Variations in Demand across England for the Magnetic Resonance-Linac Technology, Simulated Utilising Local-level Demographic and Cancer Data in the Malthus Project.

AIMS: Cancer incidence varies across England, which affects the local-level demand for treatments. The magnetic resonance-linac (MR-linac) is a new radiotherapy technology that combines imaging and treatment. Here we model the demand and demand variations for the MR-linac across England. MATERIALS AND METHODS: Initial clinical indications were provided by the MR-linac consortium and introduced into the Malthus radiotherapy clinical decision trees. The Malthus model contains Clinical Commissioning Group (CCG) population, cancer incidence and stage presentation data (for lung and prostate) and simulated the demand for the MR-linac for all CCGs and Radiotherapy Operational Delivery Networks (RODN) across England. RESULTS: Based on the initial target clinical indications, the MR-linac could service 16% of England's fraction burden. The simulated fractions/million population demand/annum varies between 3000 and 10 600 fractions/million at the CCG level. Focussing only on the cancer population, the simulated fractions/1000 cancer cases demand/annum ranges from 1028 to 1195 fractions/1000 cases. If a national average for fractions/million demand was then used, at the RODN level, the variation from actual annual demand ranges from an overestimation of 8400 fractions to an underestimation of 5800 fractions. When using the national average fractions/1000 cases, the RODN demand varies from an overestimation of 3200 fractions to an underestimation of 3000 fractions. CONCLUSIONS: Planning cancer services is complex due to regional variations in cancer burden. The variations in simulated demand of the MR-linac highlight the requirement to use local-level data when planning to introduce a new technology.

Selecting Patients with Favorable Risk, Grade Group 2 Prostate Cancer for Active Surveillance-Does Magnetic Resonance Imaging Have a Role?

PURPOSE: The National Comprehensive Cancer Network® recommends that selected men with grade group 2 prostate cancer be considered for active surveillance. However, selecting which patients with grade group 2 disease can be safely managed by active surveillance remains controversial. The aim of this study was to evaluate the association of multiparametric magnetic resonance imaging with adverse pathology in the radical prostatectomy specimen of men with favorable risk grade group 2 prostate cancer, which could help select patients for active surveillance. MATERIALS AND METHODS: We retrospectively analyzed a cohort of patients with favorable grade group 2 disease who underwent radical prostatectomy between 2010 and 2019. Preoperative multiparametric magnetic resonance imaging was scored as negative (no identifiable lesion), positive (identifiable lesion) or equivocal. We defined a multivariable logistic regression model with multiparametric magnetic resonance imaging score as the predictor and adverse pathology (up staging to T3a/b disease, upgrading to ≥grade group 3 or lymph node invasion) as the outcome, adjusting for preoperative prostate specific antigen, biopsy Gleason grade, clinical stage, and number of negative and positive prostate biopsy cores. Secondary outcomes of biochemical recurrence, grade group upgrading alone and the added value of incorporating multiparametric magnetic resonance imaging data into the nomogram were also investigated. RESULTS: We identified 1,117 patients with favorable risk grade group 2 disease who underwent radical prostatectomy. Positive multiparametric magnetic resonance imaging was associated with higher rates of adverse pathology (OR 2.55, 95% CI 1.75-3.40, p <0.0001) and upgrading (OR 3.89, 95% CI 2.00-7.56, p <0.0001). However, as our study included only grade group 2 patients who underwent radical prostatectomy, our cohort may represent a higher risk group than grade group 2 patients as a whole. Adding multiparametric magnetic resonance imaging results to a standard prediction model led to higher net benefit on decision curve analysis. An identifiable lesion on multiparametric magnetic resonance imaging was associated with an increased risk of aggressive pathological features in the radical prostatectomy specimen of patients with favorable risk grade group 2 prostate cancer who were potential active surveillance candidates. This information could be used to inform biopsy strategy, counsel patients on treatment options and guide strategies for those on active surveillance. CONCLUSIONS: Combining multiple magnetic resonance imaging modalities (multiparametric magnetic resonance imaging) provides a more accurate prediction of the risk presented by prostate cancer than current prediction methods. In this study, positive magnetic resonance imaging results approximately doubled the chances that a patient with favorable risk prostate cancer would be found to have adverse pathology when their prostate was removed. Thus, multiparametric magnetic resonance imaging could help select patients with favorable risk cancer who may be good candidates for active surveillance, and help guide biopsy and surveillance strategies for such patients.

