Ocular antisense oligonucleotide delivery by cationic nanoemulsion for improved treatment of ocular neovascularization: an in-vivo study in rats and mice.

The efficacy of an antisense oligonucleotide (ODN17) cationic nanoemulsion directed at VEGF-R2 to reduce neovascularization was evaluated using rat corneal neovascularization and retinopathy of prematurity (ROP) mouse models. Application of saline solution or scrambled ODN17 solution on eyes of rats led to the highest extent of corneal neovascularization. The groups treated with blank nanoemulsion or scrambled ODN17 nanoemulsion showed moderate inhibition in corneal neovascularization with no significant difference with the saline and scrambled ODN17 control solution groups, while the groups treated with ODN17 solution or Avastin® (positive ODN17 control) clearly elicited marked significant inhibition in corneal neovascularization confirming the results reported in the literature. The highest significant corneal neovascularization inhibition efficiency was noted in the groups treated with ODN17 nanoemulsion (topical and subconjunctivally). However, in the ROP mouse model, the ODN17 in PBS induced a 34% inhibition of retinal neovascularization when compared to the aqueous-vehicle-injected eyes. A significantly higher inhibition of vitreal neovascularization (64%) was observed in the group of eyes treated with ODN17 nanoemulsion. No difference in extent of neovascularization was observed between blank nanoemulsion, scrambled ODN17 nanoemulsion, vehicle or non-treated eyes. The overall results indicate that cationic nanoemulsion can be considered a promising potential ocular delivery system and an effective therapeutic tool of high clinical significance in the prevention and forthcoming treatment of ocular neovascular diseases.

Prévention quaternaire: agir est-il toujours justifié en médecine de famille [Quaternary prevention: is acting always justified in family medicine?].

Quaternary prevention aims to protect the patient or population against overmedicalisation. Quaternary prevention influences all the activities of family medicine by questioning the utility of primary prevention and early diagnosis, identifying the risks of creating new pathological entities and practicing a maximalist medicine. Family doctors can support quaternary prevention by focusing on their patients' priorities and the local resources of an efficient health system.

Counselling overweight and obese patients in primary care: a prospective cohort study.

BACKGROUND: Primary care physicians are well positioned to provide counselling for overweight and obese patients, but no prospective study has assessed the effectiveness of this counselling in primary care. We aimed to evaluate weight reduction counselling by primary care physicians, and its relationship with weight change and patients' behaviour to control weight. DESIGN: A prospective cohort study. METHODS: We enrolled 523 consecutive overweight and obese patients from two Swiss academic primary care clinics. Physicians and patients were blinded to the study aims. We assessed the use of 10 predefined counselling strategies for weight reduction, and weight change and behaviour to control weight after 1 year. RESULTS: Sixty-five per cent of patients received some form of weight reduction counselling whereas 35% received no counselling. A total of 407 patients completed the 1-year follow-up. Those who received counselling lost on average (SD) 1.0 (5.0) kg after 1 year, whereas those who were not advised gained 0.3 (5.0) kg (P = 0.02). In multivariate analysis, each additional counselling strategy was associated with a mean weight loss of 0.2 kg (95% confidence interval 0.03-0.4, P = 0.02). Patients counselled by their physician had more favourable behaviour to control weight than those not counselled, such as setting a target weight (56 versus 36%) or visiting a dietician (23 versus 10%, both P < 0.001). CONCLUSIONS: Weight reduction counselling by primary care physicians is associated with a modest weight loss and favourable behaviour to control weight. However, many obese and overweight patients receive no advice on weight loss during primary care visits.

Ecotoxicological approaches to assess the long-term effects of four anticancer drugs and metabolites on Daphnia pulex

