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1.  Estimating the returns to UK publicly funded cancer-related research in terms of the net value of improved health outcomes 
BMC Medicine  2014;12:99.
Background
Building on an approach developed to assess the economic returns to cardiovascular research, we estimated the economic returns from UK public and charitable funded cancer-related research that arise from the net value of the improved health outcomes.
Methods
To assess these economic returns from cancer-related research in the UK we estimated: 1) public and charitable expenditure on cancer-related research in the UK from 1970 to 2009; 2) net monetary benefit (NMB), that is, the health benefit measured in quality adjusted life years (QALYs) valued in monetary terms (using a base-case value of a QALY of GB£25,000) minus the cost of delivering that benefit, for a prioritised list of interventions from 1991 to 2010; 3) the proportion of NMB attributable to UK research; 4) the elapsed time between research funding and health gain; and 5) the internal rate of return (IRR) from cancer-related research investments on health benefits. We analysed the uncertainties in the IRR estimate using sensitivity analyses to illustrate the effect of some key parameters.
Results
In 2011/12 prices, total expenditure on cancer-related research from 1970 to 2009 was £15 billion. The NMB of the 5.9 million QALYs gained from the prioritised interventions from 1991 to 2010 was £124 billion. Calculation of the IRR incorporated an estimated elapsed time of 15 years. We related 17% of the annual NMB estimated to be attributable to UK research (for each of the 20 years 1991 to 2010) to 20 years of research investment 15 years earlier (that is, for 1976 to 1995). This produced a best-estimate IRR of 10%, compared with 9% previously estimated for cardiovascular disease research. The sensitivity analysis demonstrated the importance of smoking reduction as a major source of improved cancer-related health outcomes.
Conclusions
We have demonstrated a substantive IRR from net health gain to public and charitable funding of cancer-related research in the UK, and further validated the approach that we originally used in assessing the returns from cardiovascular research. In doing so, we have highlighted a number of weaknesses and key assumptions that need strengthening in further investigations. Nevertheless, these cautious estimates demonstrate that the returns from past cancer research have been substantial, and justify the investments made during the period 1976 to 1995.
doi:10.1186/1741-7015-12-99
PMCID: PMC4058434  PMID: 24930803
Medical research investment; QALYs; Cancer; Medical research charities; Value of health; Rate of return; Time lags; Research payback
2.  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
3.  Dark matter RNA illuminates the puzzle of genome-wide association studies 
BMC Medicine  2014;12:97.
In the past decade, numerous studies have made connections between sequence variants in human genomes and predisposition to complex diseases. However, most of these variants lie outside of the charted regions of the human genome whose function we understand; that is, the sequences that encode proteins. Consequently, the general concept of a mechanism that translates these variants into predisposition to diseases has been lacking, potentially calling into question the validity of these studies. Here we make a connection between the growing class of apparently functional RNAs that do not encode proteins and whose function we do not yet understand (the so-called ‘dark matter’ RNAs) and the disease-associated variants. We review advances made in a different genomic mapping effort – unbiased profiling of all RNA transcribed from the human genome – and provide arguments that the disease-associated variants exert their effects via perturbation of regulatory properties of non-coding RNAs existing in mammalian cells.
doi:10.1186/1741-7015-12-97
PMCID: PMC4054906  PMID: 24924000
Genome-wide association study; Non-coding RNA; vlincRNA; Intronic RNA; lncRNA; RNA scaffold; LincRNA; Long Non-coding RNA; Long intergenic non-coding RNA; Very long intergenic non-coding RNA
4.  Towards the clinical implementation of pharmacogenetics in bipolar disorder 
BMC Medicine  2014;12:90.
Background
Bipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.
Discussion
A number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.
Summary
Based upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD.
doi:10.1186/1741-7015-12-90
PMCID: PMC4039055  PMID: 24885933
Bipolar Disorder; Pharmacogenomics; Lithium; Antidepressants; Antipsychotics
5.  Are weekend inpatient rehabilitation services value for money? An economic evaluation alongside a randomized controlled trial with a 30 day follow up 
BMC Medicine  2014;12:89.
Background
Providing additional Saturday rehabilitation can improve functional independence and health related quality of life at discharge and it may reduce patient length of stay, yet the economic implications are not known. The aim of this study was to determine from a health service perspective if the provision of rehabilitation to inpatients on a Saturday in addition to Monday to Friday was cost effective compared to Monday to Friday rehabilitation alone.
Methods
Cost utility and cost effectiveness analyses were undertaken alongside a multi-center, single-blind randomized controlled trial with a 30-day follow up after discharge. Participants were adults admitted for inpatient rehabilitation in two publicly funded metropolitan rehabilitation facilities. The control group received usual care rehabilitation services from Monday to Friday and the intervention group received usual care plus an additional rehabilitation service on Saturday. Incremental cost utility ratio was reported as cost per quality adjusted life year (QALY) gained and an incremental cost effectiveness ratio (ICER) was reported as cost for a minimal clinically important difference (MCID) in functional independence.
