Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells.

5-hydroxymethylcytosine (5hmC) is a modified base present at low levels in diverse cell types in mammals. 5hmC is generated by the TET family of Fe(II) and 2-oxoglutarate-dependent enzymes through oxidation of 5-methylcytosine (5mC). 5hmC and TET proteins have been implicated in stem cell biology and cancer, but information on the genome-wide distribution of 5hmC is limited. Here we describe two novel and specific approaches to profile the genomic localization of 5hmC. The first approach, termed GLIB (glucosylation, periodate oxidation, biotinylation) uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulphonate (CMS) by treatment of genomic DNA with sodium bisulphite, followed by immunoprecipitation of CMS-containing DNA with a specific antiserum to CMS. High-throughput sequencing of 5hmC-containing DNA from mouse embryonic stem (ES) cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 4 trimethylation (H3K4me3) marks. Our results indicate that 5hmC has a probable role in transcriptional regulation, and suggest a model in which 5hmC contributes to the 'poised' chromatin signature found at developmentally-regulated genes in ES cells.

Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells.

Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells.

Effectiveness of the influenza vaccine in preventing admission to hospital and death in people with type 2 diabetes.

BACKGROUND: The health burden caused by seasonal influenza is substantial. We sought to examine the effectiveness of influenza vaccination against admission to hospital for acute cardiovascular and respiratory conditions and all-cause death in people with type 2 diabetes. METHODS: We conducted a retrospective cohort study using primary and secondary care data from the Clinical Practice Research Datalink in England, over a 7-year period between 2003/04 and 2009/10. We enrolled 124 503 adults with type 2 diabetes. Outcome measures included admission to hospital for acute myocardial infarction (MI), stroke, heart failure or pneumonia/influenza, and death. We fitted Poisson regression models for influenza and off-season periods to estimate incidence rate ratios (IRR) for cohorts who had and had not received the vaccine. We used estimates for the summer, when influenza activity is low, to adjust for residual confounding. RESULTS: Study participants contributed to 623 591 person-years of observation during the 7-year study period. Vaccine recipients were older and had more comorbid conditions compared with nonrecipients. After we adjusted for covariates and residual confounding, vaccination was associated with significantly lower admission rates for stroke (IRR 0.70, 95% confidence interval [CI] 0.53-0.91), heart failure (IRR 0.78, 95% CI 0.65-0.92) and pneumonia or influenza (IRR 0.85, 95% CI 0.74-0.99), as well as all-cause death (IRR 0.76, 95% CI 0.65-0.83), and a nonsignificant change for acute MI (IRR 0.81, 95% CI 0.62-1.04) during the influenza seasons. INTERPRETATION: In this cohort of patients with type 2 diabetes, influenza vaccination was associated with reductions in rates of admission to hospital for specific cardiovascular events. Efforts should be focused on improvements in vaccine uptake in this important target group as part of comprehensive secondary prevention.

Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.

Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells.

B cells and plasma cells possess distinct RNA processing environments that respectively promote the expression of membrane-associated Ig by B cells versus the secretion of Ig by plasma cells. Through a combination of transcriptional profiling and screening using a lentiviral short-hairpin RNA interference library, we show that both the splicing factor hnRNPLL and the transcription elongation factor ELL2 modulate the ratio of secreted versus membrane-encoding Ighg2b transcripts in MPC11 plasmacytoma cell lines. hnRNPLL and ELL2 are both highly expressed in primary plasma cells relative to B cells, but hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in levels of the membrane-encoding Ighg2b isoform at the expense of the secreted Ighg2b isoform, whereas ELL2 counteracts this effect and drives Ig secretion by increasing the frequency of the secreted Ighg2b isoform. As in T cells, hnRNPLL also alters the splicing pattern of mRNA encoding the adhesion receptor CD44, promoting exon inclusion, and decreasing the overall level of CD44 expression. Further characterization of ELL2-dependent transcription by RNA-Seq revealed that ∼12% of transcripts expressed by plasma cells were differentially processed because of the activities of ELL2, including B-cell maturation antigen BCMA, a receptor with a defined role in plasma cell survival. Taken together, our data identify hnRNPLL and ELL2 as regulators of pre-mRNA processing in plasma cells.

Impact of ethnic-specific guidelines for anti-hypertensive prescribing in primary care in England: a longitudinal study.

