The frequencies of IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+ T-cells correlate with the magnitude of the QuantiFERON® gold in-tube response in a prospective study of healthy Indian adolescents

Background: QuantiFERON-TB Gold In-Tube (QFT) is an IFNγ-release assay used in the diagnosis of Mycobacterium tuberculosis (MTB) infection. The risk of TB progression increases with the magnitude of the MTB-specific IFNγ-response. QFT reversion, also associated with low Tuberculin Skin Test responses, may therefore represent a transient immune response with control of M. tuberculosis infection. However, studies at the single cell level have suggested that the quality (polyfunctionality) of the T-cell response is more important than the quantity of cytokines produced. Objective: To explore the quality and/or magnitude of mycobacteria-specific T-cell responses associated with QFT reversion and persistent QFT-positivity. Methods: Multi-color flowcytometry on prospectively collected peripheral blood mononuclear cells was applied to assess mycobacteria-specific T-cell responses in 42 QFT positive Indian adolescents of whom 21 became QFT negative (reverters) within one year. Ten QFT consistent negatives were also included as controls. Results: There was no difference in the qualitative PPD-specific CD4+ T-cell response between QFT consistent positives and reverters. However, compared with QFT consistent positives, reverters displayed lower absolute frequencies of polyfunctional (IFNγ+IL2+TNFα+) CD4+ T-cells at baseline, which were further reduced to the point where they were not different to QFT negative controls one year later. Moreover, absolute frequencies of these cells correlated well with the magnitude of the QFT-response. Conclusion: Whereas specific polyfunctional CD4+ T-cells have been suggested to protect against TB progression, our data do not support that higher relative or absolute frequencies of PPD-specific polyfunctional CD4+ T-cells in peripheral blood can explain the reduced risk of TB progression observed in QFT reverters. On the contrary, absolute frequencies of these cells correlated with the QFT-response, suggesting that this readout reflects antigenic load

Evaluating Active U: an Internet-mediated physical activity program.

Background: Engaging in regular physical activity can be challenging, particularly during the winter months. To promote physical activity at the University of Michigan during the winter months, an eight-week Internet-mediated program (Active U) was developed providing participants with an online physical activity log, goal setting, motivational emails, and optional team participation and competition. Methods: This study is a program evaluation of Active U. Approximately 47,000 faculty, staff, and graduate students were invited to participate in the online Active U intervention in the winter of 2007. Participants were assigned a physical activity goal and were asked to record each physical activity episode into the activity log for eight weeks. Statistics for program reach, effectiveness, adoption, and implementation were calculated using the Re-Aim framework. Multilevel regression analyses were used to assess the decline in rates of data entry and goal attainment during the program, to assess the likelihood of joining a team by demographic characteristics, to test the association between various predictors and the number of weeks an individual met his or her goal, and to analyze server load. Results: Overall, 7,483 individuals registered with the Active U website (≈16% of eligible), and 79% participated in the program by logging valid data at least once. Staff members, older participants, and those with a BMI < 25 were more likely to meet their weekly physical activity goals, and average rate of meeting goals was higher among participants who joined a competitive team compared to those who participated individually (IRR = 1.28, P < .001). Conclusion: Internet-mediated physical activity interventions that focus on physical activity logging and goal setting while incorporating team competition may help a significant percentage of the target population maintain their physical activity during the winter months

An adapted version of the long International Physical Activity Questionnaire (IPAQ-L): Construct validity in a low-income, multiethnic population study from Oslo, Norway

Conclusion: Weak, but consistent correlations with baseline biological and anthropometrical measurements were found in both sexes, but for changes in PA such a pattern was seen in men only. The total energy expenditure in summer and winter were highly correlated although the absolute volume was higher in summer than in winter

A 2-Dose AERAS-402 Regimen Boosts CD8+ Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients

Despite the widespread use of BCG, tuberculosis (TB) remains a global threat. Existing vaccine candidates in clinical trials are designed to replace or boost BCG which does not provide satisfying long-term protection. AERAS-402 is a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis (Mtb) antigens 85A, 85B, and TB10.4. The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India – a highly TB-endemic area. Healthy male participants aged 18–45 years with a negative QuantiFERON-TB Gold in-tube test (QFT) were recruited. Enrolled participants (n=12) were randomized 2:1 to receive two intramuscular injections of either AERAS-402 (3 x 1010 viral particles [vp]); (n=8) or placebo (n=4) on study days 0 and 28. Safety and immunogenicity parameters were evaluated for up to 182 days post the second injection. Immunogenicity was assessed by a flow cytometry-based intracellular cytokine staining (ICS) assay and transcriptional profiling. The latter was examined using dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA) assay. AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine-induced CD8+ T-cell responses were dominated by cells co-expressing IFN-γ, TNF-α, and IL-2 (“polyfunctional” cells) and were more robust than CD4+ T-cell responses. Five genes (CXCL10, GNLY, IFI35, IL1B and PTPRCv2) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes (CLEC7A, PTPRCv1 and TAGAP) were consistently up-regulated following two doses of vaccination in the AERAS-402-group. No safety concerns were observed for AERAS-402 in healthy Indian adult males. The vaccine-induced predominantly polyfunctional CD8+ T cells in response to Ag85B, humoral immunity, and altered gene expression profiles in peripheral blood mononuclear cells (PBMCs) indicative of activation of various immunologically relevant biological pathways.publishedVersio