The persistence of the effects of acupuncture after a course of treatment: a meta-analysis of patients with chronic pain.

There is uncertainty regarding how long the effects of acupuncture treatment persist after a course of treatment. We aimed to determine the trajectory of pain scores over time after acupuncture, using a large individual patient data set from high-quality randomized trials of acupuncture for chronic pain. The available individual patient data set included 29 trials and 17,922 patients. The chronic pain conditions included musculoskeletal pain (low back, neck, and shoulder), osteoarthritis of the knee, and headache/migraine. We used meta-analytic techniques to determine the trajectory of posttreatment pain scores. Data on longer term follow-up were available for 20 trials, including 6376 patients. In trials comparing acupuncture to no acupuncture control (wait-list, usual care, etc), effect sizes diminished by a nonsignificant 0.011 SD per 3 months (95% confidence interval: -0.014 to 0.037, P = 0.4) after treatment ended. The central estimate suggests that approximately 90% of the benefit of acupuncture relative to controls would be sustained at 12 months. For trials comparing acupuncture to sham, we observed a reduction in effect size of 0.025 SD per 3 months (95% confidence interval: 0.000-0.050, P = 0.050), suggesting approximately a 50% diminution at 12 months. The effects of a course of acupuncture treatment for patients with chronic pain do not seem to decrease importantly over 12 months. Patients can generally be reassured that treatment effects persist. Studies of the cost-effectiveness of acupuncture should take our findings into account when considering the time horizon of acupuncture effects. Further research should measure longer term outcomes of acupuncture.

External Evaluation of a Novel Prostate Cancer Risk Calculator (ProstateCheck) Based on Data from the Swiss Arm of the ERSPC.

PURPOSE: We externally validated a novel prostate cancer risk calculator based on data from the Swiss arm of the ERSPC and assessed whether the risk calculator (ProstateCheck) is superior to the PCPT-RC and SWOP-RC in an independent Swiss cohort. MATERIALS AND METHODS: Data from all men who underwent prostate biopsy at an academic tertiary care center between 2004 and 2012 were retrospectively analyzed. The probability of having any prostate cancer or high grade prostate cancer (Gleason score 7 or greater) on prostate biopsy was calculated using the ProstateCheck. Risk calculator performance was assessed using calibration and discrimination, and additionally compared with the PCPT-RC and SWOP-RC by decision curve analyses. RESULTS: Of 1,615 men 401 (25%) were diagnosed with any prostate cancer and 196 (12%) with high grade prostate cancer. Our analyses of the ProstateCheck-RC revealed good calibration in the low risk range (0 to 0.4) and moderate overestimation in the higher risk range (0.4 to 1) for any and high grade prostate cancer. The AUC for the discrimination of any prostate cancer and high grade prostate cancer was 0.69 and 0.72, respectively, which was slightly but significantly higher compared to the PCPT-RC (0.66 and 0.69, respectively) and SWOP-RC (0.64 and 0.70, respectively). Decision analysis, taking into account the harms of transrectal ultrasound measurement of prostate volume, showed little benefit for ProstateCheck-RC, with properties inferior to those of the PCPT-RC and SWOP-RC. CONCLUSIONS: Our independent external evaluation revealed moderate performance of the ProstateCheck-RC. Its clinical benefit is limited, and inferior to that of the PCPT-RC and SWOP-RC.

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients. METHODS: We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models. RESULTS: With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients. CONCLUSION: The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.

A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer screening in Rotterdam, Netherlands.

BACKGROUND: Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA. METHODS: The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (>or=3 ng ml(-1)), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy. RESULTS: The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P<0.001, and high-grade cancer (Gleason >or=7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P=0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less. CONCLUSIONS: Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies.

Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes.

