critical Appraisal. Continuous variables are presented as means with SD and dichotomous variables as frequency and percentages. The weighted mean, standardized weighted mean differences, and 95% confidence interval were calculated. A pooled analysis could not be performed because of differences in outcome measures, time-points, and heterogeneity. Fourteen studies with 1447 patients were analyzed. The weighted incidence of anterior knee pain was 29% after SP-nailing and 39% after IP-nailing, without reported significance. There was a significant lower rate of malalignment after the SP-approach (4% vs. 26%) with small absolute differences in all planes. No substantial differences were observed in retropatellar chondropathy, infection, physical functioning, and quality of life. This systematic review does not reveal superiority of either technique in any of the respective outcomes of interest. Definitive choice should depend on the surgeon's experience and available resources. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction: A meta-analysis.

To explore the effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction (AMI). PubMed, Embase, Cochrane Library, and Web of Science were used to retrieve literature through 11th May 2019. Standardized weighted mean difference (SMD) and relative risk (RR) with 95% confidence intervals (CI), P-value, and I2 value were used to assess the strength of the association in this meta-analysis. Outcomes included platelet reactivity, high residual platelet reactivity (HRPR), ticagrelor maximum concentration (Cmax), ticagrelor area under curve (AUC), death rate, reinfarction rate, stroke, stent thrombosis, thrombolysis in myocardial infarction (TIMI) hemorrhage, dyspnea, emesis, contrast-induced nephropathy, and pulmonary edema. A total of 13 articles were included in this study, containing 5688 patients (morphine group: n=2014, control group: n=3674). Results illustrated that the morphine group had a higher platelet reactivity (SMD: 0.834, 95%CI: 0.483-1.186, P<0.001) and HRPR rate (RR: 1.994, 95%CI: 1.536-2.588, P<0.001) than the control group, while the Cmax of ticagrelor (WMD: -481.838, 95%CI: -841.242-122.434, P=0.009) was lower than that of the control group. The death rate of the morphine group was lower than that in the control group (RR: 0.561, 95%CI: 0.337-0.933, P=0.026). The morphine group had a higher emesis rate than the control group (RR: 4.486, 95%CI: 2.263-8.891, P<0.001). Morphine effectively suppresses the inhibition effect of P2Y12 platelet inhibitors in patients with AMI.

Fluoride Exposure and Blood Pressure: a Systematic Review and Meta-Analysis.

Fluoride exposure may cause changes in blood pressure, but this conclusion is controversial. Therefore, this meta-analysis aims to investigate the potential relationship between fluoride exposure and blood pressure or hypertension. PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), WANFANG MED ONLINE, and Chinese Scientific Journals Full-Text Databases (VIP) were searched; in addition, two related studies were added manually. In total, 7 observational studies were identified, the pooled odds ratios (ORs) for hypertension between high and reference fluoride exposure groups were calculated, and the pooled standardized weighted mean difference (SMD) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using an inverse-variance weighted random-effects model; next, sensitivity analysis and subgroup analysis were used to assess potential sources of heterogeneity; furthermore, publication bias was assessed using the Begg and Egger test. In brief, there were no statistical differences between exposure groups and control groups in terms of blood pressure or hypertension when all included studies considered. However, subgroup analysis indicated that blood pressure will rise with the increase of fluoride exposure concentrations in endemic fluorosis areas. The corresponding pooled SMD estimates were 0.31 (95% CI 0.11, 0.51) and 0.27 (95% CI 0.11, 0.43) for SBP and DBP. Funnel plots suggested no asymmetry. Our findings support the possibility of a positive correlation between fluoride exposure and blood pressure in endemic fluorosis areas. Additional evidence is needed to assess the dose-response relationship between fluoride exposure and blood pressure.

Is low body mass index a risk factor for semen quality? A PRISMA-compliant meta-analysis.

Background:Male infertility has become a worldwide public health problem. However, the effect of low body mass index (BMI) is still controversial.Methods:Relevant articles in Pubmed, Embase, Web of science, and Wanfang database published until September 2017 were searched without language restriction. We performed a meta-analysis about low BMI and semen parameters containing total sperm count, concentration, semen volume, and sperm motility (overall and progressive), including 709 men with low BMI and 14,622 men with normal BMI.Results:Thirteen studies were included in this meta-analysis and a total of 15,331 individuals were accumulated. We pooled data from these articles and found standardized weighted mean differences in semen parameters (total sperm count and semen volume) showed significant difference between low BMI and normal BMI.Conclusions:This systematic review with meta-analysis has confirmed that there was a relationship between low BMI and semen quality, which suggesting low BMI may be a harmful factor of male infertility. Yet lacking of the raw data may influence the accuracy of the results. Further researches are needed to identify the role of underweight in male sterility.

