Anticonvulsants for alcohol withdrawal.

BACKGROUND: Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of anticonvulsants' use in the treatment of alcohol withdrawal symptoms. OBJECTIVES: To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004); MEDLINE (1966 to October 2004); EMBASE (1988 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions and references of articles. SELECTION CRITERIA: All randomized controlled trials examining the effectiveness, safety and overall risk-benefit of an anticonvulsant in comparison with a placebo or other pharmacological treatment or another anticonvulsant were considered. DATA COLLECTION AND ANALYSIS: The authors independently assessed trial quality extracted data. MAIN RESULTS: Forty-eight studies, involving 3610 people were included. Despite the considerable number of randomized controlled trials, there was a variety of outcomes and of different rating scales that led to a limited quantitative synthesis of data. For the anticonvulsant versus placebo comparison, therapeutic success tended to be more common among the anticonvulsant-treated patients (relative risk (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.91), and anticonvulsant tended to show a protective benefit against seizures (RR 0.57; 95% CI 0.27 to 1.19), but no effect reached formal statistical significance. For the anticonvulsant versus other drug comparison, CIWA-Ar score showed non-significant differences for the anticonvulsants compared to the other drugs at the end of treatment (weighted mean difference (WMD) -0.73; 95% CI -1.76 to 0.31). For the subgroup analysis of carbamazepine versus benzodiazepine, a statistically significant protective effect was found for the anticonvulsant (WMD -1.04; 95% CI -1.89 to -0.20), p = 0.02), but this was based on only 260 randomized participants. There was a non-significant decreased incidence of seizures (RR 0.50; 95% CI 0.18 to 1.34) favouring the patients that were treated with anticonvulsants than other drugs, and side-effects tended to be less common in the anticonvulsant-group (RR 0.56; 95% CI 0.31 to 1.02). AUTHORS' CONCLUSIONS: It is not possible to draw definite conclusions about the effectiveness and safety of anticonvulsants in alcohol withdrawal, because of the heterogeneity of the trials both in interventions and the assessment of outcomes. The extremely small mortality rate in all these studies is reassuring, but data on other safety outcomes are sparse and fragmented.

Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for upper respiratory tract infections.

We carried out a meta-analysis of randomized controlled trials comparing 3-5 days of azithromycin with other antibiotics that are typically given in longer courses for the treatment of upper respiratory tract infections. For acute otitis media (19 comparisons including 3421 patients), acute sinusitis (11 comparisons including 1742 patients) and acute pharyngitis (16 comparisons including 2447 patients), azithromycin had similar clinical failure rates to the other antibiotics [random effects odds ratios 1.12, 95% confidence interval (CI) 0.81-1.54; 0.91, 95% CI 0.60-1.39; and 1.07, 95% CI 0.59-1.94, respectively]. The difference in clinical failures was <0.5%, and no 95% CIs exceeded 2.0%. There was no heterogeneity between studies. Subtle differences between comparators could have been due to chance. There were no significant differences in bacteriological outcomes. Azithromycin was discontinued because of adverse events in only 37 of 4870 (0.8%) patients. Short courses of azithromycin are as effective as longer courses of other antibiotics for upper respiratory tract infections. Convenience of dosing should be balanced against the increased cost of this regimen for the treatment of these common infections, where often no antibiotic may be indicated at all.

Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for lower respiratory tract infections.

We carried out a meta-analysis of randomized controlled trials of azithromycin compared with other antibiotics in the treatment of lower respiratory tract infections, including acute bronchitis (five comparisons including 1372 patients), acute exacerbations of chronic bronchitis (13 comparisons including 1342 patients) and community-acquired pneumonia (18 comparisons with 1664 patients). For the first two indications, azithromycin did not offer any statistically significant reduction in clinical failures [random effects odds ratios 0.84, 95% confidence interval (CI) 0.54-1.31 and 0.64, 95% CI 0.31-1.32, respectively] and absolute risk differences were small. For community-acquired pneumonia, azithromycin significantly reduced clinical failures by about one-third (random effects odds ratio 0.63, 95% CI 0.41-0.95). The absolute incremental benefit was approximately one clinical failure prevented per 50 treated patients with community-acquired pneumonia. There was no significant heterogeneity for different comparators and for bacterial versus atypical pneumonias. Azithromycin was discontinued because of adverse events in only 23 of 3487 patients (0.7%). Although results should be interpreted cautiously as most trials were open-label and susceptible to bias, the meta-analysis indicates that, compared with antibiotics with traditional pharmacokinetics that require more prolonged courses, azithromycin offers no significant advantage for bronchitis, but may be more effective in community-acquired pneumonia.

