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Survival from lung cancer remains low, yet is the most common cancer diagnosed worldwide. With survival contrasting between the main histological groupings, small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), it is important to assess the extent that geographical differences could be from varying proportions of cancers with unspecified histology across countries. Lung cancer cases diagnosed 2010-2014, followed until 31st December 2015 were provided by cancer registries from seven countries for the ICBP SURVMARK-2 project. Multiple imputation was used to reassign cases with unspecified histology into SCLC, NSCLC, other. One- and three-year age-standardised net survival were estimated by histology, sex, age group and country. 404,617 lung cancer cases were included, 47,533 (11.7%) and 262,040 (64.8%) were SCLC and NSCLC. The proportion of unspecified cases varied, from 11.2% (Denmark) to 29.0% (U.K). Following imputation with unspecified histology, survival variations remained: 1-year SCLC survival ranged from 28.0% (New Zealand) to 35.6% (Australia) NSCLC survival from 39.4% (U.K.) to 49.5% (Australia). The largest survival change following imputation was for 1-year NSCLC (4.9 percentage point decrease). Similar variations were observed for 3-year survival. The oldest age group had lowest survival and largest decline following imputation. International variations in SCLC and NSCLC survival are only partially attributable to differences in the distribution of unspecified histology. While it is important that registries and clinicians aim to improve completeness in classifying cancers, it is likely that other factors play a larger role, including underlying risk factors, stage, comorbidity and care management which warrants investigation. This article is protected by copyright. All rights reserved.

Background: Familial hypercholesterolemia (FH) is a monogenic disease characterized by a high concentration of low-density lipoprotein cholesterol. This population is considered to be at high cardiovascular risk; however, disease evolution remains heterogeneous among individuals. The coronary artery calcium (CAC) score is currently the best predictor of incidental major cardiovascular events in primary prevention in the general population. Few studies have described the CAC score in FH populations. Methods: The objective of our study was to determine the predictors of the CAC score in FH patients. We retrospectively studied FH patients followed at the Montreal Clinical Research Institute (IRCM) Lipid Clinic who had a cardiac scan for CAC score, using the Agatston method, between 2013 and 2019. Results: Final analysis included 62 FH patients. Mean age was 48 ± 14 years old, and 48% were men. Overall, 25 patients had a CAC score of 0 (40%), and 37 patients had a nonzero CAC score (60%). Sex, age, Montreal-FH-SCORE (MFHS), waist circumference, and statin exposure in years were significant predictors (P ≤ 0,05) of a nonzero CAC score in a univariate model. MFHS was the only factor that remained significant in a multivariate model (odds ratio 1.34, 95% confidence interval 1.11–1.61, P = 0.002). Conclusions: In conclusion, we found that MFHS, which includes traditional cardiovascular risk factors, was a predictor of a nonzero CAC score in FH patients. This finding suggests that MFHS may play a role in determining the cardiovascular risk and therefore the intensity of treatment in FH patients. Résumé: Contexte: L’hypercholestérolémie familiale (HF) est une maladie monogénique caractérisée par une forte concentration de cholestérol des lipoprotéines de basse densité. La population touchée est considérée comme étant exposée à un risque cardiovasculaire élevé; toutefois, l’évolution de la maladie demeure hétérogène d’une personne à l’autre. À l’heure actuelle, le score calcique coronaire (SCC) est le meilleur outil prédictif de manifestations cardiovasculaires majeures fortuites en prévention primaire dans la population générale. Peu d’études ont décrit le SCC dans des populations atteintes de HF. Méthodologie: L’objectif de notre étude était de déterminer les facteurs prédictifs du SCC chez les patients atteints de HF. Nous avons étudié de façon rétrospective des patients atteints de HF qui étaient suivis à la clinique de lipides de l’Institut de recherches cliniques de Montréal (IRCM) et chez qui le score SCC avait été mesuré pendant un examen de tomodensitométrie cardiaque, au moyen de la méthode d’Agatston, entre 2013 et 2019. Résultats: L’analyse finale a porté sur 62 patients atteints de HF. L’âge moyen était de 48 ± 14 ans et la proportion d’hommes était de 48 %. Dans l’ensemble, 25 patients avaient un SCC de 0 (40 %) et 37, un SCC différent de zéro (60 %). Le sexe, l’âge, le score MFHS (Montreal-FH-SCORE), le tour de taille et le nombre d’années d’exposition aux statines ont été des facteurs prédictifs significatifs (p ≤ 0,05) d’un SCC différent de zéro dans un modèle à une variable. Le score MFHS est le seul facteur qui est demeuré significatif dans un modèle à plusieurs variables (rapport de cotes : 1,34; intervalle de confiance à 95 % : 1,11 à 1,61; p = 0,002). Conclusions: En conclusion, nous avons observé que le score MFHS, qui englobe les facteurs classiques de risque cardiovasculaire, était un facteur prédictif d’un SCC différent de zéro chez les patients atteints de HF. Cette observation semble indiquer que le score MFHS pourrait jouer un rôle dans la détermination du risque cardiovasculaire et, par conséquent, dans l’intensité du traitement chez les patients atteints de HF.

ObjectivesAs part of the International Cancer Benchmarking Partnership (ICBP) SURVMARK-2 project, we provide the most recent estimates of colon and rectal cancer survival in seven high-income countries by age and stage at diagnosis.MethodsData from 386 870 patients diagnosed during 2010–2014 from 19 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were analysed. 1-year and 5-year net survival from colon and rectal cancer were estimated by stage at diagnosis, age and country,Results(One1-year) and 5-year net survival varied between (77.1% and 87.5%) 59.1% and 70.9% and (84.8% and 90.0%) 61.6% and 70.9% for colon and rectal cancer, respectively. Survival was consistently higher in Australia, Canada and Norway, with smaller proportions of patients with metastatic disease in Canada and Australia. International differences in (1-year) and 5-year survival were most pronounced for regional and distant colon cancer ranging between (86.0% and 94.1%) 62.5% and 77.5% and (40.7% and 56.4%) 8.0% and 17.3%, respectively. Similar patterns were observed for rectal cancer. Stage distribution of colon and rectal cancers by age varied across countries with marked survival differences for patients with metastatic disease and diagnosed at older ages (irrespective of stage).ConclusionsSurvival disparities for colon and rectal cancer across high-income countries are likely explained by earlier diagnosis in some countries and differences in treatment for regional and distant disease, as well as older age at diagnosis. Differences in cancer registration practice and different staging systems across countries may have impacted the comparisons.

