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1.  Vascular risk factors and Alzheimer’s disease 
BMC Medicine  2014;12(1):218.
Vascular factors are now established risk factors for cognitive decline, both for dementia and its two main subtypes: Alzheimer’s disease (AD) and vascular dementia. Their impact likely goes beyond causing an increase in concurrent vascular pathology, since they have been associated with increasing the risk of degenerative Alzheimer (plaque and tangle) pathology, either by increasing its rate of formation or reducing elimination from the brain, or a mixture of the two. A comprehensive series of reviews published in BMC Medicine, investigates the relationship between AD and cardiovascular diseases and risk factors from a clinical, pathological and therapeutic perspective. Whilst links between vascular factors and AD have clearly been demonstrated at both the clinical and pathological level, the nature of the relationship remains to be fully established and there is a lack of high quality treatment studies examining the extent to which vascular risk modification alters AD disease course. Further longitudinal mechanistic and therapeutic studies are required, especially to determine whether treatment of vascular risk can prevent or delay the onset of AD and/or reduce its rate of clinical progression.
doi:10.1186/s12916-014-0218-y
PMCID: PMC4226870  PMID: 25385509
Alzheimer’s disease; Vascular risk; Stroke; Dementia; Risk factors; Prevention; Treatment; Hypertension
2.  [No title available] 
PMCID: PMC4289388  PMID: 25156753
3.  Does reductio ad absurdum have a place in evidence-based medicine? 
BMC Medicine  2014;12:106.
In a meta-analysis published in BMC Medicine, we explored whether evidence-based medicine can actually be sure that ‘sucrose = sucrose’ in the treatment of depression. This paper, based upon a reductio ad absurdum, addressed an epistemological question using a ‘scientific’ approach, and could be disconcerting as suggested by Cipriani and Geddes’ commentary. However, most papers are based upon a mixture of observations and discussions about sense and meaning. Ultimately, there is nothing more than a story, told with words or numbers. Randomised controlled trials provide information about average patients that do not exist. These results ignores an entire segment of therapeutics that plays a crucial role, namely care. This information is usually set out using a ‘grammar’ that is ambiguous, since statistical tests of hypothesis have raised epistemological questions that are not as yet solved. Moreover, many of these stories remain untold, and unpublished. For these reasons evidence-based medicine is a vehicle for many paradoxes and controversies. Reductio ad absurdum can be useful in precisely this case, to underline how and why the medical literature can sometimes give an impression of absurdity of this sort. Even if the data analysis in our paper was rather rhetorical, we agree that it should comply with the classic standards of reporting and we provide the important extra data that Cipriani and Geddes have requested.
Please see related articles: http://www.biomedcentral.com/1741-7015/11/230 and http://www.biomedcentral.com/1741-7015/12/105.
doi:10.1186/1741-7015-12-106
PMCID: PMC4070092  PMID: 24962765
Epistemology; Evidence-based medicine; Publication bias; Reductio ad absurdum; Statistics
4.  Do statins increase and Mediterranean diet decrease the risk of breast cancer? 
BMC Medicine  2014;12:94.
Background
Physical exercise and healthy dietary habits are recommended to prevent breast cancer.
Discussion
Increased intake of omega-3 fatty acids associated with decreased omega-6 - resulting in higher omega-3 to omega-6 ratio compared with Western-type diet - is inversely associated with breast cancer risk. The modernized Mediterranean diet with high omega-3 to omega-6 ratio, high fiber and polyphenol intake, and consumption of low-glycemic index foods reduces overall cancer risk and specifically breast cancer risk. It has been suggested that consuming no more than one alcoholic drink per day, preferably wine, is preferable. Eliminating environmental contaminants, including endocrine disruptors, and favoring organic foods to increase polyphenol intake and the omega-3 to omega-6 ratios were also shown to be beneficial. Cholesterol-lowering statins may decrease antitumor defenses; are toxic for the mitochondria; decrease the omega-3 to omega-6 ratio; increase body mass index, insulin resistance and diabetic risk; and have been associated with an increased breast cancer risk.