Replication validity of genetic association studies.

The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.

Comparison of evidence of treatment effects in randomized and nonrandomized studies.

CONTEXT: There is substantial debate about whether the results of nonrandomized studies are consistent with the results of randomized controlled trials on the same topic. OBJECTIVES: To compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between randomized and nonrandomized studies. DATA SOURCES: MEDLINE (1966-March 2000), the Cochrane Library (Issue 3, 2000), and major journals were searched. STUDY SELECTION: Forty-five diverse topics were identified for which both randomized trials (n = 240) and nonrandomized studies (n = 168) had been performed and had been considered in meta-analyses of binary outcomes. DATA EXTRACTION: Data on events per patient in each study arm and design and characteristics of each study considered in each meta-analysis were extracted and synthesized separately for randomized and nonrandomized studies. DATA SYNTHESIS: Very good correlation was observed between the summary odds ratios of randomized and nonrandomized studies (r = 0.75; P<.001); however, nonrandomized studies tended to show larger treatment effects (28 vs 11; P =.009). Between-study heterogeneity was frequent among randomized trials alone (23%) and very frequent among nonrandomized studies alone (41%). The summary results of the 2 types of designs differed beyond chance in 7 cases (16%). Discrepancies beyond chance were less common when only prospective studies were considered (8%). Occasional differences in sample size and timing of publication were also noted between discrepant randomized and nonrandomized studies. In 28 cases (62%), the natural logarithm of the odds ratio differed by at least 50%, and in 15 cases (33%), the odds ratio varied at least 2-fold between nonrandomized studies and randomized trials. CONCLUSIONS: Despite good correlation between randomized trials and nonrandomized studies-in particular, prospective studies-discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.

Pathways for inappropriate dispensing of antibiotics for rhinosinusitis: a randomized trial.

We evaluated the extent of and factors that determine the inappropriate use of antibiotics that are obtained without a physician's prescription. Ninety-eight Greek pharmacists were visited by actress-researchers who played clients requesting antibiotics without a physician's prescription. Pharmacists were randomly challenged in a scenario that involved simulated cases of acute uncomplicated rhinosinusitis with either low fever (38.5 degrees C) or high fever (40 degrees C). Antibiotics were offered by 34 (69%) of 49 pharmacists who were presented with the high-fever scenario and by 42 (86%) of 49 pharmacists who were presented with the low-fever scenario (risk difference, 16.3%; P = .05). Thirty-two (65%) and 35 (71%) pharmacists in the high- and low-fever study arms, respectively, agreed to sell the actress-researchers broad-spectrum antibiotics. Only 28 (57%) and 17 (35%) pharmacists, respectively, recommended that the patient visit a physician (P = .03). Inappropriate recommendations regarding antibiotic use were very common in the studied setting. Antibiotics were more likely to be offered to persons who did not have a prescription when they were less likely to be clinically indicated.

Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions.

BACKGROUND: Guidelines published in major medical journals are very influential in determining clinical practice. It would be essential to evaluate whether conflicts of interests are disclosed in these publications. We evaluated the reporting of conflicts of interest and the factors that may affect such disclosure in a sample of 191 guidelines on therapeutic and/or preventive measures published in 6 major clinical journals (Annals of Internal Medicine, BMJ, JAMA, Lancet, New England Journal of Medicine, Pediatrics) in 1979, 1984, 1989, 1994 and 1999. RESULTS: Only 7 guidelines (3.7%) mentioned conflicts of interest and all were published in 1999 (17.5% (7/40) of guidelines published in 1999 alone). Reporting of conflicts of interest differed significantly by journal (p=0.026), availability of disclosure policy by the journal (p=0.043), source of funding (p < 0.001) and number of authors (p=0.004). In the entire database of 191 guidelines, a mere 18 authors disclosed a total of 24 potential conflicts of interest and most pertained to minor issues. CONCLUSIONS: Despite some recent improvement, reporting of conflicts of interest in clinical guidelines published in influential journals is largely neglected.