The aquatic environment is exposed continuously and increasingly to chemical substances such as pharmaceuticals. These medical compounds are released into the environment after having being consumed and body-excreted by patients. Pharmaceutical residues are synthetic molecules that are not always removed by traditional sewage treatment processes and thus escape degradation. Among pharmaceuticals that escape sewage treatment plants (STPs), the anticancer drugs were measured in STP effluents and natural waters. In the aquatic environment, their long-term effects at low concentrations are sparsely known on non-target species. Tamoxifen is an anticancer drug that is widely prescribed worldwide for the prevention and treatment of hormone receptor-positive breast cancers. Two of its metabolites, i.e., endoxifen and 4-hydroxy- tamoxifen (4OHTam), have high pharmacological potency in vivo and such as tamoxifen, they are excreted via faeces by patients. Tamoxifen was measured in STP effluents and natural waters but, to the best of our knowledge, its metabolites concentrations in waters have never been reported. Imatinib is another and recent anticancer compound that targets specific tumour cells. This pharmaceutical is also body excreted and because of its increasing use in cancer treatment, imatinib may reach the natural water. The effects of tamoxifen and imatinib are unknown upon more than one generation of aquatic species. And the effects of 4OHTam, endoxifen have never been studied in ecotoxicology so far. The aims of this thesis were threefold. First, the sensitivity of D. pulex exposed to tamoxifen, 4OHTam, endoxifen or imatinib was assessed using ecotoxicological experiments. Ecotoxicology is the science that considers the toxic effects of natural or synthetic substances, such as pharmaceuticals, on organisms, populations, community and ecosystem. Acute and multigenerational (2-4 generations) tests were performed on daphnids considering several studied endpoints, such as immobilisation, size, reproduction, viability and intrinsic rate of natural increase. Additional prospective assays were designed to evaluate whether 1) low concentrations of tamoxifen and 4OHTam were able to induce toxic effects when used in combination, and 2) daphnids were able to recover when offspring were withdrawn from solutions carrying the pharmaceutical. Second, the stability of tamoxifen, 4OHTam and endoxifen in incubation medium was evaluated in solution exempted from daphnids. Because the nominal concentrations of tamoxifen, 4OHTam and endoxifen did not correspond to the measured, we provide a predictive method to estimate the concentrations of these chemicals during long-term ecotoxicological tests. Finally, changes in protein expressions were analysed in D. pulex exposed 2 or 7 seven days to tamoxifen using ecotoxicoproteomic experiments with a shot-gun approach inducing a peptide fractionation step. Our results show that tamoxifen, 4OHTam and endoxifen induced adverse effects in D. pulex at environmentally relevant concentrations. At very low concentrations, these molecules displayed unusual and teratogenic effects because morphological abnormalities were observed in offspring, such as thick and short antennas, curved spines, premature neonates and aborted eggs. Tamoxifen was the most toxic compound among the test chemicals, followed by 4OHTam, endoxifen and imatinib. Tamoxifen no-observed effect concentrations (NOECs) that were calculated for size, reproduction and intrinsic rate were below or in the range of the concentrations measured in natural waters, i.e., between 0.12 µg/L and 0.67 µg/L. For instance, the tamoxifen NOECs that were calculated for reproduction were between 0.67 and 0.72 µg/L, whereas the NOEC was < 0.15 µg/L when based on morphological abnormalities. The NOECs of 4OHTam were higher but still in the same order of magnitude as tamoxifen environmental concentrations, with a value of 1.48 µg/L. Endoxifen NOEC for the intrinsic rate of natural increase (r) and the reproduction were 0.4 and 4.3 µg/L, respectively. Daphnids that were withdrawn from tamoxifen and 4OHTam were not able to recover. Also, the reproduction of D. pulex was reduced when the treated animals were exposed to the combination of tamoxifen and 4OHTam while no effects were observed when these chemicals were tested individually at the same concentration. Among the anticancer drugs that were tested during this thesis, imatinib was the less toxic molecule towards D. pulex. No effects on size and reproduction were observed within two generations, except for the first whose reproduction decreased at the highest test concentration, i.e., 626 µg/L. Our results also underline the need to use measured or predicted concentrations instead of the nominal during aquatic experiments, particularly when lipophilic molecules are tested. Indeed, notable differences between nominal (i.e., theoretical) and measured concentrations were found with tamoxifen, 4OHTam and endoxifen at all test concentrations. A cost and time sustainable method was proposed to predict the test exposure levels of these chemicals during long-term