Search PubMed⌕ Search

Biomedical subjects

J Lau

Publications and source records attributed to J Lau.

At least 73 records · Page 4Linked to original sources
PubMed2001

Evolution of treatment effects over time: empirical insight from recursive cumulative metaanalyses.

Evidence on how much medical interventions work may change over time. It is important to determine what fluctuations in the treatment effect reported by randomized trials and their metaanalyses may be expected and whether extreme fluctuations signal future major changes. We applied recursive cumulative metaanalysis of randomized controlled trials to evaluate the relative change in the pooled treatment effect (odds ratio) over time for 60 interventions in two medical fields (pregnancy/perinatal medicine, n = 45 interventions; myocardial infarction, n = 15 interventions). We evaluated the scatter of relative changes for different numbers of total patients in previous trials. Outlier cases were noted with changes greater than 2.5 standard deviations of the expected. With 500 accumulated patients, the pooled odds ratio may change by 0.6- to 1.7-fold in the immediate future. When 2000 patients have already been randomized, the respective figures are between 0.74- and 1.35-fold for pregnancy/perinatal medicine and between 0.83- and 1.21-fold for myocardial infarction studies. Extreme early fluctuations in the treatment effect were observed in three interventions (magnesium in myocardial infarction, calcium and antiplatelet agents for prevention of preeclampsia), where recent mega-trials have contradicted prior metaanalyses, as well as in four other examples where early large treatment effects were dissipated when more data appeared. Past experience may help quantify the uncertainty surrounding the treatment effects reported in early clinical trials and their metaanalyses. Early wide oscillations in the evolution of the treatment effect for specific interventions may sometimes signal further major changes in the future.

Calcium↗
PubMed2001

Synthesis of novel GABA uptake inhibitors. Part 6: preparation and evaluation of N-Omega asymmetrically substituted nipecotic acid derivatives.

In a previous series of potent GABA uptake inhibitors published from this laboratory, we noticed that asymmetry in the substitution pattern of the bis-aromatic moiety in known GABA uptake inhibitors such as 4 [1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid] and 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid] was beneficial for high affinity. This led us to investigate asymmetric analogues of known symmetric GABA uptake inhibitors in which one of the aryl groups has been exchanged with an alkyl, alkylene or cycloalkylene moiety as well as other modifications in the lipophilic part. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound, and it was found that several of the novel compounds inhibit GABA uptake as potently as their known symmetrical reference analogues. Several of the novel compounds were also evaluated for their ability to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in vivo. Some of the compounds, for example 18 [(R)-1-(2-(((1,2-bis(2-fluorophenyl)ethylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid], show a high in vivo potency and protective index comparable with that of our recently launched anticonvulsant product, 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid], and may therefore serve as second-generation drug candidates.

Animals↗
PubMed2001

Evidence on interventions to reduce medical errors: an overview and recommendations for future research.

OBJECTIVE: To critically review the existing evidence on interventions aimed at reducing errors in health care delivery. DESIGN: Systematic review of randomized trials on behavioral, educational, informational and management interventions relating to medical errors. Pertinent studies were identified from MEDLINE, EMBASE, the Cochrane Clinical Trials Registry, and communications with experts. SETTING: Both inpatients and outpatients qualified. No age or disease restrictions were set. MEASUREMENTS: Outcomes were medical errors, including medication, prescription, and diagnostic errors, and excluding preventive medicine errors and simple ordering of redundant tests. MAIN RESULTS: Thirteen randomized studies qualified for evaluation. The trials varied extensively in their patient populations (mean age, 2 weeks to 83 years), study setting, definition of errors, and interventions. Most studies could not afford masking and rigorous allocation concealment. In 9 of 13 studies, error rates in the control arms were very high (10% to 63%), and large treatment benefits from the studied interventions were demonstrated for the main outcome. Interventions were almost always effective in a sample of 24 nonrandomized studies evaluated for comparison. Actual patient harm from serious errors was rarely recorded. CONCLUSIONS: Medical errors were very frequent in the studies we identified, arising sometimes in more than half of the cases where there is an opportunity for error. Relatively simple interventions may achieve large reductions in error rates. Evidence on reduction of medical errors needs to be better categorized, replicated, and tested in study designs maximizing protection from bias. Emphasis should be placed on serious errors.

