Showing papers in "BMC Medicine in 2018"

Studying complexity in health services research: desperately seeking an overdue paradigm shift

Abstract: Complexity is much talked about but sub-optimally studied in health services research. Although the significance of the complex system as an analytic lens is increasingly recognised, many researchers are still using methods that assume a closed system in which predictive studies in general, and controlled experiments in particular, are possible and preferred. We argue that in open systems characterised by dynamically changing inter-relationships and tensions, conventional research designs predicated on linearity and predictability must be augmented by the study of how we can best deal with uncertainty, unpredictability and emergent causality. Accordingly, the study of complexity in health services and systems requires new standards of research quality, namely (for example) rich theorising, generative learning, and pragmatic adaptation to changing contexts. This framing of complexity-informed health services research provides a backdrop for a new collection of empirical studies. Each of the initial five papers in this collection illustrates, in different ways, the value of theoretically grounded, methodologically pluralistic, flexible and adaptive study designs. We propose an agenda for future research and invite researchers to contribute to this on-going series.

When complexity science meets implementation science: a theoretical and empirical analysis of systems change

Abstract: Implementation science has a core aim – to get evidence into practice. Early in the evidence-based medicine movement, this task was construed in linear terms, wherein the knowledge pipeline moved from evidence created in the laboratory through to clinical trials and, finally, via new tests, drugs, equipment, or procedures, into clinical practice. We now know that this straight-line thinking was naive at best, and little more than an idealization, with multiple fractures appearing in the pipeline. The knowledge pipeline derives from a mechanistic and linear approach to science, which, while delivering huge advances in medicine over the last two centuries, is limited in its application to complex social systems such as healthcare. Instead, complexity science, a theoretical approach to understanding interconnections among agents and how they give rise to emergent, dynamic, systems-level behaviors, represents an increasingly useful conceptual framework for change. Herein, we discuss what implementation science can learn from complexity science, and tease out some of the properties of healthcare systems that enable or constrain the goals we have for better, more effective, more evidence-based care. Two Australian examples, one largely top-down, predicated on applying new standards across the country, and the other largely bottom-up, adopting medical emergency teams in over 200 hospitals, provide empirical support for a complexity-informed approach to implementation. The key lessons are that change can be stimulated in many ways, but a triggering mechanism is needed, such as legislation or widespread stakeholder agreement; that feedback loops are crucial to continue change momentum; that extended sweeps of time are involved, typically much longer than believed at the outset; and that taking a systems-informed, complexity approach, having regard for existing networks and socio-technical characteristics, is beneficial. Construing healthcare as a complex adaptive system implies that getting evidence into routine practice through a step-by-step model is not feasible. Complexity science forces us to consider the dynamic properties of systems and the varying characteristics that are deeply enmeshed in social practices, whilst indicating that multiple forces, variables, and influences must be factored into any change process, and that unpredictability and uncertainty are normal properties of multi-part, intricate systems.

Adaptive designs in clinical trials: why use them, and how to run and report them

Abstract: Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented. We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

How and why weight stigma drives the obesity 'epidemic' and harms health.

Abstract: In an era when obesity prevalence is high throughout much of the world, there is a correspondingly pervasive and strong culture of weight stigma. For example, representative studies show that some forms of weight discrimination are more prevalent even than discrimination based on race or ethnicity. In this Opinion article, we review compelling evidence that weight stigma is harmful to health, over and above objective body mass index. Weight stigma is prospectively related to heightened mortality and other chronic diseases and conditions. Most ironically, it actually begets heightened risk of obesity through multiple obesogenic pathways. Weight stigma is particularly prevalent and detrimental in healthcare settings, with documented high levels of ‘anti-fat’ bias in healthcare providers, patients with obesity receiving poorer care and having worse outcomes, and medical students with obesity reporting high levels of alcohol and substance use to cope with internalized weight stigma. In terms of solutions, the most effective and ethical approaches should be aimed at changing the behaviors and attitudes of those who stigmatize, rather than towards the targets of weight stigma. Medical training must address weight bias, training healthcare professionals about how it is perpetuated and on its potentially harmful effects on their patients. Weight stigma is likely to drive weight gain and poor health and thus should be eradicated. This effort can begin by training compassionate and knowledgeable healthcare providers who will deliver better care and ultimately lessen the negative effects of weight stigma.

Gestational weight gain across continents and ethnicity: systematic review and meta-analysis of maternal and infant outcomes in more than one million women

