The nature of mutations induced by replication­transcription collisions.

The DNA replication and transcription machineries share a common DNA template and thus can collide with each other co-directionally or head-on. Replication­transcription collisions can cause replication fork arrest, premature transcription termination, DNA breaks, and recombination intermediates threatening genome integrity. Collisions may also trigger mutations, which are major contributors to genetic disease and evolution. However, the nature and mechanisms of collision-induced mutagenesis remain poorly understood. Here we reveal the genetic consequences of replication­transcription collisions in actively dividing bacteria to be two classes of mutations: duplications/deletions and base substitutions in promoters. Both signatures are highly deleterious but are distinct from the previously well-characterized base substitutions in the coding sequence. Duplications/deletions are probably caused by replication stalling events that are triggered by collisions; their distribution patterns are consistent with where the fork first encounters a transcription complex upon entering a transcription unit. Promoter substitutions result mostly from head-on collisions and frequently occur at a nucleotide that is conserved in promoters recognized by the major σ factor in bacteria. This substitution is generated via adenine deamination on the template strand in the promoter open complex, as a consequence of head-on replication perturbing transcription initiation. We conclude that replication­transcription collisions induce distinct mutation signatures by antagonizing replication and transcription, not only in coding sequences but also in gene regulatory elements.

Hepatic Oleate Regulates Insulin-like Growth Factor-Binding Protein 1 Partially through the mTORC1-FGF21 Axis during High-Carbohydrate Feeding.

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-liming step of monounsaturated fatty acid biosynthesis and is a key regulator of systemic glucose metabolism. Mice harboring either a global (GKO) or liver-specific deletion (LKO) of Scd1 display enhanced insulin signaling and whole-body glucose uptake. Additionally, GKO and LKO mice are protected from high-carbohydrate diet-induced obesity. Given that high-carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how Scd1 deficiency confers metabolically beneficial phenotypes. Here we show that insulin-like growth factor-binding protein 1 (IGFBP1), a hepatokine that has been reported to enhance insulin signaling, is significantly elevated in the liver and plasma of GKO and LKO mice fed a low-fat high-carbohydrate diet. We also observed that the expression of hepatic Igfbp1 is regulated by oleic acid (18:1n9), a product of SCD1, through the mTORC1-FGF21 axis both in vivo and in vitro.

Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α-FGF21 axis in mice.

Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of two monounsaturated fatty acids, oleate and palmitoleate, from the saturated fatty acids stearate and palmitate, respectively. SCD1-deficient mouse models are protected against diet-induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection by SCD1 deficiency is unclear. Using liver-specific SCD1 knockout (LKO) mice fed a high-carbohydrate, low-fat diet, we show that hepatic SCD1 deficiency increases systemic glucose uptake. Hepatic SCD1 deficiency enhanced glucose transporter type 1 (GLUT1) expression in the liver and also up-regulated GLUT4 and adiponectin expression in adipose tissue. The enhanced glucose uptake correlated with increased liver expression and elevated plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole-body lipid metabolism. Feeding LKO mice a triolein-supplemented but not tristearin-supplemented high-carbohydrate, low-fat diet reduced FGF21 expression and plasma levels. Consistently, SCD1 inhibition in primary hepatocytes induced FGF21 expression, which was repressed by treatment with oleate but not palmitoleate. Moreover, deletion of the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) reduced hepatic and plasma FGF21 and white adipocyte tissue-specific GLUT4 expression and raised plasma glucose levels in LKO mice. These results suggest that hepatic oleate regulates glucose uptake in adipose tissue either directly or partially by modulating the hepatic PGC-1α-FGF21 axis.

Six-month outcomes following an emergency hospital admission for older adults with co-morbid mental health problems indicate complexity of care needs.

