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1.  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.
doi:10.1186/s12916-014-0234-y
PMCID: PMC4286914  PMID: 25573005
Diet; Prostate cancer; Nutrients; Dietary pattern; Lifestyle; Prevention; Treatment; Nutrition; Dietary intervention; Review
2.  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.
doi:10.1186/s12916-014-0232-0
PMCID: PMC4286146  PMID: 25564342
Molecular diagnostics; Diabetic foot infection; Microbiology; Metagenomics; High-throughput sequencing
3.  Cardiovascular risk factors and future risk of Alzheimer’s disease 
BMC Medicine  2014;12(1):130.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder in elderly people, but there are still no curative options. Senile plaques and neurofibrillary tangles are considered hallmarks of AD, but cerebrovascular pathology is also common. In this review, we summarize findings on cardiovascular disease (CVD) and risk factors in the etiology of AD. Firstly, we discuss the association of clinical CVD (such as stroke and heart disease) and AD. Secondly, we summarize the relation between imaging makers of pre-clinical vascular disease and AD. Lastly, we discuss the association of cardiovascular risk factors and AD. We discuss both established cardiovascular risk factors and emerging putative risk factors, which exert their effect partly via CVD.
doi:10.1186/s12916-014-0130-5
PMCID: PMC4226863  PMID: 25385322
Cardiovascular disease; Imaging markers; Risk factors; Dementia; Alzheimer’s disease
4.  The overlap between vascular disease and Alzheimer’s disease – lessons from pathology 
BMC Medicine  2014;12(1):206.
Recent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease (CVD) and Alzheimer’s disease (AD) and suggest additive or synergistic effects of both pathologies on cognitive decline. The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia. Further studies are warranted to elucidate the many hitherto unanswered questions regarding the overlap between CVD and AD as well as the impact of both CVD and AD pathologies on the development and progression of dementia.
doi:10.1186/s12916-014-0206-2
PMCID: PMC4226890  PMID: 25385447
Alzheimer’s disease; Cerebrovascular lesions; Cerebral amyloid angiopathy; Cognitive impairment; Lacunes; Microinfarcts; Small vessel disease; White matter lesions
5.  Transmission dynamics and control of Ebola virus disease (EVD): a review 
BMC Medicine  2014;12(1):196.
The complex and unprecedented Ebola epidemic ongoing in West Africa has highlighted the need to review the epidemiological characteristics of Ebola Virus Disease (EVD) as well as our current understanding of the transmission dynamics and the effect of control interventions against Ebola transmission. Here we review key epidemiological data from past Ebola outbreaks and carry out a comparative review of mathematical models of the spread and control of Ebola in the context of past outbreaks and the ongoing epidemic in West Africa. We show that mathematical modeling offers useful insights into the risk of a major epidemic of EVD and the assessment of the impact of basic public health measures on disease spread. We also discuss the critical need to collect detailed epidemiological data in real-time during the course of an ongoing epidemic, carry out further studies to estimate the effectiveness of interventions during past outbreaks and the ongoing epidemic, and develop large-scale modeling studies to study the spread and control of viral hemorrhagic fevers in the context of the highly heterogeneous economic reality of African countries.
doi:10.1186/s12916-014-0196-0
PMCID: PMC4207625  PMID: 25300956
Ebola Virus Disease; Transmission model; Control interventions; Basic reproduction number; West Africa; Incubation; Serial interval; Case fatality ratio; Isolation; Behavior change
6.  Feasibility of HIV point-of-care tests for resource-limited settings: challenges and solutions 
BMC Medicine  2014;12(1):173.
