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1.  Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients 
European heart journal  2013;35(13):844-852.
Aims
The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD.
Methods and results
Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan–Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13-16 life years or 15-18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation.
Conclusion
These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.
doi:10.1093/eurheartj/eht533
PMCID: PMC3971383  PMID: 24353280
Stable coronary artery disease; Stable angina; Prognosis; Myocardial infarction; Electronic health records; CALIBER
2.  Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals 
Background At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).
Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for ε2/ε2; 0.85 (95% CrI: 0.78–0.92) for ε2/ε3; 1.05 (95% CrI: 0.89–1.24) for ε2/ε4; 1.05 (95% CrI: 0.99–1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94–1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.
Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
doi:10.1093/ije/dyt034
PMCID: PMC3619955  PMID: 23569189
Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers
3.  Rationale and cross-sectional study design of the Research on Obesity and type 2 Diabetes among African Migrants: the RODAM study 
BMJ Open  2014;4(3):e004877.
Introduction
Obesity and type 2 diabetes (T2D) are highly prevalent among African migrants compared with European descent populations. The underlying reasons still remain a puzzle. Gene–environmental interaction is now seen as a potential plausible factor contributing to the high prevalence of obesity and T2D, but has not yet been investigated. The overall aim of the Research on Obesity and Diabetes among African Migrants (RODAM) project is to understand the reasons for the high prevalence of obesity and T2D among sub-Saharan Africans in diaspora by (1) studying the complex interplay between environment (eg, lifestyle), healthcare, biochemical and (epi)genetic factors, and their relative contributions to the high prevalence of obesity and T2D; (2) to identify specific risk factors within these broad categories to guide intervention programmes and (3) to provide a basic knowledge for improving diagnosis and treatment.
Methods and analysis
RODAM is a multicentre cross-sectional study among homogenous sub-Saharan African participants (ie, Ghanaians) aged >25 years living in rural and urban Ghana, the Netherlands, Germany and the UK (http://rod-am.eu/). Standardised data on the main outcomes, genetic and non-genetic factors are collected in all locations. The aim is to recruit 6250 individuals comprising five subgroups of 1250 individuals from each site. In Ghana, Kumasi and Obuasi (urban stratum) and villages in the Ashanti region (rural stratum) are served as recruitment sites. In Europe, Ghanaian migrants are selected through the municipality or Ghanaian organisations registers.
Ethics and dissemination
Ethical approval has been obtained in all sites. This paper gives an overview of the rationale, conceptual framework and methods of the study. The differences across locations will allow us to gain insight into genetic and non-genetic factors contributing to the occurrence of obesity and T2D and will inform targeted intervention and prevention programmes, and provide the basis for improving diagnosis and treatment in these populations and beyond.
doi:10.1136/bmjopen-2014-004877
PMCID: PMC3963103  PMID: 24657884
Epidemiology
4.  Prescription of antiviral therapy after herpes zoster in general practice: who receives therapy? 
The British Journal of General Practice  2012;62(605):e808-e814.
Background
Antivirals can accelerate rash healing during an acute zoster episode and can limit the severity and duration of pain. Their use within 7 days of rash onset is recommended among specific patient groups.
Aim
To describe antiviral prescription patterns and patient characteristics associated with antiviral receipt after zoster diagnosis.
Design and setting
Descriptive study and risk factor analysis using electronic healthcare records from UK general practice.
Method
Incident adult zoster cases occurring between 2000 and 2011 were identified in the General Practice Research Database. Therapy records were searched for antiviral prescriptions of aciclovir, famciclovir, or valaciclovir within 7 days of zoster diagnosis. The proportion of incident zoster cases receiving antivirals was calculated and multivariable logistic regression used to assess associations between patient characteristics and antiviral use.
Results
Of 142 216 incident zoster cases 58.1% received an antiviral prescription. The majority (69.0%) were aciclovir. The proportion receiving antiviral prescriptions increased with age up to 65 years, then declined to 56.8% among patients aged ≥85 years. Being female and of higher socioeconomic status were associated with higher antiviral receipt. Antivirals were more commonly prescribed to immunosuppressed patients with herpes zoster (odds ratio 1.27; 95% CI = 1.22 to 1.33), however they were not given routinely to this patient group.