BACKGROUND: Influenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum is a patented, commercially available homoeopathic medicine. The rationale for its use in influenza comes from the homoeopathic principle of 'let like be cured by like'. This medicine is manufactured from wild duck heart and liver, which are said to be reservoirs for influenza viruses. OBJECTIVES: To determine whether homoeopathic Oscillococcinum or similar medicines are more effective than placebo in the prevention and treatment of influenza and influenza-like syndromes. SEARCH STRATEGY: We updated the electronic searches on the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006); MEDLINE (January 1966 to February 2006) and EMBASE (1980 to February 2006). The manufacturers of Oscillococcinum were contacted for information. SELECTION CRITERIA: Placebo-controlled trials of Oscillococcinum or homeopathically-prepared influenza virus, influenza vaccine or avian liver in the prevention and treatment of influenza and influenza-like syndromes. DATA COLLECTION AND ANALYSIS: Two authors extracted data and assessed methodological quality independently. MAIN RESULTS: Seven studies were included in the review, three prevention trials (number of participants (n) = 2265) and four treatment trials (n = 1194). Only two studies reported sufficient information to complete data extraction fully. There was no evidence that homoeopathic treatment can prevent influenza-like syndrome (relative risk (RR) 0.64, 95% confidence interval (CI) 0.28 to 1.43). Oscillococcinum treatment reduced the length of influenza illness by 0.28 days (95% CI 0.50 to 0.06). Oscillococcinum also increased the chances that a patient considered treatment to be effective (RR 1.08; 95% CI 1.17 to 1.00). AUTHORS' CONCLUSIONS: Though promising, the data were not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndromes. Further research is warranted but the required sample sizes are large. Current evidence does not support a preventative effect of Oscillococcinum-like homeopathic medicines in influenza and influenza-like syndromes.

Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

OBJECTIVES: To determine the effects of a policy of using acupuncture, compared with a policy of avoiding acupuncture, on headache in primary care patients with chronic headache disorders. The effects of acupuncture on medication use, quality of life, resource use and days off sick in this population and the cost-effectiveness of acupuncture were also examined. DESIGN: Randomised, controlled trial. SETTING: General practices in England and Wales. PARTICIPANTS: The study included 401 patients with chronic headache disorder, predominantly migraine. INTERVENTIONS: Patients were randomly allocated to receive up to 12 acupuncture treatments over 3 months or to a control intervention offering usual care. MAIN OUTCOME MEASURES: Outcome measures included headache score; assessment of Short Form 36 (SF-36) health status and use of medication at baseline, 3 months and 12 months; assessment of use of resources every 3 months; and assessment of incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: Headache score at 12 months, the primary end-point, was lower in the acupuncture group than in controls. The adjusted difference between means was 4.6. This result was robust to sensitivity analysis incorporating imputation for missing data. Patients in the acupuncture group experienced the equivalent of 22 fewer days of headache per year. SF-36 data favoured acupuncture, although differences reached significance only for physical role functioning, energy and change in health. Compared with controls, patients randomised to acupuncture used 15% less medication, made 25% fewer visits to GPs and took 15% fewer days off sick. Total costs during the 1-year period of the study were on average higher for the acupuncture group than for controls because of the acupuncture practitioners' costs. The mean health gain from acupuncture during the year of the trial was 0.021 QALYs, leading to a base-case estimate of GBP9180 per QALY gained. This result was robust to sensitivity analysis. Cost per QALY dropped substantially when the analysis incorporated likely QALY differences for the years after the trial. CONCLUSIONS: The study suggests that acupuncture leads to persisting, clinically relevant benefits for primary care patients with chronic headache, particularly migraine. It is relatively cost-effective compared with a number of other interventions provided by the NHS. Further studies could examine the duration of acupuncture effects beyond 1 year and the relative benefit to patients with migraine with compared to tension-type headache. Trials are also warranted examining the effectiveness and cost-effectiveness of acupuncture in patients with headache receiving more aggressive pharmacological management.

Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes.

