Predicting the chance of live birth for women undergoing IVF: a novel pretreatment counselling tool.

STUDY QUESTION: Which pretreatment patient variables have an effect on live birth rates following assisted conception? SUMMARY ANSWER: The predictors in the final multivariate logistic regression model found to be significantly associated with reduced chances of IVF/ICSI success were increasing age (particularly above 36 years), tubal factor infertility, unexplained infertility and Asian or Black ethnicity. WHAT IS KNOWN ALREADY: The two most widely recognized prediction models for live birth following IVF were developed on data from 1991 to 2007; pre-dating significant changes in clinical practice. These existing IVF outcome prediction models do not incorporate key pretreatment predictors, such as BMI, ethnicity and ovarian reserve, which are readily available now. STUDY DESIGN, SIZE, DURATION: In this cohort study a model to predict live birth was derived using data collected from 9915 women who underwent IVF/ICSI treatment at any CARE (Centres for Assisted Reproduction) clinic from 2008 to 2012. Model validation was performed on data collected from 2723 women who underwent treatment in 2013. The primary outcome for the model was live birth, which was defined as any birth event in which at least one baby was born alive and survived for more than 1 month. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 12 fertility clinics within the CARE consortium in the UK. Multivariable logistic regression was used to develop the model. Discriminatory ability was assessed using the area under receiver operating characteristic (AUROC) curve, and calibration was assessed using calibration-in-the-large and the calibration slope test. MAIN RESULTS AND THE ROLE OF CHANCE: The predictors in the final model were female age, BMI, ethnicity, antral follicle count (AFC), previous live birth, previous miscarriage, cause and duration of infertility. Upon assessing predictive ability, the AUROC curve for the final model and validation cohort was (0.62; 95% confidence interval (CI) 0.61-0.63) and (0.62; 95% CI 0.60-0.64) respectively. Calibration-in-the-large showed a systematic over-estimation of the predicted probability of live birth (Intercept (95% CI) = -0.168 (-0.252 to -0.084), P < 0.001). However, the calibration slope test was not significant (slope (95% CI) = 1.129 (0.893-1.365), P = 0.28). Due to the calibration-in-the-large test being significant we recalibrated the final model. The recalibrated model showed a much-improved calibration. LIMITATIONS, REASONS FOR CAUTION: Our model is unable to account for factors such as smoking and alcohol that can affect IVF/ICSI outcome and is somewhat restricted to representing the ethnic distribution and outcomes for the UK population only. We were unable to account for socioeconomic status and it may be that by having 75% of the population paying privately for their treatment, the results cannot be generalized to people of all socioeconomic backgrounds. In addition, patients and clinicians should understand this model is designed for use before treatment begins and does not include variables that become available (oocyte, embryo and endometrial) as treatment progresses. Finally, this model is also limited to use prior to first cycle only. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to present a novel, up-to-date model encompassing three readily available prognostic factors; female BMI, ovarian reserve and ethnicity, which have not previously been used in prediction models for IVF outcome. Following geographical validation, the model can be used to build a user-friendly interface to aid decision-making for couples and their clinicians. Thereafter, a feasibility study of its implementation could focus on patient acceptability and quality of decision-making. STUDY FUNDING/COMPETING INTEREST: None.

S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study.

OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Meta-analysis of test accuracy studies using imputation for partial reporting of multiple thresholds.

INTRODUCTION: For tests reporting continuous results, primary studies usually provide test performance at multiple but often different thresholds. This creates missing data when performing a meta-analysis at each threshold. A standard meta-analysis (no imputation [NI]) ignores such missing data. A single imputation (SI) approach was recently proposed to recover missing threshold results. Here, we propose a new method that performs multiple imputation of the missing threshold results using discrete combinations (MIDC). METHODS: The new MIDC method imputes missing threshold results by randomly selecting from the set of all possible discrete combinations which lie between the results for 2 known bounding thresholds. Imputed and observed results are then synthesised at each threshold. This is repeated multiple times, and the multiple pooled results at each threshold are combined using Rubin's rules to give final estimates. We compared the NI, SI, and MIDC approaches via simulation. RESULTS: Both imputation methods outperform the NI method in simulations. There was generally little difference in the SI and MIDC methods, but the latter was noticeably better in terms of estimating the between-study variances and generally gave better coverage, due to slightly larger standard errors of pooled estimates. Given selective reporting of thresholds, the imputation methods also reduced bias in the summary receiver operating characteristic curve. Simulations demonstrate the imputation methods rely on an equal threshold spacing assumption. A real example is presented. CONCLUSIONS: The SI and, in particular, MIDC methods can be used to examine the impact of missing threshold results in meta-analysis of test accuracy studies.