Responsiveness of Oral Health-Related Quality of Life Questionnaires to Dental Caries Interventions: Systematic Review and Meta-Analysis

This systematic review and meta-analysis were undertaken to assess the responsiveness of validated oral health-related quality of life (OHRQoL) questionnaires to dental caries interventions in children, adolescents, and young adults. Studies eligible were randomized clinical trials (RCTs), controlled clinical trials (CCTs), and prospective case series (PCS), which had OHRQoL questionnaires answered before and after caries intervention(s). The main outcome was improvement in OHRQoL mean scores following caries intervention. Twenty-six studies were selected for the quality assessment and 14 were selected for the meta-analysis. Most of the studies were PCS with a single group pretest and posttest study design (n = 19). Five studies were CCT and only 2 were RCT. The numbers of participants were 3,522 in the control group (baseline = 2,002; final = 1,520) and 5,917 in the test group (baseline = 3,102; final = 2,815). The age of the subjects ranged from 3 to 19 years. All studies showed significant improvement in OHRQoL following caries intervention. Most of nonrandomized studies (n = 15) had low or moderate risk of bias. The meta-analysis showed the effect of caries interventions (standardized weighted mean differences = –1.24; 95% CI: –1.68 to –0.81; p < 0.001). However, high heterogeneity between the studies was found. The Grading of Recommendations Assessment, Development and Evaluation approach classified the quality of evidence as very low and its strength weak. In conclusion, there is evidence that the OHRQoL of children and adolescents improved following caries intervention procedures, but the quality of the evidence was very low. In spite of that, caries interventions are highly recommended as abstaining from treatment is likely to result in a deterioration of OHRQoL.

Effect of Ramadan fasting on glycaemic parameters & body mass index in type II diabetic patients: A meta-analysis.

Background & objectives:There has been an ongoing debate about the impact of Ramadan fasting (RF) on the health of these individuals who fast during Ramadan. The aim of this meta-analysis was to evaluate the relationship between RF and glycaemic parameters in type 2 diabetes mellitus (T2DM) patients.Methods:Search terms were decided and databases such as MEDLINE EBSCO, Google Scholar and EMBASE were searched for eligible studies. Standardized mean differences and 95 per cent confidence intervals (CIs) of post-prandial plasma glucose (PPG), fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) (%) and fructosamine levels were calculated for different treatment regimens.Results:Of the 40 studies, 19 were found eligible for inclusion in the meta-analysis. Based on pooled results, significant reductions in FPG were found in single oral antidiabetics (OAD) [standardized weighted mean difference (SMD)=0.47, 95% CI=(0.20-0.74)], multi-OAD [SMD=0.36, 95% CI=(0.11-0.61)] and multitreatment subgroups [SMD=0.65, 95% CI=(0.03-1.27)] and overall [SMD=0.48, 95% CI=(0.27-0.70)]. Furthermore, HbA1c (%) [SMD=0.26, 95% CI=(0.03-0.49)] and body mass index (BMI) [SMD=0.18, 95% CI=(0.04-0.31)] were significantly decreased in the multi-OAD group.Interpretation & conclusions:The meta-analysis showed that RF was not associated with any significant negative effects on PPG and fructosamine levels. However, BMI and FPG and HbA1c (%) were positively affected by RF.

The impact of BMI on sperm parameters and the metabolite changes of seminal plasma concomitantly.

The development of male infertility increased rapidly worldwide, which coinciding with the epidemic of obesity. However, the impact of weight abnormalities on sperm quality is still contestable. To assess the correlation between BMI and sperm parameters, we searched relevant articles in PubMed, Embase, Web of science, and Wanfang database published until June 2015 without language restriction. Otherwise, we also recruited some participants who attended fertility clinic as well as some general populations in this report. We performed a systematic review and meta-analysis about BMI and sperm parameters containing total sperm count, concentration, semen volume and sperm motility (overall and progressive). Metabolomic analysis of seminal plasma was performed to explore the mechanism from a new perspective. This study found standardized weighted mean differences (SMD) in sperm parameters (total sperm count, sperm concentration, and semen volume) of abnormal weight groups decreased to different degree compared to normal weight. Dose-response analysis found SMD of sperm count, sperm concentration and semen volume respectively fell 2.4%, 1.3% and 2.0% compared with normal weight for every 5-unit increase in BMI. Metabolomic analysis of seminal plasma showed that spermidine and spermine were likely to play a vital role in the spermatogenesis progress. This systematic review with meta-analysis has confirmed there was a relationship between BMI and sperm quality, suggesting obesity may be a detrimental factor of male infertility.

