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Vaccination is a life-saving endeavour, yet risk and uncertainty are unavoidable in science and medicine. Vaccination remains contentious in the public mind, and vaccine hesitancy is a serious public health issue. This has recently been reignited in the discussion over potential side effects of COVID-19 vaccines, and the decision by several countries to suspend measures such as the AstraZeneca vaccine. In these instances, the precautionary principle has often been invoked as a rationale, yet such heuristics do not adequately weigh potential harms against real benefits. How we analyse, communicate and react to potential harms is absolutely paramount to ensure the best decisions and outcomes for societal health, and maintaining public confidence. While balancing benefits and risks is an essential undertaking, it cannot be achieved without due consideration of several other pertinent factors, especially in the context of vaccination, where misguided or exaggerated fears have in the past imperilled public health. While well meaning, over reactions to potential hazards of vaccination and other health interventions can have unintended consequences, and cause lingering damage to public trust. In this analysis, we explore the challenges of assessing risk and benefit, and the limitations of the precautionary principle in these endeavours. When risk is unclear, cautious vigilance might be a more pragmatic and useful policy than reactionary suspensions.

There is increasing awareness throughout biomedical science that many results do not withstand the trials of repeat investigation. The growing abundance of medical literature has only increased the urgent need for tools to gauge the robustness and trustworthiness of published science. Dichotomous outcome designs are vital in randomized clinical trials, cohort studies, and observational data for ascertaining differences between experimental and control arms. It has however been shown with tools like the fragility index (FI) that many ostensibly impactful results fail to materialize when even small numbers of patients or subjects in either the control or experimental arms are recoded from event to non-event. Critics of this metric counter that there is no objective means to determine a meaningful FI. As currently used, FI is not multidimensional and is computationally expensive. In this work, a conceptually similar geometrical approach is introduced, the ellipse of insignificance. This method yields precise deterministic values for the degree of manipulation or miscoding that can be tolerated simultaneously in both control and experimental arms, allowing for the derivation of objective measures of experimental robustness. More than this, the tool is intimately connected with sensitivity and specificity of the event/non-event tests, and is readily combined with knowledge of test parameters to reject unsound results. The method is outlined here, with illustrative clinical examples.Science and medicine are vital to the well-being of humankind. Yet for all the incredible advances science has made, the unfortunate reality is that a worrying fraction of biological research is not reliable. Erroneous results might arise by chance or because of scientists’ mistakes or ineptitude. Very occasionally, researchers may behave unethically and fabricate or inappropriately manipulate their data. Inevitably, this can lead to untrustworthy research that misleads scientists and the public on questions integral to our health. Indeed, a recent study showed the results of several high-profile cancer papers could not be fully replicated. This problem is not unique to cancer, and studies on various other diseases have also not stood up to scrutiny from outside investigators. Finding ways to detect dubious results is therefore essential to protect the public’s well-being and maintain public trust in science. Here, Grimes demonstrates a new tool called the ‘Ellipse of Insignificance’ for measuring the reliability of dichotomous studies which are commonly used in many branches of biomedical sciences, including clinical trials. These studies typically compare two groups: one which was subjected to a specific treatment, and a control group which was not. Statistical methods are then applied to estimate how likely it is that differences in the number of observed events between the groups are real or due to chance. The tool created by Grimes explores what would happen to seemingly strong results if some of the events in both the control and experimental arm of the study are recoded. It then assesses how much nudging is needed to change the statistical outcome of the experiment: the more interventions the result can withstand, the more robust the experiment. Grimes tested the tool and showed that a study suggesting a link between miscarriage and magnetic field exposure was likely unreliable because shifting the outcomes of less than two participants would change the result. Scientists could use the Ellipse of Insignificance tool to quickly identify misleading published results or potential research fraud. Doing this could benefit researchers and protect the public from potential harm. It may also help preserve research integrity, increase transparency, and bolster public trust in science.

Background: Few areas of health have been as insidiously influenced by misinformation as cancer. Thus, interventions that can help people impacted by cancer reduce the extent to which they are victims of misinformation are necessary. The Informed Health Choices (IHC) initiative has developed Key Concepts that can be used in the development of interventions for evaluating the trustworthiness of claims about the effects of health treatments. We are developing an online education programme called Informed Health Choices-Cancer (IHC-C) based on the IHC Key Concepts. We will provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make informed choices. Methods: We will establish a steering group (SG) of 12 key stakeholders, including oncology specialists and academics. In addition, we will establish a patient and public involvement (PPI) panel of 20 people impacted by cancer. After training the members on the Key Concepts and the prioritisation process, we will conduct a two-round prioritisation process. In the first round, 12 SG members and four PPI panel members will prioritise Key Concepts for inclusion. In the second round, the remaining 16 PPI members will undertake the prioritisation based on the prioritised Key Concepts from the first round. Participants in both rounds will use a structured judgement form to rate the importance of the Key Concepts for inclusion in the online IHC-C programme. A consensus meeting will be held, where members will reach a consensus on the Key Concepts to be included and rank the order in which the prioritised Key Concepts will be addressed in the IHC-C programme. Conclusions: At the end of this process, we will identify which Key Concepts should be included and the order in which they should be addressed in the IHC-C programme.

Key Points Question As human papillomavirus (HPV)–based cervical screening modalities change and HPV vaccination becomes more widespread, what are the likely outcomes for the interpretation of screening modalities? Findings In this decision analytical model with a simulated population of women aged 25 years and older, HPV-based screening modalities detected more abnormal cervical cells than traditional liquid-based cytology (LBC) approaches, but they did so at the cost of increased false positives. However, as HPV vaccination increased, HPV-based modalities resulted in fewer unnecessary colposcopies than LBC methods. Meaning These findings suggest that the ideal screening modality for a given population should account for HPV vaccination status to maximize the efficiency of screening., This decision analytical model estimates the likely outcomes of different screening modalities and models the effect of growing uptake of the human papillomavirus (HPV) vaccine on the interpretation of screening results., Importance Cervical cancer screening is a lifesaving intervention, with an array of approaches, including liquid-based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and combinations via parallel cotesting or sequential triage. Maximizing screening efficacy while minimizing overtreatment is vital, especially when considering how the HPV vaccine will affect the interpretation of results. Objectives To estimate the likely outcomes of different screening modalities and to model how the increasing uptake of the HPV vaccine could affect the interpretation of screening results. Design, Setting, and Participants This decision analytic model established a simple Markov model to compare the outcomes of different cervical cancer screening modalities on a simulated population of women (aged ≥25 years), considering different levels of HPV vaccination. Main Outcomes and Measures The number of cases of cervical intraepithelial neoplasia (CIN) grade 2 and 3 detected and missed, the number of false positives, and the number of tests required to achieve a given level of accuracy. Positive and negative predictive values of different modalities were simulated under varying levels of HPV vaccination and therefore HPV prevalence. Results In a simulated population of 1000 women aged 25 years and older with an HPV prevalence of 2%, HPV-based modalities outperformed LBC-based approaches, detecting 19% more true positives (HPV test sensitivity, 89.9% [95% CI, 88.6%-91.1%]; LBC test sensitivity, 75.5% [95% CI, 66.6%-82.7%]). While cotesting markedly reduced missed cases, detecting 29% more true positives than LBC alone (19.5 [95% CI, 19.3-19.7] per 1000 women screened vs 15.1 [95% CI, 13.3-16.5] per 1000 women screened), it unacceptably increased excess colposcopy referral by 94% (184.4 [95% CI, 181.8-188.0] false positives per 1000 women screened vs 95.1 [95% CI, 93.1-97.0] false positives per 1000 women screened). By contrast, triage testing with reflex screening substantially reduced false positives by a factor of approximately 10 (eg, HPV with LBC triage, 9.6 [95% CI, 9.3-10.0] per 1000 women screened). Over a lifetime of screening, reflex approaches with appropriate test intervals maximized therapeutic efficacy; as HPV vaccination rates increased, HPV-based screening approaches resulted in fewer unnecessary colposcopies than LBC approaches (HPV testing, 80% vaccine coverage: 44.1 [95% CI, 40-45.9] excess colposcopies; LBC testing, 80% vaccine coverage: 96.9 [95% CI, 96.8-97.0] excess colposcopies). Conclusions and Relevance In this decision analytic model, the effectiveness of cervical cancer screening was dependent on the prevalence of cervical dysplasia and/or HPV infection or vaccination in a population as well as the sensitivity and specificity of various modalities. Although screening is lifesaving, overtesting or modalities inappropriate to the target population may cause significant harm, including overtreatment.

