Aalborg University Hospital

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

BACKGROUND: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. METHODS: We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. RESULTS: The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. CONCLUSIONS: Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

BACKGROUND: Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. METHODS: A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level. RESULTS: The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P< 0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.081 for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02). CONCLUSIONS: Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

BACKGROUND: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. METHODS: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. RESULTS: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. CONCLUSIONS: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2011, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception, and the postpartum period. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. Results: The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.

BACKGROUND: Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer, but whether it prolongs survival remains controversial. We conducted a randomized trial of radiotherapy after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS: A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were randomly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone (856 women). The median length of follow-up was 114 months. The end points were locoregional recurrence, distant metastases, disease-free survival, and overall survival. RESULTS: The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF (P<0.001). Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival, irrespective of tumor size, the number of positive nodes, or the histopathological grade. CONCLUSIONS: The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer.

INTRODUCTION: Microalbuminuria and hypertension are risk factors for the development of diabetic nephropathy. Blockade of the renin-angiotensin system reduces progression to diabetic nephropathy in type 1 diabetic patients, whereas similar data are lacking for hypertensive type 2 diabetic subjects. We evaluated the renoprotective effect of an angiotensin II receptor antagonist, irbesartan, in hypertensive type 2 diabetic patients with microalbuminuria. MATERIAL AND METHODS: Five hundred and ninety hypertensive type 2 diabetic patients with microalbuminuria were enrolled in this multinational, randomised, double-blind, placebo-controlled study of irbesartan 150 mg/daily or 300 mg/daily or matching placebo for two years. The primary outcome was time to progression to diabetic nephropathy, defined as a persistent overnight albuminuria > 200 micrograms/min and at least a 30 per cent increase from baseline. RESULTS: Baseline characteristics in the three groups were similar. Ten patients (5.2 per cent) receiving irbesartan 300 mg and 19 patients (9.7 per cent) receiving irbesartan 150 mg daily reached the primary end point, as compared to 30 (14.9 per cent) patients on placebo (hazard ratio 0.30 [95 per cent confidence interval 0.14 to 0.61], p < 0.001 and 0.61 [95 per cent confidence interval 0.34 to 1.08] p = 0.08), respectively). The average blood pressure throughout the study was 144/83, 143/83, and 141/81 mmHg in the placebo, irbesartan 150 mg and 300 mg group, respectively (p = 0.004 for systolic blood pressure). Serious adverse events were less frequent in the patients treated with irbesartan (p = 0.02). DISCUSSIONS: Irbesartan is renoprotective independently of its blood pressure lowering effect in type 2 diabetic subjects with microalbuminuria. It is safe and well tolerated.

BACKGROUND: The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS: In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS: After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS: In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

BACKGROUND: Little is known about the prognosis of cancer discovered during or after an episode of venous thromboembolism. METHODS: We linked the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files to obtain data on the survival of patients who received a diagnosis of cancer at the same time as or after an episode of venous thromboembolism. Their survival was compared with that of patients with cancer who did not have venous thromboembolism (control patients), who were matched in terms of type of cancer, age, sex, and year of diagnosis. RESULTS: Of 668 patients who had cancer at the time of an episode of deep venous thromboembolism, 44.0 percent of those with data on the spread of disease (563 patients) had distant metastasis, as compared with 35.1 percent of 5371 control patients with data on spread (prevalence ratio, 1.26; 95 percent confidence interval, 1.13 to 1.40). In the group with cancer at the time of venous thromboembolism, the one-year survival rate was 12 percent, as compared with 36 percent in the control group (P<0.001), and the mortality ratio for the entire follow-up period was 2.20 (95 percent confidence interval, 2.05 to 2.40). Patients in whom cancer was diagnosed within one year after an episode of venous thromboembolism had a slightly increased risk of distant metastasis at the time of the diagnosis (prevalence ratio, 1.23 [95 percent confidence interval, 1.08 to 1.40]) and a relatively low rate of survival at one year (38 percent, vs. 47 percent in the control group; P<0.001). CONCLUSIONS: Cancer diagnosed at the same time as or within one year after an episode of venous thromboembolism is associated with an advanced stage of cancer and a poor prognosis.

