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26.  Unexpected plateauing of childhood obesity rates in developed countries 
BMC Medicine  2014;12:17.
Surveys performed in the past 10 to 15 years show a yet unexplained stabilization or decline in prevalence rates of childhood obesity in developed countries. The projected continuous increase in obesity prevalence throughout future decades seems not to occur at present. Apparently, saturation has been reached, which might be related to societal adjustments. Hence, we postulate a cumulative effect of public health programs for obesity prevention resulting, for example, in an increase in physical activity, and a decline in television viewing and in the consumption of sugar-sweetened soft drinks by children. Effective public health programs are urgently needed for developing countries, where obesity rates in children still continued to increase during the past decade.
PMCID: PMC3908468  PMID: 24485015
Obesity; Children and adolescents; Extreme obesity; Prevalence; Trend societal and environmental determinants
27.  Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial 
BMC Medicine  2014;12:16.
In this study, a combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated.
In total, 99 patients with stage III or IV oral carcinoma who had refused or were ineligible for surgery were enrolled in a randomized, placebo-controlled, double-blind, phase III clinical trial. They were randomly assigned to group I (n = 35; intra-arterial infusion of rAd-p53 plus chemotherapy), group II (n = 33; intra-arterial infusion of rAd-p53 plus placebo chemotherapy), or group III (n = 31; intra-arterial infusion of placebo rAd-p53 plus chemotherapy).
The median length of follow-up was 36 months (range, 3 to 86 months). During follow-up, 16 patients in group I, 20 in group II, and 22 in group III died. Group I (48.5%) had a higher complete response rate than groups II (16.7%) and III (17.2%) (P = 0.006). The rate of non-responders in group I was significantly lower than that in groups II and III (P < 0.020). A log-rank test for survival rate indicated that group I had a significantly higher survival rate than group III (P = 0.019). The survival rate of patients with stage III but not stage IV oral cancer was significantly higher in group I than in group III (P = 0.015, P = 0.200, respectively). The survival rate of patients with stage IV did not differ significantly among the three groups. Or the 99 patients, 63 patients experienced adverse events of either transient flu-like symptoms or bone marrow suppression, while 13 patients had both these conditions together. No replication-deficient virus was detected in patient serum, urine, or sputum. rAd-p53 treatment increased Bax expression in the primary tumor of 80% of patients, as shown by immunohistochemical staining.
Intra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma.
Trial registration
ChiCTR-TRC-09000392 (Date of registration: 2009-05-18).
PMCID: PMC3922639  PMID: 24479409
Oral carcinoma; Gene therapy; Chemotherapy; Intra-arterial infusion; p53
28.  Global collaborative networks on meta-analyses of randomized trials published in high impact factor medical journals: a social network analysis 
BMC Medicine  2014;12:15.
Research collaboration contributes to the advancement of knowledge by exploiting the results of scientific efforts more efficiently, but the global patterns of collaboration on meta-analysis are unknown. The purpose of this research was to describe and characterize the global collaborative patterns in meta-analyses of randomized trials published in high impact factor medical journals over the past three decades.
This was a cross-sectional, social network analysis. We searched PubMed for relevant meta-analyses of randomized trials published up to December 2012. We selected meta-analyses (including at least randomized trials as primary evidence source) published in the top seven high impact factor general medical journals (according to Journal Citation Reports 2011): The New England Journal of Medicine, The Lancet, the BMJ, JAMA, Annals of Internal Medicine, Archives of Internal Medicine (now renamed JAMA Internal Medicine), and PLoS Medicine. Opinion articles, conceptual papers, narrative reviews, reviews without meta-analysis, reviews of reviews, and other study designs were excluded.
Overall, we included 736 meta-analyses, in which 3,178 authors, 891 institutions, and 51 countries participated. The BMJ was the journal that published the greatest number of articles (39%), followed by The Lancet (18%), JAMA (15%) and the Archives of Internal Medicine (15%). The USA, the UK, and Canada headed the absolute global productivity ranking in number of papers. The 64 authors and the 39 institutions with the highest publication rates were identified. We also found 82 clusters of authors (one group with 55 members and one group with 54 members) and 19 clusters of institutions (one major group with 76 members). The most prolific authors were mainly affiliated with the University of Oxford (UK), McMaster University (Canada), and the University of Bern (Switzerland).