Results
996 patients (mean age 74 (standard deviation 13) years) were randomly assigned to the intervention (n = 496) or the control group (n = 500). Mean difference in cost of AUD$1,673 (95% confidence interval (CI) -271 to 3,618) was a saving in favor of the intervention group. The incremental cost utility ratio found a saving of AUD$41,825 (95% CI -2,817 to 74,620) per QALY gained for the intervention group. The ICER found a saving of AUD$16,003 (95% CI -3,074 to 87,361) in achieving a MCID in functional independence for the intervention group. If the willingness to pay per QALY gained or for a MCID in functional independence was zero dollars the probability of the intervention being cost effective was 96% and 95%, respectively. A sensitivity analysis removing Saturday penalty rates did not significantly alter the outcome.
Conclusions
From a health service perspective, the provision of rehabilitation to inpatients on a Saturday in addition to Monday to Friday, compared to Monday to Friday rehabilitation alone, is likely to be cost saving per QALY gained and for a MCID in functional independence.
Trial registration
Australian and New Zealand Clinical Trials Registry November 2009 ACTRN12609000973213
doi:10.1186/1741-7015-12-89
PMCID: PMC4053313  PMID: 24885811
Rehabilitation; Economic evaluation; Randomized controlled trial; Allied health
6.  CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells 
BMC Medicine  2014;12:87.
Background
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene lead to the disease cystic fibrosis (CF). Although patients with CF often have disturbances in glucose metabolism including impaired insulin release, no previous studies have tested the hypothesis that CFTR has a biological function in pancreatic beta-cells.
Methods
Experiments were performed on islets and single beta-cells from human donors and NMRI-mice. Detection of CFTR was investigated using PCR and confocal microscopy. Effects on insulin secretion were measured with radioimmunoassay (RIA). The patch-clamp technique was used to measure ion channel currents and calcium-dependent exocytosis (as changes in membrane capacitance) on single cells with high temporal resolution. Analysis of ultrastructure was done on transmission electron microscopy (TEM) images.
Results
We detected the presence of CFTR and measured a small CFTR conductance in both human and mouse beta-cells. The augmentation of insulin secretion at 16.7 mM glucose by activation of CFTR by cAMP (forskolin (FSK) or GLP-1) was significantly inhibited when CFTR antagonists (GlyH-101 and/or CFTRinh-172) were added. Likewise, capacitance measurements demonstrated reduced cAMP-dependent exocytosis upon CFTR-inhibition, concomitant with a decreased number of docked insulin granules. Finally, our studies demonstrate that CFTR act upstream of the chloride channel Anoctamin 1 (ANO1; TMEM16A) in the regulation of cAMP- and glucose-stimulated insulin secretion.
Conclusion
Our work demonstrates a novel function for CFTR as a regulator of pancreatic beta-cell insulin secretion and exocytosis, and put forward a role for CFTR as regulator of ANO1 and downstream priming of insulin granules prior to fusion and release of insulin. The pronounced regulatory effect of CFTR on insulin secretion is consistent with impaired insulin secretion in patients with CF.
doi:10.1186/1741-7015-12-87
PMCID: PMC4035698  PMID: 24885604
CFTR; Cystic Fibrosis; Diabetes; Insulin secretion; Islet of Langerhans; Beta-cell; Exocytosis
7.  Non-celiac gluten sensitivity - why worry? 
BMC Medicine  2014;12:86.
Wheat, once thought to be a critical ingredient in a healthy diet, has become a major threat, according to public opinion. The term non-celiac gluten sensitivity has been widely adopted to describe a clinical entity characterized by symptoms induced by gluten without the diagnostic criteria found in other gluten-related disorders. However, it has not been shown that gluten per se is involved, and it can be debated if the condition is a disease. Nevertheless, a large number of individuals go gluten-free, avoiding wheat, rye and barley, even without a defined medical cause. In a study in BMC Medicine, Volta and colleagues from Italy report on a large, multicenter attempt to enumerate the prevalence of non-celiac gluten sensitivity in secondary gastroenterology care. They found that approximately 3% of their more than 12,000 patients fulfilled their criteria for non-celiac gluten sensitivity. However, we are still challenged with finding stricter clinical criteria for the condition, developing a usable clinical approach for gluten challenge in these individuals, and understanding the pathogenesis of the condition.
Please see related article http://www.biomedcentral.com/1741-7015/12/85.
doi:10.1186/1741-7015-12-86
PMCID: PMC4031484  PMID: 24885490
Celiac disease; Diagnosis; FODMAP; Gluten; Gluten-free diet; Irritable bowel syndrome; Multicenter study; Non-celiac gluten sensitivity
8.  An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity 
BMC Medicine  2014;12:85.
Background
Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers for the diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and to establish roughly its prevalence compared with celiac disease.
Methods
From November 2012 to October 2013, 38 Italian centers (27 adult gastroenterology, 5 internal medicine, 4 pediatrics, and 2 allergy) participated in this prospective survey. A questionnaire was used in order to allow uniform and accurate collection of clinical, biochemical, and instrumental data.
