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Background: E-values are a recently introduced approach to evaluate confounding in observational studies. We aimed to empirically assess the current use of E-values in published literature.Methods: We conducted a systematic literature search for all publications, published up till the end of 2018, which cited at least one of two inceptive E-value papers and presented E-values for original data. For these case publications we identified control publications, matched by journal and issue, where the authors had not calculated E-values.Results: In total, 87 papers presented 516 E-values. Of the 87 papers, 14 concluded that residual confounding likely threatens at least some of the main conclusions. Seven of these 14 named potential uncontrolled confounders. 19 of 87 papers related E-value magnitudes to expected strengths of field-specific confounders. The median E-value was 1.88, 1.82, and 2.02 for the 43, 348, and 125 E-values where confounding was felt likely to affect the results, unlikely to affect the results, or not commented upon, respectively. The 69 case-control publication pairs dealt with effect sizes of similar magnitude. Of 69 control publications, 52 did not comment on unmeasured confounding and 44/69 case publications concluded that confounding was unlikely to affect study conclusions.Conclusions: Few papers using E-values conclude that confounding threatens their results, and their E-values overlap in magnitude with those of papers acknowledging susceptibility to confounding. Facile automation in calculating E-values may compound the already poor handling of confounding. E-values should not be a substitute for careful consideration of potential sources of unmeasured confounding. If used, they should be interpreted in the context of expected confounding in specific fields. [ABSTRACT FROM AUTHOR]

The incidence of many hormone-dependent diseases, including testicular cancer, has sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and nonseminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14, 2020 in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDC multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring [summary risk ratios: 2.16, (95% CI:1.78-2.62), 1.93 (95% CI:1.49-2.48), and 2.78 (95% CI:2.27-3.41) for all, seminoma, and nonseminoma, respectively]. Similarly, high maternal exposures to grouped organochlorines and organohalogens were associated with higher risk of seminoma and nonseminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent. Maternal, but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of nonseminomas. However, the quality of studies was mixed, and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed. [ABSTRACT FROM AUTHOR]

Study Question: Are there temporal trends of sperm concentration (SC) and total sperm count (TSC) in Chinese healthy males from 1981 to 2019?Summary Answer: Our result indicated a temporal decrease in SC and TSC among 327 373 healthy Chinese men in the recent four decades.What Is Known Already: A review of 61 papers reported a temporal decline in SC and TSC from 1938 to 1990. This trend was later confirmed by a systematic review of 185 published papers from 1981 to 2013. However, the majority of the included individuals were from western countries. In China, whether SC and TSC have declined remains controversial.Study Design, Size, Duration: This systematic review of published articles used data extracted from Pubmed, Science Direct, Embase, China-National-Knowledge-Infrastructure (CNKI) and Wanfang Data to assess changes in SC and TSC in China from 1981 to 2019.Participants/materials, Setting, Methods: A total of 111 studies including 327 373 individuals who provided semen samples from 1981 to 2019 were extracted for the present analysis. Study selection and data extraction were performed by two independent researchers. The trends in SC and TSC were analysed using liner-regression and meta-regression before and after adjusting for potential covariates. Moreover, subgroups, categorised based on geographic region, fertility status or recruitment source, were also analysed.Main Results and the Role Of Chance: SC declined significantly (slope liner-regression = -0.748 million/ml/year; P = 0.005; slope meta-regression = -0.824 million/ml/year; P < 0.001) between 1981 and 2019 in China. Trends for TSC was similar to that for SC (slope liner-regression = -2.073 million/year; P = 0.032; slope meta-regression = -2.188 million/year; P = 0.003). In subgroup meta-regression analyses, males with definite fertility had continuous declines in SC (slope northern group=-2.268, P = 0.009; slope southern group=-1.014, P = 0.009) and TSC (slope northern group=-9.675, P = 0.010; slope southern group=-3.215, P = 0.042). However, in the unselected group, where fertility status was unknown, the obvious downward trend in SC was only seen in males from Northern regions (slope = -0.836, P = 0.003). Another subgroup analysis demonstrated that obvious decreases in SC (slope = -1.432, P < 0.001) and TSC (slope=-4.315, P = 0.001) were only seen in volunteer groups but not in pre-pregnancy examination groups and other recruitment groups. The results changed minimally in multiple sensitivity analyses.Limitations, Reasons For Caution: The validity of the meta-analysis results was limited mainly by the quality of the included studies. Additionally, our study spanned many decades and the recommended criteria for some semen parameter assessments have significantly changed, which may bring about some unavoidable bias. Moreover, the data remain insufficient especially in some provinces of China.Wider Implications Of the Findings: The present study is the first study to report significant decreases in SC and TSC in 327 373 healthy Chinese men between 1981 and 2019, indicating a serious reproductive health warning. Further studies on the causes of the declines are urgently needed.Study Funding/competing Interest(s): D.Z. is supported by the National Natural Science Funding of China, Natural Science Funding of Shaanxi Province, Science Funding of Health Department, Shaanxi Province, Fundamental Research Funds for the Central University and the Project of Independent Innovative Experiment for Postgraduates in Medicine in Xi'an Jiaotong University. The authors have no conflicts of interests to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of 'good cholesterol', strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies-that began to appear at the same time as the initial negative randomized controlled trials-made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure-such as that with respect to vitamin E supplementation and CHD risk-rather than pass them over in silence. [ABSTRACT FROM AUTHOR]

Background: Rigorously designed longitudinal studies can inform how best to reduce the widening health gap between Indigenous and non-Indigenous children.Methods: A systematic review was performed to identify and present the breadth and depth of longitudinal studies reporting the health and well-being of Indigenous children (aged 0-18 years) globally. Databases were searched up to 23 June 2020. Study characteristics were mapped according to domains of the life course model of health. Risk of bias was assessed using the National Institutes of Health (NIH) Study Quality Assessment Tools. Reported level of Indigenous involvement was also appraised; PROSPERO registration CRD42018089950.Results: From 5545 citations, 380 eligible papers were included for analysis, representing 210 individual studies. Of these, 41% were located in Australia (n = 88), 22.8% in the USA (n = 42), 11.9% in Canada (n = 25) and 10.9% in New Zealand (n = 23). Research tended to focus on either health outcomes (50.9%) or health-risk exposures (43.8%); 55% of studies were graded as 'good' quality; and 89% of studies made at least one reference to the involvement of Indigenous peoples over the course of their research.Conclusions: We identified gaps in the longitudinal assessment of cultural factors influencing Indigenous child health at the macrosocial level, including connection to culture and country, intergenerational trauma, and racism or discrimination. Future longitudinal research needs to be conducted with strong Indigenous leadership and participation including holistic concepts of health. This is critical if we are to better understand the systematic factors driving health inequities experienced by Indigenous children globally. [ABSTRACT FROM AUTHOR]

Objective: We aimed to compare the number of submissions until acceptance and the time to publication between articles co-authored and articles not co-authored by statisticians.Methods: We randomly selected 781 articles published in 2016 in 18 high impact factor journals of general internal medicine and primary care. For each article, we retrieved its date of submission to the journal and its first publication; we also contacted its corresponding author and asked about the number of submissions necessary from the first submission to a journal until acceptance and whether the article was co-authored by a statistician. After having excluded qualitative studies, we compared the articles co-authored with those not co-authored by statisticians in terms of number of submissions and submission-to-publication time, using negative binomial and Cox regressions, adjusted for intracluster correlations.Results: One hundred fifty-eight authors completed the questionnaire (20%); 136 articles with quantitative design were included in the study. Overall, 63 articles (46%) were co-authored by statisticians. There was no statistically significant difference in the number of submissions (statistician group: mean 2.1 (SD 1.1) versus 2.2 (SD 1.2), P value 0.87). By contrast, we found a statistically significant difference in the submission-to-publication time (statistician group: median 211 days [interquartile range (IQR) 171] versus 260 (IQR 144); hazard ratio 1.44 (95% CI 1.01-2.03), adjusted P value 0.04).Conclusions: Papers co-authored by statisticians have a shorter time to publication. We encourage researchers to closely involve statisticians in the design, conduct and statistical analysis of research, not only to ensure high standards of quality but also to speed up its publication. [ABSTRACT FROM AUTHOR]

The Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) were developed to address widespread deficiencies in the reporting of such studies. The REMARK checklist consists of 20 items to report for published tumor marker prognostic studies. A detailed paper was published explaining the rationale behind checklist items, providing positive examples and giving empirical evidence of the quality of reporting. REMARK provides a comprehensive overview to educate on good reporting and provide a valuable reference for the many issues to consider when designing, conducting, and analyzing tumor marker studies and prognostic studies in medicine in general. Despite support for REMARK from major cancer journals, prognostic factor research studies remain poorly reported. To encourage dissemination and uptake of REMARK, we have produced this considerably abridged version of the detailed explanatory manuscript, which may also serve as a brief guide to key issues for investigators planning tumor marker prognostic studies. To summarize the current situation, more recent papers investigating the quality of reporting and related reporting guidelines are cited, but otherwise the literature is not updated. Another important impetus for this paper is that it serves as a basis for literal translations into other languages. Translations will help to bring key information to a larger audience world-wide. Many more details can be found in the original paper. [ABSTRACT FROM AUTHOR]

Background: Point-of-care tests (POCT) can assist general practitioners (GPs) in diagnosing and treating patients with acute cardiopulmonary symptoms, but it is currently unknown if POCT impact relevant clinical outcomes in these patients.Objective: To assess whether using POCT in primary care patients with acute cardiopulmonary symptoms leads to more accurate diagnosis and impacts clinical management.Methods: We performed a systematic review in four bibliographic databases. Articles published before February 2016 were screened by two reviewers. Studies evaluating the effect of GP use of POCT on clinical diagnostic accuracy and/or effect on treatment and referral rate in patients with cardiopulmonary symptoms were included.Results: Our search yielded nine papers describing data from seven studies, on the clinical diagnostic accuracy of POCT in a total of 2277 primary care patients with acute cardiopulmonary symptoms. Four papers showed data on GP use of D-dimer POCT in pulmonary embolism (two studies); two studies on Troponin T in acute coronary syndrome; one on heart-type fatty acid-binding protein (H-FABP) in acute coronary syndrome; one on B-type natriuretic peptide (BNP) in heart failure; one on 3-in-1 POCT (Troponin T, BNP, D-dimer) in acute coronary syndrome, heart failure and/or pulmonary embolism. Only one study assessed the effect of GP use of POCT on treatment initiation and one on actual referral rates.Conclusion: There is currently limited and inconclusive evidence that actual GP use of POCT in primary care patients with acute cardiopulmonary symptoms leads to more accurate diagnosis and affects clinical management. However, some studies show promising results, especially when a POCT is combined with a clinical decision rule. [ABSTRACT FROM AUTHOR]

Good data curation is integral to cohort studies, but it is not always done to a level necessary to ensure the longevity of the data a study holds. In this opinion paper, we introduce the concept of data curation debt-the data curation equivalent to the software engineering principle of technical debt. Using the context of UK cohort studies, we define data curation debt-describing examples and their potential impact. We highlight that accruing this debt can make it more difficult to use the data in the future. Additionally, the long-running nature of cohort studies means that interest is accrued on this debt and compounded over time-increasing the impact a debt could have on a study and its stakeholders. Primary causes of data curation debt are discussed across three categories: longevity of hardware, software and data formats; funding; and skills shortages. Based on cross-domain best practice, strategies to reduce the debt and preventive measures are proposed-with importance given to the recognition and transparent reporting of data curation debt. Describing the debt in this way, we encapsulate a multi-faceted issue in simple terms understandable by all cohort study stakeholders. Data curation debt is not only confined to the UK, but is an issue the international community must be aware of and address. This paper aims to stimulate a discussion between cohort studies and their stakeholders on how to address the issue of data curation debt. If data curation debt is left unchecked it could become impossible to use highly valued cohort study data, and ultimately represents an existential risk to studies themselves. [ABSTRACT FROM AUTHOR]

Background: In the UK, general practitioners (GPs) are the most commonly used providers of care for emotional concerns.Objective: To update and synthesize literature on barriers and facilitators to GP-patient communication about emotional concerns in UK primary care.Design: Systematic review and qualitative synthesis.Method: We conducted a systematic search on MEDLINE (OvidSP), PsycInfo and EMBASE, supplemented by citation chasing. Eligible papers focused on how GPs and adult patients in the UK communicated about emotional concerns. Results were synthesized using thematic analysis.Results: Across 30 studies involving 342 GPs and 720 patients, four themes relating to barriers were: (i) emotional concerns are difficult to disclose; (ii) tension between understanding emotional concerns as a medical condition or arising from social stressors; (iii) unspoken assumptions about agency resulting in too little or too much involvement in decisions and (iv) providing limited care driven by little time. Three facilitative themes were: (v) a human connection improves identification of emotional concerns and is therapeutic; (vi) exploring, explaining and negotiating a shared understanding or guiding patients towards new understandings and (vii) upfront information provision and involvement manages expectations about recovery and improves engagement in treatment.Conclusion: The findings suggest that treatment guidelines should acknowledge: the therapeutic value of a positive GP-patient relationship; that diagnosis is a two-way negotiated process rather than an activity strictly in the doctor's domain of expertise; and the value of exploring and shaping new understandings about patients' emotional concerns and their management. [ABSTRACT FROM AUTHOR]

Background: Many studies examined gender inequalities in research, but only a few data are available for general biomedical journals. We assessed the prevalence of female first authorship in general biomedical journals and examined its variations across a number of author, article and journal characteristics.Methods: This study was nested within a larger project designed to analyze the bibliometric characteristics of scientific articles. We retrieved 767 randomly selected articles published in 2016 in high impact factor journals of primary healthcare (n = 9) and general internal medicine (n = 9). We extracted the following data: author (gender, number of publications and affiliation of the first author), paper (number of authors, number of participants and study design) and journal characteristics (journal discipline and 2015 impact factor). We compared the proportion of articles authored by women and men using univariate and multivariate logistic regressions adjusted for intra-cluster correlations.Results: The female authorship proportion was 48% (63% for primary healthcare and 33% for general internal medicine, P-value < 0.001). In multivariate analysis, women published fewer articles (<5 versus >15 publications: OR 1.6 [95% CI 1.1-2.4]), were more often affiliated with institutions in the Western world (OR 2.2 [95% CI 1.2-3.9]), were more likely to publish qualitative studies (versus systematic reviews or experiments: OR 2.7 [95% CI 1.5-4.8]) and to publish in primary healthcare journals (OR 1.7 [95% CI 1.1-2.7]).Conclusions: The underrepresentation of women in articles published by general internal medicine journals, in articles from the non-Western world and in systematic reviews and trials should be addressed. [ABSTRACT FROM AUTHOR]

Background: The endocannabinoid system (ECS) consists of the cannabinoid receptors CB1 and CB2, the main endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their metabolic enzymes N-acylphosphatidylethanolamine-specific phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase and monoacylglycerol lipase. This system is involved in the modulation of essential physiological processes. Its role in the reproductive system has become significantly important in recent years, given its major role in events such as gametogenesis, decidualisation, implantation and placentation.Objective and Rationale: In this paper, we review the literature and summarize the role of the ECS elements in reproduction and their potential as early markers for diagnosis of reproductive disorders or as pharmacological targets for treatment.Search Methods: Original research and review papers published from 1964 to June 2019 were selected in terms of relevance, reliability and quality by searching PubMed, MEDLINE and Web of Science, using the following search terms: endocannabinoid system and endometriosis; endocannabinoid system and ectopic pregnancy; endocannabinoid system and miscarriage; endocannabinoid system and pre-eclampsia; endocannabinoid system and endometrial cancer; endocannabinoid system and reproduction; endocannabinoid, endometrium; placenta; N-acylethanolamines; anandamide; 2-arachidonoylglycerol; and cannabinoids.Outcomes: This review demonstrates relevant information concerning ECS alterations in endometriosis, ectopic pregnancy, miscarriage, pre-eclampsia and endometrial cancer. We highlight the importance of the endocannabinoids in endometrial and placental physiology and pathophysiology, from studies in vitro and in vivo and in clinical observations. The most studied of the endogenous cannabinoids is AEA. The levels of AEA were increased in plasma of patients with endometriosis and miscarriage, as well as in the fallopian tube of women with ectopic pregnancy and in endometrial biopsies of endometrial cancer. Changes in the pattern of expression of the cannabinoid receptor CB1 were also observed in endometrial biopsies of endometriosis, fallopian tube and decidua of patients with ectopic pregnancy and pre-eclamptic placenta. Moreover, alterations in CB2 expression have been reported in association with endometrial cancer. In general, studies on the cannabinoid signalling through CB2 and on the biological activities of the other major endocannabinoid, namely 2-AG, as well as its metabolic enzymes are scarce and avidly required.Wider Implications: The pathophysiological mechanisms involved in the described endometrial and placental pathologies are still unclear and lack the means for an early diagnosis. Based on current evidence, though alterations in ECS are demonstrated at tissue level, it is difficult to associate plasmatic changes in AEA with specific endometrial and placental diseases. Thus, pairing alterations in AEA levels with 2-AG and/or other endocannabinoid-like molecules may provide more accurate and early diagnoses. In addition, patients may benefit from new therapies that target the ECS and endocannabinoid signalling. [ABSTRACT FROM AUTHOR]

