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1.  Substantial and reversible brain gray matter reduction but no acute brain lesions in ultramarathon runners: experience from the TransEurope-FootRace Project 
BMC Medicine  2012;10:170.
Background
During the extremely challenging 4,487 km ultramarathon TransEurope-FootRace 2009, runners showed considerable reduction of body weight. The effects of this endurance run on brain volume changes but also possible formation of brain edema or new lesions were explored by repeated magnetic resonance imaging (MRI) studies.
Methods
A total of 15 runners signed an informed consent to participate in this study of planned brain scans before, twice during, and about 8 months after the race. Because of dropouts, global gray matter volume analysis could only be performed in ten runners covering three timepoints, and in seven runners who also had a follow-up scan. Scanning was performed on three identical 1.5 T Siemens MAGNETOM Avanto scanners, two of them located at our university. The third MRI scanner with identical sequence parameters was a mobile MRI unit escorting the runners. Volumetric 3D datasets were acquired using a magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence. Additionally, diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) imaging was performed.
Results
Average global gray matter volume as well as body weight significantly decreased by 6% during the race. After 8 months, gray matter volume returned to baseline as well as body weight. No new brain lesions were detected by DWI or FLAIR imaging.
Conclusions
Physiological brain volume reduction during aging is less than 0.2% per year. Therefore a volume reduction of about 6% during the 2 months of extreme running appears to be substantial. The reconstitution in global volume measures after 8 months shows the process to be reversible. As possible mechanisms we discuss loss of protein, hypercortisolism and hyponatremia to account for both substantiality and reversibility of gray matter volume reductions. Reversible brain volume reduction during an ultramarathon suggests that extreme running might serve as a model to investigate possible mechanisms of transient brain volume changes. However, despite massive metabolic load, we found no new lesions in trained athletes participating in a multistage ultramarathon.
See related commentary http://www.biomedcentral.com/1741-7015/10/171
doi:10.1186/1741-7015-10-170
PMCID: PMC3566943  PMID: 23259507
body weight; brain volume; catabolism; DWI; lesion; MRI; ultramarathon
2.  Characteristics, changes and influence of body composition during a 4486 km transcontinental ultramarathon: results from the Transeurope Footrace mobile whole body MRI-project 
BMC Medicine  2013;11:122.
Background
Almost nothing is known about the medical aspects of runners doing a transcontinental ultramarathon over several weeks. The results of differentiated measurements of changes in body composition during the Transeurope Footrace 2009 using a mobile whole body magnetic resonance (MR) imager are presented and the proposed influence of visceral and somatic adipose and lean tissue distribution on performance tested.
Methods
22 participants were randomly selected for the repeated MR measurements (intervals: 800 km) with a 1.5 Tesla MR scanner mounted on a mobile unit during the 64-stage 4,486 km ultramarathon. A standardized and validated MRI protocol was used: T1 weighted turbo spin echo sequence, echo time 12 ms, repetition time 490 ms, slice thickness 10 mm, slice distance 10 mm (breath holding examinations). For topographic tissue segmentation and mapping a modified fuzzy c-means algorithm was used. A semi-automatic post-processing of whole body MRI data sets allows reliable analysis of the following body tissue compartments: Total body volume (TV), total somatic (TSV) and total visceral volume (TVV), total adipose (TAT) and total lean tissue (TLT), somatic (SLT) and visceral lean tissue (VLT), somatic (SAT) and visceral adipose tissue (VAT) and somatic adipose soft tissue (SAST). Specific volume changes were tested on significance. Tests on difference and relationship regarding prerace and race performance and non-finishing were done using statistical software SPSS.
Results
Total, somatic and visceral volumes showed a significant decrease throughout the race. Adipose tissue showed a significant decrease compared to the start at all measurement times for TAT, SAST and VAT. Lean adipose tissues decreased until the end of the race, but not significantly. The mean relative volume changes of the different tissue compartments at the last measurement compared to the start were: TV −9.5% (SE 1.5%), TSV −9.4% (SE 1.5%), TVV −10.0% (SE 1.4%), TAT −41.3% (SE 2.3%), SAST −48.7% (SE 2.8%), VAT −64.5% (SE 4.6%), intraabdominal adipose tissue (IAAT) −67.3% (SE 4.3%), mediastinal adopose tissue (MAT) −41.5% (SE 7.1%), TLT −1.2% (SE 1.0%), SLT −1.4% (SE 1.1%). Before the start and during the early phase of the Transeurope Footrace 2009, the non-finisher group had a significantly higher percentage volume of TVV, TAT, SAST and VAT compared to the finisher group. VAT correlates significantly with prerace training volume and intensity one year before the race and with 50 km- and 24 hour-race records. Neither prerace body composition nor specific tissue compartment volume changes showed a significant relationship to performance in the last two thirds of the Transeurope Footrace 2009.
