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26.  Major dietary patterns and risk of frailty in older adults: a prospective cohort study 
BMC Medicine  2015;13:11.
There is emerging evidence of the role of certain nutrients as risk factors for frailty. However, people eat food, rather than nutrients, and no previous study has examined the association between dietary patterns empirically derived from food consumption and the risk of frailty in older adults.
This is a prospective cohort study of 1,872 non-institutionalized individuals aged ≥60 years recruited between 2008 and 2010. At baseline, food consumption was obtained with a validated diet history and, by using factor analysis, two dietary patterns were identified: a ‘prudent’ pattern, characterized by high intake of olive oil and vegetables, and a ‘Westernized’ pattern, with a high intake of refined bread, whole dairy products, and red and processed meat, as well as low consumption of fruit and vegetables. Participants were followed-up until 2012 to assess incident frailty, defined as at least three of the five Fried criteria (exhaustion, weakness, low physical activity, slow walking speed, and unintentional weight loss).
Over a 3.5-year follow-up, 96 cases of incident frailty were ascertained. The multivariate odds ratios (95% confidence interval) of frailty among those in the first (lowest), second, and third tertile of adherence to the prudent dietary pattern were 1, 0.64 (0.37–1.12), and 0.40 (0.2–0.81), respectively; P-trend = 0.009. The corresponding values for the Westernized pattern were 1, 1.53 (0.85–2.75), and 1.61 (0.85–3.03); P-trend = 0.14. Moreover, a greater adherence to the Westernized pattern was associated with an increasing risk of slow walking speed and weight loss.
In older adults, a prudent dietary pattern showed an inverse dose-response relationship with the risk of frailty while a Westernized pattern had a direct relationship with some of their components. Clinical trials should test whether a prudent pattern is effective in preventing or delaying frailty.
PMCID: PMC4298966  PMID: 25601152
Cohort study; Diet; Frailty; Older adults; Spain
27.  Effects of mineralocorticoid receptor antagonists in patients with preserved ejection fraction: a meta-analysis of randomized clinical trials 
BMC Medicine  2015;13:10.
Mineralocorticoid receptor antagonists (MRAs) have been shown to be effective in patients with heart failure or myocardial infarction complicated by a reduced ejection fraction. However, the role of MRAs in patients with preserved ejection fraction (PEF) remains to be clarified. We aimed to summarize the evidence for the efficacy of MRAs in patients with either heart failure with PEF (HF-PEF) or myocardial infarction with PEF (MI-PEF).
We searched PubMed, EMBASE, Cochrane Library, and clinical trials databases for randomized controlled trials, through June 2014, assessing MRA treatment in HF-PEF or MI-PEF patients. Fourteen randomized controlled trials (MI-PEF, 5; HF-PEF, 9; n = 6,428 patients) were included.
MRA treatment reduced the risk of hospitalization for heart failure (relative risk, 0.83; 95% confidence interval [CI], 0.70 to 0.98), improved quality of life (weighted mean difference [WMD], −5.16; 95% CI, −8.03 to −2.30), left ventricular end-diastolic diameter (standardized mean difference, −0.21; 95% CI, 0.32 to −0.11), and serum amino-terminal peptide of procollagen type-III level (WMD, −1.50, 95% CI, −1.72 to −1.29) in patients with PEF. In addition, MRAs reduced E/e'(an echocardiographic estimate of filling pressure for assessment of diastolic function; WMD, −1.82; 95% CI, −2.23 to −1.42) in HF-PEF patients and E/A ratio (the ratio of early to late diastolic transmitral flow; WMD, 0.12; 95% CI, 0.10 to 0.14) in MI-PEF patients. However, all-cause mortality was not improved by MRAs in either HF-PEF (P = 0.90) or MI-PEF (P = 0.27) patients.
MRA treatment in PEF patients led to reduced hospitalization for heart failure, quantifiable improvements in quality of life and diastolic function, and reversal of cardiac remodeling, but did not provide any all-cause mortality benefit.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0261-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4307751  PMID: 25598008
Meta-analysis; Mineralocorticoid receptor antagonists; Preserved ejection fraction; Randomized controlled trial
28.  The intriguing relationship between the ABO blood group, cardiovascular disease, and cancer 
BMC Medicine  2015;13:7.
