Holbæk Sygehus

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The management of acute myocardial infarction (AMI)1 has evolved over the past century and particularly in the past 50 years. Important milestones include the development of the electrocardiogram, coronary care units, coronary angiography, reperfusion therapies, and troponin assays. These innovations are the foundation of contemporary AMI management strategies that include a diagnosis centred on elevated troponin values associated with corroborative clinical evidence,1 early use of coronary angiography, and reperfusion therapies.2–4 Pivotal in the evolution of these contemporary strategies were the early AMI coronary angiography studies undertaken by DeWood et al. These pioneering studies demonstrated that, in patients presenting with ST elevation myocardial infarction (STEMI), almost 90% had an occluded coronary artery provided that angiography was undertaken within 4 h of chest pain onset.5 In contrast, in AMI patients who did not present with ST elevation (non-ST elevation myocardial infarction or NSTEMI), only 26% had an occluded coronary artery when angiography was performed within 24 h of symptom onset.6 In both of these landmark studies,5,6 >90% of the acute MI patients had angiographic evidence of obstructive coronary artery disease (CAD), underscoring the importance of the atherosclerotic process in the pathogenesis of AMI. Although DeWood's studies underscore the importance of obstructive CAD in AMI, it is fascinating that ∼10% had no significant CAD on coronary angiography. This is confirmed in several large AMI registries7–9 where 1–13% of AMI's occurred in the absence of obstructive CAD thereby eliciting an important set of questions—what is the mechanism of the myocardial damage in these patients? Do these patients differ from those with obstructive CAD? Should they be managed with the same clinical strategies? Do patients with non-obstructive atherosclerosis differ in pathophysiology and outcomes from those with angiographically normal coronary arteries? These and other issues have prompted clinical researchers to coin the term myocardial infarction with non-obstructive coronary arteries (MINOCA). This position paper is the first authoritative international expert opinion regarding this intriguing condition. We seek to define MINOCA, describe its associated clinical features and mechanisms, detail an assessment pathway for its evaluation, as well as stimulate research into its mechanisms and treatment.10 As the name implies, the formulation of the MINOCA diagnosis requires both clinical documentation of an AMI and demonstration of non-obstructive coronary arteries (Table 1). Accordingly, the diagnosis is made following coronary angiography in the evaluation of a clinical presentation consistent with AMI. It should be noted that the Universal Definition of Myocardial Infarction specifies that the combination of symptoms and a positive cardiac biomarker in the appropriate clinical scenario is diagnostic of AMI. Therefore, if there is no clinically apparent alternative diagnosis, such as myocarditis or pulmonary embolism, the diagnosis of MINOCA is applicable. The rationale for establishing MINOCA as a clinical diagnosis includes: (i) providing a common nomenclature for this group of patients who are often overlooked in contemporary clinical practice, (ii) encouraging routine evaluation for underlying causes in these patients, and (iii) stimulating further studies into its responsible mechanisms, outcomes, and most appropriate management strategies. Myocardial infarction with non-obstructive coronary arteries should be considered as a ‘working diagnosis’, analogous to heart failure, and thus prompts further evaluation regarding its underlying mechanism(s). Diagnostic criteria for myocardial infarction with non-obstructive coronary arteries AMI criteria.1 (a) Positive cardiac biomarker (preferably cardiac troponin) defined as a rise and/or fall in serial levels, with at least one value above the 99th percentile upper reference limit. (b) Corroborative clinical evidence of infarction evidenced by at least one of the following: Symptoms of ischaemia New or presumed new significant ST-T changes or new LBBB Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new RWMA Intracoronary thrombus evident on angiography or at autopsy Non-obstructive coronary arteries on angiography: Defined as the absence of obstructive CAD on angiography, (i.e. no coronary artery stenosis ≥50%), in any potential infarct-related artery. This includes both patients with: o normal coronary arteries (no stenosis >30%) o mild coronary atheromatosis (stenosis >30% but <50%). No clinically overt specific cause for the acute presentation: At the time of angiography, the cause and thus a specific diagnosis for the clinical presentation is not apparent. Accordingly, there is a necessity to further evaluate the patient for the underlying cause of the MINOCA presentation. AMI criteria.1 (a) Positive cardiac biomarker (preferably cardiac troponin) defined as a rise and/or fall in serial levels, with at least one value above the 99th percentile upper reference limit. (b) Corroborative clinical evidence of infarction evidenced by at least one of the following: Symptoms of ischaemia New or presumed new significant ST-T changes or new LBBB Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new RWMA Intracoronary thrombus evident on angiography or at autopsy Non-obstructive coronary arteries on angiography: Defined as the absence of obstructive CAD on angiography, (i.e. no coronary artery stenosis ≥50%), in any potential infarct-related artery. This includes both patients with: o normal coronary arteries (no stenosis >30%) o mild coronary atheromatosis (stenosis >30% but <50%). No clinically overt specific cause for the acute presentation: At the time of angiography, the cause and thus a specific diagnosis for the clinical presentation is not apparent. Accordingly, there is a necessity to further evaluate the patient for the underlying cause of the MINOCA presentation. LBBB, left bundle branch block. RWMA, regional wall motion abnormality. Diagnostic criteria for myocardial infarction with non-obstructive coronary arteries AMI criteria.1 (a) Positive cardiac biomarker (preferably cardiac troponin) defined as a rise and/or fall in serial levels, with at least one value above the 99th percentile upper reference limit. (b) Corroborative clinical evidence of infarction evidenced by at least one of the following: Symptoms of ischaemia New or presumed new significant ST-T changes or new LBBB Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new RWMA Intracoronary thrombus evident on angiography or at autopsy Non-obstructive coronary arteries on angiography: Defined as the absence of obstructive CAD on angiography, (i.e. no coronary artery stenosis ≥50%), in any potential infarct-related artery. This includes both patients with: o normal coronary arteries (no stenosis >30%) o mild coronary atheromatosis (stenosis >30% but <50%). No clinically overt specific cause for the acute presentation: At the time of angiography, the cause and thus a specific diagnosis for the clinical presentation is not apparent. Accordingly, there is a necessity to further evaluate the patient for the underlying cause of the MINOCA presentation. AMI criteria.1 (a) Positive cardiac biomarker (preferably cardiac troponin) defined as a rise and/or fall in serial levels, with at least one value above the 99th percentile upper reference limit. (b) Corroborative clinical evidence of infarction evidenced by at least one of the following: Symptoms of ischaemia New or presumed new significant ST-T changes or new LBBB Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new RWMA Intracoronary thrombus evident on angiography or at autopsy Non-obstructive coronary arteries on angiography: Defined as the absence of obstructive CAD on angiography, (i.e. no coronary artery stenosis ≥50%), in any potential infarct-related artery. This includes both patients with: o normal coronary arteries (no stenosis >30%) o mild coronary atheromatosis (stenosis >30% but <50%). No clinically overt specific cause for the acute presentation: At the time of angiography, the cause and thus a specific diagnosis for the clinical presentation is not apparent. Accordingly, there is a necessity to further evaluate the patient for the underlying cause of the MINOCA presentation. LBBB, left bundle branch block. RWMA, regional wall motion abnormality. As summarized in Table 1, the AMI criteria for MINOCA constitute those defined by the well-established ‘Third Universal Definition of Myocardial Infarction’.1 This contemporary definition is focused upon a positive cardiac biomarker and corroborative clinical evidence of an AMI. Compared with previous AMI definitions (pre-dating the troponin assay), the criteria are more sensitive, and may be further enhanced with the introduction of ultra-high-sensitivity troponin