Comparison of different methods to forecast hospital bed needs

Objectives : This study compares three methods to forecast the number of acute somatic hospital beds needed in a Swiss academic hospital over the period 2010-2030. Design : Information about inpatient stays is provided through a yearly mandatory reporting of Swiss hospitals, containing anonymized data. Forecast of the numbers of beds needed compares a basic scenario relying on population projections with two other methods in use in our country that integrate additional hypotheses on future trends in admission rates and length of stay (LOS).

Development of Elispot and CFSE flow cytometric assays for detecting beryllium sensitivity

Background: Beryllium sensitization (BeS) is caused by exposure to beryllium in the workplace and may progress to chronic beryllium disease (CBD). This granulomatous lung disorder mimicks sarcoidosis clinically, but is characterized by beryllium specific CD4+ T-cells immune response. BeS is classically detected by beryllium lymphocyte proliferation test (BeLPT), but this assay requires radioactivity and is not very sensitive. In the context of a study aiming to evaluate if CBD patients are misdiagnosed as sarcoidosis patients in Switzerland, we developed EliSpot and CFSE beryllium flow cytometric test. Methods: 23 patients considered as having sarcoidosis (n = 21), CBD (n = 1) and possible CBD (n = 1) were enrolled. Elispot was performed using plate covered with gamma-IFN mAb. Cells were added to wells and incubated overnight at 37 °C with medium (neg ctrl), SEB (pos ctrl) or BeSO4 at 1, 10 and 100 microM. Anti-IFN-gamma biotinylated mAb were added and spots were visualized using streptavidinhorseradish peroxidase and AEC substrate reagent. Results were reported as spot forming unit (SFU). For Beryllium specific CFSE flow cytometry analysis, CFSE labelled cells were cultured in the presence of SEB and 1, 10 or 100 microM BeSO4. Unstimulated CFSE labeled cells were defined as controls. The cells were incubated for 6 days at 37 °C and 5% CO2. Surface labelling of T-lymphocytes and vivid as control of cells viability was performed at the time of harvest. Results: Using EliSpot technology, we were able to detect a BeS in 1/23 enrolled patients with a mean of 780 SFU (cut off value at 50 SFU). This positive result was confirmed using different concentration of BeSO4. Among the 23 patients tested, 22 showed negative results with EliSpot. Using CFSE flow cytometry, 1/7 tested patients showed a positive result with a beryllium specific CD4+ count around 30% versus 45% for SEB stimulation as positif control and 0.6 % for negative control. This patient was the one with a positive EliSpot assay. Conclusions: The preliminary data demonstrated the feasibility of Elispot and CFSE flow cytometry to detect BeS. The patient with a beryllium specific positive EliSpot and CFSE flow cytometry result had been exposed to beryllium at her workplace 20 years ago and is still regularly controlled for her pulmonary status. A positive BeLPT had already been described in 2001 in France for this patient. Further validation of these techniques are in progress.

Long-term in vivo regeneration of peripheral nerves through bioengineered nerve grafts.

Although autologous nerve graft is still the first choice strategy in nerve reconstruction, it has the severe disadvantage of the sacrifice of a functional nerve. Cell transplantation in a bioartificial conduit is an alternative strategy to improve nerve regeneration. Nerve fibrin conduits were seeded with various cell types: primary Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC). Two further control groups were fibrin conduits without cells and autografts. Conduits were used to bridge a 1 cm rat sciatic nerve gap in a long term experiment (16 weeks). Functional and morphological properties of regenerated nerves were investigated. A reduction in muscle atrophy was observed in the autograft and in all cell-seeded groups, when compared with the empty fibrin conduits. SC showed significant improvement in axon myelination and average fiber diameter of the regenerated nerves. dASC were the most effective cell population in terms of improvement of axonal and fiber diameter, evoked potentials at the level of the gastrocnemius muscle and regeneration of motoneurons, similar to the autografts. Given these results and other advantages of adipose derived stem cells such as ease of harvest and relative abundance, dASC could be a clinically translatable route towards new methods to enhance peripheral nerve repair.