Improved access to anti-retroviral therapy increases the need for affordable monitoring using assays such as CD4 and/or viral load in resource-limited settings. Barriers to accessing treatment, high rates of loss to initiation and poor retention in care are prompting the need to find alternatives to conventional centralized laboratory testing in certain countries. Strong advocacy has led to a rapidly expanding repertoire of point-of-care tests for HIV. point-of-care testing is not without its challenges: poor regulatory control, lack of guidelines, absence of quality monitoring and lack of industry standards for connectivity, to name a few. The management of HIV increasingly requires a multidisciplinary testing approach involving hematology, chemistry, and tests associated with the management of non-communicable diseases, thus added expertise is needed. This is further complicated by additional human resource requirements and the need for continuous training, a sustainable supply chain, and reimbursement strategies. It is clear that to ensure appropriate national implementation either in a tiered laboratory model or a total decentralized model, clear country-specific assessments need to be conducted.
doi:10.1186/s12916-014-0173-7
PMCID: PMC4157150  PMID: 25197773
Anti-retroviral therapy; CD4; Challenges; HIV; Implementation; Point-of-care; Viral load
7.  Predicting outcome from dengue 
BMC Medicine  2014;12(1):147.
Dengue is emerging as one of the most abundant vector-borne disease globally. Although the majority of infections are asymptomatic or result in only a brief systemic viral illness, a small proportion of patients develop potentially fatal complications. These severe manifestations, including a unique plasma leakage syndrome, a coagulopathy sometimes accompanied by bleeding, and organ impairment, occur relatively late in the disease course, presenting a window of opportunity to identify the group of patients likely to progress to these complications. However, as yet, differentiating this group from the thousands of milder cases seen each day during outbreaks remains challenging, and simple and inexpensive strategies are urgently needed in order to improve case management and to facilitate appropriate use of limited resources. This review will cover the current understanding of the risk factors associated with poor outcome in dengue. We focus particularly on the clinical features of the disease and on conventional investigations that are usually accessible in mid-level healthcare facilities in endemic areas, and then discuss a variety of viral, immunological and vascular biomarkers that have the potential to improve risk prediction. We conclude with a description of several novel methods of assessing vascular function and intravascular volume status non-invasively.
doi:10.1186/s12916-014-0147-9
PMCID: PMC4154521  PMID: 25259615
Dengue; Severity; Outcome; Risk factors; Biomarkers; Vascular
8.  Type 2 diabetes as a disease of ectopic fat? 
BMC Medicine  2014;12(1):123.
Background
Although obesity and diabetes commonly co-exist, the evidence base to support obesity as the major driver of type 2 diabetes mellitus (T2DM), and the mechanisms by which this occurs, are now better appreciated.
Discussion
This review briefly examines several sources of evidence – epidemiological, genetic, molecular, and clinical trial – to support obesity being a causal risk factor for T2DM. It also summarises the ectopic fat hypothesis for this condition, and lists several pieces of evidence to support this concept, extending from rare conditions and drug effects to sex- and ethnicity-related differences in T2DM prevalence. Ectopic liver fat is the best-studied example of ectopic fat, but more research on pancreatic fat as a potential cause of β-cell dysfunction seems warranted. This ectopic fat concept, in turn, broadly fits with the observation that individuals of similar ages can develop diabetes at markedly different body mass indexes (BMIs). Those with risk factors leading to more rapid ectopic fat gain – for example, men (compared with women), certain ethnicities, and potentially those with a family history of diabetes, as well as others with genes linked to a reduced subcutaneous adiposity – are more likely to develop diabetes at a younger age and/or lower BMI than those without.
Summary
Obesity is the major risk factor for T2DM and appears to drive tissue insulin resistance in part via gain of ectopic fat, with the best-studied organ being the liver. However, ectopic fat in the pancreas may contribute to β-cell dysfunction. In line with this observation, rapid resolution of diabetes linked to a preferential and rapid reduction in liver fat has been noted with significant caloric reduction. Whether these observations can help develop better cost-effective and sustainable lifestyle /medical interventions in patients with T2DM requires further study.
doi:10.1186/s12916-014-0123-4
PMCID: PMC4143560  PMID: 25159817
Insulin resistance; NAFLD; Pancreas; Adiposity; Sex; Ethnicity; Family history of diabetes
9.  Update on the NCEP ATP-III emerging cardiometabolic risk factors 
BMC Medicine  2014;12(1):115.
