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Aim: To develop age-, sex-, and ethnic-Appropriate normative reference ranges for standard echocardiographic measurements of the left heart by combining echocardiographic measurements obtained from adult volunteers without clinical cardiovascular disease or significant cardiovascular risk factors, from multiple studies around the world.Methods and results: The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL) collaboration was established and population-based data sets of echocardiographic measurements combined to perform an individual person data meta-Analysis. Data from 43 studies were received, representing 51 222 subjects, of which 22 404 adults aged 18-80 years were without clinical cardiovascular or renal disease, hypertension or diabetes. Quantile regression or an appropriate parametric regression method will be used to derive reference values at the 5th and 95th centile of each measurement against age. Conclusion: This unique data set represents a large, multi-ethnic cohort of subjects resident in a wide range of countries. The resultant reference ranges will have wide applicability for normative data based on age, sex, and ethnicity. © The Author 2013.

To investigate the efficacy of water preloading before meals as a weight loss strategy for adults with obesity.A two-group randomized controlled trial was conducted in Birmingham, England. Eighty-four adults with obesity were recruited from general practices. All participants were given a face-to-face weight management consultation at baseline (30 min) and a follow-up telephone consultation at 2 weeks (10 min). At baseline, participants were randomized to either drinking 500 ml of water 30 min before their main meals or an attention control group where participants were asked to imagine their stomach was full before meals. The primary outcome was weight change at 12-week follow-up. Several measures of adherence were also used, including 24 h total urine collections.41 participants were randomized to the intervention group and 43 to the comparator group. The water preloading group lost -1.3 kg (95% CI -2.4 to -0.1, P = 0.028) more than comparators at follow up. Adjusting for ethnicity, deprivation, age, and gender resulted in the intervention group losing -1.2 kg (95% CI -2.4 to 0.07, P = 0.063) more than the comparator.There is preliminary evidence that water preloading before main meals leads to a moderate weight loss at follow up. ISRCTN33238158.

The role of CD19 + CD5 + and CD19 + CD5 − B cell subpopulations in the antibody response to pneumococcal capsular polysaccharides (caps-PSs) is controversial. In the present study, we evaluated the role of human CD19 + CD5 + and CD19 + CD5 − cell populations in the serotype-specific antibody response to caps-PS. After vaccination of 5 healthy human adults with Pneumovax (23-valent pneumococcal polysaccharide vaccine [PPV23]), IgG anti-caps-PS serotype 4 antibody-producing cells resided mainly in the CD19 + CD5 − B cell subset, as assessed by enzyme-linked immunosorbent spot (ELISpot) analysis. Moreover, in a humanized SCID mouse model, CD19 + CD5 − B cells were more effective than CD19 + CD5 + cells in producing IgG anti-cap-PS antibodies. Finally, an association was found between the level of IgG anti-caps-PS antibodies and the number of CD19 + CD5 − B cells in 33 humans vaccinated with PPV23. Taken together, our data suggest that CD5 defines a functionally distinct population of B cells in humans in the anti-caps-PS immune response.

Background Heart failure (HF) is a common condition affecting more than 10% of those over 70 years of age. Reliable estimates of survival following a diagnosis of HF are important to guide management and facilitate advanced care planning. Most existing research has focused on survival rates for patients admitted to hospital with acute HF. However, the majority of patients with HF are diagnosed in the outpatient setting and can have periods of sustained symptom stability in the chronic phase of their illness. There has not been a systematic review of the literature to determine the prognosis of patients with chronic HF in the community. Methods We will undertake a comprehensive search of the following databases: CINAHL, Database of Abstracts of Reviews of Effects, Embase, MEDLINE and the Clinical Trials Register (clinicaltrials.gov). Two reviewers will independently complete screening, data extraction and quality appraisal with the option of input from a third reviewer to arbitrate. We will include data from observational or database studies conducted in either community or outpatient settings. Studies of acute HF or specific subgroups of patients will be excluded. There is no restriction by geographical setting, publication language or study date. We will complete QUIPS and GRADE assessments to systematically appraise the quality of evidence within and between studies. Where possible, we will seek to pool results to conduct a meta-analysis and undertake relevant subgroup analysis including by study setting, participant age and study decade. The primary outcome will be survival time from diagnosis. The secondary outcomes will be HF-related hospital admissions, symptom burden and measures of morbidity. Discussion This systematic review will provide up to date evidence on the current survival rates and prognostic indicators for patients with chronic HF. We will put this into historical perspective, comparing outcomes across time to help understand the impact of advances in evidence-based treatment on average survival. This information is important in facilitating informed decision-making for patients and health professionals as well as highlighting areas to focus resources and improve public health planning. Systematic review registration PROSPERO 2017 CRD42017075680 Electronic supplementary material The online version of this article (10.1186/s13643-018-0810-x) contains supplementary material, which is available to authorized users.