BACKGROUND: In England, the National Institute for Health and Care Excellence (NICE) produces guidelines for the management of hypertension. In 2006, the NICE guidelines introduced an ethnic-age group algorithm based on the 2004 British Hypertension Society guidelines to guide antihypertensive drug prescription. METHODS: A longitudinal retrospective study with 15933 hypertensive patients aged 18 years or over and registered with 28 general practices in Wandsworth, London in 2007 was conducted to assess variations in antihypertensive prescribing. Logistic models were used to measure variations in the odds of being prescribed the 2006 NICE first line recommended monotherapy among NICE patient groups over the period. RESULTS: From 2000 to 2007, the percentage of patients prescribed the recommended monotherapy increased from 54.2% to 61.4% (p < 0.0001 for annual trend). Over the study period, black patients were more likely to be prescribed the recommended monotherapy than younger non-black patients (OR 0.16, 95% CI 0.12-0.21) and older non-black patients (OR 0.49, 95% CI 0.37-0.65). After the introduction of the NICE guidelines there was an increase in the NICE recommended monotherapy (OR 1.44, 95% CI 1.19-1.75) compared with the underlying trend. Compared to black patients, an increase in the use of recommended monotherapy was observed in younger non-black patients (OR 1.49, 95% CI 1.17-1.91) but not in older non-black patients (OR 0.58, 95% CI 0.46-0.74). CONCLUSION: The introduction of the 2006 NICE guideline had the greatest impact on prescribing for younger non-black patients. Lower associated increases among black patients may be due to their higher levels of recommended prescribing at baseline. The analysis suggests that guidelines did not impact equally on all patient groups.

A gene expression map of Arabidopsis thaliana development.

Regulatory regions of plant genes tend to be more compact than those of animal genes, but the complement of transcription factors encoded in plant genomes is as large or larger than that found in those of animals. Plants therefore provide an opportunity to study how transcriptional programs control multicellular development. We analyzed global gene expression during development of the reference plant Arabidopsis thaliana in samples covering many stages, from embryogenesis to senescence, and diverse organs. Here, we provide a first analysis of this data set, which is part of the AtGenExpress expression atlas. We observed that the expression levels of transcription factor genes and signal transduction components are similar to those of metabolic genes. Examining the expression patterns of large gene families, we found that they are often more similar than would be expected by chance, indicating that many gene families have been co-opted for specific developmental processes.

Patients' ratings of family physician practices on the internet: usage and associations with conventional measures of quality in the English National Health Service.

BACKGROUND: Patients are increasingly rating their family physicians on the Internet in the same way as they might rate a hotel on TripAdvisor or a seller on eBay, despite physicians' concerns about this process. OBJECTIVE: This study aims to examine the usage of NHS Choices, a government website that encourages patients to rate the quality of family practices in England, and associations between web-based patient ratings and conventional measures of patient experience and clinical quality in primary care. METHODS: We obtained all (16,952) ratings of family practices posted on NHS Choices between October 2009 and December 2010. We examined associations between patient ratings and family practice and population characteristics. Associations between ratings and survey measures of patient experience and clinical outcomes were examined. RESULTS: 61% of the 8089 family practices in England were rated, and 69% of ratings would recommend their family practice. Practices serving younger, less deprived, and more densely populated areas were more likely to be rated. There were moderate associations with survey measures of patient experience (Spearman ρ 0.37-0.48, P<.001 for all 5 variables), but only weak associations with measures of clinical process and outcome (Spearman ρ less than ± 0.18, P<.001 for 6 of 7 variables). CONCLUSION: The frequency of patients rating their family physicians on the Internet is variable in England, but the ratings are generally positive and are moderately associated with other measures of patient experience and weakly associated with clinical quality. Although potentially flawed, patient ratings on the Internet may provide an opportunity for organizational learning and, as it becomes more common, another lens to look at the quality of primary care.

Association of practice size and pay-for-performance incentives with the quality of diabetes management in primary care.