experiments. This predictive method was efficient particularly for low concentrations, which corresponded to the test concentrations in multigenerational tests. In the ecotoxicoproteomic experiments a total of 3940 proteins were identified and quantified in D. pulex exposed to tamoxifen. These results are currently the largest dataset from D. pulex that is published and the results of proteomic analyses are available for the scientific community. Among these 3940 proteins, 189 were significantly different from controls. After protein annotation, we assumed that treated daphnids with tamoxifen had shifted cost-energy functions, such as reproduction, to maintain their basic metabolism necessary to survive. This metabolic cost hypothesis was supported by the presence of proteins involved in oxidative stress. Biomarkers for early detection of tamoxifen harmful effects on D. pulex were not discovered but the proteins of the vitellogenin-2 family (E9H8K5) and the ryanodine receptor (E9FTU9) are promising potential biomarkers because their expression was already modified after 2 days of treatment. In this thesis, the effects of tamoxifen, 4OHTam and endoxifen on daphnids raise questions about the potential impact of tamoxifen and 4OHTam in other aquatic ecosystems, and therefore, about metabolites in ecotoxicology. Because the NOECs were environmentally relevant, these results suggest that tamoxifen and 4OHTam may be interesting pharmaceuticals to consider in risk assessment. Our findings also emphasize the importance of performing long-term experiments and of considering multi-endpoints instead of the standard reproductive endpoint. Finally, we open the discussion about the importance to measure test exposures or not, during ecotoxicological studies. -- Les milieux aquatiques sont exposés continuellement à un nombre croissant de substances chimiques, notamment les médicaments issus de la médecine vétérinaire et humaine. Chez les patients, les substances administrées sont utilisées par le corps avant d'être éliminées par l'intermédiaire des excrétas dans le système d'eaux usées de la ville. Ces eaux rejoignent ensuite une station de traitement afin d'y éliminer les déchets. Dans le cas des molécules chimiques, il arrive que les processus de traitement d'eaux usées ne soient pas suffisamment efficaces et que ces molécules ne soient pas dégradées. Elles sont alors libérées dans le milieu aquatique avec les effluents de la station d'épuration. Une fois dans l'environnement, ces résidus de médicaments sont susceptibles d'induire des effets sur la faune et la flore aquatique, dont les conséquences à long terme et à faibles concentrations sont peu connues. Les anticancéreux sont une famille de médicaments qui peuvent échapper aux traitements des stations d'épuration et qui sont retrouvées dans le milieu aquatique naturel. Parmi ces substances, le tamoxifen est une molécule utilisée dans le monde entier pour prévenir et traiter les cancers hormonaux dépendant du sein, notamment. Une fois ingéré, le tamoxifen est transformé par le foie en métabolites dont deux d'entre eux, le 4-hydroxy-tamoxifen (4OHTam) et l'endoxifen, possèdent un affinité pour les récepteurs aux estrogènes et une efficacité sur les cellules tumorales supérieure au tamoxifen lui- même. Tout comme la molécule mère, ces métabolites sont principalement éliminés par l'intermédiaire des fèces. Le tamoxifen a déjà été mesuré dans les effluents de stations d'épuration et dans les eaux naturelles, mais aucune valeur n'a été reportée pour ses métabolites jusqu'à présent. Un autre anticancéreux, également éliminé par voie biliaire et susceptible d'atteindre l'environnement, est l'imatinib. Cette récente molécule a révolutionné le traitement et la survie des patients souffrant de leucémie myéloïde chronique et de tumeur stromales gastrointestinales. Les effets du tamoxifen et de l'imatinib sur plusieurs générations d'organismes aquatiques, tels que les microcrustacés Daphnia, sont inconnus et le 4OHTam et l'endoxifen n'ont même jamais été testés en écotoxicologie. Cette thèse s'est articulée autour de trois objectifs principaux. Premièrement, la sensibilité des D. pulex exposés au tamoxifen, 4OHTam, endoxifen et imatinib a été évaluée par l'intermédiaire de tests aigus et de tests sur deux à quatre générations. La mobilité, la taille, la reproduction, la viabilité et la croissance potentielle de la population ont été relevées au cours de ces expériences. Des tests supplémentaires, à but prospectifs, ont également été réalisés afin d'évaluer 1) la capacité de récupération des daphnies, lorsque leurs descendants ont été placés dans un milieu exempté de tamoxifen ou de 4OHTam, 2) les effets chez les daphnies exposées à une solution contenant de faibles concentration de tamoxifen et de 4OHTam mélangés. Le deuxième objectif a été d'évaluer la stabilité du tamoxifen, 4OHTam et endoxifen dilué dans le milieu des daphnies. Après analyses, les concentrations mesurées ne correspondaient pas aux concentrations nominales (c.