Abstract: The association between Institute of Medicine (IOM) guidelines and pregnancy outcomes across ethnicities is uncertain. We evaluated the associations of gestational weight gain (GWG) outside 2009 IOM guidelines, with maternal and infant outcomes across the USA, western Europe and east Asia, with subgroup analyses in Asia. The aim was to explore ethnic differences in maternal prepregnancy body mass index (BMI), GWG and health outcomes across these regions. Systematic review, meta-analysis and meta-regression of observational studies were used for the study. MEDLINE, MEDLINE In-Process, Embase and all Evidence-Based Medicine (EBM) Reviews were searched from 1999 to 2017. Studies were stratified by prepregnancy BMI category and total pregnancy GWG. Odds ratio (ORs) 95% confidence intervals (CI) applied recommended GWG within each BMI category as the reference. Primary outcomes were small for gestational age (SGA), preterm birth and large for gestational age (LGA). Secondary outcomes were macrosomia, caesarean section and gestational diabetes. Overall, 5874 studies were identified and 23 were included (n = 1,309,136). Prepregnancy overweight/obesity in the USA, Europe and Asia was measured at 42%, 30% and 10% respectively, with underweight 5%, 3% and 17%. GWG below guidelines in the USA, Europe and Asia was 21%, 18% and 31%, and above was 51%, 51% and 37% respectively. Applying regional BMI categories in Asia showed GWG above guidelines (51%) was similar to that in the USA and Europe. GWG below guidelines was associated with a higher risk of SGA (USA/Europe [OR 1.51; CI 1.39, 1.63]; Asia [1.63; 1.45, 1.82]) and preterm birth (USA/Europe [1.35; 1.17, 1.56]; Asia [1.06; 0.78, 1.44]) than GWG within guidelines. GWG above guidelines was associated with a higher risk of LGA (USA/Europe [1.93; 1.81, 2.06]; Asia [1.68; 1.51 , 1.87]), macrosomia (USA/Europe [1.87; 1.70, 2.06]; Asia [2.18; 1.91, 2.49]) and caesarean (USA/Europe [1.26; 1.21, 1.33]; Asia [1.37; 1.30, 1.45]). Risks remained elevated when regional BMI categories were applied for GWG recommendations. More women in Asia were categorised as having GWG below guidelines using World Health Organization (WHO) (60%) compared to regional BMI categories (16%), yet WHO BMI was not accompanied by increased risks of adverse outcomes. Women in the USA and western Europe have higher prepregnancy BMI and higher rates of GWG above guidelines than women in east Asia. However, when using regional BMI categories in east Asia, rates of GWG above guidelines are similar across the three continents. GWG outside guidelines is associated with adverse outcomes across all regions. If regional BMI categories are used in east Asia, IOM guidelines are applicable in the USA, western Europe and east Asia.

From hype to reality: data science enabling personalized medicine

Abstract: Personalized, precision, P4, or stratified medicine is understood as a medical approach in which patients are stratified based on their disease subtype, risk, prognosis, or treatment response using specialized diagnostic tests. The key idea is to base medical decisions on individual patient characteristics, including molecular and behavioral biomarkers, rather than on population averages. Personalized medicine is deeply connected to and dependent on data science, specifically machine learning (often named Artificial Intelligence in the mainstream media). While during recent years there has been a lot of enthusiasm about the potential of ‘big data’ and machine learning-based solutions, there exist only few examples that impact current clinical practice. The lack of impact on clinical practice can largely be attributed to insufficient performance of predictive models, difficulties to interpret complex model predictions, and lack of validation via prospective clinical trials that demonstrate a clear benefit compared to the standard of care. In this paper, we review the potential of state-of-the-art data science approaches for personalized medicine, discuss open challenges, and highlight directions that may help to overcome them in the future. There is a need for an interdisciplinary effort, including data scientists, physicians, patient advocates, regulatory agencies, and health insurance organizations. Partially unrealistic expectations and concerns about data science-based solutions need to be better managed. In parallel, computational methods must advance more to provide direct benefit to clinical practice.

Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?

Abstract: Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD. Their morphological hallmarks – cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies – are similar, but clinical differences at onset suggest some dissimilar profiles. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is provided herein. The clinical constellations of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and postmortem studies have revealed a more pronounced cortical atrophy, elevated cortical and limbic Lewy body pathologies, higher Aβ and tau loads in cortex and striatum in DLB compared to PDD, and earlier cognitive defects in DLB. Conversely, multitracer PET studies have shown no differences in cortical and striatal cholinergic and dopaminergic deficits. Clinical management of both DLB and PDD includes cholinesterase inhibitors and other pharmacologic and non-drug strategies, yet with only mild symptomatic effects. Currently, no disease-modifying therapies are available. DLB and PDD are important dementia syndromes that overlap in many clinical features, genetics, neuropathology, and management. They are currently considered as subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), from incidental Lewy body disease and non-demented Parkinson’s disease to PDD, DLB, and DLB with Alzheimer’s disease at the most severe end. Cognitive impairment in these disorders is induced not only by α-synuclein-related neurodegeneration but by multiple regional pathological scores. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with Alzheimer’s disease and other proteinopathies. While we prefer to view DLB and PDD as extremes on a continuum, there remains a pressing need to more clearly differentiate these syndromes and to understand the synucleinopathy processes leading to either one.

Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin

Abstract: Preterm prelabour rupture of the fetal membranes (PPROM) precedes 30% of preterm births and is a risk factor for early onset neonatal sepsis. As PPROM is strongly associated with ascending vaginal infection, prophylactic antibiotics are widely used. The evolution of vaginal microbiota compositions associated with PPROM and the impact of antibiotics on bacterial compositions are unknown. We prospectively assessed vaginal microbiota prior to and following PPROM using MiSeq-based sequencing of 16S rRNA gene amplicons and examined the impact of erythromycin prophylaxis on bacterial load and community structures. In contrast to pregnancies delivering at term, vaginal dysbiosis characterised by Lactobacillus spp. depletion was present prior to the rupture of fetal membranes in approximately a third of cases (0% vs. 27%, P = 0.026) and persisted following membrane rupture (31%, P = 0.005). Vaginal dysbiosis was exacerbated by erythromycin treatment (47%, P = 0.00009) particularly in women initially colonised by Lactobacillus spp. Lactobacillus depletion and increased relative abundance of Sneathia spp. were associated with subsequent funisitis and early onset neonatal sepsis. Our data show that vaginal microbiota composition is a risk factor for subsequent PPROM and is associated with adverse short-term maternal and neonatal outcomes. This highlights vaginal microbiota as a potentially modifiable antenatal risk factor for PPROM and suggests that routine use of erythromycin for PPROM be re-examined.

