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1.  Is atherosclerosis an autoimmune disease? 
BMC Medicine  2014;12:47.
Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds β2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that β2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.
doi:10.1186/1741-7015-12-47
PMCID: PMC3984678  PMID: 24642015
Atherosclerosis; Auto-inflammatory disease; Autoimmunity; β2-glycoprotein I; Innate immunity; Inflammasome; Oxidized LDL
2.  Laboratory biomarkers or imaging in the diagnostics of rheumatoid arthritis? 
BMC Medicine  2014;12:49.
Rheumatoid arthritis (RA) is a common autoimmune disease in which a heterogeneous course and different pathogenic mechanisms are implicated in chronic inflammation and joint destruction. Despite the diagnostic contribution of anti-citrullinated protein/peptide antibodies (ACPAs) and rheumatoid factors, about one-third of RA patients remain seronegative. ACPAs belong to a heterogeneous family of autoantibodies targeting citrullinated proteins, including myelin-basic protein, several histone proteins, filaggrin and fibrin, fibrinogen or vimentin. In addition to ACPAs, antibodies directed against other post-translationally modified-carbamylated proteins (anti-CarP) were detected in up to 30% of ACPA-negative patients. Using phage display technology, further autoantibodies were recently discovered as candidate biomarkers for seronegative RA patients. Furthermore, in clinical practice, ultrasound may reveal subclinical synovitis and radiographically undetected bone erosions. To improve diagnostic certainty in undifferentiated arthritis and seronegative patients, ultrasound imaging and several new biomarkers may help to identify at risk patients and those with early disease. In this commentary we summarize recent advances in joint ultrasound and future potential of serological biomarkers to improve diagnosis of RA.
doi:10.1186/1741-7015-12-49
PMCID: PMC3984686  PMID: 24642071
Rheumatoid arthritis; Autoimmunity; Disease activity; Laboratory biomarkers; Ultrasound imaging
3.  Biologics, cardiovascular effects and cancer 
BMC Medicine  2014;12:48.
Rheumatoid arthritis (RA) is associated with increased cardiovascular risk. Treatment with tumor necrosis factor (TNF)-inhibitors leads to about a 50% reduction in the first cardiovascular event. TNF-inhibitors could transiently improve flow-mediated vasodilation and improve carotid intima-media thickness (ccIMT) during the treatment of RA. Treatment with TNF-inhibitors is associated with an increased total cholesterol (TC) and HDL-cholesterol (HDLc) level, without sustained change of the atherogenic index. The overall cancer risk in RA patients is comparable to that of the general population, but patients with RA slightly more often have lymphomas and lung tumors, and less often have colorectal and breast tumors in comparison to the general population. In randomized controlled trials (RCT) TNF-inhibitors did not increase the risk of solid malignancies, except for non-melanoma skin cancer (risk doubled compared to control treatment). Meta-analysis of registries and long-term extension studies showed no increased risk for total malignancies as well as for non-melanoma skin cancer when comparing TNF-inhibitors and the classical disease modifying anti-rheumatic drugs (DMARDs) treatment.
doi:10.1186/1741-7015-12-48
PMCID: PMC3984692  PMID: 24642038
Rheumatoid arthritis; TNF-inhibitors; Cardiovascular risk; Cancer risk; Malignancies
4.  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
5.  Global mental health: an interview with Vikram Patel 
BMC Medicine  2014;12:44.
In this podcast, we talk to Professor Vikram Patel about the impact of global mental health in the field of medicine, and discuss the initiatives and platforms being developed to promote capacity building, research, policy and advocacy within the established Centre for Global Mental Health. The anticipated challenges, controversies, and future directions for this discipline of global health are highlighted as well.
The podcast for this interview is available at: http://www.biomedcentral.com/sites/2999/download/Patel.mp3.
doi:10.1186/1741-7015-12-44
PMCID: PMC3975269  PMID: 24625028
6.  What is the future of targeted therapy in rheumatology: biologics or small molecules? 
BMC Medicine  2014;12:43.