BACKGROUND: two-thirds of older patients admitted as an emergency to a general hospital have co-existing mental health problems including delirium, dementia and depression. This study describes the outcomes of older adults with co-morbid mental health problems after an acute hospital admission. METHODS: a follow-up study of 250 patients aged over 70 admitted to 1 of 12 wards (geriatric, medical or orthopaedic) of an English acute general hospital with a co-morbid mental health problem and followed up at 180 days. RESULTS: twenty-seven per cent did not return to their original place of residence after the hospital admission. After 180 days 31% had died, 42% had been readmitted and 24% of community residents had moved to a care home. Only 31% survived without being readmitted or moving to a care home. However, 16% spent >170 of the 180 days at home. Significant predictors for poor outcomes were co-morbidity, nutrition, cognitive function, reduction in activities of daily living ability prior to admission, behavioural and psychiatric problems and depression. Only 42% of survivors recovered to their pre-acute illness level of function. Clinically significant behavioural and psychiatric symptoms were present at follow-up in 71% of survivors with baseline cognitive impairment, and new symptoms developed frequently in this group. CONCLUSIONS: the variable, but often adverse, outcomes in this group implies a wide range of health and social care needs. Community and acute services to meet these needs should be anticipated and provided for.

Thin-filament length correlates with fiber type in human skeletal muscle.

Force production in skeletal muscle is proportional to the amount of overlap between the thin and thick filaments, which, in turn, depends on their lengths. Both thin- and thick-filament lengths are precisely regulated and uniform within a myofibril. While thick-filament lengths are essentially constant across muscles and species (∼1.65 µm), thin-filament lengths are highly variable both across species and across muscles of a single species. Here, we used a high-resolution immunofluorescence and image analysis technique (distributed deconvolution) to directly test the hypothesis that thin-filament lengths vary across human muscles. Using deltoid and pectoralis major muscle biopsies, we identified thin-filament lengths that ranged from 1.19 ± 0.08 to 1.37 ± 0.04 µm, based on tropomodulin localization with respect to the Z-line. Tropomodulin localized from 0.28 to 0.47 µm further from the Z-line than the NH(2)-terminus of nebulin in the various biopsies, indicating that human thin filaments have nebulin-free, pointed-end extensions that comprise up to 34% of total thin-filament length. Furthermore, thin-filament length was negatively correlated with the percentage of type 2X myosin heavy chain within the biopsy and shorter in type 2X myosin heavy chain-positive fibers, establishing the existence of a relationship between thin-filament lengths and fiber types in human muscle. Together, these data challenge the widely held assumption that human thin-filament lengths are constant. Our results also have broad relevance to musculoskeletal modeling, surgical reattachment of muscles, and orthopedic rehabilitation.

The motivators and barriers to a smoke-free home among disadvantaged caregivers: identifying the positive levers for change.

INTRODUCTION: The aims of this study were to explore home smoking behaviors and the motivators and barriers to smoke-free homes among a group of disadvantaged caregivers for young children and to identify the positive levers that health care professionals can utilize when supporting smoking behavior change. METHODS: In-depth qualitative interviews were conducted between July and September 2009, with 22 disadvantaged smoking caregivers, accessing Children's Centre Services in Nottingham, UK. Interviews were audiorecorded and transcribed verbatim. Data were coded and analyzed thematically to identify emergent main and subthemes. RESULTS: Caregivers had some general understanding of the dangers of secondhand smoke (SHS), but their knowledge appeared incomplete and confused. All interviewees described rules around smoking in the home; however, these tended to be transient and fluid and unlikely to be effective. Caregivers were often living in difficult and complex circumstances and experienced significant barriers to creating a smoke-free home. The motivators for change were more strongly linked to house decor and smell than children's health, suggesting that visible evidence of the harm done by SHS to children might help promote smoke-free homes. CONCLUSIONS: Findings suggest that further tailored information on the effect of SHS is required, but to instigate caregiver behavior change, providing demonstrable evidence of the impact that their smoking is having on their children's health is more likely to be effective.

Can primary care data be used to monitor regional smoking prevalence? An analysis of The Health Improvement Network primary care data.

