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Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.

IntroductionOver the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model.MethodA specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement.ResultsA total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge.ConclusionEarly exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed.

Neutron tomography has emerged as a promising imaging technique for specific applications in bone research. Neutrons have a strong interaction with hydrogen, which is abundant in biological tissues, and they can penetrate through dense materials such as metallic implants. However, in addition to long imaging times, two factors have led to challenges in running in situ mechanical characterization experiments on bone tissue using neutron tomography: 1) the high water content in specimens reduces the visibility of internal trabecular structures; 2) the mechanical properties of bone are dependent on the hydration state of the tissue, with drying being reported to cause increased stiffness and brittleness. This study investigates the possibility of improving image quality in terms of neutron transmission and contrast between material phases by drying and rehydrating in heavy water. Rat tibiae and trabecular bovine bone plugs were imaged with neutron tomography at different hydration states and mechanical testing of the bone plugs was carried out to assess effects of drying and rehydration on the mechanical properties of bone. From analysis of image histograms, it was found that drying reduced the contrast between bone and soft tissue, but the contrast was restored with rehydration. Contrast-to-noise ratios and line profiles revealed that the contrast between bone tissue and background was reduced with increasing rehydration duration but remained sufficient for identifying internal structures as long as no free liquid was present inside the specimen. The mechanical analysis indicated that the proposed fluid exchange protocol had no adverse effects on the mechanical properties.

Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

Abstract The evolution of bone tissue quantity and quality in contact with the surface of orthopedic and dental implants is a strong determinant of the surgical outcome but remains difficult to be assessed quantitatively. The aim of this study was to investigate the performance of a quantitative ultrasound (QUS) method to measure bone-implant interface (BII) properties. A dedicated animal model considering coin-shaped titanium implants with two levels of surface roughness (smooth, S a = 0.49 µm and rough, S a = 3.5 µm) allowed to work with a reproducible geometry and a planar interface. The implants were inserted in rabbit femurs and tibiae for 7 or 13 weeks. The ultrasonic response of the BII was measured ex vivo, leading to the determination of the 2-D spatial variations of bone in contact with the implant surface. Histological analysis was carried out to determine the bone-implant contact (BIC) ratio. The amplitude of the echo was significantly higher after 7 weeks of healing time compared to 13 weeks, for both smooth (p

Indoor air quality is an important consideration for the health and well-being of building occupants, and the SARS CoV-2 pandemic highlighted the importance of maintaining proper ventilation in buildings. Air handling units (AHUs) are used to provide fresh air and maintain occupant comfort. The objective of this work was to study the evolution of filtration efficiency in an AHU fitted with bag filters, installed to treat office air in a low-energy building, over a 12-month period. The particulate filtration efficiency (PFE) and the microbial filtration efficiency (MFE) were quantified by measuring particle size distribution and bacterial and fungal concentration in the air circulating in the AHU. The resulting microbial concentration measurements in the fresh air (between 10²–103 CFU/m3 for fungi and around 103 CFU/m3 for bacteria) were higher than those in the extracted air from the offices (between 101 and 102 CFU/m3 for fungi and around 102 CFU/m3 for bacteria). The PFE and MFE measured were almost constant throughout the 12 months, with an increase of the filter pressure drop from 70 to 90 Pa. The PFE and MFE were quite comparable for a particle diameter. Therefore, the measurement of PFE is a reliable indicator of the MFE.

Abstract Long bone mineralization occurs through endochondral ossification, where a cartilage template mineralizes into bone‐like tissue with a hierarchical organization from the whole bone‐scale down to sub‐nano scale. Whereas this process has been extensively studied at the larger length scales, it remains unexplored at some of the smaller length scales. In this study, the changes in morphology, composition, and structure during embryonic mineralization of murine humeri are investigated using a range of high‐resolution synchrotron‐based imaging techniques at several length scales. With micro‐ and nanometer spatial resolution, the deposition of elements and the shaping of mineral platelets are followed. Rapid mineralization of the humeri occurs over approximately four days, where mineral to matrix ratio and calcium content in the most mineralized zone reach adult values shortly before birth. Interestingly, zinc is consistently found to be localized at the sites of ongoing new mineralization. The mineral platelets in the most recently mineralized regions are thicker, longer, narrower, and less aligned compared to those further into the mineralized region. In summary, this study demonstrates a specific spatial distribution of zinc, with highest concentration where new mineral is being deposited and that the newly formed mineral platelets undergo slight reshaping and reorganization during embryonic development.

