RAGE: a new frontier in chronic airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.     

Trends in HIV Testing Among U.S. Older Adults Prior to and Since Release of CDC's Routine HIV Testing Recommendations: National Findings from the BRFSS

Objective

This study examined temporal trends in HIV testing among U.S. older adults (50–64 years of age) before and after the release of CDC''s routine HIV testing recommendations in 2006.

Methods

The sample (n=872,797; 51.4% female) comprised 2003–2010 Behavioral Risk Factor Surveillance System respondents in the oldest categories to which the recommendations apply: 50–54 years (34.5%, n=301,519), 55–59 years (34.1%, n=297,865), and 60–64 years (31.3%, n=273,413). We calculated (1) four-year pooled prevalences of past-year HIV testing before and after 2006, when the recommendations were released; and (2) annual prevalences of HIV testing overall and by age category from 2003–2010. Using weighted, multivariable logistic regression analyses, we examined binary (pre- vs. post-recommendations) and annual changes in testing, controlling for covariates. We stratified the data by recent doctor visits, examined racial/ethnic differences, and tested for linear and quadratic temporal trends.

Results

Overall and within age categories, the pooled prevalence of past-year HIV testing decreased following release of the recommendations (p<0.001). The annual prevalence decreased monotonically from 2003 (5.5%) to 2006 (3.6%) (b=–0.16, p<0.001) and then increased immediately after release of the recommendations, but decreased to 3.7% after 2009 (b=0.01, p<0.001). By race/ethnicity, testing increased over time among non-Hispanic black people only. Annual prevalence also increased among respondents with recent doctor visits.

Conclusion

CDC''s HIV testing recommendations were associated with a reversal in the downward trend in past-year HIV testing among older adults; however, the gains were neither universal nor sustained over time.In 2006, the Centers for Disease Control and Prevention (CDC) began recommending routine opt-out human immunodeficiency virus (HIV) testing of all adults <65 years of age seeking health care in any setting where HIV prevalence is ≥0.1%.¹ Routine testing is an efficient, cost-effective strategy for early detection of HIV infection.² It involves screening every patient (except those who decline testing) regardless of any reported risk behaviors; therefore, it can facilitate detection of undiagnosed HIV infection among people unlikely to seek an HIV test, including those presumed to have little or no HIV risk.³Routine testing may be particularly important for older adults (i.e., those aged ≥50 years), among whom 11% of U.S. HIV infections occur. Of concern, HIV-infected older adults are disproportionately diagnosed late in the course of HIV disease.^4,5 Late diagnosis is associated with rapid progression to acquired immunodeficiency syndrome (AIDS), and it exacerbates the management of both HIV disease and the non-HIV conditions that are prevalent among older adults (e.g., hypertension).^6–9 Rates of HIV testing generally decrease with age;^10–13 however, it is unclear if the release and implementation of the recommendations have helped to improve HIV testing levels in this age group.^14,15To understand the recommendations'' potential influence on HIV testing among older adults, we examined trends in HIV testing from January 1, 2003, to December 31, 2010, among Behavioral Risk Factor Surveillance System (BRFSS) respondents in the three categories of older adulthood (50–54, 55–59, and 60–64 years of age) to which the routine HIV testing recommendations apply. The study period began four years prior to CDC''s publication of the recommendations and concluded four years thereafter, enabling us to compare HIV testing levels before and after their release. Full implementation should produce a sustained increase in testing that begins in 2007 and is most apparent among people with a recent doctor visit. This study sought to determine if:

1. The annual prevalence of past-year HIV testing increased among older adults since release of the routine HIV testing recommendations,
2. Racial/ethnic differences in past-year HIV testing exist over time among older adults,
3. The odds of testing increased more for those with vs. without a recent doctor visit since release of the recommendations, and
4. The characteristics of older testers changed over time.

     

Seroprevalence of HIV,hepatitis b,and hepatitis c among opioid drug users on methadone treatment in the netherlands

Background  

Injecting drug users (IDU) remain an important population at risk for blood-borne infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). In the Netherlands, a program is being implemented to offer annual voluntary screening for these infections to opioid drug users (ODUs) screened in methadone care. At two care sites where the program is now operating, our study aimed to estimate the seroprevalence among ODUs screened for HIV, HBV and HCV; to evaluate HBV vaccination coverage; and to assess the feasibility of monitoring seroprevalence trends by using routine annual screening data.     

