The process of interpreting the results of clinical studies and translating them into clinical practice is being debated. Here we examine the role of p values and confidence intervals in clinical decision-making, and draw attention to confusion in their interpretation. To improve result reporting, we propose the use of confidence levels and plotting of clinical significance curves and risk-benefit contours. These curves and contours provide degrees of probability of both the potential benefit of treatment and the detriment due to toxicity. Additionally, they provide clinicians with a mechanism of translating the results of studies into treatment for individual patients, thus improving the clinical decision-making process. We illustrate the application of these curves and contours by reference to published studies. Confidence levels, clinical significance curves, and risk-benefit contours can be easily calculated with a hand calculator or standard statistical packages. We advocate their incorporation into the published results of clinical studies.

Implantable cardioverter defibrillators (ICDs) have evolved from the treatment of last resort to the gold standard therapy for patients at high risk for ventricular tachyarrhythmias. High-risk patients include those who have survived life-threatening arrhythmias, and individuals with cardiac diseases who are at risk for such arrhythmias, but are symptomless. Use of an ICD will affect the patient's quality of life. Some drugs can substantially affect defibrillator function and efficacy, and possible drug-device interactions should be considered. Patients with ICDs may encounter cell phones, antitheft detectors, and many other sources of potential electromagnetic Interference. In addition to treating ventricular tachyarrhythmias, new defibrillators provide full featured dual chamber pacing, and could treat atrial arrhythmias, and congestive heart failure by means of biventricular pacing.

This review covers major advances in clinical issues related to systemic lupus erythematosus (SLE) published between 1995 and 2000. The classification criteria for both SLE and antiphospholipid syndrome (APS) have been updated, and up to 19 different subsets of neuropsychiatric lupus have been defined. New epidemiological data show that the incidence of new cases and the survival of patients with SLE are both increasing. Several randomised controlled trials have defined the role of cyclophosphamide, methotrexate, antimalarials, and hormonal treatment in the management of SLE. New data are available for drugs such as ciclosporin and thalidomide. Finally, several new treatments for severe refractory cases, such as mycophenolate mofetil and stem-cell transplantation, are being increasingly used. New data also refer to management of thrombosis in APS and high-risk pregnancies in women with SLE or APS.

The development of glycoconjugate vaccines for Streptococcus pneumoniae that are effective in very young children has renewed interest in identification of which among the more than 90 pneumococcal serotypes are most likely to cause invasive pneumococcal disease (IPD). Serotype distribution is thought to vary geographically, even between regions as socioeconomically similar as western Europe and North America. To explain these variations, we note the considerable variation that exists between reported rates of IPD in young children in the USA and west European countries. We postulate that this variation is attributable to different blood-culture rates and practices, and that mild IPD is probably underdiagnosed and under-reported in western Europe. On the basis of a comparison of serotype distributions between the two regions, we also postulate that those serotypes found at similar frequencies in both regions are virulent and rarely cause mild disease. As a result, reported distributions of IPD serotypes, especially when expressed as percentages, might be strongly skewed by the distribution of clinical presentations in a particular study population.

Tests of clinical competence, which allow decisions to be made about medical qualification and fitness to practise, must be designed with respect to key issues including blueprinting, validity, reliability, and standard setting, as well as clarity about their formative or summative function. Multiple choice questions, essays, and oral examinations could be used to test factual recall and applied knowledge, but more sophisticated methods are needed to assess clincial performance, including directly observed long and short cases, objective structured clinical examinations, and the use of standardised patients. The goal of assessment in medical education remains the development of reliable measurements of student performance which, as well as having predictive value for subsequent clinical competence, also have a formative, educational role.

Observational studies and randomised trials can contribute complementary evidence about the effects of treatment on mortality and on major non-fatal outcomes. In particular, observational studies have an important role in the identification of large adverse effects of treatment on infrequent outcomes (ie, rare, but serious, side-effects) that are not likely to be related to the indications for (or contraindications to) the treatment of interest. Such studies can also provide useful information about the risks of death and disability in particular circumstances that can help to generalise from clinical trials to clinical practice. But, due to their inherent potential for moderate or large biases, observational studies have little role in the direct assessment of any moderate effects of treatment on major outcomes that might exist. Instead, sufficiently large-scale evidence from randomised trials is needed to assess such treatment effects appropriately reliably. Wider appreciation of the different strengths and weaknesses of these two types of epidemiological study should increase the likelihood that the most reliable evidence available informs decisions about the treatments doctors use--and patients receive--for the management of a wide range of life-threatening conditions.