Poor indoor air quality can have adverse effects on human health, especially in susceptible populations. The aim of this study was to measure the concentrations of dioxide carbon (CO2), fine particulate matter (PM2.5) and total volatile organic compounds (TVOCs) in situ in private healthcare and elderly care facilities. These pollutants were continuously measured in two rooms of six private healthcare facilities (general practitioner’s offices, dental offices and pharmacies) and four elderly care facilities (nursing homes) in two French urban areas during two seasons: summer and winter. The mean CO2 concentrations ranged from 764 ± 443 ppm in dental offices to 624 ± 198 ppm in elderly care facilities. The mean PM2.5 concentrations ranged from 13.4 ± 14.4 µg/m3 in dental offices to 5.7 ± 4.8 µg/m3 in general practitioner offices. The mean TVOC concentrations ranged from 700 ± 641 ppb in dental offices to 143 ± 239 ppb in general practitioner offices. Dental offices presented higher levels of indoor air pollutants, associated with the dental activities. Increasing the ventilation of these facilities by opening a window is probably an appropriate method for reducing pollutant concentrations and maintaining good indoor air quality.

Previous studies have described the chemical pollution in indoor air of healthcare and care facilities. From these studies, the main objective of this work was to conduct a quantitative health risk assessment of the chronic inhalation of chemical compounds by workers in healthcare and elderly care facilities (hospitals, dental and general practitioner offices, pharmacies and nursing homes). The molecules of interest were 36 volatile and 13 semi-volatile organic compounds. Several professional exposure scenarios were developed in these facilities. The likelihood and severity of side effects that could occur were assessed by calculating the hazard quotient for deterministic effects, and the excess lifetime cancer risk for stochastic effects. No hazard quotient was greater than 1. Three compounds had a hazard quotient above 0.1: 2-ethyl-1-hexanol in dental and general practitioner offices, ethylbenzene and acetone in dental offices. Only formaldehyde presented an excess lifetime cancer risk greater than 1 × 10−5 in dental and general practitioner offices (maximum value of 3.8 × 10−5 for general practitioners). The health risk for chronic inhalation of most compounds investigated did not appear to be of concern. Some values tend to approach the acceptability thresholds justifying a reflection on the implementation of corrective actions such as the installation of ventilation systems.

Better understanding of the local deformation of the bone network around metallic implants subjected to loading is of importance to assess the mechanical resistance of the bone-implant interface and limit implant failure. In this study, four titanium screws were osseointegrated into rat tibiae for 4 weeks and screw pullout was conducted in situ under x-ray microtomography, recording macroscopic mechanical behavior and full tomographies at multiple load steps before failure. Images were analyzed using Digital Volume Correlation (DVC) to access internal displacement and deformation fields during loading. A repeatable failure pattern was observed, where a ∼300–500 μm-thick envelope of bone detached from the trabecular structure. Fracture initiated close to the screw tip and propagated along the implant surface, at a distance of around 500 μm. Thus, the fracture pattern appeared to be influenced by the microstructure of the bone formed closely around the threads, which confirmed that the model is relevant for evaluating the effect of pharmacological treatments affecting local bone formation. Moreover, cracks at the tibial plateau were identified by DVC analysis of the tomographic images acquired during loading. Moderate strains were first distributed in the trabecular bone, which localized into higher strains regions with subsequent loading, revealing crack-formation not evident in the tomographic images. The in situ loading methodology followed by DVC is shown to be a powerful tool to study internal deformation and fracture behavior of the newly formed bone close to an implant when subjected to loading. A better understanding of the interface failure may help improve the outcome of surgical implants.

BackgroundThe exposure of house occupants to indoor air pollutants has increased in recent decades. Among microbiological contaminants, bacterial and fungal aerosols remain poorly studied and the debate on the impact of these aerosols on respiratory health is still open. This study aimed to assess the diversity of indoor microbial communities in relationship with the health of occupants.MethodsMeasurements were taken from dwellings of 2 cohorts in Brittany (France), one with children without any pathology and the other with children and adults with asthma. Thirty dust samples were analyzed by next generation sequencing with a 16S and 18S targeted metagenomics approach. Analysis of sequencing data was performed using qiime 2, and univariate and multivariate statistical analysis using R software and phyloseq package.ResultsA total of 2,637 prokaryotic (589 at genus level) and 2,153 eukaryotic taxa were identified (856 fungal taxa (39%) and 573 metazoa (26%)). The four main bacterial phyla were identified: Proteobacteria (53%), Firmicutes (27%), Actinobacteria (11%), Bacteroidetes (8%). Among Fungi, only 136 taxa were identified at genus level. Three main fungal phyla were identified: Ascomycota (84%), Basidiomycota (12%) and Mucoromycota (3%). No bacterial nor fungal phyla were significantly associated with asthma versus control group. A significant over representation in control group versus asthma was observed for Christensenellaceae family (p-value = 0.0015, adj. p-value = 0.033). Besides, a trend for over representation in control group was observed with Dermabacteraceae family (p-value = 0.0002, adj. p-value = 0.815).ConclusionsOur findings provide evidence that dust samples harbor a high diversity of human-associated bacteria and fungi. Molecular methods such as next generation sequencing are reliable tools for identifying and tracking the bacterial and fungal diversity in dust samples, a less easy strategy for the detection of eukaryotes at least using18S metagenomics approach. This study showed that the detection of some bacteria might be associated to indoor air of asthmatic patients. Regarding fungi, a higher number of samples and sequencing with more depth could allow reaching significant signatures.