Structural macro factors and the affine term structure of interest rates

This work consists of three essays investigating the ability of structural macroeconomic models to price zero coupon U.S. government bonds. 1. A small scale 3 factor DSGE model implying constant term premium is able to provide reasonable a fit for the term structure only at the expense of the persistence parameters of the structural shocks. The test of the structural model against one that has constant but unrestricted prices of risk parameters shows that the exogenous prices of risk-model is only weakly preferred. We provide an MLE based variance-covariance matrix of the Metropolis Proposal Density that improves convergence speeds in MCMC chains. 2. Affine in observable macro-variables, prices of risk specification is excessively flexible and provides term-structure fit without significantly altering the structural parameters. The exogenous component of the SDF is separating the macro part of the model from the term structure and the good term structure fit has as a driving force an extremely volatile SDF and an implied average short rate that is inexplicable. We conclude that the no arbitrage restrictions do not suffice to temper the SDF, thus there is need for more restrictions. We introduce a penalty-function methodology that proves useful in showing that affine prices of risk specifications are able to reconcile stable macro-dynamics with good term structure fit and a plausible SDF. 3. The level factor is reproduced most importantly by the preference shock to which it is strongly and positively related but technology and monetary shocks, with negative loadings, are also contributing to its replication. The slope factor is only related to the monetary policy shocks and it is poorly explained. We find that there are gains in in- and out-of-sample forecast of consumption and inflation if term structure information is used in a time varying hybrid prices of risk setting. In-sample yield forecast are better in models with non-stationary shocks for the period 1982-1988. After this period, time varying market price of risk models provide better in-sample forecasts. For the period 2005-2008, out of sample forecast of consumption and inflation are better if term structure information is incorporated in the DSGE model but yields are better forecasted by a pure macro DSGE model.

Spatial predictions of land-use transitions and associated threats to biodiversity: the case of forest regrowth in mountain grasslands

Question Can we predict where forest regrowth caused by abandonment of agricultural activities is likely to occur? Can we assess how it may conflict with grassland diversity hotspots? Location Western Swiss Alps (4003210m a.s.l.). Methods We used statistical models to predict the location of land abandonment by farmers that is followed by forest regrowth in semi-natural grasslands of the Western Swiss Alps. Six modelling methods (GAM, GBM, GLM, RF, MDA, MARS) allowing binomial distribution were tested on two successive transitions occurring between three time periods. Models were calibrated using data on land-use change occurring between 1979 and 1992 as response, and environmental, accessibility and socio-economic variables as predictors, and these were validated for their capacity to predict the changes observed from 1992 to 2004. Projected probabilities of land-use change from an ensemble forecast of the six models were combined with a model of plant species richness based on a field inventory, allowing identification of critical grassland areas for the preservation of biodiversity. Results Models calibrated over the first land-use transition period predicted the second transition with reasonable accuracy. Forest regrowth occurs where cultivation costs are high and yield potential is low, i.e. on steeper slopes and at higher elevations. Overlaying species richness with land-use change predictions, we identified priority areas for the management and conservation of biodiversity at intermediate elevations. Conclusions Combining land-use change and biodiversity projections, we propose applied management measures for targeted/identified locations to limit the loss of biodiversity that could otherwise occur through loss of open habitats. The same approach could be applied to other types of land-use changes occurring in other ecosystems.

Continuing declines in cancer mortality in the European Union

BACKGROUND: From 1988 to 1997 age-standardised total cancer mortality rates in the European Union (EU) fell by around 9% in both sexes. Available cancer mortality data in Europe up to 2002 allow a first check of the forecast of further declines in cancer mortality. PATIENTS AND METHODS: We considered trends in age-standardised mortality from major cancer sites in the EU during the period 1980-2002. RESULTS: For men, total cancer mortality, after a peak of 191.1/100,000 in 1987 declined to 177.8 in 1997 (-7%), and to 166.5 in 2002. Corresponding figures for females were 107.9/100,000, 100.5 and 95.2, corresponding to falls of 7% from 1987 to 1997, and to 5% from 1997 to 2002. Over the last 5 years, lung cancer declined by 1.9% per year in men, to reach 44.4/100,000, but increased by 1.7% in women, to reach 11.4. In 2002, for the first year, lung cancer mortality in women was higher than that for intestinal cancer (11.1/100,000), and lung cancer became the second site of cancer deaths in women after breast (17.9/100,000). From 1997 to 2002, appreciable declines were observed in mortality from intestinal cancer in men (-1.6% per year, to reach 18.8/100,000), and in women (-2.5%), as well as for breast (-1.7% per year) and prostate cancer (-1.4%). CONCLUSIONS: Despite the persisting rises in female lung cancer, the recent trends in cancer mortality in the EU are encouraging and indicate that an 11% reduction in total cancer mortality from 2000 to 2015 is realistic and possible.