Results
In total, 486 patients with suspected NCGS were identified in this 1-year period. The female/male ratio was 5.4 to 1, and the mean age was 38 years (range 3–81). The clinical picture was characterized by combined gastrointestinal (abdominal pain, bloating, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and systemic manifestations (tiredness, headache, fibromyalgia-like joint/muscle pain, leg or arm numbness, 'foggy mind,' dermatitis or skin rash, depression, anxiety, and anemia). In the large majority of patients, the time lapse between gluten ingestion and the appearance of symptoms varied from a few hours to 1 day. The most frequent associated disorders were irritable bowel syndrome (47%), food intolerance (35%) and IgE-mediated allergy (22%). An associated autoimmune disease was detected in 14% of cases. Regarding family history, 18% of our patients had a relative with celiac disease, but no correlation was found between NCGS and positivity for HLA-DQ2/-DQ8. IgG anti-gliadin antibodies were detected in 25% of the patients tested. Only a proportion of patients underwent duodenal biopsy; for those that did, the biopsies showed normal intestinal mucosa (69%) or mild increase in intraepithelial lymphocytes (31%). The ratio between suspected NCGS and new CD diagnoses, assessed in 28 of the participating centers, was 1.15 to 1.
Conclusions
This prospective survey shows that NCGS has a strong correlation with female gender and adult age. Based on our results, the prevalence of NCGS seems to be only slightly higher than that of celiac disease.
Please see related article http://www.biomedcentral.com/1741-7015/12/86.
doi:10.1186/1741-7015-12-85
PMCID: PMC4053283  PMID: 24885375
Non-celiac gluten sensitivity; Celiac disease; Prospective survey; Clinical picture; Duodenal biopsy; Anti-gliadin antibodies
9.  Are school-based mental health interventions for war-affected children effective and harmless? 
BMC Medicine  2014;12:84.
In recent years, different approaches to large-scale mental health service provision for children in war-affected, mainly low- and middle-income, countries have been developed. Some school-based programs aiming at both strengthening resilience and reducing symptoms of trauma-related distress have been evaluated. In an article published in BMC Medicine, Tol and colleagues integrate their findings of the efficacy of universal school-based intervention across four countries and do not recommend classroom-based intervention as a treatment of trauma-related symptoms, since no consistent positive effects were found. On the contrary, for some children this type of universal intervention may impair recovery. Since universal school-based programs similar to the one evaluated here are widely implemented, Tol et al.’s results are highly relevant to inform the field of mental health service provision in war-affected countries.
Please see related article http://www.biomedcentral.com/1741-7015/12/56.
doi:10.1186/1741-7015-12-84
PMCID: PMC4029806  PMID: 24885265
Trauma; Children; War; PTSD; Depression; Treatment; Prevention; Trial; Effectiveness
10.  The ‘placement’ of people with profound impairments across the lifespan: re-thinking age criteria 
BMC Medicine  2014;12:83.
Background
Advances in lifesaving technologies and treatments make it possible for children with profound physical and cognitive impairments to survive into adulthood. Questions regarding how and where they should live are discussed rarely and, when they are, primarily focus on safety and/or containing costs. Since models of long-term care provision are age-based, children who reside in institutions are ‘discharged’ to adult facilities when they reach an arbitrary age. Such transfers may not be in the best interests of these young people or their families. Our aim in this debate is to highlight why age is a problematic criterion for placement decisions, with the goal of stimulating further research and inquiry.
Discussion
Transfers from pediatric to adult institutions are driven primarily by funding arrangements and underpinned by stage-based theories of human development. Arguments supporting such transfers point to the value of communal living with same age peers, and engagement in age-appropriate activities. These goals are questionable for individuals who are minimally interactive and/or where equally worthy interactions are feasible in intergenerational settings. Instead their accommodation needs might more closely align with palliative care principles of supporting individuals and families to enjoy what they bring to each other’s lives and minimize suffering. Innovative models of ‘vertical care’ and ‘lifetime homes’, which enable continuous flexible services across the lifespan, are discussed as examples of alternative approaches requiring further debate and research.
Summary
Entrenched funding and service models that require the transfer of profoundly impaired young people from pediatric to adult facilities need to be re-examined with considerations of best interests, needs, and preferences of individuals and their families. Questions of what constitutes a ‘good life’ for these individuals are tenacious and require further thought and research. Nevertheless, they need to be regarded as citizens of our human community deserving of a good life in whatever form that may take, in settings that enable them to flourish.
doi:10.1186/1741-7015-12-83
PMCID: PMC4029835  PMID: 24885127
Complex care; Impairment; Long term care; Children and young people; Transitions; Life course; Disability; Chronic care; Home
11.  suPAR and Team Nephrology 
BMC Medicine  2014;12:82.
Primary focal segmental glomerulosclerosis (FSGS) accounts for nearly 10 % of patients who require renal replacement therapy. Elevated circulating levels of soluble urokinase receptor (suPAR) have been identified as a biomarker to discriminate primary FSGS from other glomerulopathies. Subsequent reports have questioned the diagnostic utility of this test. In a study in BMC Medicine, Huang et al. demonstrate that urinary soluble urokinase receptor (suPAR) excretion assists in distinguishing primary FSGS from other glomerular diseases, and that high plasma suPAR concentrations are not directly linked to a decline in glomerular filtration rate (GFR). This observation suggests that further investigation of suPAR is warranted in patients with FSGS. It should be interpreted in light of a recent report that B7-1 is expressed in the podocytes of a subset of patients with FSGS, and that blocking this molecule may represent the first successful targeted intervention for this disease. These advances highlight the rapid pace of scientific progress in the field of nephrology. Nephrologists should work together, share resources, and expedite the design of protocols to evaluate these novel biomarkers in a comprehensive and scientifically valid manner.