Conclusions
With this mobile MRI field study the complex changes in body composition during a multistage ultramarathon could be demonstrated in detail in a new and differentiated way. Participants lost more than half of their adipose tissue. Even lean tissue volume (mainly skeletal muscle tissue) decreased due to the unpreventable chronic negative energy balance during the race. VAT has the fastest and highest decrease compared to SAST and lean tissue compartments during the race. It seems to be the most sensitive morphometric parameter regarding the risk of non-finishing a transcontinental footrace and shows a direct relationship to prerace-performance. However, body volume or body mass and, therefore, fat volume has no correlation with total race performances of ultra-athletes finishing a 4,500 km multistage race.
doi:10.1186/1741-7015-11-122
PMCID: PMC3668188  PMID: 23657091
Magnetic resonance imaging; MRI; Body mass; Body volume; Body composition; Running; Marathon; Ultramarathon; Performance; Adipose tissue; Body fat; Lean tissue; Visceral; Somatic; Topography; Segmentation; Mapping
3.  Born to run. Studying the limits of human performance 
BMC Medicine  2012;10:76.
It is recognised that regular physical activity and a high level of fitness are powerful predictors of positive health outcomes. There is a long and rich history of significant feats of human endurance with some, for example, the death of the first marathon runner, Pheidippides, associated with negative health outcomes.
Early studies on endurance running used X-ray and interview techniques to evaluate competitors and comment on performance. Since then, comparatively few studies have looked at runners competing in distances longer than a marathon. Those that have, tend to show significant musculoskeletal injuries and a remarkable level of adaptation to this endurance load.
The TransEurope Footrace Project followed ultra-endurance runners aiming to complete 4,500 Km of running in 64 days across Europe. This pioneering study will assess the impact of extreme endurance on human physiology; analysing musculoskeletal and other tissue/organ injuries, and the body's potential ability to adapt to extreme physiological stress. The results will be of interest not only to endurance runners, but to anyone interested in the limits of human performance.
Please see related article: http://www.biomedcentral.com/1741-7015/10/78
doi:10.1186/1741-7015-10-76
PMCID: PMC3409846  PMID: 22812408
Physical inactivity; ultra-marathon; endurance; runners; musculoskeletal; nutrition; hydration; race; Trans-Continental
4.  The foot in multistage ultra-marathon runners: experience in a cohort study of 22 participants of the Trans Europe Footrace Project with mobile MRI 
BMJ Open  2012;2(3):e001118.
Objectives
67 runners participated in the Trans Europe FootRace 2009 (TEFR09), a 4487 km (2789 mi) multistage ultra-marathon covering the south of Europe (Bari, Italy) to the North Cape. Reports on ultra-marathons are lacking, but the literature reports overuse injuries in athletes, especially to the Achilles tendon (AT), ankle or hind foot. Bone oedema may be related to exposure and is present in fatigue fractures. Therefore, the aim of this study was to determine prospectively if sustained maximal load during an ultra-marathon leads to damage to the foot.
Design and participants
In a cohort study, repeated scanning of the 22 athletes participating in the study was performed before and during (approximately every 1000 km) the race. Using the obtained fat saturated inversion recovery sequence, two experienced readers blinded to the clinical data rated the images regarding foot lesions. Statistical analysis included regression analysis and computation of the inter-rater reliability.
Setting
The TEFR09 course. MRI scanning was performed according to prearranged schedules for every participant, using a mobile 1.5 Tesla MRI unit on a trailer following the race.
Primary outcome measures
MRI data such as AT diameter, bone or tendon lesions, subcutaneous, plantar fascia or intraosseous oedema.
Results
The 22 study participants did not differ significantly from the total of the 67 TEFR09 runners regarding height, weight and age. The AT diameter increased significantly from 6.8 to 7.8 mm as did intraosseous signal, bone lesions and subcutaneous oedema. However, finishers differed only regarding plantar aponeurosis and subcutaneous oedema from participants aborting the TEFR09. Inter-rater reliability was 0.88–0.98.
Conclusion
Under the extreme stress of the TEFR09, an increase of the AT diameter as well as bone signal are thought to be adaptive since only subcutaneous oedema and plantar fascia oedema were related to abortion of the race.
Trial registration number
University of Ulm, Germany Ethics Committee Number 78/08-UBB/se.
Article summary
Article focus
A study on effects of ultra-marathon running, in this case, the multistage Trans Europe FootRace covering a distance of 4487 km from Bari (Italy) to the North Cape.
Observational cohort study using MRI to look for possible lesions to the foot.
Key messages
During sustained maximal load, AT diameter and bone MRI short τ inversion recovery signal (hinting at subtle oedema) increases. This is thought to be adaptive.
Subcutaneous oedema and plantar fascia signal were related to abortion of the race. These measurements seem to be related to relevant changes leading to discontinuation of the run.
No relevant new foot joint or tendon lesions were detected during the race over 4487 km.
Strengths and limitations of this study
Repeated measurement prospectively during the run was possible only because of the mobile MRI unit used for this research project.
The number of included runners (22) is high compared with other MRI-based studies but may have been too small to detect less frequent lesions.
doi:10.1136/bmjopen-2012-001118
PMCID: PMC3364457  PMID: 22619270
5.  Evidence from neuroimaging to explore brain plasticity in humans during an ultra-endurance burden 
BMC Medicine  2012;10:171.