-à-d., théoriques) et il a été nécessaire de développer une méthode efficace de prédiction des niveaux d'exposition lors de tests de longue durée réalisés avec ces trois molécules. Finalement, des changements dans l'expression des protéines chez des daphnies exposées au tamoxifen ont été investigués par l'intermédiaire d'expériences écotoxicoprotéomiques avec une approche dite de shot-gun avec une étape de fractionnement des protéines. Les résultats obtenus dans cette thèse montrent que le tamoxifen, le 4OHTam et l'endoxifen induisent des effets indésirables chez les daphnies à des niveaux d'exposition proches ou identiques aux concentrations du tamoxifen mesurées dans l'environnement, c'est-à-dire 0.12 et 0.67 µg/L de tamoxifen. Ces molécules ont induit des effets inhabituels tels que la production de : nouveau-nés anormaux, avec des antennes et des queues déformées, des prématurés et des oeufs avortés. Le tamoxifen fut la molécule la plus toxique pour les D. pulex suivie du 4OHTam, de l'endoxifen et enfin de l'imatinib. Lors des expériences sur plusieurs générations, les concentrations n'ayant statistiquement pas d'effet (c.à.d. NOEC en anglais) sur la taille, la reproduction et la croissance intrinsèque de la population étaient du même ordre de grandeur que les concentrations environnementales du tamoxifen. Par exemple, les NOECs du tamoxifen calculées pour la reproduction étaient de 0.67 et 0.72 µg/L, tandis que celle calculée sur la base des anomalies chez les nouveau-nés était < 0.15 µg/L. Les NOECs du 4OHTam se situaient entre 0.16 et 1.48 µg/L et celles de l'endoxifen pour la croissance intrinsèque de la population, ainsi que pour la reproduction, étaient de 0.4 et 4.3 µg/L, respectivement. Dans l'expérience basée sur la récupération des daphnies, la taille et la reproduction ont diminué bien que la descendance fût placée dans un milieu sans substances chimiques. Les daphnies exposées au mélange de tamoxifen et de 4OHTam ont produit moins de nouveau-nés que les contrôles, alors que ces concentrations n'ont pas induit d'effets lorsque testées individuellement. Finalement, l'imatinib n'a pas montré d'effets sur les deux générations testées. Seule la première génération exposée à la plus haute concentration (626 µg/L) a montré une diminution de la reproduction. Les résultats obtenus lors de l'évaluation de la stabilité du tamoxifen, 4OHTam et endoxifen dans le milieu des daphnies ont souligné l'importance d'utiliser des concentrations mesurées ou prédites en écotoxicologie. En effet, des différences notables entre concentrations nominales et mesurées ont été observées à toutes les concentrations et l'hypothèse d'un phénomène d'adsorption sur le verre des récipients a été posée. De ce fait, il a été nécessaire d'élaborer une méthode prédictive efficace et acceptable, en terme de temps et de coûts. Une régression polynomiale basée sur des concentrations mesurées et nominales a permis de prédire avec efficacité les faibles niveaux d'exposition utilisés lors d'expériences écotoxicologiques à long terme, sur plusieurs générations. Suite aux expériences d'écotoxicoprotéomiques, un total de 3940 protéines ont été identifiées et quantifiées chez des daphnies exposées au tamoxifen. Ce nombre est actuellement la plus large série de données publiées et mises à disposition pour la communauté scientifique. Parmi ces protéines, 189 sont significatives et possiblement reliées à des processus de reproduction et de stress. Sur cette base, nous avons émis l'hypothèse que les individus subissant un stress, lié à l'exposition au tamoxifen, ont utilisé leur énergie de base pour favoriser leur survie plutôt que la reproduction. Enfin, la détermination de bio-marqueurs exprimant des dommages précoces des daphnies exposées au tamoxifen n'a pas abouti en tant que telle, mais des protéines prometteuses, telle que la famille de viellogenin-2 (E9H8K5) et le récepteur à la ryanodine (E9FTU9), ont été exprimées après deux jours d'exposition déjà. Ces protéines pourraient faire l'objet d'investigations écotoxicoprotéomiques futures. Les résultats de cette thèse posent certaines questions quant au risque du tamoxifen, du 4OHTam et de l'endoxifen sur la faune et la flore aquatique et plus particulièrement sur les anticancéreux présents dans l'environnement. Les effets toxiques de ces molécules ont été observés à des concentrations environnementales et sur plusieurs générations. La question de considérer les métabolites, et ainsi les pro-médicaments, en écotoxicologie est soulevée, notamment parce que ces molécules peuvent être plus actives et efficaces que la molécule mère. Les expériences chroniques, sur plusieurs générations sont également à favoriser car elles offrent un meilleur reflet de la réalité environnementale que des essais aigus ou d'une génération. L'utilisation de la protéomique permet d'agrandir les connaissances sur les effets des médicaments à un niveau inférieur de l'organisation biologique et ainsi, de mieux comprendre de potentiels mécanismes d'action ou de déterminer de potentiels biomarqueurs. Finalement, il semble important de discuter de l'opportunité de mesurer les concentrations qui sont testées en écotoxicologie afin de ne pas sous-estimer le risque pour la faune et la flore aquatique.