Perinatal health outcomes and care among asylum seekers and refugees: a systematic review of systematic reviews

Abstract: Global migration is at an all-time high with implications for perinatal health. Migrant women, especially asylum seekers and refugees, represent a particularly vulnerable group. Understanding the impact on the perinatal health of women and offspring is an important prerequisite to improving care and outcomes. The aim of this systematic review was to summarise the current evidence base on perinatal health outcomes and care among women with asylum seeker or refugee status. Twelve electronic database, reference list and citation searches (1 January 2007–July 2017) were carried out between June and July 2017. Quantitative and qualitative systematic reviews, published in the English language, were included if they reported perinatal health outcomes or care and clearly stated that they included asylum seekers or refugees. Screening for eligibility, data extraction, quality appraisal and evidence synthesis were carried out in duplicate. The results were summarised narratively. Among 3415 records screened, 29 systematic reviews met the inclusion criteria. Only one exclusively focussed on asylum seekers; the remaining reviews grouped asylum seekers and refugees with wider migrant populations. Perinatal outcomes were predominantly worse among migrant women, particularly mental health, maternal mortality, preterm birth and congenital anomalies. Access and use of care was obstructed by structural, organisational, social, personal and cultural barriers. Migrant women’s experiences of care included negative communication, discrimination, poor relationships with health professionals, cultural clashes and negative experiences of clinical intervention. Additional data for asylum seekers and refugees demonstrated complex obstetric issues, sexual assault, offspring mortality, unwanted pregnancy, poverty, social isolation and experiences of racism, prejudice and stereotyping within perinatal healthcare. This review identified adverse pregnancy outcomes among asylum seeker and refugee women, representing a double burden of inequality for one of the most globally vulnerable groups of women. Improvements in the provision of perinatal healthcare could reduce inequalities in adverse outcomes and improve women’s experiences of care. Strategies to overcome barriers to accessing care require immediate attention. The systematic review evidence base is limited by combining heterogeneous migrant, asylum seeker and refugee populations, inconsistent use of definitions and limited data on some perinatal outcomes and risk factors. Future research needs to overcome these limitations to improve data quality and address inequalities. Systematic review registration number: PROSPERO CRD42017073315 .

Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection.

Abstract: Various recent studies have focused on analyzing tumor genetic material released into the blood stream, known as circulating tumor DNA (ctDNA) Herein, we describe current research on the application of ctDNA to cancer management, including prognosis determination, monitoring for treatment efficacy/relapse, treatment selection, and quantification of tumor size and disease burden Specifically, we examine the utility of ctDNA for early cancer diagnostics focusing on the development of a blood test to detect cancer in asymptomatic individuals by sequencing and analyzing mutations in ctDNA Next, we discuss the prospect of using ctDNA to test for cancer, and present our calculations based on previously published empirical findings in cancer and prenatal diagnostics We show that very early stage (asymptomatic) tumors are not likely to release enough ctDNA to be detectable in a typical blood draw of 10 mL Data are also presented showing that mutations in circulating free DNA can be found in healthy individuals and will likely be very difficult to distinguish from those associated with cancer We conclude that the ctDNA test, in addition to its high cost and complexity, will likely suffer from the same issues of low sensitivity and specificity as traditional biomarkers when applied to population screening and early (asymptomatic) cancer diagnosis

Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease

Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. It affects an estimated 20% of the general population, based on cohort studies of varying size and heterogeneous selection. However, the prevalence and incidence of recorded NAFLD diagnoses in unselected real-world health-care records is unknown. We harmonised health records from four major European territories and assessed age- and sex-specific point prevalence and incidence of NAFLD over the past decade. Data were extracted from The Health Improvement Network (UK), Health Search Database (Italy), Information System for Research in Primary Care (Spain) and Integrated Primary Care Information (Netherlands). Each database uses a different coding system. Prevalence and incidence estimates were pooled across databases by random-effects meta-analysis after a log-transformation. Data were available for 17,669,973 adults, of which 176,114 had a recorded diagnosis of NAFLD. Pooled prevalence trebled from 0.60% in 2007 (95% confidence interval: 0.41–0.79) to 1.85% (0.91–2.79) in 2014. Incidence doubled from 1.32 (0.83–1.82) to 2.35 (1.29–3.40) per 1000 person-years. The FIB-4 non-invasive estimate of liver fibrosis could be calculated in 40.6% of patients, of whom 29.6–35.7% had indeterminate or high-risk scores. In the largest primary-care record study of its kind to date, rates of recorded NAFLD are much lower than expected suggesting under-diagnosis and under-recording. Despite this, we have identified rising incidence and prevalence of the diagnosis. Improved recognition of NAFLD may identify people who will benefit from risk factor modification or emerging therapies to prevent progression to cardiometabolic and hepatic complications.

Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic?

Abstract: Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as “pragmatic” or “naturalistic”. We focused on 89 of these trials that assessed medicines (drugs or biologics). 36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term ‘pragmatic’ to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as ‘pragmatic’ and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic). To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.