Please see related article http://www.biomedcentral.com/1741-7015/12/81.
doi:10.1186/1741-7015-12-82
PMCID: PMC4026824  PMID: 24885021
Focal segmental glomerulosclerosis (FSGS); Soluble urokinase receptor (suPAR); Podocyte; B7.1
12.  Risk stratification in emergency patients by copeptin 
BMC Medicine  2014;12:80.
Background
Rapid risk stratification is a core task in emergency medicine. Identifying patients at high and low risk shortly after admission could help clinical decision-making regarding treatment, level of observation, allocation of resources and post discharge follow-up. The purpose of the present study was to determine short-, mid- and long-term mortality by plasma measurement of copeptin in unselected admitted patients.
Method
Consecutive patients >40-years-old admitted to an inner-city hospital were included. Within the first 24 hours after admission, a structured medical interview was conducted and self-reported medical history was recorded. All patients underwent a clinical examination, an echocardiographic evaluation and collection of blood for later measurement of risk markers.
Results
Plasma for copeptin measurement was available from 1,320 patients (average age 70.5 years, 59.4% women). Median follow-up time was 11.5 years (range 11.0 to 12.0 years). Copeptin was elevated (that is, above the 97.5 percentile in healthy individuals).
Mortality within the first week was 2.7% (17/627) for patients with elevated copeptin (above the 97.5 percentile, that is, >11.3 pmol/L) compared to 0.1% (1/693) for patients with normal copeptin concentrations (that is, ≤11.3 pmol/L) (P <0.01). Three-month mortality was 14.5% (91/627) for patients with elevated copeptin compared to 3.2% (22/693) for patients with normal copeptin. Similar figures for one-year mortality and for the entire observation period were 27.6% (173/627) versus 8.7% (60/693) and 82.9% (520/527) versus 57.5% (398/693) (P <0.01 for both), respectively.
Using multivariable Cox regression analyses shows that elevated copeptin was significantly and independently related to short-, mid- and long-term mortality. Adjusted hazard ratios were 2.4 for three-month mortality, 1.9 for one-year mortality and 1.4 for mortality in the entire observation period.
Conclusions
In patients admitted to an inner-city hospital, copeptin was strongly associated with short-, mid- and long-term mortality. The results suggest that rapid copeptin measurement could be a useful tool for both disposition in an emergency department and for mid- and long-term risk assessment.
doi:10.1186/1741-7015-12-80
PMCID: PMC4053286  PMID: 24884642
Biomarker; Mortality; Inflammation
13.  Corticosteroid therapy in regressive autism: Preliminary findings from a retrospective study 
BMC Medicine  2014;12:79.
Some children with autism spectrum disorders (ASD; 15% to 30% of patients) show a significant and persistent regression in speech and social function during early childhood. There are no established treatments for the regressive symptoms. However, there are some known causes of this type of regression, such as Rett syndrome and Landau-Kleffner syndrome (LKS). In LKS, steroids have been used as a treatment. Some evidence suggests an autoimmune contribution to the pathophysiology of autism (Chez MG, Guido-Estrada N: Immune therapy in autism: historical experience and future directions with immunomodulatory therapy. Neurotherapeutics 2010, 7:293–301, Wasilewska J, Kaczmarski M, Stasiak-Barmuta A, Tobolczyk J, Kowalewska E: Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Arch Med Sci 2012, 8:324–331, Stefanatos G: Changing perspectives on Landau-Kleffner syndrome. Clin Neuropsychol 2011, 25:963–988), raising the possibility that steroids might be a useful therapy for regression in ASD. A retrospective study published in BMC Neurology by Duffy et al. (Duffy, et al: Corticosteroid therapy in regressive autism: A retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior. BMC Neurol 2014, 14:70) reviewed 20 steroid treated R-ASD (STAR) patients and 24 ASD control patients not treated with steroids (NSA). Improvements in clinical function and in a neurophysiological biomarker were seen in the steroid-treated children pre- to post-prednisolone treatment. This research provides a rationale for a randomized trial with steroid therapy to determine the longer term benefits and complications of steroids in this population.
Please see related article http://www.biomedcentral.com/1471-2377/14/70/abstract.
doi:10.1186/1741-7015-12-79
PMCID: PMC4022409  PMID: 24884537
Autism; Regression; Corticosteroids; FMAER; Language; Behavior
14.  Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study 
BMC Medicine  2014;12:78.
Background
It is unknown whether individuals at high cardiovascular risk sustain a benefit in cardiovascular disease from increased olive oil consumption. The aim was to assess the association between total olive oil intake, its varieties (extra virgin and common olive oil) and the risk of cardiovascular disease and mortality in a Mediterranean population at high cardiovascular risk.