assays, although the specificity may be compromised. Hence, the emphasis of corroborating the bioassay findings with the clinical presentation is of paramount importance in the definition. Moreover, this definition introduces the concept of types of infarcts,1 reflecting the underlying cause of the AMI. Type-1 (spontaneous) and type 2 (supply-demand mismatch, including coronary artery spasm) are most relevant to this document. A potential problem with current AMI criteria is their central focus upon troponins, since clinicians encounter elevated troponins in clinical scenarios other than AMI. A detailed discussion of troponins in the diagnosis of AMI is beyond the scope the present paper, but has been detailed in other reviews.11 There are three central concepts in interpreting troponins in the context of a coronary angiogram showing non-obstructive coronary arteries. First, it should be appreciated that cardiac troponins are ‘organ specific’ and not ‘disease specific’. An elevated cardiac troponin is not necessarily indicative of an AMI but reflects myocardial injury or necrosis. One example of a disease process causing myocardial injury and troponin elevation without an AMI is pulmonary embolism. Thus, there must be corroborative clinical evidence in addition to elevated cardiac troponins to establish the diagnosis of AMI, including MINOCA. However, there is no imaging technology, including cardiac magnetic resonance (CMR) imaging, which can definitively exclude an ischaemic cause of troponin elevation (see ‘MINOCA with normal cardiac MR imaging’). Only a pathologic examination is definitive. Second, rarely the troponin assays may provide spurious results due to analytical issues such as heterophilic antibodies.11 Finally, there are several differential diagnoses for MINOCA, which may arise from both coronary and non-coronary mechanisms as listed in Table 2 and summarized later in this paper. Certainly, the presence of coronary atherosclerotic obstructions, does not exclude other non-cardiac causes of troponin rise. Potential causes of an elevated troponin adapted from Agewall et al.11 Coronary causes Plaque rupture or erosion Coronary artery coronary with coronary Coronary coronary Coronary causes with cardiac with Coronary causes Plaque rupture or erosion Coronary artery coronary with coronary Coronary coronary Coronary causes with cardiac with Potential causes of an elevated troponin adapted from Agewall et al.11 Coronary causes Plaque rupture or erosion Coronary artery coronary with coronary Coronary coronary Coronary causes with cardiac with Coronary causes Plaque rupture or erosion Coronary artery coronary with coronary Coronary coronary Coronary causes with cardiac with The angiographic criteria for coronary detailed in the MINOCA definition the of which is consistent with contemporary angiographic This is and there is and in of angiographic the of an acute coronary may in significant angiographic changes from coronary and the coronary a and of have to patients with angiographically normal coronary arteries with the of those patients in atherosclerosis does not a in the AMI. this is not since studies have demonstrated significant atherosclerotic in patients with coronary this is by (i) the use of and other atherosclerotic imaging in routine clinical practice, (ii) coronary and may in the of and (iii) coronary atherosclerosis may be an in non-coronary causes of an elevated troponin and Coronary angiography is more and may be considered for of atherosclerosis when imaging is not performed the diagnostic The of angiographically coronary arteries does not an of disease in MINOCA. non-obstructive atherosclerosis may development of not to be atherosclerotic in such as myocarditis and Coronary artery may be the underlying cause of MI in patients with or without Therefore, the is to define MINOCA on the of absence of a obstructive stenosis on coronary angiography than on the presence or absence of any coronary these from a research it is to patients with mild coronary atheromatosis on angiography from those with since it may have diagnostic and/or the importance of the clinical context in a diagnosis of MINOCA and the that it is a ‘working diagnosis’, it is not appropriate to use this when a specific clinical diagnosis is apparent. a with a presenting with chest ST troponin and to have normal angiography should be as clinically myocarditis with or without associated to criteria (Table than MINOCA. Definition of clinically myocarditis to the CAD stenosis disease or causes that the heart the patient is diagnostic criteria should be of and diagnosis of myocarditis requires by coronary with or without normal or regional left and/or on or with or without troponin may have a time to AMI or a and over several or New or heart heart of and left features and/or and/or any of the following: to or bundle branch or and Q and elevated cardiac troponins and on cardiac imaging and/or and abnormality. by and/or of to CAD stenosis disease or causes that the heart the patient is diagnostic criteria should be of and diagnosis of myocarditis requires by coronary with or without normal or regional left and/or on or with or without troponin may have a time to AMI or a and over several or New or heart heart of and left features and/or and/or any of the following: to or bundle branch or and Q and elevated cardiac troponins and on cardiac imaging and/or and abnormality. by and/or of to Definition of clinically myocarditis to the CAD stenosis disease or causes that the heart the patient is diagnostic criteria should be of and diagnosis of myocarditis requires by coronary with or without normal or regional left and/or on or with or without troponin may have a time to AMI or a and over several or New or heart heart of and left features and/or and/or any of the following: to or bundle branch or and Q and elevated cardiac troponins and on cardiac imaging and/or and abnormality. by and/or of to CAD stenosis disease or causes that the heart the patient is diagnostic criteria should be of and diagnosis of myocarditis requires by coronary with or without normal or regional left and/or on or with or without troponin may have a time to AMI or a and over several or New or heart heart of and left features and/or and/or any of the following: to or bundle branch or and Q and elevated cardiac troponins and on cardiac imaging and/or and abnormality. by and/or of to with MINOCA are than those with obstructive CAD and have a in patients with obstructive the of AMI is in and than in MINOCA there is only a This that the underlying MINOCA are and that and/or may a Myocardial infarction with non-obstructive coronary arteries may present with or without ST elevation on the of the underlying The of non-obstructive CAD is these for and in than As MINOCA is a diagnosis and should the to underlying analogous to heart This for diagnostic in to or exclude potential in or should be performed in the acute to wall This the in is a diagnostic magnetic resonance imaging is the diagnostic to be in MINOCA when of the of myocardial damage and into an of in the an ischaemic cause of although it does not the cause of ischaemia or a in of In other patients, a of may a diagnosis of myocarditis or an Imaging for myocardial and may the of with Intracoronary imaging at the time of cardiac with or may be to atherosclerotic and erosion as well as coronary or which may not have been appreciated angiography. research is to the potential of routine of imaging at the time of coronary in patients with MINOCA. Coronary angiography is to further regarding underlying atherosclerosis the acute angiogram but does not rupture or We that clinicians pulmonary as a cause of myocardial damage and exclude this diagnosis with elevated in the of and/or pulmonary angiography as However, no pulmonary was patients with MINOCA who pulmonary angiography in one it is important to in which a other than coronary to an myocardial and and cause myocardial such as and as potential causes of MINOCA. clinically apparent the most common causes of MINOCA that the must are rupture or coronary artery coronary and other of myocardial is a cause of MINOCA. Plaque is within AMI in the Universal Definition of Myocardial when no thrombus can be the Universal definition MINOCA of AMI The term imaging and pathologic findings of or may a studies rupture or in of patients with imaging an of but this has not been in studies within the MINOCA Plaque erosion has been in MINOCA and is by thrombus on with an or without a with thrombus has been as a cause of AMI on on angiography, the in MINOCA patients and is this does not for of the Plaque may in of the which normal on However, of if is on coronary angiography in patients with in MINOCA with is by or a combination of these One that has been as an for MINOCA in the presence of myocardial infarction is or of a coronary is to be an mechanism thrombus in the presence of a coronary imaging may large of myocardial with or without of patients