Editor – Weir and colleagues timidly state that ‘If vitamin D does in fact reduce the severity of COVID-19 … [then] supplements would offer a relatively easy option to decrease the impact of the pandemic.’[1][1] This reticence ignores about 40 years of developing scientific knowledge of the

ObjectivesDisinformation on medical matters has become an increasing public health concern. Public engagement by scientists, clinicians and patient advocates can contribute towards public understanding of medicine. However, depth of feeling on many issues (notably vaccination and cancer) can lead to adverse reactions for those communicating medical science, including vexatious interactions and targeted campaigns. Our objective in this work is to establish a taxonomy of common negative experiences encountered by those communicating medical science, and suggest guidelines so that they may be circumvented.DesignWe establish a taxonomy of the common negative experiences reported by those communicating medical science, informed by surveying medical science communicators with public platforms.Participants142 prominent medical science communicators (defined as having >1000 Twitter followers and experience communicating medical science on social and traditional media platforms) were invited to take part in a survey, with 101 responses.Results101 responses were analysed. Most participants experienced abusive behaviour (91.9%), including persistent harassment (69.3%) and physical violence and intimidation (5.9%). A substantial number (38.6%) received vexatious complaints to their employers, professional bodies or legal intimidation. The majority (62.4%) reported negative mental health sequelae due to public outreach, including depression, anxiety and stress. A significant minority (19.8%) were obligated to seek police advice or legal counsel due to actions associated with their outreach work. While the majority targeted with vexatious complaints felt supported by their employer/professional body, 32.4% reported neutral, poor or non-existent support.ConclusionsThose engaging in public outreach of medical science are vulnerable to negative repercussions, and we suggest guidelines for professional bodies and organisations to remedy some of these impacts on front-line members.

Random assignment of individual participants in clinical trials entails two steps: (i) generating an unbiased treatment allocation schedule; and (ii) applying the schedule without foreknowledge of upcoming allocations. These two steps were implicit in the famous randomized trial of streptomycin for pulmonary tuberculosis in 1948, and were recognized explicitly in some early books on controlled trials. However, half a century later, no widely accepted term denoting the process of concealing upcoming allocations had been adopted. In 1983 Thomas Chalmers and colleagues termed that process “randomization blinding,” and showed that blinded randomization and unblinded randomization were associated with differing estimates of treatment effects; however, their terminology was subsequently rarely used. In the mid-1990s we suggested that the term “allocation concealment” would be preferable to “blinded randomization,” particularly to avoid terminology that might be confused with blinding of treatments after random allocation. After controlling for more factors than had been accounted for by Chalmers and colleagues, we demonstrated an association between allocation concealment and estimates of treatment effects. Moreover, as further indication of bias, inadequately concealed trials displayed more heterogeneity than adequately concealed trials. Notably, our modeling and methodological approach to examine the associations between trial quality and estimates of treatment effects has gained recognition and achieved replication. A PubMed search for the term “allocation concealment” between 1972 and 1993 in “any field” yielded no instances, compared with 1471 between 1995 and 2016. Google Scholar found 25 matches before 1994 and over 30,000 matches after. Although the term might still be improved to avoid occasional misconceptions about its meaning, we assume that it has been widely adopted by authors and editors because they find the term useful.

Ultraviolet radiation (UVR) has been an effective treatment for a number of chronic skin disorders, and its ability to alleviate these conditions has been well documented. Although nonionizing, exposure to ultraviolet (UV) radiation is still damaging to deoxyribonucleic acid integrity, and has a number of unpleasant side effects ranging from erythema (sunburn) to carcinogenesis. As the conditions treated with this therapy tend to be chronic, exposures are repeated and can be high, increasing the lifetime probability of an adverse event or mutagenic effect. Despite the potential detrimental effects, quantitative ultraviolet dosimetry for phototherapy is an underdeveloped area and better dosimetry would allow clinicians to maximize biological effect whilst minimizing the repercussions of overexposure. This review gives a history and insight into the current state of UVR phototherapy, including an overview of biological effects of UVR, a discussion of UVR production, illness treated by this modality, cabin design and the clinical implementation of phototherapy, as well as clinical dose estimation techniques. Several dose models for ultraviolet phototherapy are also examined, and the need for an accurate computational dose estimation method in ultraviolet phototherapy is discussed.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are among the most frequently prescribed groups of drugs worldwide. The use of NSAIDs is associated with a high number of significant adverse effects. Recently, the safety of PPIs has also been challenged. Capsule endoscopy studies reveal that even low-dose NSAIDs are responsible for gut mucosal injury and numerous clinical adverse effects, for example, bleeding and anemia, that might be difficult to diagnose. The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy. In this review, we discuss this important clinical problem and review relevant aspects of epidemiology, pathophysiology, and management. We also present the hypothesis that even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual. PubMed was searched using the following key words (each key word alone and in combination): gut microbiota, microbiome, non-steroidal anti inflammatory drugs, proton pump inhibitors, enteropathy, probiotic, antibiotic, mucosal injury, enteroscopy, and capsule endoscopy. Google engine search was also carried out to identify additional relevant articles. Both original and review articles published in English were reviewed.

In early pregnancy, medical abortion avoids surgery but is associated with more pain and bleeding and a slightly higher risk of incomplete abortion. Data show that neither type of abortion increases the risk of long-term mental health problems or breast cancer or adversely affects fertility.