Developmental Fluoride Neurotoxicity: Choi et al. Respond

Sabour and Ghorbani’s comments about the reported mean difference in IQ (intelligence quotient) scores reported in our article (Choi et al. 2012) suggest a misunderstanding of the scale unit we used and the public health significance of even a small decrease in the average IQ associated with exposure. We appreciate this opportunity to clarify the factual information about the reported IQ measure. The standardized weighted mean difference (SMD) in IQ score between exposed and reference populations was –0.45 (95% confidence interval: –0.56, –0.35) using a random-effects model (Choi et al. 2012). We used the SMD because the studies we included used different scales to measure the general intelligence. The SMD is a weighted mean difference standardized across studies, giving the average difference in standard deviations for the measure of that outcome. For commonly used IQ scores with a mean of 100 and an SD of 15, 0.45 SDs is equivalent to 6.75 points (rounded to 7 points). As research on other neurotoxicants has shown, a shift to the left of IQ distributions in a population will have substantial impacts, especially among those in the high and low ranges of the IQ distribution (Bellinger 2007).

Developmental Fluoride Neurotoxicity: A Systematic Review and Meta-Analysis

Background: Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children’s neurodevelopment.Objective: We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development.Methods: We searched the MEDLINE, EMBASE, Water Resources s, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, because many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, end points of IQ scores, or related cognitive function measures with means and variances for the two exposure groups. Using random-effects models, we estimated the standardized mean difference between exposed and reference groups across all studies. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking-water fluoride as the only exposure. We performed the Cochran test for heterogeneity between studies, Begg’s funnel plot, and Egger test to assess publication bias, and conducted meta-regressions to explore sources of variation in mean differences among the studies.Results: The standardized weighted mean difference in IQ score between exposed and reference populations was –0.45 (95% confidence interval: –0.56, –0.35) using a random-effects model. Thus, children in high-fluoride areas had significantly lower IQ scores than those who lived in low-fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease.Conclusions: The results support the possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment. Future research should include detailed individual-level information on prenatal exposure, neurobehavioral performance, and covariates for adjustment.

Cognitive-Behavioral and Pharmacological Interventions for Premenstrual Syndrome or Premenstrual Dysphoric Disorder: A Meta-Analysis

The current meta-analysis investigates the efficacy of psychotherapeutic interventions and psychopharmacotherapy for premenstrual syndrome (PMS) and premenstrual dysphoric disorder. Based on a multiple-phase literature search, controlled trials were selected according to a priori defined inclusion criteria. Data were extracted on the basis of a standardized coding scheme. The standardized weighted mean difference (random effects model) was used as effect size index. Dependent on outcome, 22 included studies obtained small to medium effect sizes for cognitive-behavioral interventions (range: d(+) = 0.24-0.70) and for serotonergic antidepressants (range: d(+) = 0.29-0.58), at post-assessment. Follow-ups were performed only in studies of cognitive-behavioral interventions (range: d(+) = 0.46-0.74). There was no evidence of a publication bias. For both cognitive-behavioral interventions and serotonergic antidepressants, efficacy in treatment of PMS was found to not be satisfactory. Future research should possibly focus more on a combination of both approaches.

Meta-analytic methods for pooling rates when follow-up duration varies: a case study.