OBJECTIVE: To investigate the effect of a restricted intravenous fluid regimen versus a standard regimen on complications after colorectal resection. SUMMARY BACKGROUND DATA: Current fluid administration in major surgery causes a weight increase of 3-6 kg. Complications after colorectal surgery are reported in up to 68% of patients. Associations between postoperative weight gain and poor survival as well as fluid overload and complications have been shown. METHODS: We did a randomized observer-blinded multicenter trial. After informed consent was obtained, 172 patients were allocated to either a restricted or a standard intraoperative and postoperative intravenous fluid regimen. The restricted regimen aimed at maintaining preoperative body weight; the standard regimen resembled everyday practice. The primary outcome measures were complications; the secondary measures were death and adverse effects. RESULTS: The restricted intravenous fluid regimen significantly reduced postoperative complications both by intention-to-treat (33% versus 51%, P = 0.013) and per-protocol (30% versus 56%, P = 0.003) analyses. The numbers of both cardiopulmonary (7% versus 24%, P = 0.007) and tissue-healing complications (16% versus 31%, P = 0.04) were significantly reduced. No patients died in the restricted group compared with 4 deaths in the standard group (0% versus 4.7%, P = 0.12). No harmful adverse effects were observed. CONCLUSION: The restricted perioperative intravenous fluid regimen aiming at unchanged body weight reduces complications after elective colorectal resection.

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

BACKGROUND: Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients. METHODS: We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding. RESULTS: Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97). CONCLUSIONS: In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].).