Summary
Therefore, as well as making lifestyle changes to decrease breast cancer risk, we argue that physicians should carefully consider (and often avoid) therapies that may increase breast cancer or diabetes risk in high-risk women and women who wish to decrease their breast cancer risk.
doi:10.1186/1741-7015-12-94
PMCID: PMC4229881  PMID: 24903828
Cholesterol; Diabetes; Endocrine disruptors; Insulin resistance; Organic foods; Polyphenols; Statins
5.  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
6.  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
7.  The Lives Saved Tool (LiST) as a model for diarrhea mortality reduction 
BMC Medicine  2014;12:70.
Background
Diarrhea is a leading cause of morbidity and mortality among children under five years of age. The Lives Saved Tool (LiST) is a model used to calculate deaths averted or lives saved by past interventions and for the purposes of program planning when costly and time consuming impact studies are not possible.
Discussion
LiST models the relationship between coverage of interventions and outputs, such as stunting, diarrhea incidence and diarrhea mortality. Each intervention directly prevents a proportion of diarrhea deaths such that the effect size of the intervention is multiplied by coverage to calculate lives saved. That is, the maximum effect size could be achieved at 100% coverage, but at 50% coverage only 50% of possible deaths are prevented. Diarrhea mortality is one of the most complex causes of death to be modeled. The complexity is driven by the combination of direct prevention and treatment interventions as well as interventions that operate indirectly via the reduction in risk factors, such as stunting and wasting. Published evidence is used to quantify the effect sizes for each direct and indirect relationship. Several studies have compared measured changes in mortality to LiST estimates of mortality change looking at different sets of interventions in different countries. While comparison work has generally found good agreement between the LiST estimates and measured mortality reduction, where data availability is weak, the model is less likely to produce accurate results. LiST can be used as a component of program evaluation, but should be coupled with more complete information on inputs, processes and outputs, not just outcomes and impact.
Summary
LiST is an effective tool for modeling diarrhea mortality and can be a useful alternative to large and expensive mortality impact studies. Predicting the impact of interventions or comparing the impact of more than one intervention without having to wait for the results of large and expensive mortality studies is critical to keep programs focused and results oriented for continued reductions in diarrhea and all-cause mortality among children under five years of age.
doi:10.1186/1741-7015-12-70
PMCID: PMC4234397  PMID: 24779400
Diarrhea; Modeling; Enteric diseases; Child health; Maternal health
8.  The intergenerational effects of war on the health of children 
BMC Medicine  2014;12:57.
Background
The short- and medium-term effects of conflict on population health are reasonably well documented. Less considered are its consequences across generations and potential harms to the health of children yet to be born.
Discussion
Looking first at the nature and effects of exposures during conflict, and then at the potential routes through which harm may propagate within families, we consider the intergenerational effects of four features of conflict: violence, challenges to mental health, infection and malnutrition. Conflict-driven harms are transmitted through a complex permissive environment that includes biological, cultural and economic factors, and feedback loops between sources of harm and weaknesses in individual and societal resilience to them. We discuss the multiplicative effects of ongoing conflict when hostilities are prolonged.
Summary
We summarize many instances in which the effects of war can propagate across generations. We hope that the evidence laid out in the article will stimulate research and – more importantly – contribute to the discussion of the costs of war; particularly in the longer-term in post-conflict situations in which interventions need to be sustained and adapted over many years.
doi:10.1186/1741-7015-12-57
PMCID: PMC3997818  PMID: 24694212
War; Conflict; Developmental origins; Children; Mental health
9.  Open questions in autoimmunity: discussions from the 2013 Controversies in Rheumatology and Autoimmunity Meeting 
BMC Medicine  2014;12:50.
The recent CORA (Controversies in Rheumatology and Autoimmunity) meeting held in 2013 represented a unique opportunity for rheumatologists to address several topics. Among these, four topics include: (i) the role of epigenetic changes in the pathogenesis of rheumatoid arthritis (RA), as shown by studies in monozygotic twins; (ii) the cardiovascular and atherosclerotic risk in patients with RA treated with biologics; (iii) the use of new biomarkers for the diagnosis and follow-up of RA and other autoimmune diseases, as represented by the new automatic machines for anti-nuclear antibodies detection, or ultrasound imaging to follow RA progression; and (iv) the latest guidelines on how to use and manage biologic therapies in RA and other autoimmune diseases, such as lupus. In summary, we will herein present these topics of discussion and underline the conclusions obtained by rheumatologists during the 2013 CORA Meeting.
doi:10.1186/1741-7015-12-50
PMCID: PMC3984700  PMID: 24642104
Anti-nuclear antibodies; Atherosclerosis; Cardiovascular system; DNA methylation; microRNA; Rheumatoid arthritis; Ultrasonography
10.  Comment: Head and Neck Oncology 
BMC Medicine  2014;12:24.