Background
Until late in the 20th century, the therapy of rheumatic diseases relied on the use of drugs that had been developed through empirical approaches without detailed understanding of the molecular mechanisms involved. That approach changed with the introduction of biologic therapeutics at the end of the 20th century and by the recent development of small-molecule inhibitors of intracellular signal transduction pathways. Here we compare and discuss the advantages and disadvantages of those two groups of targeted anti-inflammatory therapeutics.
Discussion
TNF-blocking biologic agents were introduced into the therapy of rheumatoid arthritis and other autoimmune and inflammatory diseases in the late 1990s. Further biologic agents targeting cytokine networks or specific lymphocyte subsets have since been added to the armamentarium of anti-rheumatic therapy. During the last few years, another wave of novel discoveries led to the development of a new class of small molecule anti-inflammatory compounds targeting intracellular signal transduction molecules, such as tyrosine kinases. In all those cases, the specific targets of the drugs are well defined and significant knowledge about their role in the disease pathomechanism is available, qualifying them for being targeted therapeutics for inflammatory rheumatic diseases. While both groups of targeted therapeutics offer significant clinical benefit, they clearly differ in several aspects, such as the localization of their targets, their route of administration and target specificity, as well as technical details such as manufacturing procedures and cost basis. In this debate paper, we compare the advantages and disadvantages of the two different approaches, aiming to shed light on the possible future of targeted therapies.
Summary
Biologic therapeutics and small-molecule inhibitors both have significant advantages and disadvantages in the therapy of rheumatic diseases. The future of targeted therapies is one of the most exciting questions of current rheumatology research and therapy.
doi:10.1186/1741-7015-12-43
PMCID: PMC3975154  PMID: 24620738
Rheumatoid arthritis; Biologic therapies; TNF antagonists; Small molecule therapeutics; Kinase inhibitors; Tofacitinib
7.  Automated tests of ANA immunofluorescence as throughput autoantibody detection technology: strengths and limitations 
BMC Medicine  2014;12:38.
Anti-nuclear antibody (ANA) assay is a screening test used for almost all autoimmune rheumatic diseases, and in a number of these cases, it is a diagnostic/classification parameter. In addition, ANA is also a useful test for additional autoimmune disorders. The indirect immunofluorescence technique on monolayers of cultured epithelial cells is the current recommended method because it has higher sensitivity than solid phase assays. However, the technique is time-consuming and requires skilled operators. Automated ANA reading systems have recently been developed, which offer the advantage of faster and much easier performance as well as better harmonization in the interpretation of the results. Preliminary validation studies of these systems have given promising results in terms of analytical specificity and reproducibility. However, these techniques require further validation in clinical studies and need improvement in their recognition of mixed or less common staining patterns.
doi:10.1186/1741-7015-12-38
PMCID: PMC3939809  PMID: 24589329
Anti-nuclear antibodies; Indirect immunofluorescence; Autoimmunity
8.  Personalized medicine: risk prediction, targeted therapies and mobile health technology 
BMC Medicine  2014;12:37.
Personalized medicine is increasingly being employed across many areas of clinical practice, as genes associated with specific diseases are discovered and targeted therapies are developed. Mobile apps are also beginning to be used in medicine with the aim of providing a personalized approach to disease management. In some areas of medicine, patient-tailored risk prediction and treatment are applied routinely in the clinic, whereas in other fields, more work is required to translate scientific advances into individualized treatment. In this forum article, we asked specialists in oncology, neurology, endocrinology and mobile health technology to discuss where we are in terms of personalized medicine, and address their visions for the future and the challenges that remain in their respective fields.
doi:10.1186/1741-7015-12-37
PMCID: PMC3938085  PMID: 24580858
Diabetes; Genetics; Mobile health; Oncology; Personalized medicine; Smartphone; Stroke; Targeted therapy
9.  Epigenetics in the pathogenesis of rheumatoid arthritis 
BMC Medicine  2014;12:35.