In 2019, the National Institutes of Health combined the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) into the MACS/WIHS Combined Cohort Study (MWCCS). In this paper, participants who made a study visit during October 2018–September 2019 (targeted for MWCCS enrollment) are described by human immunodeficiency virus (HIV) serostatus and compared with people living with HIV (PLWH) in the United States. Participants include 2,115 women and 1,901 men with a median age of 56 years (interquartile range, 48–63); 62% are PLWH. Study sites encompass the South (18%), the Mid-Atlantic/Northeast (45%), the West Coast (22%), and the Midwest (15%). Participant race/ethnicity approximates that of PLWH throughout the United States. Longitudinal data and specimens collected for 35 years (men) and 25 years (women) were combined. Differences in data collection and coding were reviewed, and key risk factor and comorbidity data were harmonized. For example, recent use of alcohol (62%) and tobacco (28%) are common, as are dyslipidemia (64%), hypertension (56%), obesity (42%), mildly or severely impaired daily activities (31%), depressive symptoms (28%), and diabetes (22%). The MWCCS repository includes serum, plasma, peripheral blood mononuclear cells, cell pellets, urine, cervicovaginal lavage samples, oral samples, B-cell lines, stool, and semen specimens. Demographic differences between the MACS and WIHS can confound analyses by sex. The merged MWCCS is both an ongoing observational cohort study and a valuable resource for harmonized longitudinal data and specimens for HIV-related research. [ABSTRACT FROM AUTHOR]

Background: A nudge corresponds to any procedure that influences choice architecture, without using persuasion or financial incentives. Nudges are effective in increasing vaccination with heterogeneous levels of acceptability.Objective: To evaluate the effectiveness and acceptability of a nudge promoting influenza vaccination for general practice trainees, also called residents.Methods: The hypothesis was that a reminder would be efficient and accepted and that prior exposure to a nudge increases its acceptability. Residents were randomly divided into three parallel experimental arms: a nudge group, a no-nudge group and a control group in order to evaluate the Hawthorne effect. The nudge consisted of providing a paper form for the free delivery of the vaccine and contacts for occupational health services.Results: The analysis included 161 residents. There was a strong consensus among the residents that it is very acceptable to nudge their peers and patients. Acceptability was better with residents exposed to the nudge and with residents included in step 1 (Hawthorne effect). The nudge did not increase vaccination coverage.Conclusion: The failure of this nudge highlights the importance of matching an intervention to the population's needs. The experimental approach is innovative in this context and deserves further attention.Clinicaltrials.gov Pre-registration: NCT03768596. [ABSTRACT FROM AUTHOR]

Background: Policy encourages health care providers to listen and respond to feedback from patients, expecting that it will enhance care experiences. Enhancement of patients' experiences may not yet be a reality, particularly in primary health care settings.Objective: To identify the issues that influence the use and impact of feedback in this context.Design and Setting: A realist synthesis of studies of the use of patient feedback within primary health care settings.Methods: Structured review of published studies between 1971 and January 2015.Results: Eighteen studies were reported in 20 papers. Eleven studies reported patient survey scores as a primary outcome. There is little evidence that formal patient feedback led to enhanced experiences. The likelihood of patient feedback to health care staff stimulating improvements in future patients' experiences appears to be influenced predominantly by staff perceptions of the purpose of such feedback; the validity and type of data that is collected; and where, when and how it is presented to primary health care teams or practitioners and teams' capacity to change.Conclusions: There is limited research into how patient feedback has been used in primary health care practices or its usefulness as a stimulant to improve health care experience. Using a realist synthesis approach, we have identified a number of contextual and intervention-related factors that appear to influence the likelihood that practitioners will listen to, act on and achieve improvements in patient experience. Consideration of these may support research and improvement work in this area. [ABSTRACT FROM AUTHOR]

Study Question: How many twins are born in human populations and how has this changed over recent decades?Summary Answer: Since the 1980s, the global twinning rate has increased by a third, from 9.1 to 12.0 twin deliveries per 1000 deliveries, to about 1.6 million twin pairs each year.What Is Known Already: It was already known that in the 1980s natural twinning rates were low in (East) Asia and South America, at an intermediate level in Europe and North America, and high in many African countries. It was also known that in recent decades, twinning rates have been increasing in the wealthier parts of our world as a result of the rise in medically assisted reproduction (MAR) and delayed childbearing.Study Design, Size, Duration: We have brought together all information on national twinning rates available from statistical offices, demographic research institutes, individual survey data and the medical literature for the 1980-1985 and the 2010-2015 periods.Participants/materials, Setting, Methods: For 165 countries, covering over 99% of the global population, we were able to collect or estimate twinning rates for the 2010-2015 period. For 112 countries, we were also able to obtain twinning rates for 1980-1985.Main Results and the Role Of Chance: Substantial increases in twinning rates were observed in many countries in Europe, North America and Asia. For 74 out of 112 countries the increase was more than 10%. Africa is still the continent with highest twinning rates, but Europe, North America and Oceania are catching up rapidly. Asia and Africa are currently home to 80% of all twin deliveries in the world.Limitations, Reasons For Caution: For some countries, data were derived from reports and papers based on hospital registrations which are less representative for the country as a whole than data based on public administrations and national surveys.Wider Implications Of the Findings: The absolute and relative number of twins for the world as a whole is peaking at an unprecedented level. An important reason for this is the tremendous increase in medically assisted reproduction in recent decades. This is highly relevant, as twin deliveries are associated with higher infant and child mortality rates and increased complications for mother and child during pregnancy and during and after delivery.Study Funding/competing Interest(s): The contribution of CM was partially supported by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant No 681546, FAMSIZEMATTERS), Nuffield College, and the Leverhulme Trust. The contribution of GP was partially supported by the French Agence Nationale de la Recherche (grant No ANR-18-CE36-0007-07). The authors declare no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Directed acyclic graphs (DAGs) are of great help when researchers try to understand the nature of causal relationships and the consequences of conditioning on different variables. One fundamental feature of causal relations that has not been incorporated into the standard DAG framework is interaction, i.e. when the effect of one variable (on a chosen scale) depends on the value that another variable is set to. In this paper, we propose a new type of DAG-the interaction DAG (IDAG), which can be used to understand this phenomenon.Methods: The IDAG works like any DAG but instead of including a node for the outcome, it includes a node for a causal effect. We introduce concepts such as confounded interaction and total, direct and indirect interaction, showing that these can be depicted in ways analogous to how similar concepts are depicted in standard DAGs. This also allows for conclusions on which treatment interactions to account for empirically. Moreover, since generalizability can be compromised in the presence of underlying interactions, the framework can be used to illustrate threats to generalizability and to identify variables to account for in order to make results valid for the target population.Conclusions: The IDAG allows for a both intuitive and stringent way of illustrating interactions. It helps to distinguish between causal and non-causal mechanisms behind effect variation. Conclusions about how to empirically estimate interactions can be drawn-as well as conclusions about how to achieve generalizability in contexts where interest lies in estimating an overall effect. [ABSTRACT FROM AUTHOR]