Erratum to: Methods for evaluating medical tests and biomarkers.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Indirect comparisons of competing interventions.

OBJECTIVES: To survey the frequency of use of indirect comparisons in systematic reviews and evaluate the methods used in their analysis and interpretation. Also to identify alternative statistical approaches for the analysis of indirect comparisons, to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within reviews. DATA SOURCES: Electronic databases. REVIEW METHODS: The Database of Abstracts of Reviews of Effects (DARE) was searched for systematic reviews involving meta-analysis of randomised controlled trials (RCTs) that reported both direct and indirect comparisons, or indirect comparisons alone. A systematic review of MEDLINE and other databases was carried out to identify published methods for analysing indirect comparisons. Study designs were created using data from the International Stroke Trial. Random samples of patients receiving aspirin, heparin or placebo in 16 centres were used to create meta-analyses, with half of the trials comparing aspirin and placebo and half heparin and placebo. Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin. The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results. Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken. RESULTS: Of the reviews identified through DARE, 31/327 (9.5%) included indirect comparisons. A further five reviews including indirect comparisons were identified through electronic searching. Few reviews carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest. Few methodological papers were identified. Some valid approaches for aggregate data that could be applied using standard software were found: the adjusted indirect comparison, meta-regression and, for binary data only, multiple logistic regression (fixed effect models only). Simulation studies showed that the naive method is liable to bias and also produces over-precise answers. Several methods provide correct answers if strong but unverifiable assumptions are fulfilled. Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly randomised comparisons. Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies, but the direction of such discrepancy is unpredictable. CONCLUSIONS: Direct evidence from good-quality RCTs should be used wherever possible. Without this evidence, it may be necessary to look for indirect comparisons from RCTs. However, the results may be susceptible to bias. When making indirect comparisons within a systematic review, an adjusted indirect comparison method should ideally be used employing the random effects model. If both direct and indirect comparisons are possible within a review, it is recommended that these be done separately before considering whether to pool data. There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect. Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons. Research into how evidence from indirect comparisons compares to that from non-randomised studies may also be warranted. Investigations using individual patient data from a meta-analysis of several RCTs using different protocols and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful.

Risks of delivery during the 20th to the 36th week of gestation.

Using routinely collected maternity discharge data from 250,000 women in Scotland, we examined the risks of late spontaneous abortion and preterm delivery during the period 20 up to 36 weeks of gestation. Gestational age is treated as a fetal survival time and the risks of delivery associated with a history of spontaneous abortion, induced abortion and perinatal death are examined in a survival model controlling for several demographic and socioeconomic variables. The main objective of the study is to identify factors which are associated with high relative hazard of delivery early in the period, but with decreasing relative hazard of delivery as pregnancy progresses. The factor most clearly associated with converging hazards is a history of two or more spontaneous abortions, and this may reflect the tendency to repeat pregnancy outcome.

Home parenteral nutrition: a systematic review.