The intent of this review is to update the science of emerging cardiometabolic risk factors that were listed in the National Cholesterol Education Program (NCEP) Adult Treatment Panel-III (ATP-III) report of 2001 (updated in 2004). At the time these guidelines were published, the evidence was felt to be insufficient to recommend these risk factors for routine screening of cardiovascular disease risk. However, the panel felt that prudent use of these biomarkers for patients at intermediate risk of a major cardiovascular event over the subsequent 10 years might help identify patients who needed more aggressive low density lipoprotein (LDL) or non-high density lipoprotein (HDL) cholesterol lowering therapy. While a number of other emerging risk factors have been identified, this review will be limited to assessing the data and recommendations for the use of apolipoprotein B, lipoprotein (a), homocysteine, pro-thrombotic factors, inflammatory factors, impaired glucose metabolism, and measures of subclinical atherosclerotic cardiovascular disease for further cardiovascular disease risk stratification.
doi:10.1186/1741-7015-12-115
PMCID: PMC4283079  PMID: 25154373
Apolipoprotein B; Lipoprotein (a); C-reactive protein; Homocysteine
10.  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
11.  Early life programming as a target for prevention of child and adolescent mental disorders 
BMC Medicine  2014;12:33.
This paper concerns future policy development and programs of research for the prevention of mental disorders based on research emerging from fetal and early life programming. The current review offers an overview of findings on pregnancy exposures such as maternal mental health, lifestyle factors, and potential teratogenic and neurotoxic exposures on child outcomes. Outcomes of interest are common child and adolescent mental disorders including hyperactive, behavioral and emotional disorders. This literature suggests that the preconception and perinatal periods offer important opportunities for the prevention of deleterious fetal exposures. As such, the perinatal period is a critical period where future mental health prevention efforts should be focused and prevention models developed. Interventions grounded in evidence-based recommendations for the perinatal period could take the form of public health, universal and more targeted interventions. If successful, such interventions are likely to have lifelong effects on (mental) health.
doi:10.1186/1741-7015-12-33
PMCID: PMC3932730  PMID: 24559477
Child and adolescent mental health; Developmental origins (DOHaD); Fetal programming; Maternal mental health; Obesity; Prevention; Teterogenic exposures
12.  Molecular determinants of context-dependent progesterone receptor action in breast cancer 
BMC Medicine  2014;12:32.
The ovarian steroid hormone, progesterone, and its nuclear receptor, the progesterone receptor, are implicated in the progression of breast cancer. Clinical trial data on the effects of hormone replacement therapy underscore the importance of understanding how progestins influence breast cancer growth. The progesterone receptor regulation of distinct target genes is mediated by complex interactions between the progesterone receptor and other regulatory factors that determine the context-dependent transcriptional action of the progesterone receptor. These interactions often lead to post-translational modifications to the progesterone receptor that can dramatically alter receptor function, both in the normal mammary gland and in breast cancer. This review highlights the molecular components that regulate progesterone receptor transcriptional action and describes how a better understanding of the complex interactions between the progesterone receptor and other regulatory factors may be critical to enhancing the clinical efficacy of anti-progestins for use in the treatment of breast cancer.
doi:10.1186/1741-7015-12-32
PMCID: PMC3929904  PMID: 24552158
Breast cancer; Post-translational modifications; Progesterone receptor; Signal transduction
13.  Managing the changing burden of cancer in Asia 
BMC Medicine  2014;12:3.
Asia accounts for 60% of the world population and half the global burden of cancer. The incidence of cancer cases is estimated to increase from 6.1 million in 2008 to 10.6 million in 2030, due to ageing and growing populations, lifestyle and socioeconomic changes. Striking variations in ethnicity, sociocultural practices, human development index, habits and dietary patterns are reflected in the burden and pattern of cancer in different regions. The existing and emerging cancer patterns and burden in different regions of Asia call for political recognition of cancer as an important public health problem and for balanced investments in public and professional awareness. Prevention as well as early detection of cancers leads to both better health outcomes and considerable savings in treatment costs. Cancer health services are still evolving, and require substantial investment to ensure equitable access to cancer care for all sections of the population. In this review, we discuss the changing burden of cancer in Asia, along with appropriate management strategies. Strategies should promote healthy ageing via healthy lifestyles, tobacco and alcohol control measures, hepatitis B virus (HBV) and human papillomavirus (HPV) vaccination, cancer screening services, and vertical investments in strengthening cancer healthcare infrastructure to improve equitable access to services.