Conclusion
Antiviral therapies for zoster are under-prescribed in UK general practice even among groups, such as immunosuppressed and older individuals, for whom guidelines recommend treatment. Patients may present too late to receive treatment or physicians may decide that antivirals are not essential treatment. Consideration could be given to reviewing the guidelines.
doi:10.3399/bjgp12X659277
PMCID: PMC3505413  PMID: 23211260
antivirals; database; epidemiology; general practice; GPRD; herpes zoster; shingles; United Kingdom
5.  Chickenpox and Risk of Stroke: A Self-controlled Case Series Analysis 
Children who experience chickenpox are at a 4-fold increased risk of ischemic stroke in the subsequent 6 months. The evidence is less strong for adults, possibly due to mechanistic differences in the role of inflammation in adult stroke risk.
Background. There is good evidence that respiratory and other infections that cause systemic inflammation can trigger strokes; however, the role of specific infections is unclear. Case reports have highlighted chickenpox as a possible risk factor for arterial ischemic stroke, particularly in children, but rigorous studies are needed to determine and quantify any increased risk.
Methods. We used anonymized electronic health records totaling >100 million person-years of observation from 4 UK primary care databases to identify individuals who had documented clinical chickenpox and a stroke or transient ischemic attack (TIA). Self-controlled case series methods were used to quantify any increased risk of first stroke or TIA in the 0–6 and 7–12 months following chickenpox compared to other observed time periods. We analyzed data within each database, and performed meta-analyses to obtain summary age-adjusted incidence ratios (IRs) separately for adults and children.
Results. Five hundred sixty eligible individuals (including 60 children) were identified who experienced chickenpox and a stroke or TIA during follow-up. Among children, there was a 4-fold increased risk of stroke in the 0–6 months after chickenpox (summary IR = 4.07; 95% confidence interval [CI], 1.96–8.45; I2 = 0%). Among adults, there was a less marked increased risk with moderate between-database heterogeneity (random-effects summary IR = 2.13; 95% CI, 1.05–4.36; I2 = 51%). There was no significant increased risk of stroke in the 7–12 months after chickenpox in children or adults, nor was there evidence of increased risk of TIA in either time period.
Conclusions. Our study provides new evidence that children who experience chickenpox are at increased risk of stroke in the subsequent 6 months.
doi:10.1093/cid/cit659
PMCID: PMC3864501  PMID: 24092802
chickenpox; stroke; child; adult; risk factors
6.  Representativeness and optimal use of body mass index (BMI) in the UK Clinical Practice Research Datalink (CPRD) 
BMJ Open  2013;3(9):e003389.
Objectives
To assess the completeness and representativeness of body mass index (BMI) data in the Clinical Practice Research Datalink (CPRD), and determine an optimal strategy for their use.
Design
Descriptive study.
Setting
Electronic healthcare records from primary care.
Participants
A million patient random sample from the UK CPRD primary care database, aged ≥16 years.
Primary and secondary outcome measures
BMI completeness in CPRD was evaluated by age, sex and calendar period. CPRD-based summary BMI statistics for each calendar year (2003–2010) were age-standardised and sex-standardised and compared with equivalent statistics from the Health Survey for England (HSE).
Results
BMI completeness increased over calendar time from 37% in 1990–1994 to 77% in 2005–2011, was higher among females and increased with age. When BMI at specific time points was assigned based on the most recent record, calendar–year-specific mean BMI statistics underestimated equivalent HSE statistics by 0.75–1.1 kg/m2. Restriction to those with a recent (≤3 years) BMI resulted in mean BMI estimates closer to HSE (≤0.28 kg/m2 underestimation), but excluded up to 47% of patients. An alternative strategy of imputing up-to-date BMI based on modelled changes in BMI over time since the last available record also led to mean BMI estimates that were close to HSE (≤0.37 kg/m2 underestimation).
Conclusions
Completeness of BMI in CPRD increased over time and varied by age and sex. At a given point in time, a large proportion of the most recent BMIs are unlikely to reflect current BMI; consequent BMI misclassification might be reduced by employing model-based imputation of current BMI.
doi:10.1136/bmjopen-2013-003389
PMCID: PMC3773634  PMID: 24038008
Epidemiology; Primary Care; Statistics & Research Methods
7.  Incidence of Community-Acquired Lower Respiratory Tract Infections and Pneumonia among Older Adults in the United Kingdom: A Population-Based Study 
PLoS ONE  2013;8(9):e75131.
Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations.
doi:10.1371/journal.pone.0075131
PMCID: PMC3770598  PMID: 24040394
8.  Acute Maternal Infection and Risk of Pre-Eclampsia: A Population-Based Case-Control Study 
PLoS ONE  2013;8(9):e73047.
Background
Infection in pregnancy may be involved in the aetiology of pre-eclampsia. However, a clear association between acute maternal infection and pre-eclampsia has not been established. We assessed whether acute urinary tract infection, respiratory tract infection, and antibiotic drug prescriptions in pregnancy (a likely proxy for maternal infection) are associated with an increased risk of pre-eclampsia.
Methods and Findings
We used a matched nested case-control design and data from the UK General Practice Research Database to examine the association between maternal infection and pre-eclampsia. Primiparous women aged at least 13 years and registered with a participating practice between January 1987 and October 2007 were eligible for inclusion. We selected all cases of pre-eclampsia and a random sample of primiparous women without pre-eclampsia (controls). Cases (n = 1533) were individually matched with up to ten controls (n = 14236) on practice and year of delivery. We calculated odds ratios and 95% confidence intervals for pre-eclampsia comparing women exposed and unexposed to infection using multivariable conditional logistic regression. After adjusting for maternal age, pre-gestational hypertension, diabetes, renal disease and multifetal gestation, the odds of pre-eclampsia were increased in women prescribed antibiotic drugs (adjusted odds ratio 1.28;1.14–1.44) and in women with urinary tract infection (adjusted odds ratio 1.22;1.03–1.45). We found no association with maternal respiratory tract infection (adjusted odds ratio 0.91;0.72–1.16). Further adjustment for maternal smoking and pre-pregnancy body mass index made no difference to our findings.
Conclusions
Women who acquire a urinary infection during pregnancy, but not those who have a respiratory infection, are at an increased risk of pre-eclampsia. Maternal antibiotic prescriptions are also associated with an increased risk. Further research is required to elucidate the underlying mechanism of this association and to determine whether, among women who acquire infections in pregnancy, prompt treatment or prophylaxis against infection might reduce the risk of pre-eclampsia.
doi:10.1371/journal.pone.0073047
PMCID: PMC3760871  PMID: 24019891
9.  Type and timing of heralding in ST-elevation and non-ST-elevation myocardial infarction: an analysis of prospectively collected electronic healthcare records linked to the national registry of acute coronary syndromes 
Aims:
It is widely thought that ST-elevation myocardial infarction (STEMI) is more likely to occur without warning (i.e. an unanticipated event in a previously healthy person) than non-ST-elevation myocardial infarction (NSTEMI), but no large study has evaluated this using prospectively collected data. The aim of this study was to compare the evolution of atherosclerotic disease and cardiovascular risk between people going on to experience STEMI and NSTEMI.
Methods:
We identified patients experiencing STEMI and NSTEMI in the national registry of myocardial infarction for England and Wales (Myocardial Ischaemia National Audit Project), for whom linked primary care records were available in the General Practice Research Database (as part of the CALIBER collaboration). We compared the prevalence and timing of atherosclerotic disease and major cardiovascular risk factors including smoking, hypertension, diabetes, and dyslipidaemia, between patients later experiencing STEMI to those experiencing NSTEMI.
Results:
A total of 8174 myocardial infarction patients were included (3780 STEMI, 4394 NSTEMI). Myocardial infarction without heralding by previously diagnosed atherosclerotic disease occurred in 71% STEMI (95% CI 69–72%) and 50% NSTEMI patients (95% CI 48–51%). The proportions of myocardial infarctions with no prior atherosclerotic disease, major risk factors, or chest pain was 14% (95% CI 13–16%) in STEMI and 9% (95% CI 9–10%) in NSTEMI. The rate of heralding coronary diagnoses was particularly high in the 12 months before infarct; 4.1-times higher (95% CI 3.3–5.0) in STEMI and 3.6-times higher (95% CI 3.1–4.2) in NSTEMI compared to the rate in earlier years.