Methods
We included 7,216 men and women at high cardiovascular risk, aged 55 to 80 years, from the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter, randomized, controlled, clinical trial. Participants were randomized to one of three interventions: Mediterranean Diets supplemented with nuts or extra-virgin olive oil, or a control low-fat diet. The present analysis was conducted as an observational prospective cohort study. The median follow-up was 4.8 years. Cardiovascular disease (stroke, myocardial infarction and cardiovascular death) and mortality were ascertained by medical records and National Death Index. Olive oil consumption was evaluated with validated food frequency questionnaires. Multivariate Cox proportional hazards and generalized estimating equations were used to assess the association between baseline and yearly repeated measurements of olive oil intake, cardiovascular disease and mortality.
Results
During follow-up, 277 cardiovascular events and 323 deaths occurred. Participants in the highest energy-adjusted tertile of baseline total olive oil and extra-virgin olive oil consumption had 35% (HR: 0.65; 95% CI: 0.47 to 0.89) and 39% (HR: 0.61; 95% CI: 0.44 to 0.85) cardiovascular disease risk reduction, respectively, compared to the reference. Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality. For each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. No significant associations were found for cancer and all-cause mortality. The associations between cardiovascular events and extra virgin olive oil intake were significant in the Mediterranean diet intervention groups and not in the control group.
Conclusions
Olive oil consumption, specifically the extra-virgin variety, is associated with reduced risks of cardiovascular disease and mortality in individuals at high cardiovascular risk.
Trial registration
This study was registered at controlled-trials.com (http://www.controlled-trials.com/ISRCTN35739639). International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.
doi:10.1186/1741-7015-12-78
PMCID: PMC4030221  PMID: 24886626
Olive oil; Cardiovascular; Mortality; Mediterranean Diet; PREDIMED
15.  Preventing the development of depression at work: a systematic review and meta-analysis of universal interventions in the workplace 
BMC Medicine  2014;12:74.
Background
Depression is a major public health problem among working-age adults. The workplace is potentially an important location for interventions aimed at preventing the development of depression, but to date, the mental health impact of universal interventions in the workplace has been unclear.
Method
A systematic search was conducted in relevant databases to identify randomized controlled trials of workplace interventions aimed at universal prevention of depression. The quality of studies was assessed using the Downs and Black checklist. A meta-analysis was performed using results from studies of adequate methodological quality, with pooled effect size estimates obtained from a random effects model.
Results
Nine workplace-based randomized controlled trials (RCT) were identified. The majority of the included studies utilized cognitive behavioral therapy (CBT) techniques. The overall standardized mean difference (SMD) between the intervention and control groups was 0.16 (95% confidence interval (CI): 0.07, 0.24, P = 0.0002), indicating a small positive effect. A separate analysis using only CBT-based interventions yielded a significant SMD of 0.12 (95% CI: 0.02, 0.22, P = 0.01).
Conclusions
There is good quality evidence that universally delivered workplace mental health interventions can reduce the level of depression symptoms among workers. There is more evidence for the effectiveness of CBT-based programs than other interventions. Evidence-based workplace interventions should be a key component of efforts to prevent the development of depression among adults.
doi:10.1186/1741-7015-12-74
PMCID: PMC4014627  PMID: 24886246
Depression; Prevention; Workplace; Occupational health; Occupational stress; Mental disorder; Resilience
16.  Prevention of mental disorders: evidence, challenges and opportunities 
BMC Medicine  2014;12:75.
Modelling studies suggest that less than 30% of the burden of mental disorders can be averted, even with optimal care and access to services. This points to the need to reduce the incidence of mental disorders, utilising evidence-based prevention strategies and policy action. In this cross-journal article collection (http://www.biomedcentral.com/series/PMD), the case for prevention is made by identifying initiatives with established efficacy, as well as opportunities and targets for the prevention of mental disorders in early life, in the workplace and at the population level. These articles provide reviews, systematic and narrative, outlining the evidence base for prevention approaches, as well as comment and debate designed to prompt discussion and a reconsideration of strategies for prevention. Barriers to expanding the research into prevention include the reluctance of governments and funding bodies to invest in research and policy action that may take many years to manifest benefits. The case for the cost-effectiveness of preventing mental disorders needs to be strongly argued and new cross-disciplinary, intersectoral initiatives and policies developed for the prevention of mental disorders across the lifespan.
doi:10.1186/1741-7015-12-75
PMCID: PMC4014629  PMID: 24886356
Prevention; depression; mental disorders; mental health; policy
17.  The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder 
BMC Medicine  2014;12:73.
Background
Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either ‘reactive’ or ‘endogenous’ subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of ‘reactive’ or ‘endogenous’ subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of ‘reactive’ and ‘endogenous’ depression. We then translated these findings to clinical samples using a human post-mortem mRNA study.
Methods
Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic ‘stress’ protocols (maternal separation and Unpredictable Chronic Mild Stress) to model ‘reactive’ depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of ‘endogenous’ depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium.
Results
In the mouse ‘reactive’ model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the ‘endogenous’ rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing.