An increasing number of studies show that besides the inherited genetic architecture (that is, genomic DNA), various environmental factors significantly contribute to the etiology of rheumatoid arthritis. Epigenetic factors react to external stimuli and form bridges between the environment and the genetic information-harboring DNA. Epigenetic mechanisms are implicated in the final interpretation of the encoded genetic information by regulating gene expression, and alterations in their profile influence the activity of the immune system. Overall, epigenetic mechanisms further increase the well-known complexity of rheumatoid arthritis by providing additional subtle contributions to rheumatoid arthritis susceptibility. Although there are controversies regarding the involvement of epigenetic and genetic factors in rheumatoid arthritis etiology, it is becoming obvious that the two systems (genetic and epigenetic) interact with each other and are ultimately responsible for rheumatoid arthritis development. Here, epigenetic factors and mechanisms involved in rheumatoid arthritis are reviewed and new, potential therapeutic targets are discussed.
doi:10.1186/1741-7015-12-35
PMCID: PMC3936819  PMID: 24568138
Chromatin modifications; DNA methylation; Epigenetics; Rheumatoid arthritis
10.  Autoantibodies against MHC class I polypeptide-related sequence A are associated with increased risk of concomitant autoimmune diseases in celiac patients 
BMC Medicine  2014;12:34.
Background
Overexpression of autologous proteins can lead to the formation of autoantibodies and autoimmune diseases. MHC class I polypeptide-related sequence A (MICA) is highly expressed in the enterocytes of patients with celiac disease, which arises in response to gluten. The aim of this study was to investigate anti-MICA antibody formation in patients with celiac disease and its association with other autoimmune processes.
Methods
We tested serum samples from 383 patients with celiac disease, obtained before they took up a gluten-free diet, 428 patients with diverse autoimmune diseases, and 200 controls for anti-MICA antibodies. All samples were also tested for anti-endomysium and anti-transglutaminase antibodies.
Results
Antibodies against MICA were detected in samples from 41.7% of patients with celiac disease but in only 3.5% of those from controls (P <0.0001) and 8.2% from patients with autoimmune disease (P <0.0001). These antibodies disappeared after the instauration of a gluten-free diet. Anti-MICA antibodies were significantly prevalent in younger patients (P <0.01). Fifty-eight patients with celiac disease (15.1%) presented a concomitant autoimmune disease. Anti-MICA-positive patients had a higher risk of autoimmune disease than MICA antibody-negative patients (P <0.0001; odds ratio = 6.11). The risk was even higher when we also controlled for age (odds ratio = 11.69). Finally, we found that the associated risk of developing additional autoimmune diseases was 16 and 10 times as high in pediatric patients and adults with anti-MICA, respectively, as in those without.
Conclusions
The development of anti-MICA antibodies could be related to a gluten-containing diet, and seems to be involved in the development of autoimmune diseases in patients with celiac disease, especially younger ones.
doi:10.1186/1741-7015-12-34
PMCID: PMC3945941  PMID: 24565339
Autoantibodies; Autoimmune diseases; Celiac disease; MICA; NKG2D; Type 1 diabetes mellitus
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.  Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review 
BMC Medicine  2014;12:31.
Background
Severe malaria remains a major cause of pediatric hospital admission across Africa. Invasive bacterial infection (IBI) is a recognized complication of Plasmodium falciparum malaria, resulting in a substantially worse outcome. Whether a biological relationship exists between malaria infection and IBI susceptibility remains unclear. We, therefore, examined the extent, nature and evidence of this association.
Methods
We conducted a systematic search in August 2012 of three major scientific databases, PubMed, Embase and Africa Wide Information, for articles describing bacterial infection among children with P. falciparum malaria using the search string ‘(malaria OR plasmodium) AND (bacteria OR bacterial OR bacteremia OR bacteraemia OR sepsis OR septicaemia OR septicemia).’ Eligiblity criteria also included studies of children hospitalized with malaria or outpatient attendances in sub-Saharan Africa.
