The effect of a smoking ban introduction to environmental tobacco smoke exposure in Swiss hospitality workers : Abstracts of the 23rd Annual Conference of the International Society of Environmental Epidemiology (ISEE), September 13-16, 2011, Barcelona, Spain

Background and Aims: To protect the population from environmental tobacco smoke (ETS) Switzerland introduced a nationwide rather heterogeneous smoking ban in May 2010. The exposure situation of non-smoking hospitality workers before and after implementation of the new law is being assessed in a prospective cohort study. Methods: Exposure to ETS was measured using a novel method developed by the Institute for Work and Health in Lausanne. It is a passive sampler called MoNIC (Monitor of NICotine). The nicotine of the ETS is fixed onto a filter and transformed into salt of not volatile nicotine. Subsequently the number of passively smoked cigarettes is calculated. Badges were placed at the workplace as well as distributed to the participants for personal measuring. Additionally a salivary sample was taken to determine nicotine concentration. Results: At baseline Spearman's correlation between workplace and personal badge was 0.47. The average cigarette equivalents per day at the workplace obtained by badge significantly dropped from 5.1 (95%- CI: 2.4 to 7.9) at baseline to 0.3 (0.2 to 0.4) at first follow-up (n=29) three months later (p<0.001). For personal badges the number of passively smoked cigarettes declined from 1.5 (2.7 to 0.4) per day to 0.5 (0.3 to 0.8) (n=16).Salivary nicotine concentration in a subset of 13 participants who had worked on the day prior to the examination was 2.63 ng/ml before and 1.53 ng/ml after the ban (p=0.04). Spearman's correlation of salivary nicotine was 0.56 with workplace badge and 0.79 with personal badge concentrations. Conclusions: Workplace measurements clearly reflect the smoking regulation in a venue. The MoNIC badge proves to be a sensitive measuring device to determine personal ETS exposure and it is a demonstrative measure for communication with lay audiences and study participants as the number of passively smoked cigarettes is an easily conceivable result.

Rate and predictors of service disengagement in an epidemiological first-episode psychosis cohort.

OBJECTIVES: To assess the prevalence and predictors of service disengagement in a treated epidemiological cohort of first-episode psychosis (FEP) patients. METHODS: The Early Psychosis Prevention and Intervention Centre (EPPIC) in Australia admitted 786 FEP patients from January 1998 to December 2000. Treatment at EPPIC is scheduled for 18 months. Data were collected from patients' files using a standardized questionnaire. Seven hundred four files were available; 44 were excluded, because of a non-psychotic diagnosis at endpoint (n=43) or missing data on service disengagement (n=1). Rate of service disengagement was the outcome of interest, as well as pre-treatment, baseline, and treatment predictors of service disengagement, which were examined via Cox proportional hazards models. RESULTS: 154 patients (23.3%) disengaged from service. A past forensic history (Hazard ratio [HR]=1.69; 95%CI 1.17-2.45), lower severity of illness at baseline (HR=0.59; 95%CI 0.48-0.72), living without family at discharge (HR=1.75; 95%CI 1.22-2.50) and persistence of substance use disorder during treatment (HR=2.30; 95%CI 1.45-3.66) were significant predictors of disengagement from service. CONCLUSIONS: While engagement strategies are a core element in the treatment of first-episode psychosis, particular attention should be paid to these factors associated with disengagement. Involvement of the family in the treatment process, and focusing on reduction of substance use, need to be pursued in early intervention services.

Differential outcome of concurrent radiotherapy plus epidermal growth factor receptor inhibitors versus radiotherapy plus cisplatin in patients with human papillomavirus-related head and neck cancer.

