Symptomless colonisation by Clostridium difficile and risk of diarrhoea.
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Carrier State↗
Biomedical subjects
J Lau
Publications and source records attributed to J Lau.
Antilymphocyte antibodies, renal transplantation, and meta-analysis.
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Antilymphocyte Serum↗
Issues in comparisons between meta-analyses and large trials.
CONTEXT: The extent of concordance between meta-analyses and large trials on the same topic has been investigated with different protocols. Inconsistent conclusions created confusion regarding the validity of these major tools of clinical evidence. OBJECTIVE: To evaluate protocols comparing meta-analyses and large trials in order to understand if and why they disagree on the concordance of these 2 clinical research methods. DESIGN: Systematic comparison of protocol designs, study selection, definitions of agreement, analysis methods, and reported discrepancies between large trials and meta-analyses. RESULTS: More discrepancies were claimed when large trials were selected from influential journals (which may prefer trials disagreeing with prior evidence) than from already performed meta-analyses (which may target homogeneous trials) and when both primary and secondary (rather than only primary) end points were considered. Depending on how agreement was defined, kappa coefficients varied from 0.22 (low agreement) to 0.72 (excellent agreement). The correlation of treatment effects between large trials and meta-analyses varied from -0.12 to 0.76, but was more similar (0.50-0.76) when only primary end points were considered. When both the magnitude and uncertainty of treatment effects were considered, large trials disagreed with meta-analyses 10% to 23% of the time. Discrepancies were attributed to different disease risks, variable protocols, quality, and publication bias. CONCLUSIONS: Comparisons of large trials with meta-analyses may reach different conclusions depending on how trials and meta-analyses are selected and how end points and agreement are defined. Scrutiny of these 2 major research methods can enhance our appreciation of both for guiding medical practice.
Bias↗
Functional orientation of the acyltransferase domain in a module of the erythromycin polyketide synthase.
Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), catalyze the biosynthesis of structurally complex and medicinally important natural products. These large multienzymes are organized into a series of functional units known as modules. Each dimeric module contains two catalytically independent clusters of active sites homologous to those of vertebrate fatty acid synthases. Earlier studies have shown that modules consist of head-to-tail homodimers in which ketosynthase (KS) and acyl carrier protein (ACP) domains are contributed by opposite subunits to form a catalytic center. Here, we probe the functional topology of the acyltransferase (AT) domain which transfers the methylmalonyl moiety of methylmalonyl-CoA onto the phosphopantetheine arm of the ACP domain. Using a bimodular derivative of DEBS, the AT domain of module 2 (AT2) was inactivated by site-directed mutagenesis. Heterodimeric protein pairs were generated in vitro between the inactivated AT2 (AT2 degrees) polypeptide and an inactive KS1 (KS1 degrees) or KS2 (KS2 degrees) protein. Both of these hybrid proteins supported polyketide synthesis, suggesting that AT2 can perform its function from either subunit. The apparent catalytic rate constants for each of the two hybrid protein pairs, KS1 degrees/AT2 degrees and KS2 degrees/AT2 degrees, were identical, indicating that no significant kinetic preference exists for a particular AT2-ACP2 combination. These results suggest that the AT domain can be shared between the two clusters of active sites within the same dimeric module. Such a novel structural organization might provide a functional advantage for the efficient biosynthesis of polyketides.
Acyltransferases↗
Summing up evidence: one answer is not always enough.
Are meta-analyses the brave new world, or are the critics of such combined analyses right to say that the biases inherent in clinical trials make them uncombinable? Negative trials are often unreported, and hence can be missed by meta-analysts. And how much heterogeneity between trials is acceptable? A recent major criticism is that large randomised trials do not always agree with a prior meta-analysis. Neither individual trials nor meta-analyses, reporting as they do on population effects, tell how to treat the individual patient. Here we take a more rounded approach to meta-analyses, arguing that their strengths outweigh their weaknesses, although the latter must not be brushed aside.
Evidence-Based Medicine↗
Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity.
