Intradermal substance P as a challenge agent in healthy individuals.

Pharmacological challenge models are deployed to evaluate drug effects during clinical development. Intradermal injection of Substance P (SP) neuropeptide, a potential challenge agent for investigating local mediators, is associated with wheal and flare response mediated by the MRGPRX2 receptor. Although dose-dependent data on SP effects exist, full characterization and information on potential carryover effect after repeated challenge are lacking. This open-label, two-part, prospective enabling study of SP intradermal challenge in healthy participants aimed to understand and distinguish between wheal and flare responses following various SP doses. Part 1 included one challenge visit to determine optimum SP dose range for evaluation in part 2, which determined variability in 20 participants and used intradermal microdialysis (IDM) for SP-challenged skin sampling. At 5, 15, 50, and 150 pmol doses, respectively, posterior median area under the curve (AUC; AUC0-2h ) was 4090.4, 5881.2, 8846.8, and 9212.8 mm2 /min, for wheal response, and 12020.9, 38154.3, 65470.6, and 67404.4 mm2 /min for flare response (SP-challenge visit 2). When the challenge was repeated ~2 weeks later, no carryover effect was observed. IDM histamine levels were relatively low, resulting in low confidence in the data to define temporal characteristics for histamine release following SP challenge. No safety concerns were identified using SP. Wheal and flare responses following intradermal SP challenge were dose-dependent and different. The results indicate that this challenge model is fit-for-purpose in future first-in-human studies and further assessment of novel drugs targeting dermal inflammatory disease responses, such as chronic spontaneous urticaria, chronic inducible urticaria, and pseudo-allergic reactions.

Depletion of LAG-3+ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781.

Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.

AIM: Interleukin (IL)-7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL-7 receptor-α subunit (CD127) monoclonal antibody. METHODS: A double-blind (sponsor-unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg-1 or 2.0 mg kg-1 ) or placebo was carried out in 18 healthy subjects over 24 weeks. RESULTS: GSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half-life was 5 (±1) days (2.0 mg kg-1 ), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg-1 ) and day 22 (2.0 mg kg-1 ). Maximal inhibition of IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg-1 ). Mean circulating IL-7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg-1 ) and days 2 and 22 (2.0 mg kg-1 ). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL-6, tumour necrosis factor-α, interferon-γ, IL-2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg-1 (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg-1 (neutralizing in 5/6). CONCLUSION: GSK2618960 was well tolerated and blocked IL-7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half-life is likely the result of target-mediated rather than ADA-mediated clearance.

Associations between urban metrics and mortality rates in England.

BACKGROUND: Seventy-five percent of the population in Europe live in urban areas and analysing the effects of urban form on the health of the urban population is of great public health interest. Not much is known, however, on the effects of urban form on the health of city dwellers. This study uses a novel approach to investigate whether associations exist between different measures of urban form and mortality risks in cities in England. METHODS: We conducted an ecological, cross-sectional study for urban areas in England with more than 100,000 residents (n = 50) and included all registered premature deaths (<65 years) between 1(st) January 2002 and 31(st) December 2009. To describe and categorise urban form we quantified the distribution and density of population, land cover and transport networks and measures of geographical characteristics. We used Poisson regression models to examine associations between the measures of urban form and age-standardised risks of deaths from all causes, cardiovascular disease, and traffic accidents after adjustment for socioeconomic status and smoking. Analysis was stratified by gender to explore differential associations between females and males. RESULTS: There were a total of 200,200 premature deaths during the study period (Females: 37 %; Males: 63 %). Transport network patterns were associated with overall and cardiovascular mortality rates in cities. We saw 12 % higher mortality risk after adjustment in cities with high junction density compared to cities with low density [Females: RR 1.12 (95 % CI 1.10 - 1.15); Males: RR 1.12 (95 % CI 1.10-1.14)]; the risk was slightly higher for cardiovascular mortality [Females: RR 1.16 (95 % CI 1.10 - 1.22); Males: RR 1.12 (95 % CI 1.09 - 1.16)]. Associations between mortality and population patterns were of similar magnitude [Females: RR 1.10 (95 % CI 1.09 - 1.13); Males: RR 1.09 (95 % CI 1.07-1.10)]; associations between mortality and land cover patterns were inconclusive. CONCLUSIONS: We found an association between transport patterns and risk of premature mortality. Associations between urban form and mortality observed in this study suggest that characteristics of city structure might have negative effects on the overall health of urban communities. Future urban planning and regeneration strategies can benefit from such knowledge to promote a healthy living environment for an increasing urban population.

Geographical and socioeconomic inequalities in women and children's nutritional status in Pakistan in 2011: an analysis of data from a nationally representative survey.