The indoor air quality of healthcare and care facilities is poorly studied. The aim of this study was to qualitatively and quantitatively describe the chemical pollution and the microbiological contaminations of the indoor environment of these facilities. Methods: A wide range of chemical compounds (39 volatile and 13 semi-volatile organic compounds, carbon dioxide, fine particulate matter) and microorganisms (fungi and bacteria) were studied. Sampling campaigns were conducted in two French cities in summer 2018 and winter 2019 in six private healthcare facilities (general practitioner’s offices, dental offices, pharmacies) and four care facilities (nursing homes). Results: The highest median concentrations of chemical compounds (μg/m3) were measured for alcohols (ethanol: 378.9 and isopropanol: 23.6), ketones (acetone: 18.8), aldehydes (formaldehyde: 11.4 and acetaldehyde: 6.5) and terpenes (limonene: 4.3). The median concentration of PM2.5 was 9.0 µg/m3. The main bacteria of these indoor environments were Staphylococcus, Micrococcus and Bacillus genera, with median bacterial concentrations in the indoor air of 14 cfu/m3. The two major fungal genera were Cladosporium and Penicillium, with median fungal concentrations of 7 cfu/m3. Conclusions: Indoor air in healthcare and care facilities contains a complex mixture of many pollutants found in higher concentrations compared to the indoor air in French hospitals in a previous study.

Long-term stability of endosseous implants depends on successful bone formation, ingrowth and adaptation to the implant. Specifically, it will define the mechanical properties of the newly formed bone-implant interface. 3D imaging during mechanical loading tests (in situ loading) can improve the understanding of the local processes leading to bone damage and failure. In this study, titanium screws were implanted into rat tibiae and were allowed to integrate for 4 weeks with or without the addition of the growth factor Bone Morphogenetic Protein and the bisphosphonate Zoledronic Acid. Samples were subjected to in situ pullout using high-resolution synchrotron x-ray tomography at the Tomcat beamline (SLS, PSI, Switzerland) at 30 keV with 25 ms exposure time, resulting in a total acquisition time of 45 s per scan, with a 3.6 μm isotropic voxel size. Using a custom-made loading device positioned inside the beamline, screws were pulled out with 0.05 mm increment, acquiring multiple scans until rupture of the sample. The in situ loading protocol was adapted to ensure short imaging time, which enabled multiple samples to be tested with short loading steps, while keeping the total testing time low and reducing dose deposition. Higher trabecular bone content was quantified in the surrounding of the screw in the treated groups, which correlated with increased mechanical strength and stiffness. Differences in screw implantation, such as contact between threads and cortex as well as minor tilt of the screw were also correlated to the mechanical parameters. In situ loading enabled the investigation of crack propagation during the pullout, highlighting the mechanical behavior of the interface. Three typical crack types were observed: (1) rupture at the interface of trabecular and cortical bone tissues, close to the screw, (2) large crack inside the cortex connected to the implant, and (3) first failure away from the screw with cracks propagating toward the screw-bone interface. Mechanical properties of in vivo integrated bone-metal screws rely on a combination of multiple parameters that are difficult to identify and separate one from the other.