BACKGROUND: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. FUNDING: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability.1 CD can affect individuals of any age, from children to the elderly,2,3 and may cause significant morbidity and impact on quality of life. Up to one-third of patients present with complicated behaviour [strictures, fistula, or abscesses] at diagnosis.4 Most patients over time will develop a complication, with roughly 50% of patients requiring surgery within 10 years of diagnosis.5–7 As the precise aetiology of CD remains unknown, a curative therapy is not yet available.8 Several agents are available for the medical treatment of CD. Medical agents include mesalazine [5-ASA], locally active steroids [such as budesonide], systemic steroids, thiopurines such as azathioprine [AZA] and mercaptopurine [MP], methotrexate [MTX], and biologic therapies (such as anti-tumour necrosis factor [TNF], anti-integrins, and anti-interleukin [IL] 12/23]. The European Crohn’s and Colitis Organisation [ECCO] produces and regularly updates several guidelines aimed at providing evidence-based guidance on critical aspects of IBD care to all health care professionals who manage patients with IBD. To provide high-quality evidence-based recommendations on medical treatment in CD, ECCO decided to develop these guidelines by adopting the GRADE [Grading of Recommendations Assessment, Development, and Evaluation] approach.9 GRADE is a systematic process for developing guidelines which addresses how to frame the health care questions, summarise the evidence, formulate the recommendations, and grade their strength and the quality of the associated evidence. GRADE increases transparency at all levels of this process and makes explicit the three considerations that lead to a particular recommendation: the quality of the evidence, the balance of benefits and harms, and the patients’ values and preferences. Therefore ECCO reviewed the available high-quality evidence on the medical management of CD and developed evidence-based recommendations on the medical treatment of adult patients with CD. These guidelines do not cover specific situations, such as postoperative management of adult patients with CD, which was already covered in the latest ECCO Guidelines on Crohn’s disease.10 Based on the GRADE workflow, the Guidelines Committee of ECCO [GuiCom] selected a panel of 48 experts supported by a team of methodologists and librarians. Selection was based on IBD expertise, scientific background, and knowledge of the GRADE methodology. All panellists received adequate training in GRADE before starting the process. Additionally, four patients with CD representing the European Federation of Crohn’s and Colitis Associations [EFCCA] were invited to participate in all face-to-face meetings and to provide their experiences and state their preferences. Three domains for medical treatment of CD were identified: 1] induction therapy; 2] maintenance therapy; 3] therapy of fistulising perianal disease. All panellists were assigned to one of three working groups coordinated by one to two working group leaders under the supervision of two Guideline coordinators. The panellists first formulated a series of specific questions using the PICO format [Population, Intervention, Comparator, Outcomes] which were deemed to be clinically important for the medical treatment of CD. The outcomes of all PICO questions were subsequently graded as ‘not important’, ‘important’, or ‘critical’ during a face-to-face kick-off meeting in Vienna, using a Delphi consensus process. A team of professional librarians performed a comprehensive literature search on EMBASE, PubMed/Medline, and Cochrane Central databases using specific search strings for each PICO question [Supplementary Files 1, 2, and 3, available as Supplementary data at ECCO-JCC online]. Two independent working group members [one assigned to the PICO and another one from the same group as a second reviewer] assessed the relevance of each abstract to PICO and included or excluded all the relevant papers for the final data extraction and analysis. Subsequently, the working group members assigned to each PICO question systematically reviewed and summarised the evidence on every outcome, to compile a Summary of Findings [SoF] table for each question. The GRADE method follows a hierarchical approach to synthesise evidence; recent high-quality systematic reviews and meta-analyses of clinical trials were preferentially used to create the recommendations. When these were not available, individual randomised clinical trials [RCTs] followed by observational studies were reviewed; results of individual studies were pooled using random-effects meta-analysis as appropriate and when needed. To define disease activity and severity [mild-to-moderate and moderate-to-severe], we accepted the definitions used by the investigators of the studies selected as an evidence basis for our work. The quality of evidence was classified into the following four categories in accordance with the GRADE approach: ‘high’ [meaning that further research is unlikely to change our in the research may change our in the research to change our in the and [meaning that any of is each PICO the quality of evidence was to the quality of evidence outcomes graded as The strength of each was graded as [meaning the of an the or or as [meaning the balance is the quality of evidence, values or and the outcomes were not in the clinical this was in the To the recommendations, we from the systematic reviews or our group of methodologists performed the All recommendations were to by the panel the ECCO for each with and from a of ECCO members who to the were not selected to be of the The final of all was panel members during a final consensus meeting in and to a final recommendations were at of the panellists with the and associated strength The of the and and the of the were reviewed by two Guideline Committee members and by the ECCO who the final of these The literature search the relevant definitions of and a of the and the the evidence can be in the Supplementary available as Supplementary data at ECCO-JCC As CD is a therapy to in the and in the The that chronic and results in to a recent in medical treatment and disease is that and may patients to their and therapy are to high-quality evidence is not available to this affect the of medical These include disease disease activity and to and of perianal or fistulising the individual for and the individual and the and of each be As is a clinical and is of to disease and therapy at based on and approach will provide the with the to therapy the of of the disease and which is to be to disease to the management of CD a series of health care maintenance be to be and be and appropriate guidance or for and be as in ECCO or the of for induction of of Crohn’s disease performed a meta-analysis of that the of or with in patients with active CD [Supplementary 1, available as Supplementary data at ECCO-JCC online]. The of from to patients with disease with or disease were was significant for induction of clinical [Supplementary 1, available as Supplementary data at ECCO-JCC online]. A recent Cochrane significant and to be in our as was significant in to when with [Supplementary 2, available as Supplementary data at ECCO-JCC online]. the trials of was over for clinical [Supplementary 3, available as Supplementary data at ECCO-JCC online]. significant in to was in trials that [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis a significant on clinical the that at of another meta-analysis was to any such A pooled of three trials of a of a in the Crohn’s with the in and was not clinically Two trials with for induction of clinical A pooled a of [Supplementary available