BACKGROUND: Influenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum is a patented, commercially available homoeopathic medicine. The rationale for its use in influenza comes from the homoeopathic principle of 'let like be cured by like'. The medicine is manufactured from wild duck heart and liver, which are said to be reservoirs for influenza viruses. OBJECTIVES: To determine whether homoeopathic Oscillococcinum or similar medicines are more effective than placebo in the prevention and treatment of influenza and influenza-like syndromes. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) issue 2, 2003; MEDLINE (January 1966 to June 2003) and EMBASE (1980 to June 2003) were searched, using the term "homeopathy" with "influenza", "respiratory tract", "infection", "cough", "virus" and "fever". The manufacturers of Oscillococcinum were contacted for information. SELECTION CRITERIA: Placebo-controlled trials of Oscillococcinum or homeopathically-prepared influenza virus, influenza vaccine or avian liver in the prevention and treatment of influenza and influenza-like syndromes. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed methodological quality independently. MAIN RESULTS: Seven studies were included in the review, three prevention trials (n = 2265) and four treatment trials (n = 1194). Only for two studies was there sufficient information to complete data extraction fully. There was no evidence that homoeopathic treatment can prevent influenza-like syndrome (relative risk 0.64, 95% confidence interval 0.28 to 1.43). Oscillococcinum treatment reduced length of influenza illness by 0.28 days (95% confidence interval 0.50 to 0.06). Oscillococcinum also increased the chance of a patient considering treatment effective (relative risk 1.08; 95% CI 1.17, 1). REVIEWER'S CONCLUSIONS: Though promising, the data are not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndrome. Further research is warranted but required sample sizes are large. Current evidence does not support a preventative effect of Oscillococcinum-like homeopathic medicines in influenza and influenza-like syndromes.

Time course of muscle soreness following different types of exercise.

BACKGROUND: Post-exercise muscle soreness is a dull, aching sensation that follows unaccustomed muscular exertion. Primarily on the basis of previous laboratory-based research on eccentric exercise, soreness is usually said to follow an inverted U-shaped curve over time, peaking 24 - 48 hours after exercise. As such, it is often described as "delayed-onset" muscle soreness. In a study of long-distance runners, soreness seemed to peak immediately and then reduce gradually over time. The study is a secondary analysis of clinical trial data that aims to determine whether the time course of soreness following a natural exercise, long-distance running, is different from that following a laboratory-based exercise, bench-stepping. METHODS: This is a reanalysis of data from three previous clinical trials. The trials included 400 runners taking part in long-distance races and 82 untrained volunteers performing a bench-stepping test. Subjects completed a Likert scale of muscle soreness every morning and evening for the five days following their exercise. RESULTS: Interaction between trial and time is highly significant, suggesting a different time course of soreness following running and bench-stepping. 45% of subjects in the bench-stepping trial experienced peak soreness at the third or fourth follow-up (approximately 36 - 48 hours after exercise) compared to only 14% of those in the running trial. The difference between groups is robust to multivariate analysis incorporating possible confounding variables. CONCLUSION: Soreness in runners following long-distance running follows a different time course to that in untrained individuals undertaking bench-stepping. Research on exercise taking place in the laboratory context does not necessarily generalize to exercise undertaken by trained athletes when engaged in their chosen sport.

The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study.

BACKGROUND: Many randomized trials involve measuring a continuous outcome - such as pain, body weight or blood pressure - at baseline and after treatment. In this paper, I compare four possibilities for how such trials can be analyzed: post-treatment; change between baseline and post-treatment; percentage change between baseline and post-treatment and analysis of covariance (ANCOVA) with baseline score as a covariate. The statistical power of each method was determined for a hypothetical randomized trial under a range of correlations between baseline and post-treatment scores. RESULTS: ANCOVA has the highest statistical power. Change from baseline has acceptable power when correlation between baseline and post-treatment scores is high;when correlation is low, analyzing only post-treatment scores has reasonable power. Percentage change from baseline has the lowest statistical power and was highly sensitive to changes in variance. Theoretical considerations suggest that percentage change from baseline will also fail to protect from bias in the case of baseline imbalance and will lead to an excess of trials with non-normally distributed outcome data. CONCLUSIONS: Percentage change from baseline should not be used in statistical analysis. Trialists wishing to report this statistic should use another method, such as ANCOVA, and convert the results to a percentage change by using mean baseline scores.

Message to complementary and alternative medicine: evidence is a better friend than power.