A cut-off of daily sedentary time and all-cause mortality in adults: a meta-regression analysis involving more than 1 million participants

Abstract: The appropriate limit to the amount of daily sedentary time (ST) required to minimize mortality is uncertain. This meta-analysis aimed to quantify the dose-response association between daily ST and all-cause mortality and to explore the cut-off point above which health is impaired in adults aged 18–64 years old. We also examined whether there are differences between studies using self-report ST and those with device-based ST. Prospective cohort studies providing effect estimates of daily ST (exposure) on all-cause mortality (outcome) were identified via MEDLINE, PubMed, Scopus, Web of Science, and Google Scholar databases until January 2018. Dose-response relationships between daily ST and all-cause mortality were examined using random-effects meta-regression models. Based on the pooled data for more than 1 million participants from 19 studies, the results showed a log-linear dose-response association between daily ST and all-cause mortality. Overall, more time spent in sedentary behaviors is associated with increased mortality risks. However, the method of measuring ST moderated the association between daily ST and mortality risk (p < 0.05). The cut-off of daily ST in studies with self-report ST was 7 h/day in comparison with 9 h/day for those with device-based ST. Higher amounts of daily ST are log-linearly associated with increased risk of all-cause mortality in adults. On the basis of a limited number of studies using device-based measures, the findings suggest that it may be appropriate to encourage adults to engage in less sedentary behaviors, with fewer than 9 h a day being relevant for all-cause mortality.

Specific microRNA signatures in exosomes of triple-negative and HER2-positive breast cancer patients undergoing neoadjuvant therapy within the GeparSixto trial

Abstract: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC). First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization. Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR). Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.

The health impacts of climate-related migration

Abstract: Changes in climate, in conjunction with other drivers of mobility, shape human migration. While there is an increasing focus on the adaptive potential of migration, the health impacts of climate-related migration, including planned relocation and forced displacement, have not been thoroughly examined. The Intergovernmental Panel on Climate Change stated that migration is currently, and will increasingly be, influenced by environmental degradation and climate change, and that it needs to be addressed in a focused and coordinated manner. This paper examines the links between climate change, migration, and health, considering diverse migration responses, including immobility, forced displacement and planned migration, as well as the associated health risks and opportunities in different contexts. Using case studies, the paper illustrates strategies to reduce the health risks associated with climate change-related migration. While there is an increasing body of research examining the climate change–migration nexus, a dual approach is now required. This approach must include debate and further research regarding the health consequences and responses associated with climate migration as well as immediate strengthening of health systems to make them both climate resilient and migrant inclusive.

The association of depression and all-cause and cause-specific mortality: an umbrella review of systematic reviews and meta-analyses

Abstract: Depression is a prevalent and disabling mental disorder that frequently co-occurs with a wide range of chronic conditions. Evidence has suggested that depression could be associated with excess all-cause mortality across different settings and populations, although the causality of these associations remains unclear. We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, PsycINFO, and Embase electronic databases were searched through January 20, 2018. Systematic reviews and meta-analyses that investigated associations of depression and all-cause and cause-specific mortality were selected for the review. The evidence was graded as convincing, highly suggestive, suggestive, or weak based on quantitative criteria that included an assessment of heterogeneity, 95% prediction intervals, small-study effects, and excess significance bias. A total of 26 references providing 2 systematic reviews and data for 17 meta-analytic estimates met inclusion criteria (19 of them on all-cause mortality); data from 246 unique studies (N = 3,825,380) were synthesized. All 17 associations had P < 0.05 per random effects summary effects, but none of them met criteria for convincing evidence. Associations of depression and all-cause mortality in patients after acute myocardial infarction, in individuals with heart failure, in cancer patients as well as in samples from mixed settings met criteria for highly suggestive evidence. However, none of the associations remained supported by highly suggestive evidence in sensitivity analyses that considered studies employing structured diagnostic interviews. In addition, associations of depression and all-cause mortality in cancer and post-acute myocardial infarction samples were supported only by suggestive evidence when studies that tried to adjust for potential confounders were considered. Even though associations between depression and mortality have nominally significant results in all assessed settings and populations, the evidence becomes weaker when focusing on studies that used structured interviews and those that tried to adjust for potential confounders. A causal effect of depression on all-cause and cause-specific mortality remains unproven, and thus interventions targeting depression are not expected to result in lower mortality rates at least based on current evidence from observational studies.

Built environmental characteristics and diabetes: a systematic review and meta-analysis

Abstract: The built environment influences behaviour, like physical activity, diet and sleep, which affects the risk of type 2 diabetes mellitus (T2DM). This study systematically reviewed and meta-analysed evidence on the association between built environmental characteristics related to lifestyle behaviour and T2DM risk/prevalence, worldwide. We systematically searched PubMed, EMBASE.com and Web of Science from their inception to 6 June 2017. Studies were included with adult populations (>18 years), T2DM or glycaemic markers as outcomes, and physical activity and/or food environment and/or residential noise as independent variables. We excluded studies of specific subsamples of the population, that focused on built environmental characteristics that directly affect the cardiovascular system, that performed prediction analyses and that do not report original research. Data appraisal and extraction were based on published reports (PROSPERO-ID: CRD42016035663). From 11,279 studies, 109 were eligible and 40 were meta-analysed. Living in an urban residence was associated with higher T2DM risk/prevalence (n = 19, odds ratio (OR) = 1.40; 95% CI, 1.2–1.6; I2 = 83%) compared to living in a rural residence. Higher neighbourhood walkability was associated with lower T2DM risk/prevalence (n = 8, OR = 0.79; 95% CI, 0.7–0.9; I2 = 92%) and more green space tended to be associated with lower T2DM risk/prevalence (n = 6, OR = 0.90; 95% CI, 0.8–1.0; I2 = 95%). No convincing evidence was found of an association between food environment with T2DM risk/prevalence. An important strength of the study was the comprehensive overview of the literature, but our study was limited by the conclusion of mainly cross-sectional studies. In addition to other positive consequences of walkability and access to green space, these environmental characteristics may also contribute to T2DM prevention. These results may be relevant for infrastructure planning.