Humans↗
PubMed2001

Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: a meta-analysis of controlled and uncontrolled trials.

The efficacy of interferon (IFN) combined with ribavirin for the treatment of patients with hepatitis C who failed to respond to initial IFN therapy is not well established. The primary goal of this study was to perform a systematic review of the literature evaluating the efficacy of combination therapy in nonresponders. Studies were retrieved from MEDLINE, abstracts of scientific meetings, and review of the bibliographies of retrieved studies. Controlled trials were included in the primary analysis whereas uncontrolled trials and trials reported as abstracts were included for sensitivity analysis. The primary endpoints were biochemical and virologic response. A combined estimate of the odds ratio (OR) for each endpoint was obtained by using the random effects model. The number needed to treat (NNT) was calculated by taking the inverse of the pooled risk difference. Nine controlled trials (789 patients) were identified. Six months after treatment, the overall sustained biochemical and virologic responses to 24 weeks of combination therapy were 15.2% and 13.2% with a common OR of 3.8 (95% confidence interval [CI] 2.2-6.7) and 4.9 (95% CI 2.1-11.2) compared with patients treated with IFN monotherapy. The pooled risk difference for the sustained virologic response (SVR) to combination therapy was 7% (95% CI 2-13). The NNT was 14 (95% CI 8-50), suggesting that approximately 14 patients would need to be treated with 6 months of combination therapy for 1 patient to have a SVR. A number of variables were associated with a high response rate in individual studies. Sensitivity analysis of preliminary trials suggest a higher response rate with longer duration of therapy and non-type 1 genotypes.

Adult↗
PubMed2001

Accuracy of imaging technologies in the diagnosis of acute cardiac ischemia in the emergency department: a meta-analysis.

STUDY OBJECTIVE: We sought to quantitatively evaluate the evidence on the diagnostic performance of imaging technologies (including rest and stress echocardiography and technetium-99m sestamibi scanning) for the diagnosis of acute cardiac ischemia and acute myocardial infarction in the emergency department. METHODS: We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. Both prospective and retrospective studies qualified for the assessment of diagnostic performance. Diagnostic performance was assessed by means of random-effect estimates of test sensitivity, specificity, and the diagnostic odds ratio and was summarized by using summary receiver-operating characteristic curves. RESULTS: Diagnostic accuracy was evaluated in 10 studies of rest echocardiography, 2 studies of dobutamine stress echocardiography, and 6 studies of technetium-99m sestamibi scanning. However, only 3 rest echocardiography and 5 technetium-99m sestamibi studies evaluated patients strictly in the ED setting. Patient populations were often highly selected to represent low- or moderate-risk groups. When limited to ED studies, rest echocardiography showed excellent sensitivity of 93% (95% CI, 81% to 97%) and good specificity of 66% (95% CI, 43% to 83%). The results were similar when all studies were considered, including data from reports of admitted patients and patients sent to the cardiac care unit. There was insufficient literature on stress echocardiography in the ED to properly assess the technology. Technetium-99m sestamibi scanning also showed excellent sensitivity (range, 91.5% to 100%) and good specificity (range, 49.3% to 84.4%) for acute myocardial infarction; for acute cardiac ischemia, the random-effects pooled sensitivity was 89% (95% CI, 73% to 96%), and the pooled specificity was 77% (95% CI, 63% to 87%). CONCLUSION: For selected low- and moderate-risk patient groups, echocardiography and technetium-99m sestamibi imaging appear to have very good diagnostic performance with a similar sensitivity and specificity profile. More evidence should be accumulated on their performance specifically in the ED setting.

Acute Disease↗
PubMed2001

Diagnosing acute cardiac ischemia in the emergency department: a systematic review of the accuracy and clinical effect of current technologies.