Physical activity, likely through induction of neuroplasticity, is a promising intervention to promote brain health. In athletes it is clear that training can and does, by physiological adaptations, extend the frontiers of performance capacity. The limits of our endurance capacity lie deeply in the human brain, determined by various personal factors yet to be explored. The human brain, with its vast neural connections and its potential for seemingly endless behaviors, constitutes one of the final frontiers of medicine. In a recent study published in BMC Medicine, the TransEurope FootRace Project followed 10 ultra-endurance runners over around 4,500 km across Europe and recorded a large data collection of brain imaging scans. This study indicates that the cerebral atrophy amounting to a reduction of approximately 6% throughout the two months of the race is reversed upon follow-up. While this study will contribute to advances in the limits of human performance on the neurophysiological processes in sports scientists, it will also bring important understanding to clinicians about cerebral atrophy in people who are vulnerable to physical and psychological stress long term.
See related research article http://www.biomedcentral.com/1741-7015/10/170
doi:10.1186/1741-7015-10-171
PMCID: PMC3566949  PMID: 23259535
cerebral atrophy; exercise behavior; fatigue; overload; plasticity; running
6.  Regionally accentuated reversible brain grey matter reduction in ultra marathon runners detected by voxel-based morphometry 
Background
During the 4,487 km ultra marathon TransEurope-FootRace 2009 (TEFR09), runners showed catabolism with considerable reduction of body weight as well as reversible brain volume reduction. We hypothesized that ultra marathon athletes might have developed changes to grey matter (GM) brain morphology due to the burden of extreme physical training. Using voxel-based morphometry (VBM) we undertook a cross sectional study and two longitudinal studies.
Methods
Prior to the start of the race 13 runners volunteered to participate in this study of planned brain scans before, twice during, and 8 months after the race. A group of matched controls was recruited for comparison. Twelve runners were able to participate in the scan before the start of the race and were taken into account for comparison with control persons. Because of drop-outs during the race, VBM could be performed in 10 runners covering the first 3 time points, and in 7 runners who also had the follow-up scan after 8 months. Volumetric 3D datasets were acquired using an MPRAGE sequence. A level of p < 0.05, family-wise corrected for multiple comparisons was the a priori set statistical threshold to infer significant effects from VBM.
Results
Baseline comparison of TEFR09 participants and controls revealed no significant differences regarding GM brain volume. During the race however, VBM revealed GM volume decreases in regionally distributed brain regions. These included the bilateral posterior temporal and occipitoparietal cortices as well as the anterior cingulate and caudate nucleus. After eight months, GM normalized.
Conclusion
Contrary to our hypothesis, we did not observe significant differences between TEFR09 athletes and controls at baseline. If this missing difference is not due to small sample size, extreme physical training obviously does not chronically alter GM.
However, during the race GM volume decreased in brain regions normally associated with visuospatial and language tasks. The reduction of the energy intensive default mode network as a means to conserve energy during catabolism is discussed. The changes were reversible after 8 months.
Despite substantial changes to brain composition during the catabolic stress of an ultra marathon, the observed differences seem to be reversible and adaptive.
doi:10.1186/2052-1847-6-4
PMCID: PMC3896776  PMID: 24438692
Voxel based morphometry; VBM; Catabolism; Plasticity; Brain; Default mode network; MRI; Ultra marathon
7.  Prospects for automated diagnosis of verbal autopsies 
BMC Medicine  2014;12:18.
Verbal autopsy is a method for assessing probable causes of death from lay reporting of signs, symptoms and circumstances by family members or caregivers of a deceased person. Several methods of automated diagnoses of causes of death from standardized verbal autopsy questionnaires have been developed recently (Inter-VA, Tariff, Random Forest and King-Lu). Their performances have been assessed in a series of papers in BMC Medicine. Overall, and despite high specificity, the current strategies of automated computer diagnoses lead to relatively low sensitivity and positive predictive values, even for causes which are expected to be easily assessed by interview. Some methods have even abnormally low sensitivity for selected diseases of public health importance and could probably be improved. Ways to improve the current strategies are proposed: more detailed questionnaires; using more information on disease duration; stratifying for large groups of causes of death by age, sex and main category; using clusters of signs and symptoms rather than quantitative scores or ranking; separating indeterminate causes; imputing unknown cause with appropriate methods.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/5; http://www.biomedcentral.com/1741-7015/12/19; http://www.biomedcentral.com/1741-7015/12/20; http://www.biomedcentral.com/1741-7015/12/21; http://www.biomedcentral.com/1741-7015/12/22; http://www.biomedcentral.com/1741-7015/12/23.
doi:10.1186/1741-7015-12-18
PMCID: PMC3912493  PMID: 24495788
Cause of death; Verbal autopsy; Automated diagnosis; Health information system; Evaluation of health programs; Public health
8.  The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on neonatal health outcomes: the LIMIT randomised trial 
BMC Medicine  2014;12(1):163.
Background
Overweight and obesity during pregnancy represents a considerable health burden. While research has focused on interventions to limit gestational weight gain, there is little information describing their impact on neonatal health. Our aim was to investigate the effect on a range of pre-specified secondary neonatal outcomes of providing antenatal dietary and lifestyle advice to women who are overweight or obese.