Measuring and mapping the global burden of antimicrobial resistance

Abstract: The increasing number and global distribution of pathogens resistant to antimicrobial drugs is potentially one of the greatest threats to global health, leading to health crises arising from infections that were once easy to treat. Infections resistant to antimicrobial treatment frequently result in longer hospital stays, higher medical costs, and increased mortality. Despite the long-standing recognition of antimicrobial resistance (AMR) across many settings, there is surprisingly poor information about its geographical distribution over time and trends in its population prevalence and incidence. This makes reliable assessments of the health burden attributable to AMR difficult, weakening the evidence base to drive forward research and policy agendas to combat AMR. The inclusion of mortality and morbidity data related to drug-resistant infections into the annual Global Burden of Disease Study should help fill this policy void.

Identifying older adults at risk of harm following elective surgery: a systematic review and meta-analysis

Abstract: Elective surgeries can be associated with significant harm to older adults. The present study aimed to identify the prognostic factors associated with the development of postoperative complications among older adults undergoing elective surgery. Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and AgeLine were searched for articles published between inception and April 21, 2016. Prospective studies reporting prognostic factors associated with postoperative complications (composite outcome of medical and surgical complications), functional decline, mortality, post-hospitalization discharge destination, and prolonged hospitalization among older adults undergoing elective surgery were included. Study characteristics and prognostic factors associated with the outcomes of interest were extracted independently by two reviewers. Random effects meta-analysis models were used to derive pooled effect estimates for prognostic factors and incidences of adverse outcomes. Of the 5692 titles and abstracts that were screened for inclusion, 44 studies (12,281 patients) reported on the following adverse postoperative outcomes: postoperative complications (n =28), postoperative mortality (n = 11), length of hospitalization (n = 21), functional decline (n = 6), and destination at discharge from hospital (n = 13). The pooled incidence of postoperative complications was 25.17% (95% confidence interval (CI) 18.03–33.98%, number needed to follow = 4). The geriatric syndromes of frailty (odds ratio (OR) 2.16, 95% CI 1.29–3.62) and cognitive impairment (OR 2.01, 95% CI 1.44–2.81) were associated with developing postoperative complications; however, there was no association with traditionally assessed prognostic factors such as age (OR 1.07, 95% CI 1.00–1.14) or American Society of Anesthesiologists status (OR 2.62, 95% CI 0.78–8.79). Besides frailty, other potentially modifiable prognostic factors, including depressive symptoms (OR 1.77, 95% CI 1.22–2.56) and smoking (OR 2.43, 95% CI 1.32–4.46), were also associated with developing postoperative complications. Geriatric syndromes are important prognostic factors for postoperative complications. We identified potentially modifiable prognostic factors (e.g., frailty, depressive symptoms, and smoking) associated with developing postoperative complications that can be targeted preoperatively to optimize care.

Syrian refugees in Greece: experience with violence, mental health status, and access to information during the journey and while in Greece

Abstract: Since 2015, Europe has been facing an unprecedented arrival of refugees and migrants: more than one million people entered via land and sea routes. During their travels, refugees and migrants often face harsh conditions, forced detention, and violence in transit countries. However, there is a lack of epidemiological quantitative evidence on their experiences and the mental health problems they face during their displacement. We aimed to document the types of violence experienced by migrants and refugees during their journey and while settled in Greece, and to measure the prevalence of anxiety disorders and access to legal information and procedures. We conducted a cross-sectional population-based quantitative survey combined with an explanatory qualitative study in eight sites (representing the range of settlements) in Greece during winter 2016/17. The survey consisted of a structured questionnaire on experience of violence and an interviewer-administered anxiety disorder screening tool (Refugee Health Screener). In total, 1293 refugees were included, of whom 728 were Syrians (41.3% females) of median age 18 years (interquartile range 7–30). Depending on the site, between 31% and 77.5% reported having experienced at least one violent event in Syria, 24.8–57.5% during the journey to Greece, and 5–8% in their Greek settlement. Over 75% (up to 92%) of respondents ≥15 years screened positive for anxiety disorder, which warranted referral for mental health evaluation, which was only accepted by 69–82% of participants. Access to legal information and assistance about asylum procedures were considered poor to non-existent for the majority, and the uncertainty of their status exacerbated their anxiety. This survey, conducted during a mass refugee crisis in a European Community country, provides important data on experiences in different refugee settings and reports the high levels of violence experienced by Syrian refugees during their journeys, the high prevalence of anxiety disorders, and the shortcomings of the international protective response.