Background Acne is a common skin disorder among women. Although no uniform approach to the management of acne exists, combination oral contraceptives (COCs), which contain an estrogen and a progestin, often are prescribed for women. Objectives To determine the effectiveness of combined oral contraceptives (COCs) for the treatment of facial acne compared to placebo or other active therapies. Search strategy We searched for randomized controlled trials of COCs and acne in the computerized databases of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, POPLINE, and LILACS. We also searched for clinical trials in ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). We wrote to authors of identified trials to seek any unpublished or published trials that we might have missed. Selection criteria All randomized controlled trials reported in any language that compared the effectiveness of a COC containing an estrogen and a progestin to placebo or another active therapy for acne in women were eligible. Data collection and analysis We extracted data on total and specific (i.e., open or closed comedones, papules, pustules and nodules) facial lesion counts; acne severity grades; global assessments by the clinician or the participant and discontinuation due to adverse events. Data were entered and analyzed in RevMan. Main results The search yielded 25 trials: 7 placebo-controlled trials made 4 different comparisons, 17 trials made 13 comparisons between 2 different COC regimens, and 1 additional trial compared a COC to an antibiotic. COCs reduced acne lesion counts, severity grades and self-assessed acne compared to placebo. Differences in the comparative effectiveness of COCs containing varying progestin types and dosages, though, were less clear. COCs that contained chlormadinone acetate or cyproterone acetate improved acne better than levonorgestrel, although this apparent advantage was based on limited data. A COC with cyproterone acetate might result in better acne outcomes than one with desogestrel; however, the three studies comparing these COCs produced conflicting results. Likewise, levonorgestrel showed a slight improvement over desogestrel in acne outcomes in one trial, but a second trial found the COC groups were similar. Authors' conclusions The four COCs evaluated in placebo-controlled trials are effective in reducing inflammatory and non-inflammatory facial acne lesions. Few important differences were found between COC types in their effectiveness for treating acne. How COCs compare to alternative acne treatments is unknown since limited data were available regarding this question. Plain Language Summary Effect of birth control pills on acne in women Acne is a common skin problem for women. Several treatments are available. Combined birth control pills, which have the hormones estrogen and progestin, are often prescribed for women with acne. This review looked at how well birth control pills worked to treat facial acne. We did a computer search for studies of birth control pills and acne treatment. Outcomes could be the amount of acne, how severe the acne was, and how many women dropped out early due to problems. We wrote to researchers to find other trials. We included randomized trials in any language that compared two types of birth control pills, a pill and a placebo or 'dummy,' or a pill and another acne treatment. We found 25 trials: 7 trials used 'dummies,' 17 compared different types of birth control pills, and 1 compared a pill and an antibiotic. The three pills studied in trials with dummies worked well to reduce facial acne. In comparing pills with different hormones, no important differences were seen. The conclusions did not change when we added trials in this update to the other studies. Most trials compared two types of pills for acne treatment. Better quality studies are needed to compare one birth control pill with another. How birth control pills compare to other acne treatments like antibiotics is unclear. Since birth control pills improve acne, they can be used to treat women with acne who also want birth control.

Purpose: Ultraviolet phototherapy is a widely used treatment which has exceptional success with a variety of skin conditions. Over-exposure to ultraviolet radiation (UVR) can however be detrimental and cause side effects such as erythema, photokeratisis, and even skin cancer. Quantifying patient dose is therefore imperative to ensure biologically effective treatment while minimizing negative repercussions. A dosemodel for treatment would be valuable in achieving these ends. Methods: Prior work by the authors concentrated on modeling the output of the lamps used in treatment and it was found a line source model described the output from the sources to a high degree. In practice, these lamps are surrounded by reflective anodized aluminum in patient treatment cabins and this work extends the model to quantify specular reflections from these planes on patient dose. Results: The extension of the model to allow for reflected images in addition to tube output shows a remarkably good fit to the actual data measured. Conclusions: The reflection model yields impressive accuracy and is a good basis for full UVR cabin modeling.

Purpose: Ultraviolet phototherapy is widely used in the treatment of numerous skin conditions. This treatment is well established and largely beneficial to patients on both physical and psychological levels; however, overexposure to ultraviolet radiation (UVR) can have detrimental effects, such as erythemal responses and ocular damage in addition to the potentially carcinogenic nature of UVR. For these reasons, it is essential to control and quantify the radiationdose incident upon the patient to ensure that it is both biologically effective and has the minimal possible impact on the surrounding unaffected tissue. Methods: To date, there has been little work on dose modeling, and the output of artificial UVR sources is an area where research has been recommended. This work characterizes these sources by formalizing an approach from first principles and experimentally examining this model. Results: An implementation of a line source model is found to give impressive accuracy and quantifies the output radiation well. Conclusions: This method could potentially serve as a basis for a full computational dose model for quantifying patient dose.

Die reiche Geschichte der Verblindung erstreckt sich uber zwei Jahrhunderte. Weltweit wissen die meisten Wissenschaftler, was mit Verblindung gemeint ist, doch hinter einem nur allgemeinen Verstandnis lauert oftmals Verwirrung. Begriffe wie einfachblind, doppelblind und dreifachblind haben fur verschiedene Personen unterschiedliche Bedeutung. Auserdem verwechseln viele medizinische Forscher die Verblindung mit der Geheimhaltung der Randomisierungsliste. Solche Verwechslungen zeigen, dass beide Begriffe missverstanden werden. Verblindung bedeutet, das Studienteilnehmer, Studienarzte (meist diejenigen, die die Behandlung verabreichen) oder Bewerter (diejenigen, die die Outcome-Daten erheben) die zugeteilte Intervention nicht kennen, sodass sie durch dieses Wissen nicht beeinflusst werden. Im Allgemeinen fuhrt die Verblindung zu einem Ruckgang der unterschiedlichen Bewertung von Behandlungsergebnissen (Informationsbias). Sie kann bei den Studienteilnehmern aber auch die Compliance und die Bereitschaft zum Verbleib in der Studie verbessern, wahrend sie die Anwendung zusatzlicher Pflege- oder Therapiemasnahmen (manchmal als Ko-Intervention bezeichnet) reduziert. Studienarzte und Leser gehen vielfach gutglaubig davon aus, dass eine randomisierte Studie einfach dann als hochwertig anzusehen ist, wenn sie doppelt verblindet wurde, als ob es sich bei der doppelten Verblindung um die Conditio sine qua non einer randomisierten, kontrollierten Studie handelte. Auch wenn die Doppelverblindung (Verblindung von Studienarzten, Studienteilnehmern und Bewertern der Behandlungsergebnisse) auf eine solide Studienplanung schliesen lasst, durfen Studien ohne Doppelverblindung nicht automatisch als minderwertig eingestuft werden. Anstatt sich ausschlieslich auf Begriffe wie Doppelverblindung zu verlassen, sollten Wissenschaftler explizit angeben, wer wie verblindet wurde. Wir empfehlen, den Ergebnissen mehr Glauben zu schenken, wenn zumindest die Bewertung der Studienergebnisse verblindet erfolgte, mit Ausnahme von objektiven Endpunkten wie etwa der Mortalitat, die kaum Raum fur systematische Fehler (Bias) lassen. Wenn Studienarzte ihre Verblindungsmasnahmen korrekt angeben, kann der Leser sie beurteilen. Leider lasst die Berichterstattung in vielen Artikeln zu wunschen ubrig. Wenn in einem Beitrag behauptet wird, es habe eine Verblindung stattgefunden, ohne dies weiter zu erklaren, sollte der Leser hinsichtlich ihrer Bias reduzierenden Wirkung skeptisch bleiben.