Study Question: Is it possible to evaluate the methylome of individual oocytes to investigate the DNA methylome alterations in metaphase II (MII) oocytes with reduced embryo developmental potential?Summary Answer: The DNA methylome of each human first polar body (PB1) closely mirrored that of its sibling MII oocyte; hypermethylated long interspersed nuclear element (LINE) and long terminal repeats (LTRs) and methylation aberrations in PB1 promoter regions may indicate poor embryo development.What Is Known Already: The developmental potential of an embryo is determined by the oocyte's developmental competence, and the PB1 is a good substitute to examine the chromosomal status of the corresponding oocyte. However, DNA methylation, a key epigenetic modification, also regulates gene expression and embryo development.Study Design, Size, Duration: Twelve pairs of PB1s and sibling MII oocytes were biopsied and sequenced to compare their methylomes. To further investigate the methylome of PB1s and the potential epigenetic factors that may affect oocyte quality, MII oocytes (n = 74) were fertilized through ICSI, while PB1s were biopsied and profiled to measure DNA methylation. The corresponding embryos were further cultured to track their development potential. The oocytes and sperm samples used in this study were donated by healthy volunteers with signed informed consent.Participants/materials, Setting, Methods: Single-cell methylome sequencing was applied to obtain the DNA methylation profiles of PB1s and oocytes. The DNA methylome of PB1s was compared between the respective group of oocytes that progressed to blastocysts and the group of oocytes that failed to develop. DNA methylation levels of corresponding regions and differentially methylated regions were calculated using customized Perl and R scripts. RNA-seq data were downloaded from a previously published paper and reanalysed.Main Results and the Role Of Chance: The results from PB1-MII oocyte pair validated that PB1 contains nearly the same methylome (average Pearson correlation is 0.92) with sibling MII oocyte. LINE and LTR expression increased markedly after fertilization. Moreover, the DNA methylation levels in LINE (including LINE1 and LINE2) and LTR were significantly higher in the PB1s of embryos that could not reach the blastocyst stage (Wilcoxon-Matt-Whitney test, P < 0.05). DNA methylation in PB1 promoters correlated negatively with gene expression of MII oocyte. Regarding the methylation status of the promoter regions, 66 genes were hypermethylated in the developmental arrested group, with their related functions (significantly enriched in several Gene Ontology terms) including transcription, positive regulation of adenylate cyclase activity, mitogen-activated protein kinase (MAPK) cascade and intracellular oestrogen receptor signalling pathway.Large Scale Data: N/A.Limitations, Reasons For Caution: Data analysis performed in this study focused on the competence of human oocytes and compared them with maternal genetic and epigenetic profiles. Therefore, data regarding the potential regulatory roles of paternal genomes in embryo development are lacking.Wider Implications Of the Findings: The results from PB1-oocyte pairs demonstrated that PB1s shared similar methylomes with their sibling oocytes. The selection of the good embryos for transfer should not only rely on morphology but also consider the DNA methylation of the corresponding PB1 and therefore MII oocyte. The application of early-stage analysis of PB1 offers an option for high-quality oocyte and embryo selection, which provides an additional tool for elective single embryo transfer in assisted reproduction.Study Funding/competing Interest(s): This study was supported by the National Key Research and Development Program of China (2018YFC1004003, 2017YFA0103801), the National Natural Science Foundation of China (81730038, 3187144, 81521002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020703). The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

Background: Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases.Objectives: To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference.Search Strategy: Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers.Selection Criteria: RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies.Data Collection and Analysis: One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome.Main Results: Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design-outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight.Conclusion: None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution.Systematic Review Registration: This study is registered with PROSPERO, registration number CRD42015015941. [ABSTRACT FROM AUTHOR]

Causal inference requires theory and prior knowledge to structure analyses, and is not usually thought of as an arena for the application of prediction modelling. However, contemporary causal inference methods, premised on counterfactual or potential outcomes approaches, often include processing steps before the final estimation step. The purposes of this paper are: (i) to overview the recent emergence of prediction underpinning steps in contemporary causal inference methods as a useful perspective on contemporary causal inference methods, and (ii) explore the role of machine learning (as one approach to 'best prediction') in causal inference. Causal inference methods covered include propensity scores, inverse probability of treatment weights (IPTWs), G computation and targeted maximum likelihood estimation (TMLE). Machine learning has been used more for propensity scores and TMLE, and there is potential for increased use in G computation and estimation of IPTWs. [ABSTRACT FROM AUTHOR]

Interrupted time series designs are a valuable quasi-experimental approach for evaluating public health interventions. Interrupted time series extends a single group pre-post comparison by using multiple time points to control for underlying trends. But history bias-confounding by unexpected events occurring at the same time of the intervention-threatens the validity of this design and limits causal inference. Synthetic control methodology, a popular data-driven technique for deriving a control series from a pool of unexposed populations, is increasingly recommended. In this paper, we evaluate if and when synthetic controls can strengthen an interrupted time series design. First, we summarize the main observational study designs used in evaluative research, highlighting their respective uses, strengths, biases and design extensions for addressing these biases. Second, we outline when the use of synthetic controls can strengthen interrupted time series studies and when their combined use may be problematic. Third, we provide recommendations for using synthetic controls in interrupted time series and, using a real-world example, we illustrate the potential pitfalls of using a data-driven approach to identify a suitable control series. Finally, we emphasize the importance of theoretical approaches for informing study design and argue that synthetic control methods are not always well suited for generating a counterfactual that minimizes critical threats to interrupted time series studies. Advances in synthetic control methods bring new opportunities to conduct rigorous research in evaluating public health interventions. However, incorporating synthetic controls in interrupted time series studies may not always nullify important threats to validity nor improve causal inference. [ABSTRACT FROM AUTHOR]

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Study Question: Is an MRI classification of deep pelvic endometriosis (DE) able to correctly predict the risk of DE surgery.Summary Answer: A new radiological classification, that we have called the deep pelvic endometriosis index (dPEI) classification, is accurate and reproducible to assess the extension of the disease in central and lateral compartments and well correlated with operating time, hospital stay duration and the risk of voiding dysfunction.What Is Known Already: Few imaging classifications are currently available to predict the extent of DE to help preoperative assessment of surgical outcomes and provide the patient with objective information about the risk of surgical complications.Study Design, Size, Duration: Retrospective monocentric observational study was conducted between 01 January 2017 and 31 December 2018 and included 150 women (mean age = 34.5 years, 20-52 years) with DE on MRI and who subsequently underwent surgery.Participants/materials, Setting, Methods: Two radiologists independently graded the disease according to MRI-based Enzian classification (A (rectovaginal septum and vagina locations), B (uterosacral locations) and C (rectosigmoid locations)) and a new radiological classification, that we have called the dPEI, that grades the severity of DE as: mild, moderate or severe DE. MRI findings and classification were correlated with surgical and pathological results.Main Results and the Role Of Chance: MRI-based and surgical Enzian classifications were concordant for A lesions in 78.7% (118/150), for B lesions in 34.7% (52/150) and for C lesions in 82.7% (124/150). Operating time and hospital stays were longer in Group A2 (rectovaginal septum and vagina, 1-3 cm) compared to A0, B2 (uterosacral, 1-3 cm) compared to B0, C3 (rectosigmoid >3 cm) compared to C2 (rectosigmoid 1-3 cm) or C0 (P < 0.001), in severe compared to moderate DE patients, and in moderate compared to mild extensive patients (P < 0.01). Patients with vaginal or rectosigmoid involvement were respectively six and three times more likely to experience high-grade complications according to Clavien-Dindo classification than patients without vaginal or rectosigmoid disease (P < 0.001). Postoperative voiding dysfunction was correlated with A lesions (odds ratio (OR) = 6.82, 95% CI 2.34-20.5), moderate or severe DE (OR = 4.15, 95% CI 1.26-17.9), the presence of at least unilateral lateral pelvic involvement (OR = 3.6, 95% CI 1.14-11.2, P = 0.03) and C lesions (OR = 2.6, 95% CI 1.03-6.8, P < 0.01).Limitations, Reasons For Caution: The study was conducted in an expert center and needs to be validated in a multicenter study. There is a limited number of patients with lateral pelvic endometriosis beyond the parietal fascia, probably due to the low prevalence of this disease presentation.Wider Implications Of the Findings: MRI imaging can be used to accurately predict postoperative complications for women with DE. This may help the clinician to preoperatively inform a patient about the risks of surgery. Larger clinical studies are required to validate these results.Study Funding/competing Interest(s): No external funding was used for this study. I.T.N.: Remunerated lecture GE, Hologic, Guerbet, Canon; Advisory board: Siemens - These relationships are on the topic of breast imaging, not related to the topic of this paper. Other coauthors have no conflict of interest to declare.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

