Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

SUPPORT Tools for evidence-informed health Policymaking (STP) 7: Finding systematic reviews

This article is part of a series written for people responsible for making decisions about health policies and programmes and for those who support these decision makers

A Model for Interprofessional Health Disparities Education: Student-Led Curriculum on Chronic Hepatitis B Infection

Although health disparities are commonly addressed in preclinical didactic curricula, direct patient care activities with affected communities are more limited. To address this problem, health professional students designed a preclinical service-learning curriculum on hepatitis B viral (HBV) infection, a major health disparity affecting the Asian/Pacific Islander (API) population, integrating lectures, skills training, and direct patient care at student-run clinics. An urban health professions campus. Medical and other health professional students at University of California, San Francisco, organized a preclinical didactic and experiential elective, and established two monthly clinics offering HBV screening, vaccination, and education to the community. Between 2004 and 2009, 477 students enrolled in the student-led HBV curriculum. Since the clinics’ inception in 2007, 804 patients have been screened for chronic HBV; 87% were API immigrants, 63% had limited English proficiency, and 46% were uninsured. Serologically, 10% were found to be chronic HBV carriers, 44% were susceptible to HBV, and 46% were immune. Our student-led didactic and experiential elective can serve as an interprofessional curricular model for learning about specific health disparities while providing important services to the local community

Rapid Suppression of Activated Rac1 by Cadherins and Nectins during De Novo Cell-Cell Adhesion

Cell-cell adhesion in simple epithelia involves the engagement of E-cadherin and nectins, and the reorganization of the actin cytoskeleton and membrane dynamics by Rho GTPases, particularly Rac1. However, it remains unclear whether E-cadherin and nectins up-regulate, maintain or suppress Rac1 activity during cell-cell adhesion. Roles for Rho GTPases are complicated by cell spreading and integrin-based adhesions to the extracellular matrix that occur concurrently with cell-cell adhesion, and which also require Rho GTPases. Here, we designed a simple approach to examine Rac1 activity upon cell-cell adhesion by MDCK epithelial cells, without cell spreading or integrin-based adhesion. Upon initiation of cell-cell contact in 3-D cell aggregates, we observed an initial peak of Rac1 activity that rapidly decreased by ∼66% within 5 minutes, and further decreased to a low baseline level after 30 minutes. Inhibition of E-cadherin engagement with DECMA-1 Fab fragments or competitive binding of soluble E-cadherin, or nectin2alpha extracellular domain completely inhibited Rac1 activity. These results indicate that cadherins and nectins cooperate to induce and then rapidly suppress Rac1 activity during initial cell-cell adhesion, which may be important in inhibiting the migratory cell phenotype and allowing the establishment of initially weak cell-cell adhesions

Systematic reviews, systematic error and the acquisition of clinical knowledge

<p>Abstract</p> <p>Background</p> <p>Since its inception, evidence-based medicine and its application through systematic reviews, has been widely accepted. However, it has also been strongly criticised and resisted by some academic groups and clinicians. One of the main criticisms of evidence-based medicine is that it appears to claim to have unique access to absolute scientific truth and thus devalues and replaces other types of knowledge sources.</p> <p>Discussion</p> <p>The various types of clinical knowledge sources are categorised on the basis of Kant's categories of knowledge acquisition, as being either 'analytic' or 'synthetic'. It is shown that these categories do not act in opposition but rather, depend upon each other. The unity of analysis and synthesis in knowledge acquisition is demonstrated during the process of systematic reviewing of clinical trials. Systematic reviews constitute comprehensive synthesis of clinical knowledge but depend upon plausible, analytical hypothesis development for the trials reviewed. The dangers of systematic error regarding the internal validity of acquired knowledge are highlighted on the basis of empirical evidence. It has been shown that the systematic review process reduces systematic error, thus ensuring high internal validity. It is argued that this process does not exclude other types of knowledge sources. Instead, amongst these other types it functions as an integrated element during the acquisition of clinical knowledge.</p> <p>Conclusions</p> <p>The acquisition of clinical knowledge is based on interaction between analysis and synthesis. Systematic reviews provide the highest form of synthetic knowledge acquisition in terms of achieving internal validity of results. In that capacity it informs the analytic knowledge of the clinician but does not replace it.</p

Transition to the new race/ethnicity data collection standards in the Department of Veterans Affairs

BACKGROUND: Patient race in the Department of Veterans Affairs (VA) information system was previously recorded based on an administrative or clinical employee's observation. Since 2003, the VA started to collect self-reported race in compliance with a new federal guideline. We investigated the implications of this transition for using race/ethnicity data in multi-year trends in the VA and in other healthcare data systems that make the transition. METHODS: All unique users of VA healthcare services with self-reported race/ethnicity data in 2004 were compared with their prior observer-recorded race/ethnicity data from 1997 – 2002 (N = 988,277). RESULTS: In 2004, only about 39% of all VA healthcare users reported race/ethnicity values other than "unknown" or "declined." Females reported race/ethnicity at a lower rate than males (27% vs. 40%; p < 0.001). Over 95% of observer-recorded data agreed with self-reported data. Compared with the patient self-reported data, the observer-recorded White and African American races were accurate for 98% (kappa = 0.89) and 94% (kappa = 0.93) individuals, respectively. Accuracy of observer-recorded races was much worse for other minority groups with kappa coefficients ranging between 0.38 for American Indian or Alaskan Natives and 0.79 for Hispanic Whites. When observer-recorded race/ethnicity values were reclassified into non-African American groups, they agreed with the self-reported data for 98% of all individuals (kappa = 0.93). CONCLUSION: For overall VA healthcare users, the agreement between observer-recorded and self-reported race/ethnicity was excellent and observer-recorded and self-reported data can be used together for multi-year trends without creating serious bias. However, this study also showed that observation was not a reliable method of race/ethnicity data collection for non-African American minorities and racial disparity might be underestimated if observer-recorded data are used due to systematic patterns of inaccurate race/ethnicity assignments