PRISMA-P 2015 Checklist. (DOCX 32 kb)

Background: Infants in the UK were first offered a pneumococcal conjugate vaccine (PCV7) in 2006, given at 2 and 4 months of age and a booster dose at 13 months (2 + 1 schedule). A 13-valent vaccine (PCV13) replaced PCV7 in 2010. We aimed to compare the post-booster antibody response in UK infants given a reduced priming schedule of PCV13 (ie, a 1 + 1 schedule) versus the current 2 + 1 schedule and to assess the potential effect on population protection. Methods: In this multicentre, parallel group, randomised controlled trial, we recuited infants due to receive their primary immunisations aged up to 13 weeks on first vaccinations by information booklets mailed out via the NHS Child Health Information Service and the UK National Health Application and Infrastructure Services. Eligible infants were randomly assigned (1:1) to receive PCV13 at 2, 4, and 12 months (2 + 1 schedule) or 3 and 12 months of age (1 + 1 schedule) delivered with other routine vaccinations. Randomisation was done by computer-generated permuted block randomisation, with a block size of six. Participants and clinical trial staff were not masked to treatment allocation. The primary endpoint was serotype-specific immunoglobulin G concentrations values (geometric mean concentrations [GMC] in μg/mL) measured in blood samples collected at 13 months of age. Analysis was by modified intention to treat with all individuals included by randomised group if they had a laboratory result. This trial is registered on the EudraCT clinical trial database, number 2015-000817-32, and ClinicalTrials.gov, number NCT02482636. Findings: Between September, 2015, and June, 2016, 376 infants were assessed for eligibility. 81 infants were excluded for not meeting the inclusion criteria (n=50) or for other reasons (n=31). 213 eligible infants were enrolled and randomly allocated to group 1 (n=106; 2 + 1 schedule) or to group 2 (n=107; 1 + 1 schedule). In group 1, 91 serum samples were available for analysis 1 month after booster immunisation versus 86 in group 2. At month 13, post-booster, GMCs were equivalent between schedules for serotypes 3 (0·61 μg/mL in group 1 vs 0·62 μg/mL in group 2), 5 (1·74 μg/mL vs 2·11 μg/mL), 7F (3·98 μg/mL vs 3·36 μg/mL), 9V (2·34 μg/mL vs 2·50 μg/mL), and 19A (8·38 μg/mL vs 8·83 μg/mL). Infants given the 1 + 1 schedule had significantly greater immunogenicity post-booster than those given the 2 + 1 schedule for serotypes 1 (8·92 μg/mL vs 3·07 μg/mL), 4 (3·43 μg/mL vs 2·55 μg/mL), 14 (16·9 μg/mL vs 10·49 μg/mL), and 19F (14·76 μg/mL vs 11·12 μg/mL; adjusted p value range Interpretation: Our findings show that for nine of the 13 serotypes in PCV13, post-booster responses in infants primed with a single dose are equivalent or superior to those seen following the standard UK 2 + 1 schedule. Introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease.

ObjectiveTo compare the cost-utility of two exercise interventions relative to a control group for vasomotor menopausal symptoms. DesignEconomic evaluation taking a UK National Health Service and Personal Social Services perspective and a societal perspective. SettingPrimary care. PopulationPeri- and postmenopausal women who have not used hormone therapy in the past 3 months and experience ≥ 5 episodes of vasomotor symptoms daily. MethodsAn individual and a social support-based exercise intervention were evaluated. The former (Exercise-DVD), aimed to prompt exercise with purpose-designed DVD and written materials, whereas the latter (Exercise-Social support) with community exercise social support groups. Costs and outcomes associated with these interventions were compared to those of a control group, who could only have an exercise consultation. An incremental cost-utility analysis was undertaken using bootstrapping to account for the uncertainty around cost-effectiveness point-estimates. Main outcome measureCost per quality-adjusted life-year (QALY). ResultsData for 261 women were available for analysis. Exercise-DVD was the most expensive and least effective intervention. Exercise-Social support was £52 (CIs: £18 to £86) and £18 (CIs: -£68 to £105) more expensive per woman than the control group at 6 and 12 months post-randomisation and led to 0.006 (CIs: -0.002 to 0.014) and 0.013 (CIs: -0.01 to 0.036) more QALYs, resulting in an incremental cost-effectiveness ratio of £8,940 and £1,413 per QALY gained respectively. Exercise-Social support had 80%-90% probability of being cost-effective in the UK context. A societal perspective of analysis and a complete-case analysis led to similar findings. ConclusionsExercise-Social support resulted in a small gain in health-related quality of life at a marginal additional cost in a context where broader wellbeing and long-term gains associated with exercise and social participation were not captured. Community exercise social support groups are very likely to be cost-effective in the management of vasomotor menopausal symptoms.

