Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open Label Extension of a Phase 3 Randomized Controlled Trial

RATIONALE: Tocilizumab, an anti-interleukin-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic sclerosis-associated interstitial lung disease in a phase 3 randomized controlled trial. OBJECTIVES: Assess long-term safety and efficacy of tocilizumab. METHODS: Adults with diffuse cutaneous systemic sclerosis for ≤60 months and elevated acute-phase reactants, including those with interstitial lung disease, received weekly placebo or tocilizumab 162 mg subcutaneously in the 48-week, double-blind period then open-label tocilizumab from weeks 48 to 96 (placebo-tocilizumab; continuous-tocilizumab). MEASUREMENTS AND MAIN RESULTS: Eighty-two of 107 placebo-tocilizumab and 85 of 105 continuous-tocilizumab patients completed 96 weeks. Mean age and disease duration were 48 years and 23 months; high-resolution computed tomography revealed interstitial lung disease in 61%. Mean (95% CI) change in modified Rodnan skin score from baseline to week 96 was -8.4 (-10.0, -6.8) for placebo-tocilizumab and -9.6 (-10.9, -8.4) for continuous-tocilizumab. Mean (95% CI) change in forced vital capacity (percent-predicted) from baseline to week 96 was -3.3 (-5.1, -1.5) for placebo-tocilizumab and -0.5 (-2.4, 1.3) for continuous-tocilizumab among completers and, in post hoc analysis, -4.1 (-6.7, -1.6) and -0.6 (-3.1, 2.0), respectively, among completers with interstitial lung disease (mean [95% CI] change from weeks 48 to 96: 0.9 [-0.8, 2.7] and -0.4 [-2.3, 1.5], respectively). Rates per 100 patient-years of serious adverse events from weeks 48 to 96 were 14.8 for placebo-tocilizumab and 15.8 for continuous-tocilizumab. CONCLUSIONS: Tocilizumab preserved lung function, slowing decline in forced vital capacity, in patients with systemic sclerosis, including those with interstitial lung disease. Long-term safety was consistent with the known safety profile of tocilizumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01791153

Socioeconomic differentials in the immediate mortality effects of the national Irish smoking ban

This article has been made available through the Brunel Open Access Publishing Fund.Background: Consistent evidence has demonstrated that smoking ban policies save lives, but impacts on health inequalities are uncertain as few studies have assessed post-ban effects by socioeconomic status (SES) and findings have been inconsistent. The aim of this study was to assess the effects of the national Irish smoking ban on ischemic heart disease (IHD), stroke, and chronic obstructive pulmonary disease (COPD) mortality by discrete and composite SES indicators to determine impacts on inequalities. Methods: Census data were used to assign frequencies of structural and material SES indicators to 34 local authorities across Ireland with a 2000–2010 study period. Discrete indicators were jointly analysed through principal component analysis to generate a composite index, with sensitivity analyses conducted by varying the included indicators. Poisson regression with interrupted time-series analysis was conducted to examine monthly age and gender-standardised mortality rates in the Irish population, ages ≥35 years, stratified by tertiles of SES indicators. All models were adjusted for time trend, season, influenza, and smoking prevalence. Results: Post-ban mortality reductions by structural SES indicators were concentrated in the most deprived tertile for all causes of death, while reductions by material SES indicators were more equitable across SES tertiles. The composite indices mirrored the results of the discrete indicators, demonstrating that post-ban mortality decreases were either greater or similar in the most deprived when compared to the least deprived for all causes of death. Conclusions: Overall findings indicated that the national Irish smoking ban reduced inequalities in smoking-related mortality. Due to the higher rates of smoking-related mortality in the most deprived group, even equitable reductions across SES tertiles resulted in decreases in inequalities. The choice of SES indicator was influential in the measurement of effects, underscoring that a differentiated analytical approach aided in understanding the complexities in which structural and material factors influence mortality

Hierarchy Theory of Evolution and the Extended Evolutionary Synthesis: Some Epistemic Bridges, Some Conceptual Rifts

Contemporary evolutionary biology comprises a plural landscape of multiple co-existent conceptual frameworks and strenuous voices that disagree on the nature and scope of evolutionary theory. Since the mid-eighties, some of these conceptual frameworks have denounced the ontologies of the Modern Synthesis and of the updated Standard Theory of Evolution as unfinished or even flawed. In this paper, we analyze and compare two of those conceptual frameworks, namely Niles Eldredge’s Hierarchy Theory of Evolution (with its extended ontology of evolutionary entities) and the Extended Evolutionary Synthesis (with its proposal of an extended ontology of evolutionary processes), in an attempt to map some epistemic bridges (e.g. compatible views of causation; niche construction) and some conceptual rifts (e.g. extra-genetic inheritance; different perspectives on macroevolution; contrasting standpoints held in the “externalism–internalism” debate) that exist between them. This paper seeks to encourage theoretical, philosophical and historiographical discussions about pluralism or the possible unification of contemporary evolutionary biology

The relationship between parental socio-economic status and episodes of drunkenness among adolescents: findings from a cross-national survey