Epstein-Barr virus (EBV) is tightly associated with certain human cancers, but there is as yet no specific treatment against EBV-related diseases. The EBV-encoded EBNA1 protein is essential to maintain viral episomes and for viral persistence. As such, EBNA1 is expressed in all EBV-infected cells, and is highly antigenic. All infected individuals, including individuals with cancer, have CD8+ T cells directed towards EBNA1 epitopes, yet the immune system fails to detect and destroy cells harboring the virus. EBV immune evasion depends on the capacity of the Gly-Ala repeat (GAr) domain of EBNA1 to inhibit the translation of its own mRNA in cis, thereby limiting the production of EBNA1-derived antigenic peptides presented by the major histocompatibility complex (MHC) class I pathway. Here we establish a yeast-based assay for monitoring GAr-dependent inhibition of translation. Using this assay we identify doxorubicin (DXR) as a compound that specifically interferes with the GAr effect on translation in yeast. DXR targets the topoisomerase-II–DNA complexes and thereby causes genomic damage. We show, however, that the genotoxic effect of DXR and various analogs thereof is uncoupled from the effect on GAr-mediated translation control. This is further supported by the observation that etoposide and teniposide, representing another class of topoisomerase-II–DNA targeting drugs, have no effect on GAr-mediated translation control. DXR and active analogs stimulate, in a GAr-dependent manner, EBNA1 expression in mammalian cells and overcome GAr-dependent restriction of MHC class I antigen presentation. These results validate our approach as an effective high-throughput screening assay to identify drugs that interfere with EBV immune evasion and, thus, constitute candidates for treating EBV-related diseases, in particular EBV-associated cancers.

The porcine model is frequently used during development and validation of new spinal devices, because of its likeness to the human spine. These spinal devices are frequently composed of pedicle screws with a reputation for stable fixation but which can suffer pullouts during preclinical implantation on young animals, leading to high morbidity. With a view to identifying the best choices to optimize pedicle screw fixation in the porcine model, this study evaluates ex vivo the impact of weight (age) of the animal, the level of the vertebrae (lumbar or thoracic) and the type of screw anchorage (mono- or bi-cortical) on pedicle screw pullouts. Among the 80 pig vertebrae (90- and 140-day-old) tested in this study, the average screw pullout forces ranged between 419.9N and 1341.2N. In addition, statistical differences were found between test groups, pointing out the influence of the three parameters stated above. We found that the the more caudally the screws are positioned (lumbar level), the greater their pullout resistance is, moreover, screw stability increases with the age, and finally, the screws implanted with a mono-cortical anchorage sustained lower pullout forces than those implanted with a bi-cortical anchorage. We conclude that the best anchorage can be obtained with older animals, using a lumbar fixation and long screws traversing the vertebra and inducing bi-cortical anchorage. In very young animals, pedicle screw fixations need to be bi-cortical and more numerous to prevent pullout.

The increased expression of the Disintegrin and Metalloprotease ADAM12 has been associated with human cancers, however its role remain unclear. We have previously reported that ADAM12 expression is induced by the transforming growth factor, TGF-β and promotes TGF-β-dependent signaling through interaction with the type II receptor of TGF-β. Here we explore the implication of ADAM12 in TGF-β-mediated epithelial to mesenchymal transition (EMT), a key process in cancer progression. We show that ADAM12 expression is correlated with EMT markers in human breast cancer cell lines and biopsies. Using a non-malignant breast epithelial cell line (MCF10A), we demonstrate that TGF-β-induced EMT increases expression of the membrane-anchored ADAM12L long form. Importantly, ADAM12L overexpression in MCF10A is sufficient to induce loss of cell-cell contact, reorganization of actin cytoskeleton, up-regulation of EMT markers and chemoresistance. These effects are independent of the proteolytic activity but require the cytoplasmic tail and are specific of ADAM12L since overexpression of ADAM12S failed to induce similar changes. We further demonstrate that ADAM12L-dependent EMT is associated with increased phosphorylation of Smad3, Akt and ERK proteins. Conversely, inhibition of TGF-β receptors or ERK activities reverses ADAM12L-induced mesenchymal phenotype. Together our data demonstrate that ADAM12L is associated with EMT and contributes to TGF-β-dependent EMT by favoring both Smad-dependent and Smad-independent pathways.

Between 1994 and 2001, several experiments (ARCANE, SEFOS, INTERAFOS) were conducted to directly measure the general and mesoscale Lagrangian circulations over the Bay of Biscay abyssal plain and slopes. Two levels (~100 m and ~450 m) were selected to cover the North Atlantic Central Water range. Two types of Lagrangian instruments, drogued surface drifters tracked by satellite (Surdrift) and acoustically tracked subsurface floats (Rafos and Marvor), were used. Overall, more than 36 instrument-years were collected in the Bay of Biscay region (43-49°N, 01-12°W). The weak general circulation in the Bay of Biscay is seen to be highly influenced by the occurrence of several mesoscale coherent features, notably slope currents and eddies, and these affect the exchanges between the abyssal plain and the slopes. The objective of this paper is to depict some specific examples of the observed mesoscale field. Selected float trajectories are shown and used to discuss observations of slope currents and of both anticyclonic and cyclonic eddies. Slope currents exhibit alternation of poleward and equatorward directions, depending on both the period and the geographic area considered. Although the generation process of mesoscale eddies is difficult to observe unambiguously from Lagrangian instruments, eddies are nevertheless ubiquitous over the abyssal plain. Some characteristics of the observed cyclonic and anticyclonic eddies are presented. Smaller anticyclones, localised over the outer shelf and interpreted in terms of ajustment of slope water intrusions, are also depicted.