OBJECTIVE: To estimate the efficacy and toxicity of typhoid fever vaccines. DESIGN: Meta-analysis of randomised efficacy trials and both randomised and non-randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. SUBJECTS: 1,866,951 subjects in 17 efficacy trials; 11,204 subjects in 20 toxicity studies. MAIN OUTCOME MEASURES: Pooled estimates of three year cumulative efficacy, year specific efficacy, and incidence of adverse events. RESULTS: Three year cumulative efficacy was 73% (95% confidence interval 65% to 80%) for two doses of whole cell vaccines (based on seven trials); 51% (35% to 63%) for three doses of Ty21a vaccine (four trials); and 55% (30% to 71%) for one dose of Vi vaccine (one trial). For whole cell and Ty21a vaccines, regimens of fewer doses were less effective. Efficacy was shown to be significant for five years for whole cell vaccines, four years for Ty21a vaccine, and two years for Vi vaccine. Neither the age of vaccine recipient nor the incidence of typhoid fever in the control group (varying from 6 to 810 cases per 100,000 person years) affected the efficacy of the whole cell or Ty21a vaccines. After vaccination, fever occurred in 15.7% (11.5% to 21.2%) of whole cell vaccine recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine recipients, and 1.1% (0.1% to 12.3%) of Vi vaccine recipients. CONCLUSIONS: Whole cell vaccines are more effective than the Ty21a and Vi vaccines but are more frequently associated with adverse events. Whether the added efficacy of the whole cell vaccines outweighs their toxicity will depend on the setting in which vaccination is used.
Administration, Oral↗
Meta-analyses and large randomized, controlled trials.
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Bias↗
Uncontrolled pearls, controlled evidence, meta-analysis and the individual patient.
Medicine has been dominated by uncontrolled data, often of unproven validity and insufficient to answer clinically important questions pertaining to individual patients. Controlled clinical trials, when designed and conducted rigorously, offer advantages over uncontrolled data, but they cannot be done for everything and often cater to the interests of sponsors rather than medical knowledge. With such sparse evidence, clinical research is doomed to look at main effects across populations rather than diversity of effects among individuals. By accumulating data from a large number of studies, meta-analysis provides a unique opportunity to address individual- and study-level heterogeneity. Diversity may be due to biases or may be real. Both sources must be scrutinized and meta-analysis may find a prime role in dissecting these components of diversity. Concurrent progress in basic sciences revolutionizing our predictive power for disease outcomes will heighten the importance of considering individual heterogeneity.
Bias↗
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.
Acyclovir↗
Impact of chronic diseases on functional limitations in elderly Chinese aged 70 years and over: a cross-sectional and longitudinal survey.
OBJECTIVE: To examine the association of some common medical conditions with functional limitation in elderly Chinese aged 70 years and over, to estimate the percentage of disability attributable to individual diseases, and to attempt to identify predisposing factors by documenting the development of functional limitation over an 18-month period in those subjects with a particular disease who were independent initially. SUBJECTS AND METHODS: The cross-sectional data set consisted of 2,032 (999 M, 1,033 F) subjects aged 70 years and over recruited by random sampling (stratified by age and sex) of all recipients of old-age and disability allowance, which covers over 90% of the elderly population. Information regarding medical condition and functional assessment of ten basic activities of daily living using the Barthel Index were obtained by personal interviews and physical assessment of the respondents at their places of residence. The longitudinal data set consisted of 1,334 subjects with no functional limitation at baseline who were alive after 18 months. Functional status was reassessed. RESULTS: After adjusting for age and sex, diseases associated with severe functional limitation (Barthel Index < 15) were dementia, stroke, Parkinson's disease, and fractures. Those associated with mild to moderate functional limitation (Barthel Index 15-19) were the same, with the addition of asthma and diabetes mellitus. The attributable fraction for severe limitation was highest for stroke, dementia, and fractures. Stroke and arthritis were identified as diseases predisposing to mild to moderate functional limitation over an 18-month period among those subjects who were independent initially. CONCLUSION: Stroke, dementia, and fractures were the main chronic diseases associated with severe functional limitation in elderly Hong Kong Chinese. Attempts to reduce the disability burden in this population should target these diseases.
Age Distribution↗
The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials.