Other than being present at the surface of red blood cells, the antigens of the ABO blood group system are efficiently expressed by a variety of human cells and tissues. Several studies recently described the involvement of the ABO blood group in the pathogenesis of many human disorders, including cardiovascular disease and cancer, so that its clinical significance extends now beyond the traditional boundaries of transfusion medicine. In a large cohort study recently published in BMC Medicine and including over 50,000 subjects, Etemadi and colleagues reported that nearly 6% of total deaths and as many as 9% of cardiovascular deaths could be attributed to having non-O blood groups, a condition that was also found to be associated with increased risk of gastric cancer. In this commentary, the clinical implications of ABO blood groups are critically discussed and a possible common pathogenic mechanism involving the von Willebrand factor is described.
Please see related article
PMCID: PMC4295232  PMID: 25592962
ABO blood group; Cancer; Cardiovascular disease; Mortality; von Willebrand factor
29.  Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial 
BMC Medicine  2015;13:9.
Intermittent preventive treatment in pregnancy has not been evaluated outside of Africa. Low birthweight (LBW, <2,500 g) is common in Papua New Guinea (PNG) and contributing factors include malaria and reproductive tract infections.
From November 2009 to February 2013, we conducted a parallel group, randomised controlled trial in pregnant women (≤26 gestational weeks) in PNG. Sulphadoxine-pyrimethamine (1,500/75 mg) plus azithromycin (1 g twice daily for 2 days) (SPAZ) monthly from second trimester (intervention) was compared against sulphadoxine-pyrimethamine and chloroquine (450 to 600 mg, daily for three days) (SPCQ) given once, followed by SPCQ placebo (control). Women were assigned to treatment (1:1) using a randomisation sequence with block sizes of 32. Participants were blinded to assignments. The primary outcome was LBW. Analysis was by intention-to-treat.
Of 2,793 women randomised, 2,021 (72.4%) were included in the primary outcome analysis (SPCQ: 1,008; SPAZ: 1,013). The prevalence of LBW was 15.1% (305/2,021). SPAZ reduced LBW (risk ratio [RR]: 0.74, 95% CI: 0.60–0.91, P = 0.005; absolute risk reduction (ARR): 4.5%, 95% CI: 1.4–7.6; number needed to treat: 22), and preterm delivery (0.62, 95% CI: 0.43–0.89, P = 0.010), and increased mean birthweight (41.9 g, 95% CI: 0.2–83.6, P = 0.049). SPAZ reduced maternal parasitaemia (RR: 0.57, 95% CI: 0.35–0.95, P = 0.029) and active placental malaria (0.68, 95% CI: 0.47–0.98, P = 0.037), and reduced carriage of gonorrhoea (0.66, 95% CI: 0.44–0.99, P = 0.041) at second visit. There were no treatment-related serious adverse events (SAEs), and the number of SAEs (intervention 13.1% [181/1,378], control 12.7% [174/1,374], P = 0.712) and AEs (intervention 10.5% [144/1,378], control 10.8% [149/1,374], P = 0.737) was similar. A major limitation of the study was the high loss to follow-up for birthweight.
SPAZ was efficacious and safe in reducing LBW, possibly acting through multiple mechanisms including the effect on malaria and on sexually transmitted infections. The efficacy of SPAZ in the presence of resistant parasites and the contribution of AZ to bacterial antibiotic resistance require further study. The ability of SPAZ to improve pregnancy outcomes warrants further evaluation.
Trial registration NCT01136850 (06 April 2010).
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0258-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4305224  PMID: 25591391
Intermittent preventive treatment; Malaria; Pregnancy; Preterm delivery; Sexually transmitted infections
30.  Mortality and cancer in relation to ABO blood group phenotypes in the Golestan Cohort Study 
BMC Medicine  2015;13:8.
A few studies have shown an association between blood group alleles and vascular disease, including atherosclerosis, which is thought to be due to the higher level of von Willebrand factor in these individuals and the association of blood group locus variants with plasma lipid levels. No large population-based study has explored this association with overall and cause-specific mortality.
We aimed to study the association between ABO blood groups and overall and cause-specific mortality in the Golestan Cohort Study. In this cohort, 50,045 people 40- to 70-years old were recruited between 2004 and 2008, and followed annually to capture all incident cancers and deaths due to any cause. We used Cox regression models adjusted for age, sex, smoking, socioeconomic status, ethnicity, place of residence, education and opium use.
During a total of 346,708 person-years of follow-up (mean duration 6.9 years), 3,623 cohort participants died. Non-O blood groups were associated with significantly increased total mortality (hazard ratio (HR) = 1.09; 95% confidence interval (CI): 1.01 to 1.17) and cardiovascular disease mortality (HR = 1.15; 95% CI: 1.03 to 1.27). Blood group was not significantly associated with overall cancer mortality, but people with group A, group B, and all non-O blood groups combined had increased risk of incident gastric cancer. In a subgroup of cohort participants, we also showed higher plasma total cholesterol and low-density lipoprotein (LDL) in those with blood group A.