Our analysis identified networks of authors, institutions and countries publishing meta-analyses of randomized trials in high impact medical journals. This valuable information may be used to strengthen scientific capacity for collaboration and to help to promote a global agenda for future research of excellence.
PMCID: PMC3913337  PMID: 24476131
Authorship; Evidence-based medicine; Meta-analysis; Randomized controlled trial; Scientific collaboration; Social network analysis
29.  The value of screening in patient populations with high prevalence of a disorder 
BMC Medicine  2014;12:14.
Thombs and colleagues have shown that screening consecutive attendees in primary care settings in high income countries for depression is not worthwhile. However, it is dangerous to generalize from high income countries such as the USA to the rest of the world. The positive predictive value of any screening test for depression is affected by the prevalence of the disorder in the population being considered. Populations with an increased prevalence of depression, such as those with chronic physical disorders, or with a history of depression or other mental health problems may benefit from screening, even in high income countries. Populations in low and middle income countries (LMIC) may also benefit from screening if they are experiencing severe social adversity, including poverty. Two examples are given, in which screening with a brief screening questionnaire was followed by collaborative stepped care, to the considerable benefit of the patients in LMIC.
Please see related article:
PMCID: PMC3904156  PMID: 24472627
Screening; Depression; Positive predictive value; Low and middle income countries
30.  There are no randomized controlled trials that support the United States Preventive Services Task Force guideline on screening for depression in primary care: a systematic review 
BMC Medicine  2014;12:13.
The United States Preventive Services Task Force (USPSTF) recommends screening adults for depression in primary care settings when staff-assisted depression management programs are available. This recommendation, however, is based on evidence from depression management programs conducted with patients already identified as depressed, even though screening is intended to identify depressed patients not already recognized or treated. The objective of this systematic review was to evaluate whether there is evidence from randomized controlled trials (RCTs) that depression screening benefits patients in primary care, using an explicit definition of screening.
We re-evaluated RCTs included in the 2009 USPSTF evidence review on depression screening, including only trials that compared depression outcomes between screened and non-screened patients and met the following three criteria: determined patient eligibility and randomized prior to screening; excluded patients already diagnosed with a recent episode of depression or already being treated for depression; and provided the same level of depression treatment services to patients identified as depressed in the screening and non-screening trial arms. We also reviewed studies included in a recent Cochrane systematic review, but not the USPSTF review; conducted a focused search to update the USPSTF review; and reviewed trial registries.
Of the nine RCTs included in the USPSTF review, four fulfilled none of three criteria for a test of depression screening, four fulfilled one of three criteria, and one fulfilled two of three criteria. There were two additional RCTs included only in the Cochrane review, and each fulfilled one of three criteria. No eligible RCTs were found via the updated review.
The USPSTF recommendation to screen adults for depression in primary care settings when staff-assisted depression management programs are available is not supported by evidence from any RCTs that are directly relevant to the recommendation. The USPSTF should re-evaluate this recommendation.
Please see related article:
PROSPERO (#CRD42013004276)
PMCID: PMC3922694  PMID: 24472580
Depression; Primary care; Screening; Systematic review
31.  Spousal diabetes as a diabetes risk factor: A systematic review and meta-analysis 
BMC Medicine  2014;12:12.
Diabetes history in biologically-related individuals increases diabetes risk. We assessed diabetes concordance in spouses (that is, biologically unrelated family members) to gauge the importance of socioenvironmental factors.
We selected cross-sectional, case–control and cohort studies examining spousal association for diabetes and/or prediabetes (impaired fasting glucose or impaired glucose tolerance), indexed in Medline, Embase or Scopus (1 January 1997 to 28 February 2013). Effect estimates (that is, odds ratios, incidence rate ratios, and so on) with body mass index (BMI) adjustment were pooled separately from those without BMI adjustment (random effects models) to distinguish BMI-dependent and independent concordance.