Conclusions:
Acute myocardial infarction occurring without prior diagnosed coronary, cerebrovascular, or peripheral arterial disease was common, especially for STEMI. However, there was a high prevalence of risk factors or symptoms in patients without previously diagnosed disease. Better understanding of the antecedents in the year before myocardial infarction is required.
doi:10.1177/2048872613487495
PMCID: PMC3821819  PMID: 24222835
Cardiovascular diseases; epidemiology; myocardial infarction; risk factors
10.  Time series regression studies in environmental epidemiology 
Time series regression studies have been widely used in environmental epidemiology, notably in investigating the short-term associations between exposures such as air pollution, weather variables or pollen, and health outcomes such as mortality, myocardial infarction or disease-specific hospital admissions. Typically, for both exposure and outcome, data are available at regular time intervals (e.g. daily pollution levels and daily mortality counts) and the aim is to explore short-term associations between them. In this article, we describe the general features of time series data, and we outline the analysis process, beginning with descriptive analysis, then focusing on issues in time series regression that differ from other regression methods: modelling short-term fluctuations in the presence of seasonal and long-term patterns, dealing with time varying confounding factors and modelling delayed (‘lagged’) associations between exposure and outcome. We finish with advice on model checking and sensitivity analysis, and some common extensions to the basic model.
doi:10.1093/ije/dyt092
PMCID: PMC3780998  PMID: 23760528
Time series; environmental epidemiology; air pollution
11.  Variability of antibiotic prescribing in patients with chronic obstructive pulmonary disease exacerbations: a cohort study 
Background
The role of antibiotics in treating mild or moderate exacerbations in patients with acute chronic obstructive pulmonary disease (COPD) is unclear. The aims were to: (i) describe patient characteristics associated with acute exacerbations amongst a representative COPD population, (ii) explore the relationship between COPD severity and outcomes amongst patients with exacerbations, and (iii) quantify variability by general practice in prescribing of antibiotics for COPD exacerbations.
Method
A cohort of 62,747 patients with COPD was identified from primary care general practices (GP) in England, and linked to hospital admission and death certificate data. Exacerbation cases were matched to three controls and characteristics compared using conditional logistic regression. Outcomes were compared using incidence rates and Cox regression, stratified by disease severity. Variability of prescribing at the GP level was evaluated graphically and by using multilevel models.
Results
COPD severity was found to be associated with exacerbation and subsequent mortality (very severe vs. mild, odds ratio for exacerbation 2.12 [95%CI 19.5–2.32]), hazard ratio for mortality 2.14 [95%CI 1.59–2.88]). Whilst 61% of exacerbation cases were prescribed antibiotics, this proportion varied considerably between GP practices (interquartile range, 48–73%). This variation is greater than can be explained by patient characteristics alone.
Conclusions
There is significant variability between GP practices in the prescribing of antibiotics to COPD patients experiencing exacerbations. Combined with a lack of evidence on the effects of treatment, this supports the need and opportunity for a large scale pragmatic randomised trial of the prescribing of antibiotics for COPD patients with exacerbations, in order to clarify their effectiveness and long term outcomes whilst ensuring the representativeness of subjects.
doi:10.1186/1471-2466-13-32
PMCID: PMC3679783  PMID: 23724907
Chronic obstructive pulmonary disease; Disease exacerbation; Clinical practice variation; Anti-bacterial agents; Primary health care; General practice
12.  Polymorphisms in ARMS2/HTRA1 and Complement Genes and Age-Related Macular Degeneration in India: Findings from the INDEYE Study 
Purpose.
Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India.
Methods.
Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1–3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center.
Results.
Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154), or CFB (rs438999) was not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13–1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15–2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02–1.23; P = 0.02); rs10490923 was not associated with early or late AMD.
Conclusions.
Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.
We report results from a genetic association study of early AMD in an Indian population. Two variants in the ARMS/HTRA1 region were associated with early AMD but variants in C2, CFH, and CFB were not.
doi:10.1167/iovs.12-10073
PMCID: PMC3490538  PMID: 23060141
13.  Herpes Zoster Vaccine Effectiveness against Incident Herpes Zoster and Post-herpetic Neuralgia in an Older US Population: A Cohort Study 
PLoS Medicine  2013;10(4):e1001420.
Sinead Marie Langan and colleagues studied a cohort of more than 750,000 individuals over the age of 65 years to assess whether herpes zoster vaccine is effective against incident zoster and post-herpetic neuralgia in an older population.