Results
A total of 25 studies across 11 African countries fulfilled our criteria. They comprised twenty cohort analyses, two randomized controlled trials and three prospective epidemiological studies. In the meta-analysis of 7,208 children with severe malaria the mean prevalence of IBI was 6.4% (95% confidence interval (CI) 5.81 to 6.98%). In a further meta-analysis of 20,889 children hospitalised with all-severity malaria and 27,641 children with non-malarial febrile illness the mean prevalence of IBI was 5.58 (95% CI 5.5 to 5.66%) in children with malaria and 7.77% (95% CI 7.72 to 7.83%) in non-malaria illness. Ten studies reported mortality stratified by IBI. Case fatality was higher at 81 of 336, 24.1% (95% CI 18.9 to 29.4) in children with malaria/IBI co-infection compared to 585 of 5,760, 10.2% (95% CI 9.3 to 10.98) with malaria alone. Enteric gram-negative organisms were over-represented in malaria cases, non-typhoidal Salmonellae being the most commonest isolate. There was weak evidence indicating IBI was more common in the severe anemia manifestation of severe malaria.
Conclusions
The accumulated evidence suggests that children with recent or acute malaria are at risk of bacterial infection, which results in an increased risk of mortality. Characterising the exact nature of this association is challenging due to the paucity of appropriate severity-matched controls and the heterogeneous data. Further research to define those at greatest risk is necessary to target antimicrobial treatment.
doi:10.1186/1741-7015-12-31
PMCID: PMC3928319  PMID: 24548672
Severe malaria; Invasive bacterial infection; Gram-negative organisms; Children; Mortality; Epidemiology; Africa
14.  In-/off-label use of biologic therapy in systemic lupus erythematosus 
BMC Medicine  2014;12:30.
Current therapies for systemic lupus erythematosus (SLE) include corticosteroids as a persistent mainstay and traditional immunosuppressants which are given according to disease severity, organ involvement and patient status. No treatment entails certain efficacy devoid of mild-to-moderate adverse effects. Nowadays, novel therapies are being developed aiming to target specific molecules involved in SLE development and progression which show variable effectiveness and safety. Biologic agents considered for SLE comprise monoclonal antibodies (chimeric, humanized or fully human) as well as fusion molecules or antibody fragments mostly consisting of B cell-targeted therapies beside anti-cytokines as well as T cell-targeted therapies. Encouraging evidence on biologics is mostly provided by case series or uncontrolled studies; conversely, larger randomized controlled clinical trials have frequently missed their primary endpoints with the exception of BLISS-52 and BLISS-76 trials. Actually, apart from belimumab, biologics are employed in clinical practice as off-label treatments for lupus and results are often promising, depending on specific SLE features, dose regimens and individual responsiveness.
doi:10.1186/1741-7015-12-30
PMCID: PMC3925951  PMID: 24528782
Systemic lupus erythematosus; Biologic therapy; Randomized controlled trials; Belimumab; Anti-B cell therapies
15.  Do smartphone applications in healthcare require a governance and legal framework? It depends on the application! 
BMC Medicine  2014;12:29.
The fast pace of technological improvement and the rapid development and adoption of healthcare applications present crucial challenges for clinicians, users and policy makers. Some of the most pressing dilemmas include the need to ensure the safety of applications and establish their cost-effectiveness while engaging patients and users to optimize their integration into health decision-making. Healthcare organizations need to consider the risk of fragmenting clinical practice within the organization as a result of too many apps being developed or used, as well as mechanisms for app integration into the wider electronic health records through development of governance framework for their use. The impact of app use on the interactions between clinicians and patients needs to be explored, together with the skills required for both groups to benefit from the use of apps. Although healthcare and academic institutions should support the improvements offered by technological advances, they must strive to do so within robust governance frameworks, after sound evaluation of clinical outcomes and examination of potential unintended consequences.
doi:10.1186/1741-7015-12-29
PMCID: PMC3929845  PMID: 24524344
Apps; Ehealth; Mhealth; Smartphone; Technology adoption
16.  Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts 
BMC Medicine  2014;12:28.