Searches yielded 2,705 articles; six were retained (n = 75,498 couples) for systematic review and five for meta-analysis. Concordance was lowest in a study that relied on women’s reports of diabetes in themselves and their spouses (effect estimate 1.1, 95% CI 1.0 to 1.30) and highest in a study with systematic assessment of glucose tolerance (2.11, 95% CI 1.74 to 5.10). The random-effects pooled estimate adjusted for age and other covariates but not BMI was 1.26 (95% CI 1.08 to 1.45). The estimate with BMI adjustment was lower (1.18, 95% CI 0.97 to 1.40). Two studies assessing between-spouse associations of diabetes/prediabetes determined by glucose testing reported high concordance (OR 1.92, 95% CI 1.55 to 2.37 without BMI adjustment; 2.32, 95% CI 1.87 to 3.98 with BMI adjustment). Two studies did not distinguish type 1 and type 2 diabetes. However given that around 95% of adults is type 2, this is unlikely to have influenced the results.
Our pooled estimate suggests that a spousal history of diabetes is associated with a 26% diabetes risk increase. Recognizing shared risk between spouses may improve diabetes detection and motivate couples to increase collaborative efforts to optimize eating and physical activity habits.
PMCID: PMC3900990  PMID: 24460622
Diabetes mellitus; Prediabetes; Spouses concordance; Risk factor; Systematic review; Meta-analysis
32.  Video Q&A: Allergies and allergen immunotherapy - an interview with Alfred William Frankland 
BMC Medicine  2014;12:11.
In this video Q&A, we talk to Dr Alfred William Frankland about the highlights of his career, including working alongside Sir Alexander Fleming, co-founding the British Allergy Society, and introducing pollen counts to UK weather forecasts. We also discuss his opinions on why misconceptions about allergies and allergen immunotherapy still exist.
Please see related article:
PMCID: PMC3897924  PMID: 24447813
33.  BMC medicine editorial board members on open access publishing 
BMC Medicine  2014;12:10.
In recognition of Open Access week (21st-27th October 2013), we asked some BMC Medicine Editorial Board Members to share their views and experiences on open access publishing. In this short video, they highlight the benefits of visibility and dissemination of their research, and discuss the future directions for this model of publishing.
PMCID: PMC3897970  PMID: 24447778
34.  Reviewer acknowledgements for 2013 
BMC Medicine  2014;12:9.
Contributing reviewers
The editors of BMC Medicine would like to thank all our reviewers who have contributed to the journal in Volume 11 (2013).
PMCID: PMC3896687
35.  Video Q&A: State-of-the-art therapy for the elite and non-elite athlete: an interview with Mike Carmont 
BMC Medicine  2014;12:8.
In this video Q&A, Mr Mike Carmont answers questions about state-of-the-art treatments for elite athletes, and the progress and challenges behind translating these into successful therapies for the non-elite athlete.
PMCID: PMC3896799  PMID: 24438069
36.  Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis 
BMC Medicine  2014;12:7.
Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction.
A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method.
The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051).
The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.
PMCID: PMC3912923  PMID: 24433458
Stress; Life events; Childhood maltreatment; Childhood adversity; Child abuse; Depression; Brain-derived neurotrophic factor; BDNF; rs6265; Gene-environment interaction
37.  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.
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.
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.
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.
PMCID: PMC3895758  PMID: 24423387
Primary care; Integrated management; Integration; Quality improvement; Health care delivery; Health systems; IMAI
38.  Using verbal autopsy to measure causes of death: the comparative performance of existing methods 
BMC Medicine  2014;12:5.
Monitoring progress with disease and injury reduction in many populations will require widespread use of verbal autopsy (VA). Multiple methods have been developed for assigning cause of death from a VA but their application is restricted by uncertainty about their reliability.