© 2017 Jowett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Clinical trials suggest that use of fixed-dose combination therapy (‘polypills’) can improve adherence to medication and control of risk factors of people at high risk of cardiovascular disease (CVD) compared to usual care, but cost-effectiveness is unknown. Objective: To determine whether a polypill is cost-effective compared to usual care and optimal guideline-recommended treatment for primary prevention in people already on statins and/or blood pressure lowering therapy. Methods: A Markov model was developed to perform a cost-utility analysis with a one year time cycle and a 10 year time horizon to compare the polypill with usual care and optimal implementation of NICE Guidelines, using patient level data from a retrospective cross-sectional study. The model was run for ten age (40 years+) and gender-specific sub-groups on treatment for raised CVD risk with no history of CVD. Published sources were used to estimate impact of different treatment strategies on risk of CVD events. Results: A polypill strategy was potentially cost-effective compared to other strategies for most subgroups ranging from dominance to up to £18,811 per QALY depending on patient subgroup. Optimal implementation of guidelines was most cost-effective for women aged 40–49 and men aged 75+. Results were sensitive to polypill cost, and if the annual cost was less than £150, this approach was cost-effective compared to the other strategies. Conclusions: For most people already on treatment to modify CVD risk, a polypill strategy may be cost-effective compared with optimising treatment as per guidelines or their current care, as long as the polypill cost is sufficiently low.

Background Heart failure is a treatable condition but making a diagnosis can be challenging. Objective To evaluate the performance of a clinical decision rule (CDR) with or without a natriuretic peptide assay for identifying heart failure in symptomatic patients presenting to primary care. Design Prospective, observational, diagnostic validation study and economic evaluation. Setting Twenty-eight general practices in central England, UK. Participants Primary care patients aged ≥ 55 years presenting with recent new-onset shortness of breath, lethargy or peripheral ankle oedema of > 48 hours’ duration. Instrument The CDR included a clinical element (male, history of myocardial infarction, crepitations at the lung bases and oedema) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) blood test. The reference standard was an expert consensus panel of three cardiology specialists. Main outcome measure The main outcome measure was test performance of the CDR and the natriuretic peptide test alone, and in combination, in estimating sensitivity and specificity, positive predictive value (PPV) and negative predictive value (NPV) for a diagnosis of heart failure. Economic evaluation of a decision tree with a NHS/Personal Social Services perspective determined the cost per quality-adjusted life-year (QALY) gained. Results In total, 304 participants were recruited to the validation cohort. The mean age was 73.9 years (standard deviation 8.8 years) and 124 (40.8%) participants were male. In total, 104 [34.2%, 95% confidence interval (CI) 28.9% to 39.8%] had a confirmed diagnosis of heart failure. The CDR had a sensitivity of 90% (95% CI 83% to 95%), specificity of 46% (95% CI 39% to 53%), PPV of 46% (95% CI 39% to 53%) and NPV of 90% (95% CI 83% to 95%). NT-proBNP level alone with a cut-off point of Conclusions Natriuretic peptide testing alone performed as well as the validated CDR in determining which patients presenting with symptoms went on to have a diagnosis of heart failure. The current NT-proBNP cut-off point of 400 pg/ml used in the UK is too high and means that one in five patients with heart failure may not be appropriately referred for further investigation and diagnosis, but this threshold was cost-effective in the REFer for EchocaRdiogram (REFER) trial. The study found only three patients with heart failure with reduced ejection fraction (HFREF), which might limit the benefits of early detection. The other diagnostic strategies with lower NT-proBNP referral levels become more cost-effective as the proportion of HFREF patients increases. International consensus on the optimal cut-off point for natriuretic peptide testing in patients with symptoms suggestive of heart failure should be sought. Trial registration Current Controlled Trials ISRCTN17635379. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