Background
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.
Methods
Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.
Results
The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).
Conclusions
Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.
doi:10.1186/1741-7015-12-28
PMCID: PMC3926686  PMID: 24521426
Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers
17.  Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen 
BMC Medicine  2014;12:26.
Background
Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.
Methods
Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).
Results
If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.
Conclusions
Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening.
doi:10.1186/1741-7015-12-26
PMCID: PMC3922189  PMID: 24512643
Prostate cancer; Early detection; Overdiagnosis; PSA; Screening
18.  Early start and stop of biologics: has the time come? 
BMC Medicine  2014;12:25.
Despite considerable advances in the management of rheumatoid arthritis, results are still not satisfactory for all patients. The treatment goal in rheumatoid arthritis is remission, and there currently are numerous conventional and biological medications available to reach this aim. There are also different treatment strategies but with only limited comparative evidence about their efficacies. More patients now achieve remission while on treatment, but it remains elusive in the majority of patients. Treatment-free remission, the ultimate goal of therapy, is only achieved in very few patients; even when this happens, it is most likely due to the natural course of the disease rather than to any specific therapies. Modern treatment is based on the initiation of aggressive therapy as soon as the diagnosis is established, and on modifying or intensifying therapy guided by frequent assessment of disease activity. In this commentary we will discuss the current treatment paradigm as well as the possibility of an induction-maintenance regimen with biological disease-modifying antirheumatic drugs in early rheumatoid arthritis.
doi:10.1186/1741-7015-12-25
PMCID: PMC3915229  PMID: 24502187
Biologics; Rheumatoid arthritis; Treatment
19.  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
20.  Performance of four computer-coded verbal autopsy methods for cause of death assignment compared with physician coding on 24,000 deaths in low- and middle-income countries 
BMC Medicine  2014;12:20.
Background
Physician-coded verbal autopsy (PCVA) is the most widely used method to determine causes of death (CODs) in countries where medical certification of death is uncommon. Computer-coded verbal autopsy (CCVA) methods have been proposed as a faster and cheaper alternative to PCVA, though they have not been widely compared to PCVA or to each other.
Methods
We compared the performance of open-source random forest, open-source tariff method, InterVA-4, and the King-Lu method to PCVA on five datasets comprising over 24,000 verbal autopsies from low- and middle-income countries. Metrics to assess performance were positive predictive value and partial chance-corrected concordance at the individual level, and cause-specific mortality fraction accuracy and cause-specific mortality fraction error at the population level.
Results
The positive predictive value for the most probable COD predicted by the four CCVA methods averaged about 43% to 44% across the datasets. The average positive predictive value improved for the top three most probable CODs, with greater improvements for open-source random forest (69%) and open-source tariff method (68%) than for InterVA-4 (62%). The average partial chance-corrected concordance for the most probable COD predicted by the open-source random forest, open-source tariff method and InterVA-4 were 41%, 40% and 41%, respectively, with better results for the top three most probable CODs. Performance generally improved with larger datasets. At the population level, the King-Lu method had the highest average cause-specific mortality fraction accuracy across all five datasets (91%), followed by InterVA-4 (72% across three datasets), open-source random forest (71%) and open-source tariff method (54%).
Conclusions
On an individual level, no single method was able to replicate the physician assignment of COD more than about half the time. At the population level, the King-Lu method was the best method to estimate cause-specific mortality fractions, though it does not assign individual CODs. Future testing should focus on combining different computer-coded verbal autopsy tools, paired with PCVA strengths. This includes using open-source tools applied to larger and varied datasets (especially those including a random sample of deaths drawn from the population), so as to establish the performance for age- and sex-specific CODs.
doi:10.1186/1741-7015-12-20
PMCID: PMC3912488  PMID: 24495855
Causes of death; Computer-coded verbal autopsy (CCVA); InterVA-4; King-Lu; Physician-certified verbal autopsy (PCVA); Random forest; Tariff method; Validation; Verbal autopsy
21.  Performance criteria for verbal autopsy-based systems to estimate national causes of death: development and application to the Indian Million Death Study 
BMC Medicine  2014;12:21.