Using species richness and functional traits predictions to constrain assemblage predictions from stacked species distribution models

Aim: Modelling species at the assemblage level is required to make effective forecast of global change impacts on diversity and ecosystem functioning. Community predictions may be achieved using macroecological properties of communities (MEM), or by stacking of individual species distribution models (S-SDMs). To obtain more realistic predictions of species assemblages, the SESAM framework suggests applying successive filters to the initial species source pool, by combining different modelling approaches and rules. Here we provide a first test of this framework in mountain grassland communities. Location: The western Swiss Alps. Methods: Two implementations of the SESAM framework were tested: a "Probability ranking" rule based on species richness predictions and rough probabilities from SDMs, and a "Trait range" rule that uses the predicted upper and lower bound of community-level distribution of three different functional traits (vegetative height, specific leaf area and seed mass) to constraint a pool of environmentally filtered species from binary SDMs predictions. Results: We showed that all independent constraints expectedly contributed to reduce species richness overprediction. Only the "Probability ranking" rule allowed slightly but significantly improving predictions of community composition. Main conclusion: We tested various ways to implement the SESAM framework by integrating macroecological constraints into S-SDM predictions, and report one that is able to improve compositional predictions. We discuss possible improvements, such as further improving the causality and precision of environmental predictors, using other assembly rules and testing other types of ecological or functional constraints.

Evaluation de la qualité de vie après prélèvement de la veine fémorale superficielle lors de reconstructions infra-inguinales [Quality of life after superficial femoral vein harvest for infra-inguinal reconstructions]

BACKGROUND: The superficial femoral vein (SFV) is a well-established alternative conduit for infra-inguinal reconstructivenous hypertension after SFV harvest may however result in significant morbidity. This study reports the efficiency of SFV as conduit for infra-inguinal reconstructions and characterize the anatomic and physiologic changes in harvest limbs and their relationship to the development of venous complications. METHODS: From May 1999 through November 2003, 23 SFV were harvested from 21 patients undergoing infra-inguinal reconstructions. Bypasses were controlled by regular duplex-ultrasound. The venous morbidity was assessed by measurements of leg circumferences, strain-gauge plethysmography and quality of life, investigated by the VEINES-QOL scale. RESULTS: At a mean follow-up of 10.4 months (range 1-56), primary, secondary patency and limb salvage rates of infra-inguinal bypasses using SFV are 71.4%, 76.2% and 85.7% respectively. No patient had major venous claudication. Oedema was significantly present in nine patients. Strain-gauge plethysmography showed outflow obstruction in all patients. The VEINES-QOL assessment showed no limitation in social and domestic activity, moderate complain about leg heaviness despite presence of oedema. CONCLUSION: The SFV harvest is a reliable conduit for infra-inguinal reconstructions and results in moderate venous morbidity in terms of functional consequences and quality of life.

Phylogeographic patterning of mtDNA in the widely distributed harvest mouse (Micromys minutus) suggests dramatic cycles of range contraction and expansion during the mid- to late Pleistocene