STUDY OBJECTIVE: Acute cardiac ischemia (ACI) encompasses the diagnoses of unstable angina pectoris and acute myocardial infarction (AMI). Accurate diagnosis and triage of patients with ACI in the emergency department should increase survival for these patients and reduce unnecessary hospital admissions. METHODS: We conducted a systematic review of the English-language literature published between 1966 and December 1998 on the accuracy and clinical effect of diagnostic technologies for ACI. We evaluated prospective and retrospective studies of adult patients who presented to the ED with symptoms suggesting ACI. Outcomes were diagnostic performance (test sensitivity and specificity) and measures of clinical effect. Meta-analyses were performed when appropriate. A decision and cost-effectiveness analysis was conducted that investigated various diagnostic strategies used in the diagnosis of ACI in the ED. RESULTS: We screened 6,667 abstracts, reviewed 407 full articles, and included 106 articles articles in the main analysis. Single measurements of biomarkers at presentation to the ED have low sensitivity for AMI, although they have high specificity. Serial measurements greatly increase the sensitivity for AMI while maintaining their excellent specificity. Diagnostic technologies to evaluate ACI in selected populations, such as electrocardiography, sestamibi perfusion imaging, and stress ECG, may have very good to excellent sensitivity; however, they have not been sufficiently studied. The Goldman Chest Pain Protocol has good sensitivity (about 90%) for AMI but has not been shown to result in any differences in hospitalization rate, length of stay, or estimated costs in the single clinical effect study performed. Its applicability to patients with unstable angina pectoris has not been evaluated. The use of an Acute Cardiac Ischemia-Time-Insensitive Predictive Instrument led to the appropriate triage of 97% of patients with ACI presenting to the ED and reduced unnecessary hospitalizations. CONCLUSION: Many of the current technologies remain underevaluated, especially regarding their clinical effect. The extent to which combinations of tests may provide better accuracy than any single test needs further study.

Acute Disease↗
PubMed2001

Accuracy and clinical effect of out-of-hospital electrocardiography in the diagnosis of acute cardiac ischemia: a meta-analysis.

STUDY OBJECTIVE: We sought to evaluate quantitatively the evidence on the diagnostic performance of out-of-hospital ECG for the diagnosis of acute cardiac ischemia (ACI) and acute myocardial infarction (AMI) and the clinical effect of out-of-hospital thrombolysis. METHODS: We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998 on the diagnostic accuracy of out-of-hospital ECG and the clinical effect of out-of-hospital thrombolysis. Both prospective and retrospective studies qualified for the assessment of diagnostic performance. For clinical effect, data from prospective nonrandomized studies were synthesized separately from data from randomized trials. Diagnostic performance was assessed by using estimates of test sensitivity, specificity, and diagnostic odds ratios and was summarized by using summary receiver-operating characteristic curves. Measures of clinical effect included time savings, early ventricular function, early mortality, and long-term survival. RESULTS: Diagnostic accuracy was evaluated in 11 studies with a total of 7,508 patients. Data were available for ACI in 5 studies and for AMI in 8 studies. For ACI, the random-effects pooled sensitivity was 76% (95% CI, 54% to 89%), the specificity was 88% (95% CI, 67% to 96%), and the diagnostic odds ratio was 23 (95% CI, 6.3 to 85). The respective figures for AMI were sensitivity of 68% (95% CI, 59% to 76%), specificity of 97% (95% CI, 89% to 92%), and diagnostic odds ratio of 104 (95% CI, 48 to 224). Both in nonrandomized (n=4, total 1,531 patients) and randomized (n=9, total 6,643 patients) studies, out-of-hospital thrombolysis shortened the time from onset of symptoms to thrombolytic treatment by 40 to 60 minutes. Data on short-term ejection fraction were sparse. Hospital mortality was reduced by 16% (95% CI, 2% to 27%) among randomized trials, and a similar estimate of effect was seen in nonrandomized studies. There was no clear effect on long-term mortality, but data were sparse. CONCLUSION: Out-of-hospital ECG has excellent diagnostic performance for AMI and very good performance for ACI. Out-of-hospital thrombolysis achieves time savings and improves short-term mortality, but the effect on long-term mortality is unknown.