as Supplementary data at ECCO-JCC online]. was not by any significant in for [Supplementary available as Supplementary data at ECCO-JCC online]. in trials that the of was to patients with The of or for the treatment of CD not in using for the induction of clinical in patients with active Crohn’s disease to the A Cochrane systematic and included three that at a of with [Supplementary 2, available as Supplementary data at ECCO-JCC online]. Two of these clinical as in or at at was in all three was to for clinical and clinical in patients with active CD in the to the As with steroids which are associated with systemic activity and systemic and and a was to be in the reviewed A Cochrane systematic and meta-analysis from reviewed two that at a of with mesalazine to a mesalazine in patients with active CD [Supplementary 3, available as Supplementary data at ECCO-JCC online]. All trials clinical in or and clinical at was not to mesalazine for clinical in patients with active CD in the [Supplementary available as Supplementary data at ECCO-JCC online]. clinical was in patients in patients mesalazine [Supplementary available as Supplementary data at ECCO-JCC online]. The of was with and in groups [Supplementary and available as Supplementary data at ECCO-JCC online]. studies the of treatment on CD. and to clinical or with the of these the European on the of to or Therefore a was not on to CD, for the treatment of patients with Crohn’s we the of systemic for the induction of clinical and Two on the of systemic or with for the treatment of active available as Supplementary data at ECCO-JCC online]. was at a of 48 and on a basis to and of from to with a of is at over an from these studies in a Cochrane systematic patients on induction of clinical was in patients as with were to be as in clinical in the two studies patients on the of patients from the of systemic was available from one patients with The of was in patients with included of and in patients with and in was for the outcomes to which a quality of evidence the of thiopurines as for the induction of of Crohn’s disease Several studies on the of thiopurines with for induction of and in [Supplementary available as Supplementary data at ECCO-JCC online]. trials the of thiopurines for induction of clinical in with or patients were The active was in four of these and the active was in the The trials were in of of active and of for of the trials for the of The pooled was performed on an basis and for induction of thiopurines and in the active with in the group Three trials on clinical not with of disease these of of disease were of the patients as with of clinical The of clinical was was and to data and the quality of evidence was for this [Supplementary available as Supplementary data at ECCO-JCC online]. one on during The pooled of any was not and thiopurines were in two of of developed The quality of evidence was deemed to a of and on a quality of The groups was at for and for of the trials on at the of the induction data were available that for a pooled trials in of such as or in thiopurines as with a of at and at and for the thiopurines and a of in the group and a significant in in and one relevant was this patients with active CD were randomised to of or for with a of at that was over a [Supplementary available as Supplementary data at ECCO-JCC online]. a of patients with were in clinical The of treatment for and was in with this is by and such as the of studies were that for the induction of of CD. was in the the of for CD and the decided to Three and studies the of and thiopurines for induction of in [Supplementary available as Supplementary data at ECCO-JCC online]. These studies used and of Two studies used at of and and one used at All patients were and received systemic steroids at of the individual studies or the pooled a significant in the to [Supplementary available as Supplementary data at ECCO-JCC online]. the of is with the data are and the quality of evidence is for can be Based on the evidence, on a for the of for clinical in patients with CD not be may be as an for patients with disease when be The to therapy in patients a be the of and to in patients with Crohn’s disease who not to therapy are and therapies for the treatment of CD include and is not in the European for CD, is available in and is a at a of at 2, and during induction and every is a at a of and followed by every is a at a of at 2, and followed by every on agents and from several meta-analyses of their for induction of clinical and clinical [Supplementary available as Supplementary data at ECCO-JCC in patients who not adequate or were to data were available for the induction two studies a the evidence was to on clinical were and data on were by to the of patients included in the meta-analysis on outcomes and and and quality of are was in of The of on and in a that with and were to for induction of The of of biologic agents is a of that patients with fistulising perianal complicated from the of to a of or of agents be the first in disease these results are based on from clinical the of and thiopurines over to clinical and one the of therapy of with as with for the induction of clinical in patients to therapies [Supplementary available as Supplementary data at ECCO-JCC online]. this therapy was not to for clinical therapy was associated with at this was at the of was in to associated with therapy the of used in this was the used in CD patients of therapy with a when starting to in patients with Crohn’s who an to therapy The and Crohn’s the of with over in patients to who to to steroids or [Supplementary available as Supplementary data at ECCO-JCC online]. therapy in of clinical at as with therapy was to result in at this was in for were of in therapy A in clinical is patients who or an to thiopurines and in therapy is in such maintenance in with the benefits in of A of of the of therapy starting therapy in this be in the of evidence, an approach be for induction of in patients with Crohn’s disease with to therapy to therapy high-quality is an that to the by the and CD, induction be using a of systematic and meta-analysis pooled the results from in which was with for induction of in patients with active available as Supplementary data at ECCO-JCC online]. patients with or induction of clinical and induction of clinical at were and a meta-analysis was an of clinical of [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence was The of clinical was [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence was CD patients that of patients at as with of The quality of evidence was on or The pooled of any was not and [Supplementary available as Supplementary data at ECCO-JCC online]. the pooled of any was not and [Supplementary available as Supplementary data at ECCO-JCC the quality of evidence was The of to be for induction of and in patients with Crohn’s disease with to therapy to therapy is a that by the in is at a of at 2, and for and every who do not at can from an at Three randomised trials patients with or on induction of clinical induction of clinical and in adult patients with active available as Supplementary data at ECCO-JCC online]. in these studies were followed for to 10 was in patients with [Supplementary available as Supplementary data at ECCO-JCC online]. clinical was in patients with [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence for these outcomes was of with were not with [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence for this was to from the of or for the treatment of active Crohn’s disease in patients who therapy systematic and meta-analysis performed an of and for induction of in patients with active CD who were or to a of patients with or on induction of clinical and clinical [Supplementary available as Supplementary data at ECCO-JCC online]. The pooled of clinical and clinical were not and the quality of evidence was for a of patients with or on or The pooled of any was not and the pooled of any was not and the quality of evidence was surgery be as an in is for the induction of in patients with CD, as a and of at or a or a Crohn’s of with and is a knowledge on how to CD in of the the and or in patients with disease. 