Background Although both the 13-valent pneumococcal conjugate vaccine (PCV13) and the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) are widely used, it is unclear how interchangeable they are in terms of immunogenicity. Methods Two phase 3, open-label, multicenter studies were conducted to assess the immunogenicity and safety of a booster dose of PCV13 in children primed with PHiD-CV or PCV13. In the Czech Republic, 12–15-month-old children received a PCV13 booster after 3-dose priming with either PHiD-CV or PCV13. In Slovakia, 11–12-month-old children received PCV13 following 2-dose priming with either PHiD-CV or PCV13. Serum IgG concentrations were assessed by enzyme-linked immunosorbent assay and functional antibodies were assessed by opsonophagocytic assay (OPA) before the booster and at 1 and 12 months afterward. The primary objective of these studies was to assess non-inferiority of OPA titers for serotype 19A in PHiD-CV-primed subjects compared to those in PCV13-primed children 1 month post-booster. Results A total of 98 subjects in the Czech Republic and 89 subjects in Slovakia were included. One month after the PCV13 booster dose, the IgG and OPA immune responses to serotype 19A in subjects primed with 2 or 3 doses of PHiD-CV were non-inferior to those in subjects primed with PCV13. Non-inferior and persistent immune responses to most other vaccine serotypes were also observed after the PCV13 booster in PHiD-CV-primed subjects. No safety issues were raised in either study. Conclusions Overall, robust IgG and OPA immunological responses were observed after booster vaccination with PCV13 in children primed with 2 or 3 doses of PHiD-CV or PCV13, including for serotypes not included in PHiD-CV. These results suggest that these vaccines are interchangeable in terms of safety and immunogenicity and that PCV13 can be used as a booster in the context of mixed schedules. (EudraCT numbers: 2012-005366-35 and 2012-005367-27).

Background It is not known whether infants exposed to intermittent maternal fasting at conception are born smaller or have a higher risk of premature birth than those who are not. Doctors are therefore unsure about what advice to give women about the safety of Ramadan fasting. This cohort study aimed to investigate these questions in Muslim mother–infant pairs to inform prenatal care. Methods Routinely collected data accessed from maternity records were the source for information. Mothers were considered exposed if they were Muslim and Ramadan overlapped with their infant conception date, estimated to be 14 days after the last menstrual period. Infants were included as exposed if their estimated conception date was in the first 21 days of Ramadan or 7 days prior to Ramadan. Results After adjusting for gestational age, maternal age, infant gender, maternal body mass index at booking, smoking status, gestational diabetes, parity and year of birth, there was no significant difference in birth weight between infants born to Muslim mothers who were conceived during Ramadan (n=479) and those who were not (n=4677) (adjusted mean difference =24.3 g, 95% CI −16.4 to 64.9). There was no difference in rates of premature births in exposed and unexposed women (5.2% vs 4.9%; OR=1.08, 95% CI 0.71 to 1.65). Conclusions Healthy Muslim women considering becoming pregnant prior to, or during Ramadan, can be advised that fasting does not seem to have a detrimental effect on the size (weight) of their baby and it appears not to increase the likelihood of giving birth prematurely.

AimTo evaluate the reliability and performance of the Xprecia Stride coagulometer under the conditions in which it is most likely to be used.MethodsThe performance of the Xprecia Stride coagulometer was compared with a local laboratory and the CoaguChek systems routinely used for international normalised ratio (INR) estimation within one primary and one secondary care based anticoagulation clinic in Birmingham. Anticoagulation clinic personnel were trained to use the Xprecia Stride. Patients attending the clinics were eligible if aged ≥18 years and had received warfarin for at least 3 months. Consenting participants provided capillary blood samples for parallel testing on the Xprecia Stride and CoaguChek systems. At the secondary care clinic, a venous blood sample was also collected for laboratory INR estimation. INR results were compared using linear regression analysis and Bland–Altman plots.ResultsA total of 102 laboratory and 205 parallel coagulometer INR tests were performed. Linear regression revealed strong correlation between the Xprecia Stride and the laboratory (r=0.83) and between the Xprecia Stride and CoaguChek systems (r=0.92). Within the therapeutic range, agreement between the systems was very good with 87% of the Xprecia Stride and laboratory INR results and 93% of the Xprecia Stride and CoaguChek INR results being within 0.5 INR units of each other.ConclusionINRs tested using the Xprecia Stride system showed good agreement with the laboratory and CoaguChek systems. Findings indicate that in the hands of the intended users the Xprecia Stride is accurate, reliable and acceptable for use in a routine clinical setting.