Identifying risk factors for disparities in breast cancer mortality among African-American and Hispanic women

BackgroundThis study evaluated the risk factors associated with racial disparities in female breast cancer mortality for African-American and Hispanic women at the census tract level in Texas from 1995 to 2005.MethodsData on female breast cancer cases were obtained from the Texas Cancer Registry. Socioeconomic and demographic data were collected from Census 2000. Network distance and driving times to mammography facilities were estimated using Geographic Information System techniques. Demographic, poverty and spatial accessibility factors were constructed using principal component analysis. Logistic regression models were developed to predict the census tracts with significant racial disparities in breast cancer mortality based on racial disparities in late-stage diagnosis and structured factors from the principal component analysis.ResultsLate-stage diagnosis, poverty factors, and demographic factors were found to be significant predictors of a census tract showing significant racial disparities in breast cancer mortality. Census tracts with higher poverty status were more likely to display significant racial disparities in breast cancer mortality for both African Americans (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.95–3.04) and Hispanics (OR, 5.30; 95% CI, 4.26–6.59). Spatial accessibility was not a consistent predictor of racial disparities in breast cancer mortality for African-American and Hispanic women.ConclusionPhysical access to mammography facilities does not necessarily reflect a greater utilization of mammogram screening, possibly owing to financial constraints. Therefore, a metric measuring access to health care facilities is needed to capture all aspects of access to preventive care. Despite easier physical access to mammography facilities in metropolitan areas, great resources and efforts should also be devoted to these areas where racial disparities in breast cancer mortality are often found.     

Good practice in social care: the views of people with severe and complex needs and those who support them

This paper reports findings drawn from a study of good practice in English social care for adults with disability and older people with severe and complex needs. People with severe and complex needs are a relatively small proportion of adult social care service users, but they are growing in numbers and have resource‐intensive needs. The study involved qualitative research with adults with disability and older people with severe and complex needs, family carers and members of specialist organisations (n = 67), focusing on the features of social care services they considered to be good practice. Data were collected between August 2010 and June 2011. The approach to data collection was flexible, to accommodate participants' communication needs and preferences, including face‐to‐face and telephone interviews, Talking Mats^© sessions and a focus group. Data were managed using Framework and analysed thematically. Features of good practice were considered at three levels: (i) everyday support; (ii) service organisation; and (iii) commissioning. Findings relating to the first two of these are presented here. Participants emphasised the importance of person‐centred ways of working at all levels. Personalisation, as currently implemented in English social care, aims to shift power from professionals to service users through the allocation of personal budgets. This approach focuses very much on the role of the individual in directing his/her own support arrangements. However, participants in this study also stressed the importance of ongoing professional support, for example, from a specialist key worker or case manager to co‐ordinate diverse services and ensure good practice at an organisational level. The paper argues that, despite the recent move to shift power from professionals to service users, people with the most complex needs still value support from professionals and appropriate organisational support. Without these, they risk being excluded from the benefits that personalisation, properly supported, could yield.     

Increasing sexually transmitted infection rates in young men having sex with men in the Netherlands, 2006–2012

Background

Men having sex with men (MSM) remain the largest high-risk group involved in on-going transmission of sexually transmitted infections (STI), including HIV, in the Netherlands. As risk behaviour may change with age, it is important to explore potential heterogeneity in risks by age. To improve our understanding of this epidemic, we analysed the prevalence of and risk factors for selected STI in MSM attending STI clinics in the Netherlands by age group.

Methods

Analysis of data from the national STI surveillance system for the period 2006–2012. Selected STI were chlamydia, gonorrhoea, infectious syphilis and/or a new HIV infection. Logistic regression was used to identify factors associated with these selected STI and with overall STI positivity. Analyses were done separately for MSM aged younger than 25 years and MSM aged 25 years and older.

Results

In young MSM a significant increase in positivity rate was seen over time (p?<?0.01), mainly driven by increasing gonorrhoea diagnoses, while in MSM aged 25 and older a significant decrease was observed (p?<?0.01). In multivariate analyses for young MSM, those who were involved in commercial sex were at higher risk (OR: 1.5, 95% CI: 1.2-1.9). For MSM aged 25 years and older this was not the case. Having a previous negative HIV test was protective among older MSM compared to those not tested for HIV before (OR: 0.8, 95% CI: 0.8-0.8), but not among younger MSM.

Conclusions

MSM visiting STI clinics remain a high-risk group for STI infections and transmission, but are not a homogenous group. While in MSM aged older than 25 years, STI positivity rate is decreasing, positivity rate in young MSM increased over time. Therefore specific attention needs to be paid towards targeted counselling and reaching particular MSM sub-groups, taken into account different behavioural profiles.