During the past 30 years, there have been advances in understanding of the pathogenesis of Cushing's syndrome and in differential diagnosis of its various forms. Improved diagnostic tests and procedures have increased the ability to recognise even mild hypercortisolism and have provided the means to obtain an accurate diagnosis. Despite these advances, the occurrence of unusual clinical presentations and laboratory shortcomings may produce diagnostic problems and challenge clinical intuition. This article reviews recent pathogenic views, new tests, and new diagnostic problems in the evaluation of Cushing's syndrome. Atypical clinical presentations of hypercortisolism and some laboratory shortcomings that may confuse the diagnosis of Cushing's syndrome are also reported.

Throughout history, doctor-patient relationships have been acknowledged as having an important therapeutic effect, irrespective of any prescribed drug or treatment. We did a systematic review to determine whether there was any empirical evidence to support this theory.

The response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing. This article reviews the links between cancer and inflammation and discusses the implications of these links for cancer prevention and treatment. We suggest that the inflammatory cells and cytokines found in tumours are more likely to contribute to tumour growth, progression, and immunosuppression than they are to mount an effective host antitumour response. Moreover cancer susceptibility and severity may be associated with functional polymorphisms of inflammatory cytokine genes, and deletion or inhibition of inflammatory cytokines inhibits development of experimental cancer. If genetic damage is the "match that lights the fire" of cancer, some types of inflammation may provide the "fuel that feeds the flames". Over the past ten years information about the cytokine and chemokine network has led to development of a range of cytokine/chemokine antagonists targeted at inflammatory and allergic diseases. The first of these to enter the clinic, tumour necrosis factor antagonists, have shown encouraging efficacy. In this article we have provided a rationale for the use of cytokine and chemokine blockade, and further investigation of non-steroidal anti-inflammatory drugs, in the chemoprevention and treatment of malignant diseases.

Uterine leiomyomas (fibroids or myomas), benign tumours of the human uterus, are the single most common indication for hysterectomy. They are clinically apparent in up to 25% of women and cause significant morbidity, including prolonged or heavy menstrual bleeding, pelvic pressure or pain, and, in rare cases, reproductive dysfunction. Thus, both the economic cost and the effect on quality of life are substantial. Surgery has been the mainstay of fibroid treatment, and various minimally invasive procedures have been developed in addition to hysterectomy and abdominal myomectomy. Formation of new leiomyomas after these conservative therapies remains a substantial problem. Although medications that manipulate concentrations of steroid hormones are effective, side-effects limit long-term use. A better approach may be manipulation of the steroid-hormone environment with specific hormone antagonists. There has been little evidence-based evaluation of therapy. New research into the basic biology of these neoplasms may add new treatment options for the future as the role of growth factors and genetic mutations in these tumours are better understood.

Epilepsy and its treatment can have deleterious cognitive and behavioural consequences. Affected individuals have a higher prevalence of neuropsychological dysfunction than the general population because of complex interactions among several multifaceted and overlapping influences--for example, underlying neuropathologies, ictal and interictal neuronal discharges, a plethora of antiepileptic drugs, and numerous psychosocial issues. Research into the clinical relevance of these factors has been dogged by a range of methodological pitfalls including lack of standardisation of neuropsychological tests, small numbers and multiple testing, and statistical failure to appreciate differential effects of interactive elements in individual patients. Although antiepileptic drugs can impair neuropsychological functioning, their positive effect on seizure control might improve cognition and behaviour. Each person should be assessed individually with respect to factors unique to his or her seizure disorder and its treatment.

Pre-eclampsia remains one of the major obstetrical problems in less-developed countries. The causes of this condition are still unknown, thus effective primary prevention is not possible at this stage. Research in the past decade has identified some major risk factors for pre-eclampsia, and manipulation of these factors might result in a decrease in its frequency. In the early 1990s aspirin was thought to be the wonder drug in secondary prevention of pre-eclampsia. Results of large trials have shown that this is not the case: if there is an indication for using aspirin it is in the patient at a very high risk of developing severe early-onset disease. The calcium story followed a more or less similar pattern, with the difference that existing evidence shows that women with a low dietary calcium intake are likely to benefit from calcium supplementation. Proper antenatal care and timed delivery are of utmost importance in tertiary prevention of pre-eclampsia. There is evidence to suggest that the intrinsic direct effect of moderate degrees of maternal hypertension is beneficial to the fetus. Severe hypertension needs treatment. If antihypertensive is indicated, there is no clear choice of a drug. Hydralazine should no longer be thought of as the primary drug, most studies show a preference for calcium channel blockers.

