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Background To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. Methods We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor. Results The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6–69.2%) in 2012 to a median of 72.5% (IQR, 65.3–78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1–69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5–67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2–79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6–76.3%). Conclusions The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.

Objectives: Using bilateral internal thoracic arteries (BITA) for coronary artery bypass grafting (CABG) has been suggested to improve survival compared to CABG using single internal thoracic arteries (SITA) for patients with advanced coronary artery disease. We used data from the Arterial Revascularisation Trial (ART) to assess long-term cost-effectiveness of BITA grafting compared to SITA grafting from an English health system perspective. Methods: Resource use, healthcare costs and quality-adjusted life-years (QALYs) were assessed across 10-years of follow-up. An intention-to-treat analysis of differences between trial arms was conducted. Missing data were addressed using multiple imputation. Incremental cost-effectiveness ratios were calculated with uncertainty characterised using non-parametric bootstrapping. Results were extrapolated beyond 10 years using Gompertz functions for survival and linear models for total cost and utility. Results: Total mean costs at 10 years of follow-up were estimated at £17,594736 in the BITA arm and £16,462594 in the SITA arm (mean difference £1,133118 95% CI £239195 to £2,026041, p= 0.01520). Total mean QALYs at 10 years were 6.54 in the BITA are and 6.57 in the SITA arm (adjusted mean difference -0.01 95% CI -0.2 to 0.1, p= 0.883). The estimated probability of BITA grafting being cost-effective compared to SITA grafting was 33% over 10 years of follow-up assuming a cost-effectiveness threshold of £20,000. Mean costs extrapolated to life-time increased to £20,760 in the SITA arm and £21,925 in the BITA arm. Mean QALYs extrapolated to life-time were 12.52 in the SITA arm and 12.61 in the BITA arm., The probability of BITA being cost-effective at a £20,000 threshold increased to 5160% when extrapolated to lifetime. Conclusions: BITA grafting has significantly higher costs but similar quality-adjusted survival at 10 years compared to SITA grafting.

Objectives To identify risk factors for antepartum stillbirth, including fetal growth restriction, among women with well‐dated pregnancies and access to antenatal care. Design Population‐based, prospective, observational study. Setting Eight international urban populations. Population Pregnant women and their babies enrolled in the Newborn Cross‐Sectional Study of the INTERGROWTH‐21st Project. Methods Cox proportional hazard models were used to compare risks among antepartum stillborn and liveborn babies. Main outcome measures Antepartum stillbirth was defined as any fetal death after 16 weeks’ gestation before the onset of labour. Results Of 60 121 babies, 553 were stillborn (9.2 per 1000 births), of which 445 were antepartum deaths (7.4 per 1000 births). After adjustment for site, risk factors were low socio‐economic status, hazard ratio (HR): 1.6 (95% CI, 1.2–2.1); single marital status, HR 2.0 (95% CI, 1.4–2.8); age ≥40 years, HR 2.2 (95% CI, 1.4–3.7); essential hypertension, HR 4.0 (95% CI, 2.7–5.9); HIV/AIDS, HR 4.3 (95% CI, 2.0–9.1); pre‐eclampsia, HR 1.6 (95% CI, 1.1–3.8); multiple pregnancy, HR 3.3 (95% CI, 2.0–5.6); and antepartum haemorrhage, HR 3.3 (95% CI, 2.5–4.5). Birth weight, Tweetable abstract International stillbirth study finds individual risks poor predictors of death but combinations promising.