BACKGROUND: Not enough is known about the association between practice size and clinical outcomes in primary care. We examined this association between 1997 and 2005, in addition to the impact of the Quality and Outcomes Framework, a pay-for-performance incentive scheme introduced in the United Kingdom in 2004, on diabetes management. METHODS: We conducted a retrospective open-cohort study using data from the General Practice Research Database. We enrolled 422 general practices providing care for 154,945 patients with diabetes. Our primary outcome measures were the achievement of national treatment targets for blood pressure, glycated hemoglobin (HbA(1c)) levels and total cholesterol. RESULTS: We saw improvements in the recording of process of care measures, prescribing and achieving intermediate outcomes in all practice sizes during the study period. We saw improvement in reaching national targets after the introduction of the Quality and Outcomes Framework. These improvements significantly exceeded the underlying trends in all practice sizes for achieving targets for cholesterol level and blood pressure, but not for HbA(1c) level. In 1997 and 2005, there were no significant differences between the smallest and largest practices in achieving targets for blood pressure (1997 odds ratio [OR] 0.98, 95% confidence interval [CI] 0.82 to 1.16; 2005 OR 0.92, 95% CI 0.80 to 1.06 in 2005), cholesterol level (1997 OR 0.94, 95% CI 0.76 to 1.16; 2005 OR 1.1, 95% CI 0.97 to 1.40) and glycated hemoglobin level (1997 OR 0.79, 95% CI 0.55 to 1.14; 2005 OR 1.05, 95% CI 0.93 to 1.19). INTERPRETATION: We found no evidence that size of practice is associated with the quality of diabetes management in primary care. Pay-for-performance programs appear to benefit both large and small practices to a similar extent.

Systematic investigation of global coordination among mRNA and protein in cellular society.

BACKGROUND: Cell functions depend on molecules organized in the cellular society. Two basic components are mRNA molecules and proteins. The interactions within and between those two components are crucial for carrying out sophisticated cell functions. The interplay can be analyzed by comparing expression levels of mRNA and proteins. This is critical for understanding the molecular interactions, (post-) transcriptional regulations and conservation of co-expression between mRNAs and proteins. By using high-throughput transcriptome and proteome data, this study aims to systematically investigate the general picture of such expression correlations. We analyze four groups of correlations: (i) transcript levels of different genes, (ii) protein levels of different genes, (iii) mRNA levels with protein levels of different genes and (iv) mRNA levels with protein levels of same genes. This helps to obtain global insights into the stability and variability of co-expression and correlation of mRNA and protein levels. RESULTS: Analysis of the simultaneous co-expression of mRNAs and proteins yields mainly weak correlations. Therefore we introduce the concept of time-delayed co-expression patterns. Based on a time-course dataset, we obtain a high fraction of time-delayed correlations. In group (i), 67% of different transcripts are significantly correlated. At the protein level (ii), 68% of different proteins are significantly correlated. Comparison of the different molecular levels results in a 74% fraction of correlated transcript and protein levels of different genes (iii) and 56% for the same genes (iv). Furthermore, a higher fraction of protein levels (simultaneously 20% and short time-delayed 29%) is correlated than at the transcript level (10% and 18% respectively). Analysis of the dynamics of the correlation shows that correlation at the transcript level is largely passed to the protein level. In contrast, specific co-expression patterns are changed in multiple ways. CONCLUSIONS: Our analysis reveals that the regulation of transcription and translation contains a time-delayed component. The correlation at the protein level is more synchronous or delayed by shorter time than those at the transcript level. This supports the hypothesis that a higher degree of direct physical interactions require a higher synchronicity between the interacting partners. The conservation of correlation between the transcript level (i) and the protein level (ii) sheds light on the processes underlying transcription, translation and regulation. A future investigation of the conditions of conservation will give comprehensive insights in the complexity of the regulatory mechanisms.

Statistical detection of cooperative transcription factors with similarity adjustment.

MOTIVATION: Statistical assessment of cis-regulatory modules (CRMs) is a crucial task in computational biology. Usually, one concludes from exceptional co-occurrences of DNA motifs that the corresponding transcription factors (TFs) are cooperative. However, similar DNA motifs tend to co-occur in random sequences due to high probability of overlapping occurrences. Therefore, it is important to consider similarity of DNA motifs in the statistical assessment. RESULTS: Based on previous work, we propose to adjust the window size for co-occurrence detection. Using the derived approximation, one obtains different window sizes for different sets of DNA motifs depending on their similarities. This ensures that the probability of co-occurrences in random sequences are equal. Applying the approach to selected similar and dissimilar DNA motifs from human TFs shows the necessity of adjustment and confirms the accuracy of the approximation by comparison to simulated data. Furthermore, it becomes clear that approaches ignoring similarities strongly underestimate P-values for cooperativity of TFs with similar DNA motifs. In addition, the approach is extended to deal with overlapping windows. We derive Chen-Stein error bounds for the approximation. Comparing the error bounds for similar and dissimilar DNA motifs shows that the approximation for similar DNA motifs yields large bounds. Hence, one has to be careful using overlapping windows. Based on the error bounds, one can precompute the approximation errors and select an appropriate overlap scheme before running the analysis. AVAILABILITY: Software to perform the calculation for pairs of position frequency matrices (PFMs) is available at http://mosta.molgen.mpg.de as well as C++ source code for downloading.