It has long been recognized that sample size calculations for cluster randomized trials require consideration of the correlation between multiple observations within the same cluster. When measurements are taken at anything other than a single point in time, these correlations depend not only on the cluster but also on the time separation between measurements and additionally, on whether different participants (cross-sectional designs) or the same participants (cohort designs) are repeatedly measured. This is particularly relevant in trials with multiple periods of measurement, such as the cluster cross-over and stepped-wedge designs, but also to some degree in parallel designs. Several papers describing sample size methodology for these designs have been published, but this methodology might not be accessible to all researchers. In this article we provide a tutorial on sample size calculation for cluster randomized designs with particular emphasis on designs with multiple periods of measurement and provide a web-based tool, the Shiny CRT Calculator, to allow researchers to easily conduct these sample size calculations. We consider both cross-sectional and cohort designs and allow for a variety of assumed within-cluster correlation structures. We consider cluster heterogeneity in treatment effects (for designs where treatment is crossed with cluster), as well as individually randomized group-treatment trials with differential clustering between arms, for example designs where clustering arises from interventions being delivered in groups. The calculator will compute power or precision, as a function of cluster size or number of clusters, for a wide variety of designs and correlation structures. We illustrate the methodology and the flexibility of the Shiny CRT Calculator using a range of examples. [ABSTRACT FROM AUTHOR]

The stepped-wedge cluster randomized trial (SW-CRT) involves the sequential transition of clusters (such as hospitals, public health units or communities) from control to intervention conditions in a randomized order. The use of the SW-CRT is growing rapidly. Yet the SW-CRT is at greater risks of bias compared with the conventional parallel cluster randomized trial (parallel-CRT). For this reason, the CONSORT extension for SW-CRTs requires that investigators provide a clear justification for the choice of study design. In this paper, we argue that all other things being equal, the SW-CRT is at greater risk of bias due to misspecification of the secular trends at the analysis stage. This is particularly problematic for studies randomizing a small number of heterogeneous clusters. We outline the potential conditions under which an SW-CRT might be an appropriate choice. Potentially appropriate and often overlapping justifications for conducting an SW-CRT include: (i) the SW-CRT provides a means to conduct a randomized evaluation which otherwise would not be possible; (ii) the SW-CRT facilitates cluster recruitment as it enhances the acceptability of a randomized evaluation either to cluster gatekeepers or other stakeholders; (iii) the SW-CRT is the only feasible design due to pragmatic and logistical constraints (for example the roll-out of a scare resource); and (iv) the SW-CRT has increased statistical power over other study designs (which will include situations with a limited number of clusters). As the number of arguments in favour of an SW-CRT increases, the likelihood that the benefits of using the SW-CRT, as opposed to a parallel-CRT, outweigh its risks also increases. We argue that the mere popularity and novelty of the SW-CRT should not be a factor in its adoption. In situations when a conventional parallel-CRT is feasible, it is likely to be the preferred design. [ABSTRACT FROM AUTHOR]

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features. [ABSTRACT FROM AUTHOR]

Epidemiologists are often confronted with datasets to analyse which contain measurement error due to, for instance, mistaken data entries, inaccurate recordings and measurement instrument or procedural errors. If the effect of measurement error is misjudged, the data analyses are hampered and the validity of the study's inferences may be affected. In this paper, we describe five myths that contribute to misjudgments about measurement error, regarding expected structure, impact and solutions to mitigate the problems resulting from mismeasurements. The aim is to clarify these measurement error misconceptions. We show that the influence of measurement error in an epidemiological data analysis can play out in ways that go beyond simple heuristics, such as heuristics about whether or not to expect attenuation of the effect estimates. Whereas we encourage epidemiologists to deliberate about the structure and potential impact of measurement error in their analyses, we also recommend exercising restraint when making claims about the magnitude or even direction of effect of measurement error if not accompanied by statistical measurement error corrections or quantitative bias analysis. Suggestions for alleviating the problems or investigating the structure and magnitude of measurement error are given. [ABSTRACT FROM AUTHOR]

Background: Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage.Objective and Rationale: This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed.Search Methods: Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents.Outcomes: Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed.Wider Implications: Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically. [ABSTRACT FROM AUTHOR]

Realist evaluation furnishes valuable insight to public health practitioners and policy makers about how and why interventions work or don't work. Moving beyond binary measures of success or failure, it provides a systematic approach to understanding what goes on in the 'Black Box' and how implementation decisions in real life contexts can affect intervention effectiveness. This paper reflects on an experience in applying the tenets of realist evaluation to identify optimal implementation strategies for scale-up of Maternal and Newborn Health (MNH) programmes in rural Bangladesh. Supported by UNICEF, the three MNH programmes under consideration employed different implementation models to deliver similar services and meet similar MNH goals. Programme targets included adoption of recommended antenatal, post-natal and essential newborn care practices; health systems strengthening through improved referral, accountability and administrative systems, and increased community knowledge. Drawing on focused examples from this research, seven steps for operationalizing the realist evaluation approach are offered, while emphasizing the need to iterate and innovate in terms of methods and analysis strategies. The paper concludes by reflecting on lessons learned in applying realist evaluation, and the unique insights it yields regarding implementation strategies for successful MNH programming. [ABSTRACT FROM AUTHOR]

Background: Home visits seem promising for improving the health of women and infants during pregnancy and postpartum. This review aimed to quantitatively analyse the effects of home visits delivered during pregnancy and postpartum on premature birth (PTB), low birth weight (LBW) and rapid repeat birth (RRB).Methods: Literature was retrieved from PubMed, EMBASE, Web of Science and the Cochrane Library from January 1960 to October 2018 and the references lists of related studies and reviews were also screened. Eligible papers were randomized controlled trials (RCTs) that focussed on home visits conducted with women during pregnancy or postpartum and reported at least one of the following results: PTB, LBW and RRB. Fixed- or random-effects models were used to analyse the pooled results.Results: Fourteen RCTs were included. Pooled estimates showed a beneficial effect on LBW (odds ratio (OR) = 0.83; P = 0.03; low-quality evidence) and RRB in the professional-visit subgroup (OR = 0.62; P = 0.003; moderate-quality evidence). However, there was insufficient evidence to support the favourable effects of home visits on PTB (OR = 0.96; P = 0.59, moderate-quality evidence) and RRB in the non-professional-visit subgroup (OR = 0.86; P = 0.53, moderate-quality evidence). The overall methodological quality was moderate. Egger's test suggested no publication bias for PTB and LBW.Conclusion: This meta-analysis is the first to suggest that home visits can prevent and decrease LBW and RRB; however, it remains unclear whether home visits benefit PTB. Therefore, home visits can be an alternative and complementary part of primary health care for women, especially those with risk factors. [ABSTRACT FROM AUTHOR]