OBJECTIVES: To identify risk factors for antepartum stillbirth, including fetal growth restriction, among women with well-dated pregnancies and access to antenatal care. DESIGN: Population-based, prospective, observational study. SETTING: Eight international urban populations. POPULATION: Pregnant women and their babies enrolled in the Newborn Cross-Sectional Study of the INTERGROWTH-21(st) Project. METHODS: Cox proportional hazard models were used to compare risks among antepartum stillborn and liveborn babies. MAIN OUTCOME MEASURES: Antepartum stillbirth was defined as any fetal death after 16 weeks' gestation before the onset of labour. RESULTS: Of 60 121 babies, 553 were stillborn (9.2 per 1000 births), of which 445 were antepartum deaths (7.4 per 1000 births). After adjustment for site, risk factors were low socio-economic status, hazard ratio (HR): 1.6 (95% CI, 1.2-2.1); single marital status, HR 2.0 (95% CI, 1.4-2.8); age ≥40 years, HR 2.2 (95% CI, 1.4-3.7); essential hypertension, HR 4.0 (95% CI, 2.7-5.9); HIV/AIDS, HR 4.3 (95% CI, 2.0-9.1); pre-eclampsia, HR 1.6 (95% CI, 1.1-3.8); multiple pregnancy, HR 3.3 (95% CI, 2.0-5.6); and antepartum haemorrhage, HR 3.3 (95% CI, 2.5-4.5). Birth weight

Background: Protein biomarkers with associations with the activity and outcomes of diseases are being identified by modern proteomic technologies. They may be simple, accessible, cheap and safe tests that can inform diagnosis, prognosis, treatment selection, monitoring of disease activity and therapy and may substitute for complex, invasive and expensive tests. However, their potential is not yet being realised. Design and methods: The study consisted of three workstreams to create a framework for research: workstream 1, methodology – to define current practice and explore methodology innovations for biomarkers for monitoring disease; workstream 2, clinical translation – to create a framework of research practice, high-quality samples and related clinical data to evaluate the validity and clinical utility of protein biomarkers; and workstream 3, the ELF to Uncover Cirrhosis as an Indication for Diagnosis and Action for Treatable Event (ELUCIDATE) randomised controlled trial (RCT) – an exemplar RCT of an established test, the ADVIA Centaur® Enhanced Liver Fibrosis (ELF) test (Siemens Healthcare Diagnostics Ltd, Camberley, UK) [consisting of a panel of three markers – (1) serum hyaluronic acid, (2) amino-terminal propeptide of type III procollagen and (3) tissue inhibitor of metalloproteinase 1], for liver cirrhosis to determine its impact on diagnostic timing and the management of cirrhosis and the process of care and improving outcomes. Results: The methodology workstream evaluated the quality of recommendations for using prostate-specific antigen to monitor patients, systematically reviewed RCTs of monitoring strategies and reviewed the monitoring biomarker literature and how monitoring can have an impact on outcomes. Simulation studies were conducted to evaluate monitoring and improve the merits of health care. The monitoring biomarker literature is modest and robust conclusions are infrequent. We recommend improvements in research practice. Patients strongly endorsed the need for robust and conclusive research in this area. The clinical translation workstream focused on analytical and clinical validity. Cohorts were established for renal cell carcinoma (RCC) and renal transplantation (RT), with samples and patient data from multiple centres, as a rapid-access resource to evaluate the validity of biomarkers. Candidate biomarkers for RCC and RT were identified from the literature and their quality was evaluated and selected biomarkers were prioritised. The duration of follow-up was a limitation but biomarkers were identified that may be taken forward for clinical utility. In the third workstream, the ELUCIDATE trial registered 1303 patients and randomised 878 patients out of a target of 1000. The trial started late and recruited slowly initially but ultimately recruited with good statistical power to answer the key questions. ELF monitoring altered the patient process of care and may show benefits from the early introduction of interventions with further follow-up. The ELUCIDATE trial was an ‘exemplar’ trial that has demonstrated the challenges of evaluating biomarker strategies in ‘end-to-end’ RCTs and will inform future study designs. Conclusions: The limitations in the programme were principally that, during the collection and curation of the cohorts of patients with RCC and RT, the pace of discovery of new biomarkers in commercial and non-commercial research was slower than anticipated and so conclusive evaluations using the cohorts are few; however, access to the cohorts will be sustained for future new biomarkers. The ELUCIDATE trial was slow to start and recruit to, with a late surge of recruitment, and so final conclusions about the impact of the ELF test on long-term outcomes await further follow-up. The findings from the three workstreams were used to synthesise a strategy and framework for future biomarker evaluations incorporating innovations in study design, health economics and health informatics.