doi:10.1186/1741-7015-12-3
PMCID: PMC4029284  PMID: 24400922
Asia; Cancer burden; Prevention; Screening; Early detection; Diagnosis; Treatment; Clinical implication; Health services; Survival
14.  Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review 
BMC Medicine  2013;11:253.
The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.
doi:10.1186/1741-7015-11-253
PMCID: PMC4220801  PMID: 24295487
15.  Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy? 
BMC Medicine  2013;11:251.
There is evidence that the life expectancy (LE) of individuals infected with the human immunodeficiency virus (HIV) has increased since the introduction of combination antiretroviral therapy (cART). However, mortality rates in recent years in HIV-positive individuals appear to have remained higher than would be expected based on rates seen in the general population. A low CD4 count, whether due to late HIV diagnosis, late initiation of cART, or incomplete adherence to cART, remains the dominant predictor of LE, and thus the individual’s disease stage at initiation of cART (or thereafter) certainly contributes to these higher mortality rates. However, individuals with HIV also tend to exhibit lifestyles and behaviors that place them at increased risk of mortality, particularly from non-AIDS causes. Thus, although mortality rates among the HIV population may indeed remain slightly higher than those seen in the general population, they may be no higher than those seen in a more appropriately matched control group. Thus, further improvements in LE may now only be possible if some of the other underlying issues (for example, modification of lifestyle or behavioral factors) are tackled.
doi:10.1186/1741-7015-11-251
PMCID: PMC4220799  PMID: 24283830
Human immunodeficiency virus; Combination antiretroviral therapy; Life expectancy; Trends; Mortality
16.  Admission prevention in COPD: non-pharmacological management 
BMC Medicine  2013;11:247.
Exacerbations of chronic obstructive pulmonary disease (COPD) are one of the commonest causes of hospital admission in Europe, Australasia, and North America. These adverse events have a large effect on the health status of the patients and impose a heavy burden on healthcare systems. While we acknowledge the contribution of pharmacotherapies to exacerbation prevention, our interpretation of the data is that exacerbations continue to be a major burden to individuals and healthcare systems, therefore, there remains great scope for other therapies to influence exacerbation frequency and preservation of quality of life. In this review, the benefits and limitations of pulmonary rehabilitation, non-invasive ventilation, smoking cessation, and long-term oxygen therapy are discussed. In addition, supported discharge, advanced care coordination, and telehealth programs to improve clinical outcome are reviewed as future directions for the management of COPD.
Please see related article: http://www.biomedcentral.com/1741-7015/11/181.
doi:10.1186/1741-7015-11-247
PMCID: PMC3834545  PMID: 24252219
17.  Managing HIV/hepatitis C co-infection in the era of direct acting antivirals 
BMC Medicine  2013;11:234.
Morbidity and mortality from co-morbid hepatitis C (HCV) infection in HIV co-infected patients are increasing; hence, the management of hepatitis co-infection in HIV is now one of the most important clinical challenges. Therefore, the development of direct acting antivirals (DAAs) for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in co-infected individuals. Indeed, the availability of the first HCV protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients has changed the gold standard of treating hepatitis C allowing for substantially improved HCV cure rates under triple HCV-PI/pegylated interferon/ribavirin therapy. Moreover, numerous other new DAAs are currently being studied in co-infected patient populations, also exploring shorter treatment durations and interferon-free treatment approaches promising much easier and better tolerated treatment regimens in the near future. Nevertheless, numerous challenges remain, including choice of patients to treat, potential for drug-drug interactions and overlapping toxicities between HIV and HCV therapy. The dramatically improved rates of HCV cure under new triple therapy, however, warrant evaluation of these new treatment options for all co-infected patients.
doi:10.1186/1741-7015-11-234
PMCID: PMC4225604  PMID: 24228933
HIV; Hepatitis C; Direct acting antivirals; Interferon; Ribavirin
18.  Venous endothelial injury in central nervous system diseases 
BMC Medicine  2013;11:219.