Acute Disease↗
PubMed2001

Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis.

STUDY OBJECTIVE: We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of acute cardiac ischemia (ACI), including acute myocardial infarction (AMI) and unstable angina. METHODS: We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. We examined the diagnostic performance of creatine kinase, creatine kinase-MB, myoglobin, and troponin I and T testing. Diagnostic performance was assessed by using estimates of test sensitivity and specificity and was summarized by summary receiver-operating characteristic curves. RESULTS: Only 4 studies were found that evaluated all patients with ACI; 73 were found that focused only on a diagnosis of AMI. To diagnose ACI, presentation biomarker tests had sensitivities of 16% to 19% and specificities of 96% to 100%; serial biomarker tests had sensitivities of 31% to 45% and specificities of 95% to 98%. Considering only the diagnosis of AMI, presentation biomarker tests had summary sensitivities of 37% to 49% and summary specificities of 87% to 97%; serial biomarker tests had summary sensitivities of 79% to 93% and summary specificities of 85% to 96%. Variation of test sensitivity was best explained by test timing. Longer symptom duration or time between serial tests yielded higher sensitivity. CONCLUSION: The limited evidence available to evaluate the diagnostic accuracy of biomarkers for ACI suggests that biomarkers have very low sensitivity to diagnose ACI. Thus, biomarkers alone will greatly underdiagnose ACI and will be inadequate to make triage decisions. For AMI diagnosis alone, multiple testing of individual biomarkers over time substantially improves sensitivity, while retaining high specificity, at the expense of additional time. Further high-quality studies are needed on the clinical effect of using biomarkers for patients with ACI in the ED and on optimal timing of serial testing and in combination with other tests.

Acute Disease↗
PubMed2001

Incidence of gastroesophageal malignancy in patients with dyspepsia in Hong Kong: implications for screening strategies.

BACKGROUND: A "test-and-treat" strategy for H pylori infection has been recommended in Europe and North America as safe and cost-effective for management of patients with dyspepsia. The primary aim of this study was to determine the frequency of gastroesophageal cancer in 2 groups of patients with dyspepsia: those 45 years of age or younger without "alarm" symptoms (low-risk group) and patients over 45 years of age or any patient with "alarm" symptoms (high-risk group). A secondary aim was to determine the frequency of gastric cancer among patients in the low-risk group with or without a positive serology for H pylori. METHODS: Patients with persistent dyspepsia were recruited from 4 regional hospitals in Hong Kong. Those in the low-risk group were evaluated for H pylori by using a whole blood serology test; they underwent endoscopy within 1 week. Those in the high-risk group and those taking nonsteroidal anti-inflammatory drugs (NSAIDs) underwent endoscopy promptly. Alarm symptoms were as follows: weight loss (10 or more pounds over 8 weeks), recurrent vomiting, dysphagia, bleeding, or anemia. RESULTS: Of 2627 patients enrolled, 1017 were in the low-risk group and 1610 in the high-risk group. Twenty-three patients (0.9%) had gastroesophageal cancers (20 gastric, 3 esophageal). Four patients with cancer (17.4%) were in the low-risk group (3 gastric, 1 esophageal); all except the patient with esophageal cancer had a positive serology test. In the high-risk group, 19 patients had cancer (17 gastric, 2 esophageal). CONCLUSION: Gastric cancer is relatively frequent among young patients with dyspepsia who have no alarm features in Hong Kong. This finding raises concerns as to the safety of the "test-and-treat" strategy for the management of patients with dyspepsia in Asia.

Adult↗
PubMed2001

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.

Acute Disease↗
PubMed2001

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.

Anti-Bacterial Agents↗
PubMed2001

Strategies for diagnosing and treating suspected acute bacterial sinusitis: a cost-effectiveness analysis.