BACKGROUND: Accurate and timely regional data on smoking trends allow tobacco control interventions to be targeted at the areas most in need and facilitate the evaluation of such interventions. Electronic primary care databases have the potential to provide a valuable source of such data due to their size, continuity and the availability of socio-demographic data. UK electronic primary care data on smoking prevalence from The Health Improvement Network (THIN) have previously been validated at the national level, but may be less representative at the regional level due to reduced sample sizes. We investigated whether this database provides valid regional data and whether it can be used to compare smoking prevalence in different UK regions. METHODS: Annual estimates of smoking prevalence by government office region (GOR) from THIN were compared with estimates of smoking prevalence from the General Lifestyle Survey (GLF) from 2000 to 2008. RESULTS: For all regions, THIN prevalence data were generally found to be highly comparable with GLF data from 2006 onwards. CONCLUSIONS: THIN primary care data could be used to monitor regional smoking prevalence and highlight regional differences in smoking in the UK.

Designing tools to predict and mitigate impacts on water quality following the Australian 2019/2020 wildfires: Insights from Sydney's largest water supply catchment.

The 2019/2020 Australian bushfires (or wildfires) burned the largest forested area in Australia's recorded history, with major socio-economic and environmental consequences. Among the largest fires was the 280 000 ha Green Wattle Creek Fire, which burned large forested areas of the Warragamba catchment. This protected catchment provides critical ecosystem services for Lake Burragorang, one of Australia's largest urban supply reservoirs delivering ~85% of the water used in Greater Sydney. Water New South Wales (WaterNSW) is the utility responsible for managing water quality in Lake Burragorang. Its postfire risk assessment, done in collaboration with researchers in Australia, the UK, and United States, involved (i) identifying pyrogenic contaminants in ash and soil; (ii) quantifying ash loads and contaminant concentrations across the burned area; and (iii) estimating the probability and quantity of soil, ash, and associated contaminant entrainment for different rainfall scenarios. The work included refining the capabilities of the new WEPPcloud-WATAR-AU model (Water Erosion Prediction Project cloud-Wildfire Ash Transport And Risk-Australia) for predicting sediment, ash, and contaminant transport, aided by outcomes from previous collaborative postfire research in the catchment. Approximately two weeks after the Green Wattle Creek Fire was contained, an extreme rainfall event (~276 mm in 72 h) caused extensive ash and sediment delivery into the reservoir. The risk assessment informed on-ground monitoring and operational mitigation measures (deployment of debris-catching booms and adjustment of the water supply system configuration), ensuring the continuity of safe water supply to Sydney. WEPPcloud-WATAR-AU outputs can prioritize recovery interventions for managing water quality risks by quantifying contaminants on the hillslopes, anticipating water contamination risk, and identifying areas with high susceptibility to ash and sediment transport. This collaborative interaction among scientists and water managers, aimed also at refining model capabilities and outputs to meet managers' needs, exemplifies the successful outcomes that can be achieved at the interface of industry and science. Integr Environ Assess Manag 2021;17:1151-1161. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Inositol-Requiring Enzyme 1α-Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus-like Autoimmune Disease.

OBJECTIVE: To explore the molecular mechanisms underlying dysregulation of lipid metabolism in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: B cells in peripheral blood from patients with SLE and healthy controls were stained with BODIPY dye for detection of lipids. Mice with targeted knockout of genes for B cell-specific inositol-requiring enzyme 1α (IRE-1α) and stearoyl-coenzyme A desaturase 1 (SCD-1) were used for studying the influence of the IRE-1α/SCD-1/SCD-2 pathway on B cell differentiation and autoantibody production. The preclinical efficacy of IRE-1α suppression as a treatment for lupus was tested in MRL.Faslpr mice. RESULTS: In cultures with mouse IRE-1α-null B cells, supplementation with monounsaturated fatty acids largely rescued differentiation of plasma cells from B cells, indicating that the compromised capacity of B cell differentiation in the absence of IRE-1α may be attributable to a defect in monounsaturated fatty acid synthesis. Moreover, activation with IRE-1α/X-box binding protein 1 (XBP-1) was required to facilitate B cell expression of SCD-1 and SCD-2, which are 2 critical enzymes that catalyze monounsaturated fatty acid synthesis. Mice with targeted Scd1 gene deletion displayed a phenotype that was similar to that of IRE-1α-deficient mice, with diminished B cell differentiation into plasma cells. Importantly, in B cells from patients with lupus, both IRE-1α expression and Xbp1 messenger RNA splicing were significantly increased, and this was positively correlated with the expression of both Scd1 and Scd2 as well as with the amount of B cell lipid deposition. In MRL.Faslpr mice, both genetic and pharmacologic suppression of IRE-1α protected against the pathologic development and progression of lupus-like autoimmune disease. CONCLUSION: The results of this study reveal a molecular link in the dysregulation of lipid metabolism in the pathogenesis of lupus, demonstrating that the IRE-1α/XBP-1 pathway controls plasma cell differentiation through SCD-1/SCD-2-mediated monounsaturated fatty acid synthesis. These findings provide a rationale for targeting IRE-1α and monounsaturated fatty acid synthesis in the treatment of patients with SLE.