Study Question: Does pre-treatment with a low dose of mifepristone improve irregular vaginal bleeding patterns during the initial 3 months after LNG-IUS placement?Summary Answer: Mifepristone treatment prior to LNG-IUS insertion results in significantly lower bleeding and spotting rates but no significant reduction post insertion.What Is Known Already: One of the leading causes of premature discontinuation of the LNG-IUS is unscheduled bleeding in the first months following its insertion. Up to now, there has been no effective treatment to prevent this side effect which reduces continuation rates for one of the most effective contraceptives.Study Design, Size, Duration: This randomized, double blinded, controlled trial was conducted between 2009 and 2015. In total, 68 women opting for a LNG-IUS were screened for eligibility, of whom 58 were randomized at a ratio of 1:1 in blocks of 10 to pre-treatment with mifepristone or a comparator. The main outcome was the rate of bleeding and spotting days reported during the first 3 months post LNG-IUS 52 mg placement.Participants/materials, Setting, Methods: Healthy women with regular and normal menstrual cycles aged 18-43 years were enrolled at a single center in a university hospital; 29 were allocated to 2 months pre-treatment with a low dose mifepristone and 29 to the comparator prior to insertion of the LNG-IUS. Women were advised to use barrier methods during the pre-treatment period. Bleeding diaries were collected for the pre-treatment period and for the first 6 months after the LNG-IUS placement.Main Results and the Role Of Chance: There were no differences in demographics or baseline characteristics between the study groups. Data for analysis of the main outcome were contributed by a per protocol population of 19 women per group. There was a significant lower bleeding and spotting rate in the mifepristone group (-17.8% points, P < 0.001) after 2 months of pretreatment but after the LNG-IUS insertion no significant difference could be seen. While no pregnancies occurred prior to LNG-IUS insertion in the mifepristone group, there were three unintended pregnancies in the comparator group which emphasizes the need for a reliable contraceptive potential in any pre-treatment regiment used in clinical practice.Limitations, Reasons For Caution: The use of mifepristone prior to the LNG-IUS insertion in this trial was used as prophylaxis against unscheduled bleeding after the placement of the device. Although this side effect constitutes a major concern in a clinical setting, only a subset of women are at risk. This is the first study using pre-treatment to attempt improved bleeding control. The differences were small and the effect was short lasting but the reduced rate of bleeding and spotting observed during the first month following LNG-IUS insertion, even though not statistically significant, indicates that this approach may be further explored. The fact that there were three pregnancies in the comparator group stresses the need for any pre-treatment to also protect against unplanned pregnancy.Wider Implications Of the Findings: Modified treatment protocols of mifepristone could be used prior to the LNG-IUS insertion to investigate possible further improvement of the outcome. The effect size of the current dose used might have been more prominent in women with LNG-IUS if the treatment also continued some weeks after the placement of the device. Although the low dose of mifepristone used in this trial is not available in Europe, other progesterone receptor modulators currently available could be investigated in larger clinical trials. To avoid unintended pregnancy in the pretreatment period, the dosage used should, ideally, also be effective for contraception and the pretreatment period should be kept as short as possible.Study Funding/competing Interest(s): This study was funded by the Swedish Research Council (2012-2844, 2017-00932), Stockholm County Council and Karolinska Institutet (ALF). Conflicts of interests for K.G.D. and H.K.K. are listed at the end of the paper. The other authors have no conflicts of interest.Trial Registration Number: EudraCT number 2009-009014-40. Regional ethical review board at Karolinska Institutet permit 2009/144-31/4.Trial Registration Date: 20 July 2009.Date Of First Patient’s Enrolment: 24 November 2009. [ABSTRACT FROM AUTHOR]

Background: The Scottish Intercollegiate Guidelines Network (SIGN) developed guidelines for the management of sore throat and indications for tonsillectomy in 1999 to address concerns of unnecessary surgery. Emergency admissions to hospital for tonsillitis have since increased. Adults experience an average of 27 episodes of tonsillitis before undergoing tonsillectomy. We wished to explore the appropriateness of the guidance and/or its implementation in primary care.Aim: To explore the attitudes of GPs to the referral criteria they use when managing adults presenting with acute tonsillitis.Design: Secondary analysis of qualitative data from the NAtional Trial of Tonsillectomy IN Adults (NATTINA) feasibility and process evaluation.Participants and Setting: Twenty-one GPs from practices throughout the UK.Method: In-depth interviews with GPs concerning both the feasibility and process evaluation phases of NATTINA. Analysis was conducted using the framework method.Results: GPs felt it was rarely necessary to refer patients. They were aware of guidelines and would refer if requested by a patient who fulfilled the guidelines criteria and/or who were missing considerable amounts of work.Conclusion: The introduction of the guidelines appears to coincide with what some may have hoped to be a desired effect of reducing adult sore throat referrals and subsequent tonsillectomies by increasing the number of episodes a patient must suffer before the referral threshold is met. GPs may find equipoise for tonsillectomy referral challenging as many patients express a strong preference for surgery. We believe this paper reinforces GP professionalism and patient-centred consultations, and challenges the role of clinical guidelines. [ABSTRACT FROM AUTHOR]

Background: It is suggested that new models of primary care should have better access to test results through the use of point-of-care testing (POCT).Objective: To determine whether quality management of POCT leads to better results.Methods: A comprehensive search of the literature on quality management of POCT in primary care, where the impact of participation in quality management programmes had been investigated with relevant outcome measures.Results: Three databases were systematically searched using key words relevant to POCT and quality management, covering from 1945 to January 2017. Titles and abstracts were reviewed for relevance and papers selected for review and data extraction. Five observational studies were found in which the performance of POCT for specific analytes in external quality assurance (EQA) programmes was used to assess improvement over a period of time, varying from 3.5 to 15 years. The tests monitored were HbA1c, urine albumin, C-reactive protein, glucose and haemoglobin. In each case, the performance of the test against defined analytical criteria was used to judge improvement in performance. Different summary performance criteria were used, including the imprecision of results over a period of time (two studies) and meeting defined target values for bias and imprecision of measurement (three studies). Performance improved with time and was associated with regular participation in EQA schemes and with the use of internal quality control (IQC) procedures.Conclusions: These findings indicate that adoption of quality management for POCT, including participation in IQC and EQA, with the support of laboratory medicine professionals, will improve the quality of the results 'produced'. [ABSTRACT FROM AUTHOR]

Study Question: Do health-related knowledge, beliefs and self-efficacy differ between women with and without polycystic ovary syndrome (PCOS)?Summary Answer: Women with PCOS felt at greater risk for adverse health outcomes, yet believed a healthy lifestyle was less beneficial to prevent weight gain relative to a comparison group.What Is Known Already: Diet and physical activity are often used to treat PCOS, but there are high attrition rates and less engagement in self-help methods. It is unclear whether there are unique psychosocial considerations in PCOS that should be incorporated into these interventions.Study Design, Size, Duration: This cross-sectional study enrolled 475 women with (N = 255) and without PCOS (N = 220).Participants/materials, Setting, Methods: Female participants were recruited through paper and web-based advertisements across the US (mean age: 28.1 ± 5.4 years). Participants were either diagnosed with PCOS by a healthcare professional (PCOS group) or had self-reported regular menstrual cycles (comparison group). A reliable and valid online instrument about health-related knowledge, beliefs and self-efficacy was administered to these participants.Main Results and the Role Of Chance: Most women with PCOS had a basic understanding of nutrition (96%), but had misconceptions about diagnostic criteria for PCOS (≥86%). PCOS was associated with greater perceived susceptibility for disease and weight gain and poorer perceived control over these health outcomes (all P < 0.05), in relation to the comparison group. Women with PCOS also perceived fewer benefits of healthy behaviors on weight gain (P = 0.03) with less than half of the PCOS group attempting to follow government diet recommendations (47%). There were no differences in the self-efficacy of dietary behaviors between groups.Limitations, Reasons For Caution: It is likely that participant self-selection occurred due to the nature of recruitment in this study and results may have limited generalizability since most participants identified as Caucasian. Additionally, it is unclear whether some results may be clinically meaningful due to small effect sizes.Wider Implications Of the Findings: These findings support that behavioral interventions should incorporate the unique psychosocial considerations associated with PCOS to encourage patient participation in lifestyle interventions.Study Funding/competing Interest(s): This manuscript was partially supported by Cornell University Human Ecology Alumni Association and College of Agriculture and Life Sciences Alumni Association. The authors have no competing interests.Trial Registration Number: NCT01859663. [ABSTRACT FROM AUTHOR]

Background: The aim of this paper is to compare three models for exploring the links between different measures of adult socioeconomic position (SEP)-education, occupation, income-and psychosocial health. Model I is a basic univariate regression model with psychosocial health as the outcome and a measure of SEP as the predictor. Model II is a multiple regression model with psychosocial health as the outcome with all three measures of SEP allocated the same temporal position as predictors. Model III treats education, a distal measure of SEP, as antecedent to the proximal measures of SEP in the prediction equations linking SEP to health.Methods: Participants were drawn from the Whitehall II study, a prospective cohort study of British civil servants. Data analysed here are from Phase 5 (1997-1999) of data collection, 7830 individuals in all. The measures of SEP and psychosocial health were assessed via a self-administered questionnaire.Results: The three models can lead to completely different conclusions. Model III, our preferred model, shows education to have a stronger indirect effect on psychosocial health when compared to its direct effect. The indirect effect is due to the effect of education on proximal measures of social position, occupation, and income in this case.Conclusions: Results reported here support the hypothesis that a comparison of the relative importance of the different measures of social position in predicting health is meaningless if the causal relationships among these measures are not accounted for. [ABSTRACT FROM AUTHOR]