Background: Women attending mammography screening units (msus) and well women’s clinics (wwcs) represent a motivated cohort likely to engage in interventions aimed at primary breast cancer (bca) prevention. Methods: We used a feasibility questionnaire distributed to women (40–49 or 50–74 years of age) attending msus and wwcs in Halifax, Nova Scotia, to examine (1) women’s views about bca primary prevention and sources of health care information, (2) prevalence of lifestyle-related bca risk factors, and, (3) predictors of prior mammography encounters within provincial screening guidelines. Variables examined included personal profiling, comorbidities, prior mammography uptake, lifestyle behaviours, socioeconomic status, health information sources, and willingness to discuss or implement lifestyle modifications, or endocrine therapy, or both. A logistic regression analysis examined associations with prior mammography encounters. Results: Of the 244 responses obtained during 1.5 months from women aged 40–49 years (n = 75) and 50–74 years (n = 169), 56% and 75% respectively sought or would prefer to receive health information from within, as opposed to outside, health care. Lifestyle-related bca risk factors were prevalent, and most women were willing to discuss or implement lifestyle modifications (93%) or endocrine therapy (67%). Of the two age groups, 49% and 93% respectively had previously undergone mammography within guidelines. Increasing age and marital status (single, separated, or divorced vs. married or partnered) were independent predictors of prior mammography encounters within guidelines for women 40–49 years of age; no independent predictors were observed in the older age group. Conclusions: Women attending msus and wwcs seem to largely adhere to mammography guidelines and appear motivated to engage in bca primary prevention strategies, including lifestyle modifications and endocrine therapy. Women’s views as observed in this study provide a rationale for the potential incorporation of bca risk assessment within the “mammogram point of care” to engage motivated women in bca primary prevention strategies.

OBJECTIVE: The study aims to evaluate the differences in ovarian cancer survival by age and stage at diagnosis within and across seven high-income countries.METHODS: We analyzed data from 58,161 women diagnosed with ovarian cancer during 2010-2014, followed until 31 December 2015, from 21 population-based cancer registries in Australia, Canada, Denmark, Ireland, New Zealand, Norway, and United Kingdom. Comparisons of 1-year and 3-year age- and stage-specific net survival (NS) between countries were performed using the period analysis approach.RESULTS: Minor variation in the stage distribution was observed between countries, with most women being diagnosed with 'distant' stage (ranging between 64% in Canada and 71% in Norway). The 3-year all-ages NS ranged from 45 to 57% with Australia (56%) and Norway (57%) demonstrating the highest survival. The proportion of women with 'distant' stage was highest for those aged 65-74 and 75-99 years and varied markedly between countries (range:72-80% and 77-87%, respectively). The oldest age group had the lowest 3-year age-specific survival (20-34%), and women aged 65-74 exhibited the widest variation across countries (3-year NS range: 40-60%). Differences in survival between countries were particularly stark for the oldest age group with 'distant' stage (3-year NS range: 12% in Ireland to 24% in Norway).CONCLUSIONS: International variations in ovarian cancer survival by stage exist with the largest differences observed in the oldest age group with advanced disease. This finding endorses further research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease.

ObjectiveTo provide the first international comparison of oesophageal and gastric cancer survival by stage at diagnosis and histological subtype across high-income countries with similar access to healthcare.MethodsAs part of the ICBP SURVMARK-2 project, data from 28 923 patients with oesophageal cancer and 25 946 patients with gastric cancer diagnosed during 2012–2014 from 14 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were included. 1-year and 3-year age-standardised net survival were estimated by stage at diagnosis, histological subtype (oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC)) and country.ResultsOesophageal cancer survival was highest in Ireland and lowest in Canada at 1 (50.3% vs 41.3%, respectively) and 3 years (27.0% vs 19.2%) postdiagnosis. Survival from gastric cancer was highest in Australia and lowest in the UK, for both 1-year (55.2% vs 44.8%, respectively) and 3-year survival (33.7% vs 22.3%). Most patients with oesophageal and gastric cancer had regional or distant disease, with proportions ranging between 56% and 90% across countries. Stage-specific analyses showed that variation between countries was greatest for localised disease, where survival ranged between 66.6% in Australia and 83.2% in the UK for oesophageal cancer and between 75.5% in Australia and 94.3% in New Zealand for gastric cancer at 1-year postdiagnosis. While survival for OAC was generally higher than that for OSCC, disparities across countries were similar for both histological subtypes.ConclusionSurvival from oesophageal and gastric cancer varies across high-income countries including within stage groups, particularly for localised disease. Disparities can partly be explained by earlier diagnosis resulting in more favourable stage distributions, and distributions of histological subtypes of oesophageal cancer across countries. Yet, differences in treatment, and also in cancer registration practice and the use of different staging methods and systems, across countries may have impacted the comparisons. While primary prevention remains key, advancements in early detection research are promising and will likely allow for additional risk stratification and survival improvements in the future.

A healthy, intact gut microbiota is often resistant to colonization by gastrointestinal pathogens. During periods of dysbiosis, however, organisms such as Clostridioides difficile can thrive. We describe an optimized in vitro colonization resistance assay for C. difficile in stool (CRACS) and demonstrate the utility of this assay by assessing changes in colonization resistance following antibiotic exposure. Fecal samples were obtained from healthy volunteers (n = 6) and from healthy subjects receiving 5 days of moxifloxacin (n = 11) or no antibiotics (n = 10). Samples were separated and either not manipulated (raw) or sterilized (autoclaved or filtered) prior to inoculation with C. difficile ribotype 027 spores and anaerobic incubation for 72 h. Different methods of storing fecal samples were also investigated in order to optimize the CRACS. In healthy, raw fecal samples, incubation with spores did not lead to increased C. difficile total viable counts (TVCs) or cytotoxin detection. In contrast, increased C. difficile TVCs and cytotoxin detection occurred in sterilized healthy fecal samples or those from antibiotic-treated individuals. The CRACS was functional with fecal samples stored at either 4°C or −80°C but not with those stored with glycerol (12% or 30% [vol/vol]). Our data show that the CRACS successfully models in vitro the loss of colonization resistance and subsequent C. difficile proliferation and toxin production. The CRACS could be used as a proxy for C. difficile infection in clinical studies or to determine if an individual is at risk of developing C. difficile infection or other potential infections occurring due to a loss of colonization resistance.

Background Data from population-based cancer registries are often used to compare cancer survival between countries or regions. The ICBP SURVMARK-2 study is an international partnership aiming to quantify and explore the reasons behind survival differences across high-income countries. However, the magnitude and relevance of differences in cancer survival between countries have been questioned, as it is argued that observed survival variations may be explained, at least in part, by differences in cancer registration practice, completeness and the availability and quality of the respective data sources. Methods As part of the ICBP SURVMARK-2 study, we used a simulation approach to better understand how differences in completeness, the characteristics of those missed and inclusion of cases found from death certificates can impact on cancer survival estimates. Results Bias in 1- and 5-year net survival estimates for 216 simulated scenarios is presented. Out of the investigated factors, the proportion of cases not registered through sources other than death certificates, had the largest impact on survival estimates. Conclusion Our results show that the differences in registration practice between participating countries could in our most extreme scenarios explain only a part of the largest observed differences in cancer survival.