Impact of adopting low sodium diet on biomarkers of inflammation and coagulation: a randomised controlled trial.

BACKGROUND: A low sodium diet is an established intervention in the treatment of impaired renal function and hypertension which may modulate cardiovascular risk independent of recognised antihypertensive effects. Epidemiological data suggest that dietary sodium intake may be associated with systemic inflammation: another potential pathophysiological mechanism by which sodium intake may modify vascular disease. METHODS: We tested the hypothesis that adopting a low sodium diet may decrease biomarkers of systemic inflammation or coagulation using data from a randomised double-blind placebo-controlled trial. Participants (n=171; aged 18-65 years) in a randomised double-blind placebo-controlled trial of a low sodium diet for 6 weeks provided paired serum samples for analysis to assess the impact of adopting a low sodium diet on biomarkers of systemic inflammation and coagulation. RESULTS: There was a significant difference in 24-hour sodium urinary excretion between the low sodium intake and the normal sodium intake groups of 43 mmol (p<0.001). In the primary analysis there was no effect of adopting a low sodium diet on serum D-dimers, but high-sensitivity C-reactive protein (hsCRP) was reduced by 1.13 mg/L (95% confidence interval [95% CI], 0.03 to 2.22). However, after elimination of outlying high values for baseline serum hsCRP (>10 mg/L), this effect was attenuated (-0.47 mg/L; 95% CI, -1.25 to 0.31). CONCLUSIONS: Using data from a randomised double-blind placebo-controlled trial in asthma with objective confirmation of adherence to the low sodium diet, we report that adopting a low sodium diet for 6 weeks has no effect on measures of systemic inflammation or coagulation.

A population-based epidemiologic study of Helicobacter pylori infection and its association with systemic inflammation.

BACKGROUND: Infection with Helicobacter pylori is associated with a variety of non-gastrointestinal sequelae. These may be mediated by an increase in systemic inflammation. We assessed if serologic evidence of infection with H. pylori is associated with increased serum C-reactive protein (CRP) levels. METHODS: The study design consisted of a randomly selected, cross-sectional population-based study of 2633 individuals phenotyped in 1991, of whom 2361 participants provided serum samples to permit measurement of H. pylori's serologic status and CRP levels. RESULTS: Male gender (odds ratio (OR): 1.65; 95% confidence interval (CI): 1.23-2.21), age (OR per year: 1.05; 95% CI: 1.04-1.06), height (OR per meter: 0.05; 95% CI: 0.01-0.24), current smoking habit (compared with never smokers, OR: 1.46; 95% CI: 1.13-1.88), and less affluent socioeconomic status were associated with increased odds of being seropositive for H. pylori. Helicobacter pylori infection was associated with increased risk of having an elevated serum CRP (above 3 mg/L) after adjustment for gender, age, height, smoking status, and socioeconomic status (OR: 1.32; 95% CI: 1.05-1.67). Similar associations were seen using a threshold for elevated serum CRP of greater than 1 mg/L. CONCLUSIONS: Our data suggest that infection with H. pylori is associated with increased systemic inflammation. This suggests one potential mechanism to explain the extra-gastrointestinal conditions associated with H. pylori infection.