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The excluded from our table was not or the adult patients with a recent of CD were randomised to or to were to active disease in this The results were not significant for any of the critical outcomes of clinical not the two groups patients with and were in The of as and were in patients in the group and in the group methotrexate for the maintenance of in patients with Crohn’s disease on the of are from one patients were of or of for [Supplementary available as Supplementary data at ECCO-JCC online]. with active CD, who to of treatment with were assigned to at a of or for for CD were the of patients who in was in the group in the group 50% of the patients in the group by the of the were in in the group as with the group over the observational [one and the a and patients in the group in the of the was one treatment of these of severity to treatment or from the The of was in patients with Crohn’s disease who with maintenance treatment using the same treatment is Two systematic reviews the of maintenance treatment with and to patients with CD who disease with the same [Supplementary available as Supplementary data at ECCO-JCC online]. trials and were pooled in the meta-analysis from one was on two on and two on A of patients were included and followed for to of the studies included and one included all was as a The of with was The following values were with with and with A significant the three are pooled data available on of all as a performed in the of a Cochrane the for for and were and with is as with for the maintenance of in CD the and of do not the of that may in and observational for clinical in patients with Crohn’s disease who with at every was to in clinical in patients with CD who with [Supplementary available as Supplementary data at ECCO-JCC online]. patients every and patients every were in clinical as with patients and was at clinical and a of with data are to the the of to clinical in patients with Crohn’s disease who with outcomes for the maintenance of with in CD patients [Supplementary available as Supplementary data at ECCO-JCC to in the induction were to every or or a of the patients were in clinical as with of A that at clinical was by of patients every and by of patients every as with in the The treatment every and was and was treatment every and Therefore was every or was in of patients of patients The pooled of any was not patients who were and are data on as this was assessed in a of patients at was significant in patients in the group as with patients in the treatment were during the of were and with significant in the and was an of in the maintenance groups patients in and data are to the are randomised trials or with agents for the maintenance of clinical in patients with CD who or with the same A included trials used the to define clinical with The a time of All were the the the quality of evidence was specific was the in the maintenance Based on is evidence to to or in patients who to induction treatment with any or is a to that and to trials that for the of who from a biologic over the Crohn’s disease patients in clinical under is evidence to for or the of to clinical outcomes as to care from two with a of patients with CD were used to this [Supplementary available as Supplementary data at ECCO-JCC online]. These two of over clinically based for any of our critical clinical [one clinical [one [one [one or [one the a of IBD patients with to maintenance therapy were randomised to or groups were or to a and of the that in patients in clinical a or was in and of in clinical or at were and based the group who received during the patients with CD, with an induction therapy with and were randomised to the following three based on clinical and levels of with of or of or based on clinical The was to a was in clinical with from to in the three in in in studies important in their which the strength of our The outcomes in studies were clinical important such as and to be The in Crohn’s that is on and and that during the induction may outcomes and treatment the that with adequate of patients are Crohn’s disease patients who to an is evidence to for or the of to clinical outcomes to the of in patients on therapy with active to the of of and to clinical was with on clinical in one in a of patients with CD with were randomised to every or based on and levels using the was in clinical the group and the group [Supplementary available as Supplementary data at ECCO-JCC online]. studies a adequate and clinical outcomes from clinical to Based on these observational recent clinical guidelines and a group of experts supported the of the quality of evidence from observational a of patients with active IBD with who and clinical were for and at a of was in of patients in the as with in the clinical was in and in the group another a of the using a of was to a at was this group and a group in which were of was significant in clinical the approach was in the evidence not an a and clinical outcomes a of thiopurines in Crohn’s disease patients in on maintenance as the of is when the treatment is our meta-analysis to the two of in CD patients in on maintenance therapy [Supplementary available as Supplementary data at ECCO-JCC online]. from four trials were included received from to before randomised to or or to or All studies a time of to results that the of clinical is [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis for was the data a with of the results were not significant [Supplementary available as Supplementary data at ECCO-JCC online]. for the be performed the data from the To the evidence for the of clinical is in of of as when the treatment was the of was not and from studies that patients treatment for are and this an important research from observational studies and for the of and in patients to treatment with The time and the of patients included in the studies of the meta-analysis are to and that may in the reviewed the literature to the approach of using thiopurines an literature we not evidence the two treatment one was of thiopurines was with thiopurines in the of therapy in patients with IBD. The was as was not to data from and CD specific was patients with Crohn’s disease who with the of and we with A Cochrane based on two the same patients who therapy with or [Supplementary available as Supplementary data at ECCO-JCC online]. The same the of for therapy or These results are to an of in the therapy studies included and studies are to the A of when agents are with the and were as 10 in one meta-analysis of patients included in the patients with Crohn’s disease who with the of and we with the basis of a meta-analysis of studies on by the data included were the and groups to be to the relevant PICO question. The result of this not any in maintenance of clinical therapy and [Supplementary and Supplementary available as Supplementary data at ECCO-JCC online]. this meta-analysis was to of in the studies with a are quality data available for clinical in the which is an that follows the of patients in the on the of were in patients with or at years of The meta-analysis by which was not any in with and therapy [Supplementary available as Supplementary data at ECCO-JCC online]. is evidence to or of therapy in Crohn’s disease patients the to therapy be and and be with the randomised