BACKGROUND: Pakistan has one of the highest levels of child and maternal undernutrition worldwide, but little information about geographical and socioeconomic inequalities is available. We aimed to analyse anthropometric indicators for childhood and maternal nutrition at a district level in Pakistan and assess the association of nutritional status with food security and maternal and household socioeconomic factors. METHODS: We used data from the 2011 Pakistan National Nutrition Survey, which included anthropometric measurements for 33 638 children younger than 5 years and 24 826 women of childbearing age. We estimated the prevalences of stunting, wasting, and underweight among children and of underweight, overweight, and obesity in women for all 143 districts of Pakistan using a Bayesian spatial technique. We used a mixed-effect linear model to analyse the association of nutritional status with individual and household sociodemographic factors and food security. FINDINGS: Stunting prevalence in Pakistan's districts ranged between 22% (95% credible interval 19-26) and 76% (69-83); the lowest figures for wasting and underweight were both less than 2·5% and the highest were 42% (34-50) for wasting and 54% (49-59) for underweight. In 106 districts, more women were overweight than were underweight; in 49 of these districts more women were obese than were underweight. Children were better nourished if their mothers were taller or had higher weight, if they lived in wealthier households, and if their mothers had 10 or more years of education. Severe food insecurity was associated with worse nutritional outcomes for both children and women. INTERPRETATION: We noted large social and geographical inequalities in child and maternal nutrition in Pakistan, masked by national and provincial averages. Pakistan is also beginning to face the concurrent challenge of high burden of childhood undernutrition and overweight and obesity among women of reproductive age. Planning, implementation, and evaluation of programmes for food and nutrition should be based on district-level needs and outcomes. FUNDING: Bill & Melinda Gates Foundation, Grand Challenges Canada, UK Medical Research Council.

Associations between green space and health in English cities: an ecological, cross-sectional study.

Green space has been identified as a modifiable feature of the urban environment and associations with physiological and psychological health have been reported at the local level. This study aims to assess whether these associations between health and green space are transferable to a larger scale, with English cities as the unit of analysis. We used an ecological, cross-sectional study design. We classified satellite-based land cover data to quantify green space coverage for the 50 largest cities in England. We assessed associations between city green space coverage with risk of death from all causes, cardiovascular disease, lung cancer and suicide between 2002 and 2009 using Poisson regression with random effect. After adjustment for age, income deprivation and air pollution, we found that at the city level the risk of death from all causes and a priori selected causes, for men and women, did not significantly differ between the greenest and least green cities. These findings suggest that the local health effects of urban green space observed at the neighbourhood level in some studies do not transfer to the city level. Further work is needed to establish how urban residents interact with local green space, in order to ascertain the most relevant measures of green space.

Associations between air pollution and socioeconomic characteristics, ethnicity and age profile of neighbourhoods in England and the Netherlands.

Air pollution levels are generally believed to be higher in deprived areas but associations are complex especially between sensitive population subgroups. We explore air pollution inequalities at national, regional and city level in England and the Netherlands comparing particulate matter (PM10) and nitrogen dioxide (NO2) concentrations and publicly available population characteristics (deprivation, ethnicity, proportion of children and elderly). We saw higher concentrations in the most deprived 20% of neighbourhoods in England (1.5 µg/m(3) higher PM10 and 4.4 µg/m(3) NO2). Concentrations in both countries were higher in neighbourhoods with >20% non-White (England: 3.0 µg/m(3) higher PM10 and 10.1 µg/m(3) NO2; the Netherlands: 1.1 µg/m(3) higher PM10 and 4.5 µg/m(3) NO2) after adjustment for urbanisation and other variables. Associations for some areas differed from the national results. Air pollution inequalities were mainly an urban problem suggesting measures to reduce environmental air pollution inequality should include a focus on city transport.

Aircraft noise and cardiovascular disease near Heathrow airport in London: small area study.

OBJECTIVE: To investigate the association of aircraft noise with risk of stroke, coronary heart disease, and cardiovascular disease in the general population. DESIGN: Small area study. SETTING: 12 London boroughs and nine districts west of London exposed to aircraft noise related to Heathrow airport in London. POPULATION: About 3.6 million residents living near Heathrow airport. Risks for hospital admissions were assessed in 12 110 census output areas (average population about 300 inhabitants) and risks for mortality in 2378 super output areas (about 1500 inhabitants). MAIN OUTCOME MEASURES: Risk of hospital admissions for, and mortality from, stroke, coronary heart disease, and cardiovascular disease, 2001-05. RESULTS: Hospital admissions showed statistically significant linear trends (P<0.001 to P<0.05) of increasing risk with higher levels of both daytime (average A weighted equivalent noise 7 am to 11 pm, L(Aeq),16 h) and night time (11 pm to 7 am, Lnight) aircraft noise. When areas experiencing the highest levels of daytime aircraft noise were compared with those experiencing the lowest levels (>63 dB v ≤ 51 dB), the relative risk of hospital admissions for stroke was 1.24 (95% confidence interval 1.08 to 1.43), for coronary heart disease was 1.21 (1.12 to 1.31), and for cardiovascular disease was 1.14 (1.08 to 1.20) adjusted for age, sex, ethnicity, deprivation, and a smoking proxy (lung cancer mortality) using a Poisson regression model including a random effect term to account for residual heterogeneity. Corresponding relative risks for mortality were of similar magnitude, although with wider confidence limits. Admissions for coronary heart disease and cardiovascular disease were particularly affected by adjustment for South Asian ethnicity, which needs to be considered in interpretation. All results were robust to adjustment for particulate matter (PM10) air pollution, and road traffic noise, possible for London boroughs (population about 2.6 million). We could not distinguish between the effects of daytime or night time noise as these measures were highly correlated. CONCLUSION: High levels of aircraft noise were associated with increased risks of stroke, coronary heart disease, and cardiovascular disease for both hospital admissions and mortality in areas near Heathrow airport in London. As well as the possibility of causal associations, alternative explanations such as residual confounding and potential for ecological bias should be considered.