with MINOCA and that was in a The that coronary than to this can be and both may a In other of MINOCA with imaging a of by a that of from the is the most mechanism of and/or almost a in pathogenesis of MINOCA with Therefore, is for by for patients with or confirmed and on a of non-obstructive is if only a of atherosclerosis is The of patients with as the cause of MINOCA has not been in with other of MINOCA. However, the of rupture on was associated with cardiac in a of patients for acute coronary the of myocardial infarction or in MINOCA patients is to Coronary artery may to the pathogenesis of AMI in patients with obstructive CAD and particularly in those with MINOCA. It reflects a to in but may in the context of or has demonstrated in of patients with MINOCA that it is a common and an important mechanism in that and are for coronary artery with the to cardiac in this diagnosis and to be Myocardial infarction with non-obstructive coronary arteries may be the presentation for patients with or an in those with the of the features of that may to the diagnosis in patients with MINOCA include of that to if associated with ischaemic changes and a as Thus, a diagnosis of can be made if of are associated with changes that to However, are to be undertaken if the diagnosis is to be This has been performed by clinical researchers in patients with a the should be in the acute of AMI. is a potential cause of MINOCA since elevated troponins have been assays following the absence of large research is into the and value of in MINOCA. may be a mechanism to AMI in the of or coronary artery or may be the cause of MI in the absence of these Coronary may arise from or and coronary may from coronary or include and studies in patients with MINOCA have a of these should be considered such as the and although these have not been in MINOCA. Coronary may in the context of the above or other such as and heart may arise from including cardiac and and The clinical assessment of coronary including embolism, as a potential cause of MINOCA is summarized in Table Although the of coronary in MINOCA is to be this in may be due to coronary with or may be on angiography. disease or may not be noted and may not be The importance of these potential causes is the of therapies, although their use in the context of MINOCA is Diagnostic cardiac Diagnostic cardiac coronary causes an AMI although this may not be apparent on coronary angiography, a diagnosis of of the coronary arteries without Intracoronary imaging is in this The is more common The for the of coronary are but is present in other in the of when is in the due to and have been in the absence of atherosclerotic disease and in these is not A management is coronary and to cause of the and outcomes are with often as an acute coronary with ST The of left has presentation is by heart associated with myocardial in the absence of The is although several studies have demonstrated significant in the acute and more studies with are The diagnostic criteria or of the left with or without the regional wall motion beyond a a is but not The absence of obstructive CAD or angiographic evidence of acute rupture it is that obstructive CAD may the in New elevation and/or or elevation in cardiac The absence of and from acute myocarditis and AMI due to CAD may be are in with AMI. but not patients present and may no have the left magnetic resonance imaging performed early to in to establish the diagnosis on a of the importance of in MINOCA. The mechanisms responsible for are and may These mechanisms have been in that a detailed of these is beyond the scope of this position paper. the of the in this over the past no to define the management of these strategies may include the of the use of in those with left in those with left in those with and of potential However, it must be that the and other of MINOCA may be in clinical presentation is the has criteria for clinically that are in Table diagnosis of myocarditis and of its specific can only be by This has a presentation including an acute coronary presentation in the of and without obstructive CAD (Table In patients with a myocarditis the specific diagnosis of myocarditis should be made or at coronary angiography, but in the diagnosis not be clinically apparent and the diagnosis of MINOCA should be made specific is The of myocarditis patients with a clinical diagnosis of MINOCA on the with a of in a The most common cause of myocarditis is confirmed with of the on causes of myocarditis are and myocarditis may with cardiac or in the context of and is by on The of myocarditis should include Although this with the of only the of the underlying cause for the et that imaging of in the new on disease is for the of myocardial as a The importance of myocarditis in patients with MINOCA to its and Although myocarditis over a in of patients, may and to heart or heart myocarditis is particularly associated with a patients with myocarditis may and/or as a to or and not in other causes of MINOCA. The diagnosis of myocarditis is the for that is in specific such as in which is associated with a cardiac as well as in to differential diagnosis with other causes of MINOCA, including 2 AMI is defined as myocardial due to mismatch, by significant and/or in troponins with at least one value above the 99th percentile of a normal reference in the absence of evidence for coronary rupture in addition to at least one of the other criteria for of myocardial include wall and heart myocardial is by coronary and underlying AMI include failure, with or without left heart failure, and of and these may underlying obstructive patients with non-obstructive a should be present to AMI. the underlying the is to be if and may be There are at present no clinical the of AMI and the patient is findings in AMI have been to be with in of the of specific must be considered in the context of the specific of AMI not be when the cause of is and a has not been magnetic resonance imaging is a in MINOCA patients it not only into potential causes but may provide of the diagnosis of AMI. In the presence and of any may a or However, of patients with MINOCA have no evidence of myocardial or wall motion on The MINOCA with normal the the troponin was a of myocardial injury or to an on imaging is to as as of myocardium with current patients with normal may have to be the normal may be the of a of may be over a with no of of to be by with normal imaging to have troponin troponin the upper of normal may be in the absence of Myocardial imaging evidence of myocardial injury but is in patients with MINOCA and normal In the this may have occurred the imaging was undertaken in the clinical or the were the evolution of for imaging of myocardial and its routine in patients with MINOCA, further may be in the is normal and diagnostic evaluation as does not the mechanism of AMI, there is a diagnostic and for there are no this first coronary or may cause MINOCA with normal In a of patients with MINOCA who both and imaging, a of those with had a normal imaging had not been performed cardiac this diagnosis have been MINOCA studies or have not performed However, coronary artery may myocardial ischaemia that is associated with a troponin An alternative is that the troponin rise is not indicative of AMI and is due to other causes such as pulmonary or These causes should be when is In the absence of evaluation of underlying mechanisms and clinical any We in of as routine since these be of for the potential underlying mechanisms of coronary coronary and diagnostic and for myocardial infarction with non-obstructive coronary arteries. be with in the acute as the definition requires imaging to of left In the patients with apparent have ischaemic injury or We when is Plaque or should be and imaging considered an of the clinical presentation such as myocarditis or has not been particularly those patients with evidence of atherosclerosis on the coronary and more atherosclerotic than may be appreciated on angiography. for imaging is to be it is appropriate to this imaging at the time of the acute cardiac diagnostic angiography. should be made of the the can provide and the in associated with for coronary artery has been performed by clinical researchers in patients with a acute myocardial However, have been and this should not be a the patients, particularly in the acute myocarditis (no angiographic stenosis on cardiac magnetic resonance by of and diagnosis of myocarditis requires by AMI, acute myocardial left magnetic resonance Myocardial infarction with non-obstructive coronary arteries is a with a of 1–13% of patients with a clinical diagnosis of AMI. There are several potential that should be by a diagnostic from an diagnosis, since that may be appropriate for one cause for or for not be appropriate for MINOCA In MINOCA patients without an evaluation including a routine examination with clinical of diagnostic and strategies are These results have on both and of these and the and the the and made of the for of