BACKGROUND: Population-based cancer registries strive to cover all cancer cases diagnosed within the population, but some cases will always be missed and no register is 100 % complete. Many cancer registries use death certificates to identify additional cases not captured through other routine sources, to hopefully add a large proportion of the missed cases. Cases notified through this route, who would not have been captured without death certificate information, are referred to as Death Certificate Initiated (DCI) cases. Inclusion of DCI cases in cancer registries increases completeness and is important for estimating cancer incidence. However, inclusion of DCI cases will generally lead to biased estimates of cancer survival, but the same is often also true if excluding DCI cases. Missed cases are probably not a random sample of all cancer cases, but rather cases with poor prognosis. Further, DCI cases have poorer prognosis than missed cases in general, since they have all died with cancer mentioned on the death certificates.METHODS: We performed a simulation study to estimate the impact of including or excluding DCI cases on cancer survival estimates, under different scenarios.RESULTS: We demonstrated that including DCI cases underestimates survival. The exclusion of DCI cases gives unbiased survival estimates if missed cases are a random sample of all cancer cases, while survival is overestimated if these have poorer prognosis.CONCLUSION: In our most extreme scenarios, with 25 % of cases initially missed, the usual practice of including DCI cases underestimated 5-year survival by at most 3 percentage points.

Arsenic in drinking water impacts health. Highest levels of arsenic have been historically observed in Taiwan and Bangladesh but the contaminant has been affecting the health of people globally. Strong associations have been confirmed between exposure to high-levels of arsenic in drinking water and a wide range of diseases, including cancer. However, at lower levels of exposure, especially near the current World Health Organization regulatory limit (10μg/L), this association is inconsistent as the effects are mostly extrapolated from high exposure studies. This ecological study used Bayesian inference to model the relative risk of bladder and kidney cancer at these lower concentrations—0–2μg/L; 2–5μg/L and; ≥5μg/L of arsenic—in 864 bladder and 525 kidney cancers diagnosed in the study area, Nova Scotia, Canada between 1998 and 2010. The model included proxy measures of lifestyle (e.g. smoking) and accounted for spatial dependencies. Overall, bladder cancer risk was 16% (2–5μg/L) and 18% (≥5μg/L) greater than that of the referent group (

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile .

© 2019 World Health Organization Background: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. Findings: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995–2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010–14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. Interpretation: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. Funding: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

Summary Background The overall incidence of colorectal cancer is decreasing in many high-income countries, yet analyses in the USA and other high-income countries such as Australia, Canada, and Norway have suggested increasing incidences among adults younger than 50 years. We aimed to examine longitudinal and generational changes in the incidence of colon and rectal cancer in seven high-income countries. Methods We obtained data for the incidence of colon and rectal cancer from 20 population-based cancer registries in Australia, Canada, Denmark, Norway, New Zealand, Ireland, and the UK for the earliest available year until 2014. We used age–period–cohort modelling to assess trends in incidence by age group, period, and birth cohort. We stratified cases by tumour subsite according to the 10th edition of the International Classification of Diseases. Age-standardised incidences were calculated on the basis of the world standard population. Findings An overall decline or stabilisation in the incidence of colon and rectal cancer was noted in all studied countries. In the most recent 10-year period for which data were available, however, significant increases were noted in the incidence of colon cancer in people younger than 50 years in Denmark (by 3·1%; per year), New Zealand (2·9% per year), Australia (2·9% per year), and the UK (1·8% per year). Significant increases in the average annual percentage change in the incidence of rectal cancer were also noted in this age group in Canada (by 3·4% per year), Australia (2·6% per year), and the UK (1·4% per year). Contemporaneously, in people aged 50–74 years, the average annual percentage change in the incidence of colon cancer decreased significantly in Australia (by 1·6% per year), Canada (1·9% per year), and New Zealand (3·4% per year) and of rectal cancer in Australia (2·4% per year), Canada (1·2% per year), and the UK (1·2% per year). Increases in the incidence of colorectal cancer in people younger than 50 years were mainly driven by increases in distal (left) tumours of the colon. In all countries, we noted non-linear cohort effects, which were more pronounced for rectal than for colon cancer. Interpretation We noted a substantial increase in the incidence of colorectal cancer in people younger than 50 years in some of the countries in this study. Future studies are needed to establish the root causes of this rising incidence to enable the development of potential preventive and early-detection strategies. Funding Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, the Cancer Society of New Zealand, NHS England, Norwegian Cancer Society, Public Health Agency Northern Ireland, Scottish Government, Western Australia Department of Health, and Wales Cancer Network.

International audience; The mechanical and cellular relationships between systole and diastole during left ventricular (LV) dysfunction remain to be established. LV contraction-relaxation coupling was examined during LV hypertrophy induced by chronic hypertension. Chronically instrumented pigs received angiotensin II infusion for4weeks to induce chronic hypertension (133 ± 7 mmHg vs 98 ± 5 mmHg for mean arterial pressure at Day 28 vs 0, respectively) and LV hypertrophy. LV function was investigated with the instrumentation and echocardiography for LV twist-untwist assessment before and after dobutamine infusion. The cellular mechanisms were investigated by exploring the intracellular Ca2+ handling. At Day 28, pigs exhibited LV hypertrophy with LV diastolic dysfunction (impaired LV isovolumic relaxation, increased LV end-diastolic pressure, decreased and delayed LV untwisting rate) and LV systolic dysfunction (impaired LV isovolumic contraction and twist) although LV ejection fraction was preserved. Isolated cardiomyocytes exhibited altered shortening and lengthening. Interestingly, contraction-relaxation coupling remained preserved both in vivo and in vitro during LV hypertrophy. LV systolic and diastolic dysfunctions were associated to post-translational remodeling and dysfunction of the type 2 cardiac ryanodine receptor/Ca2+ release channel (RyR2), i.e., PKA hyperphosphorylation of RyR2, depletion of calstabin 2 (FKBP12.6), RyR2 leak and hypersensitivity of RyR2 to cytosolic Ca2+ during both contraction and relaxation phases. In conclusion, LV contraction-relaxation coupling remained preserved during chronic hypertension despite LV systolic and diastolic dysfunctions. This implies that LV diastolic dysfunction is accompanied by LV systolic dysfunction. At the cellular level, this is linked to sarcoplasmic reticulum Ca2+ leak through PKA-mediated RyR2 hyperphosphorylation and depletion of its stabilizing partner.

Background Bladder and kidney cancers are the ninth and twelfth most common type of cancer worldwide, respectively. Internationally, rates vary ten-fold, with several countries showing rising incidence. This study describes the spatial and spatio-temporal variations in the incidence risk of these diseases for Nova Scotia, a province located in Atlantic Canada, where rates for bladder and kidney cancer exceed those of the national average by about 25 % and 35 %, respectively. Methods Cancer incidence in the 311 Communities of Nova-Scotia was analyzed with a spatial autoregressive model for the case counts of bladder and kidney cancers (3,232 and 2,143 total cases, respectively), accounting for each Community's population and including variables known to influence risk. A spatially-continuous analysis, using a geostatistical Local Expectation-Maximization smoothing algorithm, modeled finer-scale spatial variation in risk for south-western Nova Scotia (1,810 bladder and 957 kidney cases) and Cape Breton (1,101 bladder, 703 kidney). Results Evidence of spatial variations in the risk of bladder and kidney cancer was demonstrated using both aggregated Community-level mapping and continuous-grid based localized mapping; and these were generally stable over time. The Community-level analysis suggested that much of this heterogeneity was not accounted for by known explanatory variables. There appears to be a north-east to south-west increasing gradient with a number of south-western Communities have risk of bladder or kidney cancer more than 10 % above the provincial average. Kidney cancer risk was also elevated in various northeastern communities. Over a 12 year period this exceedance translated in an excess of 200 cases. Patterns of variations in risk obtained from the spatially continuous smoothing analysis generally mirrored those from the Community-level autoregressive model, although these more localized risk estimates resulted in a larger spatial extent for which risk is likely to be elevated. Conclusions Modelling the spatio-temporal distribution of disease risk enabled the quantification of risk relative to expected background levels and the identification of high risk areas. It also permitted the determination of the relative stability of the observed patterns over time and in this study, pointed to excess risk potentially driven by exposure to risk factors that act in a sustained manner over time. Electronic supplementary material The online version of this article (doi:10.1186/s12889-016-2767-9) contains supplementary material, which is available to authorized users.