The CoPanFlu-France cohort of households was set up in 2009 to study the risk factors for infection by the pandemic influenza virus (H1N1pdm) in the French general population. The authors developed an integrative data-driven approach to identify individual, collective and environmental factors associated with the post-seasonal serological H1N1pdm geometric mean titer, and derived a nested case-control analysis to identify risk factors for infection during the first season. This analysis included 1377 subjects (601 households). The GMT for the general population was 47.1 (95% confidence interval (CI): 45.1, 49.2). According to a multivariable analysis, pandemic vaccination, seasonal vaccination in 2009, recent history of influenza-like illness, asthma, chronic obstructive pulmonary disease, social contacts at school and use of public transports by the local population were associated with a higher GMT, whereas history of smoking was associated with a lower GMT. Additionally, young age at inclusion and risk perception of exposure to the virus at work were identified as possible risk factors, whereas presence of an air humidifier in the living room was a possible protective factor. These findings will be interpreted in light of the longitudinal analyses of this ongoing cohort.

Abstract Background The risk of influenza infection depends on biological characteristics, individual or collective behaviors and the environmental context. The Cohorts for Pandemic Influenza (CoPanFlu) France study was set up in 2009 after the identification of the novel swine-origin A/H1N1 pandemic influenza virus. This cohort of 601 households (1450 subjects) representative for the general population aims at using an integrative approach to study the risk and characteristics of influenza infection as a complex combination of data collected from questionnaires regarding sociodemographic, medical, behavioral characteristics of subjects and indoor environment, using biological samples or environmental databases. Methods/Design Households were included between December 2009 and July 2010. The design of this study relies on systematic follow-up visits between influenza seasons and additional visits during influenza seasons, when an influenza-like illness is detected in a household via an active surveillance system. During systematic visits, a nurse collects individual and environmental data on questionnaires and obtains blood samples from all members of the household. When an influenza-like-illness is detected, a nurse visits the household three times during the 12 following days, and collects data on questionnaires regarding exposure and symptoms, and biological samples (including nasal swabs) from all subjects in the household. The end of the follow-up period is expected in fall 2012. Discussion The large amount of data collected throughout the follow-up will permit a multidisciplinary study of influenza infections. Additional data is being collected and analyzed in this ongoing cohort. The longitudinal analysis of these households will permit integrative analyses of complex phenomena such as individual, collective and environmental risk factors of infection, routes of transmission, or determinants of the immune response to infection or vaccination.

A better understanding of bone nanostructure around the bone-implant interface is essential to improve longevity of clinical implants and decrease failure risks. This study investigates the spatio-temporal evolution of mineral crystal thickness and plate orientation in newly formed bone around the surface of a metallic implant. Standardized coin-shaped titanium implants designed with a bone chamber were inserted into rabbit tibiae for 7 and 13 weeks. Scanning measurements with micro-focused small-angle X-ray scattering (SAXS) were carried out on newly formed bone close to the implant and in control mature cortical bone. Mineral crystals were thinner close to the implant (1.8 ± 0.45 nm at 7 weeks and 2.4 ± 0.57 nm at 13 weeks) than in the control mature bone tissue (2.5 ± 0.21 nm at 7 weeks and 2.8 ± 0.35 nm at 13 weeks), with increasing thickness over healing time (+30 % in 6 weeks). These results are explained by younger bone close to the implant, which matures during osseointegration. Thinner mineral crystals parallel to the implant surface within the first 100 µm indicate that the implant affects the ultrastructure of neighbouring bone , potentially due to heterogeneous interfacial stresses, and suggest a longer maturation process of bone tissue and difficulty in binding to the metal. The bone growth kinetics within the bone chamber was derived from the spatio-temporal evolution of bone tissue's nanostructure, coupled with microtomographic imaging. The findings indicate that understanding mineral crystal thickness or plate orientation can improve our knowledge of osseointegration. Image, graphical abstract [ABSTRACT FROM AUTHOR]