We investigated the validity of five automated VA methods for assigning cause of death: InterVA-4, Random Forest (RF), Simplified Symptom Pattern (SSP), Tariff method (Tariff), and King-Lu (KL), in addition to physician review of VA forms (PCVA), based on 12,535 cases from diverse populations for which the true cause of death had been reliably established. For adults, children, neonates and stillbirths, performance was assessed separately for individuals using sensitivity, specificity, Kappa, and chance-corrected concordance (CCC) and for populations using cause specific mortality fraction (CSMF) accuracy, with and without additional diagnostic information from prior contact with health services. A total of 500 train-test splits were used to ensure that results are robust to variation in the underlying cause of death distribution.
Three automated diagnostic methods, Tariff, SSP, and RF, but not InterVA-4, performed better than physician review in all age groups, study sites, and for the majority of causes of death studied. For adults, CSMF accuracy ranged from 0.764 to 0.770, compared with 0.680 for PCVA and 0.625 for InterVA; CCC varied from 49.2% to 54.1%, compared with 42.2% for PCVA, and 23.8% for InterVA. For children, CSMF accuracy was 0.783 for Tariff, 0.678 for PCVA, and 0.520 for InterVA; CCC was 52.5% for Tariff, 44.5% for PCVA, and 30.3% for InterVA. For neonates, CSMF accuracy was 0.817 for Tariff, 0.719 for PCVA, and 0.629 for InterVA; CCC varied from 47.3% to 50.3% for the three automated methods, 29.3% for PCVA, and 19.4% for InterVA. The method with the highest sensitivity for a specific cause varied by cause.
Physician review of verbal autopsy questionnaires is less accurate than automated methods in determining both individual and population causes of death. Overall, Tariff performs as well or better than other methods and should be widely applied in routine mortality surveillance systems with poor cause of death certification practices.
PMCID: PMC3891983  PMID: 24405531
Verbal autopsy; VA; Validation; Cause of death; Symptom pattern; Random forests; InterVA; King-Lu; Tariff
39.  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.
PMCID: PMC3892052  PMID: 24405514
Open access; Translational medicine; Clinical oncology; Evidence-based medicine; Reporting guidelines
40.  Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial 
BMC Medicine  2014;12:2.
Although the use of bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT.
This was a single-center, prospective, randomized controlled trial comparing induction therapy consisting of two BD cycles followed by HDM/SCT (BD + HDM/SCT) with HDM/SCT alone in the treatment of patients with newly diagnosed AL amyloidosis. The hematological and organ responses of the patients were assessed every three months post HDM/SCT.
Fifty-six patients newly diagnosed with renal (100%), cardiac (57.1%), liver (7.1%), or nervous system (8.9%) AL amyloidosis were enrolled in this study; 28 patients were assigned to each arm. Two patients died within 100 days of HDM/SCT (3.6% treatment-related mortality). The overall hematologic response rates in the BD + HDM/SCT arm and HDM/SCT arm at three, six and twelve months were 78.5% versus 50%, 82.1% versus 53.5% and 85.7% versus 53.5%, respectively. In the BD + HDM/SCT arm, 15 (53.5%) patients achieved a hematologic response after BD and before HDM/SCT. An intention-to-treat analysis revealed a higher rate of complete remission in the BD + HDM/SCT arm at both 12 and 24 months (67.9% and 70%, respectively) than with the HDM/SCT-only therapy (35.7% and 35%, respectively, P = 0.03). After a median follow-up of 28 months, the survival rates at 24 months post-treatment start were 95.0% in the BD + HDM/SCT group and 69.4% in the HDM/SCT alone group (P = 0.03).
Our preliminary data suggest that the outcome of treating AL amyloidosis with BD induction and HDM/SCT was superior to the outcome of the HDM/SCT treatment alone.
Trial registration
This trial has been registered at with the number NCT01998503.
PMCID: PMC3895846  PMID: 24386911
AL amyloidosis; Bortezomib; Autologous stem cell transplantation
41.  Whole home exercise intervention for depression in older care home residents (the OPERA study): a process evaluation 
BMC Medicine  2014;12:1.
The ‘Older People’s Exercise intervention in Residential and nursing Accommodation’ (OPERA) cluster randomised trial evaluated the impact of training for care home staff together with twice-weekly, physiotherapist-led exercise classes on depressive symptoms in care home residents, but found no effect. We report a process evaluation exploring potential explanations for the lack of effect.