Trends and inequalities in cardiovascular disease mortality across 7932 English electoral wards, 1982-2006: Bayesian spatial analysis.

BACKGROUND: Cardiovascular disease (CVD) mortality has more than halved in England since the 1980s, but there are few data on small-area trends. We estimated CVD mortality by ward in 5-year intervals between 1982 and 2006, and examined trends in relation to starting mortality, region and community deprivation. METHODS: We analysed CVD death rates using a Bayesian spatial technique for all 7932 English electoral wards in consecutive 5-year intervals between 1982 and 2006, separately for men and women aged 30-64 years and ≥65 years. RESULTS: Age-standardized CVD mortality declined in the majority of wards, but increased in 186 wards for women aged ≥65 years. The decline was larger where starting mortality had been higher. When grouped by deprivation quintile, absolute inequality between most- and least-deprived wards narrowed over time in those aged 30-64 years, but increased in older adults; relative inequalities worsened in all four age-sex groups. Wards with high CVD mortality in 2002-06 fell into two groups: those in and around large metropolitan cities in northern England that started with high mortality in 1982-86 and could not 'catch up', despite impressive declines, and those that started with average or low mortality in the 1980s but 'fell behind' because of small mortality reductions. CONCLUSIONS: Improving population health and reducing health inequalities should be treated as related policy and measurement goals. Ongoing analysis of mortality by small area is essential to monitor local effects on health and health inequalities of the public health and healthcare systems.

Occupational cancer burden in Great Britain.

A sound knowledge base is required to target resources to reduce workplace exposure to carcinogens. This project aimed to provide an objective estimate of the burden of cancer in Britain due to occupation. This volume presents extensive analyses for all carcinogens and occupational circumstances defined as definite or probable human occupational carcinogens by the International Agency for Research on Cancer. This article outlines the structure of the supplement - two methodological papers (statistical approach and exposure assessment), eight papers presenting the cancer-specific results grouped by broad anatomical site, a paper giving industry sector results and one discussing work-related cancer-prevention strategies. A brief summary of the methods and an overview of the updated overall results are given in this introductory paper. A general discussion of the overall strengths and limitations of the study is also presented. Overall, 8010 (5.3%) total cancer deaths in Britain and 13,598 cancer registrations were attributable to occupation in 2005 and 2004, respectively. The importance of cancer sites such as mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma and stomach cancers are highlighted, as are carcinogens such as asbestos, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists, as well as occupational circumstances such as shift work and occupation as a painter or welder. The methods developed for this project are being adapted by other countries and extended to include social and economic impact evaluation.

Spatio-temporal patterns of bladder cancer incidence in Utah (1973-2004) and their association with the presence of toxic release inventory sites.

BACKGROUND: The authors analyse the spatio-temporal variations of the incidence of bladder cancer between 1973 and 2004 in Utah at the census tract level (496 areas) to highlight areas of high and low relative risks that remained so throughout the 32 year period. Using these identified areas, a novel strategy is used to carry out a geographical case-control study of association between the risk of bladder cancer and presence of Toxic Release Inventory sites, where areas with stable high RRs are 'case areas' and all remaining areas with stable non increased risks are 'control areas'. RESULTS: The time trend of bladder cancer risk fluctuated over the study period: A steady decrease was observed, followed by an abrupt increase from 1992 to 2004. Using a Bayesian space-time model, 93 census tracts were classified as having an excess relative risk and 81 a lower relative risk, sustained over the 32 years. We showed that these high relative risk areas for bladder cancer were associated with the presence of Toxic Release Inventory sites, after adjusting for the proportion of Latter-Day Saint Church members as an area level proxy for smoking habits. CONCLUSIONS: Our study has demonstrated that the modeling of data in time and space has additional benefits over a purely spatial analysis. In addition to highlighting the areas with high and low relative risks, this model also allows the simultaneous study of persistency of spatial patterns over time and detection of 'unusual' time trends that may warrant further investigation.