Background
Verbal autopsy (VA) has been proposed to determine the cause of death (COD) distributions in settings where most deaths occur without medical attention or certification. We develop performance criteria for VA-based COD systems and apply these to the Registrar General of India’s ongoing, nationally-representative Indian Million Death Study (MDS).
Methods
Performance criteria include a low ill-defined proportion of deaths before old age; reproducibility, including consistency of COD distributions with independent resampling; differences in COD distribution of hospital, home, urban or rural deaths; age-, sex- and time-specific plausibility of specific diseases; stability and repeatability of dual physician coding; and the ability of the mortality classification system to capture a wide range of conditions.
Results
The introduction of the MDS in India reduced the proportion of ill-defined deaths before age 70 years from 13% to 4%. The cause-specific mortality fractions (CSMFs) at ages 5 to 69 years for independently resampled deaths and the MDS were very similar across 19 disease categories. By contrast, CSMFs at these ages differed between hospital and home deaths and between urban and rural deaths. Thus, reliance mostly on urban or hospital data can distort national estimates of CODs. Age-, sex- and time-specific patterns for various diseases were plausible. Initial physician agreement on COD occurred about two-thirds of the time. The MDS COD classification system was able to capture more eligible records than alternative classification systems. By these metrics, the Indian MDS performs well for deaths prior to age 70 years. The key implication for low- and middle-income countries where medical certification of death remains uncommon is to implement COD surveys that randomly sample all deaths, use simple but high-quality field work with built-in resampling, and use electronic rather than paper systems to expedite field work and coding.
Conclusions
Simple criteria can evaluate the performance of VA-based COD systems. Despite the misclassification of VA, the MDS demonstrates that national surveys of CODs using VA are an order of magnitude better than the limited COD data previously available.
doi:10.1186/1741-7015-12-21
PMCID: PMC3912490  PMID: 24495287
Verbal autopsy; Physician-certified verbal autopsy; Cause of death statistics; Vital statistics; India
22.  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
23.  Prospects for automated diagnosis of verbal autopsies 
BMC Medicine  2014;12:18.
Verbal autopsy is a method for assessing probable causes of death from lay reporting of signs, symptoms and circumstances by family members or caregivers of a deceased person. Several methods of automated diagnoses of causes of death from standardized verbal autopsy questionnaires have been developed recently (Inter-VA, Tariff, Random Forest and King-Lu). Their performances have been assessed in a series of papers in BMC Medicine. Overall, and despite high specificity, the current strategies of automated computer diagnoses lead to relatively low sensitivity and positive predictive values, even for causes which are expected to be easily assessed by interview. Some methods have even abnormally low sensitivity for selected diseases of public health importance and could probably be improved. Ways to improve the current strategies are proposed: more detailed questionnaires; using more information on disease duration; stratifying for large groups of causes of death by age, sex and main category; using clusters of signs and symptoms rather than quantitative scores or ranking; separating indeterminate causes; imputing unknown cause with appropriate methods.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/5; http://www.biomedcentral.com/1741-7015/12/19; http://www.biomedcentral.com/1741-7015/12/20; http://www.biomedcentral.com/1741-7015/12/21; http://www.biomedcentral.com/1741-7015/12/22; http://www.biomedcentral.com/1741-7015/12/23.
doi:10.1186/1741-7015-12-18
PMCID: PMC3912493  PMID: 24495788
Cause of death; Verbal autopsy; Automated diagnosis; Health information system; Evaluation of health programs; Public health
24.  Usefulness of the Population Health Metrics Research Consortium gold standard verbal autopsy data for general verbal autopsy methods 
BMC Medicine  2014;12:23.