The OPERA trial included over 1,000 residents in 78 care homes in the UK. We used a mixed methods approach including quantitative data collected from all homes. In eight case study homes, we carried out repeated periods of observation and interviews with residents, care staff and managers. At the end of the intervention, we held focus groups with OPERA research staff. We reported our first findings before the trial outcome was known.
Homes showed large variations in activity at baseline and throughout the trial. Overall attendance rate at the group exercise sessions was low (50%). We considered two issues that might explain the negative outcome: whether the intervention changed the culture of the homes, and whether the residents engaged with the intervention. We found low levels of staff training, few home champions for the intervention and a culture that prioritised protecting residents from harm over encouraging activity. The trial team delivered 3,191 exercise groups but only 36% of participants attended at least 1 group per week and depressed residents attended significantly fewer groups than those who were not depressed. Residents were very frail and therefore most groups only included seated exercises.
The intervention did not change the culture of the homes and, in the case study homes, activity levels did not change outside the exercise groups. Residents did not engage in the exercise groups at a sufficient level, and this was particularly true for those with depressive symptoms at baseline. The physical and mental frailty of care home residents may make it impossible to deliver a sufficiently intense exercise intervention to impact on depressive symptoms.
PMCID: PMC3882778  PMID: 24386900
Elderly residential care; Process evaluation; Exercise; Depression; Culture change; Cluster randomised controlled trial
42.  Multimorbidity in bipolar disorder and undertreatment of cardiovascular disease: a cross sectional study 
BMC Medicine  2013;11:263.
Individuals with serious mental disorders experience poor physical health, especially increased rates of cardiometabolic morbidity and premature morbidity. Recent evidence suggests that individuals with schizophrenia have numerous comorbid physical conditions that may be under-recorded and undertreated, but to date very few studies have explored this issue for bipolar disorder.
We conducted a cross-sectional analysis of a dataset of 1,751,841 registered patients within 314 primary care practices in Scotland, UK. Bipolar disorder was identified using Read Codes recorded within electronic medical records. Data on 32 common chronic physical conditions were also assessed. Potential prescribing inequalities were evaluated by analysing prescribing data for coronary heart disease (CHD) and hypertension.
Compared to controls, individuals with bipolar disorder were significantly less likely to have no recorded physical conditions (OR 0.59, 95% CI 0.54 to 0.63) and significantly more likely to have one physical condition (OR 1.27, 95% CI 1.16 to 1.39), two physical conditions (OR 1.45, 95% CI 1.30 to 1.62) and three or more physical conditions (OR 1.44, 95% CI 1.30 to 1.64). People with bipolar disorder also had higher rates of thyroid disorders, chronic kidney disease, chronic pain, chronic obstructive airways disease and diabetes but, surprisingly, lower recorded rates of hypertension and atrial fibrillation. People with bipolar disorder and comorbid CHD or hypertension were significantly more likely to be prescribed no antihypertensive or cholesterol-lowering medications compared to controls, and bipolar individuals with CHD or hypertension were significantly less likely to be on two or more antihypertensive agents.
Individuals with bipolar disorder are similar to individuals with schizophrenia in having a wide range of comorbid and multiple physical health conditions. They are also less likely than controls to have a primary-care record of cardiovascular conditions such as hypertension and atrial fibrillation. Those with a recorded diagnosis of CHD or hypertension were less likely to be treated with cardiovascular medications and were treated less intensively. This study highlights the high physical healthcare needs of people with bipolar disorder, and provides evidence for a systematic under-recognition and undertreatment of cardiovascular disease in this group.
PMCID: PMC3880052  PMID: 24359325
Bipolar disorder; Coronary heart disease; Medication; Comorbidity
44.  Simple steps to equity in child survival 
BMC Medicine  2013;11:261.