Analysing the role of complexity in explaining the fortunes of technology programmes: Empirical application of the NASSS framework

Abstract: Failures and partial successes are common in technology-supported innovation programmes in health and social care. Complexity theory can help explain why. Phenomena may be simple (straightforward, predictable, few components), complicated (multiple interacting components or issues) or complex (dynamic, unpredictable, not easily disaggregated into constituent components). The recently published NASSS framework applies this taxonomy to explain Non-adoption or Abandonment of technology by individuals and difficulties achieving Scale-up, Spread and Sustainability. This paper reports the first empirical application of the NASSS framework. Six technology-supported programmes were studied using ethnography and action research for up to 3 years across 20 health and care organisations and 10 national-level bodies. They comprised video outpatient consultations, GPS tracking technology for cognitive impairment, pendant alarm services, remote biomarker monitoring for heart failure, care organising software and integrated case management via data warehousing. Data were collected at three levels: micro (individual technology users), meso (organisational processes and systems) and macro (national policy and wider context). Data analysis and synthesis were guided by socio-technical theories and organised around the seven NASSS domains: (1) the condition or illness, (2) the technology, (3) the value proposition, (4) the adopter system (professional staff, patients and lay carers), (5) the organisation(s), (6) the wider (institutional and societal) system and (7) interaction and mutual adaptation among all these domains over time. The study generated more than 400 h of ethnographic observation, 165 semi-structured interviews and 200 documents. The six case studies raised multiple challenges across all seven domains. Complexity was a common feature of all programmes. In particular, individuals’ health and care needs were often complex and hence unpredictable and ‘off algorithm’. Programmes in which multiple domains were complicated proved difficult, slow and expensive to implement. Those in which multiple domains were complex did not become mainstreamed (or, if mainstreamed, did not deliver key intended outputs). The NASSS framework helped explain the successes, failures and changing fortunes of this diverse sample of technology-supported programmes. Since failure is often linked to complexity across multiple NASSS domains, further research should systematically address ways to reduce complexity and/or manage programme implementation to take account of it.

Pancreatic cancer: challenges and opportunities.

Abstract: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, with increasing incidence. The mortality rate of pancreatic cancer is rising rapidly, and is projected to be the second most common of all malignant tumors by 2030. However, the diagnosis and therapy of pancreatic cancer remain a formidable challenge. Recently, enormous efforts have been made to develop several new methods for the early diagnosis and treatment of pancreatic cancer. We briefly introduce the most groundbreaking advances in pancreatic cancer diagnosis and clinical treatment strategies over the past 15 years, including surgery, chemotherapy, endoscopic therapy, immunotherapy and personalized medicine. The signaling pathways that are altered in the progression of pancreatic cancer, which may be used as therapeutic targets, are also discussed.

Efficacy, effectiveness and safety of vaccination against human papillomavirus in males: a systematic review.

Abstract: Human papillomavirus (HPV) vaccination is safe and effective in preventing cervical cancer in females. As HPV infections can also induce cancers of the anus, penis and oral cavity, male vaccination is also advocated, but systematic reviews on efficacy and safety in males are lacking. We performed a systematic review on the efficacy, effectiveness and safety of HPV vaccination in males of any age. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from inception to April 2017. We identified 5196 articles and seven studies (four randomized controlled trials (RCTs), three non-randomized studies) were included, comprising a total of 5294 participants. Vaccine efficacy against at least 6-month persisting anogenital HPV 16 infections was 46.9% (95% confidence interval (CI) 28.6–60.8%), whereas efficacy against persisting oral infections was 88% (2–98%). A vaccine efficacy of 61.9% (21.4–82.8%) and 46.8% (− 20 to –77.9%) was observed against anal intraepithelial neoplasia grade 2 and grade 3 lesions, respectively. No meaningful estimates were available on vaccine efficacy or effectiveness against penile intraepithelial neoplasia grade 2 or 3, and no data were identified for anal, penile or head and neck squamous cell cancer. In participants who were HPV-seronegative and PCR-negative at enrolment, efficacy against all outcomes was higher as compared to seropositive and/or PCR-positive individuals. Risk of bias was low in three RCTs and high in one, while the three non-randomized studies were at serious to critical risk of bias. Grading of Recommendations Assessment, Development and Evaluation evidence quality was moderate to low for most outcomes. HPV vaccination in males is moderately effective against persistent anogenital HPV infection and high-grade anal intraepithelial lesions in studies where the population consists mainly of HPV-infected males. Vaccine effectiveness was high in study groups comprising HPV-naive males. This supports a recommendation for vaccination of boys before the onset of sexual activity with the goal of establishing optimal vaccine-induced protection. Mathematical modelling studies will still be needed to assess the effects of adding males to existing HPV vaccination programs in females. Prospective Register for Systematic Reviews (PROSPERO) registration CRD42016038965 .

The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review

Abstract: Several quinoline and structurally related antimalarial drugs are associated with cardiovascular side effects, particularly hypotension and electrocardiographic QT interval prolongation. A prolonged QT interval is a sensitive but not specific risk marker for the development of Torsade de Pointes—a potentially lethal polymorphic ventricular tachyarrhythmia. The increasing use of quinoline and structurally related antimalarials in mass treatments to eliminate malaria rapidly highlights the need to review their cardiovascular safety profiles. The primary objective of this systematic review was to describe the documented clinical and electrocardiographic cardiovascular side effects of quinine, mefloquine, lumefantrine, piperaquine, halofantrine, chloroquine, sulfadoxine-pyrimethamine, amodiaquine, and primaquine. Trials in healthy subjects or patients with Plasmodium falciparum or P. vivax infection were included if at least two ECGs were conducted during the trial. All trial designs were included except case reports and pooled analyses. Secondary outcomes were the methods adopted by trials for measuring and reporting the QT interval. Data from trials published between 1982 and July 2016 were included. A total of 177 trials met the inclusion criteria. 35,448 participants received quinoline antimalarials in these trials, of which 18,436 participants underwent ECG evaluation. Subjects with co-medication use or comorbidities including cardiovascular disease were excluded from the majority of trials. Dihydroartemisinin-piperaquine was the drug most studied (5083 participants). Despite enormous use over the past 60 years, only 1076, 452, and 150 patients had ECG recordings reported in studies of chloroquine, amodiaquine, and primaquine respectively. Transiently high concentrations of quinine, quinidine, and chloroquine following parenteral administration have all been associated with hypotension, but there were no documented reports of death or syncope attributable to a cardiovascular cause, nor of electrocardiographic recordings of ventricular arrhythmia in these trials. The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes. No serious cardiac adverse effects were recorded in malaria clinical trials of 35,548 participants who received quinoline and structurally related antimalarials with close follow-up including 18,436 individuals who underwent ECG evaluation. While these findings provide further evidence of the rarity of serious cardiovascular events after treatment with these drugs, they also underscore the need for continued strengthening of pharmacovigilance systems for robust detection of rare drug adverse events in real-world populations. A standardised approach to measurement and reporting of ECG data in malaria trials is also needed. PROSPERO CRD42016036678