Background The arterial revascularization trial (ART) has been designed to answer the question whether the use of bilateral internal thoracic arteries (BITA) can improve 10-year outcomes when compared to single internal thoracic artery (SITA). In the ART, a significant proportion of patients initially allocated to BITA received other conduit strategies. We sought to investigate the incidence and clinical implication of BITA grafts conversion in the ART. Methods Among patients enrolled in the ART (n=3102), we excluded those allocated to SITA (n=1554), those who did not undergo surgery (n=16) and those operated on but withdrew after randomization (n=7). Propensity score matching was used to compare converted vs non-converted BITA groups. Results A total of 1525 patients were operated with intention to receive BITA grafting. Of those, 233 (15.3%) were converted to other conduit selection strategies. Incidence of conversion largely varied across 28 centres involved (from 0% to 42.9%). The most common reason for BITA grafts conversion was the evidence of at least one internal thoracic artery not suitable which was reported in 77 cases. Patients with intraoperative BITA graft conversion received a lower number of grafts (2.95±0.84 vs 3.21±0.74; PConclusions The incidence of intraoperative BITA graft conversion is not irrelevant . BITA graft conversion is not associated with increased operative morbidity but its effect on late outcomes remain uncertain.

BACKGROUND: The World Health Organization recommends that human growth should be monitored with the use of international standards. However, in obstetric practice, we continue to monitor fetal growth using numerous local charts or equations that are based on different populations for each body structure. Consistent with World Health Organization recommendations, the INTERGROWTH-21st Project has produced the first set of international standards to date pregnancies; to monitor fetal growth, estimated fetal weight, Doppler measures, and brain structures; to measure uterine growth, maternal nutrition, newborn infant size, and body composition; and to assess the postnatal growth of preterm babies. All these standards are based on the same healthy pregnancy cohort. Recognizing the importance of demonstrating that, postnatally, this cohort still adhered to the World Health Organization prescriptive approach, we followed their growth and development to the key milestone of 2 years of age. OBJECTIVE: The purpose of this study was to determine whether the babies in the INTERGROWTH-21st Project maintained optimal growth and development in childhood. STUDY DESIGN: In the Infant Follow-up Study of the INTERGROWTH-21st Project, we evaluated postnatal growth, nutrition, morbidity, and motor development up to 2 years of age in the children who contributed data to the construction of the international fetal growth, newborn infant size and body composition at birth, and preterm postnatal growth standards. Clinical care, feeding practices, anthropometric measures, and assessment of morbidity were standardized across study sites and documented at 1 and 2 years of age. Weight, length, and head circumference age- and sex-specific z-scores and percentiles and motor development milestones were estimated with the use of the World Health Organization Child Growth Standards and World Health Organization milestone distributions, respectively. For the preterm infants, corrected age was used. Variance components analysis was used to estimate the percentage variability among individuals within a study site compared with that among study sites. RESULTS: There were 3711 eligible singleton live births; 3042 children (82%) were evaluated at 2 years of age. There were no substantive differences between the included group and the lost-to-follow up group. Infant mortality rate was 3 per 1000; neonatal mortality rate was 1.6 per 1000. At the 2-year visit, the children included in the INTERGROWTH-21st Fetal Growth Standards were at the 49th percentile for length, 50th percentile for head circumference, and 58th percentile for weight of the World Health Organization Child Growth Standards. Similar results were seen for the preterm subgroup that was included in the INTERGROWTH-21st Preterm Postnatal Growth Standards. The cohort overlapped between the 3rd and 97th percentiles of the World Health Organization motor development milestones. We estimated that the variance among study sites explains only 5.5% of the total variability in the length of the children between birth and 2 years of age, although the variance among individuals within a study site explains 42.9% (ie, 8 times the amount explained by the variation among sites). An increase of 8.9 cm in adult height over mean parental height is estimated to occur in the cohort from low-middle income countries, provided that children continue to have adequate health, environmental, and nutritional conditions. CONCLUSION: The cohort enrolled in the INTERGROWTH-21st standards remained healthy with adequate growth and motor development up to 2 years of age, which supports its appropriateness for the construction of international fetal and preterm postnatal growth standards.