This comment relates to articles published in archived content of the journal Head and Neck Oncology and is not related to the content of BMC Medicine in any way.
doi:10.1186/1741-7015-12-24
PMCID: PMC3959645  PMID: 24499430
11.  Reliable direct measurement of causes of death in low- and middle-income countries 
BMC Medicine  2014;12:19.
Background
Most of the 48 million annual deaths in low- and middle-income countries (LMICs) occur without medical attention at the time of death so that the causes of death (COD) are largely unknown. A review of low-cost methods of obtaining nationally representative COD data is timely.
Discussion
Despite clear historic evidence of their usefulness, most LMICs lack reliable nationally representative COD data. Indirect methods to estimate COD for most countries are inadequate, mainly because they currently rely on an average ratio of 1 nationally representative COD to every 850 estimated deaths in order to measure the cause of 25 million deaths across 110 LMICs. Direct measurement of COD is far more reliable and relevant for country priorities. Five feasible methods to expand COD data are: sample registration systems (which form the basis for the ongoing Million Death Study in India; MDS); strengthening the INDEPTH network of 42 demographic surveillance sites; adding retrospective COD surveys to the demographic household and health surveys in 90 countries; post-census retrospective mortality surveys; and for smaller countries, systematic assembly of health records. Lessons learned from the MDS, especially on low-cost, high-quality methods of verbal autopsy, paired with emerging use of electronic data capture and other innovations, can make COD systems low-cost and relevant for a wide range of childhood and adult conditions.
Summary
Low-cost systems to obtain and report CODs are possible. If implemented widely, COD systems could identify disease control priorities, help detect emerging epidemics, enable evaluation of disease control programs, advance indirect methods, and improve the accountability for expenditures of disease control programs.
doi:10.1186/1741-7015-12-19
PMCID: PMC3912491  PMID: 24495839
Causes of death; Cause of death statistics; Mortality; Vital statistics; Verbal autopsy; Sample registration system
12.  Integrated care as a means to improve primary care delivery for adults and adolescents in the developing world: a critical analysis of Integrated Management of Adolescent and Adult Illness (IMAI) 
BMC Medicine  2014;12:6.
Background
More than three decades after the 1978 Declaration of Alma-Ata enshrined the goal of ‘health for all’, high-quality primary care services remain undelivered to the great majority of the world’s poor. This failure to effectively reach the most vulnerable populations has been, in part, a failure to develop and implement appropriate and effective primary care delivery models. This paper examines a root cause of these failures, namely that the inability to achieve clear and practical consensus around the scope and aims of primary care may be contributing to ongoing operational inertia. The present work also examines integrated models of care as a strategy to move beyond conceptual dissonance in primary care and toward implementation. Finally, this paper examines the strengths and weaknesses of a particular model, the World Health Organization’s Integrated Management of Adolescent and Adult Illness (IMAI), and its potential as a guidepost toward improving the quality of primary care delivery in poor settings.
Discussion
Integration and integrated care may be an important approach in establishing a new paradigm of primary care delivery, though overall, current evidence is mixed. However, a number of successful specific examples illustrate the potential for clinical and service integration to positively impact patient care in primary care settings. One example deserving of further examination is the IMAI, developed by the World Health Organization as an operational model that integrates discrete vertical interventions into a comprehensive delivery system encompassing triage and screening, basic acute and chronic disease care, basic prevention and treatment services, and follow-up and referral guidelines. IMAI is an integrated model delivered at a single point-of-care using a standard approach to each patient based on the universal patient history and physical examination. The evidence base on IMAI is currently weak, but whether or not IMAI itself ultimately proves useful in advancing primary care delivery, it is these principles that should serve as the basis for developing a standard of integrated primary care delivery for adults and adolescents that can serve as the foundation for ongoing quality improvement.