BackgroundAntibiotic disruption of the intestinal microbiota favors colonization byClostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis, and quantified the link between this intensity and mortality.MethodsWe administered either moxifloxacin (n=70) or clindamycin (n=60) to hamsters by subcutaneous injection from day 1 (D1) to D5, and challenged them with aC. difficiletoxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0and D3using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time ofC. difficilechallenge and studied their capacity to predict subsequent death of the animals.ResultsIncreasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (p−5for the change of Shannon index in moxifloxacin-treated animals and p−9in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the ROC curve of 0.89 [95%CI, 0.82;0.95] and 0.95 [0.90;0.98], respectively.ConclusionsAltogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency to the DAV131A dose; mortality afterC. difficilechallenge was related to the intensity of dysbiosis in a similar manner with the two antibiotics.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. Methods: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. Results: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age-matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. Conclusions: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non-invasive screening test for prediction and early detection of PDAC.

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) shuttles low-density lipoprotein (LDL) receptors for degradation, thus upregulates LDL plasma clearance. Although PCSK9 loss of function is cardioprotective, its role in metabolic risks remains unknown. Increased apoB-lipoproteins uptake into nonhepatic tissues such as white adipose tissue (WAT) induces their dysfunction, which may be favored by lower plasma PCSK9. We hypothesized that lower plasma PCSK9 relative to apoB, or higher apoB-to-PCSK9 ratio, is a better predictor of metabolic disturbances than PCSK9 alone in humans. Methods Thirty-three men and 48 postmenopausal women (>27 kg/m 2 , aged 45–74 years, normoglycemic) underwent in-depth assessment of glucose and fat metabolism using high-fat meals, WAT biopsies, intravenous glucose-tolerance tests, and hyperinsulinemia clamps. Results Plasma apoB correlated positively with fasting and postprandial triglycerides and chylomicron clearance (R = 0.44–0.66) and glucose-stimulated insulin secretion (R = 0.24) and negatively with insulin sensitivity (R = −0.28) and gynoid WAT in situ lipoprotein lipase activity (ie, ex vivo WAT function, R 2 = 0.34). Neither PCSK9 nor LDL cholesterol associated with these risks. In regression analysis that adjusted for body mass index, lower plasma PCSK9 strengthened the association of apoB to WAT dysfunction and insulin resistance. Moreover, plasma apoB-to-PCSK9 ratio correlated positively with all these metabolic risks and further associated positively with android-to-gynoid fat ratio (R = 0.41) and negatively with gynoid fat mass (R = −0.23, all P ≤ .05). No significant sex differences existed in these associations. Conclusions Lower plasma PCSK9 relative to apoB associates with metabolic risks and WAT dysfunction in normoglycemic obese subjects. We hypothesize that the plasma apoB-to-PCSK9 ratio provides a better clinical index than PCSK9 alone for monitoring early metabolic disturbances that may be promoted by reduction in plasma PCSK9.

International audience; Generating mosaics of orthorectified remote sensing images is a challenging task because of the colorimetric differences between adjacent images introduced by land use, surface illumination, atmospheric conditions, and sensor. Most of the existing color correction methods involve pairwise techniques, which are limited when the collection of images is large with numerous overlaps. Besides , available techniques do not operate in a color space suited for true-color processing. This paper presents a simple and robust method to perform the global colorimetric harmonization of multiple overlaping remote sensing images in natural colors (RGB). Our parameter-free method deals simultaneously with any number of images, with any spatial layout, and without any single reference image. It is based on the resolution of a quadratic programming optimization problem. It operates in the lαβ decorrelated color space, which is well suited for human vision of natural scenes. The results obtained from the mosaicking of 132 RapidEye color orthoimages over mainland France demonstrate good potential for performing colorimetric harmonization automatically and effectively.; La génération de mosaïques d'images orthorectifiées en télédétection est une tâche difficile en raison des différences colorimétriques entre les images adjacentes introduites par l'utilisation des terres, l'éclairage de surface, les conditions atmosphériques, et le capteur. La plupart des méthodes existantes de correction des couleurs impliquent des techniques par paires, qui sont limitées lorsque la collection d'images est grand avec de nombreux chevauchements. En outre, les techniques disponibles ne fonctionnent pas dans un espace de couleur adapté pour le traitement des vraies couleurs. Cet article présente une méthode de androbust simple à réaliser l'harmonisation colorimétrique mondial de distance chevauchent plusieurs images de détection dans des couleurs naturelles (RGB). Nos méthode sans paramètres traite simultanément avec un certain nombre d'images et avec un aménagement de l'espace, et sans aucune image de référence unique. Elle est basée sur la résolution d'un problème d'optimisation quadratique programmation (QP). Elle opère dans l'espace de couleur de lab décorrélés, ce qui est bien adapté pour la vision humaine de scènes naturelles. Les résultats obtenus à partir du mosaïquage de 132 RapidEye ortho-images de couleurs plus France métropolitaine démontrent un bon potentiel pour réaliser l'harmonisation colorimétrique automatiquement et efficacement.

This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.

Lowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effects of an activated charcoal-based adsorbent, DAV131A, on the fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced Clostridium difficile infection. A total of 215 hamsters receiving moxifloxacin subcutaneously (day 1 [D 1 ] to D 5 ) were orally infected at D 3 with C. difficile spores. They received various doses (0 to 1,800 mg/kg of body weight/day) and schedules (twice a day [BID] or three times a day [TID]) of DAV131A (D 1 to D 8 ). Moxifloxacin concentrations and C. difficile counts were determined at D 3 , and mortality was determined at D 12 . We compared mortality rates, moxifloxacin concentrations, and C. difficile counts according to DAV131A regimen and modeled the links between DAV131A regimen, moxifloxacin concentration, and mortality. All hamsters that received no DAV131A died, but none of those that received 1,800 mg/kg/day died. Significant dose-dependent relationships between DAV131A dose and (i) mortality, (ii) moxifloxacin concentration, and (iii) C. difficile count were evidenced. Mathematical modeling suggested that (i) lowering the moxifloxacin concentration at D 3 , which was 58 μg/g (95% confidence interval [CI] = 50 to 66 μg/g) without DAV131A, to 17 μg/g (14 to 21 μg/g) would reduce mortality by 90%; and (ii) this would be achieved with a daily DAV131A dose of 703 mg/kg (596 to 809 mg/kg). In this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing the fecal free moxifloxacin concentration.