Non-O blood groups have an increased mortality, particularly due to cardiovascular diseases, which may be due to the effect of blood group alleles on blood biochemistry or their effect on von Willebrand factor and factor VIII levels.
Please see related commentary 10.1186/s12916-014-0250-y.
PMCID: PMC4295491  PMID: 25592833
Blood group; ABO; Rh; Mortality; Cancer; Cardiovascular disease
31.  The systemic influence of platelet-derived growth factors on bone marrow mesenchymal stem cells in fracture patients 
BMC Medicine  2015;13:6.
Fracture healing is a complex process regulated by a variety of cells and signalling molecules which act both locally and systemically. The aim of this study was to investigate potential changes in patients’ mesenchymal stem cells (MSCs) in the iliac crest (IC) bone marrow (BM) and in peripheral blood (PB) in relation to the severity of trauma and to correlate them with systemic changes reflective of inflammatory and platelet responses following fracture.
ICBM samples were aspirated from two trauma groups: isolated trauma and polytrauma (n = 8 and 18, respectively) at two time-points post-fracture and from non-trauma controls (n = 7). Matched PB was collected every other day for a minimum of 14 days. BM MSCs were enumerated using colony forming-fibroblast (CFU-F) assay and flow cytometry for the CD45-CD271+ phenotype.
Regardless of the severity of trauma, no significant increase or decrease in BM MSCs was observed following fracture and MSCs were not mobilised into PB. However, direct positive correlations were observed between changes in the numbers of aspirated BM MSCs and time-matched changes in their serum PDGF-AA and -BB. In vitro, patients’ serum induced MSC proliferation in a manner reflecting changes in PDGFs. PDGF receptors CD140a and CD140b were expressed on native CD45-CD271+ BM MSCs (average 12% and 64%, respectively) and changed over time in direct relationship with platelets/PDGFs.
Platelet lysates and other platelet-derived products are used to expand MSCs ex vivo. This study demonstrates that endogenous PDGFs can influence MSC responses in vivo. This indicates a highly dynamic, rather than static, MSC nature in humans.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0202-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4293103  PMID: 25583409
Mesenchymal stem cells; MSCs; Bone marrow; PDGF; Platelets
32.  Integrating big data and actionable health coaching to optimize wellness 
BMC Medicine  2015;13:4.
The Hundred Person Wellness Project (HPWP) is a 10-month pilot study of 100 ‘well’ individuals where integrated data from whole-genome sequencing, gut microbiome, clinical laboratory tests and quantified self measures from each individual are used to provide actionable results for health coaching with the goal of optimizing wellness and minimizing disease. In a commentary in BMC Medicine, Diamandis argues that HPWP and similar projects will likely result in ‘unnecessary and potential harmful over-testing’. We argue that this new approach will ultimately lead to lower costs, better healthcare, innovation and economic growth. The central points of the HPWP are: 1) it is focused on optimizing wellness through longitudinal data collection, integration and mining of individual data clouds, enabling development of predictive models of wellness and disease that will reveal actionable possibilities; and 2) by extending this study to 100,000 well people, we will establish multiparameter, quantifiable wellness metrics and identify markers for wellness to early disease transitions for most common diseases, which will ultimately allow earlier disease intervention, eventually transitioning the individual early on from a disease back to a wellness trajectory.
Please see related commentary:
PMCID: PMC4288554  PMID: 25575752
Wellness; Personalized medicine; Whole-genome sequencing; Health behavior change; Actionable; P4 Medicine; Systems medicine; Gut microbiome
33.  The hundred person wellness project and Google’s baseline study: medical revolution or unnecessary and potentially harmful over-testing? 
BMC Medicine  2015;13:5.
The Hundred Person Wellness Project is an ambitious pilot undertaking, which aims to intensely monitor 100 individuals over 10 months. Patients with abnormal findings will be treated, in hopes that this early intervention will avoid, or delay, symptomatic disease. Google’s “Baseline Study” is of similar scope and will enroll 10,000 people over 2 to 3 years. I here speculate that these approaches will likely not be effective in preventing disease, but instead, lead to unnecessary and potentially harmful interventions. Examples from the cancer screening experience over the last 30 years are provided, which show that intensive testing may uncover indolent disease or incidental findings which, when treated, may cause more harm than good. Additional examples show that aggressive treatments for cancer and other diseases do not always lead to better patient outcomes. I conclude that the recent advances in omics provide us with unprecedented opportunities for high content clinical testing, but such testing should be used with caution to avoid the harmful consequences of over-diagnosis and over-treatment. Despite the detailed rebuttals by Hood and colleagues in another commentary in BMC Medicine, time will show the actual benefits and harms of these ambitious initiatives.