     

Cost-effectiveness of counseling and pedometer use to increase physical activity in the Netherlands: a modeling study

Background

Counseling in combination with pedometer use has proven to be effective in increasing physical activity and improving health outcomes. We investigated the cost-effectiveness of this intervention targeted at one million insufficiently active adults who visit their general practitioner in the Netherlands.

Methods

We used the RIVM chronic disease model to estimate the long-term effects of increased physical activity on the future health care costs and quality adjusted life years (QALY) gained, from a health care perspective.

Results

The intervention resulted in almost 6000 people shifting to more favorable physical-activity levels, and in 5100 life years and 6100 QALYs gained, at an additional total cost of EUR 67.6 million. The incremental cost-effectiveness ratio (ICER) was EUR 13,200 per life year gained and EUR 11,100 per QALY gained. The intervention has a probability of 0.66 to be cost-effective if a QALY gained is valued at the Dutch informal threshold for cost-effectiveness of preventive intervention of EUR 20,000. A sensitivity analysis showed substantial uncertainty of ICER values.

Conclusion

Counseling in combination with pedometer use aiming to increase physical activity may be a cost-effective intervention. However, the intervention only yields relatively small health benefits in the Netherlands.     

The effectiveness of adding cognitive behavioural therapy aimed at changing lifestyle to managed diabetes care for patients with type 2 diabetes: design of a randomised controlled trial

Background  

In patients with type 2 diabetes, the risk for cardiovascular disease is substantial. To achieve a more favourable risk profile, lifestyle changes on diet, physical activity and smoking status are needed. This will involve changes in behaviour, which is difficult to achieve. Cognitive behavioural therapies focussing on self-management have been shown to be effective. We have developed an intervention combining techniques of Motivational Interviewing (MI) and Problem Solving Treatment (PST). The aim of our study is to investigate if adding a combined behavioural intervention to managed care, is effective in achieving changes in lifestyle and cardiovascular risk profile.     

Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial

Immunotherapy in patients with HIV-1 infection aims to restore and broaden immunological competence, reduce viral load and thereby permit longer periods without combined antiretroviral treatment (cART). Twelve HIV-1-infected patients on cART were immunized on the skin with DNA plasmids containing genes of several HIV-1 subtypes with or without the addition of hydroxyurea (HU), or with placebo. The mean net gain of HIV-specific CD8+ T cell responses were higher and broader in the HIV DNA vaccine groups compared to non-vaccinated individuals (p < 0.05). The vaccine-induced immune responses per se had no direct effect on viral replication. In all patients combined, including placebo, the viral set point after a final structured therapy interruption (STI) was lower than prior to initiation of cART (p = 0.003). Nadir CD4 levels appeared to strongly influence the post-STI viral titers. After the sixth immunization or placebo, patients could stay off cART for a median time of 15 months. The study shows that HIV DNA immunization induces broader and higher magnitudes of HIV-specific immune responses compared to structured therapy interruptions alone. Although compromised by small numbers of patients, the study also demonstrates that well-monitored STI may safely function as an immunological read out of HIV vaccine efficacy.     

Pupil Dilation May Affect Retinal Vessel Caliber Measures

Purpose: To assess the effect of pupil dilation on measures of retinal vessel caliber.

Design: Observational study with self-comparisons

Methods: Retinal photographs were taken for both eyes of 25 subjects before and after pupil dilation. Three photographic graders, masked to pupil dilation status, measured the same set of images using a computer-assisted, semi-automatic method. We compared means (standard deviations) of retinal arteriolar caliber equivalent (CRAE) and retinal venular caliber equivalent (CRVE) of the same eyes between pre- and post-dilation images. We assessed concordance correlation coefficients (CC), Bland Altman limits-of-agreements, and used linear mixed models to assess CRAE and CRVE measures associated with pupil dilation (influencing image quality), graders (observers) and right-left eye variation.

Results: We found high CCs for CRAE (0.82-0.94) and CRVE (0.87-0.94) between pre- and post-dilation images of the same eyes across the graders. Bland Altman plots showed that mean differences ranged from 0.55-3.42μm for CRAE and 1.56-2.29μm for CRVE. After adjusting for right-left eye random variation, a significant fixed effect of dilation was evident in mean CRAE in two of the three graders. There was no significant fixed effect of dilation in mean CRVE across all graders. In models including data of both eyes’ measures from pre- and post-dilation images by three graders, the fixed effect for dilation status contributed significantly to CRAE and CRVE variances whereas random effects for graders and dilation status contributed minimally.

Conclusions: Contrary to our hypothesis, we found a systematic effect of pupil dilation on retinal vessel caliber measures.