With the American Medical Association's recent declaration that obesity is a serious disease [1], a critical consideration of the ethics of treating childhood obesity is especially timely. Although data suggest that the childhood obesity epidemic has stabilized in some countries [2], the levels remain too high; 18-49% of European children are overweight [3]. Consequently there is an immense and urgent need for the effective treatment of this complex disease. Unfortunately, the most recent Cochrane review concludes that, although family-based interventions can reduce excess weight in children and adolescents, long-term, effective and sustainable interventions for childhood obesity have yet to be identified [4]. Childhood obesity is a complex disease caused by a multitude of factors and it is associated with a wide range of co-morbidities. This complexity makes it challenging to design interventions and test the treatment approaches - particularly with regard to which outcome(s) should be used as the criteria for success. Most childhood obesity treatments occur in healthcare settings. As such, the randomized controlled trial (RCT), which is the ‘gold standard' of the medical/clinical research tradition, has been used to evaluate whether a given obesity treatment protocol is safe and effective. It is questionable however, if the RCT is the optimal study design to address this complex issue.Researchers investigating childhood obesity treatments face difficulties in deciding which outcomes best reflect the impact of treatment and, if a RCT is conducted, what type of treatment should it be randomized against. In light of the widespread childhood obesity epidemic, this paper will explore the ethical implications of these issues. Pediatric obesity research is conducted in a vulnerable group of patients and families. Many children who are obese suffer from significant psychological problems including anxiety, depression, attention-deficit hyperactivity as well as emotional and eating disorders [5,6]. Added to this, obesity carries a social stigma that adversely affects children as well as their families. There has been - and still is - considerable debate as to who bears the responsibility for the development of excess weight in the child and who bears the responsibility for alleviating the condition at the individual and the societal levels [7,8]. In recognition of these issues, there are discussions surrounding the ethics of community-based approaches of treating childhood obesity [9] and about mechanistic clinical studies aimed at understanding the pathophysiology of morbid obesity in children without a direct aim of reducing weight or the degree of obesity [10]. Less attention, however, has been given to the ethics of studying the individual treatment of the condition.The vast majority of childhood obesity therapy research is conducted at hospitals and their associated clinics or at universities. In this framework, treatment protocols are examined and approved by ethical review committees; thus it can be assumed that the basic premises of these studies are ethically acceptable. Nonetheless, investigators are obliged to ensure that their research fulfils the four basic principles of ethical research: respect for autonomy, beneficence, non-maleficence, and justice [11]. In the context of childhood obesity research, this can be challenging. Children who are obese and their families are often desperate for treatment because existing programs can have long waiting lists or be out of reach due to cost, time, and transportation factors.Given these circumstances, investigators must carefully consider if their protocol provides a situation in which they can scientifically test their hypotheses and balance this with creating a situation in which children and families freely make the choice to enter the study (autonomy), that the child receives a net benefit through participation in a timely manner (beneficence and non-maleficence), and that the exclusion criteria for participation are reasonable (justice). With these principles in mind, it becomes apparent that the development of treatment protocols must recognize the need for effective treatment along with consideration for the well-being of the child and his or her parent(s). The majority of childhood obesity treatments use the reduction of weight, BMI (kg/m2), waist circumference, and/or body composition as the primary outcome. These studies usually evaluate the change over a period of a few months to a maximum of a couple of years. Although weight loss or stabilization represents a reasonable target, it may be overly simplistic since childhood obesity is a complex phenotype that is associated with multiple concurrent co-morbidities. Clinical studies suggest that almost 50% of children who are obese exhibit pre- or grade 1 or 2 hypertension [12,13], another 29% have dyslipidemia [14], 44% have more than 5% fat in their livers [15], and 74% exhibit more than 5% fat in their muscles [16]. Additionally, children who are obese are at risk of serious cardiovascular [17,18], endocrinological [17,19], orthopedic [20,21] and psychological [5,6] complications that are present or not yet clinically apparent. Other complications progress silently and appear during late adolescence and young adulthood. Furthermore, future health risks loom, and a significantly increased risk of coronary heart disease [22], metabolic disease [23], and cancer [24,25] is non-ignorable in adulthood.Thus given the wide range of these co-morbidities and their potential for current and future harm to the child's health, addressing these problems individually without reducing the degree of obesity may be an acceptable and positive outcome of an obesity treatment. The reversal of adverse cardiovascular risk markers, such as increased blood pressure or dyslipidemia, is a clinical success, even without a reduction of obesity. Focusing the definition of ‘success' on the isolated outcome of a statistically significant reduction in some aspect of body size ignores the patient's well-being, emotional status, and the plethora of other obesity-associated problems that are relevant for the health of the child. In biomedical research, study designs can be ranked according to the strength of the evidence they can provide. Depending on the purpose - whether it is providing rapid treatment to a patient or to guiding a systematic review - there are different guidelines available [26]. One commonly used hierarchy ranks study designs based upon their internal validity [27]. Often depicted as a pyramid, RCTs are at the top, cohort studies are in the middle, and at the bottom are case reports [27]. In this scheme, controlled prospective trials in which subjects are not randomly allocated to the intervention but are compared with a control group fit somewhere just below RCTs. Although hierarchies of evidence are convenient groupings of types of studies, they can be overly simplistic and cannot be applied to all situations. For example, it has been shown that well designed observational studies can achieve the same results as a RCT aimed at answering the same question, yet at a lower cost and with faster data collection and analysis [28]. Further, no matter how strong a study design is, the conclusions drawn from it arise from the scientific rigor applied to examining and ruling out other potential causes of the intervention effect. Similarly, even though these hierarchies are useful, they do not imply that the RCT is the best design for all research questions from scientific, practical or even ethical points of view. In biomedical research and for validation purposes before regulatory authorities, the RCT study design is viewed as the superior approach to establish whether an intervention is efficacious or not. Most commonly, one group is assigned to receive the intervention in question, whereas the other group receives a placebo or another treatment modality available in a common setting representing the current ‘standard of care.' The RCT is well suited to studies of readily identifiable end points, such as pharmaceutical testing and surgical procedures. The design has high internal validity as well as the advantages of minimizing confounding, information and selection bias, and ruling out chance in the findings. Another advantage of this design is that it enhances the comparability of study results, especially if they are reported according to guidelines such as the CONSORT 2010 statement [29]. Inherent to the RCT design, however, is a limited generalizability of the results; a successful study in one setting does not guarantee that it can be replicated under normal conditions in another setting. Despite randomization, this study design does not eliminate confounding, but rather it allows for the measurement of the probability of confounding and thus an assessment of its effect on the outcomes of interest. Further, the RCT is a costly study design, which often limits the number of patients that can be included. This limitation has two consequences. First, a limited number of patients may be insufficient to actually test the effect of the intervention, and second, the inclusion of relatively small numbers of patients reduces the likelihood of observing side effects or complications of the treatment. Consequently, large-scale RCTs are difficult to finance. These limitations of the RCT design are especially relevant in the area of childhood obesity treatment where both the disease and its treatment are complex. In the case of testing childhood obesity treatment programs, the traditional RCT study design is not optimal and may even fail. Allocation into simple treatment modalities does not reflect clinical practice or the true effects of treatment. Childhood obesity is a chronic disease without a well-defined clinical endpoint to evaluate; simply moving from a classification of obese to overweight, reducing BMI z-score, or losing some weight does not represent the end of a treatment requirement by the child. The RCT is not well suited for assessing this type of long-term outcome. In terms of generalizability, there are methodological problems regarding eligibility criteria since most children and youth selected for RCT-based childhood obesity treatment are highly motivated and thus are not comparable to the general population of children and youth who are obese. In addition, recruitment into such studies may be limited by cultural and societal beliefs as well as the level of education of parents [30,31]. Moreover, these studies are typically performed in referral centers that treat children who are severely obese and may not be representative of the typical child who is ‘mildly obese' or without a myriad of co-morbidities. Aside from the limitations of the traditional RCT design in testing the efficacy of childhood obesity treatment protocols, it also presents an ethical dilemma of what care the control group should receive. In many childhood obesity interventions, the control group receives no treatment, is registered on a waiting list, or receives the standard care that is available at a given time (if indeed such a standard exists). From an ethical perspective, these approaches are problematic. In the era of the childhood obesity epidemic, it is questionable if randomization to no treatment is acceptable. The Helsinki declaration of 2008 states that ‘… The benefits, risks burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention except in the following circumstances: The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists …' [32]. Narrowly interpreted, as there are not yet proven long-term, effective and sustainable interventions for the treatment of childhood obesity [33], a non-treatment control group could be considered as acceptable. Viewed from a broader perspective, however, as there are interventions which produce the target outcome of weight loss or maintenance, even if it is not sustained for the long-term [4], the use of a non-treatment group is not acceptable. If one considers traditional diseases, most ethical committees would object to studies that randomize patients with diseases with known beneficial treatment options (such as cancer, diabetes, tuberculosis etc.) to no treatment. Yet, somehow, these standards are often not applied to childhood obesity. However, in recent years, given the extensive scope of the obesity epidemic and that children are becoming obese at progressively younger ages, many clinicians find this increasingly unethical and thus a violation of the Oath of Hippocrates. As an alternative, subjects in the non-treatment arm of a childhood obesity treatment study should receive, at a minimum, standard care. In this context, since a universally accepted treatment has not been developed, providing it is a challenge. A justifiable approach to treating childhood obesity can consist of a familial approach, using behavior changing techniques, as well as simple advice concerning healthy nutrition and physical activity or inactivity [4,34,35]. The behavioral approach must be accompanied by medical intervention(s) for specific obesity-related co-morbidities, where appropriate. Nonetheless, the definition of standard care remains vague as these elements are often delivered in varying combinations and intensities and in different settings (personal, group, familial approach, or separation of the treatment modalities between patient and family etc.). Further compounding the problem is that in many settings even a minimal level of care for the obese child does not exist - in developed, let alone developing countries. In the evaluation of childhood obesity treatments, an implicit assumption is made that if an intervention is to be declared successful, it should result in a sustained treatment effect. In contrast, this requirement is not met by treatments given for nearly all other pediatric chronic diseases such as asthma, diabetes, or epilepsy. Patients with these serious chronic diseases tend to have relapses, which occur even with continuous medical care, but more rapidly without. Additionally, another challenge in the evaluation of chronic care models is that patients receive complex and individually tailored treatment designs (with varying visit intervals, focus of attention, use of different types of health professionals etc.) that are difficult to evaluate using current designs. Moreover, interventions designed for clinical trials may be much more intensive and costly than what is possible and attainable in normal clinical settings, particularly with regard to time, usage, and funding. The success of interventions such as these, due to their lack of ‘real life' practicality, can result in frustration for practitioners who are unable to use these methods in their own setting. Unlike typical chronic medical conditions (such as hypertension or type 2 diabetes), the concept of childhood obesity may have cultural elements that should be incorporated and adapted into country-specific treatment and prevention programs - yet this significantly limits head-to-head evaluation of such interventions across Europe in empiric clinical trials. When considering what standard care should consist of, it is worthwhile to remember that childhood obesity is a long-term condition with associated co-morbidities, many of which are not always readily identifiable. It is clear that children with chronic diseases need a relevant diagnosis followed by regular visits to monitor the progression, the emergence of complications, and the treatment responses alongside the continuous treatment given. Such standards are fundamental in good clinical practice. Chronic diseases demand chronic treatment models and need to be evaluated using study designs that can accommodate the complexity of both the disease and its treatment. These prerogatives are obvious and universally accepted in terms of chronic diseases in pediatrics, but not so in relation childhood obesity per se. Therefore, just as with the intervention arm of a trial, the care provided to these children should address these co-morbidities in addition to weight loss or maintenance.If we are to move beyond viewing the traditional RCT as the ‘gold standard' in the evaluation of childhood obesity treatment programs, other designs must be explored. Such studies do not utilize a traditional RCT design, but rather employ a controlled trial design in which the comparison group is not randomly assigned and is often drawn from a source outside of the study. In this design, the most common sources of control subjects are: i) waiting lists, ii) usual care patients, and iii) a non-treatment group. Although appealing, many of these designs may not yield the comparison group that is expected by the researcher and each has ethical concerns, primarily that children who need treatment do not receive it. Another alternative is ‘The large simple trial' [36]. In this design, many institutions/doctors join together in different settings so that thousands of patients can be included in a study at a lower cost and with better coverage of potential side effects (than compared with studies of hundreds of patients) [36]. In this case, a detailed recording of the therapeutic approaches, the duration and frequency of visits, health personals involved, and measurement methods have to be performed in order to compare treatments. Thus, to move forward in an ethically responsible manner, RCT trials testing childhood obesity treatments should be based upon comparisons between different therapeutic modalities.Multiple observational studies have been published regarding childhood obesity interventions. Despite the known limitations and biases of such studies, large observational sample evaluations can be used to analyze the effectiveness of pre-defined interventions for specific populations. Based on investigations in other medical fields, using this approach prudently can yield conclusions that are quite similar to those derived from large RCTs [28]Given the ethical considerations, the diversity in the obesity phenotypes that require complex and individualized treatment strategies as well as the long-term follow-up, the traditional RCT is not ideally suited for testing the efficacy of childhood obesity treatments. It is timely that the research community shift towards accepting study designs that demonstrate the plausibility of an intervention rather than just a probability statement derived from a RCT. ‘Plausibility' refers to whether the intervention had an effect beyond what can be attributed to other external factors [37]. To make a strong plausibility statement, a control group still is required for comparison, but there is not a requirement that subjects are randomized to it. The commonly used sources (e.g. historical cohorts, waiting lists) can be used. A weaker statement can be made even if a control group is not used. Plausibility statements arise from the scientific rigor applied to examining and ruling out other potential causes for the treatment effect. Equally, the transparency of reports must increase, and the use of the CONSORT 2010 statement [29] would achieve this. Childhood obesity is a complex condition with a multitude of causes and complications (some of which are not readily identifiable); thus relying only upon tests of probability as the sole criteria for establishing that an intervention was successful is not reasonable. It is time that results derived from adequately designed studies that use observational designs aimed at making causal statements are accepted. Given these constraints, this study design may be the only practical and ethical design option to answer clinical questions relevant to specific populations in obesity is a chronic condition with late clinical many of are to the effectiveness of interventions in This can be using RCTs and is unethical for the arm of such In the evaluation of childhood obesity treatments it is time to move beyond viewing the RCT as the study design in terms of treatment of clinically relevant childhood obesity. It is not well suited to test the complex and chronic care required to treat these and if the control group is randomized to no treatment at it is The time has to standard care to all children who are obese and to evaluate treatment protocols by in terms of their children and who are obese both need and care. of to