The role of the venous system in the pathogenesis of inflammatory neurological/neurodegenerative diseases remains largely unknown and underinvestigated. Aside from cerebral venous infarcts, thromboembolic events, and cerebrovascular bleeding, several inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and optic neuritis, appear to be associated with venous vascular dysfunction, and the neuropathologic hallmark of these diseases is a perivenous, rather than arterial, lesion. Such findings raise fundamental questions about the nature of these diseases, such as the reasons why their pathognomonic lesions do not develop around the arteries and what exactly are the roles of cerebral venous inflammation in their pathogenesis. Apart from this inflammatory-based view, a new hypothesis with more focus on the hemodynamic features of the cerebral and extracerebral venous system suggests that MS pathophysiology might be associated with the venous system that drains the CNS. Such a hypothesis, if proven correct, opens new therapeutic windows in MS and other neuroinflammatory diseases. Here, we present a comprehensive review of the pathophysiology of MS, ADEM, pseudotumor cerebri, and optic neuritis, with an emphasis on the roles of venous vascular system programming and dysfunction in their pathogenesis. We consider the fundamental differences between arterial and venous endothelium, their dissimilar responses to inflammation, and the potential theoretical contributions of venous insufficiency in the pathogenesis of neurovascular diseases.
doi:10.1186/1741-7015-11-219
PMCID: PMC3851779  PMID: 24228622
Venous; MS; CNS; ADEM; Inflammation
19.  B. anthracis associated cardiovascular dysfunction and shock: the potential contribution of both non-toxin and toxin components 
BMC Medicine  2013;11:217.
The development of cardiovascular dysfunction and shock in patients with invasive Bacillus anthracis infection has a particularly poor prognosis. Growing evidence indicates that several bacterial components likely play important pathogenic roles in this injury. As with other pathogenic Gram-positive bacteria, the B. anthracis cell wall and its peptidoglycan constituent produce a robust inflammatory response with its attendant tissue injury, disseminated intravascular coagulation and shock. However, B. anthracis also produces lethal and edema toxins that both contribute to shock. Growing evidence suggests that lethal toxin, a metalloprotease, can interfere with endothelial barrier function as well as produce myocardial dysfunction. Edema toxin has potent adenyl cyclase activity and may alter endothelial function, as well as produce direct arterial and venous relaxation. Furthermore, both toxins can weaken host defense and promote infection. Finally, B. anthracis produces non-toxin metalloproteases which new studies show can contribute to tissue injury, coagulopathy and shock. In the future, an understanding of the individual pathogenic effects of these different components and their interactions will be important for improving the management of B. anthracis infection and shock.
doi:10.1186/1741-7015-11-217
PMCID: PMC3851549  PMID: 24107194
Bacillus anthracis; Anthrax; Cell wall components; Lethal and edema toxins; Metalloproteases; Cardiovascular dysfunction; Shock
20.  What is next after the genes for autoimmunity? 
BMC Medicine  2013;11:197.
Clinical pathologies draw us to envisage disease as either an independent entity or a diverse set of traits governed by common physiopathological mechanisms, prompted by environmental assaults throughout life. Autoimmune diseases are not an exception, given they represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. Although they are pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms, research generally focuses on a single disease. Drastic technologic advances are leading research to organize clinical genomic multidisciplinary approaches to decipher the nature of human biological systems. Once the currently costly omic-based technologies become universally accessible, the way will be paved for a cleaner picture to risk quantification, prevention, prognosis and diagnosis, allowing us to clearly define better phenotypes always ensuring the integrity of the individuals studied. However, making accurate predictions for most autoimmune diseases is an ambitious challenge, since the understanding of these pathologies is far from complete. Herein, some pitfalls and challenges of the genetics of autoimmune diseases are reviewed, and an approximation to the future of research in this field is presented.
doi:10.1186/1741-7015-11-197
PMCID: PMC3765994  PMID: 24107170
Autoimmunity; Common; Genetics; Genomics; Personalized; Predictive medicine; Polyautoimmunity; Translational medicine
21.  Rapid diagnostics of tuberculosis and drug resistance in the industrialized world: clinical and public health benefits and barriers to implementation 
BMC Medicine  2013;11:190.