BACKGROUND: Evidence-based medicine (EBM) is being embraced by an increasing number of practitioners and advocates of complementary and alternative medicine (CAM). A significant constituency within CAM, however, appears to have substantive doubts about EBM and some are expressly hostile. DISCUSSION: Many of the arguments raised against EBM within the CAM community are based on a caricature radically at odds with established, accepted and published principles of EBM practice. Contrary to what has sometimes been argued, EBM is not cookbook medicine that ignores individual needs. Neither does EBM mandate that only proven therapies should be used. Before EBM, decisions on health care tended to be based on tradition, power and influence. Such modes usually act to the disadvantage of marginal groups. CONCLUSION: By placing CAM on an equal footing with conventional medicine - what matters for both is evidence of effectiveness - EBM provides an opportunity for CAM to find an appropriate and just place in health care.

Can homeopathically prepared mercury cause symptoms in healthy volunteers? A randomized, double-blind placebo-controlled trial.

OBJECTIVE: To pilot a method for determining whether homeopathically prepared mercury causes more symptoms (a "drug proving") in healthy volunteers than placebo. METHODS: One hundred and eighteen (118) healthy volunteers ages 18 to 65 were recruited by local advertising. Subjects unfamiliar with homeopathy undertook a 1-week single-blind placebo run-in, a 1-week of double-blind, randomized treatment on either homeopathically prepared mercury 12C or placebo, and a third week of placebo run-out. Each day, symptoms were recorded on a checklist that included both true mercury symptoms and symptoms not expected to be caused by mercury (false symptoms). Additional symptoms were assessed by open reporting. Outcome was assessed by calculating a score for each day as the number of true symptoms minus the number of false symptoms. The mean score during placebo was then subtracted from the mean score for weeks two and three of the trial. RESULTS: Fourteen (14) subjects dropped out during placebo run-in. The remaining 104 completed the trial. Baseline comparability was good. Mean difference score was -0.125 (SD 3.47) for mercury and -0.221 (SD 3.01) for placebo (p > 0.2). No significant differences between groups were found for the number of subjects meeting predefined criteria for a drug-proving reaction. CONCLUSION: This pilot study failed to find evidence that mercury 12C causes significantly more symptoms in healthy volunteers than placebo. Questionnaires with a limited number of gross symptoms do not seem to be an appropriate methodological technique in drug proving research. If drug-proving phenomena exist, they appear to be rare.

Unconventional therapies for cancer and cancer-related symptoms.

A significant proportion of cancer patients try unconventional therapies and many use 'complementary' therapies, as adjuncts to mainstream care, for management of symptoms and to improve quality of life. A smaller proportion use 'alternative' therapies, which are typically invasive, biologically active, and commonly promoted as replacements for, rather than adjuncts to, mainstream therapy. Many alternative therapies, including high-dose vitamin C, the Di Bella regimen, and laetrile have been shown not to be effective. For others, such as metabolic therapy, evidence is extremely limited. Conversely, most complementary therapies are well studied and of proven benefit. There is evidence from randomised trials supporting the value of hypnosis for cancer pain and nausea; relaxation therapy, music therapy, and massage for anxiety; and acupuncture for nausea. Such complementary therapies are increasingly provided at mainstream cancer centres.

Inter-rater reliability of symptom repertorisation: a pragmatic empirical study.

OBJECTIVE: To determine the extent to which two homeopaths agree on whether symptoms reported by patients in a proving are possibly associated with Mercurius solubilis. DESIGN: Blinded, inter-rater reliability study. PARTICIPANTS: 104 subjects in a randomised, double-blind mercury proving. OUTCOME MEASURES: 557 symptom episodes spontaneously reported by subjects were classified as 'mercury' or 'not mercury' by two homeopaths working blind to each other's conclusions and to patient allocation. RESULTS: Initial agreement between homeopaths was 70.2%, a kappa of 0.39, (95% CI 0.31, 0.47). Some disagreements appear to have resulted from differing interpretations of the study instructions. After suitable correction, agreement was 76.5% and kappa 0.56 (95% CI 0.49, 0.63). CONCLUSIONS: The study homeopaths had only a moderate level degree of agreement greater than that expected by chance. The main factor seems to have been differences between data from different sources. There is an urgent need for more research on the methods of choosing homoeopathic medicines in order to improve the reliability and validity of homoeopathic diagnoses.

