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.

Controlling liver cancer internationally: A qualitative study of clinicians' perceptions of current public policy needs

<p>Abstract</p> <p>Background</p> <p>Liver cancer is the fifth most common cancer in men and the seventh for women. Usually because of late diagnosis, the prognosis for liver cancer remains poor, resulting in liver cancer being the third most common cause of death from cancer. While some countries have treatment guidelines, little is known or understood about the strategies needed for liver cancer control internationally.</p> <p>Objective</p> <p>To explore leading liver cancer clinician's perceptions of the current public policy needs to control liver cancer internationally.</p> <p>Methods</p> <p>Key informant interviews were conducted with a range of liver cancer clinicians involved in policy in eleven countries. Interviews were digitally recorded, transcribed verbatim, translated (where necessary), de-identified and analyzed by two researchers using a constant comparative method.</p> <p>Results</p> <p>Twenty in-depth semi-structured interviews were conducted in: Australia, China, France, Germany, Italy, Japan, Spain, South Korea, Taiwan, Turkey and the United States. Nine themes were identified and cluster into three groups: 1) Promoting prevention via early risk assessment, focusing on viral hepatitis and other lifestyle factors; 2) Increasing political, public and medical community awareness; and 3) Improving funding for screening, liver cancer surveillance and treatment.</p> <p>Conclusion</p> <p>This study is an important step towards developing an evidence-based approach to assessing preparedness for implementing comprehensive liver cancer control strategies. Evaluation mechanisms to assess countries' performance on the needs described are needed. Future research will concentrate of understanding how these needs vary across countries and the optimal strategies to improve the diagnosis and prognosis of patients with liver cancer internationally.</p

Epithelial Cell Stretching and Luminal Acidification Lead to a Retarded Development of Stria Vascularis and Deafness in Mice Lacking Pendrin

Loss-of-function mutations of SLC26A4/pendrin are among the most prevalent causes of deafness. Deafness and vestibular dysfunction in the corresponding mouse model, Slc26a4−/−, are associated with an enlargement and acidification of the membranous labyrinth. Here we relate the onset of expression of the HCO3− transporter pendrin to the luminal pH and to enlargement-associated epithelial cell stretching. We determined expression with immunocytochemistry, cell stretching by digital morphometry and pH with double-barreled ion-selective electrodes. Pendrin was first expressed in the endolymphatic sac at embryonic day (E) 11.5, in the cochlear hook-region at E13.5, in the utricle and saccule at E14.5, in ampullae at E16.5, and in the upper turn of the cochlea at E17.5. Epithelial cell stretching in Slc26a4−/− mice began at E14.5. pH changes occurred first in the cochlea at E15.5 and in the endolymphatic sac at E17.5. At postnatal day 2, stria vascularis, outer sulcus and Reissner's membrane epithelial cells, and utricular and saccular transitional cells were stretched, whereas sensory cells in the cochlea, utricle and saccule did not differ between Slc26a4+/− and Slc26a4−/− mice. Structural development of stria vascularis, including vascularization, was retarded in Slc26a4−/− mice. In conclusion, the data demonstrate that the enlargement and stretching of non-sensory epithelial cells precedes luminal acidification in the cochlea and the endolymphatic sac. Stretching and luminal acidification may alter cell-to-cell communication and lead to the observed retarded development of stria vascularis, which may be an important step on the path to deafness in Slc26a4−/− mice, and possibly in humans, lacking functional pendrin expression

Infant feeding practices at routine PMTCT sites, South Africa: results of a prospective observational study amongst HIV exposed and unexposed infants - birth to 9 months

<p>Abstract</p> <p>Background</p> <p>We sought to investigate infant feeding practices amongst HIV-positive and -negative mothers (0-9 months postpartum) and describe the association between infant feeding practices and HIV-free survival.</p> <p>Methods</p> <p>Infant feeding data from a prospective observational cohort study conducted at three (of 18) purposively-selected routine South African PMTCT sites, 2002-2003, were analysed. Infant feeding data (previous 4 days) were gathered during home visits at 3, 5, 7, 9, 12, 16, 20, 24, 28, 32 and 36 weeks postpartum. Four feeding groups were of interest, namely exclusive breastfeeding, mixed breastfeeding, exclusive formula feeding and mixed formula feeding. Cox proportional hazards models were fitted to investigate associations between feeding practices (0-12 weeks) and infant HIV-free survival.</p> <p>Results</p> <p>Six hundred and sixty five HIV-positive and 218 HIV-negative women were recruited antenatally and followed-up until 36 weeks postpartum. Amongst mothers who breastfed between 3 weeks and 6 months postpartum, significantly more HIV-positive mothers practiced exclusive breastfeeding compared with HIV-negative: at 3 weeks 130 (42%) versus 33 (17%) (p < 0.01); this dropped to 17 (11%) versus 1 (0.7%) by four months postpartum. Amongst mothers practicing mixed breastfeeding between 3 weeks and 6 months postpartum, significantly more HIV-negative mothers used commercially available breast milk substitutes (p < 0.02) and use of these peaked between 9 and 12 weeks. The probability of postnatal HIV or death was lowest amongst infants living in the best resourced site who avoided breastfeeding, and highest amongst infants living in the rural site who stopped breastfeeding early (mean and standard deviations: 10.7% ± 3% versus 46% ± 11%).</p> <p>Conclusions</p> <p>Although feeding practices were poor amongst HIV-positive and -negative mothers, HIV-positive mothers undertake safer infant feeding practices, possibly due to counseling provided through the routine PMTCT programme. The data on differences in infant outcome by feeding practice and site validate the WHO 2009 recommendations that site differences should guide feeding practices amongst HIV-positive mothers. Strong interventions are needed to promote exclusive breastfeeding (to 6 months) with continued breastfeeding thereafter amongst HIV-negative motherswho are still the majority of mothers even in high HIV prevalence setting like South Africa.</p

Using Qualitative Evidence in Decision Making for Health and Social Interventions: An Approach to Assess Confidence in Findings from Qualitative Evidence Syntheses (GRADE-CERQual)

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.Simon Lewin and colleagues present a methodology for increasing transparency and confidence in qualitative research synthesis.This work was supported by funding from the Department of Reproductive Health and Research, WHO (www.who.int/reproductivehealth/about_us/en/) and Norad (Norwegian Agency for Development Cooperation: www.norad.no) to the Norwegian Knowledge Centre for the Health Services. Additional funding for several of the pilot reviews was provided by the Alliance for Health Policy and Systems Research (www.who.int/alliance-hpsr/en/). We also received funding for elements of this work through the Cochrane supported "Methodological Investigation of Cochrane reviews of Complex Interventions" (MICCI) project (www.cochrane.org). SL is supported by funding from the South African Medical Research Council (www.mrc.ac.za). The funders had no role in study design, data collection and analysis, preparation of the manuscript or the decision to publish

The hidden architecture of higher education:Building a big data infrastructure for the ‘smarter university’

Universities are increasingly organized and managed through digital data. The collection, processing and dissemination of Higher Education data is enabled by complex new data infrastructures that include both human and nonhuman actors, all framed by political, economic and social contingencies. HE data infrastructures need to be seen not just as technical programs but as practical relays of political objectives to reform the sector. This article focuses on a major active data infrastructure project in Higher Education in the United Kingdom. It examines the sociotechnical networks of organizations, software programs, standards, dashboards and visual analytics technologies that constitute the infrastructure, and how these technologies are fused to governmental imperatives of market reform. The analysis foregrounds how HE is being reimagined through the utopian ideal of the &lsquo;smarter university&rsquo; while simultaneously being reformed through the political project of marketization