Summary
As integrated primary care is the standard of care in the developed world, so too must we move toward implementing integrated models of primary care delivery in poorer settings. Models such as IMAI are an important first step in this evolution. A robust and sustained commitment to innovation, research and quality improvement will be required if integrated primary care delivery is to become a reality in developing world.
doi:10.1186/1741-7015-12-6
PMCID: PMC3895758  PMID: 24423387
Primary care; Integrated management; Integration; Quality improvement; Health care delivery; Health systems; IMAI
13.  BMC Medicine: a decade of open access medical research 
BMC Medicine  2014;12:4.
On 24 November 2003, BMC Medicine published its first article. Ten years and over 900 articles later we look back at some of the most notable milestones for the journal and discuss advances and innovations in medicine over the last decade. Our editorial board members, Leslie Biesecker, Thomas Powles, Chris Del Mar, Robert Snow and David Moher, also comment on the changes they expect to see in their fields over the coming years.
doi:10.1186/1741-7015-12-4
PMCID: PMC3892052  PMID: 24405514
Open access; Translational medicine; Clinical oncology; Evidence-based medicine; Reporting guidelines
14.  Is there a link between the extracranial venous system and central nervous system pathology? 
BMC Medicine  2013;11:259.
The extracranial venous system is complex and variable between individuals. Until recently, these variations were acknowledged as developmental variants and were not considered pathological findings. However, in the last decade, the presence and severity of uni- or bi-lateral jugular venous reflux (JVR) was linked to several central nervous system (CNS) disorders such as transient global amnesia, transient monocular blindness, cough headache, primary exertional headache and, most recently, to Alzheimer's disease. The most recent introduction of a composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI), which was originally linked to multiple sclerosis, increased the interest in better understanding the role of the extracranial venous system in the pathophysiology of CNS disorders. The ultimate cause-consequence relationship between these conditions and CNS disorders has not been firmly established and further research is needed. The purpose of this article collection in BMC Medicine and BMC Neurology is to synthesize current concepts and most recent findings concerning the evaluation, etiology, pathophysiology and clinical relevance of the potential involvement of the extracranial venous system in the pathology of multiple CNS disorders and in aging.
Please see related debate: http://www.biomedcentral.com/1741-7015/11/260.
doi:10.1186/1741-7015-11-259
PMCID: PMC3866248  PMID: 24344725
Extracranial venous system; Jugular venous reflux; Chronic cerebrospinal venous insufficiency; CNS pathology; Aging
15.  Allergen immunotherapy and allergic rhinitis: false beliefs 
BMC Medicine  2013;11:255.
Background
Over the last 100 years, several persistent misconceptions or ‘false beliefs’ have built up around allergen immunotherapy and its use in allergic rhinitis. This is perhaps because enthusiastic physicians administered complex allergen extracts to a diverse population of patients suffering from heterogeneous atopic conditions. Here, we review evidence that counters seven of these ‘false beliefs.’
Discussion
1. The symptoms of allergic rhinitis can be more heterogeneous, more severe and more troublesome in everyday life than many physicians believe. Large-scale epidemiological surveys show that the majority of allergic rhinitis patients have at least one symptom severe enough to interfere with sleep quality, productivity and/or well-being. 2. Allergen immunotherapy is not necessarily suitable for all allergic rhinitis patients (notably those with mild symptoms). Recent evidence from double-blind, placebo-controlled, randomized clinical trials suggests that the more severe the disease, the greater the treatment effect. 3. Allergen immunotherapy is often accused of lack of efficacy (relative to pharmacotherapy, for example). However, there are now many meta-analyses, systematic reviews and high-quality clinical trials that find overwhelmingly in favor of the efficacy of allergen immunotherapy (including sublingual formulations) in allergic rhinitis induced by pollen and, increasingly, other allergens. 4. Natural-exposure and challenge-chamber trials have shown that symptom relief may become apparent within months or even weeks of the initiation of allergen immunotherapy. 5. In pollen-induced allergic rhinitis, several years of subcutaneous or sublingual allergen immunotherapy are associated with sustained clinical efficacy after subsequent treatment cessation – confirming the disease-modifying nature of this therapy. 6. Most patients seeking treatment for allergic rhinitis are polysensitized, and allergen immunotherapy has proven efficacy in large, robust clinical trials in these groups. Polysensitization is not a contraindication to allergen immunotherapy. 7. Sublingual allergen immunotherapy is safe for home administration. A recent review calculated that 1 billion doses were administered worldwide between 2000 and 2010 and found that the 11 case reports of anaphylaxis (all non-fatal) corresponded to non-standard practice.