OBJECTIVES: The objective of this Review was to locate, appraise and summarise evidence from scientific studies on home parenteral nutrition (HPN) in order to answer specific research questions on the effectiveness of this technology. The following questions were asked. What patients have received HPN? What has been the experience of patients on HPN programmes? How have HPN programmes been organised, and what techniques and equipment have been used, and to what effect? What comparative information is available on effectiveness? What evidence exists for the cost-effectiveness of HPN? What questions about the provision of HPN could be answered with additional research, and what studies would be most suitable? DATA SOURCES: A comprehensive list of studies was provided by an extensive search of electronic databases (including MEDLINE, Embase, Science Citation Index, Uncover, Cinahl, Caredata, Food Science and Technology Abstracts, NTIS, Pascal, Psychlit, and Economic Literature Index), relevant journals (including Journal of Parenteral and Enteral Nutrition, Clinical Nutrition, American Journal of Clinical Nutrition, Nutrition, Clinical Gastroenterology, Nutrition Reviews, Annals of Nutrition and Metabolism, Nutrition and Cancer, Nutrition and Health, and Journal of Paediatric Nutrition and Metabolism), and scanning of reference lists, as well as other search strategies outlined in the protocol. STUDY SELECTION: Studies relevant to the questions were selected. The inclusion criteria were fairly broad because of the quality of the studies located. DATA EXTRACTION: Data extraction forms were used to collect data from studies included in the review. The data was checked by a second researcher to reduce error. DATA SYNTHESIS: Quantitative analysis was difficult owing to the type of studies located. The data is discussed in a qualitative manner. Where complication rates have been given, we have attempted to combine the results in a quantitative manner. RESULTS: The age and sex of patients on HPN varies according to the underlying disease but, on the whole, patients are young (see Tables 4a and 4b). There are trends showing an increased use of the technology at the extremes of the age range. There are marked differences between countries on the underlying diseases for which HPN is indicated. For example, many more patients with an underlying malignancy are treated in Italy and the USA than in the UK (40-67% versus 8%). Morbidity rates for the majority of patients are acceptable (see Table 8), the complications tend to be related to the central venous catheter. It is fairly clear that a minority of patients are susceptible to recurrent problems and that many patients have very few complications. The mortality rate for HPN patients (see Table 10) was good for those patients with benign underlying disease (for example, 5% of Crohn's HPN patients die per year), and there are very few reports of patients dying from complications of the technology. The survival of those with malignant disease and AIDS is poor, almost all having died from the underlying disease at one year; despite this, most programme growth worldwide is due to an increase in the numbers of patients with these diagnoses (see Table 5). Quality of life is reasonable for patients with benign disease (see Table 9); no studies were found that examined the quality of life of HPN patients with malignant disease. Economic analysis shows that the cost of HPN treatment is cheaper than the alternative of in-patient care (see Table 18). There is a paucity of comparative studies examining different aspects of the technology, and this accounted for the majority of gaps in the evidence. CONCLUSIONS: The use of HPN for benign intestinal failure is supported by evidence from the scientific studies located. There are, however, large gaps in the evidence, particularly relating to the use of HPN in malignant disease and AIDS. A programme of research is suggested at the end of this review.

Evaluating non-randomised intervention studies.

OBJECTIVES: To consider methods and related evidence for evaluating bias in non-randomised intervention studies. DATA SOURCES: Systematic reviews and methodological papers were identified from a search of electronic databases; handsearches of key medical journals and contact with experts working in the field. New empirical studies were conducted using data from two large randomised clinical trials. METHODS: Three systematic reviews and new empirical investigations were conducted. The reviews considered, in regard to non-randomised studies, (1) the existing evidence of bias, (2) the content of quality assessment tools, (3) the ways that study quality has been assessed and addressed. (4) The empirical investigations were conducted generating non-randomised studies from two large, multicentre randomised controlled trials (RCTs) and selectively resampling trial participants according to allocated treatment, centre and period. RESULTS: In the systematic reviews, eight studies compared results of randomised and non-randomised studies across multiple interventions using meta-epidemiological techniques. A total of 194 tools were identified that could be or had been used to assess non-randomised studies. Sixty tools covered at least five of six pre-specified internal validity domains. Fourteen tools covered three of four core items of particular importance for non-randomised studies. Six tools were thought suitable for use in systematic reviews. Of 511 systematic reviews that included non-randomised studies, only 169 (33%) assessed study quality. Sixty-nine reviews investigated the impact of quality on study results in a quantitative manner. The new empirical studies estimated the bias associated with non-random allocation and found that the bias could lead to consistent over- or underestimations of treatment effects, also the bias increased variation in results for both historical and concurrent controls, owing to haphazard differences in case-mix between groups. The biases were large enough to lead studies falsely to conclude significant findings of benefit or harm. Four strategies for case-mix adjustment were evaluated: none adequately adjusted for bias in historically and concurrently controlled studies. Logistic regression on average increased bias. Propensity score methods performed better, but were not satisfactory in most situations. Detailed investigation revealed that adequate adjustment can only be achieved in the unrealistic situation when selection depends on a single factor. CONCLUSIONS: Results of non-randomised studies sometimes, but not always, differ from results of randomised studies of the same intervention. Non-randomised studies may still give seriously misleading results when treated and control groups appear similar in key prognostic factors. Standard methods of case-mix adjustment do not guarantee removal of bias. Residual confounding may be high even when good prognostic data are available, and in some situations adjusted results may appear more biased than unadjusted results. Although many quality assessment tools exist and have been used for appraising non-randomised studies, most omit key quality domains. Healthcare policies based upon non-randomised studies or systematic reviews of non-randomised studies may need re-evaluation if the uncertainty in the true evidence base was not fully appreciated when policies were made. The inability of case-mix adjustment methods to compensate for selection bias and our inability to identify non-randomised studies that are free of selection bias indicate that non-randomised studies should only be undertaken when RCTs are infeasible or unethical. Recommendations for further research include: applying the resampling methodology in other clinical areas to ascertain whether the biases described are typical; developing or refining existing quality assessment tools for non-randomised studies; investigating how quality assessments of non-randomised studies can be incorporated into reviews and the implications of individual quality features for interpretation of a review's results; examination of the reasons for the apparent failure of case-mix adjustment methods; and further evaluation of the role of the propensity score.

Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

OBJECTIVES: To ascertain the value of a range of methods - including clinical features, resting and exercise electrocardiography, and rapid access chest pain clinics (RACPCs) - used in the diagnosis and early management of acute coronary syndrome (ACS), suspected acute myocardial infarction (MI), and exertional angina. DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Library and electronic abstracts of recent cardiological conferences. REVIEW METHODS: Searches identified studies that considered patients with acute chest pain with data on the diagnostic value of clinical features or an electrocardiogram (ECG); patients with chronic chest pain with data on the diagnostic value of resting or exercise ECG or the effect of a RACPC. Likelihood ratios (LRs) were calculated for each study, and pooled LRs were generated with 95% confidence intervals. A Monte Carlo simulation was performed evaluating different assessment strategies for suspected ACS, and a discrete event simulation evaluated models for the assessment of suspected exertional angina. RESULTS: For acute chest pain, no clinical features in isolation were useful in ruling in or excluding an ACS, although the most helpful clinical features were pleuritic pain (LR+ 0.19) and pain on palpation (LR+ 0.23). ST elevation was the most effective ECG feature for determining MI (with LR+ 13.1) and a completely normal ECG was reasonably useful at ruling this out (LR+ 0.14). Results from 'black box' studies of clinical interpretation of ECGs found very high specificity, but low sensitivity. In the simulation exercise of management strategies for suspected ACS, the point of care testing with troponins was cost-effective. Pre-hospital thrombolysis on the basis of ambulance telemetry was more effective but more costly than if performed in hospital. In cases of chronic chest pain, resting ECG features were not found to be very useful (presence of Q-waves had LR+ 2.56). For an exercise ECG, ST depression performed only moderately well (LR+ 2.79 for a 1 mm cutoff), although this did improve for a 2 mm cutoff (LR+ 3.85). Other methods of interpreting the exercise ECG did not result in dramatic improvements in these results. Weak evidence was found to suggest that RACPCs may be associated with reduced admission to hospital of patients with non-cardiac pain, better recognition of ACS, earlier specialist assessment of exertional angina and earlier diagnosis of non-cardiac chest pain. In a simulation exercise of models of care for investigation of suspected exertional angina, RACPCs were predicted to result in earlier diagnosis of both confirmed coronary heart disease (CHD) and non-cardiac chest pain than models of care based around open access exercise tests or routine cardiology outpatients, but they were more expensive. The benefits of RACPCs disappeared if waiting times for further investigation (e.g. angiography) were long (6 months). CONCLUSIONS: Where an ACS is suspected, emergency referral is justified. ECG interpretation in acute chest pain can be highly specific for diagnosing MI. Point of care testing with troponins is cost-effective in the triaging of patients with suspected ACS. Resting ECG and exercise ECG are of only limited value in the diagnosis of CHD. The potential advantages of RACPCs are lost if there are long waiting times for further investigation. Recommendations for further research include the following: determining the most appropriate model of care to ensure accurate triaging of patients with suspected ACS; establishing the cost-effectiveness of pre-hospital thrombolysis in rural areas; determining the relative cost-effectiveness of rapid access chest pain clinics compared with other innovative models of care; investigating how rapid access chest pain clinics should be managed; and establishing the long-term outcome of patients discharged from RACPCs.

Suicide in doctors: a study of risk according to gender, seniority and specialty in medical practitioners in England and Wales, 1979-1995.

