Laura Pimpin

Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials

BACKGROUND Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood. METHODS We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression. RESULTS We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25). CONCLUSIONS Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.

Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.

BACKGROUND Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial.

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Is Butter Back? A Systematic Review and Meta-Analysis of Butter Consumption and Risk of Cardiovascular Disease, Diabetes, and Total Mortality.

Background Dietary guidelines recommend avoiding foods high in saturated fat. Yet, emerging evidence suggests cardiometabolic benefits of dairy products and dairy fat. Evidence on the role of butter, with high saturated dairy fat content, for total mortality, cardiovascular disease, and type 2 diabetes remains unclear. We aimed to systematically review and meta-analyze the association of butter consumption with all-cause mortality, cardiovascular disease, and diabetes in general populations. Methods and Findings We searched 9 databases from inception to May 2015 without restriction on setting, or language, using keywords related to butter consumption and cardiometabolic outcomes. Prospective cohorts or randomized clinical trials providing estimates of effects of butter intake on mortality, cardiovascular disease including coronary heart disease and stroke, or diabetes in adult populations were included. One investigator screened titles and abstracts; and two reviewed full-text articles independently in duplicate, and extracted study and participant characteristics, exposure and outcome definitions and assessment methods, analysis methods, and adjusted effects and associated uncertainty, all independently in duplicate. Study quality was evaluated by a modified Newcastle-Ottawa score. Random and fixed effects meta-analysis pooled findings, with heterogeneity assessed using the I2 statistic and publication bias by Egger’s test and visual inspection of funnel plots. We identified 9 publications including 15 country-specific cohorts, together reporting on 636,151 unique participants with 6.5 million person-years of follow-up and including 28,271 total deaths, 9,783 cases of incident cardiovascular disease, and 23,954 cases of incident diabetes. No RCTs were identified. Butter consumption was weakly associated with all-cause mortality (N = 9 country-specific cohorts; per 14g(1 tablespoon)/day: RR = 1.01, 95%CI = 1.00, 1.03, P = 0.045); was not significantly associated with any cardiovascular disease (N = 4; RR = 1.00, 95%CI = 0.98, 1.02; P = 0.704), coronary heart disease (N = 3; RR = 0.99, 95%CI = 0.96, 1.03; P = 0.537), or stroke (N = 3; RR = 1.01, 95%CI = 0.98, 1.03; P = 0.737), and was inversely associated with incidence of diabetes (N = 11; RR = 0.96, 95%CI = 0.93, 0.99; P = 0.021). We did not identify evidence for heterogeneity nor publication bias. Conclusions This systematic review and meta-analysis suggests relatively small or neutral overall associations of butter with mortality, CVD, and diabetes. These findings do not support a need for major emphasis in dietary guidelines on either increasing or decreasing butter consumption, in comparison to other better established dietary priorities; while also highlighting the need for additional investigation of health and metabolic effects of butter and dairy fat.

Tuberculosis and HIV co-infection in European Union and European Economic Area countries

In order to ensure the availability of resources for tuberculosis (TB) and HIV management and control, it is imperative that countries monitor and plan for co-infection in order to identify, treat and prevent TB–HIV co-infection, thereby reducing TB burden and increasing the years of healthy life of people living with HIV. A systematic review was undertaken to determine the burden of TB–HIV infection in the European Union (EU) and European Economic Area (EEA). Data on the burden of HIV infection in TB patients and risk factors for TB–HIV co-infection in the EU/EEA were extracted from studies that collected information in 1996 and later, regardless of the year of initiation of data collection, and a narrative synthesis presented. The proportion of HIV-co-infected TB patients varied from 0 to 15%. Western and eastern countries had higher levels and increasing trends of infection over time compared with central EU/EEA countries. Groups at higher risk of TB–HIV co-infection were males, young adults, foreign-born persons, the homeless, injecting drug users and prisoners. Further research is needed into the burden and associated risk factors of co-infection in Europe, to help plan effective control measures. Increased HIV testing of TB patients and targeted and informed strategies for control and prevention could help curb the co-infection epidemic.

