Ly-Mee Yu

Development and validation of MIX: comprehensive free software for meta-analysis of causal research data

BackgroundMeta-analysis has become a well-known method for synthesis of quantitative data from previously conducted research in applied health sciences. So far, meta-analysis has been particularly useful in evaluating and comparing therapies and in assessing causes of disease. Consequently, the number of software packages that can perform meta-analysis has increased over the years. Unfortunately, it can take a substantial amount of time to get acquainted with some of these programs and most contain little or no interactive educational material. We set out to create and validate an easy-to-use and comprehensive meta-analysis package that would be simple enough programming-wise to remain available as a free download. We specifically aimed at students and researchers who are new to meta-analysis, with important parts of the development oriented towards creating internal interactive tutoring tools and designing features that would facilitate usage of the software as a companion to existing books on meta-analysis.ResultsWe took an unconventional approach and created a program that uses Excel as a calculation and programming platform. The main programming language was Visual Basic, as implemented in Visual Basic 6 and Visual Basic for Applications in Excel 2000 and higher. The development took approximately two years and resulted in the MIX program, which can be downloaded from the programs website free of charge. Next, we set out to validate the MIX output with two major software packages as reference standards, namely STATA (metan, metabias, and metatrim) and Comprehensive Meta-Analysis Version 2. Eight meta-analyses that had been published in major journals were used as data sources. All numerical and graphical results from analyses with MIX were identical to their counterparts in STATA and CMA. The MIX program distinguishes itself from most other programs by the extensive graphical output, the click-and-go (Excel) interface, and the educational features.ConclusionThe MIX program is a valid tool for performing meta-analysis and may be particularly useful in educational environments. It can be downloaded free of charge via http://www.mix-for-meta-analysis.info or http://sourceforge.net/projects/meta-analysis.

Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis

Abstract Objectives To evaluate the haematological findings of patients with severe acute respiratory syndrome (SARS). Design Analysis of the demographic, clinical, and laboratory characteristics of patients with SARS. Setting Prince of Wales Hospital, Hong Kong. Subjects All patients with a diagnosis of SARS between 11 March and 29 March 2003 who had no pre-existing haematological disorders. Main outcome measures Clinical end points included the need for intensive care and death. Univariate and multivariate analyses were performed to examine factors associated with adverse outcome. Results 64 male and 93 female patients were included in this study. The most common findings included lymphopenia in 153 (98%) of the 157 patients, neutrophilia in 129 (82%), thrombocytopenia in 87 patients (55%), followed by thrombocytosis in 77 (49%), and isolated prolonged activated partial thromboplastin time in 96 patients (63%). The haemoglobin count dropped by more than 20 g/l from baseline in 95 (61%) patients. Four patients (2.5%) developed disseminated intravascular coagulation. Lymphopenia was shown in haemato-lymphoid organs at postmortem examination. Multivariate analysis showed that advanced age and a high concentration of lactate dehydrogenase at presentation were independent predictors of an adverse outcome. Subsets of peripheral blood lymphocytes were analysed in 31 patients. The counts of CD4 positive and CD8 positive T cells fell early in the course of illness. Low counts of CD4 and CD8 cells at presentation were associated with adverse outcomes. Conclusions Abnormal haematological variables were common among patients with SARS. Lymphopenia and the depletion of T lymphocyte subsets may be associated with disease activity.

Risk factors for childhood overweight in 6- to 7-y-old Hong Kong children.

OBJECTIVE: To identify risk factors for overweight in Hong Kong children aged 6–7u2009y.DESIGN: Case–control study.SETTING: Student Health Service Centres, Hong Kong.SUBJECTS: A total of 343 Hong Kong Chinese children aged 6–7u2009y old categorised into three groups, an overweight group (≥92nd centile for BMI), a normal middle-weight group (45th–55th centile for BMI) and a normal low-weight group (≤8th centile for BMI).MEASUREMENTS: Subjects and their parents/caregivers were interviewed at home. Data on lifestyle habits, dietary habits, family structure and demographic background were collected by questionnaire. A 3-day dietary record was administrated by the parents/caregivers to assess dietary intake of the children.RESULTS: Logistic regression analyses (overweight group compared with middle-weight plus low-weight groups) showed that childhood overweight was significantly associated with parental obesity (BMI ≥25u2009kg/m2, Asian reference) (paternal: OR=2.66, 95% CI=1.51–4.70; maternal: 5.07, 2.62–9.79) but not parental overweight (BMI=23–25u2009kg/m2). After adjustment for parental obesity, the odds ratio for childhood overweight was increased by birth weight (<3.0u2009kg as reference, 3.0–3.5u2009kg: 2.13, 1.18–3.84; ≥3.5u2009kg: 4.89, 2.49–9.60) and decreased by sleeping duration (<9u2009h/day as reference, 9–11u2009h/day: 0.54, 0.30–0.97; ≥11u2009h/day: 0.31, 0.11–0.87). Childhood overweight was also significantly associated with higher energy consumption (2.62, 1.20–5.74) and having a father who was a current smoker (2.08, 1.25–3.46).CONCLUSIONS: Although healthy diet and regular exercise will remain the cornerstones of obesity management in children, our data support the view that education about maintaining a healthy weight could be introduced much earlier in those families with high-risk children, as indicated by high parental BMI or high birth weight. The utility and practicality of such an approach should be carefully evaluated before becoming part of any public health policy. Further study of the role of short sleeping duration and parental smoking on childhood obesity development is warranted.

Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial

BACKGROUNDnPrevalence of Alzheimers disease in people with Downs syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimers disease. Evidence to support treatment with Alzheimers drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Downs syndrome.nnnMETHODSnIn our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Downs syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Downs syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898.nnnFINDINGSnWe randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77).nnnINTERPRETATIONnThere is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Downs syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimers disease are not necessarily effective in this group of patients.nnnFUNDINGnLundbeck.

Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak

Background: The outcome is reported of a prospective uncontrolled study based on a stepwise treatment protocol during an outbreak of severe acute respiratory syndrome (SARS) in Hong Kong. Method: One hundred and thirty eight patients were treated with broad spectrum antibiotics, a combination of ribavirin and low dose corticosteroid, and then intravenous high dose methylprednisolone according to responses. Sustained response to treatment was defined as (1) defervescence for ⩾4 consecutive days, (2) resolution of lung consolidation by >25%, and (3) oxygen independence by the fourth day without fever. Patients with defervescence who achieved either criterion 2 or 3 were classified as partial responders. Patients who fell short of criteria 2 and 3 were non-responders. Results: Laboratory confirmation of SARS coronavirus infection was established in 132 (95.7%). None responded to antibiotics but 25 (18.1%) responded to ribavirin + low dose corticosteroid. Methylprednisolone was used in 107 patients, of whom 95 (88.8%) responded favourably. Evidence of haemolytic anaemia was observed in 49 (36%). A high level of C-reactive protein at presentation was the only independent predictor for use of methylprednisolone (odds ratio 2.18 per 10 mg/dl increase, 95% confidence interval 1.12 to 4.25, pu200a=u200a0.02). Thirty seven patients (26.8%) required admission to the intensive care unit and 21 (15.2%) required invasive mechanical ventilation. There were 15 deaths (mortality rate 10.9%), most with significant co-morbidities, whereas 122 (88.4%) had been discharged home 4 months after the outbreak onset. Conclusion: The use of high dose pulse methylprednisolone during the clinical course of a SARS outbreak was associated with clinical improvement, but randomised controlled trials are needed to ascertain its efficacy in this condition.

A role for solvents in the toxicity of agricultural organophosphorus pesticides

Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12 h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.

A Simplified 4-Site Economical Intradermal Post-Exposure Rabies Vaccine Regimen: A Randomised Controlled Comparison with Standard Methods

Background The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Methods Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. Findings All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. Conclusions This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Trial Registration Controlled-Trials.com ISRCTN 30087513

Oral steroid in the treatment of carpal tunnel syndrome

A range of options are available for the conservative treatment of carpal tunnel syndrome (CTS).1-4 Non-operative methods include immobilisation of the affected hand with wrist splint; local injection of steroids and drugs such as diuretics and non-steroidal anti-inflammatory drugs.6-11 These oral drugs are thought to decrease the volume of swollen tissue within the CTS and are widely used, but there is limited clinical evidence for their role.nnThis prospective randomised, double blind, placebo controlled study aimed at evaluating the effect of oral steroids in the symptomatic treatment of CTS. We recruited patients with newly diagnosed CTS of more than three months duration with confirmatory electrophysiological results (prolonged median nerve distal motor latencies >4 ms or median ulnar palmar sensory latency difference >0.5 ms) including electromyographic recordings of the abductor …

International Child Care Practices study: breastfeeding and pacifier use.

Although the Baby-Friendly Hospital Initiative advises that no pacifiers be given to breastfeeding infants, both breastfeeding and pacifier use may protect against sudden infant death syndrome. The International Child Care Practice Study data set on child care practices associated with sudden infant death syndrome risk from 21 centers in 17 countries was used to describe infant-feeding practices and pacifier use and assess factors associated with breastfeeding. At approximately 3 months of age, rates of breastfeeding only (4%-80%) and pacifier use(12.5%-71%) varied between centers. Pacifier use was negatively associated with breastfeeding, and a dose-response effect was noted. Other negative (multiple birth, smoking by mother) and positive (intention to breastfeed, bed sharing, mothers’ education) associations with breastfeeding only were identified. Although causality should not be inferred, these associations are consistent with previous studies. Advice on pacifiers should include potential benefits as well as risks.

Reporting on covariate adjustment in randomised controlled trials before and after revision of the 2001 CONSORT statement: a literature review

ObjectivesTo evaluate the use and reporting of adjusted analysis in randomised controlled trials (RCTs) and compare the quality of reporting before and after the revision of the CONSORT Statement in 2001.DesignComparison of two cross sectional samples of published articles.Data SourcesJournal articles indexed on PubMed in December 2000 and December 2006.Study SelectionParallel group RCTs with a full publication carried out in humans and published in EnglishMain outcome measuresProportion of articles reported adjusted analysis; use of adjusted analysis; the reason for adjustment; the method of adjustment and the reporting of adjusted analysis results in the main text and abstract.ResultsIn both cohorts, 25% of studies reported adjusted analysis (84/355 in 2000 vs 113/422 in 2006). Compared with articles reporting only unadjusted analyses, articles that reported adjusted analyses were more likely to specify primary outcomes, involve multiple centers, perform stratified randomization, be published in general medical journals, and recruit larger sample sizes. In both years a minority of articles explained why and how covariates were selected for adjustment (20% to 30%). Almost all articles specified the statistical methods used for adjustment (99% in 2000 vs 100% in 2006) but only 5% and 10%, respectively, reported both adjusted and unadjusted results as recommended in the CONSORT guidelines.ConclusionThere was no evidence of change in the reporting of adjusted analysis results five years after the revision of the CONSORT Statement and only a few articles adhered fully to the CONSORT recommendations.