Although the number of child deaths has declined globally over the past 20 years, many countries still lag behind their millennium development goal targets, and inequity in child health remains a pernicious problem both between and within countries. Breastfeeding is a key intervention to reduce child mortality, and in an article published in BMC Medicine, Roberts and colleagues have shown that breastfeeding interventions can have a significant role in reducing inequity in child health. With the proper attention paid to overcoming the barriers to scaling up breastfeeding interventions, deployment of effective interventions in health facilities and the community, and improvements in support for breastfeeding interventions across society, many countries that are struggling to meet their millennium development goals could make significant gains in child survival and inequity.
Please see related research:
PMCID: PMC3866563  PMID: 24344755
Breastfeeding; Child mortality; Health inequity; Interventions; Millennium development goals
45.  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:
PMCID: PMC3866248  PMID: 24344725
Extracranial venous system; Jugular venous reflux; Chronic cerebrospinal venous insufficiency; CNS pathology; Aging
46.  Potential involvement of the extracranial venous system in central nervous system disorders and aging 
BMC Medicine  2013;11:260.
The role of the extracranial venous system in the pathology of central nervous system (CNS) disorders and aging is largely unknown. It is acknowledged that the development of the venous system is subject to many variations and that these variations do not necessarily represent pathological findings. The idea has been changing with regards to the extracranial venous system.
A range of extracranial venous abnormalities have recently been reported, which could be classified as structural/morphological, hemodynamic/functional and those determined only by the composite criteria and use of multimodal imaging. The presence of these abnormalities usually disrupts normal blood flow and is associated with the development of prominent collateral circulation. The etiology of these abnormalities may be related to embryologic developmental arrest, aging or other comorbidities. Several CNS disorders have been linked to the presence and severity of jugular venous reflux. Another composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI) was recently introduced. CCSVI is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous outflow.
Additional research is needed to better define the role of the extracranial venous system in relation to CNS disorders and aging. The use of endovascular treatment for the correction of these extracranial venous abnormalities should be discouraged, until potential benefit is demonstrated in properly-designed, blinded, randomized and controlled clinical trials.
Please see related editorial:
PMCID: PMC3866257  PMID: 24344742
Jugular vein reflux; CCSVI; Anatomy; Etiology; Pathophysiology; Classification; Diagnosis; CNS disorders; Aging; Multiple sclerosis; Compensatory mechanism
47.  Who uses emergency departments inappropriately and when - a national cross-sectional study using a monitoring data system 
BMC Medicine  2013;11:258.
Increasing pressures on emergency departments (ED) are straining services and creating inefficiencies in service delivery worldwide. A potentially avoidable pressure is inappropriate attendances (IA); typically low urgency, self-referred patients better managed by other services. This study examines demographics and temporal trends associated with IA to help inform measures to address them.
Using a national ED dataset, a cross-sectional examination of ED attendances in England from April 2011 to March 2012 (n = 15,056,095) was conducted. IA were defined as patients who were self-referred; were not attending a follow-up; received no investigation and either no treatment or ‘guidance/advice only’; and were discharged with either no follow-up or follow-up with primary care. Small, nationally representative areas were used to assign each attendance to a residential measure of deprivation. Multivariate analysis was used to predict relationships between IA, demographics (age, gender, deprivation) and temporal factors (day, month, hour, bank holiday, Christmas period).
Overall, 11.7% of attendances were categorized as inappropriate. IA peaked in early childhood (adjusted odds ratio (AOR) = 1.53 for both one and two year olds), and was elevated throughout late-teens and young adulthood, with odds reducing steadily from age 27 (reference category, age 40). Both IA and appropriate attendances (AA) were most frequent in the most deprived populations. However, relative to AA, those living in the least deprived areas had the highest odds of IA (AOR = 0.89 in most deprived quintile). Odds of IA were also higher for males (AOR = 0.95 in females). Both AA and IA were highest on Mondays, whilst weekends, bank holidays and the period between 8 am and 4 pm saw more IA relative to AA.
Prevention of IA would be best targeted at parents of young children and at older youths/young adults, and during weekends and bank holidays. Service provision focusing on access to primary care and EDs serving the most deprived communities would have the most benefit. Improvements in coverage and data quality of the national ED dataset, and the addition of an appropriateness field, would make this dataset an effective monitoring tool to evaluate interventions addressing this issue.