The cardiovascular disease situation in Seychelles.

A rising frequency of cardiovascular diseases and related risk factors has been documented in Seychelles. This epidemiological transition to chronic diseases is believed to result from the aging of the population and from changes in lifestyle associated with a rapidly improving standard of living. Since 1990 a long-term national collaborative programme has been established for the prevention and control of cardiovascular diseases. It has been designed with a view to implementing a combination of population-based and specific, high-risk target-group strategies. Objectives have been formulated, and culturally acceptable multisectoral activities have been devised, along with plans for the monitoring of cardiovascular diseases and risk factors and for the evaluation of the programme as it proceeds.

Three-dimensional interpolation of soil data: fertility and pedomorphological features in southern Brazil

The graphical representation of spatial soil properties in a digital environment is complex because it requires a conversion of data collected in a discrete form onto a continuous surface. The objective of this study was to apply three-dimension techniques of interpolation and visualization on soil texture and fertility properties and establish relationships with pedogenetic factors and processes in a slope area. The GRASS Geographic Information System was used to generate three-dimensional models and ParaView software to visualize soil volumes. Samples of the A, AB, BA, and B horizons were collected in a regular 122-point grid in an area of 13 ha, in Pinhais, PR, in southern Brazil. Geoprocessing and graphic computing techniques were effective in identifying and delimiting soil volumes of distinct ranges of fertility properties confined within the soil matrix. Both three-dimensional interpolation and the visualization tool facilitated interpretation in a continuous space (volumes) of the cause-effect relationships between soil texture and fertility properties and pedological factors and processes, such as higher clay contents following the drainage lines of the area. The flattest part with more weathered soils (Oxisols) had the highest pH values and lower Al3+ concentrations. These techniques of data interpolation and visualization have great potential for use in diverse areas of soil science, such as identification of soil volumes occurring side-by-side but that exhibit different physical, chemical, and mineralogical conditions for plant root growth, and monitoring of plumes of organic and inorganic pollutants in soils and sediments, among other applications. The methodological details for interpolation and a three-dimensional view of soil data are presented here.

Title IV-B Child and Family Service Plan 2010 Annual Progress and Service Report, June 2010

In June 2009, the Iowa Department of Human Service (IDHS) developed a Child and Family Service Plan (CFSP) that sets forth the Department’s vision and goals to be accomplished for FYs 2010 through 2014. The purpose of the CFSP is to strengthen the States’ overall child welfare system and to facilitate the state’s integration of the programs that serve children and families into a comprehensive and continuum array of child welfare services from prevention and protection through permanency. These programs include title IV-B, subparts 1 and 2 of the Act, the Child Abuse Prevention and Treatment Act (CAPTA), the Chafee Foster Care Independence Program (CFCIP), and the Education and Training Vouchers (ETV) programs for older and/or former foster care youth. IDHS administers the IV-B, CAPTA, CFCIP and the ETV programs described within Iowa’s CFSP. Iowa’s Annual Progress and Services Report (APSR) provides an annual update on the progress made toward accomplishing the goals and objectives identified in the state’s CFSP for the previous fiscal year (2009-2010) and the planned activities for next fiscal year (2010-2011) .

Flow-microfluorometric monitoring of oligoclonal CD8+ T cell responses to an immunodominant Moloney leukemia virus-encoded epitope in vivo.