Objective: To develop a model for Bayesian communication to enable readers to make reported data more relevant by including their prior knowledge and values.Background: To change their practice, clinicians need good evidence, yet they also need to make new technology applicable to their local knowledge and circumstances. Availability of the Web has the potential for greatly affecting the scientific communication process between research and clinician. Going beyond format changes and hyperlinking, Bayesian communication enables readers to make reported data more relevant by including their prior knowledge and values. This paper addresses the needs and implications for Bayesian communication. FORMULATION: Literature review and development of specifications from readers', authors', publishers', and computers' perspectives consistent with formal requirements for Bayesian reasoning.Results: Seventeen specifications were developed, which included eight for readers (express prior knowledge, view effect size and variability, express threshold, make inferences, view explanation, evaluate study and statistical quality, synthesize multiple studies, and view prior beliefs of the community), three for authors (protect the author's investment, publish enough information, make authoring easy), three for publishers (limit liability, scale up, and establish a business model), and two for computers (incorporate into reading process, use familiar interface metaphors). A sample client-only prototype is available at http://omie.med.jhmi.edu/bayes.Conclusion: Bayesian communication has formal justification consistent with the needs of readers and can best be implemented in an online environment. Much research must be done to establish whether the formalism and the reality of readers' needs can meet. [ABSTRACT FROM AUTHOR]

Background: Although there is an ever increasing literature on older drivers, there is no comprehensive up-to-date presentation of how older drivers are impacted by traffic safety, and how they impact the road safety of others.Methods: This paper uses 1994-1996 US data to determine how many rates related to traffic safety depend on the age and sex of road users (fatalities, fatalities per licensed driver, etc.) Threats drivers pose to other road users are estimated by driver involvement in pedestrian fatality crashes.Results: It is found that renewing the licence of a 70-year-old male driver for another year poses, on average, 40% less threat to other road users than renewing the license of a 40-year-old male driver. The fatality risks drivers themselves face generally increase as they age, with the increased risk of death in the same severity crash being a major contributor. If this factor is removed, crash risks for 70-year-old male drivers are not materially higher than for 40-year-old male drivers; for female drivers they are.Conclusions: Most driver rates increase substantially by age 80, in many cases to values higher than those for 20-year-olds. Given that a death occurs, the probability that it is a traffic fatality declines steeply with age, from well over 20% for late teens through mid twenties, to under one per cent at age 65, and under half a per cent at age 80. [ABSTRACT FROM AUTHOR]

Background: Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naïve patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress.Methods: Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function. Analysis of variance was used to compare three groups of participants-patients who did or did not receive chemotherapy and healthy control subjects-on age- and education-corrected cognitive performance and cognitive change. Differences that were statistically significant after correction for false discovery rate were investigated with linear mixed-effects models and mediation models. All statistical tests were two-sided.Results: Of 226 participants (166 patients and 60 control subjects), 206 completed all assessment sessions (attrition: 8.8%). Patients demonstrated overall cognitive decline (group*time effect on composite z -score: -0.13, P = .04) and scored consistently worse on Go/Nogo errors. The latter effect was mediated by PTSD symptoms (mediation effect: B = 0.15, 95% confidence interval = 0.02 to 0.38). Only chemotherapy patients showed declined reaction time on a computerized alertness test. Overall cognitive performance correlated with self-reported cognitive problems at one year ( T = -0.11, P = .02).Conclusions: Largely irrespective of chemotherapy, breast cancer patients may encounter very subtle cognitive dysfunction, part of which is mediated by cancer-related post-traumatic stress. Further factors other than treatment side effects remain to be investigated. [ABSTRACT FROM AUTHOR]

Background: The European Organisation for Research and Treatment of Cancer (EORTC) Group has developed a new multidimensional instrument measuring cancer-related fatigue to be used in conjunction with the quality of life core questionnaire (EORTC QLQ-C30). The module EORTC QLQ-FA13 assesses physical, cognitive, and emotional aspects of cancer-related fatigue.Methods: The methodology follows the EORTC guidelines for phase IV validation of modules. This paper focuses on the results of the psychometric validation of the factorial structure of the module. For validation and cross-validation confirmatory factor analysis (maximum likelihood estimation), intraclass correlation and Cronbach alpha for internal consistency were employed. The study involved an international multicenter collaboration of 11 European and non-European countries.Results: A total of 946 patients with various tumor diagnoses were enrolled. Based on the confirmatory factor analysis, we could approve the three-dimensional structure of the module. Removing one item and reassigning the factorial mapping of another item resulted in the EORTC QLQ-FA12. For the revised scale, we found evidence supporting good local (indicator reliability ≥ 0.60, factor reliability ≥ 0.82) and global model fit (GFI t1|t2 = 0.965/0.957, CFI t1|t2 = 0.976/0.972, RMSEA t1|t2 = 0.060/0.069) for both measurement points. For each scale, test-retest reliability proved to be very good (intraclass correlation: R t1-t2 = 0.905-0.921) and internal consistency proved to be good to high (Cronbach alpha = .79-.90).Conclusion: Based on the former phase III module, the multidimensional structure was revised as a phase IV module (EORTC FA12) with an improved scale structure. For a comprehensive validation of the EORTC FA12, further aspects of convergent and divergent validity as well as sensitivity to change should be determined. [ABSTRACT FROM AUTHOR]

Background: Should health systems invest more in access to care by expanding insurance coverage or in health care services including improving the quality of care? Comparing these options experimentally would shed light on the impact and cost-effectiveness of these strategies.Methods: The Quality Improvement Demonstration Study (QIDS) was a randomized policy experiment conducted across 30 districts in the Philippines. The study had a control group and two policy intervention groups intended to improve the health of young children. The demand-side intervention in QIDS was universal health insurance coverage (UHC) for children aged 5 years or younger, and a supply-side intervention, a pay-for-performance (P4P) bonus for all providers who met pre-determined quality levels. In this paper, we compare the impacts of these policies from the QIDS experiment on childhood wasting by calculating DALYs averted per US$spent.Results: The direct per capita costs to implement UHC and P4P are US$4.08 and US$1.98 higher, respectively, compared to control. DALYs due to wasting were reduced by 334,862 in UHC and 1,073,185 in P4P. When adjustments are made for the efficiency of higher quality, the DALYS averted per US$ spent is similar in the two arms, 1.56 and 1.58 for UHC and P4P, respectively. Since the P4P quality improvements touches all patients seen by qualifying providers (32% in UHC versus 100% in P4P), there is a larger reduction in DALYs. With similar programmatic costs for either intervention, in this study, each US$spent under P4P yielded 1.52 DALYs averted compared to the standard program, while UHC yielded only a 0.50 DALY reduction.Conclusion: P4P had a greater impact and was more cost-effective compared to UHC as measured by DALYs averted. While expanded insurance benefit ceilings affected only those who are covered, P4P incentivizes practice quality improvement regardless of whether children are insured or uninsured. [ABSTRACT FROM AUTHOR]

Informal payments for health care are a well-known phenomenon in many health care systems around the world. While informal payments could be an important source of health care financing, they have an adverse impact on efficiency and access to care, and are a major impediment to ongoing health care reforms. This paper aims to study the scale and patterns of informal patient payments for out-patient and in-patient services in three former-socialist countries: Bulgaria, Hungary and Ukraine. The data are collected in 2010 and 2011 based on national representative samples and are analysed in pooled models to explain variations in payments. The results of the cross-country comparison suggest a relatively higher prevalence of informal patient payments in Ukraine and Hungary than in Bulgaria, where patients also have to pay formal user charges in the public sector. Nevertheless, informal payments for hospitalization in Bulgaria are quite extensive. We observe some differences in informal payments across the years. Variations in payment size are mainly explained by the nature, type and need for services, fee awareness and, on some occasions, by household income. Interpreted within the context of structural differences (e.g. reform paths, regulations, funding, user fees, anti-corruption policies), the findings of our study have implications on how to address informal payments for health care. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCTs)-the gold standard for evaluating the effects of medical interventions-are notoriously challenging in terms of logistics, planning and costs. The cohort multiple randomized controlled trial approach is designed to facilitate randomized trials for pragmatic evaluation of (new) interventions and is a promising variation from conventional pragmatic RCTs. In this paper, we evaluate methodological challenges of conducting an RCT within a cohort. We argue that equally valid results can be obtained from trials conducted within cohorts as from pragmatic RCTs. However, whether this design is more efficient compared with conducting a pragmatic RCT depends on the amount and nature of non-compliance in the intervention arm. [ABSTRACT FROM AUTHOR]