Korrekte Randomisierung beruht auf einer angemessenen Geheimhaltung der Randomisierungsliste. Die Geheimhaltung sorgt dafur, dass Arzte und Studienteilnehmer die nachfolgenden Zuteilungen nicht kennen. Ohne Geheimhaltung konnen auch korrekt erstellte Randomisierungslisten ausgehebelt werden. Dabei geht die so wichtige Eigenschaft der Verzerrungsfreiheit randomisierter, kontrollierter Studien mit hochst argerlichen Implementierungsproblemen einher. Haufig steht eine angemessene Geheimhaltung arztlichen Neigungen entgegen, was bei denen, die Studien durchfuhren, zu Verdruss fuhrt. Randomisierte, kontrollierte Studien sind Arzten ein Grauel. Viele, die an Studien teilnehmen, kommen in Versuchung, die Zuteilungen zu entschlusseln, und unterlaufen dadurch die Randomisierung. Fur manche Studienarzte stellt die Entschlusselung des Zuteilungsschemas eine viel zu grose intellektuelle Herausforderung dar, als dass sie ihr widerstehen konnten. Ob ihre Motive nun harmloser oder boshafter Natur sind, in jedem Fall untergraben derlei Manipulationen die Validitat einer Studie. Tatsachlich fuhrt eine unzureichende Geheimhaltung im Durchschnitt zu ubertriebenen Effektschatzern, doch mit Raum fur Bias in beide Richtungen. Studienarzte sind in ihren Bemuhungen um die Entschlusselung von Zuteilungslisten sehr erfinderisch, sodass Studienplaner bei ihren Planungsanstrengungen ebenso geschickt vorgehen mussen, um dies zu verhindern. Sie mussen ihre Studien durch eine angemessene Geheimhaltung der Behandlungszuteilung wirksam vor Selektionsbias und Confounding schutzen. Vergleiche der Ausgangscharakteristika zu wichtigen prognostischen Variablen sollten angegeben werden. Hypothesentests fur Ausgangscharakteristika sind dagegen uberflussig und konnten sogar Schaden anrichten, wenn sie Studienleiter dazu verleiten, Unausgewogenheiten hinsichtlich der Ausgangscharakteristika zu verschweigen. „Der Grund dafur, warum die kontrollierte Studie des Medical Research Council uber Streptomycin zur Behandlung von Lungentuberkulose als Meilenstein betrachtet werden sollte, ist nicht, wie haufig vermutet wird, dass zur Generierung der Randomisierungsliste Zufallszahlentabellen verwendet wurden. … Der Grund sind vielmehr die eindeutig beschriebenen Vorsichtsmasnahmen, die ergriffen wurden, um die Randomisierungsliste vor den an der Rekrutierung der Patienten beteiligten Personen geheim zu halten [1] .“

Die randomisierte kontrollierte Studie ist zwar der Goldstandard der klinischen Forschung, doch ist die Randomisierung nach wie vor der dabei vermutlich am wenigsten verstandene Aspekt. Dabei fuhren Defizite bei der Randomisierung zu Selektionsbias und Storeffekten (Confounding). Wissenschaftler sollten einen weiten Bogen um alle systematischen, nicht-zufalligen Zuteilungsverfahren machen. Die Studienteilnehmer sollten den Vergleichsgruppen auf der Grundlage von Zufallsverfahren zugeteilt werden. Die elementarste der verschiedenen Methoden zur Generierung einer Randomisierungsliste ist die einfache (uneingeschrankte) Randomisierung, die dem wiederholten fairen Munzwurf vergleichbar ist. Zudem wird die einfache Randomisierung, was die Vermeidung von systematischen Fehlern (Bias) anbelangt, von keinem anderen Verfahren ubertroffen, und sei es auch noch so komplex und ausgeklugelt. Studienleiter sollten diese Methode deshalb haufiger anwenden als bisher, und der Leser sollte ungleiche Gruppengrosen erwarten und akzeptieren. Etliche andere komplizierte Verfahren der eingeschrankten Randomisierung begrenzen die Wahrscheinlichkeit unerwunschter Fallzahlunterschiede in den Interventionsgruppen. Das am haufigsten zur eingeschrankten Randomisierung angewendete Verfahren ist die Blockrandomisierung. Bei Anwendung dieses Verfahrens sollten Blockgrosen nach dem Zufallsprinzip variiert und grosere Blocklangen gewahlt werden; dies gilt vor allem fur unverblindete Studien. Weitere eingeschrankte Verfahren wie die Urnenrandomisierung vereinen die vorteilhaften Eigenschaften der einfachen mit denen der eingeschrankten Randomisierung, indem sie die Unvorhersagbarkeit zwar grostenteils bewahren, gleichzeitig aber auch ein gewisses Gleichgewicht herstellen. Die Wirksamkeit der geschichteten Randomisierung hangt davon ab, dass man ein eingeschranktes Randomisierungsverfahren verwendet, um die Gruppenzuteilung in den einzelnen Schichten (Strata) zu balancieren. Die Generierung einer angemessenen Randomisierungsliste kostet nur wenig Zeit und Muhe; der Lohn sind wissenschaftliche Genauigkeit und Glaubwurdigkeit. Untersucher sollten entsprechende Ressourcen fur die Generierung adaquat randomisierter Studien bereitstellen und ihre Methoden eindeutig darlegen.

Summary Ending the silent pandemic of unsafe abortion is an urgent public-health and human-rights imperative. As with other more visible global-health issues, this scourge threatens women throughout the developing world. Every year, about 19–20 million abortions are done by individuals without the requisite skills, or in environments below minimum medical standards, or both. Nearly all unsafe abortions (97%) are in developing countries. An estimated 68 000 women die as a result, and millions more have complications, many permanent. Important causes of death include haemorrhage, infection, and poisoning. Legalisation of abortion on request is a necessary but insufficient step toward improving women's health; in some countries, such as India, where abortion has been legal for decades, access to competent care remains restricted because of other barriers. Access to safe abortion improves women's health, and vice versa, as documented in Romania during the regime of President Nicolae Ceausescu. The availability of modern contraception can reduce but never eliminate the need for abortion. Direct costs of treating abortion complications burden impoverished health care systems, and indirect costs also drain struggling economies. The development of manual vacuum aspiration to empty the uterus, and the use of misoprostol, an oxytocic agent, have improved the care of women. Access to safe, legal abortion is a fundamental right of women, irrespective of where they live. The underlying causes of morbidity and mortality from unsafe abortion today are not blood loss and infection but, rather, apathy and disdain toward women.

Likelihood ratios can refine clinical diagnosis on the basis of signs and symptoms; however, they are underused for patients' care. A likelihood ratio is the percentage of ill people with a given test result divided by the percentage of well individuals with the same result. Ideally, abnormal test results should be much more typical in ill individuals than in those who are well (high likelihood ratio) and normal test results should be most frequent in well people than in sick people (low likelihood ratio). Likelihood ratios near unity have little effect on decision-making; by contrast, high or low ratios can greatly shift the clinician's estimate of the probability of disease. Likelihood ratios can be calculated not only for dichotomous (positive or negative) tests but also for tests with multiple levels of results, such as creatine kinase or ventilation-perfusion scans. When combined with an accurate clinical diagnosis, likelihood ratios from ancillary tests improve diagnostic accuracy in a synergistic manner.

Summary Investigators should properly calculate sample sizes before the start of their randomised trials and adequately describe the details in their published report. In these a-priori calculations, determining the effect size to detect—eg, event rates in treatment and control groups—reflects inherently subjective clinical judgments. Furthermore, these judgments greatly affect sample size calculations. We question the branding of trials as unethical on the basis of an imprecise sample size calculation process. So-called underpowered trials might be acceptable if investigators use methodological rigor to eliminate bias, properly report to avoid misinterpretation, and always publish results to avert publication bias. Some shift of emphasis from a fixation on sample size to a focus on methodological quality would yield more trials with less bias. Unbiased trials with imprecise results trump no results at all. Clinicians and patients deserve guidance now.