BACKGROUND: Behavioral factors such as (excessive) alcohol consumption play a major role in the explanation of social inequalities in health. The unequal distribution of health risk behaviors among socio-economic groups has important consequences for both the current and future health status of the younger generation. However, little is known about socio-economic differences in unhealthy lifestyles during adolescence. The purpose of the present study is to investigate socio-economic differences in adolescent drinking behaviour among 11–15 year old adolescents in Europe and North America. METHODS: Data was obtained from the Health Behaviour in School-aged Children (HBSC) study 2001/02, a cross-national survey conducted in collaboration with the World Health Organization. The present analysis is based on 69249 male and 73619 female students from 28 countries. The effect of parental occupation and family affluence on episodes of drunkenness was assessed using separate logistic regression models controlling for age. RESULTS: Socio-economic circumstances of the family had only a limited effect on repeated drunkenness in adolescence. For girls only in one out of 28 countries a significant association between family affluence and repeated drunkenness was observed, while boys from low and/or medium affluent families in nine countries faced a lower risk of drunkenness than boys from more affluent families. Regarding parental occupation, significant differences in episodes of drunkenness were found in nine countries for boys and in six countries for girls. Compared to family affluence, which was positively related to risk of drunkenness, a decreasing occupational status predicted an increasing risk of drunkenness. This pattern was identified within a number of countries, most noticeably for boys. CONCLUSION: Parental socio-economic status is only of limited importance for episodes of drunkenness in early adolescence, and this very limited role seems to apply for girls more than for boys and for parental occupation more than family affluence. For future studies it might be important to look at the effects of socio-economic status within the context of other peer, family and school related factors in order to assess to what extent those factors might mediate the effects of social class background

Role of salt intake in prevention of cardiovascular disease: controversies and challenges.

Strong evidence indicates that reduction of salt intake lowers blood pressure and reduces the risk of cardiovascular disease (CVD). The WHO has set a global target of reducing the population salt intake from the current level of approximately 10 g daily to 85 categories of food; many other developed countries are following the UK's lead. In developing countries where most of the salt is added by consumers, public health campaigns have a major role. Every country should adopt a coherent, workable strategy. Even a modest reduction in salt intake across the whole population can lead to a major improvement in public health and cost savings

Disruption of Trichoderma reesei cre2, encoding an ubiquitin C-terminal hydrolase, results in increased cellulase activity

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6750/11/103Background: The filamentous fungus Trichoderma reesei (Hypocrea jecorina) is an important source of cellulases for use in the textile and alternative fuel industries. To fully understand the regulation of cellulase production in T. reesei, the role of a gene known to be involved in carbon regulation in Aspergillus nidulans, but unstudied in T. reesei, was investigated. Results: The T. reesei orthologue of the A. nidulans creB gene, designated cre2, was identified and shown to be functional through heterologous complementation of a creB mutation in A. nidulans. A T. reesei strain was constructed using gene disruption techniques that contained a disrupted cre2 gene. This strain, JKTR2-6, exhibited phenotypes similar to the A. nidulans creB mutant strain both in carbon catabolite repressing, and in carbon catabolite derepressing conditions. Importantly, the disruption also led to elevated cellulase levels. Conclusions: These results demonstrate that cre2 is involved in cellulase expression. Since the disruption of cre2 increases the amount of cellulase activity, without severe morphological affects, targeting creB orthologues for disruption in other industrially useful filamentous fungi, such as Aspergillus oryzae, Trichoderma harzianum or Aspergillus niger may also lead to elevated hydrolytic enzyme activity in these species.Jai A Denton and Joan M Kell

Salt restriction in kidney disease—a missed therapeutic opportunity?

The importance of salt restriction in the treatment of patients with renal disease has remained highly controversial. In the following we marshal the current evidence that salt plays a definite role in the genesis of hypertension and target organ damage, point to practical problems of salt restriction, and report on novel pathomechanisms of how salt affects blood pressure and causes target organ damage

Missed, not missing: Phylogenomic evidence for the existence of Avian FoxP3

The Forkhead box transcription factor FoxP3 is pivotal to the development and function of regulatory T cells (Tregs), which make a major contribution to peripheral tolerance. FoxP3 is believed to perform a regulatory role in all the vertebrate species in which it has been detected. The prevailing view is that FoxP3 is absent in birds and that avian Tregs rely on alternative developmental and suppressive pathways. Prompted by the automated annotation of foxp3 in the ground tit (Parus humilis) genome, we have questioned this assumption. Our analysis of all available avian genomes has revealed that the foxp3 locus is missing, incomplete or of poor quality in the relevant genomic assemblies for nearly all avian species. Nevertheless, in two species, the peregrine falcon (Falco peregrinus) and the saker falcon (F. cherrug), there is compelling evidence for the existence of exons showing synteny with foxp3 in the ground tit. A broader phylogenomic analysis has shown that FoxP3 sequences from these three species are similar to crocodilian sequences, the closest living relatives of birds. In both birds and crocodilians, we have also identified a highly proline-enriched region at the N terminus of FoxP3, a region previously identified only in mammals

Communication and marketing as tools to cultivate the public's health: a proposed "people and places" framework

<p>Abstract</p> <p>Background</p> <p>Communication and marketing are rapidly becoming recognized as core functions, or core competencies, in the field of public health. Although these disciplines have fostered considerable academic inquiry, a coherent sense of precisely how these disciplines can inform the practice of public health has been slower to emerge.</p> <p>Discussion</p> <p>In this article we propose a framework – based on contemporary ecological models of health – to explain how communication and marketing can be used to advance public health objectives. The framework identifies the attributes of people (as individuals, as social networks, and as communities or populations) and places that influence health behaviors and health. Communication, i.e., the provision of information, can be used in a variety of ways to foster beneficial change among both people (e.g., activating social support for smoking cessation among peers) and places (e.g., convincing city officials to ban smoking in public venues). Similarly, marketing, i.e., the development, distribution and promotion of products and services, can be used to foster beneficial change among both people (e.g., by making nicotine replacement therapy more accessible and affordable) and places (e.g., by providing city officials with model anti-tobacco legislation that can be adapted for use in their jurisdiction).</p> <p>Summary</p> <p>Public health agencies that use their communication and marketing resources effectively to support people in making healthful decisions and to foster health-promoting environments have considerable opportunity to advance the public's health, even within the constraints of their current resource base.</p