The burden of TB–HIV in the EU: how much do we know? A survey of surveillance practices and results

Information on the burden of tuberculosis (TB)–HIV co-infection is critical for the planning and evaluation of TB–HIV control and treatment strategies. This study assessed current practices in countries of the European Union (EU) and European Economic Area (EEA) for monitoring HIV co-infection in TB surveillance systems, countries’ current co-infection burden and associated clinical practice. An online survey was distributed to all national TB surveillance nominated European Centre for Disease Prevention and Control contact points in the EU/EEA. We received 25 responses from 30 countries (83% response rate). Patients’ HIV status was collected in 18 out of the 25 TB surveillance systems, usually via clinician reporting (16 out of 18 surveillance systems). Although most countries recommended routine testing of TB patients for HIV, the proportion actually tested varied from 5% to 90%. The burden of HIV co-infection was found to be elevated in countries with higher levels of HIV testing and higher prevalence of HIV. We suggest that TB–HIV co-infection be monitored in all EU/EEA countries to facilitate the planning and evaluation of TB–HIV control strategies. Strengthening collaboration between TB and HIV clinicians and surveillance departments, and consideration of patient confidentiality restraints would be advantageous. The level of HIV testing in TB patients is low despite national recommendations and testing should be further promoted and monitored.

Dietary protein intake is associated with body mass index and weight up to 5 y of age in a prospective cohort of twins

Background: Few large epidemiologic studies have investigated the role of postweaning protein intake in excess weight and adiposity of young children, despite children in the United Kingdom consistently consuming protein in excess of their physiologic requirements. Objective: We investigated whether a higher proportion of protein intake from energy beyond weaning is associated with greater weight gain, higher body mass index (BMI), and risk of overweight or obesity in children up to 5 y of age. Design: Participants were 2154 twins from the Gemini cohort. Dietary intake was collected by using a 3-d diet diary when the children had a mean age of 21 mo. Weight and height were collected every 3 mo, from birth to 5 y. Longitudinal models investigated associations of protein intake with BMI, weight, and height, with adjustment for age at diet diary, sex, total energy intake, birth weight/length, and rate of prior growth and clustering within families. Logistic regression investigated protein intake in relation to the odds of overweight or obesity at 3 and 5 y of age. Results: A total of 2154 children had a mean ± SD of 5.7 ± 3.2 weight and height measurements up to 5 y. Total energy from protein was associated with higher BMI (β = 0.043; 95% CI: 0.011, 0.075) and weight (β = 0.052; 95% CI: 0.031, 0.074) but not height (β = 0.088; 95% CI: −0.038, 0.213) between 21 mo and 5 y. Substituting percentage energy from fat or carbohydrate for percentage energy from protein was associated with decreases in BMI and weight. Protein intake was associated with a trend in increased odds of overweight or obesity at 3 y (OR = 1.10; 95% CI 0.99, 1.22, P = 0.075), but the effect was not statistically significant at 5 y. Conclusion: A higher proportion of energy from protein during the complementary feeding stage is associated with greater increases in weight and BMI in early childhood in this large cohort of United Kingdom children.

Controversies and Unresolved Issues in Tuberculosis Prevention and Control: A Low-Burden-Country Perspective

Despite declining incidence in most high-income countries, tuberculosis shows no signs of disappearing in the near future. Although surveillance data from most Western European countries show relatively stable declines in the rate of tuberculosis over the past several decades, some have reported either an increasing rate or a decelerating pace of reduction in recent years. The burden of disease now disproportionately affects high-risk groups such as migrants, homeless persons, and prisoners. In view of the concentration of cases in urban areas and high-risk deprived groups, interventions that may not be efficient when applied to the general population may be highly cost effective when targeted at high-risk groups. In this article, we examine some controversial elements of tuberculosis prevention and control in low-burden countries and recommend issues for further research. In particular, we assess current evidence on the duration of protection by BCG vaccine, the screening of migrants and hard-to-reach groups, and the use of preventive therapy for contacts of cases of infectious multidrug-resistant tuberculosis. This analysis is presented from the perspective of low-tuberculosis-burden, high-income countries attempting to eliminate tuberculosis.