Use of control (comparison) groups is a powerful research tool. In case-control studies, controls estimate the frequency of an exposure in the population under study. Controls can be taken from known or unknown study populations. A known group consists of a defined population observed over a period, such as passengers on a cruise ship. When the study group is known, a sample of the population can be used as controls. If no population roster exists, then techniques such as random-digit dialling can be used. Sometimes, however, the study group is unknown, for example, motor-vehicle crash victims brought to an emergency department, who may come from far away. In this situation, hospital controls, neighbourhood controls, and friend, associate, or relative controls can be used. In general, one well-selected control group is better than two or more. When the number of cases is small, the ratio of controls to cases can be raised to improve the ability to find important differences. Although no ideal control group exists, readers need to think carefully about how representative the controls are. Poor choice of controls can lead to both wrong results and possible medical harm.

UNLABELLED The impact of lactation on maternal weight after delivery remains unclear. To address this question, we performed a systematic review of the literature. We searched PubMed, POPLINE, EMBASE, and LILACS computerized databases for relevant articles and classified the evidence using the U.S. Preventive Services Task Force rating system. We found 42 studies, of which 28 contained relevant information: 15 prospective cohort studies, 1 retrospective cohort study, 1 cross-sectional study, and 11 case-series reports. The methods used in these studies varied widely, thus precluding aggregation of results. Level II-2 and III evidence supports a class "C" recommendation: insufficient evidence exists to support an effect of lactation on maternal weight after delivery. Better longitudinal studies with a clear definition of breast-feeding; clear, specific outcome measures; study periods extending 1 or 2 years after delivery; and better control of potentially confounding factors will be needed to resolve this question. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES After completion of this article, the reader will be able to compile the literature on the effect of lactation on maternal weight, to compare the various studies, and to summarize the data on the effect of lactation on maternal weight gain.

Hormonal emergency contraception is safe, effective, and available by prescription in the United States. This article explains why dropping the prescription requirement for emergency contraception would pose no risk to women and would improve public health by preventing unintended pregnancies. The author points out that over-the-counter sale of emergency contraceptive products is appropriate, because women are easily able to determine when and how to use them.

In the early 1800s, Karl Baedeker, a German publisher, launched a series of travel guidebooks. By the twentieth century, the guidebooks had achieved such international fame that his name became synonymous with the genre. As clinicians wade into the flood of clinical research being published, a guidebook can be a handy navigational aid. In this article, we offer a Baedeker for reading the literature, an approach distilled from our three decades of clinical practice and research experience. Interested readers can find more detail in our recent series on research methods in The Lancet (1–11). Reading research is mandatory if a clinician is to keep up. With greater age and experience, clinical practice should improve. Paradoxically, however, greater age and clinical experience often translate into rusty practice. As has been shown for treatment of hypertension, one of the strongest determinants of appropriate practice is number of years since medical school graduation; stated alternatively, practice quality deteriorates over time (12, 13). Keeping current is difficult after leaving formal training, and that difficulty may be greater for those who practice in smaller communities (14). If one cannot (or chooses not to) read, then one’s practice is condemned to becoming obsolete. This indirectly hurts patients. A second benefit of critical reading of clinical research is appropriate adoption (or rejection) of new technologies. Obstetrics and gynecology has a long, blemished record of adoption and dissemination of new tests and procedures without evidence of benefit (15). Episiotomy, one of the most common operations performed on adults in the last century, swept into practice based on DeLee’s analogy that childbirth is tantamount to impalement on a pitchfork (16). Urinary estriol measurement to monitor a fetus thought to be in jeopardy has been replaced by an even more expensive and cumbersome test (nonstress testing) for which no evidence of benefit exists either (17). Electronic fetal monitoring took U.S. obstetrics by storm in the absence of demonstrable benefit; a quarter century of study has failed to show any lasting benefit to babies (18), and the poor predictive value of worrisome tracings has needlessly driven up the cesarean delivery rate. Liquid-based cervical cytology screening has not been shown to reduce cervical cancer incidence or mortality, and the cost per case of cancer detected is higher with this approach than with conventional cytology (19). Ironically, poor women at highest risk of this cancer may not be able to afford the screening (20). Reports of new laparoscopy operations have recently been retracted by an editor, because the reported information could not be corroborated (21, 22). This hurt patients as well. While reading clinical research is clearly important, the task is daunting. First, the volume being published is overwhelming, with an estimated 25,000 biomedical journals in print. One challenge is picking and choosing what to read. In general, most readers should limit themselves to articles that are both relevant to their practices and likely to be of high scientific value. These two criteria will immediately narrow the field. Once an article is selected, another problem emerges: many clinicians in obstetrics and gynecology report that they cannot critically read the literature (23). Our graduates leave their training full of the Correspondence to: Family Health International, P.O. Box 13950, Research Triangle Park, NC 27709. Email: dgrimes@fhi.org

Summary Proper randomisation means little if investigators cannot include all randomised participants in the primary analysis. Participants might ignore follow-up, leave town, or take aspartame when instructed to take aspirin. Exclusions before randomisation do not bias the treatment comparison, but they can hurt generalisability. Eligibility criteria for a trial should be clear, specific, and applied before randomisation. Readers should assess whether any of the criteria make the trial sample atypical or unrepresentative of the people in which they are interested. In principle, assessment of exclusions after randomisation is simple: none are allowed. For the primary analysis, all participants enrolled should be included and analysed as part of the original group assigned (an intent-to-treat analysis). In reality, however, losses frequently occur. Investigators should, therefore, commit adequate resources to develop and implement procedures to maximise retention of participants. Moreover, researchers should provide clear, explicit information on the progress of all randomised participants through the trial by use of, for instance, a trial profile. Investigators can also do secondary analyses on, for instance, per-protocol or as-treated participants. Such analyses should be described as secondary and non-randomised comparisons. Mishandling of exclusions causes serious methodological difficulties. Unfortunately, some explanations for mishandling exclusions intuitively appeal to readers, disguising the seriousness of the issues. Creative mismanagement of exclusions can undermine trial validity.

Most women and their clinicians are unaware that IUDs confer important noncontraceptive health benefits. This review summarizes the evidence from published articles on this topic. We conducted a series of systematic literature searches to identify articles on the noncontraceptive health benefits of IUD use. We reviewed the potentially pertinent ones for content, grouped them according to type of IUD, and evaluated them using the U.S. Preventive Services Task Force rating system. Over 500 titles were identified and several hundred abstracts were reviewed. Use of nonhormonal IUDs (plastic and copper) was associated with a decrease in endometrial cancer. The levonorgestrel intrauterine system can treat a variety of gynecological disorders, including menorrhagia and anemia. The levonorgestrel system has also been used successfully as part of hormone replacement therapy, as adjuvant therapy with tamoxifen, and as an alternative to hysterectomy for women with bleeding problems. Like oral contraceptives, intrauterine contraceptives confer important noncontraceptive health benefits.

Summary Epidemiologists benefit greatly from having case-control study designs in their research armamentarium. Case-control studies can yield important scientific findings with relatively little time, money, and effort compared with other study designs. This seemingly quick road to research results entices many newly trained epidemiologists. Indeed, investigators implement case-control studies more frequently than any other analytical epidemiological study. Unfortunately, case-control designs also tend to be more susceptible to biases than other comparative studies. Although easier to do, they are also easier to do wrong. Five main notions guide investigators who do, or readers who assess, case-control studies. First, investigators must explicitly define the criteria for diagnosis of a case and any eligibility criteria used for selection. Second, controls should come from the same population as the cases, and their selection should be independent of the exposures of interest. Third, investigators should blind the data gatherers to the case or control status of participants or, if impossible, at least blind them to the main hypothesis of the study. Fourth, data gatherers need to be thoroughly trained to elicit exposure in a similar manner from cases and controls; they should use memory aids to facilitate and balance recall between cases and controls. Finally, investigators should address confounding in case-control studies, either in the design stage or with analytical techniques. Devotion of meticulous attention to these points enhances the validity of the results and bolsters the reader's confidence in the findings.

