The reality that volumes of published biomedical research are not reproducible is an increasingly recognized problem. Spurious results reduce trustworthiness of reported science, increasing research ...waste. While science should be self-correcting from a philosophical perspective, that in insolation yields no information on efforts required to nullify suspect findings or factors shaping how quickly science may be corrected. There is also a paucity of information on how perverse incentives in the publishing ecosystem favouring novel positive findings over null results shape the ability of published science to self-correct. Knowledge of factors shaping self-correction of science remain obscure, limiting our ability to mitigate harms. This modelling study introduces a simple model to capture dynamics of the publication ecosystem, exploring factors influencing research waste, trustworthiness, corrective effort and time to correction. Results from this work indicate that research waste and corrective effort are highly dependent on field-specific false positive rates and time delays to corrective results to spurious findings are propagated. The model also suggests conditions under which biomedical science is self-correcting and those under which publication of correctives alone cannot stem propagation of untrustworthy results. Finally, this work models a variety of potential mitigation strategies, including researcher- and publisher-driven interventions.
Access to high quality abortion care is essential to women's health, as evidenced by the dramatic decrease in pregnancy-related morbidity and mortality since the legalization of abortion in the ...United States, and by high rates of maternal death and complications in those countries where abortion is still provided under unsafe conditions. The past two decades have brought important advances in abortion care as well as increasing cross-disciplinary use of abortion technologies in women's health care. Abortion is an important option for pregnant women who have serious medical conditions or fetal abnormalities, and fetal reduction techniques are now well-integrated into infertility treatment to reduce the risks of multiple pregnancies resulting from assisted reproductive technologies. Management of Unintended and Abnormal Pregnancy: Comprehensive Abortion Care is the textbook of the National Abortion Federation, and serves as the standard, evidence-based reference text in abortion care. This state-of-the-art textbook provides a comprehensive overview of the public health implications of unsafe abortion and reviews the best surgical and medical practices for pregnancy termination, as well as managing ectopic and other abnormal pregnancies. Management of Unintended and Abnormal Pregnancy: Comprehensive Abortion Care is the leading source for a comprehensive understanding of issues related to unintended and abnormal pregnancy. This textbook: is authored by internationally-known leaders in women's health care; addresses unintended pregnancy and abortion from historical, legal, public health, clinical, and quality care perspectives; includes chapters on pregnancy loss, ectopic pregnancy, gestational trophoblastic disease, and multifetal pregnancy reduction; covers treatment of pregnancies in the first and second trimester by both medical and surgical techniques; and provides resources for clinical, scientific, and social support for the abortion provider and patient.
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 α 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.
Rainfall information is essential for many applications in developing countries, and yet, continually updated information at fine temporal and spatial scales is lacking. In Africa, rainfall ...monitoring is particularly important given the close relationship between climate and livelihoods. To address this information gap, this paper describes two versions (v2.0 and v3.0) of the TAMSAT daily rainfall dataset based on high-resolution thermal-infrared observations, available from 1983 to the present. The datasets are based on the disaggregation of 10-day (v2.0) and 5-day (v3.0) total TAMSAT rainfall estimates to a daily time-step using daily cold cloud duration. This approach provides temporally consistent historic and near-real time daily rainfall information for all of Africa. The estimates have been evaluated using ground-based observations from five countries with contrasting rainfall climates (Mozambique, Niger, Nigeria, Uganda, and Zambia) and compared to other satellite-based rainfall estimates. The results indicate that both versions of the TAMSAT daily estimates reliably detects rainy days, but have less skill in capturing rainfall amount-results that are comparable to the other datasets.