Background
Herpes zoster is common and has serious consequences, notably post-herpetic neuralgia (PHN). Vaccine efficacy against incident zoster and PHN has been demonstrated in clinical trials, but effectiveness has not been studied in unselected general populations unrestricted by region, full health insurance coverage, or immune status. Our objective was to assess zoster vaccine effectiveness (VE) against incident zoster and PHN in a general population-based setting.
Methods and Findings
A cohort study of 766,330 fully eligible individuals aged ≥65 years was undertaken in a 5% random sample of Medicare who received and did not receive zoster vaccination between 1st January 2007 and 31st December 2009.
Incidence rates and hazard ratios for zoster and PHN were determined in vaccinated and unvaccinated individuals. Analyses were adjusted for age, gender, race, low income, immunosuppression, and important comorbidities associated with zoster, and then stratified by immunosuppression status. Adjusted hazard ratios were estimated using time-updated Cox proportional hazards models.
Vaccine uptake was low (3.9%) particularly among black people (0.3%) and those with evidence of low income (0.6%). 13,112 US Medicare beneficiaries developed incident zoster; the overall zoster incidence rate was 10.0 (9.8–10.2) per 1,000 person-years in the unvaccinated group and 5.4 (95% CI 4.6–6.4) per 1,000 person-years in vaccinees, giving an adjusted VE against incident zoster of 0.48 (95% CI 0.39–0.56). In immunosuppressed individuals, VE against zoster was 0.37 (95% CI 0.06–0.58). VE against PHN was 0.59 (95% CI 0.21–0.79).
Conclusions
Vaccine uptake was low with variation in specific patient groups. In a general population cohort of older individuals, zoster vaccination was associated with reduction in incident zoster, including among those with immunosuppression. Importantly, this study demonstrates that zoster vaccination is associated with a reduction in PHN.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chickenpox is an extremely common childhood infectious disease that is caused by the herpes varicella-zoster virus. Children usually recover quickly from chickenpox, but dormant varicella-zoster virus persists throughout life inside the nervous system. The dormant virus causes no symptoms but if it becomes reactivated, it causes shingles (zoster), a painful skin rash. Anyone who has had chickenpox can develop shingles but shingles is most common and most severe in 60–80-year-old people. Indeed, about half of people who live to 85 will have an episode of shingles. Early signs of shingles include burning or shooting pain and tingling or itching. Blister-like sores, which last from 1–14 days, then develop in a region of one side of the body or on one side of the face. The pain of shingles can be debilitating and can continue after the rash disappears—“post-herpetic neuralgia,” which can last for months to years, greatly reduces the quality of life. There is no cure for shingles but early treatment with antivirals may help to prevent lingering pain by inhibiting viral replication.
Why Was This Study Done?
Shingles vaccination can prevent shingles or lessen its effects. In clinical trials, vaccination reduced the incidence of shingles (the proportion of a population who develop shingles in a year) and the incidence of post-herpetic neuralgia, and vaccination against shingles is now recommended in the US for everyone over the age of 60 except individuals with a weakened immune system (for example, people with HIV/AIDS). However, these clinical trials determined the vaccine's efficacy in selected populations under controlled conditions. How effective is the vaccine in unselected populations in routine clinical use? In this cohort study, the researchers assess zoster (shingles) vaccine effectiveness against incident shingles and post-herpetic neuralgia in an unselected population of older individuals in the US. A cohort study follows a group of individuals who differ with respect to specific factors (in this study, vaccination against shingles) to determine how these factors affect the rates of specific outcomes (shingles and post-herpetic neuralgia).
What Did the Researchers Do and Find?
The researchers undertook their cohort study in 766,330 randomly chosen Medicare beneficiaries aged 65 years or more. Medicare is a US government health insurance scheme that mainly helps to pay the health care costs of people aged 65 or older. The researchers used Medicare administrative data to identify which cohort members received zoster vaccination between January 2007 and December 2009 and which developed incident shingles (defined as a first diagnosis of shingles combined with the use of antivirals) or post-herpetic neuralgia (defined as a code for post-herpetic neuralgia, non-specific neuralgia, or a second diagnostic code for shingles 90 days after the first diagnosis combined with a prescription for pain relief, an anticonvulsant, or an antidepressant). Vaccine uptake was low in this unselected study population—only 3.9% of the participants were vaccinated. The vaccination rate was particularly low among black people (0.6% of person-time) and among people with a low income (0.3%). About 13,000 participants developed incident shingles. The shingles incidence rate was 10.0 per 1,000 person-years among unvaccinated participants and 5.4 per 1,000 person-years among vaccinated participants. Vaccine effectiveness against incident shingles was 48%. That is, vaccination reduced the incidence of shingles by 48% (in other words, approximately half as many vaccinated individuals developed shingles as those who were not vaccinated). Vaccine effectiveness against incident shingles among immunosuppressed individuals was lower (37%). Finally, vaccine effectiveness against post-herpetic neuralgia was 59%.