Objective To investigate the effectiveness of exercise as treatment for vasomotor menopausal symptoms. Design Three-group randomised controlled trial, two exercise interventions and a control group. Setting Primary Care, West Midlands UK. Population Perimenopausal and postmenopausal women experiencing at least five hot flushes/night sweats per day and not taken MHT in previous 3 months were recruited from 23 general practices. Methods Participants in both exercise interventions groups were offered two face-to-face consultations with a physical activity facilitator to support engagement in regular exercise. In addition, one exercise group received a menopause-specific information DVD and written materials to encourage regular exercise and the other exercise group was offered the opportunity to attend exercise social support groups in their communities. Interventions lasted 6 months. Main outcome measure The primary outcome was frequency of hot flushes/night sweats at 6-month up. Results Two hundred and sixty-one women were randomised (n = 87 per group). Neither of the exercise intervention groups reported significantly less frequent hot flushes/night sweats per week than controls (exercise-DVD versus control: −8.9, 95% CI −20.0 to 2.2; exercise-social support versus control: −5.2, 95% CI −16.7 to 6.3). Conclusions This trial indicates that exercise is not an effective treatment for hot flushes/night sweats. Contrary to current clinical guidance, women should not be advised that exercise will relieve their vasomotor menopausal symptoms.

Opsonophagocytic assays (OPAs) are routinely used for assessing the immunogenicity of pneumococcal vaccines, with OPA data often being utilized for licensure of new vaccine formulations. However, no reference serum for pneumococcal OPAs is available, making evaluation of data among different laboratories difficult. This international collaboration was initiated to (i) assign consensus opsonic indexes (OIs) to FDA pneumococcal reference serum lot 007sp (here referred to as 007sp) and a panel of serum samples used for calibration of the OPA and (ii) determine if the normalization of the OPA results obtained with test samples to those obtained with 007sp decreases the variability in OPA results among laboratories. To meet these goals, six participating laboratories tested a panel of serum samples in five runs for 13 serotypes. For each serum sample, consensus OIs were obtained using a mixed-effects analysis of variance model. For the calibration serum samples, normalized consensus values were also determined on the basis of the results obtained with 007sp. For each serotype, the overall reduction in interlaboratory variability was calculated by comparing the coefficients of variation of the unadjusted and the normalized values. Normalization of the results substantially reduced the interlaboratory variability, ranging from a 15% reduction in variability for serotype 9V to a 64% reduction for serotype 7F. Normalization also increased the proportion of data within 2-fold of the consensus value from approximately 70% (average for all serotypes) to >90%. On the basis of the data obtained in this study, pneumococcal reference standard lot 007sp will likely be a useful reagent for the normalization of pneumococcal OPA results from different laboratories. The data also support the use of the 16 FDA serum samples used for calibration of the OPA as part of the initial evaluation of new assays or periodic assessment of established assays.

© 2017 Asia Oceania Association for the Study of Obesity Background Finding effective referral policies for weight management services would have important public health implications. Aim Here we compare percentage weight change by referral methods, BMI categories and participants who have had attended weight loss programmes multiple times. Design and settings A prospective cohort study of 15,621 participants referred to 12-week behavioural weight loss programmes funded by the public health service in Birmingham, UK. Methods Comparisons were made between GP versus self-referrals, BMI ≥40 kg/m2–

Objective To investigate the efficacy of water preloading before meals as a weight loss strategy for adults with obesity. Methods A two-group randomized controlled trial was conducted in Birmingham, England. Eighty-four adults with obesity were recruited from general practices. All participants were given a face-to-face weight management consultation at baseline (30 min) and a follow-up telephone consultation at 2 weeks (10 min). At baseline, participants were randomized to either drinking 500 ml of water 30 min before their main meals or an attention control group where participants were asked to imagine their stomach was full before meals. The primary outcome was weight change at 12-week follow-up. Several measures of adherence were also used, including 24 h total urine collections. Results 41 participants were randomized to the intervention group and 43 to the comparator group. The water preloading group lost −1.3 kg (95% CI −2.4 to −0.1, P = 0.028) more than comparators at follow up. Adjusting for ethnicity, deprivation, age, and gender resulted in the intervention group losing −1.2 kg (95% CI −2.4 to 0.07, P = 0.063) more than the comparator. Conclusions There is preliminary evidence that water preloading before main meals leads to a moderate weight loss at follow up. ISRCTN33238158