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when

Although biomarkers are perceived as highly relevant for future clinical practice, few biomarkers reach clinical utility for several reasons. Among them, poor reporting of studies is one of the major problems. With respect to tumour marker prognostic studies, a survey provided evidence on the poor situation[zum vollständigen Text gelangen Sie über die oben angegebene URL], 62. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Many abstracts of diagnostic accuracy studies are currently insufficiently informative. We extended the STARD (Standards for Reporting Diagnostic Accuracy) statement by developing a list of essential items that authors should consider when reporting diagnostic accuracy studies in journal or conference abstracts. After a literature review of published guidance for reporting biomedical studies, we identified 39 items potentially relevant to report in an abstract. We then selected essential items through a two round web based survey among the 85 members of the STARD Group, followed by discussions within an executive committee. Seventy three STARD Group members responded (86%), with 100% completion rate. STARD for Abstracts is a list of 11 quintessential items, to be reported in every abstract of a diagnostic accuracy study. We provide examples of complete reporting, and developed template text for writing informative abstracts.

Background: Whether the use of the radial artery (RA) can improve clinical outcomes in coronary artery bypass graft surgery remains unclear. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral internal thoracic artery (BITA) over single left internal thoracic artery (SITA). In the ART, a large proportion of patients (≈20%) also received an RA graft instead of a saphenous vein graft (SVG). We aimed to investigate the associations between using the RA instead of an SVG to supplement SITA or BITA grafts and outcomes by performing a post hoc analysis of the ART. Methods: Patients enrolled in the ART (n=3102) were classified on the basis of conduits actually received (as treated). The analysis included 2737 patients who received an RA graft (RA group; n=632) or SVG only (SVG group; n=2105) in addition to SITA or BITA grafts. The primary end point was the composite of myocardial infarction, cardiovascular death, and repeat revascularization at 5 years. Propensity score matching and stratified Cox regression were used to compare the 2 strategies. Results: Myocardial infarction, cardiovascular death, and repeat revascularization cumulative incidence was 2.3% (95% confidence interval [CI], 1.1–3.4), 3.5% (95% CI, 2.1–5.0), and 4.4% (95% CI, 2.8–6.0) in the RA group and 3.4% (95% CI, 2.0–4.8), 4.0% (95% CI, 2.5–5.6), and 7.6% (95% CI, 5.5–9.7) in the SVG group, respectively. The composite end point was significantly lower in the RA group (8.8%; 95% CI, 6.5–11.0) compared with the SVG group (13.6%; 95% CI, 10.8–16.3; P =0.005). This association was present when an RA graft was used to supplement both SITA and BITA grafts (interaction P =0.62). Conclusions: This post hoc ART analysis showed that an additional RA was associated with lower risk for midterm major adverse cardiac events when used to supplement SITA or BITA grafts. Clinical Trial Registration: URL: https://www.situ.ox.ac.uk/surgical-trials/art . Unique identifier: ISRCTN46552265.