[Departement_IRSTEA]Territoires [TR1_IRSTEA]SYNERGIE [Axe_IRSTEA]TETIS-AMOS [TR2_IRSTEA]GEUSI; International audience; We demonstrate the use of sensitivity analysis to rank sources of uncertainty in models for economic appraisal of flood risk management policies, taking into account spatial scale issues. A methodology of multi-scale variance-based global sensitivity analysis is developed, and illustrated on the NOE model on the Orb River, France. The variability of the amount of expected annual flood avoided damages, and the associated sensitivity indices, are estimated over different spatial supports, ranging from small cells to the entire floodplain. Both uncertainty maps and sensitivity maps are produced to identify the key input variables in the NOE model at different spatial scales. Our results show that on small spatial supports, variance of the output indicator is mainly due to the water depth maps and the assets map (spatially distributed model inputs), while on large spatial supports, it is mainly due to the flood frequencies and depthedamage curves (non spatial inputs).

Cost-benefit analyses (CBA) of flood management plans usually require estimating expected annual flood damages on a study area and rely on a complex modelling chain, including hydrological, hydraulic and economic modelling, as well as geographic information system-based spatial analysis. As most model-based assessments, these CBA are fraught with uncertainty. In this paper, we consider as a case study the CBA of a set of flood control structural measures on the Orb Delta, France. We demonstrate the use of variance-based global sensitivity analysis to (i) propagate uncertainty sources through the modelling chain and assess their overall impact on the outcomes of the CBA, and (ii) rank uncertainty sources according to their contribution to the variance of the CBA outcomes. All uncertainty sources prove to explain a significant share of the overall output variance. Results show that the ranking of uncertainty sources depends not only on the economic sector considered (private housing, agricultural land, other economic activities), but also on a number of averaging-out effects controlled by the number and surface area of the assets considered, the number of land use types or the number of damage functions.

Oil palm is the most rapidly expanding tropical perennial crop. Its cultivation raises environmental concerns, notably related to the use of nitrogen (N) fertilisers and the associated pollution and greenhouse gas emissions. While numerous and diverse models exist to estimate N losses from agriculture, very few are currently available for tropical perennial crops. Moreover, there is a lack of critical analysis of their performance in the specific context of tropical perennial cropping systems. We assessed the capacity of 11 models and 29 sub-models to estimate N losses in a typical oil palm plantation over a 25-year growth cycle, through leaching and runoff, and emissions of NH3, N2, N2O, and NOx. Estimates of total N losses were very variable, ranging from 21 to 139 kg N ha−1 yr−1. On average, 31 % of the losses occurred during the first 3 years of the cycle. Nitrate leaching accounted for about 80 % of the losses. A comprehensive Morris sensitivity analysis showed the most influential variables to be soil clay content, rooting depth, and oil palm N uptake. We also compared model estimates with published field measurements. Many challenges remain in modelling processes related to the peculiarities of perennial tropical crop systems such as oil palm more accurately.

Treatment uptake and elapsed times along the care path have emerged as potential quality indicators for cancer care delivery. This retrospective study examined changes in adjuvant chemotherapy uptake and elapsed times along the care path for patients in 2005 and in 2007 who had early-stage non-small-cell lung cancer (nsclc) and who underwent curative-intent surgery in Nova Scotia, Canada. All patients who underwent curative-intent surgery for stages i&ndash, iii nsclc in the two years of interest were included. Logistic regression and general linear models were used to examine factors associated with chemotherapy uptake patterns and, at various resolutions (low, intermediate, high), elapsed times between all care events in the care path. In the 223 patients who underwent curative-intent surgery (108 in 2005, 115 in 2007), several factors were associated with uptake patterns and elapsed times. Cohort year (2007 vs. 2005) was not associated with referral to medical oncology [odds ratio (or): 1.05, 95% confidence interval (ci): 0.51 to 2.15, p = 0.905], but it was associated with less treatment after referral (or: 0.34, 95% ci: 0.11 to 1.00, p = 0.057) and less overall uptake (or: 0.35, 95% ci: 0.13 to 0.95, p = 0.040). Patients were referred sooner to medical oncology in 2007 than in 2005 (21 days vs. 35 days, p = 0.008), but experienced longer waits between consultation and chemotherapy delivery (18 days vs. 7 days, p = 0.001). Significant differences were observed in care patterns over time. Frequent monitoring of care patterns at high resolution may optimize insights into emerging trends within cancer care systems.

Background: Sublingual immunotherapy (SLIT) efficacy could be improved by formulations facilitating allergen contact with the oral mucosa and uptake by antigen-presenting cells (APCs). Methods: Two types of chitosan microparticles, differing in size and surface charge, were tested in vitro for their capacity to improve antigen uptake and presentation by murine bone marrow-derived dendritic cells (BMDCs) or purified oral APCs. T-cell priming in cervical lymph nodes (LNs) was assessed by intravenous transfer of carboxyfluorescein diacetate succinimidyl ester-labelled ovalbumin (OVA)-specific CD4+ T cells and flow cytometry analysis. Ovalbumin-sensitized BALB/c mice were treated sublingually with soluble or chitosan-formulated OVA twice a week for 2 months. Airway hyperresponsiveness (AHR), lung inflammation and T-cell responses in cervical and mediastinal LNs were assessed by whole-body plethysmography, lung histology and Cytometric Bead Array technology, respectively. Results: Only a mucoadhesive (i.e. highly positively charged) and microparticulate form of chitosan enhances OVA uptake, processing and presentation by murine BMDCs and oral APCs. Targeting OVA to dendritic cells with this formulation increases specific T-cell proliferation and IFN-γ/IL-10 secretion in vitro, as well as T-cell priming in cervical LNs in vivo. Sublingual administration of such chitosan-formulated OVA particles enhances tolerance induction in mice with established asthma, with a dramatic reduction of both AHR, lung inflammation, eosinophil numbers in bronchoalveolar lavages, as well as antigen-specific Th2 responses in mediastinal LNs. Conclusions: Mucoadhesive chitosan microparticles represent a valid formulation for sublingual allergy vaccines.

Introduction Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) has become a new standard of care. This study examines the uptake patterns for adjuvant chemotherapy outside of clinical trials. Methods A retrospective study of all patients diagnosed with NSCLC in the year 2005 who underwent curative-intent surgery in Nova Scotia, Canada was conducted. Logistic regression models and discriminant function analyses were employed to identify cofactors associated with referral to medical oncology and/or utilization of adjuvant chemotherapy. Results Of 540 patients with NSCLC, 108 underwent curative-intent surgery (67% lobectomy; 15% pneumonectomy; 19% wedge resection) for NSCLC (39% IA; 24% IB; 25% II; 14% III). Referral to medical oncology was observed in 44% (47 of 108) of all patients including 73% (30 of 41) of those with stage II–III. Adjuvant chemotherapy utilization was observed in 62% (29 of 47) of those referred including 73% (22 of 30) of those with stage II–III. Overall, 27% (29 of 108) of all patients received adjuvant chemotherapy, including 54% (22 of 41) of those with stage II–III. Higher uptake was significantly associated with age (younger versus older), stage (II/III versus I), and surgery type (pneumonectomy versus wedge). Weaker associations were observed with other cofactors including surgeon, health center, mean household income, and surgery-medical oncologist consult timeline. Conclusions The uptake of adjuvant chemotherapy in patients with resected NSCLC outside of clinical trials is low overall, but is higher among younger patients and those with more advanced stages. These uptake patterns may allow future planning of health resource utilization and/or improvement of chemotherapy utilization rates.