We would like to thank Zito et al for their letter in response to our article.1 We agree that comprehensive geriatric assessment of the study population would have aided interpretation of the study, but note that the randomized nature of the study means that differences between groups in this domain are unlikely to have contributed to the null finding. We agree that there are limitations with the Mini-Mental State Examination and that detailed …

Background and Purpose— Oral anticoagulants are effective at reducing stroke compared with aspirin in atrial fibrillation patients older than 75 years. Although the benefits of reduced stroke risk outweigh the risks of bleeding, the cost effectiveness of warfarin in this patient population has not yet been established. Methods— An economic evaluation was conducted alongside a randomized, controlled trial; 973 patients ≥75 years of age with atrial fibrillation were recruited from primary care and randomly assigned to either take warfarin or aspirin. Follow-up was for a mean of 2.7 years. Costs of thrombotic and hemorrhagic events, anticoagulation clinic visits, and primary care utilization were determined. Clinical benefits were expressed in terms of a primary event avoided: fatal/nonfatal disabling stroke, intracranial hemorrhage, or systemic embolism. A cost-utility analysis was performed using quality-adjusted life years as the benefit measure. Results— Total costs over 4 years were lower in the warfarin group (difference, −£165; 95% CI, −£452–£89), primarily driven by the difference in primary event costs. The primary event rate over 4 years was lower in the warfarin group (0.049 versus 0.099), and the quality-adjusted life years score was higher (difference, 0.02; 95% CI, −0.07–0.11). With lower costs and a higher quality-adjusted life years score, warfarin is the dominant treatment, but the differences in both costs and effects are small. Conclusions— Warfarin is cost-effective compared with aspirin in atrial fibrillation patients age ≥75 years. These data support the anticoagulant therapy option in this high-risk patient population. However, the small differences in costs and effects indicate the importance of exploring patient preferences.

The pneumococcus is a leading pathogen infecting children and adults. Safe, effective vaccines exist, and they work by inducing antibodies to the polysaccharide capsule (unique for each serotype) that surrounds the cell; however, current vaccines are limited by the fact that only a few of the nearly 100 antigenically distinct serotypes are included in the formulations. Within the serotypes, serogroup 6 pneumococci are a frequent cause of serious disease and common colonizers of the nasopharynx in children. Serotype 6E was first reported in 2004 but was thought to be rare; however, we and others have detected serotype 6E among recent pneumococcal collections. Therefore, we analyzed a diverse data set of ∼1,000 serogroup 6 genomes, assessed the prevalence and distribution of serotype 6E, analyzed the genetic diversity among serogroup 6 pneumococci, and investigated whether pneumococcal conjugate vaccine-induced serotype 6A and 6B antibodies mediate the killing of serotype 6E pneumococci. We found that 43% of all genomes were of serotype 6E, and they were recovered worldwide from healthy children and patients of all ages with pneumococcal disease. Four genetic lineages, three of which were multidrug resistant, described ∼90% of the serotype 6E pneumococci. Serological assays demonstrated that vaccine-induced serotype 6B antibodies were able to elicit killing of serotype 6E pneumococci. We also revealed three major genetic clusters of serotype 6A capsular sequences, discovered a new hybrid 6C/6E serotype, and identified 44 examples of serotype switching. Therefore, while vaccines appear to offer protection against serotype 6E, genetic variants may reduce vaccine efficacy in the longer term because of the emergence of serotypes that can evade vaccine-induced immunity.