The sequence and antiapoptotic functional domains of the human cytomegalovirus UL37 exon 1 immediate early protein are conserved in multiple primary strains.

The human cytomegalovirus UL37 exon 1 gene encodes the immediate early protein pUL37x1 that has antiapoptotic and regulatory activities. Deletion mutagenesis analysis of the open reading frame of UL37x1 identified two domains that are necessary and sufficient for its antiapoptotic activity. These domains are confined within the segments between amino acids 5 to 34, and 118 to 147, respectively. The first domain provides the targeting of the protein to mitochondria. Direct PCR sequencing of UL37 exon 1 amplified from 26 primary strains of human cytomegalovirus demonstrated that the promoter, polyadenylation signal, and the two segments of pUL37x1 required for its antiapoptotic function were invariant in all sequenced strains and identical to those in AD169 pUL37x1. In total, UL37 exon 1 varies between 0.0 and 1.6% at the nucleotide level from strain AD169. Only 11 amino acids were found to vary in one or more viral strains, and these variations occurred only in the domains of pUL37x1 dispensable for its antiapoptotic function. We infer from this remarkable conservation of pUL37x1 in primary strains that this protein and, probably, its antiapoptotic function are required for productive replication of human cytomegalovirus in humans.

Predictors and impact of losses to follow-up in an HIV-1 perinatal transmission cohort in Malawi.

BACKGROUND: Large simple trials which aim to study therapeutic interventions and epidemiological associations of human immunodeficiency virus (HIV) infection, including perinatal transmission, in Africa may have substantial rates of loss to follow-up. A better understanding of the characteristics and the impact of women and children lost to follow-up is needed. METHODS: We studied predictors and the impact of losses to follow-up of infants born in a large cohort of delivering women in urban Malawi. The cohort was established as part of a trial of vaginal cleansing with chlorhexidine during delivery to prevent mother-to-infant transmission of HIV. RESULTS: The HIV infection status could not be determined for 797 (36.9%) of 2156 infants born to HIV-infected mothers; 144 (6.7%) with missing status because of various sample problems and 653 (30.3%) because they never returned to the clinic. Notably, the observed rates of perinatal transmission were significantly lower in infants who returned later for determination of their infection status (odds ratio = 0.94 per month, P = 0.03), even though these infants must have had an additional risk of infection from breastfeeding. In multivariate models, infants of lower birthweight (P = 0.003) and, marginally, singletons (P = 0.09) were less likely to return for follow-up. The parents of infants lost to follow-up tended to be less educated (P < 0.001) and more likely to be in farming occupations, although one educated group, teachers and students, were also significantly less likely to return. Of these variables, infant birthweight, twins versus singletons, and maternal education were also associated with significant variation in the observed risk of perinatal transmission among infants of known HIV status. CONCLUSIONS: Several predictors of loss to follow-up were identified in this large HIV perinatal cohort. Losses to follow-up can impact the observed transmission rate and the risk associations in different studies.

PIP: Predictors and the impact of losses to follow-up of infants born to a large HIV- infected cohort of delivering women in urban Malawi were studied. The women enrolled in an intervention trial including vaginal cleansing with chlorhexidine at the time of delivery. Findings showed that of the 2156 infants born to HIV- infected mothers, about 1359 (63.1%) had been diagnosed with HIV infection, 797 (36.9%) with undetermined status, 144 (6.7%) with missing status, and about 653 (30.3%) were never brought back for follow-up. The odds of HIV positivity decreased in the determination of infectious status (P = 0.03) despite the probability of additional transmission from breast-feeding. Late-coming and lost children of less educated parents had similar birth weight (P = 0.50) and were likely less to return. This was probably due to the fact that the fathers of the lost children were farmers. Besides, infant birth weight, twins vs. singletons, and maternal education were affiliated with significant variation in the observed risk of perinatal transmission among HIV-positive infants. Thus, with regard to the intervention trial, the LFU were approximately equal in both groups. There was no evidence that the losses were unbalanced between arms in relation to the predictors of transmission.