UNLABELLED: We performed meta-analyses of randomized, control trials to assess the effects of seven analgesic therapies on postoperative pulmonary function after a variety of procedures: epidural opioid, epidural local anesthetic, epidural opioid with local anesthetic, thoracic versus lumbar epidural opioid, intercostal nerve block, wound infiltration with local anesthetic, and intrapleural local anesthetic. Measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), vital capacity (VC), peak expiratory flow rate (PEFR), PaO2, and incidence of atelectasis, pulmonary infection, and pulmonary complications overall were analyzed. Compared with systemic opioids, epidural opioids decreased the incidence of atelectasis (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.33-0.85) and had a weak tendency to reduce the incidence of pulmonary infections (RR 0.53, 95% CI 0.18-1.53) and pulmonary complications overall (RR 0.51, 95% CI 0.20-1.33). Epidural local anesthetics increased PaO2 (difference 4.56 mm Hg, 95% CI 0.058-9.075) and decreased the incidence of pulmonary infections (RR 0.36, 95% CI 0.21-0.65) and pulmonary complications overall (RR 0.58, 95% CI 0.42-0.80) compared with systemic opioids. Intercostal nerve blockade tends to improve pulmonary outcome measures (incidence of atelectasis: RR 0.65, 95% CI 0.27-1.57, incidence of pulmonary complications overall: RR 0.47, 95% CI 0.18-1.22), but these differences did not achieve statistical significance. There were no clinically or statistically significant differences in the surrogate measures of pulmonary function (FEV1, FVC, and PEFR). These analyses support the utility of epidural analgesia for reducing postoperative pulmonary morbidity but do not support the use of surrogate measures of pulmonary outcome as predictors or determinants of pulmonary morbidity in postoperative patients. IMPLICATIONS: When individual trials are unable to produce significant results, it is often because of insufficient patient numbers. It may be impossible for a single institution to study enough patients. Meta-analysis is a useful tool for combining the data from multiple trials to increase the patient numbers. These meta-analyses confirm that postoperative epidural pain control can significantly decrease the incidence of pulmonary morbidity.
Administration, Oral↗
A survey of multicultural awareness among hospital and clinical staff.
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Cultural Diversity↗
Cardiovascular risk factors and 18-month mortality and morbidity in an elderly Chinese population aged 70 years and over.
OBJECTIVE: To determine the influence of some cardiovascular risk factors (hypertension, diabetes mellitus, smoking habit, physical activity, obesity, adverse lipid profile) in elderly Chinese aged 70 years and over, on overall mortality and morbidity from stroke and ischaemic heart disease. DESIGN: Longitudinal study relating 18-month outcome to baseline values. SUBJECTS: 2,032 subjects (999 men, 1,033 women), mean age 80 years, recruited by random sampling of the Old Age and Disability Allowance Schemes, which covers 90% of the Hong Kong elderly subjects, stratified by sex and 5-year age groups from 70 years onwards. METHODS: At baseline, subjects were visited by interviewers to collect information regarding medical conditions, smoking habit, physical activity, and to measure their height, weight, skinfold thickness, and waist/hip ratio. A follow-up survey was carried out 18 months later to establish the development of any new stroke or ischaemic heart disease, and to note any deaths and the cause of such deaths from death certification. RESULTS: In multivariate analysis overall mortality was negatively associated with body mass index and participation in physical activity, after adjusting for age and sex. Death from stroke was associated with a higher systolic blood pressure at baseline. Among survivors, the only significant associations observed were a negative association between body mass index and the development of heart disease, and a positive association between systolic blood pressure and development of stroke. CONCLUSIONS: Few associations between cardiovascular risk factors and morbidity and mortality were demonstrated in elderly Chinese with a mean age of 80 years. The only modifiable risk factor appears to be systolic blood pressure.
Aged↗
Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis.
PURPOSE: To perform a meta-analysis to estimate the efficacy of quinolone antibiotics in preventing infections, fevers, and deaths among cancer patients neutropenic following chemotherapy. METHODS: We searched MEDLINE to identify randomized trials of quinolone prophylaxis, controlled either with no prophylaxis or trimethoprim/sulfamethoxazole (TMS) prophylaxis. We pooled relative risks for outcomes using a random-effects model. RESULTS: Eighteen trials with 1,408 subjects were included. Compared with no prophylaxis, quinolones significantly reduced the incidence of gram-negative bacterial infections (relative risk, 0.21; 95% confidence interval [CI], 0.12 to 0.37), microbiologically documented infections (0.65; 0.50 to 0.85), total infections (0.54; 0.31 to 0.95), and fevers (0.85; 0.73 to 0.99). Quinolone prophylaxis did not alter the incidence of gram-positive bacterial, fungal, or clinically documented infections, or infection-related deaths. Results were similar for trials that used TMS as the control regimen. Among those who received quinolones, the incidence of infections due to quinolone-resistant organisms was 3.0% (95% CI, 1.7% to 5.2%) for gram-negative species and 9.4% (95% CI, 5.3% to 16.3%) for gram-positive species. Based on limited data, the incidence of quinolone-resistant infections was not higher among quinolone recipients than controls. With fever as outcome, blinded trials found quinolones less efficacious than did unblinded trials. CONCLUSION: Quinolone prophylaxis substantially reduces the incidence of various infection-related outcomes, but not deaths, in these patients. Although this reduction in infections may translate into a decrease in morbidity, the reduction in fevers (and by extension, use of empiric antibiotics) appears small, and blinded trials provided less evidence for benefit than unblinded trials. Quinolone-resistant infections are uncommon, but continued vigilance is warranted.