Background: The consequences of the move towards a primary-care-led NHS are shifts in activity from secondary care to primary care and more involvement of GPs in purchasing decisions. Although there are many anecdotal reports of an increasing primary care workload, there is little empirical evidence on the extent of such shifts. This paper reports the results of a survey of GPs in Grampian, in the north-east of Scotland, in which we attempted to gather information on the effects of shifts in the balance of care on general practice.Objective: We aimed to examine GPs perceptions of the extent to which general practice workload has changed due to planned and unplanned shifts in the balance of care.Methods: The design of the study was a self-reported questionnaire, which was administered in general practices in the Grampian Health Board, Scotland. The subjects were senior partners of all general practices and the main outcome measures were the types of changes which have taken place in general practice, their source, their effect on practice workload and how practices have reacted.Results: A 60% response rate was achieved (52/86); 85% (44/52) of GPs claimed that their workload had increased due to shifts in the balance of care and that 72% of the shifts were initiated outside the practice. Geriatric care, early discharge and psychiatric and psychology services, as well as nursing home care, were reported to have had the greatest impact on workload. The main aspects of practice workload which had increased included the number of GP consultations, general stress at work and number of home visits, whereas the net income of the practice and health outcome of patients were reported to have decreased. Practices have dealt with the increase in workload by shifting tasks from GPs to nurses and absorbing the workload into existing practices/patterns. Responders reported that ideally more nursing and GP staffing would be required. Overall, GPs welcomed the shifts in the balance of care, were more concerned about poor communication rather than actual increases in workload and claimed that morale had fallen.Conclusion: GPs perceive that the move towards a primary-care-led NHS is increasing the workload in general practice. If the shift in the balance of care away from secondary care is to be successful, then more information is required about such shifts to support practices as change continues. [ABSTRACT FROM AUTHOR]

Study Question: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature?Summary Answer: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI.What Is Known Already: NA.Study Design, Size, Duration: This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline.Participants/materials, Setting, Methods: NA.Main Results and the Role Of Chance: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations.Limitations, Reasons For Caution: The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome.Wider Implications Of the Findings: Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI.Study Funding/competing Interests: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose.Trial Registration Number: NA. [ABSTRACT FROM AUTHOR]

Since 1990 mortality and morbidity decline has been more extensive for some conditions prevalent in low- and middle-income countries than for others. One reason may be differences in the effectiveness of global health networks, which have proliferated in recent years. Some may be more capable than others in attracting attention to a condition, in generating funding, in developing interventions and in convincing national governments to adopt policies. This article introduces a supplement on the emergence and effectiveness of global health networks. The supplement examines networks concerned with six global health problems: tuberculosis (TB), pneumonia, tobacco use, alcohol harm, maternal mortality and newborn deaths. This article presents a conceptual framework delineating factors that may shape why networks crystallize more easily surrounding some issues than others, and once formed, why some are better able than others to shape policy and public health outcomes. All supplement papers draw on this framework. The framework consists of 10 factors in three categories: (1) features of the networks and actors that comprise them, including leadership, governance arrangements, network composition and framing strategies; (2) conditions in the global policy environment, including potential allies and opponents, funding availability and global expectations concerning which issues should be prioritized; (3) and characteristics of the issue, including severity, tractability and affected groups. The article also explains the design of the project, which is grounded in comparison of networks surrounding three matched issues: TB and pneumonia, tobacco use and alcohol harm, and maternal and newborn survival. Despite similar burden and issue characteristics, there has been considerably greater policy traction for the first in each pair. The supplement articles aim to explain the role of networks in shaping these differences, and collectively represent the first comparative effort to understand the emergence and effectiveness of global health networks. [ABSTRACT FROM AUTHOR]

Study Question: Is there an association between air pollution exposures and incident infertility?Summary Answer: Increased exposure to air pollution is associated with an increased incidence of infertility.What Is Known Already: Exposures to air pollution have been associated with lower conception and fertility rates. However, the impact of pollution on infertility incidence is unknown.Study Design, Size, Duration: Prospective cohort study using data collected from 116 430 female nurses from September 1989 to December 2003 as part of the Nurses' Health Study II cohort.Participants/materials, Setting, Methods: Infertility was defined by report of attempted conception for ≥12 months without success. Participants were able to report if evaluation was sought and if so, offer multiple clinical indications for infertility. After exclusion, 36 294 members were included in the analysis. Proximity to major roadways and ambient exposures to particulate matter less than 10 microns (PM10), between 2.5 and 10 microns (PM2.5-10), and less than 2.5 microns (PM2.5) were determined for residential addresses for the 36 294 members between the years of 1993 and 2003. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariable adjusted Cox proportional hazard models with time-varying covariates.Main Results and the Role Of Chance: Over 213 416 person-years, there were 2508 incident reports of infertility. Results for overall infertility were inconsistent across exposure types. We observed a small increased risk for those living closer to compared to farther from a major road, multivariable adjusted HR = 1.11 (CI: 1.02-1.20). This was consistent for those reporting primary or secondary infertility. For women living closer to compared to farther from a major road, for primary infertility HR = 1.05 (CI: 0.94-1.17), while for secondary infertility HR = 1.21 (CI: 1.07-1.36). In addition, the HR for every 10 µg/m(3) increase in cumulative PM2.5-10 among women with primary infertility was 1.10 (CI: 0.96-1.27), and similarly was 1.10 (CI: 0.94-1.28) for those with secondary infertility.Limitations, Reasons For Caution: Within the 2 year window of infertility diagnosis, we do not have the exact date of diagnosis or the exact timing of the start of attempting conception. As infertility status and subtypes of infertility were prospectively collected biennially, we were unable to tightly examine the timing of exposures on incidence of infertility. In terms of exposure quantification, we used ambient air pollution exposures as a proxy for personal exposures, potentially leading to exposure misclassification. However, several studies suggest that ambient measurements are an acceptable surrogate for individual level exposures in most populations.Wider Implications Of the Findings: We observed an association between all size fractions of PM exposure, as well as traffic-related air pollution, and incidence of infertility. Of note, the strongest association was observed between cumulative average exposures over the course of follow-up and the risk of infertility, suggesting that chronic exposures may be of greater importance than short-term exposures.Study Funding/competing Interests: The work for this paper was supported by the following: S.M.: Reproductive Scientist Development Program HD000849, and the Building Interdisciplinary Research Careers in Women's Health HD043444, the Boston University CTSI 1UL1TR001430, and a research grant from the Boston University Department of Obstetrics and Gynecology, S.A.M.: R01HD57210 from the National Institute of Child Health and Human Development and the Massachusetts Institute of Technology Center for Environmental Health Sciences Translational Pilot Project Program, R01CA50385 from the National Cancer Institute, J.E.H. and F.L.: 5R01ES017017 from the National Institute for Environmental Health Sciences, 5 P42 ES007381 from the National Institute of Environmental Health at the National Institute of Health. L.V.F.: T32HD060454 in reproductive, perinatal, and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Nurses' Health Study II is additionally supported by infrastructure grant UM1CA176726 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. The authors have no actual or potential competing financial interests to disclose. [ABSTRACT FROM AUTHOR]

Risk and rate advancement periods (RAP) measure the impact of an exposure on the relation of age to disease. Specifically, they quantify the time by which the risk or rate of a disease is advanced among exposed subjects conditional on disease-free survival to a certain baseline age. The fact that these measures incorporate timing of disease occurrence makes them appealing for risk communication, and their use has increased over recent years. Unfortunately, their misinterpretations have also increased. In particular, RAP is often misinterpreted as the difference in mean survival time, when in fact it is a distinct concept and a profoundly different quantity. Other misinterpretations include interpreting RAP as the time by which a survival curve is shifted between exposed and unexposed, and equating RAP to a simple function of relative risks. In this paper we review RAP and show why common misinterpretations are flawed. We also show how RAP is profoundly sensitive to the specification of disease dependence on age. We conclude that whereas RAP remains a potentially useful measure, it requires multiple cautions beyond those needed for traditional measures of association, especially when computed for rates. [ABSTRACT FROM AUTHOR]