Natural similarity measures between position frequency matrices with an application to clustering.

MOTIVATION: Transcription factors (TFs) play a key role in gene regulation by binding to target sequences. In silico prediction of potential binding of a TF to a binding site is a well-studied problem in computational biology. The binding sites for one TF are represented by a position frequency matrix (PFM). The discovery of new PFMs requires the comparison to known PFMs to avoid redundancies. In general, two PFMs are similar if they occur at overlapping positions under a null model. Still, most existing methods compute similarity according to probabilistic distances of the PFMs. Here we propose a natural similarity measure based on the asymptotic covariance between the number of PFM hits incorporating both strands. Furthermore, we introduce a second measure based on the same idea to cluster a set of the Jaspar PFMs. RESULTS: We show that the asymptotic covariance can be efficiently computed by a two dimensional convolution of the score distributions. The asymptotic covariance approach shows strong correlation with simulated data. It outperforms three alternative methods. The Jaspar clustering yields distinct groups of TFs of the same class. Furthermore, a representative PFM is given for each class. In contrast to most other clustering methods, PFMs with low similarity automatically remain singletons. AVAILABILITY: A website to compute the similarity and to perform clustering, the source code and Supplementary Material are available at http://mosta.molgen.mpg.de.

A new statistical model to select target sequences bound by transcription factors.

Transcription factors (TFs) play a key role in gene regulation by binding to target sequences. In silico prediction of potential binding to a sequence is a main task in computational biology. Although many methods have been proposed to tackle this problem, the statistical significance of the prediction is still not solved. We propose an approach to give a good approximation for the potential of a sequence to be bound by a TF. Instead of assessing distinct binding sites, we motivate to focus on the number of binding sites. Based on a suitable statistical model, probabilities for scoring are approximated for a TF to bind to a sequence. Two examples show the necessity of such a model as well as the superiority of the proposed method compared to standard approaches.

Impact of 'stretch' targets for cardiovascular disease management within a local pay-for-performance programme.

Pay-for-performance programs are often aimed to improve the management of chronic diseases. We evaluate the impact of a local pay for performance programme (QOF+), which rewarded financially more ambitious quality targets ('stretch targets') than those used nationally in the Quality and Outcomes Framework (QOF). We focus on targets for intermediate outcomes in patients with cardiovascular disease and diabetes. A difference-in-difference approach is used to compare practice level achievements before and after the introduction of the local pay for performance program. In addition, we analysed patient-level data on exception reporting and intermediate outcomes utilizing an interrupted time series analysis. The local pay for performance program led to significantly higher target achievements (hypertension: p-value <0.001, coronary heart disease: p-values <0.001, diabetes: p-values <0.061, stroke: p-values <0.003). However, the increase was driven by higher rates of exception reporting (hypertension: p-value <0.001, coronary heart disease: p-values <0.03, diabetes: p-values <0.05) in patients with all conditions except for stroke. Exception reporting allows practitioners to exclude patients from target calculations if certain criteria are met, e.g. informed dissent of the patient for treatment. There were no statistically significant improvements in mean blood pressure, cholesterol or HbA1c levels. Thus, achievement of higher payment thresholds in the local pay for performance scheme was mainly attributed to increased exception reporting by practices with no discernable improvements in overall clinical quality. Hence, active monitoring of exception reporting should be considered when setting more ambitious quality targets. More generally, the study suggests a trade-off between additional incentive for better care and monitoring costs.

Rural, urban and migrant differences in non-communicable disease risk-factors in middle income countries: a cross-sectional study of WHO-SAGE data.