BACKGROUND: For the treatment of myocardial infarction with ST-segment elevation, primary angioplasty is considered superior to fibrinolysis for patients who are admitted to hospitals with angioplasty facilities. Whether this benefit is maintained for patients who require transportation from a community hospital to a center where invasive treatment is available is uncertain. METHODS: We randomly assigned 1572 patients with acute myocardial infarction to treatment with angioplasty or accelerated treatment with intravenous alteplase; 1129 patients were enrolled at 24 referral hospitals and 443 patients at 5 invasive-treatment centers. The primary study end point was a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days. RESULTS: Among patients who underwent randomization at referral hospitals, the primary end point was reached in 8.5 percent of the patients in the angioplasty group, as compared with 14.2 percent of those in the fibrinolysis group (P=0.002). The results were similar among patients who were enrolled at invasive-treatment centers: 6.7 percent of the patients in the angioplasty group reached the primary end point, as compared with 12.3 percent in the fibrinolysis group (P=0.05). Among all patients, the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfarction (1.6 percent in the angioplasty group vs. 6.3 percent in the fibrinolysis group, P<0.001); no significant differences were observed in the rate of death (6.6 percent vs. 7.8 percent, P=0.35) or the rate of stroke (1.1 percent vs. 2.0 percent, P=0.15). Ninety-six percent of patients were transferred from referral hospitals to an invasive-treatment center within two hours. CONCLUSIONS: A strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes two hours or less.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines.

The health status questionnaire Short-Form 36 (SF-36) includes subscales measuring both physical health and mental health. Psychometrically, the mental health subscale contains a mixture of mental symptoms and psychological well-being items, among other things, to prevent a ceiling effect when used in general population studies. Three of the mental health well-being items are also included in the WHO-Five well-being scale. In a Danish general population study, the mental health subscale was compared psychometrically with the WHO-Five in order to evaluate the ceiling effect. Tests for unidimensionality were used in the psychometric analyses, and the sensitivity of the scales in differentiating between changes in self-reported health over the past year has been tested. The results of the study on 9,542 respondents showed that, although the WHO-Five and the mental health subscale were found to be unidimensional, the WHO-Five had a significantly lower ceiling effect than the mental health subscale. The analysis identified the three depression symptoms in the mental health subscale as responsible for the ceiling effect. The WHO-Five was also found to be significantly superior to the mental health subscale in terms of its sensitivity in differentiating between those persons whose health had deteriorated over the past year and those whose health had not. In conclusion, the WHO-Five, which measures psychological well-being, reflects aspects other than just the absence of depressive symptoms.

STUDY QUESTION: What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. WHAT IS KNOWN ALREADY: A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. LIMITATIONS REASONS FOR CAUTION: Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. 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 dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.