The TCR repertoire of CD8+ T cells specific for Moloney murine leukemia virus (M-MuLV)-associated Ags has been investigated in vitro and in vivo. Analysis of a large panel of established CD8+ CTL clones specific for M-MuLV indicated an overwhelming bias for V beta4 in BALB/c mice and for V beta5.2 in C57BL/6 mice. These V beta biases were already detectable in mixed lymphocyte:tumor cell cultures established from virus-immune spleen cells. Furthermore, direct ex vivo analysis of PBL from BALB/c or C57BL/6 mice immunized with syngeneic M-MuLV-infected tumor cells revealed a dramatic increase in CD8+ cells expressing V beta4 or V beta5.2, respectively. M-MuLV-specific CD8+ cells with an activated (CD62L-) phenotype persisted in blood of immunized mice for at least 2 mo, and exhibited decreased TCR and CD8 levels compared with their naive counterparts. In C57BL/6 mice, most M-MuLV-specific CD8+ CTL clones and immune PBL coexpressed V alpha3.2 in association with V beta5.2. Moreover, these V beta5.2+ V alpha3.2+ cells were shown to recognize the recently described H-2Db-restricted epitope (CCLCLTVFL) encoded in the leader sequence of the M-MuLV gag polyprotein. Collectively, our data demonstrate a highly restricted TCR repertoire in the CD8+ T cell response to M-MuLV-associated Ags in vivo, and suggest the potential utility of flow-microfluorometric analysis of V beta and V alpha expression in the diagnosis and monitoring of viral infections.

EULAR recommendations for the management of primary small and medium vessel vasculitis.

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

Seismic detection and characterization of landslides and other mass movements

Seismic methods used in the study of snow avalanches may be employed to detect and characterize landslides and other mass movements, using standard spectrogram/sonogram analysis. For snow avalanches, the spectrogram for a station that is approached by a sliding mass exhibits a triangular time/frequency signature due to an increase over time in the higher-frequency constituents. Recognition of this characteristic footprint in a spectrogram suggests a useful metric for identifying other mass-movement events such as landslides. The 1 June 2005 slide at Laguna Beach, California is examined using data obtained from the Caltech/USGS Regional Seismic Network. This event exhibits the same general spectrogram features observed in studies of Alpine snow avalanches. We propose that these features are due to the systematic relative increase in high-frequency energy transmitted to a seismometer in the path of a mass slide owing to a reduction of distance from the source signal. This phenomenon is related to the path of the waves whose high frequencies are less attenuated as they traverse shorter source-receiver paths. Entrainment of material in the course of the slide may also contribute to the triangular time/frequency signature as a consequence of the increase in the energy involved in the process; in this case the contribution would be a source effect. By applying this commonly observed characteristic to routine monitoring algorithms, along with custom adjustments for local site effects, we seek to contribute to the improvement in automatic detection and monitoring methods of landslides and other mass movements.

Detection of millimetric deformation using a terrestrial laser scanner: experiment and application to a rockfall event

Terrestrial laser scanning (TLS) is one of the most promising surveying techniques for rockslope characterization and monitoring. Landslide and rockfall movements can be detected by means of comparison of sequential scans. One of the most pressing challenges of natural hazards is combined temporal and spatial prediction of rockfall. An outdoor experiment was performed to ascertain whether the TLS instrumental error is small enough to enable detection of precursory displacements of millimetric magnitude. This consists of a known displacement of three objects relative to a stable surface. Results show that millimetric changes cannot be detected by the analysis of the unprocessed datasets. Displacement measurement are improved considerably by applying Nearest Neighbour (NN) averaging, which reduces the error (1¿) up to a factor of 6. This technique was applied to displacements prior to the April 2007 rockfall event at Castellfollit de la Roca, Spain. The maximum precursory displacement measured was 45 mm, approximately 2.5 times the standard deviation of the model comparison, hampering the distinction between actual displacement and instrumental error using conventional methodologies. Encouragingly, the precursory displacement was clearly detected by applying the NN averaging method. These results show that millimetric displacements prior to failure can be detected using TLS.

Recommendations for the use of ultrasound in rheumatoid arthritis: literature review and SONAR score experience.

Ultrasound (US) has become a useful tool in the detection of early disease, differential diagnosis, guidance of treatment decisions and treatment monitoring of rheumatoid arthritis (RA). In 2008, the Swiss Sonography in Arthritis and Rheumatism (SONAR) group was established to promote the use of US in inflammatory arthritis in clinical practice. A scoring system was developed and taught to a large number of Swiss rheumatologists who already contributed to the Swiss Clinical Quality Management (SCQM) database, a national patient register. This paper intends to give a Swiss consensus about best clinical practice recommendations for the use of US in RA on the basis of the current literature knowledge and experience with the Swiss SONAR score. Literature research was performed to collect data on current evidence. The results were discussed among specialists of the Swiss university centres and private practice, following a structured procedure. Musculoskelatal US was found to be very helpful in establishing the diagnosis and monitoring the evolution of RA, and to be a reliable tool if used by experienced examiners. It influences treatment decisions such as continuing, intensifying or stepping down therapy. The definite modalities of integrating US into the diagnosis and monitoring of RA treatments will be defined within a few years. There are, however, strong arguments to use US findings as of today in daily clinical care. Some practical recommendations about the use of US in RA, focusing on the diagnosis and the use of the SONAR score, are proposed.