BACKGROUND Human papillomavirus (HPV)-related head and neck cancer has been associated with an improved prognosis in patients treated with radiotherapy (RT) +/- chemotherapy (CT); however, RT combined with epidermal growth factor receptor (EGFR) inhibitors has not been fully studied in this group of patients. METHODS Immunohistochemical expression of p16 and PCR of HPV16 DNA were retrospectively analyzed in tumor blocks from 108 stage III/IV head and neck cancer patients treated with RT+CT (56) or RT+EGFR inhibitors (52). Disease-free survival (DFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. RESULTS DNA of HPV16 was found in 12 of 108 tumors (11%) and p16 positivity in 18 tumors (17%), with similar rates in both arms of treatment. After a median follow-up time of 35 months (range 6-135), p16-positive patients treated with RT+EGFR inhibitors showed improved survival compared with those treated with RT+CT (2-year OS 88% vs. 60%, HR 0.18; 95% CI 0.04 to 0.88; p = 0.01; and 2-year DFS 75% vs. 47%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.01). However, no differences were observed in p16-negative patients (2-year OS 56% vs. 53%, HR 0.97; 95% CI 0.55 to 1.7; p = 0.9; and 2-year DFS 43% vs. 45%, HR 0.99; 95% CI 0.57 to 1.7; p = 0.9). CONCLUSIONS This is the first study to show that p16-positive patients may benefit more from RT+EGFR inhibitors than conventional RT+CT. These results are hypothesis-generating and should be confirmed in prospective trials.

Levofloxacin versus ciprofloxacin, flucloxacillin, or vancomycin for treatment of experimental endocarditis due to methicillin-susceptible or -resistant Staphylococcus aureus.

Levofloxacin is the L isomer of ofloxacin, a racemic mixture in which the L stereochemical form carries the antimicrobial activity. Levofloxacin is more active than former quinolones against gram-positive bacteria, making it potentially useful against such pathogens. In this study, levofloxacin was compared to ciprofloxacin, flucloxacillin, and vancomycin for the treatment of experimental endocarditis due to two methicillin-susceptible Staphylococcus aureus (MSSA) and two methicillin-resistant S. aureus (MRSA) isolates. The four test organisms were susceptible to ciprofloxacin, the levofloxacin MICs for the organisms were low (0.12 to 0.25 mg/liter), and the organisms were killed in vitro by drug concentrations simulating both the peak and trough levels achieved in human serum (5 and 0.5 mg/liter, respectively) during levofloxacin therapy. Rats with aortic endocarditis were treated for 3 days. Antibiotics were injected with a programmable pump to simulate the kinetics of either levofloxacin (350 mg orally once a day), ciprofloxacin (750 mg orally twice a day), flucloxacillin (2 g intravenously four times a day), or vancomycin (1 g intravenously twice a day). Levofloxacin tended to be superior to ciprofloxacin in therapeutic experiments (P = 0.08). More importantly, levofloxacin did not select for resistance in the animals, in contrast to ciprofloxacin. The lower propensity of levofloxacin than ciprofloxacin to select for quinolone resistance was also clearly demonstrated in vitro. Finally, the effectiveness of this simulation of oral levofloxacin therapy was at least equivalent to that of standard treatment for MSSA or MRSA endocarditis with either flucloxacillin or vancomycin. This is noteworthy, because oral antibiotics are not expected to succeed in the treatment of severe staphylococcal infections. These good results obtained with animals suggest that levofloxacin might deserve consideration for further study in the treatment of infections due to ciprofloxacin-susceptible staphylococci in humans.

Reproducibility of straylight measurement by C-Quant for assessment of retinal straylight using the compensation comparison method.

BACKGROUND: Straylight gives the appearance of a veil of light thrown over a person's retinal image when there is a strong light source present. We examined the reproducibility of the measurements by C-Quant, and assessed its correlation to characteristics of the eye and subjects' age. PARTICIPANTS AND METHODS: Five repeated straylight measurements were taken using the dominant eye of 45 healthy subjects (age 21-59) with a BCVA of 20/20: 14 emmetropic, 16 myopic, eight hyperopic and seven with astigmatism. We assessed the extent of reproducibility of straylight measures using the intraclass correlation coefficient. RESULTS: The mean straylight value of all measurements was 1.01 (SD 0.23, median 0.97, interquartile range 0.85-1.1). Per 10 years of age, straylight increased in average by 0.10 (95%CI 0.04 to 0.16, p < 0.01]. We found no independent association of refraction (range -5.25 dpt to +2 dpt) on straylight values (0.001; 95%CI -0.022 to 0.024, p = 0.92). Compared to emmetropic subjects, myopia reduced straylight (-.011; -0.024 to 0.02, p = 0.11), whereas higher straylight values (0.09; -0.01 to 0.20, p = 0.09) were observed in subjects with blue irises as compared to dark-colored irises when correcting for age. The intraclass correlation coefficient (ICC) of repeated measurements was 0.83 (95%CI 0.76 to 0.90). CONCLUSIONS: Our study showed that straylight measurements with the C-Quant had a high reproducibility, i.e. a lack of large intra-observer variability, making it appropriate to be applied in long-term follow-up studies assessing the long-term effect of surgical procedures on the quality of vision.