Please see related commentary:
PMCID: PMC4288557  PMID: 25575898
Cancer screening; Incidental findings; Indolent disease; Over-diagnosis; Over-treatment; Population screening
34.  Nutrition, dietary interventions and prostate cancer: the latest evidence 
BMC Medicine  2015;13:3.
Prostate cancer (PCa) remains a leading cause of mortality in US men and the prevalence continues to rise world-wide especially in countries where men consume a ‘Western-style’ diet. Epidemiologic, preclinical and clinical studies suggest a potential role for dietary intake on the incidence and progression of PCa. 'This minireview provides an overview of recent published literature with regard to nutrients, dietary factors, dietary patterns and PCa incidence and progression. Low carbohydrates intake, soy protein, omega-3 (w-3) fat, green teas, tomatoes and tomato products and zyflamend showed promise in reducing PCa risk or progression. A higher saturated fat intake and a higher β-carotene status may increase risk. A ‘U’ shape relationship may exist between folate, vitamin C, vitamin D and calcium with PCa risk. Despite the inconsistent and inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa is promising. The combination of all the beneficial factors for PCa risk reduction in a healthy dietary pattern may be the best dietary advice. This pattern includes rich fruits and vegetables, reduced refined carbohydrates, total and saturated fats, and reduced cooked meats. Further carefully designed prospective trials are warranted.
PMCID: PMC4286914  PMID: 25573005
Diet; Prostate cancer; Nutrients; Dietary pattern; Lifestyle; Prevention; Treatment; Nutrition; Dietary intervention; Review
35.  Microbiology of diabetic foot infections: from Louis Pasteur to ‘crime scene investigation’ 
BMC Medicine  2015;13:2.
Were he alive today, would Louis Pasteur still champion culture methods he pioneered over 150 years ago for identifying bacterial pathogens? Or, might he suggest that new molecular techniques may prove a better way forward for quickly detecting the true microbial diversity of wounds? As modern clinicians faced with treating complex patients with diabetic foot infections (DFI), should we still request venerated and familiar culture and sensitivity methods, or is it time to ask for newer molecular tests, such as 16S rRNA gene sequencing? Or, are molecular techniques as yet too experimental, non-specific and expensive for current clinical use? While molecular techniques help us to identify more microorganisms from a DFI, can they tell us ‘who done it?’, that is, which are the causative pathogens and which are merely colonizers? Furthermore, can molecular techniques provide clinically relevant, rapid information on the virulence of wound isolates and their antibiotic sensitivities? We herein review current knowledge on the microbiology of DFI, from standard culture methods to the current era of rapid and comprehensive ‘crime scene investigation’ (CSI) techniques.
PMCID: PMC4286146  PMID: 25564342
Molecular diagnostics; Diabetic foot infection; Microbiology; Metagenomics; High-throughput sequencing
36.  Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD Statement 
BMC Medicine  2015;13:1.
Prediction models are developed to aid health care providers in estimating the probability or risk that a specific disease or condition is present (diagnostic models) or that a specific event will occur in the future (prognostic models), to inform their decision making. However, the overwhelming evidence shows that the quality of reporting of prediction model studies is poor. Only with full and clear reporting of information on all aspects of a prediction model can risk of bias and potential usefulness of prediction models be adequately assessed. The Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Initiative developed a set of recommendations for the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. This article describes how the TRIPOD Statement was developed. An extensive list of items based on a review of the literature was created, which was reduced after a Web-based survey and revised during a 3-day meeting in June 2011 with methodologists, health care professionals, and journal editors. The list was refined during several meetings of the steering group and in e-mail discussions with the wider group of TRIPOD contributors. The resulting TRIPOD Statement is a checklist of 22 items, deemed essential for transparent reporting of a prediction model study. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. The TRIPOD Statement is best used in conjunction with the TRIPOD explanation and elaboration document. To aid the editorial process and readers of prediction model studies, it is recommended that authors include a completed checklist in their submission (also available at
Editors’ note: In order to encourage dissemination of the TRIPOD Statement, this article is freely accessible on the Annals of Internal Medicine Web site ( and will be also published in BJOG, British Journal of Cancer, British Journal of Surgery, BMC Medicine, British Medical Journal, Circulation, Diabetic Medicine, European Journal of Clinical Investigation, European Urology, and Journal of Clinical Epidemiology. The authors jointly hold the copyright of this article. An accompanying Explanation and Elaboration article is freely available only on; Annals of Internal Medicine holds copyright for that article.