The health of people classified as lesbian, gay and bisexual attending family practitioners in London: a controlled study

BACKGROUND: The morbidity of gay, lesbian or bisexual people attending family practice has not been previously assessed. We compared health measures of family practice attendees classified as lesbian, gay and bisexual. METHODS: We conducted a cross-sectional, controlled study conducted in 13 London family practices and compared the responses of 26 lesbian and 85 bisexual classified women, with that of 934 heterosexual classified women and 38 gay and 23 bisexual classified men with that of 373 heterosexual classified men. Our outcomes of interest were: General health questionnaire; CAGE questionnaire; short form12; smoking status; sexual experiences during childhood; number of sexual partners and sexual function and satisfaction. RESULTS: In comparison to people classified as heterosexuals: men classified as gay reported higher levels of psychological symptoms (OR 2.48, CI 1.05–5.90); women classified as bisexual were more likely to misuse alcohol (OR 2.73, 1.70–4.40); women classified as bisexual (OR 2.53, 1.60–4.00) and lesbian (OR 3.13, 1.41–6.97) and men classified as bisexual (OR 2.48, 1,04, 5.86) were more likely to be smokers and women classified as bisexual (OR 3.27, 1.97–5.43) and men classified as gay (OR 4.86, 2.28–10.34) were much more likely to report childhood sexual experiences in childhood. Psychological distress was associated with reporting sexual experiences in childhood in men classified as gay and bisexual and women classified as heterosexual. Men classified as bisexual (OR 5.00, 1.73–14.51) and women classified as bisexual (OR 2.88, 1.24- 6.56) were more likely than heterosexuals to report more than one sexual partner in the preceding four weeks. Lesbian, gay and bisexual classified people encountered no more sexual function problems than heterosexuals but men classified as bisexual (OR 2.74, 1.12–6.70) were more dissatisfied with their sex lives. CONCLUSION: Bisexual and lesbian classified people attending London general practices were more likely to be smokers and gay classified men were at increased risk of psychological distress in comparison to heterosexual classified people. Increased awareness of the sexuality of people seen in primary care can provide opportunities for health promotion

Ethnic discrimination prevalence and associations with health outcomes: data from a nationally representative cross-sectional survey of secondary school students in New Zealand

<p>Abstract</p> <p>Background</p> <p>Reported ethnic discrimination is higher among indigenous and minority adult populations. There is a paucity of nationally representative prevalence studies of ethnic discrimination among adolescents. Experiencing ethnic discrimination has been associated with a range of adverse health outcomes. NZ has a diverse ethnic population. There are health inequalities among young people from Māori and Pacific ethnic groups.</p> <p>Methods</p> <p>9107 randomly selected secondary school students participated in a nationally representative cross-sectional health and wellbeing survey conducted in 2007. The prevalence of ethnic discrimination by health professionals, by police, and ethnicity-related bullying were analysed. Logistic regression was used to examine the associations between ethnic discrimination and six health/wellbeing outcomes: self-rated health status, depressive symptoms in the last 12 months, cigarette smoking, binge alcohol use, feeling safe in ones neighbourhood, and self-rated school achievement.</p> <p>Results</p> <p>There were significant ethnic differences in the prevalences of ethnic discrimination. Students who experienced ethnic discrimination were less likely to report excellent/very good/good self-rated general health (OR 0.51; 95% CI 0.39, 0.65), feel safe in their neighbourhood (OR 0.48; 95% CI 0.40, 0.58), and more likely to report an episode of binge drinking in the previous 4 weeks (OR 1.77; 95% CI 1.45, 2.17). For all these outcomes the odds ratios for the group who were 'unsure' if they had experienced ethnic discrimination were similar to those of the 'yes' group.</p> <p>Ethnicity stratified associations between ethnic discrimination and the depression, cigarette smoking, and self-rated school achievement are reported. Within each ethnic group participants reporting ethnic discrimination were more likely to have adverse outcomes for these three variables. For all three outcomes the direction and size of the association between experience of ethnic discrimination and the outcome were similar across all ethnic groups.</p> <p>Conclusions</p> <p>Ethnic discrimination is more commonly reported by Indigenous and minority group students. Both experiencing and being 'unsure' about experiencing ethnic discrimination are associated with a range of adverse health/wellbeing outcomes. Our findings highlight the progress yet to be made to ensure that rights to be free from ethnic discrimination are met for young people living in New Zealand.</p

Demographic, Psychological, and Social Characteristics of Self-Identified Lesbian, Gay, and Bisexual Adults in a US Probability Sample

Using data from a US national probability sample of self-identified lesbian, gay, and bisexual adults (N = 662), this article reports population parameter estimates for a variety of demographic, psychological, and social variables. Special emphasis is given to information with relevance to public policy and law. Compared with the US adult population, respondents were younger, more highly educated, and less likely to be non-Hispanic White, but differences were observed between gender and sexual orientation groups on all of these variables. Overall, respondents tended to be politically liberal, not highly religious, and supportive of marriage equality for same-sex couples. Women were more likely than men to be in a committed relationship. Virtually all coupled gay men and lesbians had a same-sex partner, whereas the vast majority of coupled bisexuals were in a heterosexual relationship. Compared with bisexuals, gay men and lesbians reported stronger commitment to a sexual-minority identity, greater community identification and involvement, and more extensive disclosure of their sexual orientation to others. Most respondents reported experiencing little or no choice about their sexual orientation. The importance of distinguishing among lesbians, gay men, bisexual women, and bisexual men in behavioral and social research is discussed