Introduction Wait times in cancer care continue to be an important clinical, social, and political issue. This study examines wait times along the care path from suspicious imaging study (Detection) to adjuvant chemotherapy initiation (Chemotherapy) for patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgical resection. Methods A retrospective chart review of patients diagnosed in 2005 with NSCLC who underwent curative-intent surgery in Nova Scotia, Canada was conducted to abstract dates of care events (Detection, Surgery Consultation, Surgery, Medical Oncology [MO] Referral, MO Consultation and Chemotherapy) and patient characteristics. Multifactorial regression methods were used to identify statistically-significant cofactors associated with wait times at various resolutions of care intervals (low, intermediate, high). Results A median wait time of 141 days elapsed between Detection-Chemotherapy; and a median 107 and 52 days elapsed between Detection-Surgery and Surgery-Chemotherapy, respectively. A number of demographic, clinical, epidemiological, and system resource dependant factors influenced wait times at different resolutions, and were best detailed utilizing high resolution analysis. Wait time between MO referral-MO Consultation was inversely related to that experienced in the preceding interval of Surgery-MO Referral. Conclusions This study provides a first detailed examination of wait times experienced by NSCLC patients undergoing curative-intent surgery according to care interval definitions; demonstrates the value of high care interval resolution analysis to detect bottlenecks in access to care; and reports on the interdependence of elapsed times between care events along the care path for cancer patients.

Background/Objective: Plasma apoB predicts the incidence of type 2 diabetes (T2D); however, the link between apoB-linpoproteins and risks for T2D remain unclear. Insulin resistance (IR) and compensatory hyperinsulinemia characterize prediabetes, and the involvement of an activated interleukin-1 (IL-1) family, mainly IL-1β and its receptor antagonist (IL-Ra), is well documented. ApoB-lipoproteins were reported to promote IL-1β secretion in immune cells; however, in vivo evidence is lacking. We hypothesized that obese subjects with hyperapoB have an activated IL-1 system that explains hyperinsulinemia and IR in these subjects. Subjects/Methods: We examined 81 well-characterized normoglycemic men and postmenopausal women (⩾27 kg m−2, 45–74 years, non-smokers, sedentary, free of chronic disease). Insulin secretion and sensitivity were measured by the gold-standard Botnia clamp, which is a combination of a 1-h intravenous glucose tolerance test (IVGTT) followed by 3-h hyperinsulinemic euglycemic clamp. Results: Plasma IL-1β was near detection limit (0.071–0.216 pg ml−1), while IL-1Ra accumulated at 1000-folds higher (77–1068 pg ml−1). Plasma apoB (0.34–1.80 g l−1) associated significantly with hypersinsulinemia (totalIVGTT: C-peptide r=0.27, insulin r=0.22), IR (M/I=−0.29) and plasma IL-1Ra (r=0.26) but not with IL-1β. Plasma IL-1Ra associated with plasma IL-1β (r=0.40), and more strongly with hyperinsulinemia and IR than apoB, while the association of plasma IL-1β was limited to second phase and total insulin secretion (r=0.23). Adjusting the association of plasma apoB to hyperinsulinemia and IR for IL-1Ra eliminated these associations. Furthermore, despite equivalent body composition, subjects with hyperapoB (⩾80th percentile, 1.14 g l−1) had higher C-peptide secretion and lower insulin sensitivity than those with low plasma apoB (⩽20th percentile, 0.78 g l−1). Adjustment for plasma IL-1 Ra eliminated all group differences. Conclusion: Plasma apoB is associated with hyperinsulinemia and IR in normoglycemic obese subjects, which is eliminated upon adjustment for plasma IL-1Ra. This may implicate the IL-1 family in elevated risks for T2D in obese subjects with hyperapoB.

Background C. difficile (C diff) infection results from antibiotic-induced changes in colonic microbiota. DAV131A, an oral adsorbent-based product, can sequester antibiotic (AB) residues in the gut and reduce mortality in a hamster model of moxifloxacin (MXF) or clindamycin (CM) induced C diffcolitis. We studied the link between changes of the bacterial diversity within the fecal microbiota and mortality in this model. Methods Male Syrian hamsters were administered 30 mg/kg MXF or 5 mg/kg CM subcutaneously once a day for 5 days (D1 to D5) and orally infected at D3 with 104C diffspores. They were orally administered various doses of DAV131A (0, and 200 to 900 mg/kg twice a day), from D1 to D8. Survival was monitored up to D16 and feces were collected (D1 and D3) to characterize the microbiota by 16S rRNA gene profiling. Changes of various α- (Shannon, Observed OTUs and Chao1) and β- (Bray-Curtis dissimilarity and [un]weighted UniFrac) diversity indices between D1 and D3 were obtained for each animal. We analyzed links between (i) DAV131A dose and changes of bacterial diversity and (ii) changes of bacterial diversity and mortality using non parametric tests and logistic regression. Results Data from 70 and 60 animals were available in the MXF and CM studies, among which 10 and 28 died, respectively. Increasing doses of DAV131A reduced mortality from 100% to 0% and reduced changes in bacterial diversity of the fecal microbiota. Very strong predictors of mortality were changes in Shannon and unweighted UniFrac indices, which were markedly less affected in hamsters who survived (see table below median (min; max) according to vital status and area under the ROC curve, AUROC). Conclusion The extent of AB-induced changes in gut bacterial diversity correlated with increased mortality in a hamster model of C diff colitis. Higher doses of DAV131A protected fecal microbiota disruption and hence mortality. Disclosures C. Burdet, Da Volterra: Consultant and Research Contractor, Consulting fee; N. Saint-Lu, Da Volterra: Employee, Salary; S. Sayah-Jeanne, Da Volterra: Employee, Salary; P. Hugon, Da Volterra: Employee, Salary; F. Sablier-Gallis, Da Volterra: Employee, Salary; S. Ferreira, Genoscreen: Employee, Salary; A. Andremont, Da Volterra: Consultant, Consulting fee; F. Mentré, Da Volterra: Consultant and Research Contractor, Consulting fee; J. De Gunzburg, Da Volterra: Consultant and Shareholder, Consulting fee

Introduction Inequalities in health attributable to inequalities in society have long been recognized. Typically, those most privileged experience better health, regardless of universal access to health care. Associations between social and material deprivation and mortality from all causes of death— a measure of population health, have been described for some regions of Canada. This study further examines the link between deprivation and health, focusing on major causes of mortality for both rural and urban populations. In addition, it quantifies the burden of premature mortality attributable to social and material deprivation in a Canadian setting where health care is accessible to all. Methods The study included 35,266 premature deaths (1995–2005), grouped into five causes and aggregated over census dissemination areas. Two indices of deprivation (social and material) were derived from six socioeconomic census variables. Premature mortality was modeled as a function of these deprivation indices using Poisson regression. Results Premature mortality increased significantly with increasing levels of social and material deprivation. The impact of material deprivation on premature mortality was similar in urban and rural populations, whereas the impact of social deprivation was generally greater in rural populations. There were a doubling in premature mortality for those experiencing a combination of the most extreme levels of material and social deprivation. Conclusions Socioeconomic deprivation is an important determinant of health equity and affects every segment of the population. Deprivation accounted for 40% of premature deaths. The 4.3% of the study population living in extreme levels of socioeconomic deprivation experienced a twofold increased risk of dying prematurely. Nationally, this inequitable risk could translate into a significant public health burden.