Summary The randomised controlled trial sets the gold standard of clinical research. However, randomisation persists as perhaps the least-understood aspect of a trial. Moreover, anything short of proper randomisation courts selection and confounding biases. Researchers should spurn all systematic, non-random methods of allocation. Trial participants should be assigned to comparison groups based on a random process. Simple (unrestricted) randomisation, analogous to repeated fair coin-tossing, is the most basic of sequence generation approaches. Furthermore, no other approach, irrespective of its complexity and sophistication, surpasses simple randomisation for prevention of bias. Investigators should, therefore, use this method more often than they do, and readers should expect and accept disparities in group sizes. Several other complicated restricted randomisation procedures limit the likelihood of undesirable sample size imbalances in the intervention groups. The most frequently used restricted sequence generation procedure is blocked randomisation. If this method is used, investigators should randomly vary the block sizes and use larger block sizes, particularly in an unblinded trial. Other restricted procedures, such as urn randomisation, combine beneficial attributes of simple and restricted randomisation by preserving most of the unpredictability while achieving some balance. The effectiveness of stratified randomisation depends on use of a restricted randomisation approach to balance the allocation sequences for each stratum. Generation of a proper randomisation sequence takes little time and effort but affords big rewards in scientific accuracy and credibility. Investigators should devote appropriate resources to the generation of properly randomised trials and reporting their methods clearly.

Immediate postabortal insertion of an intrauterine contraceptive device (IUCD) has many benefits, including the imminent return of ovulation, immediate protection, and avoiding the discomfort and bleeding of a separate procedure. Some clinicians, however, are concerned that IUCD perforation and expulsion may be more frequent in the postabortal uterus and that immediate insertion may increase the risk of upper genital tract infection. In addition, the contraceptive efficacy of the IUCD in this setting is not clear. Consequently, the authors reviewed eight randomized trials with at least one treatment arm entailing IUCD insertion immediately after induced or spontaneous miscarriage. Women of any age and gravidity were eligible for inclusion. The trials, in general, were of fair methodological quality. After 2 years of follow-up in a trial of IUCD insertion immediately after induced abortion, there were three perforations, representing 1 per 1000 insertions, and 157 expulsions (7%). The 70 intrauterine or ectopic pregnancies represented 2 per 100 woman-years. Twelve cases of pelvic inflammatory disease translated into 0.4 per 100 woman-years. In this trial and one of IUCD insertion after miscarriage, continuation rates at 12 months ranged from 54% to 64%. The Copper T 220C proved better than the Lippes Loop D and Copper 7 models in World Health Organization trials. Pregnancy rates after 1 year ranged from 0.6% to 2.1%. There were no significant differences in the one trial that directly compared immediate with delayed postabortal insertion. The risk of expulsion increased with advancing gestational age. The investigators believe that postabortal IUCD insertion is an effective and safe practice. Rates of pelvic inflammatory disease are low. A higher risk of IUCD expulsion with increasing gestational age may be outweighed by the opportunity for immediate, highly effective contraception in a single procedure.

The alleged association between induced abortion and breast cancer is one of the most controversial and important questions in women's health today.To help clinicians provide appropriate counseling, we reviewed both the primary data and review articles on this topic. We identified the studies and re

Summary Background The value of antibiotic prophylaxis before insertion of an intrauterine device (IUD) remains uncertain. We undertook a triple-masked, randomised, placebo-controlled trial to find out whether such prophylaxis reduces the rate of IUD removal within 90 days. Methods 11 clinic sites in southern California enrolled women who requested IUD insertion and were at low risk of sexually transmitted infection according to self-reported medical history. We randomly assigned 1985 participants either 500 mg azithromycin or placebo capsules of identical appearance taken about 1 h before insertion of a Copper T 380A IUD. 118 women did not have an IUD inserted. We followed up 1833 of the remaining 1867 (98%) participants for at least 90 days after insertion. Findings The rate of IUD removal for any reason other than partial expulsion was 3·8% (35/918) in the antibiotic group and 3·4% (31/915) in the placebo group (relative risk 1·1 [95% Cl 0·7–1·8]). The two treatment groups sought medical attention with equal frequency (mean 38 visits per 100 women). During the 90 days after IUD insertion, only one woman from each assignment group had salpingitis, as defined by established criteria. Interpretation Prophylaxis with azithromycin did not affect the likelihood that a woman would retain her IUD at 90 days or the frequency of postinsertion medical attention. In appropriately screened women, the risk of upper-genitaltract infection is negligible after IUD insertion, with or without the administration of prophylactic antibiotics.

Contraceptive education is generally considered a standard component of postpartum care but the effectiveness is seldom examined. Two-thirds of postpartum women may have unmet needs for contraception and many adolescents become pregnant again within a year of giving birth. Women may prefer to discuss contraception prenatally or after hospital discharge. The objective of this systematic review was to assess the effects of educational interventions for postpartum mothers about contraceptive use. We searched computerized databases for randomized controlled trials that evaluated the effectiveness of postpartum contraceptive education. The intervention must have started within 1 month after delivery. The Mantel-Haenszel odds ratio was calculated with 95% confidence interval for the dichotomous outcomes. Eight trials met the inclusion criteria. Of 4 short-term interventions 1 did not have sufficient data and 1 was statistically underpowered. The remaining 2 showed a positive effect on contraceptive use. Of 4 multifaceted programs 2 showed fewer pregnancies or births among adolescents in the experimental group that had enhanced services and 1 structured home-visiting program showed more contraceptive use. The effective interventions were conducted in Australia Nepal Pakistan and the United States. Postpartum education about contraception led to more contraception use and fewer unplanned pregnancies. Short-term interventions were limited by self-reported outcomes or showing no effect for many comparisons. The longer-term programs were promising and not necessarily more costly than usual care. Health care providers can determine if 1 of these interventions suits their setting and level of resources. Target Audience: Obstetricians & Gynecologist Family Physicians Learning Objectives: After completing this educational activity the participant should be better able to assess the importance of assessing delivery methods when examining intervention quality evaluate the evidence from randomized trials on the effectiveness of postpartum education and employ why additional research on postpartum education is needed for improving clinical practice.