Proper randomisation rests on adequate allocation concealment. An allocation concealment process keeps clinicians and participants unaware of upcoming assignments. Without it, even properly developed ...random allocation sequences can be subverted. Within this concealment process, the crucial unbiased nature of randomised controlled trials collides with their most vexing implementation problems. Proper allocation concealment frequently frustrates clinical inclinations, which annoys those who do the trials. Randomised controlled trials are anathema to clinicians. Many involved with trials will be tempted to decipher assignments, which subverts randomisation. For some implementing a trial, deciphering the allocation scheme might frequently become too great an intellectual challenge to resist. Whether their motives indicate innocent or pernicious intents, such tampering undermines the validity of a trial. Indeed, inadequate allocation concealment leads to exaggerated estimates of treatment effect, on average, but with scope for bias in either direction. Trial investigators will be crafty in any potential efforts to decipher the allocation sequence, so trial designers must be just as clever in their design efforts to prevent deciphering. Investigators must effectively immunise trials against selection and confounding biases with proper allocation concealment. Furthermore, investigators should report baseline comparisons on important prognostic variables. Hypothesis tests of baseline characteristics, however, are superfluous and could be harmful if they lead investigators to suppress reporting any baseline imbalances.
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.
To determine the effectiveness of combined oral contraceptives (COCs) for the treatment of facial acne compared to placebo or other active therapies.
In January 2012, 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) (Aug 2011). For the initial review, we wrote to researchers to seek any unpublished or published trials that we might have missed.
We considered 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.
We extracted data on facial lesion counts, both total and specific (i.e., open or closed comedones, papules, pustules and nodules); acne severity grades; global assessments by the clinician or the participant, and discontinuation due to adverse events. Data were entered and analyzed in RevMan. For continuous data, we calculated the mean difference (MD) and 95% confidence interval (CI). For dichotomous data, we calculated the Peto odds ratio (OR) and 95% CI.
The review includes 31 trials with 12,579 participants. Of 24 comparisons made, 6 compared a COC to placebo, 17 different COCs, and 1 compared a COC to an antibiotic. Of nine placebo-controlled trials with data for analysis, all showed COCs reduced acne lesion counts, severity grades and self-assessed acne compared to placebo. A levonorgestrel-COC group had fewer total lesion counts (MD -9.98; 95% CI -16.51 to -3.45), inflammatory and non-inflammatory lesion counts, and were more likely to have a clinician assessment of clear or almost clear lesions and participant self-assessment of improved acne lesions. A norethindrone acetate COC had better results for clinician global assessment of no acne to mild acne (OR 1.86; 95% CI 1.32 to 2.62). In two combined trials, a norgestimate COC showed reduced total lesion counts (MD-9.32; 95% CI -14.19 to -4.45), reduced inflammatory lesion and comedones counts, and more with clinician assessment of improved acne. For two combined trials of a drospirenone COC, the investigators' assessment of clear or almost clear skin favored the drospirenone group (OR 3.02; 95% CI 1.99 to 4.59). In one trial, the drospirenone-COC group showed greater (more positive) percent changes for total lesion count (MD 29.08; 95% CI 3.13 to 55.03), inflammatory and non-inflammatory lesion counts, and papule and closed comedone counts. A dienogest-COC group had greater percentage decreases in total lesion count (MD -15.30; 95% CI -19.98 to -10.62) and inflammatory lesion count, and more women assessed with overall improvement of facial acne. A CMA-COC group had more 'responders,' those with 50% or greater decrease in facial papules and pustules (OR 2.31; 95% CI 1.50 to 3.55)Differences in the comparative effectiveness of COCs containing varying progestin types and dosages were less clear, and data were limited for any particular comparison. COCs that contained chlormadinone acetate or cyproterone acetate improved acne better than levonorgestrel. A COC with cyproterone acetate showed better acne outcomes than one with desogestrel, but the studies produced conflicting results. Likewise, levonorgestrel showed a slight improvement over desogestrel in acne outcomes, but results were not consistent. A drospirenone COC appeared to be more effective than norgestimate or nomegestrol acetate plus 17β-estradiol but less effective than cyproterone acetate.
This update yielded six new trials but no change in conclusions. The six COCs evaluated in placebo-controlled trials are effective in reducing inflammatory and non-inflammatory facial acne lesions. Few important and consistent differences were found between COC types in their effectiveness for treating acne. How COCs compare to alternative acne treatments is unknown since only one trial addressed this issue. The use of standardized methods for assessing acne severity would help in synthesizing results across trials as well as aid in interpretation.