Methods
We report a range of pre-specified secondary neonatal outcomes from a large randomised trial in which antenatal dietary and lifestyle advice was provided to women who were overweight or obese. Pregnant women were eligible for participation with a body mass index of 25 kg/m2 or over, and singleton gestation between 10+0 and 20+0 weeks. Outcome measures included gestational age at birth; Apgar score below 7 at 5 minutes of age; need for resuscitation at birth; birth weight above 4.5 kg or below 2.5 kg; birth weight, length and head circumference (and Z-scores); admission to the nursery; respiratory distress syndrome; and postnatal length of stay. Data relating to the primary outcome (large for gestational age infants defined as birth weight above the 90th centile) and birth weight above 4 kg have been reported previously. Analyses used intention-to-treat principles.
Results
In total, 2,142 infants were included in the analyses. Infants born to women following lifestyle advice were significantly less likely to have birth weight above 4.5 kg (2.15% versus 3.69%; adjusted risk ratio (aRR) = 0.59; 95% confidence interval (CI) 0.36 to 0.98; P = 0.04), or respiratory distress syndrome (1.22% versus 2.57%; aRR = 0.47; 95% CI 0.24 to 0.90; P = 0.02), particularly moderate or severe disease, and had a shorter length of postnatal hospital stay (3.94 ± 7.26 days versus 4.41 ± 9.87 days; adjusted ratio of means 0.89; 95% CI 0.82 to 0.97; P = 0.006) compared with infants born to women who received Standard Care.
Conclusions
For women who are overweight or obese, antenatal dietary and lifestyle advice has health benefits for infants, without an increase in the risk of harm. Continued follow-up into childhood will be important to assess the longer-term effects of a reduction in high infant birth weight on risk of child obesity.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/161 and http://www.biomedcentral.com/1741-7015/12/201.
Clinical trial registration
Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426)
doi:10.1186/s12916-014-0163-9
PMCID: PMC4194368  PMID: 25315325
Pregnancy; Overweight and obesity; Neonatal health; Randomised trial; Dietary and lifestyle intervention
9.  The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on maternal diet and physical activity: the LIMIT randomised trial 
BMC Medicine  2014;12(1):161.
Background
Overweight and obesity is a significant health concern during pregnancy. Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity.
Methods
We conducted a randomised controlled trial, in which pregnant women with a body mass index ≥25 kg/m2, and singleton gestation between 10+0 to 20+0 weeks were recruited and randomised to Lifestyle Advice (involving a comprehensive dietary and lifestyle intervention over their pregnancy) or Standard Care. Within the intervention group, we conducted a nested randomised trial in which a subgroup of women were further randomised to receive access to supervised group walking sessions in addition to the standard information presented during the intervention contacts (the Walking group) or standard information only.
The outcome measures were maternal dietary intake, (including food groups, macronutrient and micronutrient intake, diet quality (using the Healthy Eating Index; HEI), dietary glycaemic load, and glycaemic index) and maternal physical activity. Women completed the Harvard Semi-Structured Food Frequency Questionnaire, and the Short Questionnaire to Assess Health-enhancing Physical Activity (SQUASH), at trial entry, 28 and 36 weeks’ gestational age, and 4 months postpartum.
Analyses were performed on an intention-to-treat basis, using linear mixed effects models with adjustment for the stratification variables.
Results
Women randomised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day, as well as increased consumption of fibre, and reduced percentage energy intake from saturated fats (P < 0.05 for all). Maternal HEI was significantly improved at both 28 (73.35 ± 6.62 versus 71.86 ± 7.01; adjusted difference in means 1.58; 95% CI 0.89 to 2.27; P < 0.0001) and 36 (72.95 ± 6.82 versus 71.17 ± 7.69; adjusted difference in means 1.77; 95% CI 1.01 to 2.53; P < 0.0001) weeks. There were no differences in dietary glycaemic index or glycaemic load. Women randomised to Lifestyle Advice also demonstrated greater total physical activity (adjusted difference in means 359.76 metabolic equivalent task units (MET) minutes/week; 95% CI 74.87 to 644.65; P = 0.01) compared with women receiving Standard Care. The supervised walking group was poorly utilised.
Conclusions
For women who are overweight or obese, antenatal lifestyle advice improves maternal diet and physical activity during pregnancy.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/163 and http://www.biomedcentral.com/1741-7015/12/201.
Trial registration
Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426)
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0161-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0161-y
PMCID: PMC4194375  PMID: 25315237
Pregnancy; Overweight and obesity; Diet composition; Physical activity; Randomised trial; Dietary and lifestyle intervention
10.  RAMESES publication standards: realist syntheses 
BMC Medicine  2013;11:21.
Background
There is growing interest in realist synthesis as an alternative systematic review method. This approach offers the potential to expand the knowledge base in policy-relevant areas - for example, by explaining the success, failure or mixed fortunes of complex interventions. No previous publication standards exist for reporting realist syntheses. This standard was developed as part of the RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for realist systematic reviews.
Methods
We (a) collated and summarized existing literature on the principles of good practice in realist syntheses; (b) considered the extent to which these principles had been followed by published syntheses, thereby identifying how rigor may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, realist research, policy and/or publishing to produce and iteratively refine a draft set of methodological steps and publication standards; (d) provided real-time support to ongoing realist syntheses and the open-access RAMESES online discussion list so as to capture problems and questions as they arose; and (e) synthesized expert input, evidence syntheses and real-time problem analysis into a definitive set of standards.