Conclusions
Our results suggest that ‘endogenous’ and ‘reactive’ subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of ‘reactive’ depression caused by early stressors differs considerably from that of ‘reactive’ depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.
doi:10.1186/1741-7015-12-73
PMCID: PMC4046519  PMID: 24886127
Endogenous Depression; Reactive Depression; GENDEP; VAMP-2; DSM-IV; Stanley Brain Consortium; mRNA; Stress
18.  Reporting funding source or conflict of interest in abstracts of randomized controlled trials, no evidence of a large impact on general practitioners’ confidence in conclusions, a three-arm randomized controlled trial 
BMC Medicine  2014;12:69.
Background
Systematic reporting of funding sources is recommended in the CONSORT Statement for abstracts. However, no specific recommendation is related to the reporting of conflicts of interest (CoI). The objective was to compare physicians’ confidence in the conclusions of abstracts of randomized controlled trials of pharmaceutical treatment indexed in PubMed.
Methods
We planned a three-arm parallel-group randomized trial. French general practitioners (GPs) were invited to participate and were blinded to the study’s aim. We used a representative sample of 75 abstracts of pharmaceutical industry-funded randomized controlled trials published in 2010 and indexed in PubMed. Each abstract was standardized and reported in three formats: 1) no mention of the funding source or CoI; 2) reporting the funding source only; and 3) reporting the funding source and CoI. GPs were randomized according to a computerized randomization on a secure Internet system at a 1:1:1 ratio to assess one abstract among the three formats. The primary outcome was GPs’ confidence in the abstract conclusions (0, not at all, to 10, completely confident). The study was planned to detect a large difference with an effect size of 0.5.
Results
Between October 2012 and June 2013, among 605 GPs contacted, 354 were randomized, 118 for each type of abstract. The mean difference (95% confidence interval) in GPs’ confidence in abstract findings was 0.2 (-0.6; 1.0) (P = 0.84) for abstracts reporting the funding source only versus no funding source or CoI; -0.4 (-1.3; 0.4) (P = 0.39) for abstracts reporting the funding source and CoI versus no funding source and CoI; and -0.6 (-1.5; 0.2) (P = 0.15) for abstracts reporting the funding source and CoI versus the funding source only.
Conclusions
We found no evidence of a large impact of trial report abstracts mentioning funding sources or CoI on GPs’ confidence in the conclusions of the abstracts.
Trial Registration
ClinicalTrials.gov identifier: NCT01679873
doi:10.1186/1741-7015-12-69
PMCID: PMC4022327  PMID: 24779384
Funding; Conflict of interest; General Practitioner; Abstract; Reporting
19.  Risks and benefits of transfusion for children with severe anemia in Africa 
BMC Medicine  2014;12:68.
Severe anemia contributes significantly to child mortality in sub-Saharan Africa. Blood transfusion is used in emergencies but carries risks. In BMC Medicine, Olupot-Olupot and colleagues report the findings of a phase II trial in children with severe anemia in Eastern Uganda. They provide important early safety and efficacy data supporting large volume whole blood transfusion (30 ml/kg) compared with the World Health Organization recommendation of 20 ml/kg. Large volume transfusions result in more rapid and frequent correction of severe anemia; they can be expected to reduce the risk of transfusions, and help manage the scarce resource of donor blood. However, severe anemia arises from varying combinations of acute, sub-acute and chronic etiologies.
The Fluid Expansion As Supportive Therapy study reminds us that the risks and benefits of even simple interventions are complex, and that rapid normalization of physiology may not always be the best strategy. There is no substitute for high quality evidence and to this end we strongly support Olupot-Oluput and colleagues’ call for a definitive trial of large volume transfusions in severe anemia.
Please see related research article http://www.biomedcentral.com/1741-7015/12/67/abstract.
doi:10.1186/1741-7015-12-68
PMCID: PMC3999736  PMID: 24767140
Africa; Physiology; Anemia; Children; Commentary; Infectious disease; Malaria; Transfusion
20.  Predictive score for mortality in patients with COPD exacerbations attending hospital emergency departments 
BMC Medicine  2014;12:66.
Background
Limited information is available about predictors of short-term outcomes in patients with exacerbation of chronic obstructive pulmonary disease (eCOPD) attending an emergency department (ED). Such information could help stratify these patients and guide medical decision-making. The aim of this study was to develop a clinical prediction rule for short-term mortality during hospital admission or within a week after the index ED visit.
Methods
This was a prospective cohort study of patients with eCOPD attending the EDs of 16 participating hospitals. Recruitment started in June 2008 and ended in September 2010. Information on possible predictor variables was recorded during the time the patient was evaluated in the ED, at the time a decision was made to admit the patient to the hospital or discharge home, and during follow-up. Main short-term outcomes were death during hospital admission or within 1 week of discharge to home from the ED, as well as at death within 1 month of the index ED visit. Multivariate logistic regression models were developed in a derivation sample and validated in a validation sample. The score was compared with other published prediction rules for patients with stable COPD.