Sir, ‘ The statins trials resolved the controversy ’1 is an error of scientific thought, and it is sad that so many respected clinical scientists such as Prof. G.R. Thompson fail to appreciate this. Yes, there has been a controversy concerning cholesterol, which is clearly a risk indicator, not for just coronary heart disease (CHD) but for all deaths, but only in men of working age.2,3 We know from Framingham studies that cholesterol is neutral in women and older men4 and we know from other studies that a high blood cholesterol is a survival advantage in elderly people.5,6 The question following the MRFIT2 and Whitehall3 studies is whether the elevated level of cholesterol is a risk indicator on a causative pathway or whether it is a reflection of existing sub-clinical CHD. Subsequent studies have shown that it matches the inflammatory marker C-reactive protein …

From 1977 to 1988, an epidemic of antiabortion violence took place in the United States, involving 110 cases of arson, firebombing, or bombing. The epidemic peaked in 1984, when there were 29 attacks. Nearly all sites (98%) were clinics that provided abortions. Facilities in 28 states and the District of Columbia were involved. The national rate of violence was 3.7 per 100 abortion providers and 7.2 per 100 nonhospital abortion providers. The national ratio of violence per 100,000 abortions performed was 0.6 Arson was both the most frequent (39% of all cases) and the most damaging (mean cost $141,000) type of violence. The epidemic appears partially attributable to multiple point-source outbreaks of violence caused by small numbers of individuals or groups. Thirty-three persons have been convicted to date. Vigorous prosecution of perpetrators and the reemergence of clinics after damage probably helped to curb the epidemic.Between 1977-88 there was an epidemic of violence directed against abortion clinics. These attacks consisted of 110 cases of arson, firebombing, or bombing. In 1984 the epidemic reached a peak with 29 attacks. 98% of the sites were clinics that provided abortion services. This study surveys the frequency of attacks per states based on 3 different denominators: 1) number of abortion providers, 2) cumulative number of abortions performed from 1977-88, 3) estimated number of women in the 15-44 age group as of July 1, 1982. During the study period 1977-88, the National Abortion Federation reported the following violent acts against clinics: 222 clinic invasions, 220 acts of clinic vandalism, 216 bomb threats, 65 death threats, 46 assault and batteries, 20 burglaries, and 2 kidnapings. Vigorous investigation and convictions have slowed the epidemic. The longest sentence handed down was 30 years and the largest fine was $350,000. The biggest effect it has had is financial. The direct cost is $7.6 million, but this does not include the cost of clinics that were destroyed and not rebuilt. It does not include the cost of related expenses for lawyers and security, increased insurance, new licensing requirements, and staff recruitment. Also, lost time waiting for repairs and rescheduling of patients to other facilities are not included in this figure. Violence of this nature does nothing to end the debate over abortion, it also does not reduce the number of abortions. It only raises the cost of abortion, and inconveniences women seeking abortion. Sex education, personal responsibility, and more widespread and effective contraceptive use would all reduce the need for abortion.

UNLABELLED In 2006, the Accreditation Council for Continuing Medical Education highlighted the need for linking educational activities to changes in competence, performance, or patient outcomes. Hence, educational providers increasingly need to know what strategies are effective. The Cochrane Library is widely regarded as the best source of credible evidence concerning health care. The authors searched the Cochrane Database of Systematic Reviews (issue 4 for 2006) using the search terms "continuing medical education," "medical education," and "continuing education." They conducted a second complementary search of this database by review group (Effective Practice and Organization of Care). Finally, the authors examined the references of recent review articles for Cochrane reviews and found 9 relevant reviews. The most effective educational methods were the most interactive. Combined didactic presentations and workshops were more effective than traditional didactic presentations alone. Medical education was more effective when more than 1 intervention occurred, especially if these interventions occurred over an extended period. Targeted education should focus on changing a behavior that is simple, because effect size is inversely proportional to the complexity of the behavior. In the era of evidence-based medicine, interventions-including educational ones-should reflect the best available evidence. Cochrane reviews of randomized controlled trials of educational methods provide important guidance that often challenges traditional didactic approaches. Integrating the findings from the Cochrane reviews may allow continuing medical education to be more successful in bringing about changes to healthcare providers' behavior. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES After completion of this article, the reader should be able to explain the scientific evidence concerning the effectiveness of various techniques used for continuing medical education, state the relative value of such techniques as traditional didactic lectures, conferences led by local opinion leaders, interactive workshops, and educational outreach visits, and identify the value and limitations of teaching critical appraisal skills.

There are many reasons why the dietary-heart-cholesterol hypothesis should be questioned, and why statins might be acting in some other way to reduce the risk of coronary heart disease. Here, I propose that rather than being cholesterol-lowering drugs per se, statins act as vitamin D analogues, and explain why. This proposition is based on published observations that the unexpected and unexplained clinical benefits produced by statins have also been shown to be properties of vitamin D. It seems likely that statins activate vitamin D receptors.

UNLABELLED The postcoital test has poor diagnostic and prognostic characteristics. Nevertheless, some physicians believe it can identify scanty or abnormal mucus that might impair fertility. One way to avoid "hostile" cervical mucus is intrauterine insemination. With this technique, the physician injects sperm directly into the uterine cavity through a small catheter passed through the cervix; the theory is to bypass the "hostile" cervical mucus. Although most gynecologic societies do not endorse use of intrauterine insemination for hostile cervical mucus, some physicians consider it an effective treatment for women with infertility thought the result of cervical mucus problems. The aim of this review was to determine the effectiveness of intrauterine insemination with or without ovarian stimulation in women with cervical hostility who failed to conceive.We searched Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 2, 2005, MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), POPLINE (to June 2005), and LILACS (to June 2005). In addition, we contacted experts and searched the reference list of relevant articles and book chapters. We included randomized and quasirandomized, controlled trials comparing intrauterine insemination with intercourse timed at the presumed fertile period. Participants were women with cervical hostility who failed to conceive for at least 1 year. We assessed the titles and abstracts of 386 publications and 2 reviewers independently abstracted data on methods and results from 5 studies identified for inclusion. The main outcome is pregnancy rate per couple. We did not pool the outcomes of the included 5 studies in a meta-analysis resulting from the methodological quality of the trials and variations in the patient characteristics and interventions. Narrative summaries of the outcomes are provided. Each study was too small for a clinically relevant conclusion. None of the studies provided information on important outcomes such as spontaneous abortion, multiple pregnancies, and ovarian hyperstimulation syndrome. There is no evidence from the published studies that intrauterine insemination is an effective treatment for cervical hostility. Given the poor diagnostic and prognostic properties of the postcoital test and the observation that the test has no benefit on pregnancy rates, intrauterine insemination (with or without ovarian stimulation) is unlikely to be a useful treatment for putative problems identified by postcoital testing. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES After completion of this article, the reader should be able to recall that there is a lack of adequate studies that support that intrauterine insemination (IUI) is an effective treatment of cervical hostility, explain that the postcoital test has poor diagnostic and prognostic properties, and state that the use of both tests has no benefit on pregnancy rates. EDITOR'S NOTE Although many assisted reproductive technology (ART) programs no longer perform postcoital tests, many perform intrauterine insemination (IUI), often with gonadotropins or clomiphene citrate, in their subfertile patients. Therefore, this review article will be of value to our readers who treat subfertile patients with IUI, whether or not they perform postcoital tests. For additional explanations of the statistical tests employed in this review, see D. Grimes, KF Schulz, Obstetrical and Gynecologic Survey, 57; Supplement 3: S35, September 2002; and D. Grimes, KF Schulz, Obstetrical and Gynecologic Survey, Supplement 2, S53-S69, September 2005.-RBJ.

Nonhormonal drugs for contraception in men may have advantages over hormonal methods. The nonhormonal methods can have more rapid onset and less interference with androgen-dependent functions. This systematic review summarizes the clinical studies evaluating nonhormonal drugs administered to men for contraception. Relevant clinical results were found for gossypol, which is derived from the cotton plant, and for extracts of Tripterygium, a plant used in Chinese traditional medicine. Randomized, controlled trials were available on the efficacy of gossypol and on the effect of gossypol on potassium levels. Gossypol had problems with low efficacy and toxicity. For Tripterygium, 2 observational studies described men who were treated for rheumatoid arthritis. Although sperm density was lower among those taking Tripterygium, later reports indicated some toxicity. Nonclinical research continues on isolates of Tripterygium. No clinical studies for contraception in men were found for nonhormonal vaccines or neem, which is also a plant used for medicinal purposes. Clinical trials studied injecting styrene maleic anhydride into the vas deferens, but no comparative data were provided. At this time, no safe and effective nonhormonal drug is available for contraception in men.ObstetriciansGynecologists, Family Physicians.After completion of this article, the reader should be able to state that the number of studies concerning the use of nonhormonal drugs for male contraception are very limited, point out that the two nonhormonal drugs used to a small degree have varying results and serious side effects, and recall that there are limited clinical studies on use of vas deferens injections and vaccines in humans.