The selection of appropriate outcomes is crucial when designing clinical trials in order to compare the effects of different interventions directly. For the findings to influence policy and practice, the outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. It is now widely acknowledged that insufficient attention has been paid to the choice of outcomes measured in clinical trials. Researchers are increasingly addressing this issue through the development and use of a core outcome set, an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area.Accumulating work in this area has identified the need for guidance on the development, implementation, evaluation and updating of core outcome sets. This Handbook, developed by the COMET Initiative, brings together current thinking and methodological research regarding those issues. We recommend a four-step process to develop a core outcome set. The aim is to update the contents of the Handbook as further research is identified.

BACKGROUND: The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF). OBJECTIVES: This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo. METHODS: The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization. RESULTS: A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 0.79; p < 0.001), regardless of baseline heart rate (interaction p = 0.35). Beta-blockers had no effect on mortality in patients with AF (HR: 0.96, 95% CI: 0.81 to 1.12; p = 0.58) at any heart rate (interaction p = 0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR: 1.16 per 10 beats/min increase, 95% CI: 1.11 to 1.22; p < 0.0001). CONCLUSIONS: Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Oversights in the design and conduct of phase I trials have resulted in morbidity and mortality1,2. Empirical evidence to improve regulatory review of phase I trials is lacking. We studied the characteristics of phase I trials, frequency of harms, and dissemination of results.

Objective Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH‐21st Fetal Growth Standards that are available for use worldwide. Methods Women with an accurate gestational‐age assessment, who were enrolled in the prospective, international, multicenter, population‐based Fetal Growth Longitudinal Study (FGLS) and INTERBIO‐21st Fetal Study (FS), two components of the INTERGROWTH‐21st Project, had ultrasound scans every 5 weeks from 9–14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second‐degree fractional polynomial models. Results Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0–14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 − 54.06633 × (AC/100)3 − 95.80076 × (AC/100)3 × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis–fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age‐specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH‐21st Newborn Size Standards but, at

Objective: Although symphysis-fundal height (SFH) measurement is routinely performed during antenatal care to screen for fetal growth disturbances, across the world the methodology has never been standardised, and a range of different, locally-derived SFH charts are currently in use. Here we create international SFH standards derived from the pregnancies of healthy women with good maternal and perinatal outcomes. Design: Prospective longitudinal observational study. Setting: Eight geographically diverse urban regions in Brazil, China, India, Italy, Kenya, Oman, United Kingdom, and United States. Participants: Healthy, well-nourished pregnant women enrolled into the Fetal Growth Longitudinal Study component of the INTERGROWTH-21st Project at 9-14 weeks’ gestation, and followed up until birth. Main outcome measures: SFH was measured every 5 weeks from 14 weeks’ gestation until birth using standardised methods and dedicated research staff who were blinded to the SFH measurements by turning the tape measure so that numbers were not visible during the examination. The best fitting curve was selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. Results: We screened 13,108 women in the first trimester of whom 4,607 (35.1%) met the study entry criteria. Of these eligible women, 4,321 (93.8%) had pregnancies without major complications and delivered live singletons without congenital malformations. The median number of SFH measurements was 5.0 (range 1–7); 3,976 (92.0%) had four or more measurements. SFH measurements increased almost linearly with gestational age; data were used to determine fitted 3rd, 50th and 97th centile curves, and these showed excellent agreement with observed values. Conclusions: We present international standards to measure SFH as a first-level screening tool for fetal growth disturbances.

INTERGROWTH-21st is a multicentre, multiethnic, populationbased project, being conducted in eight geographical areas (Brazil, China, India, Italy, Kenya, Oman, UK and USA), with technical support from four global specialised units, to study growth, health and nutrition from early pregnancy to infancy. It aims to produce prescriptive growth standards, which conceptually extend the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) to cover fetal and newborn life. The new international standards will describe: (1) fetal growth assessed by clinical and ultrasound measures; (2) postnatal growth of term and preterm infants up to 2 years of age; and (3) the relationship between birthweight, length and head circumference, gestational age and perinatal outcomes. As the project has selected healthy cohorts with no obvious risk factors for intrauterine growth restriction, these standards will describe how all fetuses and newborns should grow, as opposed to traditional charts that describe how some have grown at a given place and time. These growth patterns will be related to morbidity and mortality to identify levels of perinatal risk. Additional aims include phenotypic characterisation of the preterm and impaired fetal growth syndromes and development of a prediction model, based on multiple ultrasound measurements, to estimate gestational age for use in pregnant women without access to early/frequent antenatal care. © 2013 Royal College of Obstetricians and Gynaecologists.