We examined sequence variation in the mitochondrial cytochrome b gene (1140 bp, n = 73) and control region (842-851 bp, n = 74) in the Eurasian harvest mouse (Micromys minutus (Pallas, 1771)), with samples drawn from across its range, from Western Europe to Japan. Phylogeographic analyses revealed region-specific haplotype groupings combined with overall low levels of inter-regional genetic divergence. Despite the enormous intervening distance, European and East Asian samples showed a net nucleotide divergence of only 0.36%. Based on an evolutionary rate for the cytochrome b gene of 2.4%(.)(site(.)lineage(.)million years)(-1), the initial divergence time of these populations is estimated at around 80 000 years before present. Our findings are consistent with available fossil evidence that has recorded repeated cycles of extinction and recolonization of Europe by M. minutus through the Quaternary. The molecular data further suggest that recolonization occurred from refugia in the Central to East Asian region. Japanese haplotypes of M. minutus, with the exception of those from Tsushima Is., show limited nucleotide diversity (0.15%) compared with those found on the adjacent Korean Peninsula. This finding suggests recent colonization of the Japanese Archipelago, probably around the last glacial period, followed by rapid population growth.

Harvest site influences the growth properties of adipose derived stem cells.

The therapeutic potential of adult stem cells may become a relevant option in clinical care in the future. In hand and plastic surgery, cell therapy might be used to enhance nerve regeneration and help surgeons and clinicians to repair debilitating nerve injuries. Adipose-derived stem cells (ASCs) are found in abundant quantities and can be harvested with a low morbidity. In order to define the optimal fat harvest location and detect any potential differences in ASC proliferation properties, we compared biopsies from different anatomical sites (inguinal, flank, pericardiac, omentum, neck) in Sprague-Dawley rats. ASCs were expanded from each biopsy and a proliferation assay using different mitogenic factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) was performed. Our results show that when compared with the pericardiac region, cells isolated from the inguinal, flank, omental and neck regions grow significantly better in growth medium alone. bFGF significantly enhanced the growth rate of ASCs isolated from all regions except the omentum. PDGF had minimal effect on ASC proliferation rate but increases the growth of ASCs from the neck region. Analysis of all the data suggests that ASCs from the neck region may be the ideal stem cell sources for tissue engineering approaches for the regeneration of nervous tissue.

Identification of new MHC class I-restricted human tumor antigens for immunotherapy

Summary Cancer is a leading cause of morbidity and mortality in Western countries (as an example, colorectal cancer accounts for about 300'000 new cases and 200'000 deaths each year in Europe and in the USA). Despite that many patients with cancer have complete macroscopic clearance of their disease after resection, radiotherapy and/or chemotherapy, many of these patients develop fatal recurrence. Vaccination with immunogenic peptide tumor antigens has shown encouraging progresses in the last decade; immunotherapy might therefore constitute a fourth therapeutic option in the future. We dissect here and critically evaluate the numerous steps of reverse immunology, a forecast procedure to identify antigenic peptides from the sequence of a gene of interest. Bioinformatic algorithms were applied to mine sequence databases for tumor-specific transcripts. A quality assessment of publicly available sequence databanks allowed defining strengths and weaknesses of bioinformatics-based prediction of colon cancer-specific alternative splicing: new splice variants could be identified, however cancer-restricted expression could not be significantly predicted. Other sources of target transcripts were quantitatively investigated by polymerase chain reactions, as cancer-testis genes or reported overexpressed transcripts. Based on the relative expression of a defined set of housekeeping genes in colon cancer tissues, we characterized a precise procedure for accurate normalization and determined a threshold for the definition of significant overexpression of genes in cancers versus normal tissues. Further steps of reverse immunology were applied on a splice variant of the Melan¬A gene. Since it is known that the C-termini of antigenic peptides are directly produced by the proteasome, longer precursor and overlapping peptides encoded by the target sequence were synthesized chemically and digested in vitro with purified proteasome. The resulting fragments were identified by mass spectroscopy to detect cleavage sites. Using this information and based on the available anchor motifs for defined HLA class I molecules, putative antigenic peptides could be predicted. Their relative affinity for HLA molecules was confirmed experimentally with functional competitive binding assays and they were used to search patients' peripheral blood lymphocytes for the presence of specific cytolytic T lymphocytes (CTL). CTL clones specific for a splice variant of Melan-A could be isolated; although they recognized peptide-pulsed cells, they failed to lyse melanoma cells in functional assays of antigen recognition. In the conclusion, we discuss advantages and bottlenecks of reverse immunology and compare the technical aspects of this approach with the more classical procedure of direct immunology, a technique introduced by Boon and colleagues more than 10 years ago to successfully clone tumor antigens.