Quality of Care for Patients With Type 2 Diabetes in Primary Care in Norway Is Improving: Results of cross-sectional surveys of 33 general practices in 1995 and 2005

OBJECTIVE—To assess changes in the quality of care in Norway for patients with type 2 diabetes

How can health promotion interventions be adapted for minority ethnic communities? Five principles for guiding the development of behavioural interventions.

The term ‘culturally sensitive’ is often used to describe interventions adapted for minority ethnic communities. However, understanding of strategies for adapting behavioural interventions for such communities is limited. The questions addressed in this paper are: What are the main strategies for adapting interventions to reduce coronary heart disease (CHD) for minority ethnic communities? Why have interventions been adapted in these ways? A systematic review was carried out to investigate interventions for preventing CHD, including promoting physical activity, smoking cessation and healthier diets in Pakistani, Chinese and Indian communities in countries where these groups are minorities. International databases and key websites were searched, and 23 477 titles and abstracts were initially identified. Seventeen papers met inclusion and quality criteria. A ‘meta-ethnographic’ approach to data synthesis was employed to identify underlying principles for adapting interventions. The rationale underpinning adaptations is not made explicit in individual studies, limiting generalizability. Five principles for adapting behavioural interventions for minority ethnic communities were identified: (i) use community resources to publicize the intervention and increase accessibility; (ii) identify and address barriers to access and participation; (iii) develop communication strategies which are sensitive to language use and information requirements; (iv) work with cultural or religious values that either promote or hinder behavioural change; and (v) accommodate varying degrees of cultural identification. While the principles require further testing and verification, they have been generated through a systematic approach to study identification, quality appraisal and data synthesis. This represents significant progress in advancing understanding of adapted behavioural interventions for minority ethnic communities

Variation in the achievement of HbA1c, blood pressure and LDL cholesterol targets in type 2 diabetes in general practice and characteristics associated with risk factor control.

Aims To identify population, general practitioner, and practice characteristics associated with the achievement of HbA1c, blood pressure and LDL cholesterol targets, and to describe variation in the achievement of risk factor control. Methods We conducted a cross‐sectional survey of 9342 people with type 2 diabetes, 281 general practitioners and 77 general practices in Norway. Missing values (7.4%) were imputed using multiple imputation by chained equations. We used three‐level logistic regression with the achievement of HbA1c, blood pressure and LDL cholesterol targets as dependent variables, and factors related to population, general practitioners, and practices as independent variables. Results Treatment targets were achieved for HbA1c in 64%, blood pressure in 50%, and LDL cholesterol in 52% of people with type 2 diabetes, and 17% met all three targets. There was substantial heterogeneity in target achievement among general practitioners and among practices; the estimated proportion of a GPs diabetes population at target was 55–73% (10–90 percentiles) for HbA1c, 36–63% for blood pressure, and 47–57% for LDL cholesterol targets. The models explained 11%, 5% and 14%, respectively, of the total variation in the achievement of HbA1c, blood pressure and LDL cholesterol targets. Use among general practitioners of a structured diabetes form was associated with 23% higher odds of achieving the HbA1c target (odds ratio 1.23, 95% confidence interval (CI) 1.02–1.47) and 17% higher odds of achieving the LDL cholesterol target (odds ratio 1.17, 95% CI 1.01–1.35). Conclusions Clinical diabetes management is difficult, and few people meet all three risk factor control targets. The proportion of people reaching target varied among general practitioners and practices. Several population, general practitioner and practice characteristics only explained a small part of the total variation. The use of a structured diabetes form is recommended.publishedVersio

Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans

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Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans

Context Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. Objective This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. Methods We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization. Results In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] −0.19 [−0.21 to −0.17]), body fat (−0.12 [−0.14 to −0.10), and fasting C-peptide (−2.04 [−2.46 to −1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (−0.5 [−0.7 to −0.4] and −0.5 [−0.6 to −0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, −1.72 [−2.86 to −0.58], and −0.20 [−0.36 to −0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. Conclusion BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.publishedVersio