BackgroundMeta-analysis can be used to pool rate measures across studies, but challenges arise when follow-up duration varies. Our objective was to compare different statistical approaches for pooling count data of varying follow-up times in terms of estimates of effect, precision, and clinical interpretability.MethodsWe examined data from a published Cochrane Review of asthma self-management education in children. We selected two rate measures with the largest number of contributing studies: school absences and emergency room (ER) visits. We estimated fixed- and random-effects standardized weighted mean differences (SMD), stratified incidence rate differences (IRD), and stratified incidence rate ratios (IRR). We also fit Poisson regression models, which allowed for further adjustment for clustering by study.ResultsFor both outcomes, all methods gave qualitatively similar estimates of effect in favor of the intervention. For school absences, SMD showed modest results in favor of the intervention (SMD -0.14, 95% CI -0.23 to -0.04). IRD implied that the intervention reduced school absences by 1.8 days per year (IRD -0.15 days/child-month, 95% CI -0.19 to -0.11), while IRR suggested a 14% reduction in absences (IRR 0.86, 95% CI 0.83 to 0.90). For ER visits, SMD showed a modest benefit in favor of the intervention (SMD -0.27, 95% CI: -0.45 to -0.09). IRD implied that the intervention reduced ER visits by 1 visit every 2 years (IRD -0.04 visits/child-month, 95% CI: -0.05 to -0.03), while IRR suggested a 34% reduction in ER visits (IRR 0.66, 95% CI 0.59 to 0.74). In Poisson models, adjustment for clustering lowered the precision of the estimates relative to stratified IRR results. For ER visits but not school absences, failure to incorporate study indicators resulted in a different estimate of effect (unadjusted IRR 0.77, 95% CI 0.59 to 0.99).ConclusionsChoice of method among the ones presented had little effect on inference but affected the clinical interpretability of the findings. Incidence rate methods gave more clinically interpretable results than SMD. Poisson regression allowed for further adjustment for heterogeneity across studies. These data suggest that analysts who want to improve the clinical interpretability of their findings should consider incidence rate methods.

Intravenous iron therapy in pediatric hemodialysis patients: a meta-analysis

Dialysis guidelines recommend aggressive management of anemia, including the use of intravenous iron (i.v.Fe) when indicated. However, few published data are available to guide the use of i.v.Fe in children, and studies are difficult to compare. In this meta-analysis we sought to combine evidence by pooling clinical trial data to determine if i.v.Fe therapy helped increase hematocrit, serum levels of hemoglobin, ferritin, and transferrin saturation (TSAT), and reduce erythropoietin use. We searched MEDLINE and other databases, publications, and other sources to identify as many published and unpublished trials as possible. Of 379 possible studies, nine met the criteria for inclusion and analysis. Across all nine studies, 141 patients were studied, for durations of 2 weeks to 12 months. Pooled results identified an increase in hemoglobin, hematocrit, ferritin, and TSAT levels, and reduced use of erythropoietin, with effect sizes (in standardized weighted mean differences) ranging from 0.62 (95% confidence interval 0.11-1.13) to 1.86 (1.58-2.15) standard deviation improvements. Current practice is based largely on extrapolation from adult data and a few small pediatric trials. The pooled pediatric data suggest that i.v.Fe is effective and produces moderate to large effects on the reported outcomes. Prospective, multi-center trials are needed to determine the optimal utilization of i.v.Fe in children.

Meta-analysis of randomized controlled trials on the benefits and risks of using cisapride for the treatment of gastroesophageal reflux in children.

Gastroesophageal reflux is a common problem in infancy. Cisapride is a commonly used therapy for gastroesophageal reflux in children. In view of recent concern regarding adverse effects this study aims to evaluate the benefits and risks of cisapride for the treatment of gastroesophageal reflux in children. A meta-analysis of randomized controlled trials of cisapride using a random-effects model. Ten trials involving 415 children were identified. There was no evidence of a significant reduction in vomiting severity with cisapride as measured by a clinical score (five trials, standardized weighted mean difference -0.18; 95% confidence interval (CI) -0.51 to 0.15). Twenty-four-hour esophageal pH monitoring data showed the mean reflux index was significantly lower in the children treated with cisapride compared with controls (five trials, weighted mean difference -6.24; 95% CI -8.81 to -3.67). With cisapride treatment, there was no reduction in the mean number of reflux episodes lasting greater than 5 min (three trials, weighted mean difference -0.72; 95% CI -1.92 to 0.47) or in the number of children with esophagitis at final follow up compared with baseline (two trials, relative risk 0.80; 95% CI 0.40 to 1.61). There was no significant difference in reported side-effects or adverse events (six trials, relative risk 1.16; 95% CI 0.95 to 1.41). No clinically important benefits of cisapride in children with gastroesophageal reflux have been demonstrated. Nor was there any evidence of adverse or harmful events.

Meta-analysis combining parallel and cross-over clinical trials. I: Continuous outcomes.