Recursive cumulative meta-analysis: a diagnostic for the evolution of total randomized evidence from group and individual patient data.

Meta-analyses of randomized evidence may include published, unpublished, and updated data in an ongoing estimation process that continuously accommodates more data. Synthesis may be performed either with group data or with meta-analysis of individual patient data (MIPD). Although MIPD with updated data is considered the gold standard of evidence, there is a need for a careful study of the impact different sources of data have on a meta-analysis and of the change in the treatment effect estimates over sequential information steps. Unpublished data and late-appearing data may be different from early-appearing data. Updated information after the end of the main study follow-up may be affected by cross-overs, missing information, and unblinding. The estimated treatment effect may thus depend on the completeness and updating of the available evidence. To address these issues, we present recursive cumulative meta-analysis (RCM) as an extension of cumulative metaanalysis. Recursive cumulative meta-analysis is based on the principle of recalculating the results of a cumulative meta-analysis with each new or updated piece of information and focuses on the evolution of the treatment effect as a more complete and updated picture of the evidence becomes available. An examination of the perturbations of the cumulative treatment effect over sequential information steps may signal the presence of bias or heterogeneity in a meta-analysis. Recursive cumulative meta-analysis may suggest whether there is a true underlying treatment effect to which the meta-analysis is converging and how treatment effects are sequentially altered by new or modified evidence. The method is illustrated with an example from the conduct of an MIPD on acyclovir in human immunodeficiency virus infection. The relative strengths and limitations of both metaanalysis of group data and MIPD are discussed through the RCM perspective.

Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data.

A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (> or = 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P < .001), higher hemoglobin level (P < .001), and younger age (P < .001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (> or = 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the meta-analysis supports the importance of pathogenetic interactions between herpesviruses and HIV.

Maternal cell-free viremia in the natural history of perinatal HIV-1 transmission: a meta-analysis.

We performed a meta-analysis of the predictive value of maternal cell-free viral load in vertical HIV-1 transmission, including 9 cohorts with 1115 mother-infant pairs (696 untreated and 419 treated women). The pooled rate of transmission in untreated women was 21.3% (95% confidence interval [CI], 18.3%-24.5%). The rates of transmission for untreated women in the <1000 copies/ml, 1000 to 9999 copies/ml, and > or = 10,000 copies/ml categories were 5% (95% CI, 2%-11%), 15% (95% CI, 11%-20%) and 37% (95% CI, 29%-46% by random effects), respectively. The area under the receiver operating characteristic (ROC) curve in individual studies ranged from 0.67 to 1.00. The predictive performance of RNA differed between cohorts in which different percentages of transmitters had RNA values >10,000 copies/ml. When 95% of transmitters have RNA values >1000 copies/ml, 77% of nontransmitters would also have values above this cutoff. Transmission rates for treated women in the 1000 to 9999 copies/ml category (7%; 95% CI, 4%-11%,) and > or = 10,000 copies/ml category (18%; 95% CI, 12%-27%) were probably lower than those for untreated women, whereas the transmission rate for treated women with <1000 copies/ml was 5% (95% CI, 2%-11 %). Thus, the risk gradient between RNA categories seems attenuated in treated women. Several aspects of the design, analysis, and reporting of research in this area may be improved in the future with attention to selection and observer biases, multivariate adjustment, and technical consistency. Maternal HIV-1 RNA is a modest predictor of transmission for individual mothers, but a strong predictor of the average risk in groups of untreated mothers. Its discriminatory power is better in untreated than in treated populations and is better in cohorts with a high prevalence of elevated viral load values than in cohorts with generally low levels of viremia.

PCR detection of human cytomegalovirus DNA in clinical specimens using novel UL37 exon 3 and US3 primers.

The sensitivity and specificity of novel UL37 exon 3 (UL37x3) and US3 immediate-early (IE) gene PCR primers to detect human cytomegalovirus (HCMV) DNA in clinical specimens are comparable to those of HCMV DNA polymerase (UL54) primers. The use of these IE primers increases the diagnostic performance of HCMV PCR.