Simple rules for evidence translation in complex systems: A qualitative study

Abstract: Ensuring patients benefit from the latest medical and technical advances remains a major challenge, with rational-linear and reductionist approaches to translating evidence into practice proving inefficient and ineffective. Complexity thinking, which emphasises interconnectedness and unpredictability, offers insights to inform evidence translation theories and strategies. Drawing on detailed insights into complex micro-systems, this research aimed to advance empirical and theoretical understanding of the reality of making and sustaining improvements in complex healthcare systems. Using analytical auto-ethnography, including documentary analysis and literature review, we assimilated learning from 5 years of observation of 22 evidence translation projects (UK). We used a grounded theory approach to develop substantive theory and a conceptual framework. Results were interpreted using complexity theory and ‘simple rules’ were identified reflecting the practical strategies that enhanced project progress. The framework for Successful Healthcare Improvement From Translating Evidence in complex systems (SHIFT-Evidence) positions the challenge of evidence translation within the dynamic context of the health system. SHIFT-Evidence is summarised by three strategic principles, namely (1) ‘act scientifically and pragmatically’ – knowledge of existing evidence needs to be combined with knowledge of the unique initial conditions of a system, and interventions need to adapt as the complex system responds and learning emerges about unpredictable effects; (2) ‘embrace complexity’ – evidence-based interventions only work if related practices and processes of care within the complex system are functional, and evidence-translation efforts need to identify and address any problems with usual care, recognising that this typically includes a range of interdependent parts of the system; and (3) ‘engage and empower’ – evidence translation and system navigation requires commitment and insights from staff and patients with experience of the local system, and changes need to align with their motivations and concerns. Twelve associated ‘simple rules’ are presented to provide actionable guidance to support evidence translation and improvement in complex systems. By recognising how agency, interconnectedness and unpredictability influences evidence translation in complex systems, SHIFT-Evidence provides a tool to guide practice and research. The ‘simple rules’ have potential to provide a common platform for academics, practitioners, patients and policymakers to collaborate when intervening to achieve improvements in healthcare.

Efficacy and safety of methylene blue in the treatment of malaria: a systematic review.

Abstract: Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax. In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P. falciparum. MB has, thus, been considered a potentially useful partner drug for artemisinin-based combination therapy (ACT), particularly when elimination is the final goal. The aim of this study was to review the scientific literature published until early 2017 to summarise existing knowledge on the efficacy and safety of MB in the treatment of malaria. This systematic review followed PRISMA guidelines. Studies reporting on the efficacy and safety of MB were systematically searched for in relevant electronic databases according to a pre-designed search strategy. The search (without language restrictions) was limited to studies of humans published until February 2017. Out of 474 studies retrieved, a total of 22 articles reporting on 21 studies were eligible for analysis. The 21 included studies that reported data on 1504 malaria patients (2/3 were children). Older studies were case series and reports on MB monotherapy while recent studies were mainly controlled trials of combination regimens. MB was consistently shown to be highly effective in all endemic areas and demonstrated a strong effect on P. falciparum gametocyte reduction and synergy with ACT. MB treatment was associated with mild urogenital and gastrointestinal symptoms as well as blue coloration of urine. In G6PD-deficient African individuals, MB caused a slight but clinically non-significant haemoglobin reduction. More studies are needed to define the effects of MB in P. falciparum malaria in areas outside Africa and against P. vivax malaria. Adding MB to ACT could be a valuable approach for the prevention of resistance development and for transmission reduction in control and elimination programs. This study is registered at PROSPERO (registration number CRD42017062349 ).

A longitudinal, observational study of the features of transitional healthcare associated with better outcomes for young people with long-term conditions