In this article, we give an overview of new technologies for the diagnosis of tuberculosis (TB) and drug resistance, consider their advantages over existing methodologies, broad issues of cost, cost-effectiveness and programmatic implementation, and their clinical as well as public health impact, focusing on the industrialized world. Molecular nucleic-acid amplification diagnostic systems have high specificity for TB diagnosis (and rifampicin resistance) but sensitivity for TB detection is more variable. Nevertheless, it is possible to diagnose TB and rifampicin resistance within a day and commercial automated systems make this possible with minimal training. Although studies are limited, these systems appear to be cost-effective. Most of these tools are of value clinically and for public health use. For example, whole genome sequencing of Mycobacterium tuberculosis offers a powerful new approach to the identification of drug resistance and to map transmission at a community and population level.
doi:10.1186/1741-7015-11-190
PMCID: PMC3765611  PMID: 23987891
Diagnosis; Drug resistance; Tuberculosis; Public health; Whole genome sequencing
22.  Challenges and opportunities for oral pre-exposure prophylaxis in the prevention of HIV infection: where are we in Europe? 
BMC Medicine  2013;11:186.
Following US Food and Drugs Administration approval in July 2012 of daily oral tenofovir and emtricitabine for pre-exposure prophylaxis (PrEP) to prevent HIV infection in high-risk individuals in the USA, there has been much controversy about the implementation of this PrEP regimen in other countries throughout the world, and in Europe in particular. In this review, we focus on the challenges and opportunities of a daily oral PrEP regimen to curb the rising incidence of HIV infection in high-risk groups, and particularly in men who have sex with men. A number of issues would need to be addressed before PrEP could be implemented, including assessing the real effectiveness and cost-effectiveness of daily PrEP, the sustainability of daily adherence, the risk of selecting resistance, the long-term safety, and the risk of change in sexual behavior that might offset the benefit of PrEP. Alternatives to a daily oral PrEP regimen are being explored.
doi:10.1186/1741-7015-11-186
PMCID: PMC3751938  PMID: 23972284
HIV; Tenofovir; Emtricitabine; Men who have sex with men; Intermittent; PrEP; Adherence
23.  Pharmacological treatments in ARDS; a state-of-the-art update 
BMC Medicine  2013;11:166.
Despite its high incidence and devastating outcomes, acute respiratory distress syndrome (ARDS) has no specific treatment, with effective therapy currently limited to minimizing potentially harmful ventilation and avoiding a positive fluid balance. Many pharmacological therapies have been investigated with limited success to date. In this review article we provide a state-of-the-art update on recent and ongoing trials, as well as reviewing promising future pharmacological therapies in ARDS.
doi:10.1186/1741-7015-11-166
PMCID: PMC3765621  PMID: 23957905
Acute lung injury; Acute respiratory distress syndrome
24.  Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease 
BMC Medicine  2013;11:181.
Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.
doi:10.1186/1741-7015-11-181
PMCID: PMC3750926  PMID: 23945277
Chronic obstructive pulmonary disease (COPD); Exacerbations; Frequent exacerbator phenotype; Comorbidities
25.  Personalizing health care: feasibility and future implications 
BMC Medicine  2013;11:179.
Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.
doi:10.1186/1741-7015-11-179
PMCID: PMC3750765  PMID: 23941275
Biomarkers; Drug development; Genomics; Genotyping; Healthcare policy; Pharmacogenetics precision medicine; Personalized medicine; Health authorities; Rational use of medicines; Reimbursement; Targeted treatments

Results 1-25 (129)