STUDY OBJECTIVE: To investigate the suicide risk of doctors in England and Wales, according to gender, seniority and specialty. DESIGN: Retrospective cohort study. Suicide rates calculated by gender, age, specialty, seniority and time period. Standardised mortality ratios calculated for suicide (1991-1995), adjusted for age and sex. SETTING: England and Wales. SUBJECTS: Doctors in the National Health Service who died by suicide between 1979 and 1995, identified by death certificates. Population at risk based on Department of Health manpower data. MAIN RESULTS: Two hundred and twenty three medical practitioners in the National Health Service who died by suicide or undetermined cause were identified. The annual suicide rates in male and female doctors were 19.2 and 18.8 per 100 000 respectively. The suicide rate in female doctors was higher than in the general population (SMR 201.8; 95% CI 99.7, 303.9), whereas the rate in male doctors was less than that of the general population (SMR 66.8; 95% CI 46.6, 87.0). The difference between the mortality ratios of the female and male doctors was statistically significant (p=0.01), although the absolute suicide risk was similar in the two genders. There were significant differences between specialties (p=0.0001), with anaesthetists, community health doctors, general practitioners and psychiatrists having significantly increased rates compared with doctors in general hospital medicine. There were no differences with regard to seniority and time period. CONCLUSIONS: There is an increased risk of suicide in female doctors, but male doctors seem to be at less risk than men in the general population. The excess risk of suicide in female doctors highlights the need to tackle stress and mental health problems in doctors more effectively. The risk requires particular monitoring in the light of the very large increase in the numbers of women entering medicine.

Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. The gamma-aminobutyric acid (GABA) agonist drugs have been trialed as a treatment for TD, but these drugs have intense sedative properties and can possibly exacerbate psychotic symptoms. OBJECTIVES: To determine the effects of GABA agonist drugs (baclofen, gamma-vinyl-GABA, gamma-acetylenic-GABA, progabide, muscimol, sodium valproate and tetrahydroisoxazolopyridine (THIP)) in people with neuroleptic-induced tardive dyskinesia (TD) and schizophrenia or other chronic mental illnesses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1998), The Cochrane Library CENTRAL (1998), Cochrane Schizophrenia Group's Register of Trials (1998), EMBASE (1980-1998), LILACS (1982-1996), MEDLINE (1966-1998), PsycLIT (1974-1998), and SCISEARCH were undertaken. References of all identified studies were searched for further trial citations. First authors of each included trial were contacted. SELECTION CRITERIA: The inclusion criteria for all relevant randomised studies were that they should focus on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced TD and compare the use of GABA agonist drugs to placebo or no intervention. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and the odds ratio (OR) and its 95% confidence interval (CI) or the weighted mean difference with 95% CI were estimated. The reviewers assumed that people who dropped out had no improvement. MAIN RESULTS: Eight studies were able to be included. Results were equivocal, showing only a tendency for clinical improvement for those using GABA agonist drugs but, when analysis of any improvement (rather than clinical improvement) was performed, a significant reduction was noted in the GABA group (OR 0.36 CI 0.15-0.85). This suggests that for every 10 people treated with GABA drugs one person would benefit with a reduction in TD symptoms. People using the interventions had more confusion (OR 7.4 CI 1.3-40.9) and sedation (OR 3.0 CI 1.2-7.6). The numbers of people needed to treat to cause one extra person to experience these side effects were three and six, respectively. Tendency for more deterioration of the TD symptoms (OR 1.72 CI 0. 54-5.5), deterioration of the mental state (OR 3.07 CI 0.78-12.05), and to drop out before the end of the trial (OR 2.05 CI 0.8-5.21) were also observed in those using GABA agonists. REVIEWER'S CONCLUSIONS: No clear statement about the efficacy of GABA agonist drugs could be provided. From the combined data, GABA agonist drugs tend to be associated with some degree of improvement in TD symptoms, but also with side effects such as confusion and sedation and a deterioration of the person's mental state.

Amantadine and rimantadine for preventing and treating influenza A in adults.

OBJECTIVES: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their properties and concerns about possible adverse effects. The objective of this review was to assess the effects and safety of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, Medline, Embase and reference lists of articles. We also contacted manufacturers, researchers and authors. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prevention trials the numbers of participants with clinically defined influenza, with serologically confirmed clinical influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever and adverse effects. MAIN RESULTS: Amantadine prevented 23% of clinical influenza cases (95% confidence interval 11% to 34%), and 63% of serologically confirmed clinical influenza A cases (95% confidence interval 42% to 76%) Amantadine reduced duration of fever by one day (95% confidence interval 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system adverse and study withdrawals were significantly more common with amantadine than rimantadine. REVIEWER'S CONCLUSIONS: Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine.