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis.

INTRODUCTION Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

Concentrations plasmatiques et articulaires pendant l'administration de céfacétrile pour arthrite septique (6 cas) [Serum and joint levels of cefacetrile during its administration for septic arthritis]

Six patients, five of whom had normal and one impaired renal function, and all suffering from purulent arthritis caused by cephalosporin-sensitive germs, were given a seven-day course of 8 g cephacetrile daily. On the first day, 6 g were administered by continuous intravenous infusion at the rate of 500 mg/h, followed by 2 g over a further 45 min. On days 2 to 7, the patients received 2 short infusions of 4 g each at an interval of 12 h. In four patients with normal renal function, serum half-life ranged from 0.8 to 1.4 h, serum levels during continuous infusion from 19 to 31 microgram/ml, and total clearances from 265 to 434 ml/min. In one patients, these values were 1.6 h, 70 microgram/ml and 131 ml/min respectively (small volume of distribution). The concentrations in the synovial fluid varied from 2 to 29 mcirogram/ml; they were generally lower than the serum levels, but clearly exceeded the minimum inhibitory concentrations for germs commonly present in purulent arthritis. In five patients, the synovial fluid became germ-free and the arthritis was clinically cured. In the case presenting with renal insufficiency, the serum half-life was 5.8 h. During continuous administration, a steady state was not attained; peak serum levels amo9nted to 75 microgram/ml and the total clearance to 61 ml/min. The cephacetrile concentrations in the synovial fluid were very high (26 and 67 microgram/ml). In this case, in which the renal insufficiency associated with mycosis fungoides was present before the treatment, renal function deteriorated futher during treatment while the arthritis improved.

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.

Characteristics and effectiveness of diabetes self-management educational programs targeted to racial/ethnic minority groups: a systematic review, meta-analysis and meta-regression.

BACKGROUND It is not clear to what extent educational programs aimed at promoting diabetes self-management in ethnic minority groups are effective. The aim of this work was to systematically review the effectiveness of educational programs to promote the self-management of racial/ethnic minority groups with type 2 diabetes, and to identify programs' characteristics associated with greater success. METHODS We undertook a systematic literature review. Specific searches were designed and implemented for Medline, EMBASE, CINAHL, ISI Web of Knowledge, Scirus, Current Contents and nine additional sources (from inception to October 2012). We included experimental and quasi-experimental studies assessing the impact of educational programs targeted to racial/ethnic minority groups with type 2 diabetes. We only included interventions conducted in countries members of the OECD. Two reviewers independently screened citations. Structured forms were used to extract information on intervention characteristics, effectiveness, and cost-effectiveness. When possible, we conducted random-effects meta-analyses using standardized mean differences to obtain aggregate estimates of effect size with 95% confidence intervals. Two reviewers independently extracted all the information and critically appraised the studies. RESULTS We identified thirty-seven studies reporting on thirty-nine educational programs. Most of them were conducted in the US, with African American or Latino participants. Most programs obtained some benefits over standard care in improving diabetes knowledge, self-management behaviors and clinical outcomes. A meta-analysis of 20 randomized controlled trials (3,094 patients) indicated that the programs produced a reduction in glycated hemoglobin of -0.31% (95% CI -0.48% to -0.14%). Diabetes knowledge and self-management measures were too heterogeneous to pool. Meta-regressions showed larger reduction in glycated hemoglobin in individual and face to face delivered interventions, as well as in those involving peer educators, including cognitive reframing techniques, and a lower number of teaching methods. The long-term effects remain unknown and cost-effectiveness was rarely estimated. CONCLUSIONS Diabetes self-management educational programs targeted to racial/ethnic minority groups can produce a positive effect on diabetes knowledge and on self-management behavior, ultimately improving glycemic control. Future programs should take into account the key characteristics identified in this review.