Animal viruses, some of which are probably unable to replicate in human cells, could be transmitted to people where they may be linked to tumours currently not attributed to viruses. Several human virus types have oncogenic potential in animals. A potential risk for acquiring such infections by handling and preparation of animal products was analysed against the background of available epidemiological reports. Human tumours should be systematically assessed for proliferation-inducing viruses in non-permissive systems.

This two-part review is intended principally for practising clinicians who want to know why some types of evidence about the effects of treatment on survival, and on other major aspects of chronic disease outcome, are much more reliable than others. Although there are a few striking examples of treatments for serious disease which really do work extremely well, most claims for big improvements turn out to be evanescent. Unrealistic expectations about the chances of discovering large treatment effects could misleadingly suggest that evidence from small randomised trials or from non-randomised studies will suffice. By contrast, the reliable assessment of any more moderate effects of treatment on major outcomes--which are usually all that can realistically be expected from most treatments for most common serious conditions--requires studies that guarantee both strict control of bias (which, in general, requires proper randomisation and appropriate analysis, with no unduly data-dependent emphasis on specific parts of the overall evidence) and strict control of random error (which, in general, requires large numbers of deaths or of some other relevant outcome). Past failures to produce such evidence, and to interpret it appropriately, have already led to many premature deaths and much unnecessary suffering.

Pre-eclampsia is usually defined on the basis of new onset hypertension and albuminuria developing after 20 weeks of pregnancy. There are difficulties with measurement of these variables. Conventional sphygmomanometry remains the gold standard for blood-pressure measurement. The value of ambulatory blood-pressure measurement has yet to be established. Oedema is now omitted from all definitions of preeclampsia, although the finding of widespread severe oedema of sudden onset should not be ignored for clinical purposes. Definitions of pre-eclampsia based solely on hypertension and proteinuria ignore the wide clinical variability in this syndrome. Women with no proteinuria but who do have hypertension and other features such as severe headache or other symptoms, thrombocytopenia, hyperuricaemia, disordered liver function, and fetal compromise are likely to have pre-eclampsia. This notion is accepted in the new Australasian definition of pre-eclampsia and more than hinted at in the new American College of Obstetricians and Gynecologists' definition. Definitions used for clinical purposes should be as safe as practical; they are likely to include a considerable number of false positives. Most research studies are weakened if patients without the disease are included. Therefore, a separate stringent research definition of pre-eclampsia we also suggest.

After more than a century of intensive research, pre-eclampsia and eclampsia remain an enigmatic set of conditions. Aberration of the interaction between placental and maternal tissue is probably the primary cause, but the exact nature of the differences from normal pregnancy remain elusive. In this review attempts to understand the sequence of physiological changes have concentrated on vascular endothelium and oxidative stress issues. There are genetic components to susceptibility, but the relative contributions of maternal and fetal genotypes are still unclear. Whole-genome mapping could ultimately define the causative genes.

A major goal of antidepressant development is to improve on preceding drug classes with agents with greater specificity (and therefore fewer unwanted side-effects) and with more rapid onset of antidepressant action. To this end, four antidepressants with significantly distinct pharmacological characteristics have been recently introduced: venlafaxine, nefazodone, mirtazapine, and reboxetine. Venlafaxine is the first antidepressant in a new drug class referred to as the serotonin noradrenergic reuptake inhibitors (SNaRIs). Nefazodone is a weaker serotonin and norepinephrine reuptake inhibitor, but a potent serotonin 5-HT2 receptor antagonist. Mirtazapine is a potent antagonist of central 2alpha-adrenergic autoreceptors, and heteroreceptors and is an antagonist of serotonin 5-HT2 and 5-HT3 receptors. The result of these actions is to increase both noradrenergic and specific (5-HT1) serotonergic transmission, and mirtazapine has therefore been termed a noradrenergic and specific serotonergic antidepressant (NaSSA). Reboxetine is the first selective noradrenaline reuptake inhibitor (NaRI) to be introduced since the tricyclics, and lacks immediate serotonergic effects.

The supremacy of combined oral contraceptives (OCs) is being challenged. For too long combined OCs have been seen as synonymous with contraception, helping to maintain ignorance of alternative methods. Further, the efficacy of these OCs and condoms is often compromised by incorrect or inconsistent use. We particularly welcome developments in male systemic methods, that allow men to share not only in conception but also in contraception, and methods that are completely forgettable once instituted, especially if usable by adolescents.