Subgroup analyses can pose serious multiplicity concerns. By testing enough subgroups, a false-positive result will probably emerge by chance alone. Investigators might undertake many analyses but only report the significant effects, distorting the medical literature. In general, we discourage subgroup analyses. However, if they are necessary, researchers should do statistical tests of interaction, rather than analyse every separate subgroup. Investigators cannot avoid interim analyses when data monitoring is indicated. However, repeatedly testing at every interim raises multiplicity concerns, and not accounting for multiplicity escalates the false-positive error. Statistical stopping methods must be used. The O'Brien-Fleming and Peto group sequential stopping methods are easily implemented and preserve the intended alpha level and power. Both adopt stringent criteria (low nominal p values) during the interim analyses. Implementing a trial under these stopping rules resembles a conventional trial, with the exception that it can be terminated early should a treatment prove greatly superior. Investigators and readers, however, need to grasp that the estimated treatment effects are prone to exaggeration, a random high, with early stopping.

Multiplicity problems emerge from investigators looking at many additional endpoints and treatment group comparisons. Thousands of potential comparisons can emanate from one trial. Investigators might only report the significant comparisons, an unscientific practice if unwitting, and fraudulent if intentional. Researchers must report all the endpoints analysed and treatments compared. Some statisticians propose statistical adjustments to account for multiplicity. Simply defined, they test for no effects in all the primary endpoints undertaken versus an effect in one or more of those endpoints. In general, statistical adjustments for multiplicity provide crude answers to an irrelevant question. However, investigators should use adjustments when the clinical decision-making argument rests solely on one or more of the primary endpoints being significant. In these cases, adjustments somewhat rescue scattershot analyses. Readers need to be aware of the potential for under-reporting of analyses.

Objective: To assess the methodological quality of approaches to blinding and to handling of exclusions as reported in randomised trials from one medical specialty. Design: Survey of published, parallel group randomised controlled trials. Data sources: A random sample of 110 reports in which allocation was described as randomised from the 1990 and 1991 volumes of four journals of obstetrics and gynaecology. Main outcome measures: The adequacy of the descriptions of double blinding and exclusions after randomisation. Results: Though 31 trials reported being double blind, about twice as many could have been. Of the 31 trials only eight (26%) provided information on the protection of the allocation schedule and only five (16%) provided some written assurance of successful implemention of double blinding. Of 38 trials in which the authors provided sufficient information for readers to infer that no exclusions after randomisation had occurred, six (16%) reported adequate allocation concealment and none stated that an intention to treat analysis had been performed. That compared with 14 (27%) and six (12%), respectively, for the 52 trials that reported exclusions. Conclusions: Investigators could have double blinded more often. When they did double blind, they reported poorly and rarely evaluated it. Paradoxically, trials that reported exclusions seemed generally of a higher methodological standard than those that had no apparent exclusions. Exclusions from analysis may have been made in some of the trials in which no exclusions were reported. Editors and readers of reports of randomised trials should understand that flawed reporting of exclusions may often provide a misleading impression of the quality of the trial. Key messages Key messages Poor reporting of methods used for double blinding raises concerns about how effective blinding was in many of the studies Some investigators may have excluded some patients from the analysis but not reported these exclusions in their published paper Given the apparent failure to report exclusions, some of the more biased trials may be mistaken as unbiased and vice versa Investigators must pay more attention to executing and reporting their approaches to blinding and the handling of exclusions

An estimated 19 million unsafe abortions occur worldwide each year, resulting in the deaths of about 70,000 women. Legalization of abortion is a necessary but insufficient step toward improving women's health. Without skilled providers, adequate facilities and easy access, the promise of safe, legal abortion will remain unfulfilled, as in India and Zambia. Both suction curettage and pharmacological abortion are safe methods in early pregnancy; sharp curettage is inferior and should be abandoned. For later abortions, either dilation and evacuation or labour induction are appropriate. Hysterotomy should not be used. Timely and appropriate management of complications can reduce morbidity and prevent mortality. Treatment delays are dangerous, regardless of their origin. Misoprostol may reduce the risks of unsafe abortion by providing a safer alternative to traditional clandestine abortion methods. While the debate over abortion will continue, the public health record is settled: safe, legal, accessible abortion improves health.

We cringe at the pervasive notion that a randomised trial needs to yield equal sample sizes in the comparison groups. Unfortunately, that conceptual misunderstanding can lead to bias by investigators who force equality, especially if by non-scientific means. In simple, unrestricted, randomised trials (analogous to repeated coin-tossing), the sizes of groups should indicate random variation. In other words, some discrepancy between the numbers in the comparison groups would be expected. The appeal of equal group sizes in a simple randomised controlled trial is cosmetic, not scientific. Moreover, other randomisation schemes, termed restricted randomisation, force equality by departing from simple randomisation. Forcing equal group sizes, however, potentially harms the unpredictability of treatment assignments, especially when using permuted-block randomisation in non-double-blinded trials. Diminished unpredictability can allow bias to creep into a trial. Overall, investigators underuse simple randomisation and overuse fixed-block randomisation. For non-double-blinded trials larger than 200 participants, investigators should use simple randomisation more often and accept moderate disparities in group sizes. Such unpredictability reflects the essence of randomness. We endorse the generation of mildly unequal group sizes and encourage an appreciation of such inequalities. For non-double-blinded randomised controlled trials with a sample size of less than 200 overall or within any principal stratum or subgroup, urn randomisation enhances unpredictability compared with blocking. A simpler alternative, our mixed randomisation approach, attains unpredictability within the context of the currently understood simple randomisation and permuted-block methods. Simple randomisation contributes the unpredictability whereas permuted-block randomisation contributes the balance, but avoids the perfect balance that can result in selection bias.

Summary Screening tests are ubiquitous in contemporary practice, yet the principles of screening are widely misunderstood. Screening is the testing of apparently well people to find those at increased risk of having a disease or disorder. Although an earlier diagnosis generally has intuitive appeal, earlier might not always be better, or worth the cost. Four terms describe the validity of a screening test: sensitivity, specificity, and predictive value of positive and negative results. For tests with continuous variables-eg, blood glucose-sensitivity and specificity are inversely related; where the cutoff for abnormal is placed should indicate the clinical effect of wrong results. The prevalence of disease in a population affects screening test performance: in low-prevalence settings, even very good tests have poor predictive value positives. Hence, knowledge of the approximate prevalence of disease is a prerequisite to interpreting screening test results. Tests are often done in sequence, as is true for syphilis and HIV-1 infection. Lead-time and length biases distort the apparent value of screening programmes; randomised controlled trials are the only way to avoid these biases. Screening can improve health; strong indirect evidence links cervical cytology programmes to declines in cervical cancer mortality. However, inappropriate application or interpretation of screening tests can rob people of their perceived health, initiate harmful diagnostic testing, and squander health-care resources.