Abstract: Most evidence about what works in transitional care comes from small studies in single clinical specialties. We tested the hypothesis that exposures to nine recommended features of transitional healthcare were associated with better outcomes for young people with long-term conditions during transition from child-centred to adult-oriented health services. This is a longitudinal, observational cohort study in UK secondary care including 374 young people, aged 14–18.9 years at recruitment, with type 1 diabetes (n = 150), cerebral palsy (n = 106) or autism spectrum disorder with an associated mental health problem (n = 118). All were pre-transfer and without significant learning disability. We approached all young people attending five paediatric diabetes centres, all young people with autism spectrum disorder attending four mental health centres, and randomly selected young people from two population-based cerebral palsy registers. Participants received four home research visits, 1 year apart and 274 participants (73%) completed follow-up. Outcome measures were Warwick Edinburgh Mental Wellbeing Scale, Mind the Gap Scale (satisfaction with services), Rotterdam Transition Profile (Participation) and Autonomy in Appointments. Exposure to recommended features was 61% for ‘coordinated team’, 53% for ‘age-banded clinic’, 48% for ‘holistic life-skills training’, 42% for ‘promotion of health self-efficacy’, 40% for ‘meeting the adult team before transfer’, 34% for ‘appropriate parent involvement’ and less than 30% for ‘written transition plan’, ‘key worker’ and ‘transition manager for clinical team’. Three features were strongly associated with improved outcomes. (1) ‘Appropriate parent involvement’, example association with Wellbeing (b = 4.5, 95% CI 2.0–7.0, p = 0.001); (2) ‘Promotion of health self-efficacy’, example association with Satisfaction with Services (b = − 0.5, 95% CI – 0.9 to – 0.2, p = 0.006); (3) ‘Meeting the adult team before transfer’, example associations with Participation (arranging services and aids) (odds ratio 5.2, 95% CI 2.1–12.8, p < 0.001) and with Autonomy in Appointments (average 1.7 points higher, 95% CI 0.8–2.6, p < 0.001). There was slightly less recruitment of participants from areas with greater socioeconomic deprivation, though not with respect to family composition. Three features of transitional care were associated with improved outcomes. Results are likely to be generalisable because participants had three very different conditions, attending services at many UK sites. Results are relevant for clinicians as well as for commissioners and managers of health services. The challenge of introducing these three features across child and adult healthcare services, and the effects of doing so, should be assessed.

Musculoskeletal conditions may increase the risk of chronic disease: a systematic review and meta-analysis of cohort studies

Abstract: Chronic diseases and musculoskeletal conditions have a significant global burden and frequently co-occur. Musculoskeletal conditions may contribute to the development of chronic disease; however, this has not been systematically synthesised. We aimed to investigate whether the most common musculoskeletal conditions, namely neck or back pain or osteoarthritis of the knee or hip, contribute to the development of chronic disease. We searched CINAHL, Embase, Medline, Medline in Process, PsycINFO, Scopus and Web of Science to February 8, 2018, for cohort studies reporting adjusted estimates of the association between baseline musculoskeletal conditions (neck or back pain or osteoarthritis of the knee or hip) and subsequent diagnosis of a chronic disease (cardiovascular disease, cancer, diabetes, chronic respiratory disease or obesity). Two independent reviewers performed data extraction and assessed study quality. Adjusted hazard ratios were pooled using the generic inverse variance method in random effect models, regardless of the type of musculoskeletal condition or chronic disease. PROSPERO: CRD42016039519. There were 13 cohort studies following 3,086,612 people. In the primary meta-analysis of adjusted estimates, osteoarthritis (n = 8 studies) and back pain (n = 2) were the exposures and cardiovascular disease (n = 8), cancer (n = 1) and diabetes (n = 1) were the outcomes. Pooled adjusted estimates from these 10 studies showed that people with a musculoskeletal condition have a 17% increase in the rate of developing a chronic disease compared to people without (hazard ratio 1.17, 95% confidence interval 1.13–1.22; I2 52%, total n = 2,686,113 people). This meta-analysis found that musculoskeletal conditions may increase the risk of chronic disease. In particular, osteoarthritis appears to increase the risk of developing cardiovascular disease. Prevention and early treatment of musculoskeletal conditions and targeting associated chronic disease risk factors in people with long standing musculoskeletal conditions may play a role in preventing other chronic diseases. However, a greater understanding about why musculoskeletal conditions may increase the risk of chronic disease is needed.

Poor reporting of multivariable prediction model studies: towards a targeted implementation strategy of the TRIPOD statement

Abstract: As complete reporting is essential to judge the validity and applicability of multivariable prediction models, a guideline for the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) was introduced. We assessed the completeness of reporting of prediction model studies published just before the introduction of the TRIPOD statement, to refine and tailor its implementation strategy. Within each of 37 clinical domains, 10 journals with the highest journal impact factor were selected. A PubMed search was performed to identify prediction model studies published before the launch of TRIPOD in these journals (May 2014). Eligible publications reported on the development or external validation of a multivariable prediction model (either diagnostic or prognostic) or on the incremental value of adding a predictor to an existing model. We included 146 publications (84% prognostic), from which we assessed 170 models: 73 (43%) on model development, 43 (25%) on external validation, 33 (19%) on incremental value, and 21 (12%) on combined development and external validation of the same model. Overall, publications adhered to a median of 44% (25th–75th percentile 35–52%) of TRIPOD items, with 44% (35–53%) for prognostic and 41% (34–48%) for diagnostic models. TRIPOD items that were completely reported for less than 25% of the models concerned abstract (2%), title (5%), blinding of predictor assessment (6%), comparison of development and validation data (11%), model updating (14%), model performance (14%), model specification (17%), characteristics of participants (21%), model performance measures (methods) (21%), and model-building procedures (24%). Most often reported were TRIPOD items regarding overall interpretation (96%), source of data (95%), and risk groups (90%). More than half of the items considered essential for transparent reporting were not fully addressed in publications of multivariable prediction model studies. Essential information for using a model in individual risk prediction, i.e. model specifications and model performance, was incomplete for more than 80% of the models. Items that require improved reporting are title, abstract, and model-building procedures, as they are crucial for identification and external validation of prediction models.

Determinants of the urinary and serum metabolome in children from six European populations.

Abstract: Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project ( http://www.projecthelix.eu ). Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit). We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythronic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum. We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children.