Background Arsenic in drinking water is a public health issue affecting hundreds of millions of people worldwide. This review summarizes 30 years of epidemiological studies on arsenic exposure in drinking water and the risk of bladder or kidney cancer, quantifying these risks using a meta-analytical framework. Methods Forty studies met the selection criteria. Seventeen provided point estimates of arsenic concentrations in drinking water and were used in a meta-analysis of bladder cancer incidence (7 studies) and mortality (10 studies) and kidney cancer mortality (2 studies). Risk estimates for incidence and mortality were analyzed separately using Generalized Linear Models. Predicted risks for bladder cancer incidence were estimated at 10, 50 and 150 μg/L arsenic in drinking water. Bootstrap randomizations were used to assess robustness of effect size. Results Twenty-eight studies observed an association between arsenic in drinking water and bladder cancer. Ten studies showed an association with kidney cancer, although of lower magnitude than that for bladder cancer. The meta-analyses showed the predicted risks for bladder cancer incidence were 2.7 [1.2–4.1]; 4.2 [2.1–6.3] and; 5.8 [2.9–8.7] for drinking water arsenic levels of 10, 50, and 150 μg/L, respectively. Bootstrapped randomizations confirmed this increased risk, but, lowering the effect size to 1.4 [0.35–4.0], 2.3 [0.59–6.4], and 3.1 [0.80–8.9]. The latter suggests that with exposures to 50 μg/L, there was an 83% probability for elevated incidence of bladder cancer; and a 74% probability for elevated mortality. For both bladder and kidney cancers, mortality rates at 150 ug/L were about 30% greater than those at 10 μg/L. Conclusion Arsenic in drinking water is associated with an increased risk of bladder and kidney cancers, although at lower levels (

Resume L’immunotherapie sublinguale (ITSL) constitue un traitement efficace des allergies respiratoires de type I. Pour identifier des adjuvants et des formulations susceptibles d’augmenter l’induction de tolerance par voie sublinguale, un premier criblage a ete effectue sur des cocultures de cellules dendritiques humaines derivees de monocytes et des lymphocytes T CD4+ naifs. Les molecules selectionnees ont ensuite ete testees dans un modele murin d’ITSL chez des souris BALB/c sensibilisees a l’ovalbumine. Dans ce modele, nous avons evalue l’impact de ces adjuvants et formulations sublinguaux sur l’hyperreactivite bronchique (mesuree par plethysmographie) l’inflammation pulmonaire (evaluee par histologie) et les reponses immunitaires de type Th2 (suivies par Elispot et Elisa). Quatre categories d’adjuvants, ayant la particularite d’induire la production d’IL-10 +/− IFNγ par les lymphocytes T CD4+ naifs (reponse T Reg/Th1) sont capables d’augmenter l’efficacite de l’ITSL in vivo chez la souris. Ces adjuvants comprennent l’association vitamine D3/dexamethasone, Lactobacillus plantarum, le ligand de TLR2 Pam3CSK4 et l’agoniste du recepteur TLR4 OM-294-BA-MP. Par ailleurs, une formulation mucoadhesive de l’antigene a base de maltodextrine de mais augmente l’induction de tolerance par voie sublinguale, en favorisant le ciblage des cellules dendritiques et la stimulation des lymphocytes T au niveau des ganglions cervicaux/submaxillaires drainants. En conclusion, une meilleure comprehension des reponses immunitaires specifiques de l’allergene au niveau de la muqueuse sublinguale permet d’envisager la conception de nouveaux vaccins sublinguaux. Ces vaccins du futur incorporeront des adjuvants T Reg/Th1, ainsi que des formulations galeniques mucoadhesives pour faciliter le ciblage des cellules dendritiques au niveau de la muqueuse sublinguale.

Background: UTC cancer rates in NS are amongst the highest in Canada. Understanding spatial variations in UTC risk is necessary to elucidate factors responsible for this excess risk. Arsenic (AS) i...

Environmental models often involve complex dynamic and spatial inputs and outputs. This raises specific issues when performing uncertainty and sensitivity analyses (SA). Based on appli- cations in flood risk assessment and agro-ecology, we present current research to adapt the methods of variance-based SA to such models. After recalling the basic principles, we propose a metamodelling approach of dynamic models based on a reduced-basis approximation of PDEs and we show how the error on the subsequent sensitivity indices can be quantified. We then present a mix of pragmatic and methodological solutions to perform the SA of a dynamic agro-climatic model with non standard input factors. SA is then applied to a flood risk model with spatially distributed inputs and outputs. Block sensitivity indices are defined and a precise relationship between these indices and their support size is established. Finally, we show how the whole support landscape and its key features can be incorporated in the SA of a spatial model., Les modèles environnementaux contiennent souvent des entrées-sorties complexes de par leur nature dynamique et spatiale, ce qui soulève des problèmes spécifiques pour leurs analyses d'incertitude et de sensibilité (AS). A partir d'applications en évaluation des risques d'inondation et en agro-écologie, nous présentons des recherches en cours pour adapter les méthodes d'AS à de tels modèles. Après un rappel des principes de base, nous proposons une approche de métamodélisation de modèles dynamiques basée sur une approximation par base réduite d'EDPs et nous montrons comment l'erreur sur les indices de sensibilité qui en découle peut être quantifiée. Nous présentons ensuite un cocktail de solutions pragmatiques et méthodologiques pour l'AS d'un modèle agro-climatique dynamique avec des facteurs d'entrée non standards. Puis l'AS est appliquée à un modèle de risque d'inondation avec des entrées-sorties spatialisées. On définit des indices de sensibilité par bloc et une relation précise est établie entre ces indices et leur taille de support. Enfin, nous montrons comment l'ensemble du paysage et de ses caractéristiques clés peut être incorpore à l'AS d'un modèle spatial.