Vaccines for preventing influenza in healthy adults.

OBJECTIVES: To identify, retrieve and assess all studies evaluating the effects of vaccines on influenza in healthy adults. To assess the effectiveness of vaccines in preventing cases of influenza in healthy adults. To estimate the frequency of adverse effects associated with influenza vaccination in healthy adults. SEARCH STRATEGY: MEDLINE was searched using the strategy of the Cochrane Acute Respiratory Infections Group. The bibliography of retrieved articles, the Cochrane Controlled Trials Register (CCTR), and EMBASE (1990 to 1997) were also searched. Handsearch of the journal Vaccine from its first issue to the end of 1997 (Jefferson and Jefferson, 1996; Jefferson, 1998). We wrote to vaccine manufacturers and first or corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised or quasi-randomised studies comparing influenza vaccines in humans with placebo, control vaccines or no intervention, or comparing types, doses or schedules of influenza vaccine. Live, attenuated or killed vaccines or fractions thereof administered by any route, irrespective of antigenic configuration were considered. Only studies assessing protection from exposure to naturally occurring influenza in healthy individuals aged 14 to 60 (irrespective of influenza immune status) were considered. DATA COLLECTION AND ANALYSIS: Both clinically defined cases and serologically confirmed cases of influenza were considered as outcomes according to the authors' definitions. Time off work, complication and hospitalisation rates were considered, together with adverse effects. Vaccine schedules were analysed including one component matching the recommended vaccine (WHO or government recommendations) for the year of the study, and whether they matched the circulating viral subtypes. MAIN RESULTS: The recommended live aerosol vaccines reduced the number of cases of serologically confirmed influenza A by 48% (95% confidence interval 24% to 64%), whilst recommended inactivated parenteral vaccines had a vaccine efficacy of 68% (95% confidence interval 49% to 79%). The vaccines were less effective in reducing clinical influenza cases, with efficacies of 13% and 24% respectively. Use of the vaccine significantly reduced time off work, but only by 0.4 days for each influenza episode (95% confidence interval 0.1 to 0.8 days). Analysis of vaccines matching the circulating strain gave higher estimates of efficacy, whilst inclusion of all other vaccines reduced the efficacy. REVIEWER'S CONCLUSIONS: Influenza vaccines are effective in reducing serologically confirmed cases of influenza A. However, they are not as effective in reducing cases of clinical influenza. The use of WHO recommended vaccines appears to enhance their effectiveness in practice.

Amantadine and rimantadine for preventing and treating influenza A in adults.

BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but these drugs are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. OBJECTIVES: The objective of this review was to assess the effectiveness and safety ("effects") of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2003), MEDLINE (January 1966 to November week 2, 2003), EMBASE (January 1990 to September 2003) and the reference lists of articles. We also contacted manufacturers, researchers and authors. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prevention trials the numbers of participants with clinical influenza (influenza-like-illness or ILI), i.e. confirmed influenza A, and adverse effects were analysed. Analysis for treatment trials included the mean duration of fever and length of hospital stay, and the number of adverse effects. MAIN RESULTS: Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. REVIEWERS' CONCLUSIONS: Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine causes fewer adverse effects than amantadine.

Vaccines for preventing influenza in healthy adults.

BACKGROUND: Three different types of influenza vaccines are currently produced worldwide. None is traditionally targeted to healthy adults. Despite the publication of a large number of clinical trials, there is still substantial uncertainty about the clinical effectiveness of influenza vaccines and this has negative impact on the vaccines acceptance and uptake. OBJECTIVES: To assess the effects of vaccines on influenza in healthy adults. To assess the effectiveness of vaccines in preventing cases of influenza in healthy adults. To estimate the frequency of adverse effects associated with influenza vaccination in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2004) which contains the Cochrane Acute Respiratory Infections Group trials register; MEDLINE (January 1966 to December 2003); and EMBASE (1990 to December 2003). We wrote to vaccine manufacturers and first or corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised or quasi-randomised studies comparing influenza vaccines in humans with placebo, control vaccines or no intervention, or comparing types, doses or schedules of influenza vaccine. Live, attenuated or killed vaccines or fractions thereof administered by any route, irrespective of antigenic configuration were considered. Only studies assessing protection from exposure to naturally occurring influenza in healthy individuals aged 14 to 60 (irrespective of influenza immune status) were considered. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Twenty five reports of studies involving 59,566 people were included. The recommended live aerosol vaccines reduced the number of cases of serologically confirmed influenza by 48% (95% confidence interval (CI) 24% to 64%), whilst recommended inactivated parenteral vaccines had a vaccine efficacy of 70% (95% CI 56% to 80%). The yearly recommended vaccines had low effectiveness against clinical influenza cases: 15%(95% CI 8% to 21%) and 25% (95% CI 13% to 35%) respectively. Overall the percentage of participants experiencing clinical influenza decreased by 6%. Use of the vaccine significantly reduced time off work but only by 0.16 days for each influenza episode (95% CI 0.04 to 0.29 days); Analysis of vaccines matching the circulating strain gave higher estimates of efficacy, whilst inclusion of all other vaccines reduced the efficacy. REVIEWERS' CONCLUSIONS: Influenza vaccines are effective in reducing serologically confirmed cases of influenza. However, they are not as effective in reducing cases of clinical influenza and number of working days lost. Universal immunisation of healthy adults is not supported by the results of this review.