Extended and standard duration weight-loss programme referrals for adults in primary care (WRAP): a randomised controlled trial

Summary Background Evidence exist that primary care referral to an open-group behavioural programme is an effective strategy for management of obesity, but little evidence on optimal intervention duration is available. We aimed to establish whether 52-week referral to an open-group weight-management programme would achieve greater weight loss and improvements in a range of health outcomes and be more cost-effective than the current practice of 12-week referrals. Methods In this non-blinded, parallel-group, randomised controlled trial, we recruited participants who were aged 18 years or older and had body-mass index (BMI) of 28 kg/m2 or higher from 23 primary care practices in England. Participants were randomly assigned (2:5:5) to brief advice and self-help materials, a weight-management programme (Weight Watchers) for 12 weeks, or the same weight-management programme for 52 weeks. We followed-up participants over 2 years. The primary outcome was weight at 1 year of follow-up, analysed with mixed-effects models according to intention-to-treat principles and adjusted for centre and baseline weight. In a hierarchical closed-testing procedure, we compared combined behavioural programme arms with brief intervention, then compared the 12-week programme and 52-week programme. We did a within-trial cost-effectiveness analysis using person-level data and modelled outcomes over a 25-year time horizon using microsimulation. This study is registered with Current Controlled Trials, number ISRCTN82857232. Findings Between Oct 18, 2012, and Feb 10, 2014, we enrolled 1269 participants. 1267 eligible participants were randomly assigned to the brief intervention (n=211), the 12-week programme (n=528), and the 52-week programme (n=528). Two participants in the 12-week programme had been found to be ineligible shortly after randomisation and were excluded from the analysis. 823 (65%) of 1267 participants completed an assessment at 1 year and 856 (68%) participants at 2 years. All eligible participants were included in the analyses. At 1 year, mean weight changes in the groups were −3·26 kg (brief intervention), −4·75 kg (12-week programme), and −6·76 kg (52-week programme). Participants in the behavioural programme lost more weight than those in the brief intervention (adjusted difference −2·71 kg, 95% CI −3·86 to −1·55; p<0·0001). The 52-week programme was more effective than the 12-week programme (−2·14 kg, −3·05 to −1·22; p<0·0001). Differences between groups were still significant at 2 years. No adverse events related to the intervention were reported. Over 2 years, the incremental cost-effectiveness ratio (ICER; compared with brief intervention) was £159 per kg lost for the 52-week programme and £91 per kg for the 12-week programme. Modelled over 25 years after baseline, the ICER for the 12-week programme was dominant compared with the brief intervention. The ICER for the 52-week programme was cost-effective compared with the brief intervention (£2394 per quality-adjusted life-year [QALY]) and the 12-week programme (£3804 per QALY). Interpretation For adults with overweight or obesity, referral to this open-group behavioural weight-loss programme for at least 12 weeks is more effective than brief advice and self-help materials. A 52-week programme produces greater weight loss and other clinical benefits than a 12-week programme and, although it costs more, modelling suggests that the 52-week programme is cost-effective in the longer term. Funding National Prevention Research Initiative, Weight Watchers International (as part of an UK Medical Research Council Industrial Collaboration Award).

Dietary intake of young twins: nature or nurture?

Background: The early years in life are increasingly recognized as a critical period for the development of diet-related behavioral traits. However, discussions continue on the relative role of genes and the environment in determining dietary intake, particularly in young children for whom detailed dietary information is limited. Objectives: This study tested the hypothesis that diet in early childhood is primarily determined by the environment rather than by genes. A secondary aim was to characterize the early childhood diet. Design: A classic twin design used 3-d dietary data collected at age 21 mo from the Gemini cohort. From the full sample of 2402 families with twins, dietary diaries were available for 1216 twin pairs (384 monozygotic and 832 dizygotic pairs) after exclusions. Intakes of macronutrients, food, and beverages were estimated. Twin analyses quantified the contributions of genetic and environmental factors to population variation in intake. Results: At age 21 mo, children consumed small portions of a wide range of family foods. The shared environment was the predominant determinant, contributing between 66% (95% CI: 52%, 77%; milk-based desserts) and 97% (95% CI: 95%, 98%; juice) of the variation in intake. Genetic factors were estimated to account for between 4% (95% CI: 0%, 10%; savory snacks) and 18% (95% CI: 14%, 23%; bread) of dietary intake variation. Conclusion: Shared environmental influences are the predominant drivers of dietary intake in very young children, indicating the importance of factors such as the home food environment and parental behaviors.