Results
We identified 35 published realist syntheses, provided real-time support to 9 on-going syntheses and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature and common questions and challenges into briefing materials for the Delphi panel, comprising 37 members. Within three rounds this panel had reached consensus on 19 key publication standards, with an overall response rate of 91%.
Conclusion
This project used multiple sources to develop and draw together evidence and expertise in realist synthesis. For each item we have included an explanation for why it is important and guidance on how it might be reported. Realist synthesis is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of realist syntheses.
To encourage dissemination of the RAMESES publication standards, this article is co-published in the Journal of Advanced Nursing and is freely accessible on Wiley Online Library (http://www.wileyonlinelibrary.com/journal/jan).
Please see related article http://www.biomedcentral.com/1741-7015/11/20 and http://www.biomedcentral.com/1741-7015/11/22
doi:10.1186/1741-7015-11-21
PMCID: PMC3558331  PMID: 23360677
realist synthesis; realist review; publication standards
11.  RAMESES publication standards: meta-narrative reviews 
BMC Medicine  2013;11:20.
Background
Meta-narrative review is one of an emerging menu of new approaches to qualitative and mixed-method systematic review. A meta-narrative review seeks to illuminate a heterogeneous topic area by highlighting the contrasting and complementary ways in which researchers have studied the same or a similar topic. No previous publication standards exist for the reporting of meta-narrative reviews. This publication standard was developed as part of the RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for meta-narrative reviews.
Methods
We (a) collated and summarized existing literature on the principles of good practice in meta-narrative reviews; (b) considered the extent to which these principles had been followed by published reviews, thereby identifying how rigor may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, meta-narrative reviews, policy and/or publishing to produce and iteratively refine a draft set of methodological steps and publication standards; (d) provided real-time support to ongoing meta-narrative reviews and the open-access RAMESES online discussion list so as to capture problems and questions as they arose; and (e) synthesized expert input, evidence review and real-time problem analysis into a definitive set of standards.
Results
We identified nine published meta-narrative reviews, provided real-time support to four ongoing reviews and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature, and common questions and challenges into briefing materials for the Delphi panel, comprising 33 members. Within three rounds this panel had reached consensus on 20 key publication standards, with an overall response rate of 90%.
Conclusion
This project used multiple sources to draw together evidence and expertise in meta-narrative reviews. For each item we have included an explanation for why it is important and guidance on how it might be reported. Meta-narrative review is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further theoretical and methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of meta-narrative reviews.
To encourage dissemination of the RAMESES publication standards, this article is co-published in the Journal of Advanced Nursing and is freely accessible on Wiley Online Library (http://www.wileyonlinelibrary.com/journal/jan).
Please see related articles http://www.biomedcentral.com/1741-7015/11/21 and http://www.biomedcentral.com/1741-7015/11/22
doi:10.1186/1741-7015-11-20
PMCID: PMC3558334  PMID: 23360661
meta-narrative review; meta-narrative synthesis; publication standards
12.  Selecting the right medical student 
BMC Medicine  2013;11:245.
Medical student selection is an important but difficult task. Three recent papers by McManus et al. in BMC Medicine have re-examined the role of tests of attainment of learning (A’ levels, GCSEs, SQA) and of aptitude (AH5, UKCAT), but on a much larger scale than previously attempted. They conclude that A’ levels are still the best predictor of future success at medical school and beyond. However, A’ levels account for only 65% of the variance in performance that is found. Therefore, more work is needed to establish relevant assessment of the other 35%.
Please see related research articles http://www.biomedcentral.com/1741-7015/11/242, http://www.biomedcentral.com/1741-7015/11/243 and http://www.biomedcentral.com/1741-7015/11/244.
doi:10.1186/1741-7015-11-245
PMCID: PMC3827327  PMID: 24229397
Medical School Admission; Predictors of performance; Aptitude testing
13.  Making mobility-related disability better: a complex response to a complex problem 
BMC Medicine  2012;10:121.
Mobility disability in older adults can arise from single system problems, such as discrete musculoskeletal injury. In frail older adults, however, mobility disability is part of a complex web of problems. The approach to their rehabilitation must take that complexity into account, as is reported by Fairhall et al. First, their overall health state must be assessed, which is achieved by a comprehensive geriatric assessment. The assessment can show how a particular patient came to be disabled, so that an individualized care plan can be worked out. Whether this approach works in general can be evaluated by looking at group differences in mean mobility test scores. Knowing whether it has worked in the individual patient requires an individualized measure. This is because not every patient starts from the same point, and not every patient achieves success by aiming for the same goal. For one patient, walking unassisted for three metres would be a triumph; for another it would be a tragedy. Unless we understand the complexity of the needs of frail older adults, we will neither be able to treat them effectively nor evaluate our efforts sensibly.
Please see related article http://www.biomedcentral.com/1741-7015/10/120
doi:10.1186/1741-7015-10-121
PMCID: PMC3522543  PMID: 23067377
frailty; mobility; disability; multimorbidity; aged
14.  MRI plaque imaging reveals high-risk carotid plaques especially in diabetic patients irrespective of the degree of stenosis 
BMC Medical Imaging  2010;10:27.