Summary
Modern, evidence-based medicine has generated more than enough robust evidence to remove misconceptions about allergen immunotherapy and allergic rhinitis.
doi:10.1186/1741-7015-11-255
PMCID: PMC4029303  PMID: 24314210
Allergen; Immunotherapy; Specific; Sublingual; Subcutaneous; Desensitization; Vaccination
16.  What if HIV were unable to develop resistance against a new therapeutic agent? 
BMC Medicine  2013;11:249.
Background
The HIV integrase inhibitor, Dolutegravir (DTG), was recently approved by the Food and Drug Administration in the United States and is the only HIV drug that has not selected for resistance mutations in the clinic when used as part of first-line therapy. This has led to speculation that DTG might have a higher genetic barrier for the development of drug resistance than the other compounds that are used in therapy.
Discussion
In this Opinion article, we speculate that this is due to greatly diminished replication capacity on the part of viruses that might become resistant to DTG when the drug is used in initial therapy and that DTG might be able to be used in HIV prevention and eradication strategies. We also note that no compensatory mutation that might restore viral replication fitness to HIV in the aftermath of the appearance of a single drug resistance mutation has yet to be observed.
Summary
DTG is a valuable addition to the anti-HIV armamentarium of drugs and its long-term utility may potentially exceed its obvious use in treatment of HIV disease.
doi:10.1186/1741-7015-11-249
PMCID: PMC3842747  PMID: 24267867
Human immunodeficiency virus type 1; Integrase inhibitors; Antiretroviral therapy; Dolutegravir; HIV prevention strategies; Viral fitness; Drug resistance
17.  Cognitive health begins at conception: addressing dementia as a lifelong and preventable condition 
BMC Medicine  2013;11:246.
Background
Dementia is a major public health problem that poses an increasing burden on the health and wealth of societies worldwide. Because the efficacy of current treatments is limited, increasing efforts are required to prevent the diseases that cause dementia.
Discussion
We consider the evidence that lifelong prevention strategies may be an effective way to tackle the national burden of dementia in the absence of a cure. The links between lifestyle and cardiovascular disease are widely understood and accepted, but health professionals and patients remain unconvinced about the extent to which risk for dementia can be modified. However, there is strong evidence that at least half of risk for dementia is attributable to lifestyle factors such as diet, exercise and smoking. Moreover, the disease processes that result in dementia develop over several decades, implying that attempts to ameliorate them need to start early in life. Some modifiable risk factors for dementia act from the earliest stages of life, including in utero.
Summary
Rebalancing efforts from the development of treatments to increased emphasis on prevention may be an alternative means to reducing the impact of dementia on society.
doi:10.1186/1741-7015-11-246
PMCID: PMC3832877  PMID: 24252204
Dementia; Alzheimer’s disease; Prevention; Epidemiology
18.  The link between chronic periodontitis and COPD: a common role for the neutrophil? 
BMC Medicine  2013;11:241.
Background
The possible relationship between chronic inflammatory diseases and their co-morbidities has become an increasing focus of research. Both chronic periodontitis and chronic obstructive pulmonary disease are neutrophilic, inflammatory conditions characterized by the loss of local connective tissue. Evidence suggests an association and perhaps a causal link between the two diseases. However, the nature of any relationship between them is unclear, but if pathophysiologically established may have wide-reaching implications for targeted treatments to improve outcomes and prognosis.