Results
In total, 2,487 patients were included in the study. Predictors of death during hospital admission, or within 1 week of discharge to home from the ED were patient age, baseline dyspnea, previous need for long-term home oxygen therapy or non-invasive mechanical ventilation, altered mental status, and use of inspiratory accessory muscles or paradoxical breathing upon ED arrival (area under the curve (AUC) = 0.85). Addition of arterial blood gas parameters (oxygen and carbon dioxide partial pressures (PO2 and PCO2)) and pH) did not improve the model. The same variables were predictors of death at 1 month (AUC = 0.85). Compared with other commonly used tools for predicting the severity of COPD in stable patients, our rule was significantly better.
Conclusions
Five clinical predictors easily available in the ED, and also in the primary care setting, can be used to create a simple and easily obtained score that allows clinicians to stratify patients with eCOPD upon ED arrival and guide the medical decision-making process.
doi:10.1186/1741-7015-12-66
PMCID: PMC4021970  PMID: 24758312
COPD exacerbations; Mortality; Prediction Rule; Prospective Cohort Study; Risk analysis
21.  Verbal autopsy as a tool for identifying children dying of sickle cell disease: a validation study conducted in Kilifi district, Kenya 
BMC Medicine  2014;12:65.
Background
Sickle cell disease (SCD) is common in many parts of sub-Saharan Africa (SSA), where it is associated with high early mortality. In the absence of newborn screening, most deaths among children with SCD go unrecognized and unrecorded. As a result, SCD does not receive the attention it deserves as a leading cause of death among children in SSA. In the current study, we explored the potential utility of verbal autopsy (VA) as a tool for attributing underlying cause of death (COD) in children to SCD.
Methods
We used the 2007 WHO Sample Vital Registration with Verbal Autopsy (SAVVY) VA tool to determine COD among child residents of the Kilifi Health and Demographic Surveillance System (KHDSS), Kenya, who died between January 2008 and April 2011. VAs were coded both by physician review (physician coded verbal autopsy, PCVA) using COD categories based on the WHO International Classification of Diseases 10th Edition (ICD-10) and by using the InterVA-4 probabilistic model after extracting data according to the 2012 WHO VA standard. Both of these methods were validated against one of two gold standards: hospital ICD-10 physician-assigned COD for children who died in Kilifi District Hospital (KDH) and, where available, laboratory confirmed SCD status for those who died in the community.
Results
Overall, 6% and 5% of deaths were attributed to SCD on the basis of PCVA and the InterVA-4 model, respectively. Of the total deaths, 22% occurred in hospital, where the agreement coefficient (AC1) for SCD between PCVA and hospital physician diagnosis was 95.5%, and agreement between InterVA-4 and hospital physician diagnosis was 96.9%. Confirmatory laboratory evidence of SCD status was available for 15% of deaths, in which the AC1 against PCVA was 87.5%.
Conclusions
Other recent studies and provisional data from this study, outlining the importance of SCD as a cause of death in children in many parts of the developing world, contributed to the inclusion of specific SCD questions in the 2012 version of the WHO VA instruments, and a specific code for SCD has now been included in the WHO and InterVA-4 COD listings. With these modifications, VA may provide a useful approach to quantifying the contribution of SCD to childhood mortality in rural African communities. Further studies will be needed to evaluate the generalizability of our findings beyond our local context.
doi:10.1186/1741-7015-12-65
PMCID: PMC4022330  PMID: 24755265
Sickle cell disease; Verbal autopsy; Agreement coefficient; Child mortality; Kenya
22.  The impact of excess body weight at the hospital frontline 
BMC Medicine  2014;12:64.
Quantification of disease burden by deaths or years lived with disability is a useful indicator as it informs prevention by accounting for health loss but it does not reflect the needs for health services. An alternative indicator is to quantify the impact of a risk factor on health care utilization. In an article published in BMC Medicine, Reeves and colleagues describe the relationship between body mass index in 1.2 million women (England) and hospital admission rates. The main finding was that around one in eight hospital admissions was attributable to overweight or obesity, translating to around 420,000 extra hospital admissions, and two million extra days spent in hospital, annually. These findings reinforce the evidence that excess body weight is associated with extensive healthcare utilization and emphasize the need to scale-up and speed-up research if global problems, such as obesity, are to be tackled with due alacrity.
Please see related research: http://www.biomedcentral.com/1741-7015/12/45.
doi:10.1186/1741-7015-12-64
PMCID: PMC3990237  PMID: 24742301
Body mass index; Hospital admission rates; Data linkage
23.  The effect of a pre- and postoperative orthogeriatric service on cognitive function in patients with hip fracture: randomized controlled trial (Oslo Orthogeriatric Trial) 
BMC Medicine  2014;12:63.
Background
Delirium is a common complication in patients with hip fractures and is associated with an increased risk of subsequent dementia. The aim of this trial was to evaluate the effect of a pre- and postoperative orthogeriatric service on the prevention of delirium and longer-term cognitive decline.
Methods
This was a single-center, prospective, randomized controlled trial in which patients with hip fracture were randomized to treatment in an acute geriatric ward or standard orthopedic ward. Inclusion and randomization took place in the Emergency Department at Oslo University hospital. The key intervention in the acute geriatric ward was Comprehensive Geriatric Assessment including daily interdisciplinary meetings. Primary outcome was cognitive function four months after surgery measured using a composite outcome incorporating the Clinical Dementia Rating Scale (CDR) and the 10 words learning and recalls tasks from the Consortium to Establish a Registry for Alzheimer’s Disease battery (CERAD). Secondary outcomes were pre- and postoperative delirium, delirium severity and duration, mortality and mobility (measured by the Short Physical Performance Battery (SPPB)). Patients were assessed four and twelve months after surgery by evaluators blind to allocation.