PMCID: PMC4284921  PMID: 25563062
Prediction models; Prognostic; Diagnostic; Model development; Validation; Transparency; Reporting
37.  Influenza vaccination in patients with end-stage renal disease: systematic review and assessment of quality of evidence related to vaccine efficacy, effectiveness, and safety 
BMC Medicine  2014;12(1):244.
Vaccination against influenza is recommended in patients with end-stage renal disease (ESRD). However, so far, no systematic review has summarized the available evidence on the effectiveness and safety of influenza vaccination in this patient group.
We conducted a systematic review and meta-analysis and assessed the quality of evidence using the GRADE methodology. We searched MEDLINE, EMBASE, Cochrane Library databases,, and reference lists for studies on efficacy, effectiveness, and/or safety of seasonal influenza vaccination in patients with ESRD receiving dialysis. All reported clinical outcomes were considered, including all-cause mortality, cardiac death, infectious death, all-cause hospitalization, hospitalization due to influenza or pneumonia, hospitalization due to bacteremia, viremia, or septicemia, hospitalization due to respiratory infection, ICU admission, and influenza-like illness.
Five observational studies and no randomized-controlled trial were identified. In four studies, risk of bias was high regarding all reported outcomes. Strong residual confounding was likely to be present in one study reporting on three outcomes, as indicated by significant protective effects of vaccination outside influenza seasons. Therefore, the statistically significant protective effects on all-cause mortality (vaccine effectiveness (VE), 32%; 95% CI, 24–39%), cardiac death (VE, 16%; 95% CI, 1–29%), hospitalization due to influenza or pneumonia (VE, 14%; 95% CI, 7–20%), ICU admission (VE, 81%; 95% CI, 63–86%), and influenza-like illness (VE, 12%; 95% CI, 10–14%) have to be taken with caution. According to GRADE, the quality of the body of evidence was considered very low for all outcomes. No study reported on laboratory-confirmed influenza virus infections or on safety endpoints.
Evidence on the protective effects of influenza vaccination in patients with ESRD is limited and of very low quality. Since VE estimates in the available literature are prone to unmeasured confounding, studies using randomization or quasi-experimental designs are needed to determine the extent by which vaccination prevents influenza and related clinical outcomes in this at-risk population. However, given the high rates of health-endangering events in these patients, even a low VE can be considered as sufficient to recommend annual influenza vaccination.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0244-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4298993  PMID: 25523432
Dialysis; Effectiveness; End-stage renal disease; GRADE; Influenza; Systematic review; Vaccine
38.  Prevalence, distribution, and social determinants of tobacco use in 30 sub-Saharan African countries 
BMC Medicine  2014;12(1):243.
Although the Framework Convention on Tobacco Control prioritizes monitoring of tobacco use by population-based surveys, information about the prevalence and patterns of tobacco use in sub-Saharan Africa is limited. We provide country-level prevalence estimates for smoking and smokeless tobacco (SLT) use and assess their social determinants.
We analyzed population-based data of the most recent Demographic Health Surveys performed between 2006 and 2013 involving men and women in 30 sub-Saharan African countries. Weighted country-level prevalence rates were estimated for ‘current smoking’ (cigarettes, pipe, cigars, etc.) and ‘current SLT use’ (chewing, snuff, etc.). From the pooled datasets for men and women, social determinants of smoking and SLT use were assessed through multivariate analyses using a dummy country variable as a control and by including a within-country sample weight for each country.
Among men, smoking prevalence rates were high in Sierra Leone (37.7%), Lesotho (34.1%), and Madagascar (28.5%); low (<10%) in Ethiopia, Benin, Ghana, Nigeria, and Sao Tome & Principe; the prevalence of SLT use was <10% in all countries except for Madagascar (24.7%) and Mozambique (10.9%). Among women, smoking and SLT prevalence rates were <5% in most countries except for Burundi (9.9%), Sierra Leone (6%), and Namibia (5.9%) (smoking), and Madagascar (19.6%) and Lesotho (9.1%) (SLT use). The proportion of females who smoked was lower than SLT users in most countries. Older age was strongly associated with both smoking and SLT use among men and women. Smoking among both men and women was weakly associated, but SLT use was strongly associated, with education. Similarly, smoking among men and women was weakly associated, but SLT use was strongly associated, with the wealth index. Smoking and SLT use were also associated with marital status among both men and women, as well as with occupation (agriculturists and unskilled workers).