Incorporating data from dissertations in systematic reviews.

OBJECTIVES: To determine whether unpublished dissertations are an important source of trials for systematic reviews. METHODS: In a review of infant massage, we identified 17 dissertations. We recorded whether each dissertation was included in the review and, if so, whether it contributed data to any analyses. RESULTS: Thirteen dissertations were excluded, 11 because of poor reporting of methodology. Three dissertations were also published as journal papers. The data from the remaining dissertation were not included in any analysis. Reviewing data on the Cochrane Library, only one of 878 reviews included data from a dissertation that might have changed a review's conclusions. CONCLUSIONS: Searching for and retrieving unpublished dissertations involves considerable time and effort and appears to influence the conclusions of a review only rarely.

Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes.

BACKGROUND: Influenza is a highly infectious viral disease that is particularly common in the winter months. Conventional management options are limited to bed rest and treatment of complications such as secondary bacterial infections. Oscillococcinum is a patented, commercially available homoeopathic medicine. The rationale for its use in influenza comes from the homoeopathic principle of 'let like be cured by like'. The medicine is manufactured from wild duck heart and liver, a well-known reservoir for influenza viruses. OBJECTIVES: To determine whether homoeopathic Oscillococcinum or similar medicines are more effective than placebo in the prevention and treatment of influenza and influenza-like syndromes. SEARCH STRATEGY: The registry of randomised trials for the Cochrane Complementary Medicine Field was searched using the term "homeopathy" with "influenza", "respiratory tract", "infection", "cough", "virus" and "fever". The manufacturers of Oscillococcinum were contacted for information about other trials. Date of the most recent search: February 1999. SELECTION CRITERIA: Placebo-controlled trials of Oscillococcinum or homeopath-prepared influenza virus, influenza vaccine or avian liver in the prevention and treatment of influenza and influenza-like syndromes. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed methodological quality independently. MAIN RESULTS: Seven studies were included in the review, three prevention trials (n=2265) and four treatment trials (n=1194). Only for two studies was there sufficient information to complete data extraction fully. There was no evidence that ic treatment can prevent influenza-like syndrome (relative risk 0.64, 95% confidence interval 0.28 to 1.43). Oscillococcinum treatment reduced length of influenza illness by 0.28 days (95% confidence interval 0.50 to 0.06). Oscillococcinum also increased the chance of a patient considering treatment effective (relative risk 1.08; 95% CI 1.17, 1). REVIEWER'S CONCLUSIONS: Oscillococcinum probably reduces the duration of illness in patients presenting with influenza symptoms. Though promising, the data are not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndrome. Further research is warranted but required sample sizes are large. Current evidence does not support a preventative effect of homeopathy in influenza and influenza-like syndromes.

Clinical trials of homeopathy and placebo: analysis of a scientific debate.

OBJECTIVE: Homeopathy is controversial, primarily because of the use of medicines diluted beyond the Avogadro limit. This article examines the scientific debate on whether homeopathy can have effects greater than placebo in humans. METHODS: Five rigorous English-language clinical studies published in high-impact journals that favored homeopathy were identified. Letters and other articles written in response to these articles were then retrieved and analyzed. RESULTS: Much of the content of responses to positive homeopathic research was rhetorical in nature and antagonistic in tone: homeopathic researchers were accused of bias and of being in the pocket of homeopathic manufacturers; arguments were raised that are demonstrably inaccurate or irrelevant to the interpretation of research; words such as "magic" or "potion" were used to paint homeopathic research as inherently unscientific. Other commentators argued that based on theoretical grounds homeopathy could not possibly be effective, any positive trial result must be due to bias. Surprisingly few responses raised substantive methodologic or statistical issues. Many of these are clearly inaccurate or irrelevant. The possibility of publication bias-selective publication of positive results-was raised by some commentators and remains an important criticism of the apparently positive nature of the clinical trial evidence. The most persuasive argument against accepting differences between homeopathy and placebo on the basis of current evidence is that homeopathy is scientifically implausible and so requires more evidence than normal. CONCLUSIONS: Investigators undertaking clinical research in homeopathy need to be responsive both to the dangers of publication bias and to the requirement for stronger than usual levels of evidence.