Early identification of ovarian cancer is an unresolved challenge and the predictive value of single symptoms is limited. We evaluated the performance of QCancer(®) (Ovarian) prediction model for predicting the risk of ovarian cancer in a UK cohort of general practice patients. A total of 1.1 million patients registered with a general practice surgery between 1 January 2000 and 30 June 2008, aged 30-84 years with 735 ovarian cancer cases, were included in the analysis. Ovarian cancer was defined as incident diagnosis of ovarian cancer during the 2 years after study entry. The results from this independent and external validation of QCancer(®) (Ovarian) prediction model demonstrated good performance on a large cohort of general practice patients. QCancer(®) (Ovarian) had very good discrimination with an area under the receiver operating characteristic curve of 0.86 and explained 59.9% of the variation. QCancer(®) (Ovarian) was well calibrated across all tenths of risk and over all age. The 10% of women with the highest predicted risks included 64% of all ovarian cancer diagnoses over the next 2 years. QCancer(®) (Ovarian) appears to be a useful tool for identifying undetected cases of ovarian cancer in primary care in the UK for early referral and investigation.

The Core Outcome Measures in Effectiveness Trials (COMET) Initiative database is an international repository of studies relevant to the development of core outcome sets. By the end of 2013, it included a unique collection of 306 studies. The website is increasingly being used, with more than 12,000 visits in 2013 (a 55% increase over 2012), 8,369 unique visitors (a 53% increase) and 6,844 new visitors (a 48% increase). There has been a rise in visits from outside the United Kingdom, with 2,405 such visits in 2013 (30% of all visits). By December 2013, a total of 4,205 searches had been completed, with 2,139 in 2013 alone.

Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes.

Objective: To examine whether exclusions of patients from the analysis of randomized trials are associated with biased estimates of treatment effects and higher heterogeneity between trials. Design: Meta-epidemiological study based on a collection of meta-analyses of randomised trials. Data sources: 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome. Methods: Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed. Results: 39 trials (23 %) had included all patients in the analysis. In 128 trials (77 %) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95 %-confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (2=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity. Conclusion: Exclusions of patients from the analysis in randomised trials often result in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.

We conducted a systematic review and meta-analysis to assess whether acute kidney injury was associated with long-term cardiovascular disease. We included cohort studies that examined adults with and without acute kidney injury and reported a multivariable adjusted relative risk for the association between acute kidney injury and cardiovascular mortality, major cardiovascular events and disease specific events: congestive heart failure, acute myocardial infarction and stroke. Twenty-five studies involving 254,408 adults (55,150 with acute kidney injury) were included. Acute kidney injury was associated with an 86% and 38% increased risk of cardiovascular mortality and major cardiovascular events respectively (relative risk 1.86, 95% CI: 1.72-2.01 and 1.38, 1.22-1.55). For disease specific events, acute kidney injury was associated with a 58% increased risk of heart failure (1.58, 1.46-1.72) and a 40% increased risk of acute myocardial infarction (1.40, 1.23-1.59). The elevated risk of heart failure and acute myocardial infarction persisted in subgroup analyses based on acute kidney injury severity and the proportion of adults with baseline ischemic heart disease. Finally, acute kidney injury was associated with a 15% increased risk of stroke (1.15, 1.04-1.28). Acute kidney injury is associated with an elevated risk of cardiovascular mortality and major cardiovascular events, particularly heart failure and acute myocardial infarction.