CNS safety at 48-week of switching to ATV/r plus 3TC or two nucleos(t)ides in HIV-suppressed patients on stable ART: the SALT neurocognitive sub-study.

INTRODUCTION Due to their low CNS penetrance, there are concerns about the capacity of non-conventional PI-based ART (monotherapy and dual therapies) to preserve neurocognitive performance (NP). METHODS We evaluated the NP change of aviremic participants of the SALT clinical trial (1) switching therapy to dual therapy (DT: ATV/r+3TC) or triple therapy (TT: ATV/r+2NRTI) who agreed to perform an NP assessment (NPZ-5) at baseline and W48. Neurocognitive impairment and NP were assessed using AAN-2007 criteria (2) and global deficit scores (GDS) (3). Neurocognitive change (GDS change: W48 - baseline) and the effect of DT on NP evolution crude and adjusted by significant confounders were determined using ANCOVA. RESULTS A total of 158 patients were included (Table 1). They had shorter times because HIV diagnosis, ART initiation and HIV-suppression and their virologic outcome at W48 by snapshot was higher (79.1% vs 72.7%; p=0.04) compared to the 128 patients not included in the sub-study. By AAN-2007 criteria, 51 patients in each ART group (68% vs 63%) were neurocognitively impaired at baseline (p=0.61). Forty-seven patients were not reassessed at W48: 30 lost of follow-up (16 DT-14 TT) and 17 had non-evaluable data (6 DT-11 TT). Patients retested were more likely to be men (78.9% vs 61.4%) and had neurological cofounders (9.6% vs 0%) than patients non-retested. At W48, 3 out of 16 (5.7%) patients on DT and 6 out of 21 (10.5%) on TT who were non-impaired at baseline became impaired (p=0.49) while 10 out of 37 (18.9%) on DT and 7 out of 36 (12.3%) on TT who were neurocognitively impaired at baseline became non-impaired (p=0.44). Mean GDS changes (95% CI) were: Overall -0.2 (-0.3 to -0.04): DT -0.26 (-0.4 to -0.07) and TT -0.08 (-0.2 to 0.07). NP was similar between DT and TT (0.15). This absence of differences was also observed in all cognitive tests. Effect of DT: -0.16 [-0.38 to 0.06]) (r(2)=0.16) on NP evolution was similar to TT (reference), even after adjusting (DT: -0.11 [-0.33 to 0.1], TT: reference) by significant confounders (geographical origin, previous ATV use and CD4 cell count) (r(2)=0.25). CONCLUSIONS NP stability was observed after 48 weeks of follow up in the majority of patients whether DT or TT was used to maintain HIV-suppression. Incidence rates of NP impairment or NP impairment recovery were also similar between DT and TT.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Statistical similarity between the compression of a porous material and earthquakes

It has been long stated that there are profound analogies between fracture experiments and earthquakes; however, few works attempt a complete characterization of the parallelisms between these so separate phenomena. We study the Acoustic Emission events produced during the compression of Vycor (SiO&sub&2&/sub&). The Gutenberg-Richter law, the modified Omori's law, and the law of aftershock productivity hold for a minimum of 5 decades, are independent of the compression rate, and keep stationary for all the duration of the experiments. The waiting-time distribution fulfills a unified scaling law with a power-law exponent close to 2.45 for long times, which is explained in terms of the temporal variations of the activity rate.