PMCID: PMC3886196  PMID: 24330758
Emergency department; Inappropriate attendance; Health service use
48.  Can breastfeeding promote child health equity? A comprehensive analysis of breastfeeding patterns across the developing world and what we can learn from them 
BMC Medicine  2013;11:254.
In 2010 more than 7.7 million children died before their fifth birthday. Over 98% of these deaths occurred in developing countries, and recent estimates have attributed hundreds of thousands of these deaths to suboptimal breastfeeding.
This study estimated prevalence of suboptimal breastfeeding for 137 developing countries from 1990 to 2010. These estimates were compared against WHO infant feeding recommendations and combined with effect sizes from existing literature to estimate associated disease burden using a standard comparative risk assessment approach. These prevalence estimates were disaggregated by wealth quintile and linked with child mortality rates to assess how improved rates of breastfeeding may affect child health inequalities.
In 2010, the prevalence of exclusive breastfeeding ranged from 3.5% in Djibouti to 77.3% in Rwanda. The proportion of child Disability Adjusted Life Years (DALYs) attributable to suboptimal breastfeeding is 7.6% at the global level and as high as 20.2% in Swaziland. Suboptimal breastfeeding is a leading childhood risk factor in all developing countries and consistently ranks higher than water and sanitation. Within most countries, breastfeeding prevalence rates do not vary considerably across wealth quintiles.
Breastfeeding is an effective child health intervention that does not require extensive health system infrastructure. Improvements in rates of exclusive and continued breastfeeding can contribute to the reduction of child mortality inequalities in developing countries.
PMCID: PMC3896843  PMID: 24305597
Breastfeeding; Health inequity; Child health; Global burden of disease; Infant feeding
49.  What if HIV were unable to develop resistance against a new therapeutic agent? 
BMC Medicine  2013;11:249.
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.
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.
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.
PMCID: PMC3842747  PMID: 24267867
Human immunodeficiency virus type 1; Integrase inhibitors; Antiretroviral therapy; Dolutegravir; HIV prevention strategies; Viral fitness; Drug resistance
50.  The effectiveness of police custody assessments in identifying suspects with intellectual disabilities and attention deficit hyperactivity disorder 
BMC Medicine  2013;11:248.
Intellectual Disabilities (ID) and Attention Deficit Hyperactivity Disorder (ADHD) are recognized psychological vulnerabilities in police interviews and court proceedings in England and Wales. The aims of this study were to investigate: (a) the prevalence of ID and/or ADHD among suspects detained at a large London metropolitan police station and their relationship with conduct disorder (CD), (b) the impact of their condition on police staff resources, (c) the effectiveness of current custody assessment tools in identifying psychological vulnerabilities, and (d) the use of ‘Appropriate Adults’ in interviews.
A total of 200 individuals in a police custody suite were interviewed and screened for ID, ADHD (current symptoms) and CD.
The screening rates for these three disorders were 6.7%, 23.5% and 76.3%, respectively. ADHD contributed significantly to increased requests being made of staff after controlling for CD and duration of time in custody. This is a novel finding. Reading and writing difficulties and mental health problems were often identified from the custody risk assessment tools, but they were not used effectively to inform on the need for the use of an Appropriate Adult. The frequency with which Appropriate Adults were provided to support detainees in police interviews (4.2%) remains almost identical to that found in a similar study conducted 20 years previously.
The current findings suggest that in spite of reforms recently made in custodial settings, procedures may not have had the anticipated impact of improving safeguards for vulnerable suspects. Detainees with ID and ADHD require an Appropriate Adult during police interviews and other formal custody procedures, which they commonly do not currently receive. The findings of the current study suggest this may be due, in large part, to the ineffective use of risk-assessment tools and healthcare professionals, which represent missed opportunities to identify such vulnerabilities.
PMCID: PMC3879086  PMID: 24261542
Intellectual disabilities; ADHD; Conduct disorder; IQ; Risk assessment; Police

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