BACKGROUND: Understanding how urbanisation and rural-urban migration influence risk-factors for non-communicable disease (NCD) is crucial for developing effective preventative strategies globally. This study compares NCD risk-factor prevalence in urban, rural and migrant populations in China, Ghana, India, Mexico, Russia and South Africa. METHODS: Study participants were 39,436 adults within the WHO Study on global AGEing and adult health (SAGE), surveyed 2007-2010. Risk ratios (RR) for each risk-factor were calculated using logistic regression in country-specific and all country pooled analyses, adjusted for age, sex and survey design. Fully adjusted models included income quintile, marital status and education. RESULTS: Regular alcohol consumption was lower in migrant and urban groups than in rural groups (pooled RR and 95%CI: 0.47 (0.31-0.68); 0.58, (0.46-0.72), respectively). Occupational physical activity was lower (0.86 (0.72-0.98); 0.76 (0.65-0.85)) while active travel and recreational physical activity were higher (pooled RRs for urban groups; 1.05 (1.00-1.09), 2.36 (1.95-2.83), respectively; for migrant groups: 1.07 (1.0 -1.12), 1.71 (1.11-2.53), respectively). Overweight, raised waist circumference and diagnosed diabetes were higher in urban groups (1.19 (1.04-1.35), 1.24 (1.07-1.42), 1.69 (1.15-2.47), respectively). Exceptions to these trends exist: obesity indicators were higher in rural Russia; active travel was lower in urban groups in Ghana and India; and in South Africa, urban groups had the highest alcohol consumption. CONCLUSION: Migrants and urban dwellers had similar NCD risk-factor profiles. These were not consistently worse than those seen in rural dwellers. The variable impact of urbanisation on NCD risk must be considered in the design and evaluation of strategies to reduce the growing burden of NCDs globally.

The uptake of integrated perinatal prevention of mother-to-child HIV transmission programs in low- and middle-income countries: a systematic review.

BACKGROUND: The objective of this review was to assess the uptake of WHO recommended integrated perinatal prevention of mother-to-child transmission (PMTCT) of HIV interventions in low- and middle-income countries. METHODS AND FINDINGS: We searched 21 databases for observational studies presenting uptake of integrated PMTCT programs in low- and middle-income countries. Forty-one studies on programs implemented between 1997 and 2006, met inclusion criteria. The proportion of women attending antenatal care who were counseled and who were tested was high; 96% (range 30-100%) and 81% (range 26-100%), respectively. However, the overall median proportion of HIV positive women provided with antiretroviral prophylaxis in antenatal care and attending labor ward was 55% (range 22-99%) and 60% (range 19-100%), respectively. The proportion of women with unknown HIV status, tested for HIV at labor ward was 70%. Overall, 79% (range 44-100%) of infants were tested for HIV and 11% (range 3-18%) of them were HIV positive. We designed two PMTCT cascades using studies with outcomes for all perinatal PMTCT interventions which showed that an estimated 22% of all HIV positive women attending antenatal care and 11% of all HIV positive women delivering at labor ward were not notified about their HIV status and did not participate in PMTCT program. Only 17% of HIV positive antenatal care attendees and their infants are known to have taken antiretroviral prophylaxis. CONCLUSION: The existing evidence provides information only about the initial PMTCT programs which were based on the old WHO PMTCT guidelines. The uptake of counseling and HIV testing among pregnant women attending antenatal care was high, but their retention in PMTCT programs was low. The majority of women in the included studies did not receive ARV prophylaxis in antenatal care; nor did they attend labor ward. More studies evaluating the uptake in current PMTCT programs are urgently needed.

Differences in the classification of hypertensive controlled patient in primary care: Cross sectional study.

OBJECTIVES: To examine differences in blood pressure control using the 2006 National Institute for Health and Clinical Excellence (NICE) guidelines and the 2007 Quality and Outcome Framework (QOF) standards. DESIGN: Cross-sectional study. SETTING: 28 general practices located in Wandsworth, London. PARTICIPANTS: Hypertensive patients aged 17 years and over. MAIN OUTCOMES MEASURES: Percentage of hypertensive patients classified as a hypertensive controlled patient (HCP) by each standard. RESULTS: 79.5% of patients were classified as a HCP by the QOF target and 60.7% by the NICE target. 93% and 14% of practices had more than 70% of patients classified as a HPC by using the QOF and NICE targets respectively. By applying the QOF target, men aged 45-64 years and 65 years and over had significantly higher probability of being classified as a HCP compared to those aged 17-44 years, OR 1.34 (1.08-.165) and OR 2.15 (1.61-2.87) respectively. Regardless of the target, for men the probability of being classified as a HCP increased with age. CONCLUSION: Better achievement of blood pressure control targets is present when the less stringent QOF target is used. Men aged 65 years and over were more likely to be classified as a HCP. Greater consistency is needed between the clinical targets in QOF and NICE guidance.