Prevalence of smoking among women was much lower than in men, although the social patterns of tobacco use were similar to those in men. Tobacco control strategies should target the poor, not/least educated, and agricultural and unskilled workers, who are the most vulnerable social groups in sub-Saharan Africa.
PMCID: PMC4296681  PMID: 25518855
39.  [No title available] 
PMCID: PMC4292997  PMID: 25515680
40.  [No title available] 
PMCID: PMC4293815  PMID: 25511686
41.  Sixty years trying to define the malaria burden in Africa: have we made any progress? 
BMC Medicine  2014;12(1):227.
Controversy surrounds the precise numbers of malaria deaths and clinical episodes in Africa. This would not have surprised malariologists working in Africa 60 years ago as they began to unravel the enigma that is ‘malaria’. Malaria is a complex disease manifesting as a multitude of symptoms, degrees of severity and indirect morbid consequences. Clinical immunity develops quickly and the presence of infection cannot always be used to distinguish between malaria and other illnesses. During the 1950s and 1960s parasite prevalence was used in preference to statistics on malaria mortality and morbidity. An argument is made for a resurrection of this measure of the quantity of malaria across Africa as a more reliable means to understand the impact of control.
PMCID: PMC4265359  PMID: 25495076
Malaria mortality; Morbidity; Parasitemia; Measurement; Monitoring; Africa
42.  Diagnosis and treatment of hyponatremia: a systematic review of clinical practice guidelines and consensus statements 
BMC Medicine  2014;12(1):1.
Hyponatremia is a common electrolyte disorder. Multiple organizations have published guidance documents to assist clinicians in managing hyponatremia. We aimed to explore the scope, content, and consistency of these documents.
We searched MEDLINE, EMBASE, and websites of guideline organizations and professional societies to September 2014 without language restriction for Clinical Practice Guidelines (defined as any document providing guidance informed by systematic literature review) and Consensus Statements (any other guidance document) developed specifically to guide differential diagnosis or treatment of hyponatremia. Four reviewers appraised guideline quality using the 23-item AGREE II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Total scores were calculated as standardized averages by domain.
We found ten guidance documents; five clinical practice guidelines and five consensus statements. Overall, quality was mixed: two clinical practice guidelines attained an average score of >50% for all of the domains, three rated the evidence in a systematic way and two graded strength of the recommendations. All five consensus statements received AGREE scores below 60% for each of the specific domains.
The guidance documents varied widely in scope. All dealt with therapy and seven included recommendations on diagnosis, using serum osmolality to confirm hypotonic hyponatremia, and volume status, urinary sodium concentration, and urinary osmolality for further classification of the hyponatremia. They differed, however, in classification thresholds, what additional tests to consider, and when to initiate diagnostic work-up. Eight guidance documents advocated hypertonic NaCl in severely symptomatic, acute onset (<48 h) hyponatremia. In chronic (>48 h) or asymptomatic cases, recommended treatments were NaCl 0.9%, fluid restriction, and cause-specific therapy for hypovolemic, euvolemic, and hypervolemic hyponatremia, respectively. Eight guidance documents recommended limits for speed of increase of sodium concentration, but these varied between 8 and 12 mmol/L per 24 h. Inconsistencies also existed in the recommended dose of NaCl, its initial infusion speed, and which second line interventions to consider.
Current guidance documents on the assessment and treatment of hyponatremia vary in methodological rigor and recommendations are not always consistent.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0231-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4276109  PMID: 25539784
Clinical practice guideline; Hyponatremia; Systematic review
43.  Why public health people are more worried than excited over e-cigarettes 
BMC Medicine  2014;12(1):226.
The research field on e-cigarettes is characterized by severe methodological problems, severe conflicts of interest, relatively few and often small studies, inconsistencies and contradictions in results, and a lack of long-term follow-up. Therefore, no firm conclusions can be drawn on the harm of e-cigarettes, but they can hardly be called safe. Experimental studies indicate negative health effects and, amongst others, the major ingredient propylene glycol warrants concern. Growing evidence raises doubt about the efficacy of e-cigarettes as a smoking cessation aid. Unfortunately, it seems that many smokers use e-cigarettes with the intention to quit but switch to long-term use of e-cigarettes or dual use. Use is spreading rapidly to minors, ex-smokers, and never-smokers. It is questionable whether the potential health benefits obtained by some smokers outweigh the potential harm by use of non-smokers, of undermining of complete cessation, smokers’ dual use, and of eventual re-normalization of smoking. Even if e-cigarettes are significantly less harmful than conventional cigarettes, the product may have a very negative impact on public health if its use is spread to a large part of the population.