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE: To identify the optimal CD4 cell count at which cART should be initiated. DESIGN: Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING: HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS: 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS: Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS: Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations: CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION: Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Application of low temperature thermochronology to understanding cooling and exhumation in the Central Swiss Alps

THESIS ABSTRACT : Low-temperature thermochronology relies on application of radioisotopic systems whose closure temperatures are below temperatures at which the dated phases are formed. In that sense, the results are interpreted as "cooling ages" in contrast to "formation ages". Owing to the low closure-temperatures, it is possible to reconstruct exhumation and cooling paths of rocks during their residence at shallow levels of the crust, i.e. within first ~10 km of depth. Processes occurring at these shallow depths such as final exhumation, faulting and relief formation are fundamental for evolution of the mountain belts. This thesis aims at reconstructing the tectono-thermal history of the Aar massif in the Central Swiss Alps by means of zircon (U-Th)/He, apatite (U-Th)/He and apatite fission track thermochronology. The strategy involved acquisition of a large number of samples from a wide range of elevations in the deeply incised Lötschen valley and a nearby NEAT tunnel. This unique location allowed to precisely constrain timing, amount and mechanisms of exhumation of the main orographic feature of the Central Alps, evaluate the role of topography on the thermochronological record and test the impact of hydrothermal activity. Samples were collected from altitudes ranging between 650 and 3930 m and were grouped into five vertical profiles on the surface and one horizontal in the tunnel. Where possible, all three radiometric systems were applied to each sample. Zircon (U-Th)/He ages range from 5.1 to 9.4 Ma and are generally positively correlated with altitude. Age-elevation plots reveal a distinct break in slope, which translates into exhumation rate increasing from ~0.4 to ~3 km/Ma at 6 Ma. This acceleration is independently confirmed by increased cooling rates on the order of 100°C/Ma constrained on the basis of age differences between the zircon (U-Th)/He and the remaining systems. Apatite fission track data also plot on a steep age-elevation curve indicating rapid exhumation until the end of the Miocene. The 6 Ma event is interpreted as reflecting tectonically driven uplift of the Aar massif. The late Miocene timing implies that the increase of precipitation in the Pliocene did not trigger rapid exhumation in the Aar massif. The Messinian salinity crisis in the Mediterranean could not directly intensify erosion of the Aar but associated erosional output from the entire Alps may have tapered the orogenic wedge and caused reactivation of thrusting in the Aar massif. The high exhumation rates in the Messinian were followed by a decrease to ~1.3 km/Ma as evidenced by ~8 km of exhumation during last 6 Ma. The slowing of exhumation is also apparent from apatite (U-Th)1He age-elevation data in the northern part of the Lötschen valley where they plot on a ~0.5km/Ma line and range from 2.4 to 6.4 Ma However, from the apatite (U-Th)/He and fission track data from the NEAT tunnel, there is an indication of a perturbation of the record. The apatite ages are youngest under the axis of the valley, in contrast to an expected pattern where they would be youngest in the deepest sections of the tunnel due to heat advection into ridges. The valley however, developed in relatively soft schists while the ridges are built of solid granitoids. In line with hydrological observations from the tunnel, we suggest that the relatively permeable rocks under the valley floor, served as conduits of geothermal fluids that caused reheating leading to partial Helium loss and fission track annealing in apatites. In consequence, apatite ages from the lowermost samples are too young and the calculated exhumation rates may underestimate true values. This study demonstrated that high-density sampling is indispensable to provide meaningful thermochronological data in the Alpine setting. The multi-system approach allows verifying plausibility of the data and highlighting sources of perturbation. RÉSUMÉ DE THÈSE : La thermochronologie de