Background and Purpose— Atrial fibrillation is associated with decline of cognitive function. Observational evidence suggests that anticoagulation might protect against this decline. We report the first randomized controlled trial evidence on the effect of anticoagulation on cognitive function in elderly patients with atrial fibrillation. Methods— A total of 973 patients aged ≥75 years with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (n=488; target international normalized ratio, 2–3) or aspirin (n=485; 75 mg/d). Neither participants nor investigators were masked to group assignment. Follow-up was for a mean of 2.7 years (SD, 1.2). Cognitive outcome was assessed using the Mini-Mental State Examination at 9-, 21-, and 33-month follow-up. Participants who had a stroke were censored from the analysis, which was by intention to treat with imputation for missing data. Results— There was no difference between mean Mini-Mental State Examination scores in people assigned to warfarin or aspirin at 9 or 21 months. At 33-month follow-up, there was a nonsignificant difference of 0.56 in favor of warfarin that decreased to 0.49 (95% confidence interval, –0.01 to 0.98) after imputation. Conclusions— We found no evidence that anticoagulation confers clinically important protection over aspirin against cognitive decline as measured by the Mini-Mental State Examination in atrial fibrillation in the first 33 months of treatment other than that provided by preventing clinical stroke. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN89345269.

Objective: To determine the potential role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in screening for and predicting prognosis in heart failure by examining diagnosis and survival of patients with a raised NT-proBNP at screening. Design: Survival analysis. Setting: Prospective substudy of the Echocardiographic Heart of England Screening study (ECHOES) to investigate 10-year survival in participants with an NT-proBNP level at baseline. Participants: 594 participants took part in the substudy. Records of all participants in the ECHOES cohort were flagged during the screening phase which ended on 25 February 1999. All deaths until 25 February 2009 were coded. Outcome measures: Logistic regression was used to examine whether NT-proBNP is useful in predicting heart failure at screening after adjustment for age, sex and cohort. Kaplan-Meier curves and log rank tests were used to compare survival times of participants according to NT-proBNP level. Cox regression was carried out to assess the prognostic effect of NT-proBNP after allowing for significant covariates and receiver operator curves were used to determine test reliability. Results: The risk of heart failure increased almost 18-fold when NT-proBNP was 150 pg/mL or above (adjusted OR=17.7, 95% CI 4.9 to 63.5). 10-year survival in the general population cohort was 61% (95% CI 48% to 71%) for those with NT-proBNP ≥150 pg/mL and 89% (95% CI 84% to 92%) for those below the cut-off at the time of the initial study. After adjustment for age, sex and risk factors for heart failure, NT-proBNP level ≥150 pg/mL was associated with a 58% increase in the risk of death within 10 years (adjusted HR=1.58, 95% CI 1.09 to 2.30). Conclusions: Raised NT-proBNP levels, when screening the general population, are predictive of a diagnosis of heart failure (at a lower threshold than guidelines for diagnosing symptomatic patients) and also predicted reduced survival at 10 years.

Context: Population-based screening has been advocated for subclinical thyroid dysfunction in the elderly because the disorder is perceived to be common, and health benefits may be accrued by detection and treatment. Objective: The objective of the study was to determine the prevalence of subclinical thyroid dysfunction and unidentified overt thyroid dysfunction in an elderly population. Design, Setting, and Participants: A cross-sectional survey of a community sample of participants aged 65 yr and older registered with 20 family practices in the United Kingdom. Exclusions: Exclusions included current therapy for thyroid disease, thyroid surgery, or treatment within 12 months. Outcome Measure: Tests of thyroid function (TSH concentration and free T 4 concentration in all, with measurement of free T3 in those with low TSH) were conducted. Explanatory Variables: These included all current medical diagnoses and drug therapies, age, gender, and socioeconomic deprivation (Index of Multiple Deprivation, 2004) Analysis: Standardized prevalence rates were analyzed. Logistic regression modeling was used to determine factors associated with the presence of subclinical thyroid dysfunction Results: A total of 5960 attended for screening. Using biochemical definitions, 94.2% [95% confidence interval (CI) 93.8-94.6%] were euthyroid. Unidentified overt hyper- and hypothyroidism were uncommon (0.3, 0.4%, respectively). Subclinical hyperthyroidism and hypothyroidism were identified with similar frequency (2.1%, 95% CI 1.8-2.3%; 2.9%, 95% CI 2.6-3.1%, respectively). Subclinical thyroid dysfunction was more common in females (P < 0.001) and with increasing age (P < 0.001). After allowing for comorbidities, concurrent drug therapies, age, and gender, an association between subclinical hyperthyroidism and a composite measure of socioeconomic deprivation remained. Conclusions: Undiagnosed overt thyroid dysfunction is uncommon. The prevalence of subclinical thyroid dysfunction is 5%. We have, for the first time, identified an independent association between the prevalence of subclinical thyroid dysfunction and deprivation that cannot be explained solely by the greater burden of chronic disease and/or consequent drug therapies in the deprived population. Copyright © 2006 by The Endocrine Society.