BACKGROUND: We previously compared the safety profile of three formulations of intravenous iron used during 1998-2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran. Since that time, iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. METHODS: We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous iron during 2001-2003, including higher and lower molecular weight iron dextran, sodium ferric gluconate complex and iron sucrose. We estimated the odds of intravenous iron-related ADEs using 2 x 2 tables and the chi(2) test. RESULTS: The total number of reported parenteral iron-related ADEs was 1141 among approximately 30,063,800 doses administered, yielding a rate of 3.8 x 10(-5), or roughly 38 per million. Eleven individuals died in association with the ADE. Relative to lower molecular weight iron dextran, total and life-threatening ADEs were significantly more frequent among recipients of higher molecular weight iron dextran and significantly less frequent among recipients of sodium ferric gluconate complex and iron sucrose. The absolute rates of life-threatening ADEs were 0.6, 0.9, 3.3 and 11.3 per million for iron sucrose, sodium ferric gluconate complex, lower molecular weight iron dextran and higher molecular weight iron dextran, respectively. Based on differences in the average wholesale price of iron sucrose and lower molecular weight iron dextran in the US, the cost to prevent one life-threatening ADE related to the use of lower molecular weight iron dextran was estimated to be 5.0-7.8 million dollars. The cost to prevent one lower molecular weight iron dextran-related death was estimated to be 33 million dollars. CONCLUSIONS: The frequency of intravenous iron-related ADEs reported to the FDA has decreased, and overall, the rates are extremely low. This is the fourth report suggesting increased risks associated with the provision of higher molecular weight iron dextran. Life-threatening and other ADEs appear to be lower with the use of non-dextran iron formulations, although the cost per ADE prevented is extremely high.