What Do These Findings Mean?
These findings show that shingles vaccine uptake is low among elderly people in the US and varies between different patient groups. They show that shingles vaccination is effective against incident shingles in a general population of older individuals, including those who are immunosuppressed, and suggest that shingles vaccination is effective against post-herpetic neuralgia. However, because these findings rely on administrative data, their accuracy may be affected by misclassification of vaccination and of outcomes. Moreover, because shingles vaccination was not randomized, the vaccinated individuals might have shared other characteristics that were actually responsible for their lower incidence of shingles and/or post-herpetic neuralgia compared to unvaccinated individuals. Despite these limitations, these findings provide useful information for policy makers in countries that are currently considering the introduction of shingles vaccination into routine practice. Moreover, they highlight the need to increase shingles vaccination among elderly individuals in the US, the section of the population at the highest risk of post-herpetic neuralgia.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001420.
The US Centers for Disease Control and Prevention have detailed information about all aspects of shingles (zoster), including information on vaccination for the public and for health care professionals, and a personal story about shingles
The NIH Senior Health website includes information on shingles and a video describing a personal experience of shingles
The UK National Health Service Choices also provides information about all aspects of shingles and a personal story
MedlinePlus provides links to other resources about shingles (in English and Spanish)
The British Association of Dermatologists website has an information leaflet on shingles
The New Zealand Dermatological Society website has a leaflet on shingles
doi:10.1371/journal.pmed.1001420
PMCID: PMC3621740  PMID: 23585738
14.  Correction: Risk of Death and Cardiovascular Outcomes with Thiazolidinediones: A Study with the General Practice Research Database and Secondary Care Data 
PLoS ONE  2013;8(2):10.1371/annotation/8eb49a9f-06ae-4c79-bfe9-56974061321b.
doi:10.1371/annotation/8eb49a9f-06ae-4c79-bfe9-56974061321b
PMCID: PMC3894296
16.  Tackling Non-Communicable Diseases In Low- and Middle-Income Countries: Is the Evidence from High-Income Countries All We Need? 
PLoS Medicine  2013;10(1):e1001377.
Shah Ebrahim and colleagues argue that more research on non-communicable diseases (NCDs) in both high-income countries and low- and middle-income countries can result in mutual benefits and will help better address the growing burden of NCDs.
doi:10.1371/journal.pmed.1001377
PMCID: PMC3558465  PMID: 23382655
17.  Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER) 
The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼105 patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail s.denaxas@ucl.ac.uk
doi:10.1093/ije/dys188
PMCID: PMC3535749  PMID: 23220717
electronic heath records; linkages; cardiovascular
18.  The association between antipsychotic agents and the risk of myocardial infarction: a systematic review 
AIM
Patient populations that are prescribed antipsychotic agents have higher cardiovascular mortality rates. The risk of myocardial infarction is influenced by various factors that are more prevalent in patients with a mental illness. The aim of this review was to determine whether the use of antipsychotic agents is associated with the incidence of myocardial infarction in adults.
METHODS
Using multiple sources, all studies of antipsychotic agents using myocardial infarction as primary or secondary outcome measures were considered for inclusion. Study populations were adult subjects who had been prescribed an antipsychotic agent at least once in their medical history.
RESULTS
It total, five studies were identified. Four studies with small numbers of events reported a moderate to strong effect of typical antipsychotic agents on the risk of myocardial infarction. The largest study had a favourable internal validity compared with all other studies and reported no association between the risk of myocardial infarction and current use of either atypical (relative risk 0.98, 95% confidence interval [CI] 0.88, 1.09) or typical antipsychotic agents (relative risk 0.99, 95% CI 0.96, 1.03).