basse température dépend de l'utilisation de systèmes radiométriques dont la température de fermeture est nettement inférieure à la température de cristallisation du minéral. Les résultats obtenus sont par conséquent interprétés comme des âges de refroidissement qui diffèrent des âges de formation obtenus par le biais d'autres systèmes de datation. Grâce aux températures de refroidissement basses, il est aisé de reconstruire les chemins de refroidissement et d'exhumation des roches lors de leur résidence dans la croute superficielle (jusqu'à 10 km). Les processus qui entrent en jeu à ces faibles profondeurs tels que l'exhumation finale, la fracturation et le faillage ainsi que la formation du relief sont fondamentaux dans l'évolution des chaînes de montagne. Ces dernières années, il est devenu clair que l'enregistrement thermochronologique dans les orogènes peut être influencé par le relief et réinitialisé par l'advection de la chaleur liée à la circulation de fluides géothermaux après le refroidissement initial. L'objectif de cette thèse est de reconstruire l'histoire tectono-thermique du massif de l'Aar dans les Alpes suisses Centrales à l'aide de trois thermochronomètres; (U-Th)/He sur zircon, (U-Th)/He sur apatite et les traces de fission sur apatite. Afin d'atteindre cet objectif, nous avons récolté un grand nombre d'échantillons provenant de différentes altitudes dans la vallée fortement incisée de Lötschental ainsi que du tunnel de NEAT. Cette stratégie d'échantillonnage nous a permis de contraindre de manière précise la chronologie, les quantités et les mécanismes d'exhumation de cette zone des Alpes Centrales, d'évaluer le rôle de la topographie sur l'enregistrement thermochronologique et de tester l'impact de l'hydrothermalisme sur les géochronomètres. Les échantillons ont été prélevés à des altitudes comprises entre 650 et 3930m selon 5 profils verticaux en surface et un dans le tunnel. Quand cela à été possible, les trois systèmes radiométriques ont été appliqués aux échantillons. Les âges (U-Th)\He obtenus sur zircons sont compris entre 5.l et 9.4 Ma et sont corrélés de manière positive avec l'altitude. Les graphiques représentant l'âge et l'élévation montrent une nette rupture de la pente qui traduisent un accroissement de la vitesse d'exhumation de 0.4 à 3 km\Ma il y a 6 Ma. Cette accélération de l'exhumation est confirmée par les vitesses de refroidissement de l'ordre de 100°C\Ma obtenus à partir des différents âges sur zircons et à partir des autres systèmes géochronologiques. Les données obtenues par traces de fission sur apatite nous indiquent également une exhumation rapide jusqu'à la fin du Miocène. Nous interprétons cet évènement à 6 Ma comme étant lié à l'uplift tectonique du massif de l'Aar. Le fait que cet évènement soit tardi-miocène implique qu'une augmentation des précipitations au Pliocène n'a pas engendré cette exhumation rapide du massif de l'Aar. La crise Messinienne de la mer méditerranée n'a pas pu avoir une incidence directe sur l'érosion du massif de l'Aar mais l'érosion associée à ce phénomène à pu réduire le coin orogénique alpin et causer la réactivation des chevauchements du massif de l'Aar. L'exhumation rapide Miocène a été suivie pas une diminution des taux d'exhumation lors des derniers 6 Ma (jusqu'à 1.3 km\Ma). Cependant, les âges (U-Th)\He sur apatite ainsi que les traces de fission sur apatite des échantillons du tunnel enregistrent une perturbation de l'enregistrement décrit ci-dessus. Les âges obtenus sur les apatites sont sensiblement plus jeunes sous l'axe de la vallée en comparaison du profil d'âges attendus. En effet, on attendrait des âges plus jeunes sous les parties les plus profondes du tunnel à cause de l'advection de la chaleur dans les flancs de la vallée. La vallée est creusée dans des schistes alors que les flancs de celle-ci sont constitués de granitoïdes plus durs. En accord avec les observations hydrologiques du tunnel, nous suggérons que la perméabilité élevée des roches sous l'axe de la vallée à permi l'infiltration de fluides géothermaux qui a généré un réchauffement des roches. Ce réchauffement aurait donc induit une perte d'Hélium et un recuit des traces de fission dans les apatites. Ceci résulterait en un rajeunissement des âges apatite et en une sous-estimation des vitesses d'exhumation sous l'axe de la vallée. Cette étude à servi à démontrer la nécessité d'un échantillonnage fin et précis afin d'apporter des données thermochronologiques de qualité dans le contexte alpin. Cette approche multi-système nous a permi de contrôler la pertinence des données acquises ainsi que