OBJECTIVE: Symptoms suggestive of acute bacterial sinusitis are common. Available diagnostic and treatment options generate substantial costs with uncertain benefits. We assessed the cost-effectiveness of alternative management strategies to identify the optimal approach. DESIGN: For such patients, we created a Markov model to examine four strategies: 1) no antibiotic treatment; 2) empirical antibiotic treatment; 3) clinical criteria-guided treatment; and 4) radiography-guided treatment. The model simulated a 14-day course of illness, included sinusitis prevalence, antibiotic side effects, sinusitis complications, direct and indirect costs, and symptom severity. Strategies costing less than 50,000 dollars per quality-adjusted life year gained were considered "cost-effective." MEASUREMENTS AND MAIN RESULTS: For mild or moderate disease, basing antibiotic treatment on clinical criteria was cost-effective in clinical settings where sinusitis prevalence is within the range of 15% to 93% or 3% to 63%, respectively. For severe disease, or to prevent sinusitis or antibiotic side effect symptoms, use of clinical criteria was cost-effective in settings with lower prevalence (below 51% or 44%, respectively); empirical antibiotics was cost-effective with higher prevalence. Sinus radiography-guided treatment was never cost-effective for initial treatment. CONCLUSIONS: Use of a simple set of clinical criteria to guide treatment is a cost-effective strategy in most clinical settings. Empirical antibiotics are cost-effective in certain settings; however, their use results in many unnecessary prescriptions. If this resulted in increased antibiotic resistance, costs would substantially rise and efficacy would fall. Newer, expensive antibiotics are of limited value. Additional testing is not cost-effective. Further studies are needed to find an accurate,low-cost diagnostic test for acute bacterial sinusitis.

Acute Disease↗
PubMed2001

Technical report: evidence for the diagnosis and treatment of acute uncomplicated sinusitis in children: a systematic overview.

OBJECTIVE: To evaluate and analyze the existing evidence for the diagnosis and treatment of acute uncomplicated sinusitis in children. DESIGN: A systematic overview and meta-analysis considered all pertinent studies with at least 10 children younger than 18 years with acute symptoms of <30 days and without serious complications. OUTCOMES: Clinical improvement rates for intervention studies of antibiotics or ancillary measures; concordance of diagnostic tests (expressed as likelihood ratios). RESULTS: Of 1857 citations originally reviewed, we identified 21 qualifying studies, compared with 450 reports on complications of acute sinusitis and 233 nonsystematic reviews of the subject. The qualifying studies included 5 randomized, controlled trials and 8 case series on antibiotic therapy, 3 randomized, controlled trials on ancillary treatments, and 8 studies with information on diagnostic tests (including 3 therapeutic trials). Definitions and inclusion criteria were heterogeneous across studies. The pooled clinical improvement rate with antibiotics was 88% (177/202) in randomized, controlled trials and 92% (318/345) in nonrandomized studies; the improvement rates on no antibiotics were 60% and 80%, respectively. Improvement rates were significantly higher in nonrandomized studies (Mantel-Haenszel odds ratio: 1.79; 95% CI: 1.05-3.04, stratified for use of antibiotics). Data on ancillary measures were sparse and heterogeneous. In studies comparing clinical findings with plain film radiography, the pooled rate of abnormal radiographic findings against a clinical diagnosis of sinusitis was 73% (596/814; range: 55% to 96% between studies). There was poor concordance between clinical criteria, plain radiographs, ultrasonography, computed tomography, and fluid on aspiration in all available paired assessments (all positive likelihood ratios were </=4 and all negative likelihood ratios were >/=0.2). CONCLUSIONS: Good, high-quality evidence for acute uncomplicated sinusitis in children is limited. Diagnostic modalities show poor concordance, and treatment options are based on inadequate data. More evidence is needed for defining the optimal treatment and diagnostic methods for this common condition.

Acute Disease↗
PubMed2001

Pharmacological approaches to inhibit endogenous glucose production as a means of anti-diabetic therapy.