Adherence to oral anticancer treatment: focus on quality of execution during continuous schema of treatment

Background and objective: Oral anti-cancer treatments have expanded rapidly over the last years. While taking oral tablets at home ensures a better quality of life, it also exposes patients to the risk of sub-optimal adherence. The objective of this study is to assess how well ambulatory cancer patients execute their prescribed dosing regimen while they are engaged with continuous anti-cancer treatments. Design: This is an on-going longitudinal study. Consecutive patients starting an oral treatment are proposed to enter the study by the oncologist. Then they are referred to the pharmacy, where their oral anticancer treatment is dispensed in a Medication Event Monitoring System (MEMSTM), which records date and time of each opening of the drug container. Electronically compiled dosing history data from the MEMS are summarized and used as feedback during semistructured interviews with the pharmacist, which are dedicated to prevention and management of side effects. Interviews are scheduled before each medical visit. Report of the interview is available to the oncologist via an on-line secured portal. Setting: Seamless care approach between a Multidisciplinary Oncology Center and the Pharmacy of an Ambulatory Care and Community Medicine Department. Main outcome measures: For each patient, the comparison between the electronically compiled dosing history and the prescribed regimen was summarized using a daily binary indicator indicating whether yes or no the patient has taken the medication as prescribed. Results: Study started in March 2008. Among 22 eligible patients, 19 were included (11 men, median age 63 years old) and 3 (14%) refused to participate. 15 patients were prescribed a QD regimen, 3 patients a BID and 1 patient switched from QD to BID during follow-up. Median follow up was 182 days (IQR 72-252). Early discontinuation happened in four patients: side effects (n = 1), psychiatric reasons (n = 1), cancer progression (n = 1) and death (n = 1). On average, the daily number of medications was taken as prescribed in 99% of the follow-up days. Conclusions: Execution of the prescribed dosing regimens was almost perfect during the first 6 months. Maintaining this high degree of regimen execution and persistence over time might however be challenging in this population and need therefore to be confirmed in larger and longer follow-up cohort studies.

Improvement of cardiovascular risk prediction: time to review current knowledge, debates, and fundamentals on how to assess test characteristics.

Cardiovascular risk assessment might be improved with the addition of emerging, new tests derived from atherosclerosis imaging, laboratory tests or functional tests. This article reviews relative risk, odds ratios, receiver-operating curves, posttest risk calculations based on likelihood ratios, the net reclassification improvement and integrated discrimination. This serves to determine whether a new test has an added clinical value on top of conventional risk testing and how this can be verified statistically. Two clinically meaningful examples serve to illustrate novel approaches. This work serves as a review and basic work for the development of new guidelines on cardiovascular risk prediction, taking into account emerging tests, to be proposed by members of the 'Taskforce on Vascular Risk Prediction' under the auspices of the Working Group 'Swiss Atherosclerosis' of the Swiss Society of Cardiology in the future.

A two-week workshop to promote cardiovascular disease prevention programs in countries with limited resources.

Training is a crucial tool for building the capacity necessary for prevention and control of cardiovascular diseases (CVDs) in developing countries. This paper summarizes some features of a 2-week workshop aimed at enabling local health professionals to initiate a comprehensive CVD prevention and control program in a context of limited resources. The workshops have been organized in the regions where CVD prevention programs are being contemplated, in cooperation with health authorities of the concerned regions. The workshop's content includes a broad variety of issues related to CVD prevention and control, and to program development. Strong emphasis is placed on "learning by doing," and groups of 5-6 participants conduct a small-scale epidemiological study during the first week; during the second week, they draft a virtual program of CVD prevention and control adapted to the local situation. This practice-oriented workshop focuses on building expertise among anticipated key players, strengthening networks among relevant health professionals, and advocating the urgent need to tackle the emerging CVD epidemic in developing countries.