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

BACKGROUND: In southern Scandinavia most babies with respiratory distress syndrome are initially treated with nasal continuous positive airway pressure. We performed a multicenter trial to investigate whether the addition of a single dose of porcine surfactant administered during a short intubation before the occurrence of serious deterioration could reduce the subsequent need for mechanical ventilation. METHODS: We randomly assigned 35 infants with moderate-to-severe respiratory distress syndrome to surfactant therapy (Curosurf, 200 mg per kilogram of body weight) plus nasal continuous positive airway pressure and 33 infants to nasal continuous positive airway pressure alone. The study was not blinded. The indications for mechanical ventilation were a ratio of arterial to alveolar oxygen tension of less than 0.15, severe apneic attacks, or both. RESULTS: Six hours after randomization, when the median age of the babies was 18 hours, the mean ratio of arterial to alveolar oxygen tension was 0.37 in the surfactant-treated babies, as compared with 0.25 in the controls (P < 0.001). The need for subsequent mechanical ventilation was reduced with surfactant therapy (to 43 percent of the surfactant-treated babies as compared with 85 percent of the controls; P = 0.003). When 17 infants with ratios of arterial-to-alveolar oxygen tension of less than 0.15 at randomization were excluded, the need for mechanical ventilation was still significantly reduced in the surfactant-treated group (to 33 percent [9 of 27 babies], as compared with 83 percent [20 of 24 babies] in the control group; (P < 0.001). After 28 days, two of the surfactant-treated babies had died, as compared with five of the control babies. CONCLUSIONS: In babies with moderate-to-severe respiratory distress syndrome treated with nasal continuous positive airway pressure, a single dose of surfactant reduced the need for subsequent mechanical ventilation.