An evaluation of the use of bronchoconstriction induced by deep inspiration as a new epidemiological measure for asthma.

RATIONALE: Bronchoconstriction after deep inhalation is associated with increased severity of asthma and is also a predictor of length of hospital stay in individuals admitted with asthma exacerbations. We hypothesized that this effect may represent a new non-invasive method to assess bronchial reactivity and other measures of asthma control. METHODS: We used a cross-sectional study design recruiting participants 18 to 65 years of age with a physician diagnosis of asthma. All participants were asked to provide three serial peak expiratory flow rate (PEFR) measurements in the morning, and bronchial reactivity was measured up to a maximum inhaled dose of 24.5 micromoL methacholine on the same day. Participants also recorded their asthma symptoms score and bronchodilator use during the 7 days before measuring bronchial reactivity. RESULTS: A total of 127 people provided data for analysis. There was no significant relationship between bronchoconstriction after deep inhalation (as measured by three serial PEFR measurements) and either bronchial reactivity to methacholine, asthma symptoms, or bronchodilator use. CONCLUSIONS: Bronchoconstriction induced by deep inspiration does not appear to be a valid marker of airway hyperresponsiveness or asthma severity in adults with mild to moderate asthma.

Exhaled carbon monoxide in asthmatic adults with bronchial reactivity: a prospective study.

HYPOTHESIS: We hypothesized that eCO may permit non-invasive assessment of disease activity in adults with asthma and bronchial reactivity. METHODS: A total of 209 participants 18 to 65 years of age with a diagnosis of asthma and bronchial reactivity provided data for analysis. The association between eCO and bronchial reactivity, forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), peak expiratory flow rate measurements (PEFR), asthma symptoms score, and bronchodilator use cross-sectionally and within-subject change in eCO were analyzed in relation to change in these variables over 6 weeks. RESULTS: There was no difference in eCO in those who were taking inhaled corticosteroids and those who were not (p = 0.33). There was also no cross-sectional or within-in subject association between eCO and bronchial reactivity, FEV(1), FVC, PEFR, symptoms score, or bronchodilator use. CONCLUSIONS: In a population of adults with bronchial reactivity, eCO has no or very limited potential as a biomarker of asthma activity.

Does a low sodium diet improve asthma control? A randomized controlled trial.

RATIONALE: Observational studies and initial randomized trials have indicated that a low sodium diet may improve asthma control. OBJECTIVES: We tested the hypothesis that a low sodium diet would improve asthma control over a 6-week period. METHODS: Participants with a physician diagnosis of asthma and measurable bronchial reactivity to methacholine entered a randomized double-blind placebo-controlled trial. All adopted a low sodium diet and were randomized to receive either 80 mmol/day of oral sodium supplements (normal sodium intake) or matched placebo (low sodium intake) for 6 weeks. The primary outcome was change in bronchial reactivity to methacholine; secondary outcomes were change in lung function, morning and evening peak expiratory flow, asthma symptoms score, daily bronchodilator use, Juniper Standardized Asthma Quality of Life Questionnaire score, and atopy. MEASUREMENTS AND MAIN RESULTS: A total of 220 individuals entered the study, of whom 199 completed the protocol. In the low sodium-intake group, mean daily urinary sodium excretion decreased by 20 mmol (SD, 64 mmol) and in the normal-sodium-intake group increased by 28 mmol (SD, 74 mmol). There were no differences between the two groups in the primary or secondary outcome measures; the mean difference in bronchial reactivity between the low- and normal-intake groups was -0.03 doubling doses of methacholine (95% confidence interval, -0.60 to 0.53). CONCLUSIONS: The use of a low sodium diet as an adjunctive therapy to normal treatment has no additional therapeutic benefit in adults with asthma and bronchial reactivity to methacholine.

Enhanced smoking cessation support for newly abstinent smokers discharged from hospital (the Hospital to Home trial): a randomized controlled trial.