Objectives: Rescreen a large community cohort to examine the progression to heart failure over time and the role of natriuretic peptide testing in screening. Design: Observational longitudinal cohort study. Setting: 16 socioeconomically diverse practices in central England. Participants: Participants from the original Echocardiographic Heart of England Screening (ECHOES) study were invited to attend for rescreening. Outcome measures: Prevalence of heart failure at rescreening overall and for each original ECHOES subgroup. Test performance of N Terminal pro-B-type Natriuretic Peptide (NT-proBNP) levels at different thresholds for screening. Results: 1618 of 3408 participants underwent screening which represented 47% of survivors and 26% of the original ECHOES cohort. A total of 176 (11%, 95% CI 9.4% to 12.5%) participants were classified as having heart failure at rescreening; 103 had heart failure with reduced ejection fraction (HFREF) and 73 had heart failure with preserved ejection fraction (HFPEF). Sixty-eight out of 1232 (5.5%, 95% CI 4.3% to 6.9%) participants who were recruited from the general population over the age of 45 and did not have heart failure in the original study, had heart failure on rescreening. An NT-proBNP cut-off of 400 pg/mL had sensitivity for a diagnosis of heart failure of 79.5% (95% CI 72.4% to 85.5%) and specificity of 87% (95% CI 85.1% to 88.8%). Conclusions: Rescreening identified new cases of HFREF and HFPEF. Progression to heart failure poses a significant threat over time. The natriuretic peptide cut-off level for ruling out heart failure must be low enough to ensure cases are not missed at screening.

Objectives: To assess the accuracy in diagnosing heart failure of clinical features and potential primary care investigations, and to perform a decision analysis to test the impact of plausible diagnostic strategies on costs and diagnostic yield in the UK health-care setting. Data sources: MEDLINE and CINAHL were searched from inception to 7 July 2006. 'Grey literature' databases and conference proceedings were searched and authors of relevant studies contacted for data that could not be extracted from the published papers. Review methods: A systematic review of the clinical evidence was carried out according to standard methods. Individual patient data (IPD) analysis was performed on nine studies, and a logistic regression model to predict heart failure was developed on one of the data sets and validated on the other data sets. Cost-effectiveness modelling was based on a decision tree that compared different plausible investigation strategies. Results: Dyspnoea was the only symptom or sign with high sensitivity (89%), but it had poor specificity (51 %). Clinical features with relatively high specificity included history of myocardial infarction (89%), orthopnoea (89%), oedema (72%), elevated jugular venous pressure (70%), cardiomegaly (85%), added heart sounds (99%), lung crepitations (81%) and hepatomegaly (97%). However, the sensitivity of these features was low, ranging from 11% (added heart sounds) to 53% (oedema). Electrocardiography (ECG), B-type natriuretic peptides (BNP) and N-terminal proB-type natriuretic peptides (NT-proBNP) all had high sensitivities (89%, 93% and 93% respectively). Chest X-ray was moderately specific (76-83%) but insensitive (67-68%). BNP was more accurate than ECG, with a relative diagnostic odds ratio of ECG/BNP of 0.32 (95% CI 0.12-0.87). There was no difference between the diagnostic accuracy of BNP and NT-proBNP. A model based upon simple clinical features and BNP derived from one data set was found to have good validity when applied to other data sets. A model substituting ECG for BNP was less predictive. From this a simple clinical rule was developed: in a patient presenting with symptoms such as breathlessness in whom heart failure is suspected, refer directly to echocardiography if the patient has a history of myocardial infarction or basal crepitations or is a male with ankle oedema; otherwise, carry out a BNP test and refer for echocardiography depending on the results of the test. On the basis of the cost-effectiveness analysis carried out, such a decision rule is likely to be considered cost-effective to the NHS in terms of cost per additional case detected. The cost-effectiveness analysis further suggested that, if likely benefit to the patient in terms of improved life expectancy is taken into account, the optimum strategy would be to refer all patients with symptoms suggestive of heart failure directly for echocardiography. Conclusions: The analysis suggests the need for important changes to the NICE recommendations. First, BNP (or NT-proBNP) should be recommended over ECG and, second, some patients should be referred straight for echocardiography without undergoing any preliminary investigation. Future work should include evaluation of the clinical rule described above in clinical practice. © 2009 Queen's Printer and Controller of HMSO. All rights reserved.