Background: IL-10-inducing adjuvants could enhance the efficacy of allergy vaccines in establishing allergen-specific tolerance.The aim of this study wasto identify such adjuvants using in vitro cultures of human and murine cells and to evaluate them in a therapeutic murine model of sublingual immunotherapy (SLIT). Methods: Adjuvants stimulating IL-10 gene expression by human or murine immune cells were tested sublingually in BALB/c mice sensitized to ovalbumin (OVA), assessing the reduction in airway hyperresponsiveness (AHR) by whole-body plethysmography. The induction of regulatory T cells (Treg) was evaluated using phenotypic and functional assays. T-cell proliferation in cervical lymph nodes (LNs) was assessed following intravenous transfer of CFSE-labelled OVA-specific T cells and FACS analysis. Results: A combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3/Dex) as well as Lactobacillus plantarum were found to induce IL-10 production by human and murine dendritic cells (DCs). The former inhibits LPS-induced DC maturation, whereas L. plantarum induces DC maturation. Following stimulation with VitD3/Dex-pretreated DCs, CD4+ naïve T cells exhibit a Treg profile.In contrast, a Th1/Treg pattern of differentiation is observed in the presence of DCs treated with L. plantarum. Both adjuvants significantly enhance SLIT efficacy in mice, in association with either induction of Foxp3+ Treg cells (for VitD3/Dex) or proliferation of OVA-specific T cells in cervical LNs (for L. plantarum). Conclusions: Both VitD3/Dex and L. plantarum polarize naïve T cells towards IL-10-expressing T cells, through distinct mechanisms. As adjuvants, they both enhance SLIT efficacy in a murine asthma model.

Background Sublingual immunotherapy is a noninvasive and efficacious treatment of type I respiratory allergies. A murine model of sublingual immunotherapy is needed to understand better the immune mechanisms involved in successful immunotherapy and to assess second-generation candidate vaccines. Objective Herein, we developed a therapeutic murine model of sublingual immunotherapy in which we document the value of mucoadhesive formulations to enhance treatment efficacy. Methods BALB/c mice were sublingually treated with soluble or formulated ovalbumin before or after sensitization with ovalbumin. Airways hyperresponsiveness and lung inflammation were assessed by whole-body plethysmography and lung histology, respectively. Humoral and cellular immune responses were monitored by ELISA and ELISPOT techniques. Results Prophylactic sublingual administration of ovalbumin completely prevents airways hyperresponsiveness as well as IL-5 secretion and IgE induction. Therapeutic administration of ovalbumin as a solution via either the sublingual or oral route has a limited efficacy. In contrast, sublingual application of ovalbumin formulated with maltodextrin to enhance mucosal adhesion results in a major reduction of established airways hyperresponsiveness, lung inflammation, and IL-5 production in splenocytes. This mucoadhesive formulation significantly enhances ovalbumin-specific T-cell proliferation in cervical but not mesenteric lymph nodes, and IgA production in the lungs. Conclusion A mucoadhesive maltodextrin formulation of ovalbumin enhances priming of the local mucosal immune system and tolerance induction via the sublingual route. Clinical implications Mucoadhesive formulations offer the opportunity to improve dramatically sublingual immunotherapy in human beings, most particularly by simplifying immunization schemes.

Waiting times for cancer care continue to be an important issue for Canadians. We evaluated 2 cohorts of breast cancer patients to compare changes in elapsed times to care, to determine the proportion of patients who received their postoperative oncology consultation within the recommended time and to examine elapsed times between date of surgery and start of first adjuvant therapy.We conducted a retrospective chart review of all women with surgically treated breast cancer who were referred to a provincial cancer centre for adjuvant therapy. The first cohort comprised women referred between Sept. 1, 1999, and Sept. 1, 2000 (n = 342), and the second cohort comprised women referred between Sept. 1, 2003, and Sept. 1, 2004 (n = 295). A general linear model with a stepwise selection was used to identify dominant factors that influenced elapsed times; covariates included cohort period, age at diagnosis, place of residence, disease stage, type of surgery, type of adjuvant therapy, distance to cancer centre, median household income and mean education level.The overall median time from disease detection to the start of first adjuvant therapy for the combined cohorts was 96 days (quartiles 76, 122); this interval was longer for patients in the second cohort (90 v. 102 days, p0.001). For the combined cohorts, significantly more patients saw a radiation oncologist within the recommended time from date of surgery than did patients referred to a medical oncologist (82.7% v. 51.7%; p0.001). Patients who received adjuvant radiation therapy as their first adjuvant treatment waited longer from the date of definitive surgery to the start of treatment than did patients who received chemotherapy or hormonal treatment (77 v. 48 or 42 days; p0.001).The median elapsed time from the detection of breast cancer to the start of first adjuvant therapy was longer in the second cohort (referred in 2003/04) than in the first cohort (referred in 1999/2000). The proportion of patients whose first oncology consultation was within the recommended timeframe varied significantly according to type of oncology specialist, favouring radiation oncology. Despite this difference in access, patients whose first adjuvant therapy was systemic therapy experienced significantly shorter elapsed times from surgery to the start of adjuvant therapy than did patients whose first adjuvant therapy was radiation therapy.

6049 Background: Wait times along the care path for non-small cell lung cancer (NSCLC) may be influenced by changes in adjuvant chemotherapy (AdjC) uptake. The aims of this study were to examine ch...

6590 Background: Adjuvant chemotherapy in Non Small Cell Lung Cancer (NSCLC) has become a new standard of care. However, referral and utilization patterns for adjuvant chemotherapy outside of clinical trials remain unknown. Methods: All patients with NSCLC who underwent curative-intent surgery in Nova Scotia, Canada, in year 2005 were identified. Data were abstracted from the provincial cancer registry, and the patients’ charts at the two provincial cancer centers. A retrospective exploratory analysis was conducted utilizing logistic regression models to determine the statistically significant variables associated with referral to medical oncology and/or utilization of adjuvant chemotherapy. Results: 108 patients who underwent curative-intent surgery (67% lobectomy, 15% pneumonectomy, and 19% wedge resection) for NSCLC (38% IA, 23% IB, 4% IIA, 21% IIB, 12% IIIA, and 2% IIIB) were identified. The median age was 66 years, and 56% were males. Common histologies included adenocarcinoma (43%), squamous cell carcinoma (32%), large cell carcinoma (7%), and broncheoalveolar carcinoma (7%). A referral to medical oncology for consideration of adjuvant chemotherapy was observed in 41% (44/108) of all patients including 62% (41/66) of those with stage > IA. Lower referral rate was associated with older age, stage I, and wedge resection while higher referral rate was associated with younger age, more advanced stage, large cell carcinoma subtype, and pneumonectomy. Adjuvant chemotherapy was prescribed in 27% (29/108) of all patients, including 41% (27/66) of those with stage > IA, and in 66% (29/44) of the patients referred to medical oncology. Of those referred to medical oncology, older patients and those who underwent wedge resection were less likely to receive chemotherapy. Of all patients, higher chemotherapy utilization was associated with younger age and more advanced stages. Conclusions: Adjuvant chemotherapy utilization in patients with resected NSCLC is low overall, especially among older patients and those with early-stage disease. However, a high proportion of the patients referred to medical oncology receive chemotherapy. Improved referral rates to medical oncology may increase the overall utilization rates of adjuvant chemotherapy in NSCLC. No significant financial relationships to disclose.