Discussion
There have been a number of epidemiological studies undertaken demonstrating an independent association between chronic periodontitis and chronic obstructive pulmonary disease. However, many of them have significant limitations, and drawing firm conclusions regarding causality may be premature. Although the pathology of both these diseases is complex and involves many cell types, such as CD8 positive cells and macrophages, both conditions are predominantly characterized by neutrophilic inflammation. Increasingly, there is evidence that the two conditions are underpinned by similar pathophysiological processes, especially centered on the functions of the neutrophil. These include a disturbance in protease/anti-protease and redox state balance. The association demonstrated by epidemiological studies, as well as emerging similarities in pathogenesis at the level of the neutrophil, suggest a basis for testing the effects of treatment for one condition upon the severity of the other.
Summary
Although the evidence of an independent association between chronic periodontitis and chronic obstructive pulmonary disease grows stronger, there remains a lack of definitive studies designed to establish causality and treatment effects. There is a need for future research to be focused on answering these questions.
doi:10.1186/1741-7015-11-241
PMCID: PMC4225606  PMID: 24229090
Chronic obstructive pulmonary disease; Emphysema; Neutrophil; Neutrophil extracellular trap; Oxidative stress; Periodontal diseases; Protease/proteinase
19.  Improving global health governance to combat counterfeit medicines: a proposal for a UNODC-WHO-Interpol trilateral mechanism 
BMC Medicine  2013;11:233.
Background
Perhaps no greater challenge exists for public health, patient safety, and shared global health security, than fake/falsified/fraudulent, poor quality unregulated drugs, also commonly known as “counterfeit medicines”, now endemic in the global drug supply chain. Counterfeit medicines are prevalent everywhere, from traditional healthcare settings to unregulated sectors, including the Internet. These dangerous medicines are expanding in both therapeutic and geographic scope, threatening patient lives, leading to antimicrobial resistance, and profiting criminal actors.
Discussion
Despite clear global public health threats, surveillance for counterfeit medicines remains extremely limited, with available data pointing to an increasing global criminal trade that has yet to be addressed appropriately. Efforts by a variety of public and private sector entities, national governments, and international organizations have made inroads in combating this illicit trade, but are stymied by ineffectual governance and divergent interests. Specifically, recent efforts by the World Health Organization, the primary international public health agency, have failed to adequately incorporate the broad array of stakeholders necessary to combat the problem. This has left the task of combating counterfeit medicines to other organizations such as UN Office of Drugs and Crime and Interpol in order to fill this policy gap.
Summary
To address the current failure of the international community to mobilize against the worldwide counterfeit medicines threat, we recommend the establishment of an enhanced global health governance trilateral mechanism between WHO, UNODC, and Interpol to leverage the respective strengths and resources of these organizations. This would allow these critical organizations, already engaged in the fight against counterfeit medicines, to focus on and coordinate their respective domains of transnational crime prevention, public health, and law enforcement field operations. Specifically, by forming a global partnership that focuses on combating the transnational criminal and patient safety elements of this pre-eminent global health problem, there can be progress against counterfeit drugs and their purveyors.
doi:10.1186/1741-7015-11-233
PMCID: PMC4225602  PMID: 24228892
Counterfeit medicines; Global health governance; Global health policy; Drug supply chain; Falsified medicines; Fraudulent medicines; Substandard medicines
20.  Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines 
BMC Medicine  2013;11:232.
Background
Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination.
Discussion
The Malaria Vaccine Technology Roadmap’s goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%’. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine.
Conclusions
Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.
doi:10.1186/1741-7015-11-232
PMCID: PMC4225678  PMID: 24228861
Malaria; Vaccine; Clinical trials
21.  Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics 
BMC Medicine  2013;11:205.
Background
‘Encephalomyelitis disseminata’ (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS.
Discussion
There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.
Summary
This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.
doi:10.1186/1741-7015-11-205
PMCID: PMC3847236  PMID: 24229326
Encephalomyelitis disseminata; Myalgic encephalomyelitis; Chronic fatigue syndrome; Inflammation; Autoimmunity; Oxidative and nitrosative stress; Mitochondria
22.  So depression is an inflammatory disease, but where does the inflammation come from? 
BMC Medicine  2013;11:200.
Background
We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’
Discussion
This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency.