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.
•Rainfall-runoff model driven using ensemble satellite rainfall inputs.•Study area is operational proxy for a semi-arid, poorly instrumented catchment.•Model calibrated using a novel ensemble-wise ...method – EnsALL.•Ensemble wise method produced more robust calibrations than deterministic methods.•Metrics adapted from ensemble forecast verification used for analysis.
The potential for satellite rainfall estimates to drive hydrological models has been long understood, but at the high spatial and temporal resolutions often required by these models the uncertainties in satellite rainfall inputs are both significant in magnitude and spatiotemporally autocorrelated. Conditional stochastic modelling of ensemble observed fields provides one possible approach to representing this uncertainty in a form suitable for hydrological modelling. Previous studies have concentrated on the uncertainty within the satellite rainfall estimates themselves, sometimes applying ensemble inputs to a pre-calibrated hydrological model. This approach does not account for the interaction between input uncertainty and model uncertainty and in particular the impact of input uncertainty on model calibration. Moreover, it may not be appropriate to use deterministic inputs to calibrate a model that is intended to be driven by using an ensemble. A novel whole-ensemble calibration approach has been developed to overcome some of these issues.
This study used ensemble rainfall inputs produced by a conditional satellite-driven stochastic rainfall generator (TAMSIM) to drive a version of the Pitman rainfall-runoff model, calibrated using the whole-ensemble approach. Simulated ensemble discharge outputs were assessed using metrics adapted from ensemble forecast verification, showing that the ensemble outputs produced using the whole-ensemble calibrated Pitman model outperformed equivalent ensemble outputs created using a Pitman model calibrated against either the ensemble mean or a theoretical infinite-ensemble expected value.
Overall, for the verification period the whole-ensemble calibration provided a mean RMSE of 61.7% of the mean wet season discharge, compared to 83.6% using a calibration based on the daily mean of the ensemble estimates. Using a Brier’s Skill Score to assess the performance of the ensemble against a climatic estimate, the whole-ensemble calibration provided a positive score for the main range of discharge events. The equivalent score for calibration against the ensemble mean was negative, indicating it showed no skill versus the climatic estimate.
Blinding embodies a rich history spanning over two centuries. Most researchers worldwide understand blinding terminology, but confusion lurks beyond a general comprehension. Terms such as single ...blind, double blind, and triple blind mean different things to different people. Moreover, many medical researchers confuse blinding with allocation concealment. Such confusion indicates misunderstandings of both. The term blinding refers to keeping trial participants, investigators (usually health-care providers), or assessors (those collecting outcome data) unaware of the assigned intervention, so that they will not be influenced by that knowledge. Blinding usually reduces differential assessment of outcomes (information bias), but can also improve compliance and retention of trial participants while reducing biased supplemental care or treatment (sometimes called co-intervention). Many investigators and readers naively consider a randomised trial as high quality simply because it is double blind, as if double-blinding is the sine qua non of a randomised controlled trial. Although double blinding (blinding investigators, participants, and outcome assessors) indicates a strong design, trials that are not double blinded should not automatically be deemed inferior. Rather than solely relying on terminology like double blinding, researchers should explicitly state who was blinded, and how. We recommend placing greater credence in results when investigators at least blind outcome assessments, except with objective outcomes, such as death, which leave little room for bias. If investigators properly report their blinding efforts, readers can judge them. Unfortunately, many articles do not contain proper reporting. If an article claims blinding without any accompanying clarification, readers should remain sceptical about its effect on bias reduction.
"Therapeutic" bed rest continues to be used widely, despite evidence of no benefit and known harms. In this commentary, we summarize the Cochrane reviews of bed rest and propose an ethical argument ...for discontinuing this practice. Cochrane systematic reviews do not support "therapeutic" bed rest for threatened abortion, hypertension, preeclampsia, preterm birth, multiple gestations, or impaired fetal growth. This assessment has been echoed in other comprehensive reviews. Prescribing bed rest is inconsistent with the ethical principles of autonomy, beneficence, and justice. Hence, if bed rest is to be used, it should be only within a formal clinical trial.
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