PMCID: PMC4260246  PMID: 25488431
Electronic cigarettes; ENDS; Harm reduction; Public health; Smoking; Vaping
44.  Electronic cigarettes have a potential for huge public health benefit 
BMC Medicine  2014;12(1):225.
Although there is no doubt that smokers switching to electronic cigarettes (EC) substantially reduce the risk to their health, some tobacco control activists and health organisations discourage smokers from using EC and lobby policy makers to reduce EC use by draconian regulation.
The hostility to EC may be related to a moral belief that nicotine use should be eradicated rather than allowed to morph into a relatively harmless activity. If EC are allowed to compete with cigarettes and develop further, smoking is likely to all but disappear. Discouraging smokers from making the switch and reducing EC competitiveness with cigarettes by unwarranted regulation will delay this opportunity or squander it altogether.
In fact, there is now sufficient evidence available for health professionals to recommend to smokers who cannot stop smoking with existing treatments or do not want to do so, to try several types of e-cigarettes to see if they can find one meeting their needs.
PMCID: PMC4260378  PMID: 25491742
E-cigarettes; Nicotine; Public health; Controversy
45.  Better management of multimorbidity: a critical look at the ‘Ariadne principles’ 
BMC Medicine  2014;12(1):222.
Primary care clinicians and researchers are growing increasingly aware of the prevalence of multimorbidity among long-term conditions, and the impact on patient experience, health, and utilisation of care. The correspondence paper by Muth et al. entitled ‘The Ariadne principles: how to handle multimorbidity in primary care consultations’ outlines new thinking on a better way to manage the challenges of decision-making in multimorbidity. The paper highlights the importance of shared treatment goals as a fundamental basis for more effective management. Although a welcome contribution to the literature, the principles raise a number of challenges: the complexities of achieving effective patient-centred assessment and goal-setting; how best to encourage implementation of new practices; and the current state of the evidence around multimorbidity and its management.
Please see related article:
PMCID: PMC4258943  PMID: 25484120
Assessment; Multimorbidity; Treatment burden; Treatment goals
46.  The Ariadne principles: how to handle multimorbidity in primary care consultations 
BMC Medicine  2014;12(1):223.
Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient’s conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient’s preferences – his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.
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Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0223-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4259090  PMID: 25484244
Comorbidity; Decision making; General practice; Goal-oriented care; Multimorbidity; Patient-centered care; Patient care planning; Patient preference; Primary care
47.  The burden of disease in Spain: results from the global burden of disease study 2010 
BMC Medicine  2014;12(1):2.
We herein evaluate the Spanish population’s trends in health burden by comparing results of two Global Burden of Diseases, Injuries, and Risk Factors Studies (the GBD studies) performed 20 years apart.
Data is part of the GBD study for 1990 and 2010. We present results for mortality, years of life lost (YLLs), years lived with disability, and disability-adjusted life years (DALYs) for the Spanish population. Uncertainty intervals for all measures have been estimated.
Non-communicable diseases accounted for 3,703,400 (95% CI 3,648,270–3,766,720) (91.3%) of 4,057,400 total deaths, in the Spanish population. Cardiovascular and circulatory diseases were the main cause of mortality among non-communicable diseases (34.7% of total deaths), followed by neoplasms (27.1% of total deaths). Neoplasms, cardiovascular and circulatory diseases, and chronic respiratory diseases were the top three leading causes for YLLs. The most important causes of DALYs in 2010 were neoplasms, cardiovascular and circulatory diseases, musculoskeletal disorders, and mental and behavioral disorders.
Mortality and disability in Spain have become even more linked to non-communicable diseases over the last years, following the worldwide trends. Cardiovascular and circulatory diseases, neoplasms, mental and behavioral disorders, and neurological disorders are the leading causes of mortality and disability. Specific focus is needed from health care providers and policy makers to develop health promotion and health education programs directed towards non-communicable disorders.
PMCID: PMC4276068
Disability-adjusted life years; Global Burden of Diseases, Injuries, and Risk Factors Studies; Spain; Mortality; Years lived with disability; Years of life lost
48.  DNA methylation profiling reveals novel diagnostic biomarkers in renal cell carcinoma 
BMC Medicine  2014;12(1):235.