Forecasting changes in population genetic structure of alpine plants in response to global warming.

Species range shifts in response to climate and land use change are commonly forecasted with species distribution models based on species occurrence or abundance data. Although appealing, these models ignore the genetic structure of species, and the fact that different populations might respond in different ways because of adaptation to their environment. Here, we introduced ancestry distribution models, that is, statistical models of the spatial distribution of ancestry proportions, for forecasting intra-specific changes based on genetic admixture instead of species occurrence data. Using multi-locus genotypes and extensive geographic coverage of distribution data across the European Alps, we applied this approach to 20 alpine plant species considering a global increase in temperature from 0.25 to 4 °C. We forecasted the magnitudes of displacement of contact zones between plant populations potentially adapted to warmer environments and other populations. While a global trend of movement in a north-east direction was predicted, the magnitude of displacement was species-specific. For a temperature increase of 2 °C, contact zones were predicted to move by 92 km on average (minimum of 5 km, maximum of 212 km) and by 188 km for an increase of 4 °C (minimum of 11 km, maximum of 393 km). Intra-specific turnover-measuring the extent of change in global population genetic structure-was generally found to be moderate for 2 °C of temperature warming. For 4 °C of warming, however, the models indicated substantial intra-specific turnover for ten species. These results illustrate that, in spite of unavoidable simplifications, ancestry distribution models open new perspectives to forecast population genetic changes within species and complement more traditional distribution-based approaches.

Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'.

The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P<0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P<0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P<0.01) if WBI was given with >6 MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis.

Spatial relationship between the atmospheric circulation and the precipitation measured in the western Swiss Alps by means of the analogue method

An adaptation technique based on the synoptic atmospheric circulation to forecast local precipitation, namely the analogue method, has been implemented for the western Swiss Alps. During the calibration procedure, relevance maps were established for the geopotential height data. These maps highlight the locations were the synoptic circulation was found of interest for the precipitation forecasting at two rain gauge stations (Binn and Les Marécottes) that are located both in the alpine Rhône catchment, at a distance of about 100 km from each other. These two stations are sensitive to different atmospheric circulations. We have observed that the most relevant data for the analogue method can be found where specific atmospheric circulation patterns appear concomitantly with heavy precipitation events. Those skilled regions are coherent with the atmospheric flows illustrated, for example, by means of the back trajectories of air masses. Indeed, the circulation recurrently diverges from the climatology during days with strong precipitation on the southern part of the alpine Rhône catchment. We have found that for over 152 days with precipitation amount above 50 mm at the Binn station, only 3 did not show a trajectory of a southerly flow, meaning that such a circulation was present for 98% of the events. Time evolution of the relevance maps confirms that the atmospheric circulation variables have significantly better forecasting skills close to the precipitation period, and that it seems pointless for the analogue method to consider circulation information days before a precipitation event as a primary predictor. Even though the occurrence of some critical circulation patterns leading to heavy precipitation events can be detected by precursors at remote locations and 1 week ahead (Grazzini, 2007; Martius et al., 2008), time extrapolation by the analogue method seems to be rather poor. This would suggest, in accordance with previous studies (Obled et al., 2002; Bontron and Obled, 2005), that time extrapolation should be done by the Global Circulation Model, which can process atmospheric variables that can be used by the adaptation method.

Psychiatrie sous double contrainte, enjeux de la planification en santé mentale [Psychiatry under double bind, issue of the planification in mental health]

Given the important modifications of the "Loi sur l'Assurance maladie (LAMal)", this article gives a contribution to the hospital planification by identifying the main factors that have determined the current organisation of the psychiatric care network. We notice a gap between the orientations of these networks and the funding scheme forecast in the framework of the LAMal. In order to preserve the progressions of these last years and to avoid the negative effects of a too restrictive funding act for the assignment of the public psychiatry, the planification must result in a consensus between the state, the insurances and the multiple actors of the mental health. Otherwise, this will be done to the detriment of the activities of secondary prevention, of coordination in the network, of support to the natural helpers, and of intervention to the vulnerable populations.