Background
Plaque imaging based on magnetic resonance imaging (MRI) represents a new modality for risk assessment in atherosclerosis. It allows classification of carotid plaques in high-risk and low-risk lesion types (I-VIII). Type 2 diabetes mellitus (DM 2) represents a known risk factor for atherosclerosis, but its specific influence on plaque vulnerability is not fully understood. This study investigates whether MRI-plaque imaging can reveal differences in carotid plaque features of diabetic patients compared to nondiabetics.
Methods
191 patients with moderate to high-grade carotid artery stenosis were enrolled after written informed consent was obtained. Each patient underwent MRI-plaque imaging using a 1.5-T scanner with phased-array carotid coils. The carotid plaques were classified as lesion types I-VIII according to the MRI-modified AHA criteria. For 36 patients histology data was available.
Results
Eleven patients were excluded because of insufficient MR-image quality. DM 2 was diagnosed in 51 patients (28.3%). Concordance between histology and MRI-classification was 91.7% (33/36) and showed a Cohen's kappa value of 0.81 with a 95% CI of 0.98-1.15. MRI-defined high-risk lesion types were overrepresented in diabetic patients (n = 29; 56.8%). Multiple logistic regression analysis revealed association between DM 2 and MRI-defined high-risk lesion types (OR 2.59; 95% CI [1.15-5.81]), independent of the degree of stenosis.
Conclusion
DM 2 seems to represent a predictor for the development of vulnerable carotid plaques irrespective of the degree of stenosis and other risk factors. MRI-plaque imaging represents a new tool for risk stratification of diabetic patients.
See Commentary: http://www.biomedcentral.com/1741-7015/8/78/abstract
doi:10.1186/1471-2342-10-27
PMCID: PMC3004802  PMID: 21118504
15.  Infant EEG activity as a biomarker for autism: a promising approach or a false promise? 
BMC Medicine  2011;9:61.
The ability to determine an infant's likelihood of developing autism via a relatively simple neurological measure would constitute an important scientific breakthrough. In their recent publication in this journal, Bosl and colleagues claim that a measure of EEG complexity can be used to detect, with very high accuracy, infants at high risk for autism (HRA). On the surface, this appears to be that very scientific breakthrough and as such the paper has received widespread media attention. But a close look at how these high accuracy rates were derived tells a very different story. This stems from a conflation between "high risk" as a population-level property and "high risk" as a property of an individual. We describe the approach of Bosl et al. and examine their results with respect to baseline prevalence rates, the inclusion of which is necessary to distinguish infants with a biological risk of autism from typically developing infants with a sibling with autism. This is an important distinction that should not be overlooked.
Please see research article: http://www.biomedcentral.com/1741-7015/9/18 and correspondence article: http://www.biomedcentral.com/1741-7015/9/60
doi:10.1186/1741-7015-9-61
PMCID: PMC3117727  PMID: 21599952
16.  Meta-narrative and realist reviews: guidance, rules, publication standards and quality appraisal 
BMC Medicine  2013;11:22.
Recently, there has been an expansion of different forms of systematic review of research and the development of guidance and standards about particular types of review. These reviews can be best understood within a broad framework of the dimensions on which reviews differ, and how the review methodology relates to the methodology of primary research. Similarly, publication standards can be understood in terms of their relation to other standards such as guidance and rules for undertaking reviews and systems for appraising the quality of reviews. This commentary is written with special reference to the publication standards for meta-narrative and realist reviews being published in BMC Medicine.
See related research articles http://www.biomedcentral.com/1741-7015/11/20 and http://www.biomedcentral.com/1741-7015/11/21
doi:10.1186/1741-7015-11-22
PMCID: PMC3606472  PMID: 23360691
Systematic reviews; Meta-narrative; Realist synthesis.
17.  Changes in Copeptin and Bioactive Vasopressin in Runners With and Without Hyponatremia 
Objective
To evaluate changes in both the N-terminal (arginine vasopressin; AVP) and C-terminal (copeptin) fragments of the vasopressin prohormone before, during, and after an ultramarathon race and to assess vasopressin and copeptin concentrations in runners with and without hyponatremia.
Design
Observational study.
Setting
Three trials (2 sodium balance and 1 hyponatremia treatment) in 2 separate approximately 160-km footraces [Western States Endurance Run (WSER) and Javelina Jundred Mile Race (JJ100)].
Participants
Six hyponatremic and 20 normonatremic runners; 19 finishers with 7 completing 100 km.
Main Outcome Measures
Plasma AVP ([AVP]p), copeptin ([copeptin]p), sodium ([Na+]p), and protein (%plasma volume change; %PV) concentrations.
Results
In the WSER Sodium Trial, a 3-fold prerace to postrace increase in both [AVP]p (0.7 ± 0.4 to 2.7 ± 1.9 pg/mL; P < 0.05) and [copeptin]p (10.3 ± 12.5 to 28.2 ± 16.3 pmol/L; nonsignificant) occurred, despite a 2 mEq/L decrease in [Na+]p (138.7 ± 2.3 to 136.7 ± 1.6 mEq/L; NS). A significant correlation was noted between [AVP]p and [copeptin]p postrace (r = 0.82; P < 0.05). In the WSER Treatment Trial, despite the presence of hyponatremia pre-treatment versus posttreatment ([Na+]p = 130.3 vs 133.5 mEq/L, respectively), both [AVP]p (3.2 vs 2.1 pg/mL) and [copeptin]p (22.5 vs 24.9 pmol/L) were well above the detectable levels. A significant correlation was noted between [AVP]p and [copeptin]p 60 minutes after treatment (r = 0.94; P < 0.05). In the JJ100 Sodium Trial, significant correlations were found between [copeptin]p change and %PV change (r = −0.34; P < 0.05) and between [AVP]p change and [Na+]p change (r = 0.39; P < 0.05) but not vice-versa.
