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.
Breast cancer; Post-translational modifications; Progesterone receptor; Signal transduction
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.
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.
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.
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.
Severe malaria; Invasive bacterial infection; Gram-negative organisms; Children; Mortality; Epidemiology; Africa
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.
Systemic lupus erythematosus; Biologic therapy; Randomized controlled trials; Belimumab; Anti-B cell therapies
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.
Apps; Ehealth; Mhealth; Smartphone; Technology adoption
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.
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.
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).
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.
Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers
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.
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).
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.
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.
Prostate cancer; Early detection; Overdiagnosis; PSA; Screening
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.
Biologics; Rheumatoid arthritis; Treatment
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.
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.
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%).
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.
Causes of death; Computer-coded verbal autopsy (CCVA); InterVA-4; King-Lu; Physician-certified verbal autopsy (PCVA); Random forest; Tariff method; Validation; Verbal autopsy
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).
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.
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.
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.
Verbal autopsy; Physician-certified verbal autopsy; Cause of death statistics; Vital statistics; India
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.
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.
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.
Causes of death; Cause of death statistics; Mortality; Vital statistics; Verbal autopsy; Sample registration system
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.
Cause of death; Verbal autopsy; Automated diagnosis; Health information system; Evaluation of health programs; Public health
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.
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.
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.
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.
Verbal autopsy; Cause of death; Death registration; Low- and middle-income countries; InterVA
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.
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.
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.
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.
Causes of death; Computer-coded verbal autopsy; InterVA; King and Lu; Physician-certified verbal autopsy; Random forest; Simplified symptom pattern; Tariff; Validity; Verbal autopsy
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.
Obesity; Children and adolescents; Extreme obesity; Prevalence; Trend societal and environmental determinants
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.
ChiCTR-TRC-09000392 (Date of registration: 2009-05-18).
Oral carcinoma; Gene therapy; Chemotherapy; Intra-arterial infusion; p53
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.
Authorship; Evidence-based medicine; Meta-analysis; Randomized controlled trial; Scientific collaboration; Social network analysis
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: http://www.biomedcentral.com/1741-7015/12/13.
Screening; Depression; Positive predictive value; Low and middle income countries
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: http://www.biomedcentral.com/1741-7015/12/14
Depression; Primary care; Screening; Systematic review
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.
Diabetes mellitus; Prediabetes; Spouses concordance; Risk factor; Systematic review; Meta-analysis
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: http://www.biomedcentral.com/1741-7015/11/255.
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.
The editors of BMC Medicine would like to thank all our reviewers who have contributed to the journal in Volume 11 (2013).
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.
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.
Stress; Life events; Childhood maltreatment; Childhood adversity; Child abuse; Depression; Brain-derived neurotrophic factor; BDNF; rs6265; Gene-environment interaction
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.
Primary care; Integrated management; Integration; Quality improvement; Health care delivery; Health systems; IMAI