Vaccines for preventing influenza in healthy adults.

BACKGROUND: Three different types of influenza vaccines are currently produced world wide. None is traditionally targeted to healthy adults. Despite the publication of a large number of clinical trials, there is still substantial uncertainty about the clinical effectiveness of influenza vaccines and this has negative impact on the vaccines acceptance and uptake. OBJECTIVES: To identify, retrieve and assess all studies evaluating the effects of vaccines on influenza in healthy adults. To assess the effectiveness of vaccines in preventing cases of influenza in healthy adults. To estimate the frequency of adverse effects associated with influenza vaccination in healthy adults. SEARCH STRATEGY: MEDLINE was searched using the strategy of the Cochrane Acute Respiratory Infections Group. The bibliography of retrieved articles, the Cochrane Controlled Trials Register (CCTR), and EMBASE (1990 to 1997) were also searched. Handsearch of the journal Vaccine from its first issue to the end of 1997 (Jefferson and Jefferson, 1996; Jefferson, 1998). We wrote to vaccine manufacturers and first or corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised or quasi-randomised studies comparing influenza vaccines in humans with placebo, control vaccines or no intervention, or comparing types, doses or schedules of influenza vaccine. Live, attenuated or killed vaccines or fractions thereof administered by any route, irrespective of antigenic configuration were considered. Only studies assessing protection from exposure to naturally occurring influenza in healthy individuals aged 14 to 60 (irrespective of influenza immune status) were considered. DATA COLLECTION AND ANALYSIS: Both clinically defined cases and serologically confirmed cases of influenza were considered as outcomes according to the authors' definitions. Time off work, complication and hospitalisation rates were considered, together with adverse effects. Vaccine schedules were analysed including one component matching the recommended vaccine (WHO or government recommendations) for the year of the study, and whether they matched the circulating viral subtypes. MAIN RESULTS: The recommended live aerosol vaccines reduced the number of cases of serologically confirmed influenza A by 48% (95% confidence interval 24% to 64%), whilst recommended inactivated parenteral vaccines had a vaccine efficacy of 68% (95% confidence interval 49% to 79%). The vaccines were less effective in reducing clinical influenza cases, with efficacies of 13% and 24% respectively. Use of the vaccine significantly reduced time off work, but only by 0.4 days for each influenza episode (95% confidence interval 0.1 to 0.8 days). Analysis of vaccines matching the circulating strain gave higher estimates of efficacy, whilst inclusion of all other vaccines reduced the efficacy. REVIEWER'S CONCLUSIONS: Influenza vaccines are effective in reducing serologically confirmed cases of influenza A. However, they are not as effective in reducing cases of clinical influenza. The use of WHO recommended vaccines appears to enhance their effectiveness in practice.

Amantadine and rimantadine for preventing and treating influenza A in adults.

BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. OBJECTIVES: The objective of this review was to assess the effects and safety of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and reference lists of articles. We also contacted manufacturers, researchers and authors. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prevention trials the numbers of participants with clinically defined influenza, with serologically confirmed clinical influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever and adverse effects. MAIN RESULTS: Amantadine prevented 23% of clinical influenza cases (95% confidence interval 11% to 34%), and 63% of serologically confirmed clinical influenza A cases (95% confidence interval 42% to 76%). Amantadine reduced duration of fever by one day (95% confidence interval 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. REVIEWER'S CONCLUSIONS: Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine. [This abstract has been prepared centrally.]