Among clinical trials assessing a given treatment, often parallel and cross-over designs are used together. In the first paper of a series of three, we explore two methods to pool continuous outcomes in a meta-analysis combining parallel and cross-over trial designs: the weighted mean difference (WMD) and the standardized weighted mean difference (SWMD). The combined design meta-analytic formulae are based on a weighted average of the two design treatment estimates. A random effects model can be implemented. Both WMD and SWMD can be used, the choice of the method is determined by the type of outcomes obtained in the trials. Compared to the number of included subjects, the relative weight of the cross-over design is large in combined-design meta-analysis. Differences in the weight estimation between WMD and SWMD can also accentuate the relative weight of cross-over trials, which must be considered a case of design-specific bias.

Topical preparations for the treatment of psoriasis: a systematic review.

There is clinical uncertainty about the appropriate use of first-line topical treatments for psoriasis. To assess the relative effectiveness and tolerability of topical treatments for psoriasis suitable for use both in primary and secondary care. All major medical databases of published literature were searched electronically; references of trial reports and recent reviews were searched; authors and companies were contacted for missing data from published reports. The study selection comprised: (1) randomized placebo-controlled trials of topical treatments for psoriasis; and (2) randomized head-to-head studies of the new vitamin D3 derivative treatments for psoriasis that reported clinical outcome using a Total Severity Score (TSS), Psoriasis Area Severity Index or Investigator Assessment of Global Improvement. Eligibility and validity were assessed and data extracted independently by two authors. Clinical outcomes were pooled using a random effect standardized weighted mean difference (SWMD) metric, including 3380 patients randomized in 41 placebo (vehicle)-controlled trials and 4898 patients randomized in 28 head-to-head studies. There was a significant benefit in favour of active treatments against vehicle, SWMD: -1.06 (95% confidence interval [CI]: -1.26 to -0.86), approximately a 2-point improvement on a 12-point TSS after 6-8 weeks of treatment. The only significantly different benefit was for very potent corticosteroids: SWMD: -1.51 (95% CI: -1.76 to -1.25), approximately a 3-point improvement on a 12-point TSS. Head-to-head studies support these findings, except that calcipotriol was estimated to be more effective than dithranol, coal tar and other vitamin D3 derivatives. Polytherapy, using a potent steroid and calcipotriol, was more effective than calcipotriol alone: SWMD 0.42 (95% CI: 0.12-0.72 ) approximately a 0.8-point improvement on a 12-point TSS. No important differences in withdrawal or reporting of adverse events were identified. Trials of short duration neither adequately inform the management of chronic disease nor describe the sequelae of treatment. The evidence base for long-term care, reflecting the disease pathway, should be improved. Combination therapy with topical vitamin D analogues and steroids, and maintenance therapy following treatment response merit further investigation.

Azathioprine for rheumatoid arthritis.

To assess the short-term effects of azathioprine for the treatment of rheumatoid arthritis (RA). We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, Medline up to and including July 1998 and Embase from 1988-1998. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. All randomized controlled trials and controlled clinical trials comparing azathioprine against placebo in patients with rheumatoid arthritis. Data was extracted independently by two reviewers (CS, EB); disagreements were resolved by discussion or third party adjudication (MS). The same reviewers (CS, EB) assessed the methodological quality of the trials using a validated quality assessment tool. Rheumatoid arthritis outcome measures were extracted from the publications for the six-month endpoint. The pooled analysis was performed using standardized mean differences for joint counts, pain and functional status assessments. Weighted mean differences were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals and for adverse reactions. The 95% confidence intervals (95% CI) are presented. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout, since no statistical heterogeneity was found. Three trials with a total of 81 patients were included in the analysis. Forty patients were randomized to azathioprine and forty-one to placebo. A pooled estimate was calculated for two outcomes. A statistically significant benefit was observed for azathioprine when compared to placebo for tender joint scores. The standardized weighted mean difference between treatment and placebo was -0.98 (95% CI -1.45, -0.50). Withdrawals from adverse reactions were significantly higher in the azathioprine group OR=4.56 (95% CI 1.16, 17.85). Azathioprine appears to have a statistically significant benefit on the disease activity in joints of patients with RA. This evidence however is based on a small number of patients, included in older trials. Its effects on long-term functional status and radiological progression were not assessed due to lack of data. Toxicity is shown to be higher and more serious than that observed with other disease-modifying anti-rheumatic drugs (DMARDs). Given this high risk to benefit ratio, there is no evidence to recommend the use of azathioprine over other DMARDs.