Renal cell carcinoma (RCC) is the tenth most commonly diagnosed cancer in the United States. While it is usually lethal when metastatic, RCC is successfully treated with surgery when tumors are confined to the kidney and have low tumor volume. Because most early stage renal tumors do not result in symptoms, there is a strong need for biomarkers that can be used to detect the presence of the cancer as well as to monitor patients during and after therapy.
We examined genome-wide DNA methylation alterations in renal cell carcinomas of diverse histologies and benign adjacent kidney tissues from 96 patients.
We observed widespread methylation differences between tumors and benign adjacent tissues, particularly in immune-, G-protein coupled receptor-, and metabolism-related genes. Additionally, we identified a single panel of DNA methylation biomarkers that reliably distinguishes tumor from benign adjacent tissue in all of the most common kidney cancer histologic subtypes, and a second panel does the same specifically for clear cell renal cell carcinoma tumors. This set of biomarkers were validated independently with excellent performance characteristics in more than 1,000 tissues in The Cancer Genome Atlas clear cell, papillary, and chromophobe renal cell carcinoma datasets.
These DNA methylation profiles provide insights into the etiology of renal cell carcinoma and, most importantly, demonstrate clinically applicable biomarkers for use in early detection of kidney cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0235-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4265327  PMID: 25472429
Cancer; Diagnostic biomarker; DNA methylation; Kidney; Renal cell carcinoma
49.  miRNAs can be generally associated with human pathologies as exemplified for miR-144* 
BMC Medicine  2014;12(1):224.
miRNA profiles are promising biomarker candidates for a manifold of human pathologies, opening new avenues for diagnosis and prognosis. Beyond studies that describe miRNAs frequently as markers for specific traits, we asked whether a general pattern for miRNAs across many diseases exists.
We evaluated genome-wide circulating profiles of 1,049 patients suffering from 19 different cancer and non-cancer diseases as well as unaffected controls. The results were validated on 319 individuals using qRT-PCR.
We discovered 34 miRNAs with strong disease association. Among those, we found substantially decreased levels of hsa-miR-144* and hsa-miR-20b with AUC of 0.751 (95% CI: 0.703–0.799), respectively. We also discovered a set of miRNAs, including hsa-miR-155*, as rather stable markers, offering reasonable control miRNAs for future studies. The strong downregulation of hsa-miR-144* and the less variable pattern of hsa-miR-155* has been validated in a cohort of 319 samples in three different centers. Here, breast cancer as an additional disease phenotype not included in the screening phase has been included as the 20th trait.
Our study on 1,368 patients including 1,049 genome-wide miRNA profiles and 319 qRT-PCR validations further underscores the high potential of specific blood-borne miRNA patterns as molecular biomarkers. Importantly, we highlight 34 miRNAs that are generally dysregulated in human pathologies. Although these markers are not specific to certain diseases they may add to the diagnosis in combination with other markers, building a specific signature. Besides these dysregulated miRNAs, we propose a set of constant miRNAs that may be used as control markers.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0224-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4268797  PMID: 25465851
Bioinformatics; Biomarker; Microarray; miRNA
50.  Towards a framework for business model innovation in health care delivery in developing countries 
BMC Medicine  2014;12(1):233.
Uncertainty and information asymmetries in health care are the basis for a supply-sided mindset in the health care industry and for a business model for hospitals and doctor’s practices; these two models have to be challenged with business model innovation. The three elements which ensure this are standardizability, separability, and patient-centeredness. As scientific evidence advances and outcomes are more predictable, standardization is more feasible. If a standardized process can also be separated from the hospital and doctor’s practice, it is more likely that innovative business models emerge. Regarding patient centeredness, it has to go beyond the oversimplifying approach to patient satisfaction with amenities and interpersonal skills of staff, to include the design of structure and processes starting from patients’ needs, expectations, and preferences. Six business models are proposed in this article, including those of hospitals and doctor’s practices.
Unravelling standardized and separable processes from the traditional hospital setting will increase hospital expenditure, however, the new business models would reduce expenses. The net effect on efficiency could be argued to be positive. Regarding equity in access to high-quality care, most of the innovations described along these business models have emerged in developing countries; it is therefore reasonable to be optimistic regarding their impact on access by the poor. These models provide a promising route to achieve sustainable universal access to high quality care by the poor.
Business model innovation is a necessary step to guarantee sustainability of health care systems; standardizability, separability, and patient-centeredness are key elements underlying the six business model innovations proposed in this article.
PMCID: PMC4253002  PMID: 25466223
Business model innovation; Quality care; Standardization; Separability; Patient-centeredness

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