The inappropriate overproduction of glucose by the liver is one of the key contributors to the hyperglycaemia of the diabetic state, and thus is a logical site of intervention for novel anti-diabetic approaches. Metformin is the only currently marketed anti-hyperglycaemic drug whose action is attributed largely to its having inhibitory effects on hepatic glucose production, but its molecular site and mechanism(s) of action remain unknown, whereas the liver acting PPAR alpha agonists have their effects primarily on lipid metabolism. This review therefore rather focuses on candidate molecular targets within the liver for anti-hyperglycaemic therapy, and describes potential rate-controlling receptors and enzymes within the glucose producing pathways (glycogenolysis and gluconeogenesis). Most focus is directed towards inhibitors of the enzymes glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase, and towards glucagon receptor antagonists, as these appear to be the most advanced in preclinical and clinical development, although progress with other potential targets is also described. Evidence of the anti-diabetic potential of such agents from animal studies is presented, and the relative merits of each approach are reviewed and compared. It is likely that such agents will become important additions to the therapeutic approaches to combat diabetes.

Animals↗
PubMed2000

Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence.

PURPOSE: To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy. MATERIALS AND METHODS: A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library's Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data. RESULTS: Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well. CONCLUSION: Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.

Antiemetics↗
PubMed2000

Substrate specificity of the loading didomain of the erythromycin polyketide synthase.

The priming of many modular polyketide synthases is catalyzed by a loading acyltransferase-acyl carrier protein (AT(L)-ACP(L)) didomain which initiates polyketide biosynthesis by transferring a primer unit to the ketosynthase domain of the first module. Because the AT(L) domain influences the choice of the starter unit incorporated into the polyketide backbone, its specificity is of considerable interest. The AT(L)-ACP(L) didomain of the 6-deoxyerythronolide B synthase (DEBS) was functionally expressed in Escherichia coli. Coexpression of the Sfp phosphopantetheinyl transferase from Bacillus subtilis in E. coli leads to efficient posttranslational modification of the ACP(L) domain with a phosphopantetheine moiety. Competition experiments were performed with the holo-protein to determine the relative rates of incorporation of a variety of unnatural substrates in the presence of comparable concentrations of labeled acetyl-CoA. Our results showed that the loading didomain of DEBS can accept a surprisingly broad range of substrates, although it exhibits a preference for unbranched alkyl chain substrates over branched alkyl chain, polar, aromatic, and charged substrates. In particular, its tolerance toward acetyl- and butyryl-CoA is unexpectedly strong. The studies described here present an attractive prototype for the expression, analysis, and engineering of acyltransferase domains in modular polyketide synthases.

Bacillus subtilis↗
PubMed2000

Heterogeneity and statistical significance in meta-analysis: an empirical study of 125 meta-analyses.

For meta-analysis, substantial uncertainty remains about the most appropriate statistical methods for combining the results of separate trials. An important issue for meta-analysis is how to incorporate heterogeneity, defined as variation among the results of individual trials beyond that expected from chance, into summary estimates of treatment effect. Another consideration is which 'metric' to use to measure treatment effect; for trials with binary outcomes, there are several possible metrics, including the odds ratio (a relative measure) and risk difference (an absolute measure). To examine empirically how assessment of treatment effect and heterogeneity may differ when different methods are utilized, we studied 125 meta-analyses representative of those performed by clinical investigators. There was no meta-analysis in which the summary risk difference and odds ratio were discrepant to the extent that one indicated significant benefit while the other indicated significant harm. Further, for most meta-analyses, summary odds ratios and risk differences agreed in statistical significance, leading to similar conclusions about whether treatments affected outcome. Heterogeneity was common regardless of whether treatment effects were measured by odds ratios or risk differences. However, risk differences usually displayed more heterogeneity than odds ratios. Random effects estimates, which incorporate heterogeneity, tended to be less precisely estimated than fixed effects estimates. We present two exceptions to these observations, which derive from the weights assigned to individual trial estimates. We discuss the implications of these findings for selection of a metric for meta-analysis and incorporation of heterogeneity into summary estimates. Published in 2000 by John Wiley & Sons, Ltd.

Bias↗