Results
A total of 329 patients were included. There was no significant difference in cognitive function four months after surgery between patients treated in the acute geriatric and the orthopedic wards (mean 54.7 versus 52.9, 95% confidence interval for the difference -5.9 to 9.5; P = 0.65). There was also no significant difference in delirium rates (49% versus 53%, P = 0.51) or four month mortality (17% versus 15%, P = 0.50) between the intervention and the control group. In a pre-planned sub-group analysis, participants living in their own home at baseline who were randomized to orthogeriatric care had better mobility four months after surgery compared with patients randomized to the orthopedic ward, measured with SPPB (median 6 versus 4, 95% confidence interval for the median difference 0 to 2; P = 0.04).
Conclusions
Pre- and postoperative orthogeriatric care given in an acute geriatric ward was not effective in reducing delirium or long-term cognitive impairment in patients with hip fracture. The intervention had, however, a positive effect on mobility in patients not admitted from nursing homes.
Trial registration
ClinicalTrials.gov NCT01009268 Registered November 5, 2009
doi:10.1186/1741-7015-12-63
PMCID: PMC4022270  PMID: 24735588
Hip fracture; Orthogeriatrics; Delirium; Cognitive decline
24.  Muscle strength in adolescent men and risk of cardiovascular disease events and mortality in middle age: a prospective cohort study 
BMC Medicine  2014;12:62.
Background
Ischemic heart disease and stroke are two severe types of cardiovascular disease (CVD), a major contributor to the global burden of disease. The preventive framework currently includes promotion of both adequate cardiorespiratory and muscular fitness. Although muscle fitness is established as an indicator of health, it is currently unknown whether muscle strength is associated with later CVD independently of cardiorespiratory fitness.
Methods
We studied 38,588 Swedish men who in 1969 to 1970 (typically aged 18 years) completed compulsory conscription. Using the mean standardized score of three isometric muscle strength tests performed at conscription (hand grip, elbow flexion and knee extension), we categorized the subjects into three groups with the 25th to 75th percentile defining the reference category. We followed the cohort until 2012 for diagnosed CVD events and mortality via national health care registers and the national cause of death register. To estimate hazard ratios (HR) for CVD events (coronary heart disease or stroke) and CVD mortality we used Cox proportional hazard models adjusted for body mass index, smoking, alcohol consumption, cardiorespiratory fitness and socioeconomic status.
Results
Men with high muscle strength in adolescence had a decreased risk of later CVD events (HR 0.88, 95% confidence interval 0.77 to 0.99), whereas we observed no increased risk in men with low muscle strength (0.99, 0.86 to 1.13). However, low muscle strength was associated with increased risk of CVD mortality during middle age (1.31, 1.02 to 1.67).
Conclusions
Muscle strength in adolescent men is inversely associated with later CVD events and CVD mortality in middle age, independently of cardiorespiratory fitness and other important confounders. Thus, the role of muscle fitness in the prevention and pathogenesis of CVD warrants increased attention.
doi:10.1186/1741-7015-12-62
PMCID: PMC4006633  PMID: 24731728
Cardiovascular disease; Coronary heart disease; Stroke; Muscle strength; Prevention; Epidemiology
25.  Obesity survival paradox in pneumonia: a meta-analysis 
BMC Medicine  2014;12:61.
Background
It is unclear whether an ‘obesity survival paradox’ exists for pneumonia. Therefore, we conducted a meta-analysis to assess the associations between increased body mass index (BMI), pneumonia risk, and mortality risk.
Methods
Cohort studies were identified from the PubMed and Embase databases. Summary relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random effects model.
Results
Thirteen cohort studies on pneumonia risk (n = 1,536,623), and ten cohort studies on mortality (n = 1,375,482) were included. Overweight and obese individuals were significantly associated with an increased risk of pneumonia (RR = 1.33, 95% CI 1.04 to 1.71, P = 0.02, I2 = 87%). In the dose–response analysis, the estimated summary RR of pneumonia per 5 kg/m2 increase in BMI was 1.04 (95% CI 1.01 to 1.07, P = 0.01, I2 = 84%). Inversely, overweight and obese subjects were significantly associated with reduced risk of pneumonia mortality (RR = 0.83, 95% CI 0.77 to 0.91, P < 0.01, I2 = 34%). The estimated summary RR of mortality per 5 kg/m2 increase in BMI was 0.95 (95% CI 0.93 to 0.98, P < 0.01, I2 = 77%).
Conclusions
This meta-analysis suggests that an ‘obesity survival paradox’ exists for pneumonia. Because this meta-analysis is based on observational studies, more studies are required to confirm the results.
doi:10.1186/1741-7015-12-61
PMCID: PMC4021571  PMID: 24722122
Body mass index; Obesity; Pneumonia; Dose–response relationship; Meta-analysis

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