Background
Verbal Autopsy (VA) is widely viewed as the only immediate strategy for registering cause of death in much of Africa and Asia, where routine physician certification of deaths is not widely practiced. VA involves a lay interview with family or friends after a death, to record essential details of the circumstances. These data can then be processed automatically to arrive at standardized cause of death information.
Methods
The Population Health Metrics Research Consortium (PHMRC) undertook a study at six tertiary hospitals in low- and middle-income countries which documented over 12,000 deaths clinically and subsequently undertook VA interviews. This dataset, now in the public domain, was compared with the WHO 2012 VA standard and the InterVA-4 interpretative model.
Results
The PHMRC data covered 70% of the WHO 2012 VA input indicators, and categorized cause of death according to PHMRC definitions. After eliminating some problematic or incomplete records, 11,984 VAs were compared. Some of the PHMRC cause definitions, such as ‘preterm delivery’, differed substantially from the International Classification of Diseases, version 10 equivalent. There were some appreciable inconsistencies between the hospital and VA data, including 20% of the hospital maternal deaths being described as non-pregnant in the VA data. A high proportion of VA cases (66%) reported respiratory symptoms, but only 18% of assigned hospital causes were respiratory-related. Despite these issues, the concordance correlation coefficient between hospital and InterVA-4 cause of death categories was 0.61.
Conclusions
The PHMRC dataset is a valuable reference source for VA methods, but has to be interpreted with care. Inherently inconsistent cases should not be included when using these data to build other VA models. Conversely, models built from these data should be independently evaluated. It is important to distinguish between the internal and external validity of VA models. The effects of using tertiary hospital data, rather than the more usual application of VA to all-community deaths, are hard to evaluate. However, it would still be of value for VA method development to have further studies of population-based post-mortem examinations.
doi:10.1186/1741-7015-12-23
PMCID: PMC3912496  PMID: 24495341
Verbal autopsy; Cause of death; Death registration; Low- and middle-income countries; InterVA
25.  Comparison of physician-certified verbal autopsy with computer-coded verbal autopsy for cause of death assignment in hospitalized patients in low- and middle-income countries: systematic review 
BMC Medicine  2014;12:22.
Background
Computer-coded verbal autopsy (CCVA) methods to assign causes of death (CODs) for medically unattended deaths have been proposed as an alternative to physician-certified verbal autopsy (PCVA). We conducted a systematic review of 19 published comparison studies (from 684 evaluated), most of which used hospital-based deaths as the reference standard. We assessed the performance of PCVA and five CCVA methods: Random Forest, Tariff, InterVA, King-Lu, and Simplified Symptom Pattern.
Methods
The reviewed studies assessed methods’ performance through various metrics: sensitivity, specificity, and chance-corrected concordance for coding individual deaths, and cause-specific mortality fraction (CSMF) error and CSMF accuracy at the population level. These results were summarized into means, medians, and ranges.
Results
The 19 studies ranged from 200 to 50,000 deaths per study (total over 116,000 deaths). Sensitivity of PCVA versus hospital-assigned COD varied widely by cause, but showed consistently high specificity. PCVA and CCVA methods had an overall chance-corrected concordance of about 50% or lower, across all ages and CODs. At the population level, the relative CSMF error between PCVA and hospital-based deaths indicated good performance for most CODs. Random Forest had the best CSMF accuracy performance, followed closely by PCVA and the other CCVA methods, but with lower values for InterVA-3.
Conclusions
There is no single best-performing coding method for verbal autopsies across various studies and metrics. There is little current justification for CCVA to replace PCVA, particularly as physician diagnosis remains the worldwide standard for clinical diagnosis on live patients. Further assessments and large accessible datasets on which to train and test combinations of methods are required, particularly for rural deaths without medical attention.
doi:10.1186/1741-7015-12-22
PMCID: PMC3912516  PMID: 24495312
Causes of death; Computer-coded verbal autopsy; InterVA; King and Lu; Physician-certified verbal autopsy; Random forest; Simplified symptom pattern; Tariff; Validity; Verbal autopsy

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