Conclusions
[Copeptin]p seems to be a reliable surrogate of stimulated [AVP]p during exercise. Nonosmotic vasopressin stimulation occurs during ultradistance running. [Copeptin]p may better reflect chronic (%PV) vasopressin secretion under conditions of endurance exercise.
doi:10.1097/JSM.0b013e31821a62c2
PMCID: PMC3690462  PMID: 21519298
exercise; ultramarathon; antidiuretic hormone; SIADH
18.  Associations between smoking, components of metabolic syndrome and lipoprotein particle size 
BMC Medicine  2013;11:195.
Background
The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.
Methods
We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m2). MetS was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.
Results
Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001).
Conclusions
Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size.
Please see related commentary: http://www.biomedcentral.com/1741-7015/11/196.
doi:10.1186/1741-7015-11-195
PMCID: PMC3766075  PMID: 24228807
Metabolic syndrome; Smoking; HDL; Cholesterol; Apolipoproteins; Triglycerides; Obesity; Cross-sectional; BMI classes
19.  Breast cancer screening: evidence of benefit depends on the method used 
BMC Medicine  2012;10:163.
In this article, we discuss the most common epidemiological methods used for evaluating the ability of mammography screening to decrease the risk of breast cancer death in general populations (effectiveness). Case-control studies usually find substantial effectiveness. However when breast cancer mortality decreases for reasons unrelated to screening, the case-control design may attribute to screening mortality reductions due to other causes. Studies based on incidence-based mortality have obtained contrasted results compatible with modest to considerable effectiveness, probably because of differences in study design and statistical analysis. In areas where screening has been widespread for a long time, the incidence of advanced breast cancer should be decreasing, which in turn would translate into reduced mortality. However, no or modest declines in the incidence of advanced breast cancer has been observed in these areas. Breast cancer mortality should decrease more rapidly in areas with early introduction of screening than in areas with late introduction of screening. Nonetheless, no difference in breast mortality trends has been observed between areas with early or late screening start. When effectiveness is assessed using incidence-based mortality studies, or the monitoring of advanced cancer incidence, or trends in mortality, the ecological bias is an inherent limitation that is not easy to control. Minimization of this bias requires data over long periods of time, careful selection of populations being compared and availability of data on major confounding factors. If case-control studies seem apparently more adequate for evaluating screening effectiveness, this design has its own limitations and results must be viewed with caution.
See related Opinion article: http://www.biomedcentral.com/1741-7015/10/106 and Commentary http://www.biomedcentral.com/1741-7015/10/164
doi:10.1186/1741-7015-10-163
PMCID: PMC3554519  PMID: 23234249
breast cancer; case-control; effectiveness; epidemiology; incidence; mortality; screening
20.  Triple P-Positive Parenting programs: the folly of basing social policy on underpowered flawed studies 
BMC Medicine  2013;11:11.
Wilson et al. provided a valuable systematic and meta-analytic review of the Triple P-Positive Parenting program in which they identified substantial problems in the quality of available evidence. Their review largely escaped unscathed after Sanders et al.'s critical commentary. However, both of these sources overlook the most serious problem with the Triple P literature, namely, the over-reliance on positive but substantially underpowered trials. Such trials are particularly susceptible to risks of bias and investigator manipulation of apparent results. We offer a justification for the criterion of no fewer than 35 participants in either the intervention or control group. Applying this criterion, 19 of the 23 trials identified by Wilson et al. were eliminated. A number of these trials were so small that it would be statistically improbable that they would detect an effect even if it were present. We argued that clinicians and policymakers implementing Triple P programs incorporate evaluations to ensure that goals are being met and resources are not being squandered.
Please see related articles http://www.biomedcentral.com/1741-7015/10/130 and http://www.biomedcentral.com/1741-7015/10/145
doi:10.1186/1741-7015-11-11
PMCID: PMC3606383  PMID: 23324495
meta-analysis; publication bias; conflict of interest; dissemination; confirmatory bias
21.  Mammographic screening debate on study design: a need to move the field forward 
BMC Medicine  2012;10:164.
The mammographic screening debate has been running for decades. The temperature of this debate is unusually high, and all participants, regardless of viewpoint, seem to have a conflict of interest. Another unusual aspect of this debate is the focus on study design, and in particular on designs that some think exceeded their usefulness decades ago. What are the questions that remain to be answered in this debate? Are there methodological issues that have not been adequately addressed? Do we have the right tools to provide up-to-date answers to how women can best protect themselves against dying from breast cancer? This commentary discusses some of the current issues.