An association mapping study of type-2-diabetes-related quantitative traits in the Greenlandic population identified a common variant in TBC1D4 that increases plasma glucose levels and serum insulin levels after an oral glucose load and type 2 diabetes risk, with effect sizes several times larger than any previous findings of large-scale genome-wide association studies for these traits. This systematic genetic association study of quantitative traits related to type 2 diabetes (T2D) has identified a nonsense variant in the gene TBC1D4 which is present in 17% of the Greenlandic population, known to be a small founder population with a high incidence of T2D. The gene variant increases the levels of plasma glucose, serum insulin, and dramatically increases T2D risk. It also modestly reduces the concentrations of fasting plasma and fasting serum insulin. This work illustrates the value of founder populations — or of small and historically isolated populations — in maximizing the effectiveness of genetic association studies of this type. The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years1. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l−1, P = 2.5 × 10−35) and serum insulin (β = 165 pmol l−1, P = 1.5 × 10−20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = −0.18 mmol l−1, P = 1.1 × 10−6) and fasting serum insulin (β = −8.3 pmol l−1, P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10−24). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l−1, P = 5.3 × 10−5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2,3,4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

OBJECTIVE: To determine whether early versus late treatment with porcine surfactant (Curosurf) reduces the requirement of mechanical ventilation in very preterm infants primarily supported by nasal continuous positive airway pressure (nasal CPAP). DESIGN: Multicenter randomized, controlled trial. PATIENTS: The study population comprised 60 infants <30 weeks' gestation with respiratory distress syndrome (RDS) who had an arterial to alveolar oxygen tension ratio (a/APO2) of 0.35 to 0.22. The cohort from which the study population was generated comprised 397 infants. RESULTS: The need for mechanical ventilation or death within 7 days of age was reduced from 63% in the late-treated infants to 21% in early-treated infants. Increasing numbers of antenatal steroid doses also improved the outcome, especially in the early-treated infants. Six hours after randomization mean a/APO2 rose to 0.48 in the early-treated infants compared with 0.36 in the late-treated. The need of mechanical ventilation before discharge was reduced from 68% in the late-treated to 25% in the early-treated infants. CONCLUSIONS: Nasal CPAP in combination with early treatment with Curosurf significantly improves oxygenation and reduces the subsequent need for mechanical ventilation in infants <30 weeks' gestational age with RDS.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.

BACKGROUND: We and other investigators previously reported that isolated nocturnal hypertension on ambulatory measurement (INH) clustered with cardiovascular risk factors and was associated with intermediate target organ damage. We investigated whether INH might also predict hard cardiovascular endpoints. METHODS AND RESULTS: We monitored blood pressure (BP) throughout the day and followed health outcomes in 8711 individuals randomly recruited from 10 populations (mean age 54.8 years, 47.0% women). Of these, 577 untreated individuals had INH (daytime BP <135/85 mmHg and night-time BP ≥120/70 mmHg) and 994 untreated individuals had isolated daytime hypertension on ambulatory measurement (IDH; daytime BP ≥135/85 mmHg and night-time BP <120/70 mmHg). During follow-up (median 10.7 years), 1284 deaths (501 cardiovascular) occurred and 1109 participants experienced a fatal or nonfatal cardiovascular event. In multivariable-adjusted analyses, compared with normotension (n = 3837), INH was associated with a higher risk of total mortality (hazard ratio 1.29, P = 0.045) and all cardiovascular events (hazard ratio 1.38, P = 0.037). IDH was associated with increases in all cardiovascular events (hazard ratio 1.46, P = 0.0019) and cardiac endpoints (hazard ratio 1.53, P = 0.0061). Of 577 patients with INH, 457 were normotensive (<140/90 mmHg) on office BP measurement. Hazard ratios associated with INH with additional adjustment for office BP were 1.31 (P = 0.039) and 1.38 (P = 0.044) for total mortality and all cardiovascular events, respectively. After exclusion of patients with office hypertension, these hazard ratios were 1.17 (P = 0.31) and 1.48 (P = 0.034). CONCLUSION: INH predicts cardiovascular outcome in patients who are normotensive on office or on ambulatory daytime BP measurement.

BACKGROUND: The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear. METHODS: Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, 'active' placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library's CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life. RESULTS: ). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious adverse events (OR 1.37; 95% CI 1.08 to 1.75; P = 0.009; 44 trials; Trial Sequential Analysis-adjusted CI 1.03 to 1.89). This corresponds to 31/1000 SSRI participants will experience a serious adverse event compared with 22/1000 control participants. SSRIs also significantly increased the number of non-serious adverse events. There were almost no data on suicidal behaviour, quality of life, and long-term effects. CONCLUSIONS: SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013004420.

OBJECTIVE: The objective was to investigate prevalence, estimate risk factors, and antenatal suspicion of abnormally invasive placenta (AIP) associated with laparotomy in women in the Nordic countries. DESIGN: Population-based cohort study. SETTING AND POPULATION: A 3-year Nordic collaboration among obstetricians to identify and report on uterine rupture, peripartum hysterectomy, excessive blood loss, and AIP from 2009 to 2012 The Nordic Obstetric Surveillance Study (NOSS). METHODS: In the NOSS study, clinicians reported AIP cases from maternity wards and the data were validated against National health registries. MAIN OUTCOME MEASURES: Prevalence, risk factors, antenatal suspicion, birth complications, and risk estimations using aggregated national data. RESULTS: A total of 205 cases of AIP in association with laparotomy were identified, representing 3.4 per 10 000 deliveries. The single most important risk factor, which was reported in 49% of all cases of AIP, was placenta praevia. The risk of AIP increased seven-fold after one prior caesarean section (CS) to 56-fold after three or more CS. Prior postpartum haemorrhage was associated with six-fold increased risk of AIP (95% confidence interval 3.7-10.9). Approximately 70% of all cases were not diagnosed antepartum. Of these, 39% had prior CS and 33% had placenta praevia. CONCLUSION: Our findings indicate that a lower CS rate in the population may be the most effective way to lower the incidence of AIP. Focused ultrasound assessment of women at high risk will likely strengthen antenatal suspicion. Prior PPH is a novel risk factor associated with an increased prevalence of AIP. TWEETABLE ABSTRACT: An ultrasound assessment in women with placenta praevia or prior CS may double the awareness for AIP.

CONTEXT: Denosumab discontinuation is characterized by an increase in bone turnover overriding pre-treatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients. METHODS: A working group of the European Calcified Tissue Society (ECTS) performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion. RESULTS: Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment. CONCLUSIONS: A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing RCTs. Patients having sustained VFx should be offered prompt treatment to reduce high bone turnover.

OBJECTIVE: Early surfactant followed by extubation to nasal continuous positive airway pressure (nCPAP) compared with later surfactant and mechanical ventilation (MV) reduce the need for MV, air leaks, and bronchopulmonary dysplasia. This randomized, controlled trial investigated whether prophylactic surfactant followed by nCPAP compared with early nCPAP application with early selective surfactant would reduce the need for MV in the first 5 days of life. METHODS: A total of 208 inborn infants who were born at 25 to 28 weeks' gestation and were not intubated at birth were randomly assigned to prophylactic surfactant or nCPAP within 30 minutes of birth. Outcomes were assessed within the first 5 days of life and until death or discharge of the infants from hospital. RESULTS: Thirty-three (31.4%) infants in the prophylactic surfactant group needed MV in the first 5 days of life compared with 34 (33.0%) in the nCPAP group (risk ratio: 0.95 [95% confidence interval: 0.64-1.41]; P = .80). Death and type of survival at 28 days of life and 36 weeks' postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the 2 groups. A total of 78.1% of infants in the prophylactic surfactant group and 78.6% in the nCPAP group survived in room air at 36 weeks' postmenstrual age. CONCLUSIONS: Prophylactic surfactant was not superior to nCPAP and early selective surfactant in decreasing the need for MV in the first 5 days of life and the incidence of main morbidities of prematurity in spontaneously breathing very preterm infants on nCPAP.