Anti-Infective Agents↗
Prevalence of dementia in Chinese elderly in Hong Kong.
This study examines the prevalence of dementia in elderly Chinese aged 70 years and older in Hong Kong using a two-phase design. In phase 1, 1,034 elderly were interviewed with the Cantonese version of the Mini-Mental State Examination. Those who scored below the cutoff points and a subsample of those with scores in the normal range were interviewed in phase 2 to identify those with dementia. The overall weighted prevalence of dementia in our subjects was 6.1 +/- 0.7%, which is at the lower end of the range of rates reported in whites. Alzheimer's disease (AD) accounted for 64.6% and vascular dementia, 29.3%. Our results, together with previous studies in Chinese populations, suggest that the rates of AD in Chinese are low compared with those in whites. Substantial differences are possible in the epidemiology of dementia across cultures related to interactions of genetic and environmental factors.
Age Distribution↗
Karaoke therapy in the rehabilitation of mental patients.
OBJECTIVES: To study the efficacy of karaoke singing and its implications in the rehabilitation of mental patients in Hong Kong Chinese. METHODS: A double blind controlled trial was conducted over six weeks in a small sample of chronic schizophrenic patients matched in age, sex and duration of illness. The index group practised karaoke and the controlled group practised simple singing. Subjects were assessed in changes in mood and social interaction. RESULTS: No significant difference was detectable within the 2 groups. However, significant differences of anxiety and social interaction at the end of the third and sixth weeks respectively, were detectable between the 2 groups. CONCLUSION: Karaoke therapy may be more effective than simple singing in improving social interaction. There is preliminary evidence that it may be anxiety-provoking for unstable schizophrenic patients. More research is required for further elucidation of the characteristics of favourable candidates, optimal schedule and active components of the therapy.
Adolescent↗
The role of functional endoscopic sinus surgery in asthmatic patients.
OBJECTIVE: This study was conducted to determine the efficacy of FESS (functional endoscopic sinus surgery) on sinus and asthma symptoms. METHOD: Seventy-nine patients with asthma and medically unresponsive sinusitis were evaluated. Maximal medical therapy was attempted to relieve both sinus and asthma symptoms. The surgical procedures involved standard FESS techniques. Fifty-six percent of patients had undergone a sinus procedure prior to the FESS. Nasal polyposis was noted in 73% of the group. The majority of patients had pansinusitis. RESULTS: Eighty-six percent of patients stated that FESS improved their sinusitis. Nine of 11 sinus symptoms recorded preoperatively diminished significantly (p < .05) following surgery. Eighty percent of patients noted improvement of their asthma following FESS. The factors associated with treatment failure and the unique characteristics of this disease process were evaluated. CONCLUSIONS: FESS is a viable option in the treatment of asthma when medical therapy fails.
Adolescent↗
Quantitative synthesis in systematic reviews.
The final common pathway for most systematic reviews is a statistical summary of the data, or meta-analysis. The complex methods used in meta-analyses should always be complemented by clinical acumen and common sense in designing the protocol of a systematic review, deciding which data can be combined, and determining whether data should be combined. Both continuous and binary data can be pooled. Most meta-analyses summarize data from randomized trials, but other applications, such as the evaluation of diagnostic test performance and observational studies, have also been developed. The statistical methods of meta-analysis aim at evaluating the diversity (heterogeneity) among the results of different studies, exploring and explaining observed heterogeneity, and estimating a common pooled effect with increased precision. Fixed-effects models assume that an intervention has a single true effect, whereas random-effects models assume that an effect may vary across studies. Meta-regression analyses, by using each study rather than each patient as a unit of observation, can help to evaluate the effect of individual variables on the magnitude of an observed effect and thus may sometimes explain why study results differ. It is also important to assess the robustness of conclusions through sensitivity analyses and a formal evaluation of potential sources of bias, including publication bias and the effect of the quality of the studies on the observed effect.
Bias↗