Summary
The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.
doi:10.1186/1741-7015-11-200
PMCID: PMC3846682  PMID: 24228900
Depression; Inflammation; Cytokines; Diet; Obesity; Exercise; Smoking; Vitamin D; Dental cares; Sleep; Atopic; Gut; Oxidative stress
23.  The Hyperferritinemic Syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome 
BMC Medicine  2013;11:185.
Background
Over the last few years, accumulating data have implicated a role for ferritin as a signaling molecule and direct mediator of the immune system. Hyperferritinemia is associated with a multitude of clinical conditions and with worse prognosis in critically ill patients.
Discussion
There are four uncommon medical conditions characterized by high levels of ferritin, namely the macrophage activation syndrome (MAS), adult onset Still’s disease (AOSD), catastrophic antiphospholipid syndrome (cAPS) and septic shock, that share a similar clinical and laboratory features, and also respond to similar treatments, suggesting a common pathogenic mechanism. Ferritin is known to be a pro-inflammatory mediator inducing expression of pro-inflammatory molecules, yet it has opposing actions as a pro-inflammatory and as an immunosuppressant. We propose that the exceptionally high ferritin levels observed in these uncommon clinical conditions are not just the product of the inflammation but rather may contribute to the development of a cytokine storm.
Summary
Here we review and compare four clinical conditions and the role of ferritin as an immunomodulator. We would like to propose including these four conditions under a common syndrome entity termed “Hyperferritinemic Syndrome”.
doi:10.1186/1741-7015-11-185
PMCID: PMC3751883  PMID: 23968282
Hyperferritinemia; Macrophage activation syndrome (MAS); Adult onset Still’s disease (AOSD); Catastrophic antiphospholipid syndrome (cAPS); Septic shock
24.  Personalizing guidelines for diabetes management: twilight or dawn of the expert? 
BMC Medicine  2013;11:161.
Background
This opinion article on the management of type 2 diabetes considers the old and new format of guidelines and critical changes in the character of such guidelines. We highlight limitations of the guidelines and make recommendations for how treatment can be more personalised.
Discussion
Published guidelines for the management of adult-onset non-insulin requiring diabetes have adopted a formulaic approach to patient management that can be overseen centrally and delivered by personnel with limited training. Recently, guidelines have taken a patient-centered, multiple risk-factor approach. Importantly, local funding issues are considered, but drive the final action and not the decision-making process. The nature of the disease can be determined by laboratory tests, including screening for diabetes-associated autoantibodies. The strategy remains step-up, with intensification of drug or insulin dose. As with past guidelines, there is an assumption that in each patient with type 2 diabetes, metformin is used initially, but targets and therapies then veer in different directions to create a matrix of options based on the features and responses of each individual. Factors to consider include: (A)ge, (B)ody weight, (C)omplications and co-morbidities, Diabetes (D)uration and (E)xpense, but also patient preference and patient response.
Summary
Guidelines for the management of type 2 diabetes have important limitations and a patient-centered, multiple target, multiple therapy approach is proposed.
doi:10.1186/1741-7015-11-161
PMCID: PMC3716722  PMID: 23841986
Type 2 diabetes; Guidelines; Personalised treatment; Diabetes management; Patient-centered therapy
25.  The DSM-5: Hyperbole, Hope or Hypothesis? 
BMC Medicine  2013;11:128.
The furore preceding the release of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is in contrast to the incremental changes to several diagnostic categories, which are derived from new research since its predecessor’s birth in 1990. While many of these changes are indeed controversial, they do reflect the intrinsic ambiguity of the extant literature. Additionally, this may be a mirror of the frustration of the field’s limited progress, especially given the false hopes at the dawn of the “decade of the brain”. In the absence of a coherent pathophysiology, the DSM remains no more than a set of consensus based operationalized adjectives, albeit with some degree of reliability. It does not cleave nature at its joints, nor does it aim to, but neither does alternate systems. The largest problem with the DSM system is how it’s used; sometimes too loosely by clinicians, and too rigidly by regulators, insurers, lawyers and at times researchers, who afford it reference and deference disproportionate to its overt acknowledged limitations.
doi:10.1186/1741-7015-11-128
PMCID: PMC3653753  PMID: 23672603
DSM-V; Diagnosis; Pathophysiology; DSM-V; Symptoms; Classification

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