CONCLUSION
Clinical and methodological heterogeneity between the studies in this review led to an inconclusive answer to the question whether the use of antipsychotics is associated with the incidence of myocardial infarction in adults. Whilst results conflicted, the largest study did not find an association between the use of antipsychotic agents and an increased risk of myocardial infarction.
doi:10.1111/j.1365-2125.2011.04043.x
PMCID: PMC3244633  PMID: 21679221
antipsychotic agents; myocardial infarction
19.  Body Mass Index and Self-Perception of Overweight and Obesity in Rural, Urban and Rural-to-Urban Migrants: PERU MIGRANT Study 
PLoS ONE  2012;7(11):e50252.
Objective
This study aimed to compare self-reported weight and body mass index (BMI) in order to determine discrepancies between subjective and objective obesity-related markers, and possible explanatory factors of overweight and obesity underestimation, in urban, rural and migrant populations.
Materials and Methods
Data from the PERU MIGRANT study, a cross-sectional study, in low-income settings, of urban, migrant (rural-to-urban), and rural groups, including BMI, self-reported weight and socio-demographic indicators were analyzed. Percentage of concurrences between BMI and self-reported weight and Kappa coefficients for inter-rater agreement were calculated. Univariate and standardized descriptive analyses were performed to identify potential explanatory variables for weight underestimation in only overweight and obese individuals, using established BMI and waist circumference cut offs.
Results
983 Participants–199 urban, 583 migrants and 201 rural–were analyzed. Based on BMI, overall prevalence of obesity was 20.1% (95% CI 17.6%–22.6%), and overweight was 38.3% (95% CI 35.2%–41.2%), with differences between study groups (p<0.001). Only 43% of the whole sample had matching self-reported weight and BMI status, whereas 54% underestimated and 3% overestimated their BMI category. Kappa coefficient, between BMI and self-reported weight, for the entire sample was 0.16, rural residents had the lowest coefficient (0.01) and the most underestimation, especially in the overweight category. In overweight and obese individuals, deprivation index (p = 0.016), age (p = 0.014) and waist circumference (p<0.001) were associated with weight underestimation.
Discussion
Overall, high levels of overweight, obesity, and underestimation of BMI status were found, with poor agreement between BMI and self-reported weight, showing the unawareness of weight status severity in this low-income setting.
doi:10.1371/journal.pone.0050252
PMCID: PMC3508895  PMID: 23209688
20.  Influenza Infection and Risk of Acute Myocardial Infarction in England and Wales: A CALIBER Self-Controlled Case Series Study 
The Journal of Infectious Diseases  2012;206(11):1652-1659.
Background. An association between infections and vascular events has been observed, but the specific effect of influenza and influenza-like illnesses on triggering acute myocardial infarction (AMI) is unclear.
Methods. Episodes of first AMI from 1 January 2003 through 31 July 2009 were identified using linked anonymized electronic medical records from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. Self-controlled case series analysis was used to investigate AMI risks after consultation for acute respiratory infection. Infections were stratified by influenza virus circulation, diagnostic code, and vaccination status to assess whether influenza was more likely than other infections to trigger AMI.
Results. Of 22 024 patients with acute coronary syndrome, 11 208 met the criterion of having had their first AMI at the age of ≥40 years, and 3927 had also consulted for acute respiratory infection. AMI risks were significantly raised during days 1–3 after acute respiratory infection (incidence ratio, 4.19 [95% confidence interval, 3.18–5.53], with the effect tapering over time. The effect was greatest in those aged ≥80 years (P = .023). Infections occurring when influenza was circulating and those coded as influenza-like illness were associated with consistently higher incidence ratios for AMI (P = .012).
Conclusions. Influenza and other acute respiratory infections can act as a trigger for AMI. This effect may be stronger for influenza than for other infections.
Clinical trials registration. NCT01106196.
doi:10.1093/infdis/jis597
PMCID: PMC3488196  PMID: 23048170
22.  Validity of diagnoses in the General Practice Research Database 
doi:10.3399/bjgp11X583092
PMCID: PMC3123481  PMID: 21722461
23.  Circulating Influenza Virus, Climatic Factors, and Acute Myocardial Infarction: A Time Series Study in England and Wales and Hong Kong 
The Journal of Infectious Diseases  2011;203(12):1710-1718.
(See the editorial commentary by Finelli and Chaves, on pages 1701-4.)