See related Opinion articles http://www.biomedcentral.com/1741-7015/10/106 and http://www.biomedcentral.com/1741-7015/10/163
doi:10.1186/1741-7015-10-164
PMCID: PMC3599232  PMID: 23234258
breast cancer; mammographic screening; study design
22.  Foods and food components in the Mediterranean diet: supporting overall effects 
BMC Medicine  2014;12:100.
The recent publication of the PREDIMED trial provided definitive evidence that a Mediterranean diet provides protection against cardiovascular disease. Two articles published in BMC Medicine provide further understanding of why this may be the case, by considering contributory effects of olive oil, a core food in the diet, and polyphenols, a class of identifiable protective compounds. Using a number of statistical models, analyses were conducted to show around a 35% cardiovascular disease risk reduction in the highest consumers of olive oil and a similar degree of risk reduction for all-cause mortality comparing highest to lowest quintiles of polyphenol intake. The effects were an advance on cohort studies not related to trials. This suggests that it may be necessary to have better control of the background diet to enable exposure of the value of individual foods and nutrients in a dietary pattern, bearing in mind that, by nature, it is difficult to separate out effects of foods, nutrients and whole diets.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/77 and http://www.biomedcentral.com/1741-7015/12/78.
doi:10.1186/1741-7015-12-100
PMCID: PMC4059093  PMID: 24935157
Mediterranean diet; Cardiovascular disease; Mortality; PREDIMED study
23.  Placebo for depression: we need to improve the quality of scientific information but also reject too simplistic approaches or ideological nihilism 
BMC Medicine  2014;12:105.
The placebo response plays a major role in psychiatry, particularly in depression. A new network meta-analysis investigates whether the effects of placebo vary in studies comparing fluoxetine and venlafaxine, two widely prescribed antidepressants. Even though data from this article indicate that the effects of placebos do not differ, publication bias cannot be ruled out. The authors use their finding to criticise the paradigm of evidence-based medicine, questioning whether there is anything certain in psychiatry and, more precisely, in the field of antidepressant treatment for major depression. This study stimulates the debate about validity of scientific knowledge in medicine and highlights the importance of considering things from a different perspective. However, the authors’ view should be considered with caution. As clinicians, we make decisions every day, integrating individual clinical expertise and patients’ preferences and values with the best, up-to-date research data. The quality of scientific information must be improved, but we still think that valid conclusions to help clinical practice can be drawn from a critical and cautious use of the best available, if flawed, evidence.
Please see related articles: http://www.biomedcentral.com/1741-7015/11/230 and http://www.biomedcentral.com/1741-7015/12/106.
doi:10.1186/1741-7015-12-105
PMCID: PMC4070084  PMID: 24962638
Antidepressants; Major depressive disorder; Meta-analysis; Placebo; Publication bias
24.  Does reductio ad absurdum have a place in evidence-based medicine? 
BMC Medicine  2014;12:106.
In a meta-analysis published in BMC Medicine, we explored whether evidence-based medicine can actually be sure that ‘sucrose = sucrose’ in the treatment of depression. This paper, based upon a reductio ad absurdum, addressed an epistemological question using a ‘scientific’ approach, and could be disconcerting as suggested by Cipriani and Geddes’ commentary. However, most papers are based upon a mixture of observations and discussions about sense and meaning. Ultimately, there is nothing more than a story, told with words or numbers. Randomised controlled trials provide information about average patients that do not exist. These results ignores an entire segment of therapeutics that plays a crucial role, namely care. This information is usually set out using a ‘grammar’ that is ambiguous, since statistical tests of hypothesis have raised epistemological questions that are not as yet solved. Moreover, many of these stories remain untold, and unpublished. For these reasons evidence-based medicine is a vehicle for many paradoxes and controversies. Reductio ad absurdum can be useful in precisely this case, to underline how and why the medical literature can sometimes give an impression of absurdity of this sort. Even if the data analysis in our paper was rather rhetorical, we agree that it should comply with the classic standards of reporting and we provide the important extra data that Cipriani and Geddes have requested.
Please see related articles: http://www.biomedcentral.com/1741-7015/11/230 and http://www.biomedcentral.com/1741-7015/12/105.
doi:10.1186/1741-7015-12-106
PMCID: PMC4070092  PMID: 24962765
Epistemology; Evidence-based medicine; Publication bias; Reductio ad absurdum; Statistics
25.  Obesity in pregnancy: could lifestyle interventions work? 
BMC Medicine  2014;12(1):201.
The increased prevalence of obesity has led to major health care issues in obstetric practice. Nevertheless, despite a major international effort, there is little evidence for interventions which can improve clinical outcome. Two reports from the LIMIT randomised controlled trial of more than 2,000 overweight and obese women, recently reported in BMC Medicine, show how a lifestyle intervention in Australian women changes dietary and physical activity behaviours without any evidence of harm to the health of the newborn infant and with some suggestion of benefit. The improvements in maternal lifestyle, albeit modest, may account for a previously reported reduction in the number of macrosomic infants born to LIMIT participants randomised to the intervention arm of the trial.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/161 and http://www.biomedcentral.com/1741-7015/12/163.
doi:10.1186/s12916-014-0201-7
PMCID: PMC4195912  PMID: 25318013
Diet; Intervention; Obesity; Randomised controlled trial; Physical activity; Pregnancy

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