d'identifier les sources possibles d'erreurs lors d'études thermochronologiques. RÉSUMÉ LARGE PUBLIC Lors d'une orogenèse, les roches subissent un cycle comprenant une subduction, de la déformation, du métamorphisme et, finalement, un retour à la surface (ou exhumation). L'exhumation résulte de la déformation au sein de la zone de collision, menant à un raccourcissement et un apaissessement de l'édifice rocheux, qui se traduit par une remontée des roches, création d'une topographie et érosion. Puisque l'érosion agit comme un racloir sur la partie supérieure de l'édifice, des tentatives de corrélation entre les épisodes d'exhumation rapide et les périodes d'érosion intensive, dues aux changements climatiques, ont été effectuées. La connaissance de la chronologie et du lieu précis est d'une importance capitale pour une quelconque reconstruction de l'évolution d'une chaîne de montagne. Ces critères sont donnés par un retraçage des changements de la température de la roche en fonction du temps, nous donnant le taux de refroidissement. L'instant auquel les roches ont refroidit, passant une certaine température, est contraint par l'application de techniques de datation par radiométrie. Ces méthodes reposent sur la désintégration des isotopes radiogéniques, tels que l'uranium et le potassium, tous deux abondants dans les roches de la croûte terrestre. Les produits de cette désintégration ne sont pas retenus dans les minéraux hôtes jusqu'au moment du refroidissement de la roche sous une température appelée 'de fermeture' , spécifique à chaque système de datation. Par exemple, la désintégration radioactive des atomes d'uranium et de thorium produit des atomes d'hélium qui s'échappent d'un cristal de zircon à des températures supérieures à 200°C. En mesurant la teneur en uranium-parent, l'hélium accumulé et en connaissant le taux de désintégration, il est possible de calculer à quel moment la roche échantillonnée est passée sous la température de 200°C. Si le gradient géothermal est connu, les températures de fermeture peuvent être converties en profondeurs actuelles (p. ex. 200°C ≈ 7km), et le taux de refroidissement en taux d'exhumation. De plus, en datant par système radiométrique des échantillons espacés verticalement, il est possible de contraindre directement le taux d'exhumation de la section échantillonnée en observant les différences d'âges entre des échantillons voisins. Dans les Alpes suisses, le massif de l'Aar forme une structure orographique majeure. Avec des altitudes supérieures à 4000m et un relief spectaculaire de plus de 2000m, le massif domine la partie centrale de la chaîne de montagne. Les roches aujourd'hui exposées à la surface ont été enfouies à plus de 10 km de profond il y a 20 Ma, mais la topographie actuelle du massif de l'Aar semble surtout s'être développée par un soulèvement actif depuis quelques millions d'années, c'est-à-dire depuis le Néogène supérieur. Cette période comprend un changement climatique soudain ayant touché l'Europe il y a environ 5 Ma et qui a occasionné de fortes précipitations, entraînant certainement une augmentation de l'érosion et accélérant l'exhumation des Alpes. Dans cette étude, nous avons employé le système de datation (U-TH)/He sur zircon, dont la température de fermeture de 200°C est suffisamment basse pour caractériser l'exhumation du Néogène sup. /Pliocène. Les échantillons proviennent du Lötschental et du tunnel ferroviaire le plus profond du monde (NEAT) situé dans la partie ouest du massif de l'Aar. Considérés dans l'ensemble, ces échantillons se répartissent sur un dénivelé de 3000m et des âges de 5.1 à 9.4 Ma. Les échantillons d'altitude supérieure (et donc plus vieux) documentent un taux d'exhumation de 0.4 km/Ma jusqu'à il y a 6 Ma, alors que les échantillons situés les plus bas ont des âges similaires allant de 6 à 5.4 Ma, donnant un taux jusqu'à 3km /Ma. Ces données montrent une accélération dramatique de l'exhumation du massif de l'Aar il y a 6 Ma. L'exhumation miocène sup. du massif prédate donc le changement climatique Pliocène. Cependant, lors de la crise de salinité d'il y a 6-5.3 Ma (Messinien), le niveau de la mer Méditerranée est descendu de 3km. Un tel abaissement de la surface d'érosion peut avoir accéléré l'exhumation des Alpes, mais le bassin sud alpin était trop loin du massif de l'Aar pour influencer son érosion. Nous arrivons à la conclusion que la datation (U-Th)/He permet de contraindre précisément la chronologie et l'exhumation du massif de l'Aar. Concernant la dualité tectonique-érosion, nous suggérons que, dans le cas du massif de l'Aar, la tectonique prédomine.