BACKGROUND AND AIMS: The United Kingdom's National Institute for Health and Care Excellence guidance (NICE PH48) recommends that pharmacotherapy combined with behavioural support be provided for all smokers admitted to hospital; however, relapse to smoking after discharge remains common. This study aimed to assess the effect of adding home support for newly abstinent smokers to conventional NICE-recommended support in smokers discharged from hospital. DESIGN: Individually randomized parallel group trial. SETTING: One UK acute hospital. PARTICIPANTS: A total of 404 smokers aged > 18 admitted to acute medical wards between June 2016 and July 2017 were randomized in equal numbers to each treatment group. INTERVENTIONS AND COMPARATORS: The intervention provided 12 weeks of at-home cessation support, which included help in maintaining a smoke-free home, help in accessing and using medication, further behavioural support and personalized feedback on home air quality. The comparator was NICE PH48 care as usual. MEASURES: The primary outcome was self-reported continuous abstinence from smoking validated by an exhaled carbon monoxide level < 6 parts per million 4 weeks after discharge from hospital. FINDINGS: In an intention-to-treat analysis at the 4-week primary end-point, 38 participants (18.8%) in the usual care group and 43 (21.3%) in the intervention group reported continuous abstinence from smoking (odds ratio = 1.17, 95% confidence interval = 0.72 to 1.90, Bayes factor = 0.33). There were no significant differences in any secondary outcomes, including self-reported cessation at 3 months, having a smoke-free home or number of cigarettes smoked per day in those who did not quit. CONCLUSIONS: Provision of a home visit and continued support to prevent relapse to smoking after hospital discharge did not appear to increase subsequent abstinence rate above usual care in accordance with UK guidance from the National Institute of Health and Care Excellence.

A prospective study of weight change and systemic inflammation over 9 y.

BACKGROUND: An increase in weight is a risk factor for cardiovascular disease and cancer. This increased risk may be mediated by inflammation, but no long-term data are available on the effect of weight gain on systemic inflammation. OBJECTIVE: We tested the hypothesis that weight gain is associated with an increase in systemic inflammation during a 9-y period. DESIGN: In 1991 data on body weight and a blood sample were collected from a random sample of 2425 randomly selected adults from a community-based cohort in Nottingham, United Kingdom. In 2000, these measures were repeated in 1301 of these participants. The main outcome measure was change in systemic inflammation as measured by serum C-reactive protein (CRP) from the 1222 participants who provided paired samples. RESULTS: The mean change in weight from 1991 to 2000 was 2.9 kg (95% CI: 2.6, 3.2 kg). The geometric mean of CRP in 1991 was 1.22 mg/L (95% CI: 0.03, 125.0 mg/L), and it increased to 1.76 mg/L (95% CI: 0.09, 62.0 mg/L) in 2000 (P<0.001). A linear association was observed between increase in weight and serum CRP, with a 1-kg increment in weight being associated with an additional increase in CRP of 0.09 mg/L (95% CI: 0.02, 0.16 mg/L) during this time period. CONCLUSION: During a 9-y period, an increase in weight is associated with an increase in systemic inflammation. This provides a mechanism that may explain some of the previously reported association of weight gain with an increased risk of both cancer and cardiovascular disease.

A multivariate analysis of serum nutrient levels and lung function.

BACKGROUND: There is mounting evidence that estimates of intakes of a range of dietary nutrients are related to both lung function level and rate of decline, but far less evidence on the relation between lung function and objective measures of serum levels of individual nutrients. The aim of this study was to conduct a comprehensive examination of the independent associations of a wide range of serum markers of nutritional status with lung function, measured as the one-second forced expiratory volume (FEV1). METHODS: Using data from the Third National Health and Nutrition Examination Survey, a US population-based cross-sectional study, we investigated the relation between 21 serum markers of potentially relevant nutrients and FEV1, with adjustment for potential confounding factors. Systematic approaches were used to guide the analysis. RESULTS: In a mutually adjusted model, higher serum levels of antioxidant vitamins (vitamin A, beta-cryptoxanthin, vitamin C, vitamin E), selenium, normalized calcium, chloride, and iron were independently associated with higher levels of FEV1. Higher concentrations of potassium and sodium were associated with lower FEV1. CONCLUSION: Maintaining higher serum concentrations of dietary antioxidant vitamins and selenium is potentially beneficial to lung health. In addition other novel associations found in this study merit further investigation.