BACKGROUND: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. METHODS: In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization. RESULTS: A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups. CONCLUSIONS: Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).

OBJECTIVE: To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study. RESEARCH DESIGN AND METHODS: We used the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors. RESULTS: When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors. CONCLUSIONS: Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted.

AIMS: It is unclear whether subclinical vascular damage adds significantly to Systemic Coronary Risk Evaluation (SCORE) risk stratification in healthy subjects. METHODS AND RESULTS: In a population-based sample of 1968 subjects without cardiovascular disease or diabetes not receiving any cardiovascular, anti-diabetic, or lipid-lowering treatment, aged 41, 51, 61, or 71 years, we measured traditional cardiovascular risk factors, left ventricular (LV) mass index, atherosclerotic plaques in the carotid arteries, carotid/femoral pulse wave velocity (PWV), and urine albumin/creatinine ratio (UACR) and followed them for a median of 12.8 years. Eighty-one subjects died because of cardiovascular causes. Risk of cardiovascular death was independently of SCORE associated with LV hypertrophy [hazard ratio (HR) 2.2 (95% CI 1.2-4.0)], plaques [HR 2.5 (1.6-4.0)], UACR > or = 90th percentile [HR 3.3 (1.8-5.9)], PWV > 12 m/s [HR 1.9 (1.1-3.3) for SCORE > or = 5% and 7.3 (3.2-16.1) for SCORE < 5%]. Restricting primary prevention to subjects with SCORE > or = 5% as well as subclinical organ damage, increased specificity of risk prediction from 75 to 81% (P < 0.002), but reduced sensitivity from 72 to 65% (P = 0.4). Broaden primary prevention from subjects with SCORE > or = 5% to include subjects with 1% < or = SCORE < 5% together with subclinical organ damage increased sensitivity from 72 to 89% (P = 0.006), but reduced specificity from 75 to 57% (P < 0.002) and positive predictive value from 11 to 8% (P = 0.07). CONCLUSION: Subclinical organ damage predicted cardiovascular death independently of SCORE and the combination may improve risk prediction.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Abstract Purpose: We investigated whether detection of ctDNA after resection of colorectal cancer identifies the patients with the highest risk of relapse and, furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention. Experimental Design: In this longitudinal cohort study, we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a 3-year follow-up period. Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA postoperatively in all relapsing patients (n = 14), but not in any of the nonrelapsing patients. ctDNA detected relapse with an average lead time of 9.4 months compared with CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 months after surgery. All six later relapsed compared with four of the remaining patients [HR, 37.7; 95% confidence interval (CI), 4.2–335.5; P &amp;lt; 0.001]. The ability of a 3-month ctDNA analysis to predict relapse was confirmed in 23 liver metastasis patients (HR 4.9; 95% CI, 1.5–15.7; P = 0.007). Changes in ctDNA levels induced by relapse intervention (n = 19) showed good agreement with changes in tumor volume (κ = 0.41; Spearman ρ = 0.4). Conclusions: Postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Longitudinal surveillance enables early detection of relapse and informs about response to intervention. These observations have implications for the postoperative management of colorectal cancer patients. Clin Cancer Res; 23(18); 5437–45. ©2017 AACR.

IMPORTANCE: End-of-life decisions occur daily in intensive care units (ICUs) around the world, and these practices could change over time. OBJECTIVE: To determine the changes in end-of-life practices in European ICUs after 16 years. DESIGN, SETTING, AND PARTICIPANTS: Ethicus-2 was a prospective observational study of 22 European ICUs previously included in the Ethicus-1 study (1999-2000). During a self-selected continuous 6-month period at each ICU, consecutive patients who died or had any limitation of life-sustaining therapy from September 2015 until October 2016 were included. Patients were followed up until death or until 2 months after the first treatment limitation decision. EXPOSURES: Comparison between the 1999-2000 cohort vs 2015-2016 cohort. MAIN OUTCOMES AND MEASURES: End-of-life outcomes were classified into 5 mutually exclusive categories (withholding of life-prolonging therapy, withdrawing of life-prolonging therapy, active shortening of the dying process, failed cardiopulmonary resuscitation [CPR], brain death). The primary outcome was whether patients received any treatment limitations (withholding or withdrawing of life-prolonging therapy or shortening of the dying process). Outcomes were determined by senior intensivists. RESULTS: Of 13 625 patients admitted to participating ICUs during the 2015-2016 study period, 1785 (13.1%) died or had limitations of life-prolonging therapies and were included in the study. Compared with the patients included in the 1999-2000 cohort (n = 2807), the patients in 2015-2016 cohort were significantly older (median age, 70 years [interquartile range {IQR}, 59-79] vs 67 years [IQR, 54-75]; P < .001) and the proportion of female patients was similar (39.6% vs 38.7%; P = .58). Significantly more treatment limitations occurred in the 2015-2016 cohort compared with the 1999-2000 cohort (1601 [89.7%] vs 1918 [68.3%]; difference, 21.4% [95% CI, 19.2% to 23.6%]; P < .001), with more withholding of life-prolonging therapy (892 [50.0%] vs 1143 [40.7%]; difference, 9.3% [95% CI, 6.4% to 12.3%]; P < .001), more withdrawing of life-prolonging therapy (692 [38.8%] vs 695 [24.8%]; difference, 14.0% [95% CI, 11.2% to 16.8%]; P < .001), less failed CPR (110 [6.2%] vs 628 [22.4%]; difference, -16.2% [95% CI, -18.1% to -14.3%]; P < .001), less brain death (74 [4.1%] vs 261 [9.3%]; difference, -5.2% [95% CI, -6.6% to -3.8%]; P < .001) and less active shortening of the dying process (17 [1.0%] vs 80 [2.9%]; difference, -1.9% [95% CI, -2.7% to -1.1%]; P < .001). CONCLUSIONS AND RELEVANCE: Among patients who had treatment limitations or died in 22 European ICUs in 2015-2016, compared with data reported from the same ICUs in 1999-2000, limitations in life-prolonging therapies occurred significantly more frequently and death without limitations in life-prolonging therapies occurred significantly less frequently. These findings suggest a shift in end-of-life practices in European ICUs, but the study is limited in that it excluded patients who survived ICU hospitalization without treatment limitations.