Impacts of a national strategy to reduce population salt intake in England: serial cross sectional study.

BACKGROUND: The UK introduced an ambitious national strategy to reduce population levels of salt intake in 2003. The aim of this study was to evaluate the impact of this strategy on salt intake in England, including potential effects on health inequalities. METHODS: Secondary analysis of data from the Health Survey for England. Our main outcome measure was trends in estimated daily salt intake from 2003-2007, as measured by spot urine. Secondary outcome measures were knowledge of government guidance and voluntary use of salt in food preparation over this time period. RESULTS: There were significant reductions in salt intake between 2003 and 2007 (-0.175 grams per day per year, p<0.001). Intake decreased uniformly across all other groups but remained significantly higher in younger persons, men, ethnic minorities and lower social class groups and those without hypertension in 2007. Awareness of government guidance on salt use was lowest in those groups with the highest intake (semi-skilled manual v professional; 64.9% v 71.0% AOR 0.76 95% CI 0.58-0.99). Self reported use of salt added at the table reduced significantly during the study period (56.5% to 40.2% p<0.001). Respondents from ethnic minority groups remained significantly more likely to add salt during cooking (white 42.8%, black 74.1%, south Asian 88.3%) and those from lower social class groups (unskilled manual 46.6%, professional 35.2%) were more likely to add salt at the table. CONCLUSIONS: The introduction a national salt reduction strategy was associated with uniform but modest reductions in salt intake in England, although it is not clear precisely which aspects of the strategy contributed to this. Knowledge of government guidance was lower and voluntary salt use and total salt intake was higher among occupational and ethnic groups at greatest risk of cardiovascular disease.

Association between primary care organisation population size and quality of commissioning in England: an observational study.

BACKGROUND: The ideal population size of healthcare commissioning organisations is not known. AIM: To investigate whether there is a relationship between the size of commissioning organisations and how well they perform on a range of performance measures. DESIGN AND SETTING: Cross-sectional, observational study of performance in all 152 primary care trusts (PCTs) in England. METHOD: Comparison of PCT size against 36 indicators of commissioning performance, including measures of clinical and preventative effectiveness, patient centredness, access, cost, financial ability, and engagement. RESULTS: Fourteen of the 36 indicators have an unadjusted relationship (P<0.05) with size of the PCT. With 10 indicators, there was increasing quality with larger size. However, when population factors including deprivation, ethnicity, rurality, and age were included in the analysis, there was no relationship between size and performance for any measure. CONCLUSION: There is no evidence to suggest that there is an optimum size for PCT performance. Observed variations in PCT performance with size were explained by the characteristics of the populations they served. These findings suggest that configuration of clinical commissioning groups should be geared towards producing organisations that can function effectively across their key responsibilities, rather than being based on the size of their population alone.

High-profile investigations into hospital safety problems in England did not prompt patients to switch providers.

Amid international concerns about health care safety and quality, there has been an escalation of investigations by health care regulators into adverse events. England has a powerful central health care regulator, the Care Quality Commission, which conducts occasional high-profile investigations into major lapses in quality at individual hospitals. The results have sometimes garnered considerable attention from the news media, but it is not known what effect the investigations have had on patients' behavior. We analyzed trends in admission for discretionary (nonemergency) care at three hospitals that were subject to high-profile investigations by the Healthcare Commission (the predecessor to the Care Quality Commission) between 2006 and 2009. We found that investigations had no impact on utilization for two of the hospitals; in the third hospital, there were significant declines in inpatient admissions, outpatient surgeries, and in numbers of patients coming for their first appointment, but the effects disappeared six months after publication of the investigation report. Thus, the publication and dissemination of highly critical reports by a health care regulator does not appear to have resulted in patients' sustained avoidance of the hospitals that were investigated. Our findings reinforce other evaluations: Reporting designed to affect providers' reputations is likely to spur more improvement in quality and safety than relying on patients to choose their providers based on quality and safety reports, and simplistic assumptions regarding the power of information to drive patient choices are unrealistic.