The effect of proactively identifying smokers and offering smoking cessation support in primary care populations: a cluster-randomized trial.

AIMS: To establish whether proactively identifying all smokers in primary care populations and offering smoking cessation support is effective in increasing long-term abstinence from smoking. DESIGN: Cluster randomized controlled trial. SETTING: Twenty-four general practices in Nottinghamshire, randomized by practice to active or control intervention. PARTICIPANTS: All adult patients registered with the practices who returned a questionnaire confirming that they were current smokers (n = 6856). INTERVENTION: Participants were offered smoking cessation support by letter and those interested in receiving it were contacted and referred into National Health Service (NHS) stop smoking services if required. MEASUREMENTS: Validated abstinence from smoking, use of smoking cessation services and number of quit attempts in continuing smokers at 6 months. FINDINGS: Smokers in the intervention group were more likely than controls to report that they had used local cessation services during the study period [16.6% and 8.9%, respectively, adjusted odds ratio (OR) 2.09, 95% confidence interval (CI) 1.57-2.78], and continuing smokers (in the intervention group) were more likely to have made a quit attempt in the last 6 months (37.4% and 33.3%, respectively, adjusted OR 1.23, 95% CI 1.01-1.51). Validated point prevalence abstinence from smoking at 6 months was higher in the intervention than the control groups (3.5% and 2.5%, respectively) but the difference was not statistically significant (adjusted OR controlling for covariates: 1.64, 95% CI 0.92-2.89). CONCLUSIONS: Proactively identifying smokers who want to quit in primary care populations, and referring them to a cessation service, increased contacts with cessation services and the number of quit attempts. We were unable to detect a significant effect on long-term cessation rates, but the study was not powered to detect the kind of difference that might be expected.

The potential to improve ascertainment and intervention to reduce smoking in primary care: a cross sectional survey.

BACKGROUND: Well established clinical guidelines recommend that systematic ascertainment of smoking status and intervention to promote cessation in all smokers should be a fundamental component of all health care provision. This study aims to establish the completeness and accuracy of smoking status recording in patients' primary care medical records and the level of interest in receiving smoking cessation support amongst primary care patients in an inner city UK population. METHODS: Postal questionnaires were sent to all patients aged over 18 from 24 general practices in Nottingham UK who were registered as smokers or had no smoking status recorded in their medical notes. RESULTS: The proportion of patients with a smoking status recorded varied between practices from 42.4% to 100% (median 90%). Of the recorded smokers who responded to our questionnaire (35.5% of the total), a median of 20.3% reported that they had not smoked cigarettes or tobacco in the last 12 months. Of respondents with no recorded smoking status, 29.8% reported themselves to be current smokers. Of the 6856 responding individuals thus identified as current smokers, 41.4% indicated that they would like to speak to a specialist smoking adviser to help them stop smoking. This proportion increased with socioeconomic disadvantage (measured by the Townsend Index) from 39.1% in the least deprived to 44.6% in the most deprived quintile. CONCLUSION: Whilst in many practices the ascertainment of smoking status is incomplete and/or inaccurate, failure to intervene appropriately on known status still remains the biggest challenge. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71514078.

The pro-oxidant activity of high-dose vitamin E supplements in vivo.

BACKGROUND: A recent meta-analysis has demonstrated that the regular administration of high-dose vitamin E supplements may be associated with increased mortality. The biological mechanism for this effect is uncertain. METHODS: A ferrous oxidation xylenol assay was used to assess plasma oxidation activity levels in samples from a randomized, placebo-controlled, 6-week trial of daily vitamin E supplementation in adults with asthma (n = 72). RESULTS AND CONCLUSION: A 27% increase in plasma oxidation activity levels was observed in patients receiving vitamin E. We demonstrate a pro-oxidant effect of high-dose vitamin E supplementation that may explain the increase in mortality observed in intervention studies using this nutrient.