Background. Previous studies identifying associations between influenza and acute cardiac events may have been confounded by climatic factors. Differing seasonal patterns of influenza activity in Hong Kong and England and Wales provide a natural experiment to examine associations with myocardial infarction (MI) independent of cold weather effects.
Methods. Weekly clinical and laboratory influenza surveillance data, environmental temperature and humidity data, and counts of MI-associated hospitalizations and deaths were obtained for England and Wales and for Hong Kong for the period 1998–2008. We used Poisson regression models that included environmental and seasonal variables to investigate the relationship between influenza and MI.
Results. There were ≥1.2 million MI-associated hospitalizations and 410,204 MI-associated deaths in England and Wales, with a marked peak in the winter season. In Hong Kong, the incidence of MI, on the basis of 65,108 hospitalizations and 18,780 deaths, had a large winter and smaller summer peak, mirroring patterns of influenza activity. There was strong evidence for a link between influenza and MI both in England and Wales, where 3.1%–3.4% of MI-associated deaths (P < .001) and 0.7%–1.2% of MI-associated hospitalizations (P < .001) were attributable to influenza, and in Hong Kong, where the corresponding figures were 3.9%–5.6% (P = .018) and 3.0%–3.3% (P = .002).
Conclusions. Influenza was associated with an increase in MI-associated deaths and hospitalizations in 2 contrasting settings.
doi:10.1093/infdis/jir171
PMCID: PMC3100509  PMID: 21606529
24.  The effect of rural-to-urban migration on social capital and common mental disorders: PERU MIGRANT study 
Objective
This study aims to investigate whether there are differences in the prevalence of common mental disorders and social capital between migrant and non-migrant groups in Peru.
Methodology
The PERU MIGRANT study is a cross-sectional study comprising three groups: an urban group from a shanty town in Lima; a rural group from a community in Ayacucho-Peru; and a migrant group originally from Ayacucho currently living in the same urban shanty town. Common mental disorders were assessed using the General Health Questionnaire (GHQ-12), and social capital was assessed using the Short Social Capital Assessment Tool (SASCAT). Poisson regression with robust standard errors was used to estimate prevalence ratios.
Results
The overall prevalence of common mental disorders was 39.4%; the highest prevalence was observed in the rural group. Similar patterns were observed for cognitive social capital and structural social capital. However after adjustment for sex, age, family income and education, all but one of the significant relationships was attenuated, suggesting that in this population migration per se does not impact on common mental health disorders or social capital.
Conclusions
In the PERU MIGRANT study, we did not observe a difference in the prevalence of common mental disorders, cognitive and structural social capital between migrant and urban groups. This pattern of associations was also similar in rural and urban groups, except that a higher prevalence ratio of structural social capital was observed in the rural group.
doi:10.1007/s00127-011-0404-6
PMCID: PMC3248919  PMID: 21667301
Peru; Migration; Social capital; Mental health
25.  Sex Differences in Risk Factors for Cardiovascular Disease: The PERU MIGRANT Study 
PLoS ONE  2012;7(4):e35127.
Introduction
Although men and women have similar risk factors for cardiovascular disease, many social behaviors in developing countries differ by sex. Rural-to-urban migrants have different cardiovascular risk profiles than rural or urban dwellers. The objective of this study was to evaluate the sex differences with specific cardiovascular risk factors in rural-to-urban migrants.
Methods and Results
We used the rural-to-urban migrant group of the PERU MIGRANT cross-sectional study to investigate the sex differences in specific cardiovascular risk factors: obesity, hypertension, metabolic syndrome, as well as exposures of socioeconomic status, acculturation surrogates and behavioral characteristics. Logistic regression analysis was used to characterize strength of association between sex and our outcomes adjusting for potential confounders. The sample of migrants was 589 (mean age 46.5 years) and 52.4% were female. In the adjusted models, women were more likely to be obese (OR=5.97; 95%CI: 3.21–11) and have metabolic syndrome (OR=2.22; 95%CI: 1.39–3.55) than men, explaining the greatest variability for obesity and metabolic syndrome but not for hypertension.
Conclusions
Our results suggest that interventions for CVD in Peru should be sex-specific and address the unique health needs of migrant populations living in urban shantytowns since the risk factors for obesity and metabolic syndrome differ between males and females.
doi:10.1371/journal.pone.0035127
PMCID: PMC3320626  PMID: 22496899

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